diff options
| author | Johannes Ranke <jranke@uni-bremen.de> | 2021-07-27 18:22:01 +0200 |
|---|---|---|
| committer | Johannes Ranke <jranke@uni-bremen.de> | 2021-07-27 18:22:01 +0200 |
| commit | 0b754ffa91b9496bdd2f892cf3ca2bd887028dea (patch) | |
| tree | 7d9926c53f6f6a5d09ce69f6e2dfaeacceb70475 /docs/dev | |
| parent | df716686122872fc148977e7ec4b51f6dc8332bd (diff) | |
Fix dimethenamid vignette problems and update docs
Diffstat (limited to 'docs/dev')
43 files changed, 1003 insertions, 1034 deletions
diff --git a/docs/dev/404.html b/docs/dev/404.html index 98c0b1e0..38898979 100644 --- a/docs/dev/404.html +++ b/docs/dev/404.html @@ -71,7 +71,7 @@ </button> <span class="navbar-brand"> <a class="navbar-link" href="https://pkgdown.jrwb.de/mkin/index.html">mkin</a> - <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.0.5</span> + <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.1.0</span> </span> </div> diff --git a/docs/dev/articles/index.html b/docs/dev/articles/index.html index 3896120a..c0338df8 100644 --- a/docs/dev/articles/index.html +++ b/docs/dev/articles/index.html @@ -71,7 +71,7 @@ </button> <span class="navbar-brand"> <a class="navbar-link" href="../index.html">mkin</a> - <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.0.5</span> + <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.1.0</span> </span> </div> @@ -161,6 +161,8 @@ <dd></dt> <dt><a href="web_only/compiled_models.html">Performance benefit by using compiled model definitions in mkin</a></dt> <dd></dt> + <dt><a href="web_only/dimethenamid_2018.html">Example evaluations of the dimethenamid data from 2018</a></dt> + <dd></dt> </dl> </div> </div> diff --git a/docs/dev/articles/web_only/dimethenamid_2018.html b/docs/dev/articles/web_only/dimethenamid_2018.html new file mode 100644 index 00000000..7648f75a --- /dev/null +++ b/docs/dev/articles/web_only/dimethenamid_2018.html @@ -0,0 +1,420 @@ +<!DOCTYPE html> +<!-- Generated by pkgdown: do not edit by hand --><html lang="en"> +<head> +<meta http-equiv="Content-Type" content="text/html; charset=UTF-8"> +<meta charset="utf-8"> +<meta http-equiv="X-UA-Compatible" content="IE=edge"> +<meta name="viewport" content="width=device-width, initial-scale=1.0"> +<title>Example evaluations of 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</div> +<!--/.container --> +</div> +<!--/.navbar --> + + + + </header><script src="dimethenamid_2018_files/header-attrs-2.9/header-attrs.js"></script><script src="dimethenamid_2018_files/accessible-code-block-0.0.1/empty-anchor.js"></script><div class="row"> + <div class="col-md-9 contents"> + <div class="page-header toc-ignore"> + <h1 data-toc-skip>Example evaluations of the dimethenamid data from 2018</h1> + <h4 class="author">Johannes Ranke</h4> + + <h4 class="date">Last change 27 July 2021, built on 27 Jul 2021</h4> + + <small class="dont-index">Source: <a href="https://github.com/jranke/mkin/blob/master/vignettes/web_only/dimethenamid_2018.rmd"><code>vignettes/web_only/dimethenamid_2018.rmd</code></a></small> + <div class="hidden name"><code>dimethenamid_2018.rmd</code></div> + + </div> + + + +<p><a href="http://www.jrwb.de">Wissenschaftlicher Berater, Kronacher Str. 12, 79639 Grenzach-Wyhlen, Germany</a><br><a href="http://chem.uft.uni-bremen.de/ranke">Privatdozent at the University of Bremen</a></p> +<div id="introduction" class="section level1"> +<h1 class="hasAnchor"> +<a href="#introduction" class="anchor"></a>Introduction</h1> +<p>During the preparation of the journal article on nonlinear mixed-effects models in degradation kinetics (submitted) and the analysis of the dimethenamid degradation data analysed therein, a need for a more detailed analysis using not only nlme and saemix, but also nlmixr for fitting the mixed-effects models was identified.</p> +<p>This vignette is an attempt to satisfy this need.</p> +</div> +<div id="data" class="section level1"> +<h1 class="hasAnchor"> +<a href="#data" class="anchor"></a>Data</h1> +<p>Residue data forming the basis for the endpoints derived in the conclusion on the peer review of the pesticide risk assessment of dimethenamid-P published by the European Food Safety Authority (EFSA) in 2018 <span class="citation">(EFSA 2018)</span> were transcribed from the risk assessment report <span class="citation">(Rapporteur Member State Germany, Co-Rapporteur Member State Bulgaria 2018)</span> which can be downloaded from the <a href="https://open.efsa.europa.eu/study-inventory/EFSA-Q-2014-00716">EFSA register of questions</a>.</p> +<p>The data are <a href="https://pkgdown.jrwb.de/mkin/reference/dimethenamid_2018.html">available in the mkin package</a>. The following code (hidden by default, please use the button to the right to show it) treats the data available for the racemic mixture dimethenamid (DMTA) and its enantiomer dimethenamid-P (DMTAP) in the same way, as no difference between their degradation behaviour was identified in the EU risk assessment. The observation times of each dataset are multiplied with the corresponding normalisation factor also available in the dataset, in order to make it possible to describe all datasets with a single set of parameters.</p> +<p>Also, datasets observed in the same soil are merged, resulting in dimethenamid (DMTA) data from six soils.</p> +<div class="sourceCode" id="cb1"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span class="kw"><a href="https://rdrr.io/r/base/library.html">library</a></span><span class="op">(</span><span class="va"><a href="https://pkgdown.jrwb.de/mkin/">mkin</a></span><span class="op">)</span> +<span class="va">dmta_ds</span> <span class="op"><-</span> <span class="fu"><a href="https://rdrr.io/r/base/lapply.html">lapply</a></span><span class="op">(</span><span class="fl">1</span><span class="op">:</span><span class="fl">8</span>, <span class="kw">function</span><span class="op">(</span><span class="va">i</span><span class="op">)</span> <span class="op">{</span> + <span class="va">ds_i</span> <span class="op"><-</span> <span class="va">dimethenamid_2018</span><span class="op">$</span><span class="va">ds</span><span class="op">[[</span><span class="va">i</span><span class="op">]</span><span class="op">]</span><span class="op">$</span><span class="va">data</span> + <span class="va">ds_i</span><span class="op">[</span><span class="va">ds_i</span><span class="op">$</span><span class="va">name</span> <span class="op">==</span> <span class="st">"DMTAP"</span>, <span class="st">"name"</span><span class="op">]</span> <span class="op"><-</span> <span class="st">"DMTA"</span> + <span class="va">ds_i</span><span class="op">$</span><span class="va">time</span> <span class="op"><-</span> <span class="va">ds_i</span><span class="op">$</span><span class="va">time</span> <span class="op">*</span> <span class="va">dimethenamid_2018</span><span class="op">$</span><span class="va">f_time_norm</span><span class="op">[</span><span class="va">i</span><span class="op">]</span> + <span class="va">ds_i</span> +<span class="op">}</span><span class="op">)</span> +<span class="fu"><a href="https://rdrr.io/r/base/names.html">names</a></span><span class="op">(</span><span class="va">dmta_ds</span><span class="op">)</span> <span class="op"><-</span> <span class="fu"><a href="https://rdrr.io/r/base/lapply.html">sapply</a></span><span class="op">(</span><span class="va">dimethenamid_2018</span><span class="op">$</span><span class="va">ds</span>, <span class="kw">function</span><span class="op">(</span><span class="va">ds</span><span class="op">)</span> <span class="va">ds</span><span class="op">$</span><span class="va">title</span><span class="op">)</span> +<span class="va">dmta_ds</span><span class="op">[[</span><span class="st">"Borstel"</span><span class="op">]</span><span class="op">]</span> <span class="op"><-</span> <span class="fu"><a href="https://rdrr.io/r/base/cbind.html">rbind</a></span><span class="op">(</span><span class="va">dmta_ds</span><span class="op">[[</span><span class="st">"Borstel 1"</span><span class="op">]</span><span class="op">]</span>, <span class="va">dmta_ds</span><span class="op">[[</span><span class="st">"Borstel 2"</span><span class="op">]</span><span class="op">]</span><span class="op">)</span> +<span class="va">dmta_ds</span><span class="op">[[</span><span class="st">"Borstel 1"</span><span class="op">]</span><span class="op">]</span> <span class="op"><-</span> <span class="cn">NULL</span> +<span class="va">dmta_ds</span><span class="op">[[</span><span class="st">"Borstel 2"</span><span class="op">]</span><span class="op">]</span> <span class="op"><-</span> <span class="cn">NULL</span> +<span class="va">dmta_ds</span><span class="op">[[</span><span class="st">"Elliot"</span><span class="op">]</span><span class="op">]</span> <span class="op"><-</span> <span class="fu"><a href="https://rdrr.io/r/base/cbind.html">rbind</a></span><span class="op">(</span><span class="va">dmta_ds</span><span class="op">[[</span><span class="st">"Elliot 1"</span><span class="op">]</span><span class="op">]</span>, <span class="va">dmta_ds</span><span class="op">[[</span><span class="st">"Elliot 2"</span><span class="op">]</span><span class="op">]</span><span class="op">)</span> +<span class="va">dmta_ds</span><span class="op">[[</span><span class="st">"Elliot 1"</span><span class="op">]</span><span class="op">]</span> <span class="op"><-</span> <span class="cn">NULL</span> +<span class="va">dmta_ds</span><span class="op">[[</span><span class="st">"Elliot 2"</span><span class="op">]</span><span class="op">]</span> <span class="op"><-</span> <span class="cn">NULL</span></code></pre></div> +</div> +<div id="parent-degradation" class="section level1"> +<h1 class="hasAnchor"> +<a href="#parent-degradation" class="anchor"></a>Parent degradation</h1> +<p>We evaluate the observed degradation of the parent compound using simple exponential decline (SFO) and biexponential decline (DFOP), using constant variance (const) and a two-component variance (tc) as error models.</p> +<div id="separate-evaluations" class="section level2"> +<h2 class="hasAnchor"> +<a href="#separate-evaluations" class="anchor"></a>Separate evaluations</h2> +<p>As a first step, to get a visual impression of the fit of the different models, we do separate evaluations for each soil using the mmkin function from the mkin package:</p> +<div class="sourceCode" id="cb2"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span class="va">f_parent_mkin_const</span> <span class="op"><-</span> <span class="fu"><a href="../../reference/mmkin.html">mmkin</a></span><span class="op">(</span><span class="fu"><a href="https://rdrr.io/r/base/c.html">c</a></span><span class="op">(</span><span class="st">"SFO"</span>, <span class="st">"DFOP"</span><span class="op">)</span>, <span class="va">dmta_ds</span>, + error_model <span class="op">=</span> <span class="st">"const"</span>, quiet <span class="op">=</span> <span class="cn">TRUE</span><span class="op">)</span> +<span class="va">f_parent_mkin_tc</span> <span class="op"><-</span> <span class="fu"><a href="../../reference/mmkin.html">mmkin</a></span><span class="op">(</span><span class="fu"><a href="https://rdrr.io/r/base/c.html">c</a></span><span class="op">(</span><span class="st">"SFO"</span>, <span class="st">"DFOP"</span><span class="op">)</span>, <span class="va">dmta_ds</span>, + error_model <span class="op">=</span> <span class="st">"tc"</span>, quiet <span class="op">=</span> <span class="cn">TRUE</span><span class="op">)</span></code></pre></div> +<p>The plot of the individual SFO fits shown below suggests that at least in some datasets the degradation slows down towards later time points, and that the scatter of the residuals error is smaller for smaller values (panel to the right):</p> +<div class="sourceCode" id="cb3"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/graphics/plot.default.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span><span class="op">)</span><span class="op">)</span></code></pre></div> +<p><img src="dimethenamid_2018_files/figure-html/f_parent_mkin_sfo_const-1.png" width="700"></p> +<p>Using biexponential decline (DFOP) results in a slightly more random scatter of the residuals:</p> +<div class="sourceCode" id="cb4"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/graphics/plot.default.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span><span class="op">)</span><span class="op">)</span></code></pre></div> +<p><img src="dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_const-1.png" width="700"></p> +<p>The population curve (bold line) in the above plot results from taking the mean of the individual transformed parameters, i.e. of log k1 and log k2, as well as of the logit of the g parameter of the DFOP model). Here, this procedure does not result in parameters that represent the degradation well, because in some datasets the fitted value for k2 is extremely close to zero, leading to a log k2 value that dominates the average. This is alleviated if only rate constants that pass the t-test for significant difference from zero (on the untransformed scale) are considered in the averaging:</p> +<div class="sourceCode" id="cb5"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/graphics/plot.default.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span><span class="op">)</span>, test_log_parms <span class="op">=</span> <span class="cn">TRUE</span><span class="op">)</span></code></pre></div> +<p><img src="dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_const_test-1.png" width="700"></p> +<p>While this is visually much more satisfactory, such an average procedure could introduce a bias, as not all results from the individual fits enter the population curve with the same weight. This is where nonlinear mixed-effects models can help out by treating all datasets with equally by fitting a parameter distribution model together with the degradation model and the error model (see below).</p> +<p>The remaining trend of the residuals to be higher for higher predicted residues is reduced by using the two-component error model:</p> +<div class="sourceCode" id="cb6"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/graphics/plot.default.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span><span class="op">)</span>, test_log_parms <span class="op">=</span> <span class="cn">TRUE</span><span class="op">)</span></code></pre></div> +<p><img src="dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_tc_test-1.png" width="700"></p> +</div> +<div id="nonlinear-mixed-effects-models" class="section level2"> +<h2 class="hasAnchor"> +<a href="#nonlinear-mixed-effects-models" class="anchor"></a>Nonlinear mixed-effects models</h2> +<p>Instead of taking a model selection decision for each of the individual fits, we fit nonlinear mixed-effects models (using different fitting algorithms as implemented in different packages) and do model selection using all available data at the same time. In order to make sure that these decisions are not unduly influenced by the type of algorithm used, by implementation details or by the use of wrong control parameters, we compare the model selection results obtained with different R packages, with different algorithms and checking control parameters.</p> +<div id="nlme" class="section level3"> +<h3 class="hasAnchor"> +<a href="#nlme" class="anchor"></a>nlme</h3> +<p>The nlme package was the first R extension providing facilities to fit nonlinear mixed-effects models. We use would like to do model selection from all four combinations of degradation models and error models based on the AIC. However, fitting the DFOP model with constant variance and using default control parameters results in an error, signalling that the maximum number of 50 iterations was reached, potentially indicating overparameterisation. However, the algorithm converges when the two-component error model is used in combination with the DFOP model. This can be explained by the fact that the smaller residues observed at later sampling times get more weight when using the two-component error model which will counteract the tendency of the algorithm to try parameter combinations unsuitable for fitting these data.</p> +<div class="sourceCode" id="cb7"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span class="kw"><a href="https://rdrr.io/r/base/library.html">library</a></span><span class="op">(</span><span class="va"><a href="https://svn.r-project.org/R-packages/trunk/nlme/">nlme</a></span><span class="op">)</span> +<span class="va">f_parent_nlme_sfo_const</span> <span class="op"><-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlme/man/nlme.html">nlme</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span><span class="op">)</span> +<span class="co">#f_parent_nlme_dfop_const <- nlme(f_parent_mkin_const["DFOP", ])</span> +<span class="co"># maxIter = 50 reached</span> +<span class="va">f_parent_nlme_sfo_tc</span> <span class="op"><-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlme/man/nlme.html">nlme</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span><span class="op">)</span> +<span class="va">f_parent_nlme_dfop_tc</span> <span class="op"><-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlme/man/nlme.html">nlme</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span><span class="op">)</span></code></pre></div> +<p>Note that overparameterisation is also indicated by warnings obtained when fitting SFO or DFOP with the two-component error model (‘false convergence’ in the ‘LME step’ in some iterations). In addition to these fits, attempts were also made to include correlations between random effects by using the log Cholesky parameterisation of the matrix specifying them. The code used for these attempts can be made visible below.</p> +<div class="sourceCode" id="cb8"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span class="va">f_parent_nlme_sfo_const_logchol</span> <span class="op"><-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlme/man/nlme.html">nlme</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span>, + random <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/pkg/nlme/man/pdLogChol.html">pdLogChol</a></span><span class="op">(</span><span class="fu"><a href="https://rdrr.io/r/base/list.html">list</a></span><span class="op">(</span><span class="va">DMTA_0</span> <span class="op">~</span> <span class="fl">1</span>, <span class="va">log_k_DMTA</span> <span class="op">~</span> <span class="fl">1</span><span class="op">)</span><span class="op">)</span><span class="op">)</span> +<span class="fu"><a href="https://rdrr.io/r/stats/anova.html">anova</a></span><span class="op">(</span><span class="va">f_parent_nlme_sfo_const</span>, <span class="va">f_parent_nlme_sfo_const_logchol</span><span class="op">)</span> <span class="co"># not better</span> +<span class="co">#f_parent_nlme_dfop_tc_logchol <- update(f_parent_nlme_dfop_tc,</span> +<span class="co"># random = pdLogChol(list(DMTA_0 ~ 1, log_k1 ~ 1, log_k2 ~ 1, g_qlogis ~ 1)))</span> +<span class="co"># using log Cholesky parameterisation for random effects (nlme default) does</span> +<span class="co"># not converge here and gives lots of warnings about the LME step not converging</span></code></pre></div> +<p>The model comparison function of the nlme package can directly be applied to these fits showing a similar goodness-of-fit of the SFO model, but a much lower AIC for the DFOP model fitted with the two-component error model. Also, the likelihood ratio test indicates that this difference is significant. as the p-value is below 0.0001.</p> +<div class="sourceCode" id="cb9"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/stats/anova.html">anova</a></span><span class="op">(</span> + <span class="va">f_parent_nlme_sfo_const</span>, <span class="va">f_parent_nlme_sfo_tc</span>, <span class="va">f_parent_nlme_dfop_tc</span> +<span class="op">)</span></code></pre></div> +<pre><code> Model df AIC BIC logLik Test L.Ratio p-value +f_parent_nlme_sfo_const 1 5 818.63 834.00 -404.31 +f_parent_nlme_sfo_tc 2 6 820.61 839.06 -404.31 1 vs 2 0.014 0.9049 +f_parent_nlme_dfop_tc 3 10 687.84 718.59 -333.92 2 vs 3 140.771 <.0001</code></pre> +<p>The selected model (DFOP with two-component error) fitted to the data assuming no correlations between random effects is shown below.</p> +<div class="sourceCode" id="cb11"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/graphics/plot.default.html">plot</a></span><span class="op">(</span><span class="va">f_parent_nlme_dfop_tc</span><span class="op">)</span></code></pre></div> +<p><img src="dimethenamid_2018_files/figure-html/plot_parent_nlme-1.png" width="700"></p> +</div> +<div id="saemix" class="section level3"> +<h3 class="hasAnchor"> +<a href="#saemix" class="anchor"></a>saemix</h3> +<p>The saemix package provided the first Open Source implementation of the Stochastic Approximation to the Expectation Maximisation (SAEM) algorithm. SAEM fits of degradation models can be performed using an interface to the saemix package available in current development versions of the mkin package.</p> +<p>The corresponding SAEM fits of the four combinations of degradation and error models are fitted below. As there is no convergence criterion implemented in the saemix package, the convergence plots need to be manually checked for every fit.</p> +<p>The convergence plot for the SFO model using constant variance is shown below.</p> +<div class="sourceCode" id="cb12"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span class="kw"><a href="https://rdrr.io/r/base/library.html">library</a></span><span class="op">(</span><span class="va">saemix</span><span class="op">)</span> +<span class="va">f_parent_saemix_sfo_const</span> <span class="op"><-</span> <span class="fu">mkin</span><span class="fu">::</span><span class="fu"><a href="../../reference/saem.html">saem</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span>, quiet <span class="op">=</span> <span class="cn">TRUE</span>, + transformations <span class="op">=</span> <span class="st">"saemix"</span><span class="op">)</span> +<span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">f_parent_saemix_sfo_const</span><span class="op">$</span><span class="va">so</span>, plot.type <span class="op">=</span> <span class="st">"convergence"</span><span class="op">)</span></code></pre></div> +<p><img src="dimethenamid_2018_files/figure-html/f_parent_saemix_sfo_const-1.png" width="700"></p> +<p>Obviously the default number of iterations is sufficient to reach convergence. This can also be said for the SFO fit using the two-component error model.</p> +<div class="sourceCode" id="cb13"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span class="va">f_parent_saemix_sfo_tc</span> <span class="op"><-</span> <span class="fu">mkin</span><span class="fu">::</span><span class="fu"><a href="../../reference/saem.html">saem</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span>, quiet <span class="op">=</span> <span class="cn">TRUE</span>, + transformations <span class="op">=</span> <span class="st">"saemix"</span><span class="op">)</span> +<span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">f_parent_saemix_sfo_tc</span><span class="op">$</span><span class="va">so</span>, plot.type <span class="op">=</span> <span class="st">"convergence"</span><span class="op">)</span></code></pre></div> +<p><img src="dimethenamid_2018_files/figure-html/f_parent_saemix_sfo_tc-1.png" width="700"></p> +<p>When fitting the DFOP model with constant variance, parameter convergence is not as unambiguous (see the failure of nlme with the default number of iterations above). Therefore, the number of iterations in the first phase of the algorithm was increased, leading to visually satisfying convergence.</p> +<div class="sourceCode" id="cb14"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span class="va">f_parent_saemix_dfop_const</span> <span class="op"><-</span> <span class="fu">mkin</span><span class="fu">::</span><span class="fu"><a href="../../reference/saem.html">saem</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, quiet <span class="op">=</span> <span class="cn">TRUE</span>, + control <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/pkg/saemix/man/saemixControl.html">saemixControl</a></span><span class="op">(</span>nbiter.saemix <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/c.html">c</a></span><span class="op">(</span><span class="fl">800</span>, <span class="fl">200</span><span class="op">)</span>, print <span class="op">=</span> <span class="cn">FALSE</span>, + save <span class="op">=</span> <span class="cn">FALSE</span>, save.graphs <span class="op">=</span> <span class="cn">FALSE</span>, displayProgress <span class="op">=</span> <span class="cn">FALSE</span><span class="op">)</span>, + transformations <span class="op">=</span> <span class="st">"saemix"</span><span class="op">)</span> +<span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_const</span><span class="op">$</span><span class="va">so</span>, plot.type <span class="op">=</span> <span class="st">"convergence"</span><span class="op">)</span></code></pre></div> +<p><img src="dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_const-1.png" width="700"></p> +<p>The same applies to the case where the DFOP model is fitted with the two-component error model. Convergence of the variance of k2 is enhanced by using the two-component error, it remains more or less stable already after 200 iterations of the first phase.</p> +<div class="sourceCode" id="cb15"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span class="va">f_parent_saemix_dfop_tc_moreiter</span> <span class="op"><-</span> <span class="fu">mkin</span><span class="fu">::</span><span class="fu"><a href="../../reference/saem.html">saem</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, quiet <span class="op">=</span> <span class="cn">TRUE</span>, + control <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/pkg/saemix/man/saemixControl.html">saemixControl</a></span><span class="op">(</span>nbiter.saemix <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/c.html">c</a></span><span class="op">(</span><span class="fl">800</span>, <span class="fl">200</span><span class="op">)</span>, print <span class="op">=</span> <span class="cn">FALSE</span>, + save <span class="op">=</span> <span class="cn">FALSE</span>, save.graphs <span class="op">=</span> <span class="cn">FALSE</span>, displayProgress <span class="op">=</span> <span class="cn">FALSE</span><span class="op">)</span>, + transformations <span class="op">=</span> <span class="st">"saemix"</span><span class="op">)</span> +<span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc_moreiter</span><span class="op">$</span><span class="va">so</span>, plot.type <span class="op">=</span> <span class="st">"convergence"</span><span class="op">)</span></code></pre></div> +<p><img src="dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc_moreiter-1.png" width="700"></p> +<p>The four combinations can be compared using the model comparison function from the saemix package:</p> +<div class="sourceCode" id="cb16"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/compare.saemix.html">compare.saemix</a></span><span class="op">(</span><span class="va">f_parent_saemix_sfo_const</span><span class="op">$</span><span class="va">so</span>, <span class="va">f_parent_saemix_sfo_tc</span><span class="op">$</span><span class="va">so</span>, + <span class="va">f_parent_saemix_dfop_const</span><span class="op">$</span><span class="va">so</span>, <span class="va">f_parent_saemix_dfop_tc_moreiter</span><span class="op">$</span><span class="va">so</span><span class="op">)</span></code></pre></div> +<pre><code>Likelihoods calculated by importance sampling</code></pre> +<pre><code> AIC BIC +1 818.37 817.33 +2 820.38 819.14 +3 725.91 724.04 +4 683.64 681.55</code></pre> +<p>As in the case of nlme fits, the DFOP model fitted with two-component error (number 4) gives the lowest AIC. The numeric values are reasonably close to the ones obtained using nlme, considering that the algorithms for fitting the model and for the likelihood calculation are quite different.</p> +<p>In order to check the influence of the likelihood calculation algorithms implemented in saemix, the likelihood from Gaussian quadrature is added to the best fit, and the AIC values obtained from the three methods are compared.</p> +<div class="sourceCode" id="cb19"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span class="va">f_parent_saemix_dfop_tc_moreiter</span><span class="op">$</span><span class="va">so</span> <span class="op"><-</span> + <span class="fu"><a href="https://rdrr.io/pkg/saemix/man/llgq.saemix.html">llgq.saemix</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc_moreiter</span><span class="op">$</span><span class="va">so</span><span class="op">)</span> +<span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc_moreiter</span><span class="op">$</span><span class="va">so</span><span class="op">)</span></code></pre></div> +<pre><code>[1] 683.64</code></pre> +<div class="sourceCode" id="cb21"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc_moreiter</span><span class="op">$</span><span class="va">so</span>, method <span class="op">=</span> <span class="st">"gq"</span><span class="op">)</span></code></pre></div> +<pre><code>[1] 683.7</code></pre> +<div class="sourceCode" id="cb23"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc_moreiter</span><span class="op">$</span><span class="va">so</span>, method <span class="op">=</span> <span class="st">"lin"</span><span class="op">)</span></code></pre></div> +<pre><code>[1] 683.17</code></pre> +<p>The AIC values based on importance sampling and Gaussian quadrature are quite similar. Using linearisation is less accurate, but still gives a similar value.</p> +</div> +<div id="nlmixr" class="section level3"> +<h3 class="hasAnchor"> +<a href="#nlmixr" class="anchor"></a>nlmixr</h3> +<p>In the last years, a lot of effort has been put into the nlmixr package which is designed for pharmacokinetics, where nonlinear mixed-effects models are routinely used, but which can also be used for related data like chemical degradation data. A current development branch of the mkin package provides an interface between mkin and nlmixr. Here, we check if we get equivalent results when using a refined version of the First Order Conditional Estimation (FOCE) algorithm used in nlme, namely First Order Conditional Estimation with Interaction (FOCEI), and the SAEM algorithm as implemented in nlmixr.</p> +<p>First, the focei algorithm is used for the four model combinations and the goodness of fit of the results is compared.</p> +<div class="sourceCode" id="cb25"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span class="kw"><a href="https://rdrr.io/r/base/library.html">library</a></span><span class="op">(</span><span class="va"><a href="https://github.com/nlmixrdevelopment/nlmixr">nlmixr</a></span><span class="op">)</span> +<span class="va">f_parent_nlmixr_focei_sfo_const</span> <span class="op"><-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"focei"</span><span class="op">)</span> +<span class="va">f_parent_nlmixr_focei_sfo_tc</span> <span class="op"><-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"focei"</span><span class="op">)</span> +<span class="va">f_parent_nlmixr_focei_dfop_const</span> <span class="op"><-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"focei"</span><span class="op">)</span> +<span class="va">f_parent_nlmixr_focei_dfop_tc</span><span class="op"><-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"focei"</span><span class="op">)</span></code></pre></div> +<div class="sourceCode" id="cb26"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_focei_sfo_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_focei_sfo_tc</span><span class="op">$</span><span class="va">nm</span>, + <span class="va">f_parent_nlmixr_focei_dfop_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_focei_dfop_tc</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span></code></pre></div> +<pre><code> df AIC +f_parent_nlmixr_focei_sfo_const$nm 5 818.63 +f_parent_nlmixr_focei_sfo_tc$nm 6 820.61 +f_parent_nlmixr_focei_dfop_const$nm 9 728.11 +f_parent_nlmixr_focei_dfop_tc$nm 10 687.82</code></pre> +<p>The AIC values are very close to the ones obtained with nlme which are repeated below for convenience.</p> +<div class="sourceCode" id="cb28"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span> + <span class="va">f_parent_nlme_sfo_const</span>, <span class="va">f_parent_nlme_sfo_tc</span>, <span class="va">f_parent_nlme_dfop_tc</span> +<span class="op">)</span></code></pre></div> +<pre><code> df AIC +f_parent_nlme_sfo_const 5 818.63 +f_parent_nlme_sfo_tc 6 820.61 +f_parent_nlme_dfop_tc 10 687.84</code></pre> +<p>Secondly, we use the SAEM estimation routine and check the convergence plots for SFO with constant variance</p> +<div class="sourceCode" id="cb30"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span class="va">f_parent_nlmixr_saem_sfo_const</span> <span class="op"><-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"saem"</span>, + control <span class="op">=</span> <span class="fu">nlmixr</span><span class="fu">::</span><span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/saemControl.html">saemControl</a></span><span class="op">(</span>logLik <span class="op">=</span> <span class="cn">TRUE</span><span class="op">)</span><span class="op">)</span> +<span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/traceplot.html">traceplot</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_sfo_const</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span></code></pre></div> +<p><img src="dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_const-1.png" width="700"></p> +<p>for SFO with two-component error</p> +<div class="sourceCode" id="cb31"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span class="va">f_parent_nlmixr_saem_sfo_tc</span> <span class="op"><-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"saem"</span>, + control <span class="op">=</span> <span class="fu">nlmixr</span><span class="fu">::</span><span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/saemControl.html">saemControl</a></span><span class="op">(</span>logLik <span class="op">=</span> <span class="cn">TRUE</span><span class="op">)</span><span class="op">)</span> +<span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/traceplot.html">traceplot</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_sfo_tc</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span></code></pre></div> +<p><img src="dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_tc-1.png" width="700"></p> +<p>For DFOP with constant variance, the convergence plots show considerable instability of the fit, which can be alleviated by increasing the number of iterations and the number of parallel chains for the first phase of algorithm.</p> +<div class="sourceCode" id="cb32"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span class="va">f_parent_nlmixr_saem_dfop_const</span> <span class="op"><-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"saem"</span>, + control <span class="op">=</span> <span class="fu">nlmixr</span><span class="fu">::</span><span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/saemControl.html">saemControl</a></span><span class="op">(</span>logLik <span class="op">=</span> <span class="cn">TRUE</span>, nBurn <span class="op">=</span> <span class="fl">1000</span><span class="op">)</span>, nmc <span class="op">=</span> <span class="fl">15</span><span class="op">)</span> +<span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/traceplot.html">traceplot</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_dfop_const</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span></code></pre></div> +<p><img src="dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_const-1.png" width="700"></p> +<p>For DFOP with two-component error, the same increase in iterations and parallel chains was used, but using the two-component error appears to lead to a less erratic convergence, so this may not be necessary to this degree.</p> +<div class="sourceCode" id="cb33"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span class="va">f_parent_nlmixr_saem_dfop_tc</span> <span class="op"><-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"saem"</span>, + control <span class="op">=</span> <span class="fu">nlmixr</span><span class="fu">::</span><span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/saemControl.html">saemControl</a></span><span class="op">(</span>logLik <span class="op">=</span> <span class="cn">TRUE</span>, nBurn <span class="op">=</span> <span class="fl">1000</span>, nmc <span class="op">=</span> <span class="fl">15</span><span class="op">)</span><span class="op">)</span> +<span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/traceplot.html">traceplot</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_dfop_tc</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span></code></pre></div> +<p><img src="dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc-1.png" width="700"></p> +<p>The AIC values are internally calculated using Gaussian quadrature. For an unknown reason, the AIC value obtained for the DFOP fit using the two-component error model is given as Infinity.</p> +<div class="sourceCode" id="cb34"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_sfo_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_saem_sfo_tc</span><span class="op">$</span><span class="va">nm</span>, + <span class="va">f_parent_nlmixr_saem_dfop_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_saem_dfop_tc</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span></code></pre></div> +<pre><code> df AIC +f_parent_nlmixr_saem_sfo_const$nm 5 820.54 +f_parent_nlmixr_saem_sfo_tc$nm 6 835.26 +f_parent_nlmixr_saem_dfop_const$nm 9 842.84 +f_parent_nlmixr_saem_dfop_tc$nm 10 684.51</code></pre> +<p>The following table gives the AIC values obtained with the three packages.</p> +<div class="sourceCode" id="cb36"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span class="va">AIC_all</span> <span class="op"><-</span> <span class="fu"><a href="https://rdrr.io/r/base/data.frame.html">data.frame</a></span><span class="op">(</span> + nlme <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/c.html">c</a></span><span class="op">(</span><span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_nlme_sfo_const</span><span class="op">)</span>, <span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_nlme_sfo_tc</span><span class="op">)</span>, <span class="cn">NA</span>, <span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_nlme_dfop_tc</span><span class="op">)</span><span class="op">)</span>, + nlmixr_focei <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/lapply.html">sapply</a></span><span class="op">(</span><span class="fu"><a href="https://rdrr.io/r/base/list.html">list</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_focei_sfo_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_focei_sfo_tc</span><span class="op">$</span><span class="va">nm</span>, + <span class="va">f_parent_nlmixr_focei_dfop_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_focei_dfop_tc</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span>, <span class="va">AIC</span><span class="op">)</span>, + saemix <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/lapply.html">sapply</a></span><span class="op">(</span><span class="fu"><a href="https://rdrr.io/r/base/list.html">list</a></span><span class="op">(</span><span class="va">f_parent_saemix_sfo_const</span><span class="op">$</span><span class="va">so</span>, <span class="va">f_parent_saemix_sfo_tc</span><span class="op">$</span><span class="va">so</span>, + <span class="va">f_parent_saemix_dfop_const</span><span class="op">$</span><span class="va">so</span>, <span class="va">f_parent_saemix_dfop_tc_moreiter</span><span class="op">$</span><span class="va">so</span><span class="op">)</span>, <span class="va">AIC</span><span class="op">)</span>, + nlmixr_saem <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/lapply.html">sapply</a></span><span class="op">(</span><span class="fu"><a href="https://rdrr.io/r/base/list.html">list</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_sfo_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_saem_sfo_tc</span><span class="op">$</span><span class="va">nm</span>, + <span class="va">f_parent_nlmixr_saem_dfop_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_saem_dfop_tc</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span>, <span class="va">AIC</span><span class="op">)</span> +<span class="op">)</span> +<span class="fu">kable</span><span class="op">(</span><span class="va">AIC_all</span><span class="op">)</span></code></pre></div> +<table class="table"> +<thead><tr class="header"> +<th align="right">nlme</th> +<th align="right">nlmixr_focei</th> +<th align="right">saemix</th> +<th align="right">nlmixr_saem</th> +</tr></thead> +<tbody> +<tr class="odd"> +<td align="right">818.63</td> +<td align="right">818.63</td> +<td align="right">818.37</td> +<td align="right">820.54</td> +</tr> +<tr class="even"> +<td align="right">820.61</td> +<td align="right">820.61</td> +<td align="right">820.38</td> +<td align="right">835.26</td> +</tr> +<tr class="odd"> +<td align="right">NA</td> +<td align="right">728.11</td> +<td align="right">725.91</td> +<td align="right">842.84</td> +</tr> +<tr class="even"> +<td align="right">687.84</td> +<td align="right">687.82</td> +<td align="right">683.64</td> +<td align="right">684.51</td> +</tr> +</tbody> +</table> +</div> +</div> +</div> +<div id="references" class="section level1"> +<h1 class="hasAnchor"> +<a href="#references" class="anchor"></a>References</h1> +<!-- vim: set foldmethod=syntax: --> +<div id="refs" class="references hanging-indent"> +<div id="ref-efsa_2018_dimethenamid"> +<p>EFSA. 2018. “Peer Review of the Pesticide Risk Assessment of the Active Substance Dimethenamid-P.” <em>EFSA Journal</em> 16 (4): 5211.</p> +</div> +<div id="ref-dimethenamid_rar_2018_b8"> +<p>Rapporteur Member State Germany, Co-Rapporteur Member State Bulgaria. 2018. “Renewal Assessment Report Dimethenamid-P Volume 3 - B.8 Environmental fate and behaviour, Rev. 2 - November 2017.” <a href="https://open.efsa.europa.eu/study-inventory/EFSA-Q-2014-00716">https://open.efsa.europa.eu/study-inventory/EFSA-Q-2014-00716</a>.</p> +</div> +</div> +</div> + </div> + + <div class="col-md-3 hidden-xs hidden-sm" id="pkgdown-sidebar"> + + <nav id="toc" data-toggle="toc"><h2 data-toc-skip>Contents</h2> + </nav> +</div> + +</div> + + + + <footer><div class="copyright"> + <p>Developed by Johannes Ranke.</p> +</div> + +<div class="pkgdown"> + <p>Site built with <a href="https://pkgdown.r-lib.org/">pkgdown</a> 1.6.1.</p> +</div> + + </footer> +</div> + + + + + </body> +</html> diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/accessible-code-block-0.0.1/empty-anchor.js b/docs/dev/articles/web_only/dimethenamid_2018_files/accessible-code-block-0.0.1/empty-anchor.js new file mode 100644 index 00000000..ca349fd6 --- /dev/null +++ b/docs/dev/articles/web_only/dimethenamid_2018_files/accessible-code-block-0.0.1/empty-anchor.js @@ -0,0 +1,15 @@ +// Hide empty <a> tag within highlighted CodeBlock for screen reader accessibility (see https://github.com/jgm/pandoc/issues/6352#issuecomment-626106786) --> +// v0.0.1 +// Written by JooYoung Seo (jooyoung@psu.edu) and Atsushi Yasumoto on June 1st, 2020. + +document.addEventListener('DOMContentLoaded', function() { + const codeList = document.getElementsByClassName("sourceCode"); + for (var i = 0; i < codeList.length; i++) { + var linkList = codeList[i].getElementsByTagName('a'); + for (var j = 0; j < linkList.length; j++) { + if (linkList[j].innerHTML === "") { + linkList[j].setAttribute('aria-hidden', 'true'); + } + } + } +}); diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_const-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_const-1.png Binary files differnew file mode 100644 index 00000000..c51afe54 --- /dev/null +++ b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_const-1.png diff 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b/docs/dev/articles/web_only/dimethenamid_2018_files/header-attrs-2.9/header-attrs.js @@ -0,0 +1,12 @@ +// Pandoc 2.9 adds attributes on both header and div. We remove the former (to +// be compatible with the behavior of Pandoc < 2.8). +document.addEventListener('DOMContentLoaded', function(e) { + var hs = document.querySelectorAll("div.section[class*='level'] > :first-child"); + var i, h, a; + for (i = 0; i < hs.length; i++) { + h = hs[i]; + if (!/^h[1-6]$/i.test(h.tagName)) continue; // it should be a header h1-h6 + a = h.attributes; + while (a.length > 0) h.removeAttribute(a[0].name); + } +}); diff --git a/docs/dev/authors.html b/docs/dev/authors.html index 4208dc24..943cba1b 100644 --- a/docs/dev/authors.html +++ b/docs/dev/authors.html @@ -71,7 +71,7 @@ </button> <span class="navbar-brand"> <a class="navbar-link" href="index.html">mkin</a> - <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.0.5</span> + <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.1.0</span> </span> </div> diff --git a/docs/dev/index.html b/docs/dev/index.html index 6e3fa6e1..8049b3a1 100644 --- a/docs/dev/index.html +++ b/docs/dev/index.html @@ -38,7 +38,7 @@ </button> <span class="navbar-brand"> <a class="navbar-link" href="index.html">mkin</a> - <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.0.5</span> + <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.1.0</span> </span> </div> diff --git a/docs/dev/news/index.html b/docs/dev/news/index.html index 234ba02f..cfe577cf 100644 --- a/docs/dev/news/index.html +++ b/docs/dev/news/index.html @@ -71,7 +71,7 @@ </button> <span class="navbar-brand"> <a class="navbar-link" href="../index.html">mkin</a> - <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.0.5</span> + <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.1.0</span> </span> </div> diff --git a/docs/dev/pkgdown.yml b/docs/dev/pkgdown.yml index b2c50e79..16f7f0d6 100644 --- a/docs/dev/pkgdown.yml +++ b/docs/dev/pkgdown.yml @@ -10,7 +10,8 @@ articles: web_only/NAFTA_examples: NAFTA_examples.html web_only/benchmarks: benchmarks.html web_only/compiled_models: compiled_models.html -last_built: 2021-06-17T12:41Z + web_only/dimethenamid_2018: dimethenamid_2018.html +last_built: 2021-07-27T15:54Z urls: reference: https://pkgdown.jrwb.de/mkin/reference article: https://pkgdown.jrwb.de/mkin/articles diff --git a/docs/dev/reference/Rplot005.png b/docs/dev/reference/Rplot005.png Binary files differindex 55aa7eec..92c7cc2d 100644 --- a/docs/dev/reference/Rplot005.png +++ b/docs/dev/reference/Rplot005.png diff --git a/docs/dev/reference/dimethenamid_2018-2.png b/docs/dev/reference/dimethenamid_2018-2.png Binary files differnew file mode 100644 index 00000000..a81b2aaf --- /dev/null +++ b/docs/dev/reference/dimethenamid_2018-2.png diff --git a/docs/dev/reference/dimethenamid_2018.html b/docs/dev/reference/dimethenamid_2018.html index e255765e..160dcaa3 100644 --- a/docs/dev/reference/dimethenamid_2018.html +++ b/docs/dev/reference/dimethenamid_2018.html @@ -77,7 +77,7 @@ constrained by data protection regulations." /> </button> <span class="navbar-brand"> <a class="navbar-link" href="../index.html">mkin</a> - <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.0.5</span> + <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.1.0</span> </span> </div> @@ -168,7 +168,7 @@ constrained by data protection regulations.</p> <p>Rapporteur Member State Germany, Co-Rapporteur Member State Bulgaria (2018) Renewal Assessment Report Dimethenamid-P Volume 3 - B.8 Environmental fate and behaviour Rev. 2 - November 2017 -<a href='http://registerofquestions.efsa.europa.eu/roqFrontend/outputLoader?output=ON-5211'>http://registerofquestions.efsa.europa.eu/roqFrontend/outputLoader?output=ON-5211</a></p> +<a href='https://open.efsa.europa.eu/study-inventory/EFSA-Q-2014-00716'>https://open.efsa.europa.eu/study-inventory/EFSA-Q-2014-00716</a></p> <h2 class="hasAnchor" id="details"><a class="anchor" href="#details"></a>Details</h2> <p>The R code used to create this data object is installed with this package @@ -295,8 +295,11 @@ specific pieces of information in the comments.</p> #> M31 ~ add(sigma_low_M31) + prop(rsd_high_M31) #> }) #> } -#> <environment: 0x555559c2bd78></div><div class='input'><span class='va'>f_dmta_nlmixr_focei</span> <span class='op'><-</span> <span class='fu'><a href='https://rdrr.io/pkg/nlmixr/man/nlmixr.html'>nlmixr</a></span><span class='op'>(</span><span class='va'>f_dmta_mkin_tc</span>, est <span class='op'>=</span> <span class='st'>"focei"</span>, - control <span class='op'>=</span> <span class='fu'>nlmixr</span><span class='fu'>::</span><span class='fu'><a href='https://rdrr.io/pkg/nlmixr/man/foceiControl.html'>foceiControl</a></span><span class='op'>(</span>print <span class='op'>=</span> <span class='fl'>500</span><span class='op'>)</span><span class='op'>)</span> +#> <environment: 0x555559c00ce8></div><div class='input'><span class='co'># The focei fit takes about four minutes on my system</span> +<span class='fu'><a href='https://rdrr.io/r/base/system.time.html'>system.time</a></span><span class='op'>(</span> + <span class='va'>f_dmta_nlmixr_focei</span> <span class='op'><-</span> <span class='fu'><a href='https://rdrr.io/pkg/nlmixr/man/nlmixr.html'>nlmixr</a></span><span class='op'>(</span><span class='va'>f_dmta_mkin_tc</span>, est <span class='op'>=</span> <span class='st'>"focei"</span>, + control <span class='op'>=</span> <span class='fu'>nlmixr</span><span class='fu'>::</span><span class='fu'><a href='https://rdrr.io/pkg/nlmixr/man/foceiControl.html'>foceiControl</a></span><span class='op'>(</span>print <span class='op'>=</span> <span class='fl'>500</span><span class='op'>)</span><span class='op'>)</span> +<span class='op'>)</span> </div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> parameter labels from comments are typically ignored in non-interactive mode</span></div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> Need to run with the source intact to parse comments</span></div><div class='output co'>#> <span class='message'>→ creating full model...</span></div><div class='output co'>#> <span class='message'>→ pruning branches (<span style='color: #262626; background-color: #DADADA;'>`if`</span>/<span style='color: #262626; background-color: #DADADA;'>`else`</span>)...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ loading into <span style='color: #0000BB;'>symengine</span> environment...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ creating full model...</span></div><div class='output co'>#> <span class='message'>→ pruning branches (<span style='color: #262626; background-color: #DADADA;'>`if`</span>/<span style='color: #262626; background-color: #DADADA;'>`else`</span>)...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ loading into <span style='color: #0000BB;'>symengine</span> environment...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ calculate jacobian</span></div><div class='output co'>#> [====|====|====|====|====|====|====|====|====|====] 0:00:02 #> </div><div class='output co'>#> <span class='message'>→ calculate sensitivities</span></div><div class='output co'>#> [====|====|====|====|====|====|====|====|====|====] 0:00:04 #> </div><div class='output co'>#> <span class='message'>→ calculate ∂(f)/∂(η)</span></div><div class='output co'>#> [====|====|====|====|====|====|====|====|====|====] 0:00:01 @@ -320,12 +323,13 @@ specific pieces of information in the comments.</p> #> |.....................| o5 | o6 | o7 | o8 | #> <span style='text-decoration: underline;'>|.....................| o9 | o10 |...........|...........|</span> #> calculating covariance matrix -#> done</div><div class='output co'>#> <span class='message'>Calculating residuals/tables</span></div><div class='output co'>#> <span class='message'>done</span></div><div class='output co'>#> <span class='warning'>Warning: initial ETAs were nudged; (can control by foceiControl(etaNudge=., etaNudge2=))</span></div><div class='output co'>#> <span class='warning'>Warning: last objective function was not at minimum, possible problems in optimization</span></div><div class='output co'>#> <span class='warning'>Warning: S matrix non-positive definite</span></div><div class='output co'>#> <span class='warning'>Warning: using R matrix to calculate covariance</span></div><div class='output co'>#> <span class='warning'>Warning: gradient problems with initial estimate and covariance; see $scaleInfo</span></div><div class='input'><span class='fu'><a href='https://rdrr.io/r/base/summary.html'>summary</a></span><span class='op'>(</span><span class='va'>f_dmta_nlmixr_focei</span><span class='op'>)</span> +#> done</div><div class='output co'>#> <span class='message'>Calculating residuals/tables</span></div><div class='output co'>#> <span class='message'>done</span></div><div class='output co'>#> <span class='warning'>Warning: initial ETAs were nudged; (can control by foceiControl(etaNudge=., etaNudge2=))</span></div><div class='output co'>#> <span class='warning'>Warning: last objective function was not at minimum, possible problems in optimization</span></div><div class='output co'>#> <span class='warning'>Warning: S matrix non-positive definite</span></div><div class='output co'>#> <span class='warning'>Warning: using R matrix to calculate covariance</span></div><div class='output co'>#> <span class='warning'>Warning: gradient problems with initial estimate and covariance; see $scaleInfo</span></div><div class='output co'>#> user system elapsed +#> 227.879 9.742 237.728 </div><div class='input'><span class='fu'><a href='https://rdrr.io/r/base/summary.html'>summary</a></span><span class='op'>(</span><span class='va'>f_dmta_nlmixr_focei</span><span class='op'>)</span> </div><div class='output co'>#> nlmixr version used for fitting: 2.0.4 -#> mkin version used for pre-fitting: 1.0.5 +#> mkin version used for pre-fitting: 1.1.0 #> R version used for fitting: 4.1.0 -#> Date of fit: Thu Jun 17 14:04:58 2021 -#> Date of summary: Thu Jun 17 14:04:58 2021 +#> Date of fit: Tue Jul 27 16:02:33 2021 +#> Date of summary: Tue Jul 27 16:02:34 2021 #> #> Equations: #> d_DMTA/dt = - ((k1 * g * exp(-k1 * time) + k2 * (1 - g) * exp(-k2 * @@ -346,7 +350,7 @@ specific pieces of information in the comments.</p> #> #> Degradation model predictions using RxODE #> -#> Fitted in 242.937 s +#> Fitted in 237.547 s #> #> Variance model: Two-component variance function #> @@ -480,13 +484,194 @@ specific pieces of information in the comments.</p> #> M23 34.99 116.24 NA NA NA #> M27 53.05 176.23 NA NA NA #> M31 48.48 161.05 NA NA NA</div><div class='input'><span class='fu'><a href='https://rdrr.io/r/graphics/plot.default.html'>plot</a></span><span class='op'>(</span><span class='va'>f_dmta_nlmixr_focei</span><span class='op'>)</span> -</div><div class='img'><img src='dimethenamid_2018-1.png' alt='' width='700' height='433' /></div><div class='input'><span class='co'># saem has a problem with this model/data combination, maybe because of the</span> -<span class='co'># overparameterised error model, to be investigated</span> -<span class='co'>#f_dmta_nlmixr_saem <- nlmixr(f_dmta_mkin_tc, est = "saem",</span> -<span class='co'># control = saemControl(print = 500))</span> -<span class='co'>#summary(f_dmta_nlmixr_saem)</span> -<span class='co'>#plot(f_dmta_nlmixr_saem)</span> -<span class='co'># }</span> +</div><div class='img'><img src='dimethenamid_2018-1.png' alt='' width='700' height='433' /></div><div class='input'><span class='co'># Using saemix takes about 18 minutes</span> +<span class='fu'><a href='https://rdrr.io/r/base/system.time.html'>system.time</a></span><span class='op'>(</span> + <span class='va'>f_dmta_saemix</span> <span class='op'><-</span> <span class='fu'><a href='saem.html'>saem</a></span><span class='op'>(</span><span class='va'>f_dmta_mkin_tc</span>, test_log_parms <span class='op'>=</span> <span class='cn'>TRUE</span><span class='op'>)</span> +<span class='op'>)</span> +</div><div class='output co'>#> Running main SAEM algorithm +#> [1] "Tue Jul 27 16:02:34 2021" +#> .... +#> Minimisation finished +#> [1] "Tue Jul 27 16:21:39 2021"</div><div class='output co'>#> user system elapsed +#> 1213.394 0.087 1213.578 </div><div class='input'> +<span class='co'># nlmixr with est = "saem" is pretty fast with default iteration numbers, most</span> +<span class='co'># of the time (about 2.5 minutes) is spent for calculating the log likelihood at the end</span> +<span class='co'># The likelihood calculated for the nlmixr fit is much lower than that found by saemix</span> +<span class='co'># Also, the trace plot and the plot of the individual predictions is not</span> +<span class='co'># convincing for the parent. It seems we are fitting an overparameterised</span> +<span class='co'># model, so the result we get strongly depends on starting parameters and control settings.</span> +<span class='fu'><a href='https://rdrr.io/r/base/system.time.html'>system.time</a></span><span class='op'>(</span> + <span class='va'>f_dmta_nlmixr_saem</span> <span class='op'><-</span> <span class='fu'><a href='https://rdrr.io/pkg/nlmixr/man/nlmixr.html'>nlmixr</a></span><span class='op'>(</span><span class='va'>f_dmta_mkin_tc</span>, est <span class='op'>=</span> <span class='st'>"saem"</span>, + control <span class='op'>=</span> <span class='fu'>nlmixr</span><span class='fu'>::</span><span class='fu'><a href='https://rdrr.io/pkg/nlmixr/man/saemControl.html'>saemControl</a></span><span class='op'>(</span>print <span class='op'>=</span> <span class='fl'>500</span>, logLik <span class='op'>=</span> <span class='cn'>TRUE</span>, nmc <span class='op'>=</span> <span class='fl'>9</span><span class='op'>)</span><span class='op'>)</span> +<span class='op'>)</span> +</div><div class='output co'>#> <span class='message'>With est = 'saem', a different error model is required for each observed variableChanging the error model to 'obs_tc' (Two-component error for each observed variable)</span></div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> parameter labels from comments are typically ignored in non-interactive mode</span></div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> Need to run with the source intact to parse comments</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='message'>→ generate SAEM model</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> 1: 98.3427 -3.5148 -3.3187 -3.7728 -2.1163 -2.8457 0.9482 -2.8064 -2.7412 -2.8745 2.7912 0.6805 0.8213 0.8055 0.8578 1.4980 2.9309 0.2850 0.2854 0.2850 4.0990 0.3821 3.5349 0.6537 5.4143 0.0002 4.5093 0.1905 +#> 500: 97.8277 -4.3506 -4.0318 -4.1520 -3.0553 -3.5843 1.1326 -2.0873 -2.0421 -2.0751 0.2960 1.2515 0.2531 0.3807 0.7928 0.8863 6.5211 0.1433 0.1082 0.3353 0.8960 0.0470 0.7501 0.0475 0.9527 0.0281 0.7321 0.0594</div><div class='output co'>#> <span class='message'>Calculating covariance matrix</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>Calculating -2LL by Gaussian quadrature (nnodes=3,nsd=1.6)</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ creating full model...</span></div><div class='output co'>#> <span class='message'>→ pruning branches (<span style='color: #262626; background-color: #DADADA;'>`if`</span>/<span style='color: #262626; background-color: #DADADA;'>`else`</span>)...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ loading into <span style='color: #0000BB;'>symengine</span> environment...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ compiling EBE model...</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>Needed Covariates:</span></div><div class='output co'>#> [1] "CMT"</div><div class='output co'>#> <span class='message'>Calculating residuals/tables</span></div><div class='output co'>#> <span class='message'>done</span></div><div class='output co'>#> user system elapsed +#> 818.782 3.808 154.926 </div><div class='input'><span class='fu'>traceplot</span><span class='op'>(</span><span class='va'>f_dmta_nlmixr_saem</span><span class='op'>$</span><span class='va'>nm</span><span class='op'>)</span> +</div><div class='output co'>#> <span class='error'>Error in traceplot(f_dmta_nlmixr_saem$nm): could not find function "traceplot"</span></div><div class='input'><span class='fu'><a href='https://rdrr.io/r/base/summary.html'>summary</a></span><span class='op'>(</span><span class='va'>f_dmta_nlmixr_saem</span><span class='op'>)</span> +</div><div class='output co'>#> nlmixr version used for fitting: 2.0.4 +#> mkin version used for pre-fitting: 1.1.0 +#> R version used for fitting: 4.1.0 +#> Date of fit: Tue Jul 27 16:25:23 2021 +#> Date of summary: Tue Jul 27 16:25:23 2021 +#> +#> Equations: +#> d_DMTA/dt = - ((k1 * g * exp(-k1 * time) + k2 * (1 - g) * exp(-k2 * +#> time)) / (g * exp(-k1 * time) + (1 - g) * exp(-k2 * time))) +#> * DMTA +#> d_M23/dt = + f_DMTA_to_M23 * ((k1 * g * exp(-k1 * time) + k2 * (1 - g) +#> * exp(-k2 * time)) / (g * exp(-k1 * time) + (1 - g) * +#> exp(-k2 * time))) * DMTA - k_M23 * M23 +#> d_M27/dt = + f_DMTA_to_M27 * ((k1 * g * exp(-k1 * time) + k2 * (1 - g) +#> * exp(-k2 * time)) / (g * exp(-k1 * time) + (1 - g) * +#> exp(-k2 * time))) * DMTA - k_M27 * M27 + k_M31 * M31 +#> d_M31/dt = + f_DMTA_to_M31 * ((k1 * g * exp(-k1 * time) + k2 * (1 - g) +#> * exp(-k2 * time)) / (g * exp(-k1 * time) + (1 - g) * +#> exp(-k2 * time))) * DMTA - k_M31 * M31 +#> +#> Data: +#> 568 observations of 4 variable(s) grouped in 6 datasets +#> +#> Degradation model predictions using RxODE +#> +#> Fitted in 154.632 s +#> +#> Variance model: Two-component variance function +#> +#> Mean of starting values for individual parameters: +#> DMTA_0 log_k_M23 log_k_M27 log_k_M31 f_DMTA_ilr_1 f_DMTA_ilr_2 +#> 98.7698 -3.9216 -4.3377 -4.2477 0.1380 0.1393 +#> f_DMTA_ilr_3 log_k1 log_k2 g_qlogis +#> -1.7571 -2.2341 -3.7763 0.4502 +#> +#> Mean of starting values for error model parameters: +#> sigma_low_DMTA rsd_high_DMTA sigma_low_M23 rsd_high_M23 sigma_low_M27 +#> 0.69793 0.02577 0.69793 0.02577 0.69793 +#> rsd_high_M27 sigma_low_M31 rsd_high_M31 +#> 0.02577 0.69793 0.02577 +#> +#> Fixed degradation parameter values: +#> None +#> +#> Results: +#> +#> Likelihood calculated by focei +#> AIC BIC logLik +#> 2036 2157 -989.8 +#> +#> Optimised parameters: +#> est. lower upper +#> DMTA_0 97.828 96.121 99.535 +#> log_k_M23 -4.351 -5.300 -3.401 +#> log_k_M27 -4.032 -4.470 -3.594 +#> log_k_M31 -4.152 -4.689 -3.615 +#> log_k1 -3.055 -3.785 -2.325 +#> log_k2 -3.584 -4.517 -2.651 +#> g_qlogis 1.133 -2.165 4.430 +#> f_DMTA_tffm0_1_qlogis -2.087 -2.407 -1.768 +#> f_DMTA_tffm0_2_qlogis -2.042 -2.336 -1.748 +#> f_DMTA_tffm0_3_qlogis -2.075 -2.557 -1.593 +#> +#> Correlation: +#> DMTA_0 l__M23 l__M27 l__M31 log_k1 log_k2 g_qlgs +#> log_k_M23 -0.031 +#> log_k_M27 -0.050 0.004 +#> log_k_M31 -0.032 0.003 0.078 +#> log_k1 0.014 -0.002 -0.002 -0.001 +#> log_k2 0.059 0.006 -0.001 0.002 -0.037 +#> g_qlogis -0.077 0.005 0.009 0.004 0.035 -0.201 +#> f_DMTA_tffm0_1_qlogis -0.104 0.066 0.009 0.006 0.000 -0.011 0.014 +#> f_DMTA_tffm0_2_qlogis -0.120 0.013 0.081 -0.033 -0.002 -0.013 0.017 +#> f_DMTA_tffm0_3_qlogis -0.086 0.010 0.060 0.078 -0.002 -0.005 0.010 +#> f_DMTA_0_1 f_DMTA_0_2 +#> log_k_M23 +#> log_k_M27 +#> log_k_M31 +#> log_k1 +#> log_k2 +#> g_qlogis +#> f_DMTA_tffm0_1_qlogis +#> f_DMTA_tffm0_2_qlogis 0.026 +#> f_DMTA_tffm0_3_qlogis 0.019 0.002 +#> +#> Random effects (omega): +#> eta.DMTA_0 eta.log_k_M23 eta.log_k_M27 eta.log_k_M31 +#> eta.DMTA_0 0.296 0.000 0.0000 0.0000 +#> eta.log_k_M23 0.000 1.252 0.0000 0.0000 +#> eta.log_k_M27 0.000 0.000 0.2531 0.0000 +#> eta.log_k_M31 0.000 0.000 0.0000 0.3807 +#> eta.log_k1 0.000 0.000 0.0000 0.0000 +#> eta.log_k2 0.000 0.000 0.0000 0.0000 +#> eta.g_qlogis 0.000 0.000 0.0000 0.0000 +#> eta.f_DMTA_tffm0_1_qlogis 0.000 0.000 0.0000 0.0000 +#> eta.f_DMTA_tffm0_2_qlogis 0.000 0.000 0.0000 0.0000 +#> eta.f_DMTA_tffm0_3_qlogis 0.000 0.000 0.0000 0.0000 +#> eta.log_k1 eta.log_k2 eta.g_qlogis +#> eta.DMTA_0 0.0000 0.0000 0.000 +#> eta.log_k_M23 0.0000 0.0000 0.000 +#> eta.log_k_M27 0.0000 0.0000 0.000 +#> eta.log_k_M31 0.0000 0.0000 0.000 +#> eta.log_k1 0.7928 0.0000 0.000 +#> eta.log_k2 0.0000 0.8863 0.000 +#> eta.g_qlogis 0.0000 0.0000 6.521 +#> eta.f_DMTA_tffm0_1_qlogis 0.0000 0.0000 0.000 +#> eta.f_DMTA_tffm0_2_qlogis 0.0000 0.0000 0.000 +#> eta.f_DMTA_tffm0_3_qlogis 0.0000 0.0000 0.000 +#> eta.f_DMTA_tffm0_1_qlogis eta.f_DMTA_tffm0_2_qlogis +#> eta.DMTA_0 0.0000 0.0000 +#> eta.log_k_M23 0.0000 0.0000 +#> eta.log_k_M27 0.0000 0.0000 +#> eta.log_k_M31 0.0000 0.0000 +#> eta.log_k1 0.0000 0.0000 +#> eta.log_k2 0.0000 0.0000 +#> eta.g_qlogis 0.0000 0.0000 +#> eta.f_DMTA_tffm0_1_qlogis 0.1433 0.0000 +#> eta.f_DMTA_tffm0_2_qlogis 0.0000 0.1082 +#> eta.f_DMTA_tffm0_3_qlogis 0.0000 0.0000 +#> eta.f_DMTA_tffm0_3_qlogis +#> eta.DMTA_0 0.0000 +#> eta.log_k_M23 0.0000 +#> eta.log_k_M27 0.0000 +#> eta.log_k_M31 0.0000 +#> eta.log_k1 0.0000 +#> eta.log_k2 0.0000 +#> eta.g_qlogis 0.0000 +#> eta.f_DMTA_tffm0_1_qlogis 0.0000 +#> eta.f_DMTA_tffm0_2_qlogis 0.0000 +#> eta.f_DMTA_tffm0_3_qlogis 0.3353 +#> +#> Variance model: +#> sigma_low_DMTA rsd_high_DMTA sigma_low_M23 rsd_high_M23 sigma_low_M27 +#> 0.89603 0.04704 0.75015 0.04753 0.95265 +#> rsd_high_M27 sigma_low_M31 rsd_high_M31 +#> 0.02810 0.73212 0.05942 +#> +#> Backtransformed parameters: +#> est. lower upper +#> DMTA_0 97.82774 96.120503 99.53498 +#> k_M23 0.01290 0.004991 0.03334 +#> k_M27 0.01774 0.011451 0.02749 +#> k_M31 0.01573 0.009195 0.02692 +#> f_DMTA_to_M23 0.11033 NA NA +#> f_DMTA_to_M27 0.10218 NA NA +#> f_DMTA_to_M31 0.08784 NA NA +#> k1 0.04711 0.022707 0.09773 +#> k2 0.02775 0.010918 0.07056 +#> g 0.75632 0.102960 0.98823 +#> +#> Resulting formation fractions: +#> ff +#> DMTA_M23 0.11033 +#> DMTA_M27 0.10218 +#> DMTA_M31 0.08784 +#> DMTA_sink 0.69965 +#> +#> Estimated disappearance times: +#> DT50 DT90 DT50back DT50_k1 DT50_k2 +#> DMTA 16.59 57.44 17.29 14.71 24.97 +#> M23 53.74 178.51 NA NA NA +#> M27 39.07 129.78 NA NA NA +#> M31 44.06 146.36 NA NA NA</div><div class='input'><span class='fu'><a href='https://rdrr.io/r/graphics/plot.default.html'>plot</a></span><span class='op'>(</span><span class='va'>f_dmta_nlmixr_saem</span><span class='op'>)</span> +</div><div class='img'><img src='dimethenamid_2018-2.png' alt='' width='700' height='433' /></div><div class='input'><span class='co'># }</span> </div></pre> </div> <div class="col-md-3 hidden-xs hidden-sm" id="pkgdown-sidebar"> diff --git a/docs/dev/reference/endpoints.html b/docs/dev/reference/endpoints.html index dc1d1f17..aa5bd773 100644 --- a/docs/dev/reference/endpoints.html +++ b/docs/dev/reference/endpoints.html @@ -78,7 +78,7 @@ advantage that the SFORB model can also be used for metabolites." /> </button> <span class="navbar-brand"> <a class="navbar-link" href="../index.html">mkin</a> - <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.0.5</span> + <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.1.0</span> </span> </div> diff --git a/docs/dev/reference/index.html b/docs/dev/reference/index.html index bb030605..d5ec387a 100644 --- a/docs/dev/reference/index.html +++ b/docs/dev/reference/index.html @@ -71,7 +71,7 @@ </button> <span class="navbar-brand"> <a class="navbar-link" href="../index.html">mkin</a> - <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.0.5</span> + <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.1.0</span> </span> </div> diff --git a/docs/dev/reference/mean_degparms.html b/docs/dev/reference/mean_degparms.html index f63dbc31..5981c625 100644 --- a/docs/dev/reference/mean_degparms.html +++ b/docs/dev/reference/mean_degparms.html @@ -72,7 +72,7 @@ </button> <span class="navbar-brand"> <a class="navbar-link" href="../index.html">mkin</a> - <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.0.5</span> + <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.1.0</span> </span> </div> diff --git a/docs/dev/reference/mkinmod.html b/docs/dev/reference/mkinmod.html index 413f0ae1..e57e7062 100644 --- a/docs/dev/reference/mkinmod.html +++ b/docs/dev/reference/mkinmod.html @@ -44,9 +44,7 @@ variable, specifying the corresponding submodel as well as outgoing pathways (see examples). Print mkinmod objects in a way that the user finds his way to get to its -components. -This is a convenience function to set up the lists used as arguments for -mkinmod." /> +components." /> <meta name="robots" content="noindex"> @@ -78,7 +76,7 @@ mkinmod." /> </button> <span class="navbar-brand"> <a class="navbar-link" href="../index.html">mkin</a> - <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.0.3.9000</span> + <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.1.0</span> </span> </div> @@ -155,8 +153,6 @@ variable, specifying the corresponding submodel as well as outgoing pathways (see examples).</p> <p>Print mkinmod objects in a way that the user finds his way to get to its components.</p> -<p>This is a convenience function to set up the lists used as arguments for -<code>mkinmod</code>.</p> </div> <pre class="usage"><span class='fu'>mkinmod</span><span class='op'>(</span> @@ -348,7 +344,7 @@ Evaluating and Calculating Degradation Kinetics in Environmental Media</p> parent <span class='op'>=</span> <span class='fu'>mkinsub</span><span class='op'>(</span><span class='st'>"SFO"</span>, <span class='st'>"m1"</span>, full_name <span class='op'>=</span> <span class='st'>"Test compound"</span><span class='op'>)</span>, m1 <span class='op'>=</span> <span class='fu'>mkinsub</span><span class='op'>(</span><span class='st'>"SFO"</span>, full_name <span class='op'>=</span> <span class='st'>"Metabolite M1"</span><span class='op'>)</span>, name <span class='op'>=</span> <span class='st'>"SFO_SFO"</span>, dll_dir <span class='op'>=</span> <span class='va'>DLL_dir</span>, unload <span class='op'>=</span> <span class='cn'>TRUE</span>, overwrite <span class='op'>=</span> <span class='cn'>TRUE</span><span class='op'>)</span> -</div><div class='output co'>#> <span class='message'>Copied DLL from /tmp/Rtmp92fCb2/file133ad522561845.so to /home/jranke/.local/share/mkin/SFO_SFO.so</span></div><div class='input'><span class='co'># Now we can save the model and restore it in a new session</span> +</div><div class='output co'>#> <span class='message'>Copied DLL from /tmp/RtmpPWWdbW/fileccff46a6d9773.so to /home/jranke/.local/share/mkin/SFO_SFO.so</span></div><div class='input'><span class='co'># Now we can save the model and restore it in a new session</span> <span class='fu'><a href='https://rdrr.io/r/base/readRDS.html'>saveRDS</a></span><span class='op'>(</span><span class='va'>SFO_SFO.2</span>, file <span class='op'>=</span> <span class='st'>"~/SFO_SFO.rds"</span><span class='op'>)</span> <span class='co'># Terminate the R session here if you would like to check, and then do</span> <span class='kw'><a href='https://rdrr.io/r/base/library.html'>library</a></span><span class='op'>(</span><span class='va'><a href='https://pkgdown.jrwb.de/mkin/'>mkin</a></span><span class='op'>)</span> @@ -397,7 +393,7 @@ Evaluating and Calculating Degradation Kinetics in Environmental Media</p> #> }) #> return(predicted) #> } -#> <environment: 0x5555572517f8></div><div class='input'> +#> <environment: 0x5555645abab8></div><div class='input'> <span class='co'># If we have several parallel metabolites</span> <span class='co'># (compare tests/testthat/test_synthetic_data_for_UBA_2014.R)</span> <span class='va'>m_synth_DFOP_par</span> <span class='op'><-</span> <span class='fu'>mkinmod</span><span class='op'>(</span> diff --git a/docs/dev/reference/nlme-1.png b/docs/dev/reference/nlme-1.png Binary files differindex 365aaef0..f739089a 100644 --- a/docs/dev/reference/nlme-1.png +++ b/docs/dev/reference/nlme-1.png diff --git a/docs/dev/reference/nlme-2.png b/docs/dev/reference/nlme-2.png Binary files differindex 40841404..d3b29bb0 100644 --- a/docs/dev/reference/nlme-2.png +++ b/docs/dev/reference/nlme-2.png diff --git a/docs/dev/reference/nlme.html b/docs/dev/reference/nlme.html index 55a94443..184585df 100644 --- a/docs/dev/reference/nlme.html +++ b/docs/dev/reference/nlme.html @@ -75,7 +75,7 @@ datasets. They are used internally by the nlme.mmkin() method." /> </button> <span class="navbar-brand"> <a class="navbar-link" href="../index.html">mkin</a> - <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.0.5</span> + <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.1.0</span> </span> </div> @@ -216,28 +216,28 @@ datasets. They are used internally by the <code><a href='nlme.mmkin.html'>nlme.m #> Model: value ~ nlme_f(name, time, parent_0, log_k_parent_sink) #> Data: grouped_data #> AIC BIC logLik -#> 300.6824 310.2426 -145.3412 +#> 278.1355 287.7946 -134.0677 #> #> Random effects: #> Formula: list(parent_0 ~ 1, log_k_parent_sink ~ 1) #> Level: ds #> Structure: Diagonal #> parent_0 log_k_parent_sink Residual -#> StdDev: 1.697361 0.6801209 3.666073 +#> StdDev: 3.406042 0.6437579 2.620833 #> #> Fixed effects: parent_0 + log_k_parent_sink ~ 1 #> Value Std.Error DF t-value p-value -#> parent_0 100.99378 1.3890416 46 72.70753 0 -#> log_k_parent_sink -3.07521 0.4018589 46 -7.65246 0 +#> parent_0 101.50173 2.123709 47 47.79457 0 +#> log_k_parent_sink -3.07597 0.379775 47 -8.09945 0 #> Correlation: #> prnt_0 -#> log_k_parent_sink 0.027 +#> log_k_parent_sink 0.01 #> #> Standardized Within-Group Residuals: -#> Min Q1 Med Q3 Max -#> -1.9942823 -0.5622565 0.1791579 0.7165038 2.0704781 +#> Min Q1 Med Q3 Max +#> -2.06889303 -0.50100169 -0.06268253 0.62557544 2.19922001 #> -#> Number of Observations: 50 +#> Number of Observations: 51 #> Number of Groups: 3 </div><div class='input'><span class='fu'><a href='https://rdrr.io/r/graphics/plot.default.html'>plot</a></span><span class='op'>(</span><span class='fu'><a href='https://rdrr.io/pkg/nlme/man/augPred.html'>augPred</a></span><span class='op'>(</span><span class='va'>m_nlme</span>, level <span class='op'>=</span> <span class='fl'>0</span><span class='op'>:</span><span class='fl'>1</span><span class='op'>)</span>, layout <span class='op'>=</span> <span class='fu'><a href='https://rdrr.io/r/base/c.html'>c</a></span><span class='op'>(</span><span class='fl'>3</span>, <span class='fl'>1</span><span class='op'>)</span><span class='op'>)</span> </div><div class='img'><img src='nlme-1.png' alt='' width='700' height='433' /></div><div class='input'><span class='co'># augPred does not work on fits with more than one state</span> <span class='co'># variable</span> diff --git a/docs/dev/reference/nlme.mmkin.html b/docs/dev/reference/nlme.mmkin.html index 2bbf4f80..866091ca 100644 --- a/docs/dev/reference/nlme.mmkin.html +++ b/docs/dev/reference/nlme.mmkin.html @@ -74,7 +74,7 @@ have been obtained by fitting the same model to a list of datasets." /> </button> <span class="navbar-brand"> <a class="navbar-link" href="../index.html">mkin</a> - <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.0.5</span> + <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.1.0</span> </span> </div> @@ -194,10 +194,9 @@ mmkin model are used as fixed parameters</p></td> </tr> <tr> <th>random</th> - <td><p>If not specified, correlated random effects are set up -for all optimised degradation model parameters using the log-Cholesky -parameterization <a href='https://rdrr.io/pkg/nlme/man/pdLogChol.html'>nlme::pdLogChol</a> that is also the default of -the generic <a href='https://rdrr.io/pkg/nlme/man/nlme.html'>nlme</a> method.</p></td> + <td><p>If not specified, no correlations between random effects are +set up for the optimised degradation model parameters. This is +achieved by using the <a href='https://rdrr.io/pkg/nlme/man/pdDiag.html'>nlme::pdDiag</a> method.</p></td> </tr> <tr> <th>groups</th> diff --git a/docs/dev/reference/nlmixr.mmkin.html b/docs/dev/reference/nlmixr.mmkin.html index d09f2ad4..328bad43 100644 --- a/docs/dev/reference/nlmixr.mmkin.html +++ b/docs/dev/reference/nlmixr.mmkin.html @@ -74,7 +74,7 @@ Expectation Maximisation algorithm (SAEM)." /> </button> <span class="navbar-brand"> <a class="navbar-link" href="../index.html">mkin</a> - <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.0.5</span> + <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.1.0</span> </span> </div> @@ -4501,7 +4501,7 @@ obtained by fitting the same model to a list of datasets using <a href='mkinfit. #> <span class='message'>k_A1=rx_expr_11;</span> #> <span class='message'>f_parent=1/(1+exp(-(ETA[4]+THETA[4])));</span> #> <span class='message'>tad=tad();</span> -#> <span class='message'>dosenum=dosenum();</span></div><div class='output co'>#> <span class='message'>Needed Covariates:</span></div><div class='output co'>#> <span class='message'>[1] "f_parent_to_A1" "CMT" </span></div><div class='output co'>#> <span class='error'>Error in (function (data, inits, PKpars, model = NULL, pred = NULL, err = NULL, lower = -Inf, upper = Inf, fixed = NULL, skipCov = NULL, control = foceiControl(), thetaNames = NULL, etaNames = NULL, etaMat = NULL, ..., env = NULL, keep = NULL, drop = NULL) { set.seed(control$seed) .pt <- proc.time() RxODE::.setWarnIdSort(FALSE) on.exit(RxODE::.setWarnIdSort(TRUE)) loadNamespace("n1qn1") if (!RxODE::rxIs(control, "foceiControl")) { control <- do.call(foceiControl, control) } if (is.null(env)) { .ret <- new.env(parent = emptyenv()) } else { .ret <- env } .ret$origData <- data .ret$etaNames <- etaNames .ret$thetaFixed <- fixed .ret$control <- control .ret$control$focei.mu.ref <- integer(0) if (is(model, "RxODE") || is(model, "character")) { .ret$ODEmodel <- TRUE if (class(pred) != "function") { stop("pred must be a function specifying the prediction variables in this model.") } } else { .ret$ODEmodel <- TRUE model <- RxODE::rxGetLin(PKpars) pred <- eval(parse(text = "function(){return(Central);}")) } .square <- function(x) x * x .ret$diagXformInv <- c(sqrt = ".square", log = "exp", identity = "identity")[control$diagXform] if (is.null(err)) { err <- eval(parse(text = paste0("function(){err", paste(inits$ERROR[[1]], collapse = ""), "}"))) } .covNames <- .parNames <- c() .ret$adjLik <- control$adjLik .mixed <- !is.null(inits$OMGA) && length(inits$OMGA) > 0 if (!exists("noLik", envir = .ret)) { .atol <- rep(control$atol, length(RxODE::rxModelVars(model)$state)) .rtol <- rep(control$rtol, length(RxODE::rxModelVars(model)$state)) .ssAtol <- rep(control$ssAtol, length(RxODE::rxModelVars(model)$state)) .ssRtol <- rep(control$ssRtol, length(RxODE::rxModelVars(model)$state)) .ret$model <- RxODE::rxSymPySetupPred(model, pred, PKpars, err, grad = (control$derivMethod == 2L), pred.minus.dv = TRUE, sum.prod = control$sumProd, theta.derivs = FALSE, optExpression = control$optExpression, interaction = (control$interaction == 1L), only.numeric = !.mixed, run.internal = TRUE, addProp = control$addProp) if (!is.null(.ret$model$inner)) { .atol <- c(.atol, rep(control$atolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.atol))) .rtol <- c(.rtol, rep(control$rtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.rtol))) .ret$control$rxControl$atol <- .atol .ret$control$rxControl$rtol <- .rtol .ssAtol <- c(.ssAtol, rep(control$ssAtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.ssAtol))) .ssRtol <- c(.ssRtol, rep(control$ssRtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.ssRtol))) .ret$control$rxControl$ssAtol <- .ssAtol .ret$control$rxControl$ssRtol <- .ssRtol } .covNames <- .parNames <- RxODE::rxParams(.ret$model$pred.only) .covNames <- .covNames[regexpr(rex::rex(start, or("THETA", "ETA"), "[", numbers, "]", end), .covNames) == -1] colnames(data) <- sapply(names(data), function(x) { if (any(x == .covNames)) { return(x) } else { return(toupper(x)) } }) .lhs <- c(names(RxODE::rxInits(.ret$model$pred.only)), RxODE::rxLhs(.ret$model$pred.only)) if (length(.lhs) > 0) { .covNames <- .covNames[regexpr(rex::rex(start, or(.lhs), end), .covNames) == -1] } if (length(.covNames) > 0) { if (!all(.covNames %in% names(data))) { message("Model:") RxODE::rxCat(.ret$model$pred.only) message("Needed Covariates:") nlmixrPrint(.covNames) stop("Not all the covariates are in the dataset.") } message("Needed Covariates:") print(.covNames) } .extraPars <- .ret$model$extra.pars } else { if (.ret$noLik) { .atol <- rep(control$atol, length(RxODE::rxModelVars(model)$state)) .rtol <- rep(control$rtol, length(RxODE::rxModelVars(model)$state)) .ret$model <- RxODE::rxSymPySetupPred(model, pred, PKpars, err, grad = FALSE, pred.minus.dv = TRUE, sum.prod = control$sumProd, theta.derivs = FALSE, optExpression = control$optExpression, run.internal = TRUE, only.numeric = TRUE, addProp = control$addProp) if (!is.null(.ret$model$inner)) { .atol <- c(.atol, rep(control$atolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.atol))) .rtol <- c(.rtol, rep(control$rtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.rtol))) .ret$control$rxControl$atol <- .atol .ret$control$rxControl$rtol <- .rtol } .covNames <- .parNames <- RxODE::rxParams(.ret$model$pred.only) .covNames <- .covNames[regexpr(rex::rex(start, or("THETA", "ETA"), "[", numbers, "]", end), .covNames) == -1] colnames(data) <- sapply(names(data), function(x) { if (any(x == .covNames)) { return(x) } else { return(toupper(x)) } }) .lhs <- c(names(RxODE::rxInits(.ret$model$pred.only)), RxODE::rxLhs(.ret$model$pred.only)) if (length(.lhs) > 0) { .covNames <- .covNames[regexpr(rex::rex(start, or(.lhs), end), .covNames) == -1] } if (length(.covNames) > 0) { if (!all(.covNames %in% names(data))) { message("Model:") RxODE::rxCat(.ret$model$pred.only) message("Needed Covariates:") nlmixrPrint(.covNames) stop("Not all the covariates are in the dataset.") } message("Needed Covariates:") print(.covNames) } .extraPars <- .ret$model$extra.pars } else { .extraPars <- NULL } } .ret$skipCov <- skipCov if (is.null(skipCov)) { if (is.null(fixed)) { .tmp <- rep(FALSE, length(inits$THTA)) } else { if (length(fixed) < length(inits$THTA)) { .tmp <- c(fixed, rep(FALSE, length(inits$THTA) - length(fixed))) } else { .tmp <- fixed[1:length(inits$THTA)] } } if (exists("uif", envir = .ret)) { .uifErr <- .ret$uif$ini$err[!is.na(.ret$uif$ini$ntheta)] .uifErr <- sapply(.uifErr, function(x) { if (is.na(x)) { return(FALSE) } return(!any(x == c("pow2", "tbs", "tbsYj"))) }) .tmp <- (.tmp | .uifErr) } .ret$skipCov <- c(.tmp, rep(TRUE, length(.extraPars))) .ret$control$focei.mu.ref <- .ret$uif$focei.mu.ref } if (is.null(.extraPars)) { .nms <- c(sprintf("THETA[%s]", seq_along(inits$THTA))) } else { .nms <- c(sprintf("THETA[%s]", seq_along(inits$THTA)), sprintf("ERR[%s]", seq_along(.extraPars))) } if (!is.null(thetaNames) && (length(inits$THTA) + length(.extraPars)) == length(thetaNames)) { .nms <- thetaNames } .ret$thetaNames <- .nms .thetaReset$thetaNames <- .nms if (length(lower) == 1) { lower <- rep(lower, length(inits$THTA)) } else if (length(lower) != length(inits$THTA)) { print(inits$THTA) print(lower) stop("Lower must be a single constant for all the THETA lower bounds, or match the dimension of THETA.") } if (length(upper) == 1) { upper <- rep(upper, length(inits$THTA)) } else if (length(lower) != length(inits$THTA)) { stop("Upper must be a single constant for all the THETA lower bounds, or match the dimension of THETA.") } if (!is.null(.extraPars)) { .ret$model$extra.pars <- eval(call(control$diagXform, .ret$model$extra.pars)) if (length(.ret$model$extra.pars) > 0) { inits$THTA <- c(inits$THTA, .ret$model$extra.pars) .lowerErr <- rep(control$atol[1] * 10, length(.ret$model$extra.pars)) .upperErr <- rep(Inf, length(.ret$model$extra.pars)) lower <- c(lower, .lowerErr) upper <- c(upper, .upperErr) } } if (is.null(data$ID)) stop("\"ID\" not found in data") if (is.null(data$DV)) stop("\"DV\" not found in data") if (is.null(data$EVID)) data$EVID <- 0 if (is.null(data$AMT)) data$AMT <- 0 for (.v in c("TIME", "AMT", "DV", .covNames)) { data[[.v]] <- as.double(data[[.v]]) } .ret$dataSav <- data .ds <- data[data$EVID != 0 & data$EVID != 2, c("ID", "TIME", "AMT", "EVID", .covNames)] .w <- which(tolower(names(data)) == "limit") .limitName <- NULL if (length(.w) == 1L) { .limitName <- names(data)[.w] } .censName <- NULL .w <- which(tolower(names(data)) == "cens") if (length(.w) == 1L) { .censName <- names(data[.w]) } data <- data[data$EVID == 0 | data$EVID == 2, c("ID", "TIME", "DV", "EVID", .covNames, .limitName, .censName)] .w <- which(!(names(.ret$dataSav) %in% c(.covNames, keep))) names(.ret$dataSav)[.w] <- tolower(names(.ret$dataSav[.w])) if (.mixed) { .lh <- .parseOM(inits$OMGA) .nlh <- sapply(.lh, length) .osplt <- rep(1:length(.lh), .nlh) .lini <- list(inits$THTA, unlist(.lh)) .nlini <- sapply(.lini, length) .nsplt <- rep(1:length(.lini), .nlini) .om0 <- .genOM(.lh) if (length(etaNames) == dim(.om0)[1]) { .ret$etaNames <- .ret$etaNames } else { .ret$etaNames <- sprintf("ETA[%d]", seq(1, dim(.om0)[1])) } .ret$rxInv <- RxODE::rxSymInvCholCreate(mat = .om0, diag.xform = control$diagXform) .ret$xType <- .ret$rxInv$xType .om0a <- .om0 .om0a <- .om0a/control$diagOmegaBoundLower .om0b <- .om0 .om0b <- .om0b * control$diagOmegaBoundUpper .om0a <- RxODE::rxSymInvCholCreate(mat = .om0a, diag.xform = control$diagXform) .om0b <- RxODE::rxSymInvCholCreate(mat = .om0b, diag.xform = control$diagXform) .omdf <- data.frame(a = .om0a$theta, m = .ret$rxInv$theta, b = .om0b$theta, diag = .om0a$theta.diag) .omdf$lower <- with(.omdf, ifelse(a > b, b, a)) .omdf$lower <- with(.omdf, ifelse(lower == m, -Inf, lower)) .omdf$lower <- with(.omdf, ifelse(!diag, -Inf, lower)) .omdf$upper <- with(.omdf, ifelse(a < b, b, a)) .omdf$upper <- with(.omdf, ifelse(upper == m, Inf, upper)) .omdf$upper <- with(.omdf, ifelse(!diag, Inf, upper)) .ret$control$nomega <- length(.omdf$lower) .ret$control$neta <- sum(.omdf$diag) .ret$control$ntheta <- length(lower) .ret$control$nfixed <- sum(fixed) lower <- c(lower, .omdf$lower) upper <- c(upper, .omdf$upper) } else { .ret$control$nomega <- 0 .ret$control$neta <- 0 .ret$xType <- -1 .ret$control$ntheta <- length(lower) .ret$control$nfixed <- sum(fixed) } .ret$lower <- lower .ret$upper <- upper .ret$thetaIni <- inits$THTA .scaleC <- double(length(lower)) if (is.null(control$scaleC)) { .scaleC <- rep(NA_real_, length(lower)) } else { .scaleC <- as.double(control$scaleC) if (length(lower) > length(.scaleC)) { .scaleC <- c(.scaleC, rep(NA_real_, length(lower) - length(.scaleC))) } else if (length(lower) < length(.scaleC)) { .scaleC <- .scaleC[seq(1, length(lower))] warning("scaleC control option has more options than estimated population parameters, please check.") } } .ret$scaleC <- .scaleC if (exists("uif", envir = .ret)) { .ini <- as.data.frame(.ret$uif$ini)[!is.na(.ret$uif$ini$err), c("est", "err", "ntheta")] for (.i in seq_along(.ini$err)) { if (is.na(.ret$scaleC[.ini$ntheta[.i]])) { if (any(.ini$err[.i] == c("boxCox", "yeoJohnson", "pow2", "tbs", "tbsYj"))) { .ret$scaleC[.ini$ntheta[.i]] <- 1 } else if (any(.ini$err[.i] == c("prop", "add", "norm", "dnorm", "logn", "dlogn", "lnorm", "dlnorm"))) { .ret$scaleC[.ini$ntheta[.i]] <- 0.5 * abs(.ini$est[.i]) } } } for (.i in .ini$model$extraProps$powTheta) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- 1 } .ini <- as.data.frame(.ret$uif$ini) for (.i in .ini$model$extraProps$factorial) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- abs(1/digamma(.ini$est[.i] + 1)) } for (.i in .ini$model$extraProps$gamma) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- abs(1/digamma(.ini$est[.i])) } for (.i in .ini$model$extraProps$log) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- log(abs(.ini$est[.i])) * abs(.ini$est[.i]) } for (.i in .ret$logitThetas) { .b <- .ret$logitThetasLow[.i] .c <- .ret$logitThetasHi[.i] .a <- .ini$est[.i] if (is.na(.ret$scaleC[.i])) { .ret$scaleC[.i] <- 1 * (-.b + .c) * exp(-.a)/((1 + exp(-.a))^2 * (.b + 1 * (-.b + .c)/(1 + exp(-.a)))) } } } names(.ret$thetaIni) <- sprintf("THETA[%d]", seq_along(.ret$thetaIni)) if (is.null(etaMat) & !is.null(control$etaMat)) { .ret$etaMat <- control$etaMat } else { .ret$etaMat <- etaMat } .ret$setupTime <- (proc.time() - .pt)["elapsed"] if (exists("uif", envir = .ret)) { .tmp <- .ret$uif$logThetasList .ret$logThetas <- .tmp[[1]] .ret$logThetasF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasList .ret$logitThetas <- .tmp[[1]] .ret$logitThetasF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasListLow .ret$logitThetasLow <- .tmp[[1]] .ret$logitThetasLowF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasListHi .ret$logitThetasHi <- .tmp[[1]] .ret$logitThetasHiF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasList .ret$probitThetas <- .tmp[[1]] .ret$probitThetasF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasListLow .ret$probitThetasLow <- .tmp[[1]] .ret$probitThetasLowF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasListHi .ret$probitThetasHi <- .tmp[[1]] .ret$probitThetasHiF <- .tmp[[2]] } else { .ret$logThetasF <- integer(0) .ret$logitThetasF <- integer(0) .ret$logitThetasHiF <- numeric(0) .ret$logitThetasLowF <- numeric(0) .ret$logitThetas <- integer(0) .ret$logitThetasHi <- numeric(0) .ret$logitThetasLow <- numeric(0) .ret$probitThetasF <- integer(0) .ret$probitThetasHiF <- numeric(0) .ret$probitThetasLowF <- numeric(0) .ret$probitThetas <- integer(0) .ret$probitThetasHi <- numeric(0) .ret$probitThetasLow <- numeric(0) } if (exists("noLik", envir = .ret)) { if (!.ret$noLik) { .ret$.params <- c(sprintf("THETA[%d]", seq_along(.ret$thetaIni)), sprintf("ETA[%d]", seq(1, dim(.om0)[1]))) .ret$.thetan <- length(.ret$thetaIni) .ret$nobs <- sum(data$EVID == 0) } } .ret$control$printTop <- TRUE .ret$control$nF <- 0 .est0 <- .ret$thetaIni if (!is.null(.ret$model$pred.nolhs)) { .ret$control$predNeq <- length(.ret$model$pred.nolhs$state) } else { .ret$control$predNeq <- 0L } .fitFun <- function(.ret) { this.env <- environment() assign("err", "theta reset", this.env) while (this.env$err == "theta reset") { assign("err", "", this.env) .ret0 <- tryCatch({ foceiFitCpp_(.ret) }, error = function(e) { if (regexpr("theta reset", e$message) != -1) { assign("zeroOuter", FALSE, this.env) assign("zeroGrad", FALSE, this.env) if (regexpr("theta reset0", e$message) != -1) { assign("zeroGrad", TRUE, this.env) } else if (regexpr("theta resetZ", e$message) != -1) { assign("zeroOuter", TRUE, this.env) } assign("err", "theta reset", this.env) } else { assign("err", e$message, this.env) } }) if (this.env$err == "theta reset") { .nm <- names(.ret$thetaIni) .ret$thetaIni <- setNames(.thetaReset$thetaIni + 0, .nm) .ret$rxInv$theta <- .thetaReset$omegaTheta .ret$control$printTop <- FALSE .ret$etaMat <- .thetaReset$etaMat .ret$control$etaMat <- .thetaReset$etaMat .ret$control$maxInnerIterations <- .thetaReset$maxInnerIterations .ret$control$nF <- .thetaReset$nF .ret$control$gillRetC <- .thetaReset$gillRetC .ret$control$gillRet <- .thetaReset$gillRet .ret$control$gillRet <- .thetaReset$gillRet .ret$control$gillDf <- .thetaReset$gillDf .ret$control$gillDf2 <- .thetaReset$gillDf2 .ret$control$gillErr <- .thetaReset$gillErr .ret$control$rEps <- .thetaReset$rEps .ret$control$aEps <- .thetaReset$aEps .ret$control$rEpsC <- .thetaReset$rEpsC .ret$control$aEpsC <- .thetaReset$aEpsC .ret$control$c1 <- .thetaReset$c1 .ret$control$c2 <- .thetaReset$c2 if (this.env$zeroOuter) { message("Posthoc reset") .ret$control$maxOuterIterations <- 0L } else if (this.env$zeroGrad) { message("Theta reset (zero gradient values); Switch to bobyqa") RxODE::rxReq("minqa") .ret$control$outerOptFun <- .bobyqa .ret$control$outerOpt <- -1L } else { message("Theta reset (ETA drift)") } } } if (this.env$err != "") { stop(this.env$err) } else { return(.ret0) } } .ret0 <- try(.fitFun(.ret)) .n <- 1 while (inherits(.ret0, "try-error") && control$maxOuterIterations != 0 && .n <= control$nRetries) { message(sprintf("Restart %s", .n)) .ret$control$nF <- 0 .estNew <- .est0 + 0.2 * .n * abs(.est0) * stats::runif(length(.est0)) - 0.1 * .n .estNew <- sapply(seq_along(.est0), function(.i) { if (.ret$thetaFixed[.i]) { return(.est0[.i]) } else if (.estNew[.i] < lower[.i]) { return(lower + (.Machine$double.eps)^(1/7)) } else if (.estNew[.i] > upper[.i]) { return(upper - (.Machine$double.eps)^(1/7)) } else { return(.estNew[.i]) } }) .ret$thetaIni <- .estNew .ret0 <- try(.fitFun(.ret)) .n <- .n + 1 } if (inherits(.ret0, "try-error")) stop("Could not fit data.") .ret <- .ret0 if (exists("parHistData", .ret)) { .tmp <- .ret$parHistData .tmp <- .tmp[.tmp$type == "Unscaled", names(.tmp) != "type"] .iter <- .tmp$iter .tmp <- .tmp[, names(.tmp) != "iter"] .ret$parHistStacked <- data.frame(stack(.tmp), iter = .iter) names(.ret$parHistStacked) <- c("val", "par", "iter") .ret$parHist <- data.frame(iter = .iter, .tmp) } if (.mixed) { .etas <- .ret$ranef .thetas <- .ret$fixef .pars <- .Call(`_nlmixr_nlmixrParameters`, .thetas, .etas) .ret$shrink <- .Call(`_nlmixr_calcShrinkOnly`, .ret$omega, .pars$eta.lst, length(.etas$ID)) .updateParFixed(.ret) } else { .updateParFixed(.ret) } if (!exists("table", .ret)) { .ret$table <- tableControl() } if (control$calcTables) { .ret <- addTable(.ret, updateObject = "no", keep = keep, drop = drop, table = .ret$table) } .ret})(data = dat, inits = .FoceiInits, PKpars = .pars, model = .mod, pred = function() { return(nlmixr_pred) }, err = uif$error, lower = uif$focei.lower, upper = uif$focei.upper, fixed = uif$focei.fixed, thetaNames = uif$focei.names, etaNames = uif$eta.names, control = control, env = env, keep = .keep, drop = .drop): Not all the covariates are in the dataset.</span></div><div class='output co'>#> <span class='message'>Timing stopped at: 5.607 0.474 6.078</span></div><div class='input'><span class='va'>f_nlmixr_fomc_sfo_focei_const</span> <span class='op'><-</span> <span class='fu'><a href='https://rdrr.io/pkg/nlmixr/man/nlmixr.html'>nlmixr</a></span><span class='op'>(</span><span class='va'>f_mmkin_const</span><span class='op'>[</span><span class='st'>"FOMC-SFO"</span>, <span class='op'>]</span>, est <span class='op'>=</span> <span class='st'>"focei"</span><span class='op'>)</span> +#> <span class='message'>dosenum=dosenum();</span></div><div class='output co'>#> <span class='message'>Needed Covariates:</span></div><div class='output co'>#> <span class='message'>[1] "f_parent_to_A1" "CMT" </span></div><div class='output co'>#> <span class='error'>Error in (function (data, inits, PKpars, model = NULL, pred = NULL, err = NULL, lower = -Inf, upper = Inf, fixed = NULL, skipCov = NULL, control = foceiControl(), thetaNames = NULL, etaNames = NULL, etaMat = NULL, ..., env = NULL, keep = NULL, drop = NULL) { set.seed(control$seed) .pt <- proc.time() RxODE::.setWarnIdSort(FALSE) on.exit(RxODE::.setWarnIdSort(TRUE)) loadNamespace("n1qn1") if (!RxODE::rxIs(control, "foceiControl")) { control <- do.call(foceiControl, control) } if (is.null(env)) { .ret <- new.env(parent = emptyenv()) } else { .ret <- env } .ret$origData <- data .ret$etaNames <- etaNames .ret$thetaFixed <- fixed .ret$control <- control .ret$control$focei.mu.ref <- integer(0) if (is(model, "RxODE") || is(model, "character")) { .ret$ODEmodel <- TRUE if (class(pred) != "function") { stop("pred must be a function specifying the prediction variables in this model.") } } else { .ret$ODEmodel <- TRUE model <- RxODE::rxGetLin(PKpars) pred <- eval(parse(text = "function(){return(Central);}")) } .square <- function(x) x * x .ret$diagXformInv <- c(sqrt = ".square", log = "exp", identity = "identity")[control$diagXform] if (is.null(err)) { err <- eval(parse(text = paste0("function(){err", paste(inits$ERROR[[1]], collapse = ""), "}"))) } .covNames <- .parNames <- c() .ret$adjLik <- control$adjLik .mixed <- !is.null(inits$OMGA) && length(inits$OMGA) > 0 if (!exists("noLik", envir = .ret)) { .atol <- rep(control$atol, length(RxODE::rxModelVars(model)$state)) .rtol <- rep(control$rtol, length(RxODE::rxModelVars(model)$state)) .ssAtol <- rep(control$ssAtol, length(RxODE::rxModelVars(model)$state)) .ssRtol <- rep(control$ssRtol, length(RxODE::rxModelVars(model)$state)) .ret$model <- RxODE::rxSymPySetupPred(model, pred, PKpars, err, grad = (control$derivMethod == 2L), pred.minus.dv = TRUE, sum.prod = control$sumProd, theta.derivs = FALSE, optExpression = control$optExpression, interaction = (control$interaction == 1L), only.numeric = !.mixed, run.internal = TRUE, addProp = control$addProp) if (!is.null(.ret$model$inner)) { .atol <- c(.atol, rep(control$atolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.atol))) .rtol <- c(.rtol, rep(control$rtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.rtol))) .ret$control$rxControl$atol <- .atol .ret$control$rxControl$rtol <- .rtol .ssAtol <- c(.ssAtol, rep(control$ssAtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.ssAtol))) .ssRtol <- c(.ssRtol, rep(control$ssRtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.ssRtol))) .ret$control$rxControl$ssAtol <- .ssAtol .ret$control$rxControl$ssRtol <- .ssRtol } .covNames <- .parNames <- RxODE::rxParams(.ret$model$pred.only) .covNames <- .covNames[regexpr(rex::rex(start, or("THETA", "ETA"), "[", numbers, "]", end), .covNames) == -1] colnames(data) <- sapply(names(data), function(x) { if (any(x == .covNames)) { return(x) } else { return(toupper(x)) } }) .lhs <- c(names(RxODE::rxInits(.ret$model$pred.only)), RxODE::rxLhs(.ret$model$pred.only)) if (length(.lhs) > 0) { .covNames <- .covNames[regexpr(rex::rex(start, or(.lhs), end), .covNames) == -1] } if (length(.covNames) > 0) { if (!all(.covNames %in% names(data))) { message("Model:") RxODE::rxCat(.ret$model$pred.only) message("Needed Covariates:") nlmixrPrint(.covNames) stop("Not all the covariates are in the dataset.") } message("Needed Covariates:") print(.covNames) } .extraPars <- .ret$model$extra.pars } else { if (.ret$noLik) { .atol <- rep(control$atol, length(RxODE::rxModelVars(model)$state)) .rtol <- rep(control$rtol, length(RxODE::rxModelVars(model)$state)) .ret$model <- RxODE::rxSymPySetupPred(model, pred, PKpars, err, grad = FALSE, pred.minus.dv = TRUE, sum.prod = control$sumProd, theta.derivs = FALSE, optExpression = control$optExpression, run.internal = TRUE, only.numeric = TRUE, addProp = control$addProp) if (!is.null(.ret$model$inner)) { .atol <- c(.atol, rep(control$atolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.atol))) .rtol <- c(.rtol, rep(control$rtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.rtol))) .ret$control$rxControl$atol <- .atol .ret$control$rxControl$rtol <- .rtol } .covNames <- .parNames <- RxODE::rxParams(.ret$model$pred.only) .covNames <- .covNames[regexpr(rex::rex(start, or("THETA", "ETA"), "[", numbers, "]", end), .covNames) == -1] colnames(data) <- sapply(names(data), function(x) { if (any(x == .covNames)) { return(x) } else { return(toupper(x)) } }) .lhs <- c(names(RxODE::rxInits(.ret$model$pred.only)), RxODE::rxLhs(.ret$model$pred.only)) if (length(.lhs) > 0) { .covNames <- .covNames[regexpr(rex::rex(start, or(.lhs), end), .covNames) == -1] } if (length(.covNames) > 0) { if (!all(.covNames %in% names(data))) { message("Model:") RxODE::rxCat(.ret$model$pred.only) message("Needed Covariates:") nlmixrPrint(.covNames) stop("Not all the covariates are in the dataset.") } message("Needed Covariates:") print(.covNames) } .extraPars <- .ret$model$extra.pars } else { .extraPars <- NULL } } .ret$skipCov <- skipCov if (is.null(skipCov)) { if (is.null(fixed)) { .tmp <- rep(FALSE, length(inits$THTA)) } else { if (length(fixed) < length(inits$THTA)) { .tmp <- c(fixed, rep(FALSE, length(inits$THTA) - length(fixed))) } else { .tmp <- fixed[1:length(inits$THTA)] } } if (exists("uif", envir = .ret)) { .uifErr <- .ret$uif$ini$err[!is.na(.ret$uif$ini$ntheta)] .uifErr <- sapply(.uifErr, function(x) { if (is.na(x)) { return(FALSE) } return(!any(x == c("pow2", "tbs", "tbsYj"))) }) .tmp <- (.tmp | .uifErr) } .ret$skipCov <- c(.tmp, rep(TRUE, length(.extraPars))) .ret$control$focei.mu.ref <- .ret$uif$focei.mu.ref } if (is.null(.extraPars)) { .nms <- c(sprintf("THETA[%s]", seq_along(inits$THTA))) } else { .nms <- c(sprintf("THETA[%s]", seq_along(inits$THTA)), sprintf("ERR[%s]", seq_along(.extraPars))) } if (!is.null(thetaNames) && (length(inits$THTA) + length(.extraPars)) == length(thetaNames)) { .nms <- thetaNames } .ret$thetaNames <- .nms .thetaReset$thetaNames <- .nms if (length(lower) == 1) { lower <- rep(lower, length(inits$THTA)) } else if (length(lower) != length(inits$THTA)) { print(inits$THTA) print(lower) stop("Lower must be a single constant for all the THETA lower bounds, or match the dimension of THETA.") } if (length(upper) == 1) { upper <- rep(upper, length(inits$THTA)) } else if (length(lower) != length(inits$THTA)) { stop("Upper must be a single constant for all the THETA lower bounds, or match the dimension of THETA.") } if (!is.null(.extraPars)) { .ret$model$extra.pars <- eval(call(control$diagXform, .ret$model$extra.pars)) if (length(.ret$model$extra.pars) > 0) { inits$THTA <- c(inits$THTA, .ret$model$extra.pars) .lowerErr <- rep(control$atol[1] * 10, length(.ret$model$extra.pars)) .upperErr <- rep(Inf, length(.ret$model$extra.pars)) lower <- c(lower, .lowerErr) upper <- c(upper, .upperErr) } } if (is.null(data$ID)) stop("\"ID\" not found in data") if (is.null(data$DV)) stop("\"DV\" not found in data") if (is.null(data$EVID)) data$EVID <- 0 if (is.null(data$AMT)) data$AMT <- 0 for (.v in c("TIME", "AMT", "DV", .covNames)) { data[[.v]] <- as.double(data[[.v]]) } .ret$dataSav <- data .ds <- data[data$EVID != 0 & data$EVID != 2, c("ID", "TIME", "AMT", "EVID", .covNames)] .w <- which(tolower(names(data)) == "limit") .limitName <- NULL if (length(.w) == 1L) { .limitName <- names(data)[.w] } .censName <- NULL .w <- which(tolower(names(data)) == "cens") if (length(.w) == 1L) { .censName <- names(data[.w]) } data <- data[data$EVID == 0 | data$EVID == 2, c("ID", "TIME", "DV", "EVID", .covNames, .limitName, .censName)] .w <- which(!(names(.ret$dataSav) %in% c(.covNames, keep))) names(.ret$dataSav)[.w] <- tolower(names(.ret$dataSav[.w])) if (.mixed) { .lh <- .parseOM(inits$OMGA) .nlh <- sapply(.lh, length) .osplt <- rep(1:length(.lh), .nlh) .lini <- list(inits$THTA, unlist(.lh)) .nlini <- sapply(.lini, length) .nsplt <- rep(1:length(.lini), .nlini) .om0 <- .genOM(.lh) if (length(etaNames) == dim(.om0)[1]) { .ret$etaNames <- .ret$etaNames } else { .ret$etaNames <- sprintf("ETA[%d]", seq(1, dim(.om0)[1])) } .ret$rxInv <- RxODE::rxSymInvCholCreate(mat = .om0, diag.xform = control$diagXform) .ret$xType <- .ret$rxInv$xType .om0a <- .om0 .om0a <- .om0a/control$diagOmegaBoundLower .om0b <- .om0 .om0b <- .om0b * control$diagOmegaBoundUpper .om0a <- RxODE::rxSymInvCholCreate(mat = .om0a, diag.xform = control$diagXform) .om0b <- RxODE::rxSymInvCholCreate(mat = .om0b, diag.xform = control$diagXform) .omdf <- data.frame(a = .om0a$theta, m = .ret$rxInv$theta, b = .om0b$theta, diag = .om0a$theta.diag) .omdf$lower <- with(.omdf, ifelse(a > b, b, a)) .omdf$lower <- with(.omdf, ifelse(lower == m, -Inf, lower)) .omdf$lower <- with(.omdf, ifelse(!diag, -Inf, lower)) .omdf$upper <- with(.omdf, ifelse(a < b, b, a)) .omdf$upper <- with(.omdf, ifelse(upper == m, Inf, upper)) .omdf$upper <- with(.omdf, ifelse(!diag, Inf, upper)) .ret$control$nomega <- length(.omdf$lower) .ret$control$neta <- sum(.omdf$diag) .ret$control$ntheta <- length(lower) .ret$control$nfixed <- sum(fixed) lower <- c(lower, .omdf$lower) upper <- c(upper, .omdf$upper) } else { .ret$control$nomega <- 0 .ret$control$neta <- 0 .ret$xType <- -1 .ret$control$ntheta <- length(lower) .ret$control$nfixed <- sum(fixed) } .ret$lower <- lower .ret$upper <- upper .ret$thetaIni <- inits$THTA .scaleC <- double(length(lower)) if (is.null(control$scaleC)) { .scaleC <- rep(NA_real_, length(lower)) } else { .scaleC <- as.double(control$scaleC) if (length(lower) > length(.scaleC)) { .scaleC <- c(.scaleC, rep(NA_real_, length(lower) - length(.scaleC))) } else if (length(lower) < length(.scaleC)) { .scaleC <- .scaleC[seq(1, length(lower))] warning("scaleC control option has more options than estimated population parameters, please check.") } } .ret$scaleC <- .scaleC if (exists("uif", envir = .ret)) { .ini <- as.data.frame(.ret$uif$ini)[!is.na(.ret$uif$ini$err), c("est", "err", "ntheta")] for (.i in seq_along(.ini$err)) { if (is.na(.ret$scaleC[.ini$ntheta[.i]])) { if (any(.ini$err[.i] == c("boxCox", "yeoJohnson", "pow2", "tbs", "tbsYj"))) { .ret$scaleC[.ini$ntheta[.i]] <- 1 } else if (any(.ini$err[.i] == c("prop", "add", "norm", "dnorm", "logn", "dlogn", "lnorm", "dlnorm"))) { .ret$scaleC[.ini$ntheta[.i]] <- 0.5 * abs(.ini$est[.i]) } } } for (.i in .ini$model$extraProps$powTheta) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- 1 } .ini <- as.data.frame(.ret$uif$ini) for (.i in .ini$model$extraProps$factorial) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- abs(1/digamma(.ini$est[.i] + 1)) } for (.i in .ini$model$extraProps$gamma) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- abs(1/digamma(.ini$est[.i])) } for (.i in .ini$model$extraProps$log) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- log(abs(.ini$est[.i])) * abs(.ini$est[.i]) } for (.i in .ret$logitThetas) { .b <- .ret$logitThetasLow[.i] .c <- .ret$logitThetasHi[.i] .a <- .ini$est[.i] if (is.na(.ret$scaleC[.i])) { .ret$scaleC[.i] <- 1 * (-.b + .c) * exp(-.a)/((1 + exp(-.a))^2 * (.b + 1 * (-.b + .c)/(1 + exp(-.a)))) } } } names(.ret$thetaIni) <- sprintf("THETA[%d]", seq_along(.ret$thetaIni)) if (is.null(etaMat) & !is.null(control$etaMat)) { .ret$etaMat <- control$etaMat } else { .ret$etaMat <- etaMat } .ret$setupTime <- (proc.time() - .pt)["elapsed"] if (exists("uif", envir = .ret)) { .tmp <- .ret$uif$logThetasList .ret$logThetas <- .tmp[[1]] .ret$logThetasF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasList .ret$logitThetas <- .tmp[[1]] .ret$logitThetasF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasListLow .ret$logitThetasLow <- .tmp[[1]] .ret$logitThetasLowF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasListHi .ret$logitThetasHi <- .tmp[[1]] .ret$logitThetasHiF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasList .ret$probitThetas <- .tmp[[1]] .ret$probitThetasF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasListLow .ret$probitThetasLow <- .tmp[[1]] .ret$probitThetasLowF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasListHi .ret$probitThetasHi <- .tmp[[1]] .ret$probitThetasHiF <- .tmp[[2]] } else { .ret$logThetasF <- integer(0) .ret$logitThetasF <- integer(0) .ret$logitThetasHiF <- numeric(0) .ret$logitThetasLowF <- numeric(0) .ret$logitThetas <- integer(0) .ret$logitThetasHi <- numeric(0) .ret$logitThetasLow <- numeric(0) .ret$probitThetasF <- integer(0) .ret$probitThetasHiF <- numeric(0) .ret$probitThetasLowF <- numeric(0) .ret$probitThetas <- integer(0) .ret$probitThetasHi <- numeric(0) .ret$probitThetasLow <- numeric(0) } if (exists("noLik", envir = .ret)) { if (!.ret$noLik) { .ret$.params <- c(sprintf("THETA[%d]", seq_along(.ret$thetaIni)), sprintf("ETA[%d]", seq(1, dim(.om0)[1]))) .ret$.thetan <- length(.ret$thetaIni) .ret$nobs <- sum(data$EVID == 0) } } .ret$control$printTop <- TRUE .ret$control$nF <- 0 .est0 <- .ret$thetaIni if (!is.null(.ret$model$pred.nolhs)) { .ret$control$predNeq <- length(.ret$model$pred.nolhs$state) } else { .ret$control$predNeq <- 0L } .fitFun <- function(.ret) { this.env <- environment() assign("err", "theta reset", this.env) while (this.env$err == "theta reset") { assign("err", "", this.env) .ret0 <- tryCatch({ foceiFitCpp_(.ret) }, error = function(e) { if (regexpr("theta reset", e$message) != -1) { assign("zeroOuter", FALSE, this.env) assign("zeroGrad", FALSE, this.env) if (regexpr("theta reset0", e$message) != -1) { assign("zeroGrad", TRUE, this.env) } else if (regexpr("theta resetZ", e$message) != -1) { assign("zeroOuter", TRUE, this.env) } assign("err", "theta reset", this.env) } else { assign("err", e$message, this.env) } }) if (this.env$err == "theta reset") { .nm <- names(.ret$thetaIni) .ret$thetaIni <- setNames(.thetaReset$thetaIni + 0, .nm) .ret$rxInv$theta <- .thetaReset$omegaTheta .ret$control$printTop <- FALSE .ret$etaMat <- .thetaReset$etaMat .ret$control$etaMat <- .thetaReset$etaMat .ret$control$maxInnerIterations <- .thetaReset$maxInnerIterations .ret$control$nF <- .thetaReset$nF .ret$control$gillRetC <- .thetaReset$gillRetC .ret$control$gillRet <- .thetaReset$gillRet .ret$control$gillRet <- .thetaReset$gillRet .ret$control$gillDf <- .thetaReset$gillDf .ret$control$gillDf2 <- .thetaReset$gillDf2 .ret$control$gillErr <- .thetaReset$gillErr .ret$control$rEps <- .thetaReset$rEps .ret$control$aEps <- .thetaReset$aEps .ret$control$rEpsC <- .thetaReset$rEpsC .ret$control$aEpsC <- .thetaReset$aEpsC .ret$control$c1 <- .thetaReset$c1 .ret$control$c2 <- .thetaReset$c2 if (this.env$zeroOuter) { message("Posthoc reset") .ret$control$maxOuterIterations <- 0L } else if (this.env$zeroGrad) { message("Theta reset (zero gradient values); Switch to bobyqa") RxODE::rxReq("minqa") .ret$control$outerOptFun <- .bobyqa .ret$control$outerOpt <- -1L } else { message("Theta reset (ETA drift)") } } } if (this.env$err != "") { stop(this.env$err) } else { return(.ret0) } } .ret0 <- try(.fitFun(.ret)) .n <- 1 while (inherits(.ret0, "try-error") && control$maxOuterIterations != 0 && .n <= control$nRetries) { message(sprintf("Restart %s", .n)) .ret$control$nF <- 0 .estNew <- .est0 + 0.2 * .n * abs(.est0) * stats::runif(length(.est0)) - 0.1 * .n .estNew <- sapply(seq_along(.est0), function(.i) { if (.ret$thetaFixed[.i]) { return(.est0[.i]) } else if (.estNew[.i] < lower[.i]) { return(lower + (.Machine$double.eps)^(1/7)) } else if (.estNew[.i] > upper[.i]) { return(upper - (.Machine$double.eps)^(1/7)) } else { return(.estNew[.i]) } }) .ret$thetaIni <- .estNew .ret0 <- try(.fitFun(.ret)) .n <- .n + 1 } if (inherits(.ret0, "try-error")) stop("Could not fit data.") .ret <- .ret0 if (exists("parHistData", .ret)) { .tmp <- .ret$parHistData .tmp <- .tmp[.tmp$type == "Unscaled", names(.tmp) != "type"] .iter <- .tmp$iter .tmp <- .tmp[, names(.tmp) != "iter"] .ret$parHistStacked <- data.frame(stack(.tmp), iter = .iter) names(.ret$parHistStacked) <- c("val", "par", "iter") .ret$parHist <- data.frame(iter = .iter, .tmp) } if (.mixed) { .etas <- .ret$ranef .thetas <- .ret$fixef .pars <- .Call(`_nlmixr_nlmixrParameters`, .thetas, .etas) .ret$shrink <- .Call(`_nlmixr_calcShrinkOnly`, .ret$omega, .pars$eta.lst, length(.etas$ID)) .updateParFixed(.ret) } else { .updateParFixed(.ret) } if (!exists("table", .ret)) { .ret$table <- tableControl() } if (control$calcTables) { .ret <- addTable(.ret, updateObject = "no", keep = keep, drop = drop, table = .ret$table) } .ret})(data = dat, inits = .FoceiInits, PKpars = .pars, model = .mod, pred = function() { return(nlmixr_pred) }, err = uif$error, lower = uif$focei.lower, upper = uif$focei.upper, fixed = uif$focei.fixed, thetaNames = uif$focei.names, etaNames = uif$eta.names, control = control, env = env, keep = .keep, drop = .drop): Not all the covariates are in the dataset.</span></div><div class='output co'>#> <span class='message'>Timing stopped at: 5.548 0.415 5.961</span></div><div class='input'><span class='va'>f_nlmixr_fomc_sfo_focei_const</span> <span class='op'><-</span> <span class='fu'><a href='https://rdrr.io/pkg/nlmixr/man/nlmixr.html'>nlmixr</a></span><span class='op'>(</span><span class='va'>f_mmkin_const</span><span class='op'>[</span><span class='st'>"FOMC-SFO"</span>, <span class='op'>]</span>, est <span class='op'>=</span> <span class='st'>"focei"</span><span class='op'>)</span> </div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> parameter labels from comments are typically ignored in non-interactive mode</span></div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> Need to run with the source intact to parse comments</span></div><div class='output co'>#> <span class='message'>→ creating full model...</span></div><div class='output co'>#> <span class='message'>→ pruning branches (<span style='color: #262626; background-color: #DADADA;'>`if`</span>/<span style='color: #262626; background-color: #DADADA;'>`else`</span>)...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ loading into <span style='color: #0000BB;'>symengine</span> environment...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ creating full model...</span></div><div class='output co'>#> <span class='message'>→ pruning branches (<span style='color: #262626; background-color: #DADADA;'>`if`</span>/<span style='color: #262626; background-color: #DADADA;'>`else`</span>)...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ loading into <span style='color: #0000BB;'>symengine</span> environment...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ calculate jacobian</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ calculate sensitivities</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ calculate ∂(f)/∂(η)</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ calculate ∂(R²)/∂(η)</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ finding duplicate expressions in inner model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ optimizing duplicate expressions in inner model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ finding duplicate expressions in EBE model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ optimizing duplicate expressions in EBE model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ compiling inner model...</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ finding duplicate expressions in FD model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ optimizing duplicate expressions in FD model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ compiling EBE model...</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ compiling events FD model...</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>Model:</span></div><div class='output co'>#> <span class='message'>cmt(parent);</span> #> <span class='message'>cmt(A1);</span> #> <span class='message'>rx_expr_6~ETA[1]+THETA[1];</span> @@ -4550,7 +4550,7 @@ obtained by fitting the same model to a list of datasets using <a href='mkinfit. #> <span class='message'>beta=exp(rx_expr_8);</span> #> <span class='message'>f_parent=1/(1+exp(-(ETA[3]+THETA[3])));</span> #> <span class='message'>tad=tad();</span> -#> <span class='message'>dosenum=dosenum();</span></div><div class='output co'>#> <span class='message'>Needed Covariates:</span></div><div class='output co'>#> <span class='message'>[1] "f_parent_to_A1" "CMT" </span></div><div class='output co'>#> <span class='error'>Error in (function (data, inits, PKpars, model = NULL, pred = NULL, err = NULL, lower = -Inf, upper = Inf, fixed = NULL, skipCov = NULL, control = foceiControl(), thetaNames = NULL, etaNames = NULL, etaMat = NULL, ..., env = NULL, keep = NULL, drop = NULL) { set.seed(control$seed) .pt <- proc.time() RxODE::.setWarnIdSort(FALSE) on.exit(RxODE::.setWarnIdSort(TRUE)) loadNamespace("n1qn1") if (!RxODE::rxIs(control, "foceiControl")) { control <- do.call(foceiControl, control) } if (is.null(env)) { .ret <- new.env(parent = emptyenv()) } else { .ret <- env } .ret$origData <- data .ret$etaNames <- etaNames .ret$thetaFixed <- fixed .ret$control <- control .ret$control$focei.mu.ref <- integer(0) if (is(model, "RxODE") || is(model, "character")) { .ret$ODEmodel <- TRUE if (class(pred) != "function") { stop("pred must be a function specifying the prediction variables in this model.") } } else { .ret$ODEmodel <- TRUE model <- RxODE::rxGetLin(PKpars) pred <- eval(parse(text = "function(){return(Central);}")) } .square <- function(x) x * x .ret$diagXformInv <- c(sqrt = ".square", log = "exp", identity = "identity")[control$diagXform] if (is.null(err)) { err <- eval(parse(text = paste0("function(){err", paste(inits$ERROR[[1]], collapse = ""), "}"))) } .covNames <- .parNames <- c() .ret$adjLik <- control$adjLik .mixed <- !is.null(inits$OMGA) && length(inits$OMGA) > 0 if (!exists("noLik", envir = .ret)) { .atol <- rep(control$atol, length(RxODE::rxModelVars(model)$state)) .rtol <- rep(control$rtol, length(RxODE::rxModelVars(model)$state)) .ssAtol <- rep(control$ssAtol, length(RxODE::rxModelVars(model)$state)) .ssRtol <- rep(control$ssRtol, length(RxODE::rxModelVars(model)$state)) .ret$model <- RxODE::rxSymPySetupPred(model, pred, PKpars, err, grad = (control$derivMethod == 2L), pred.minus.dv = TRUE, sum.prod = control$sumProd, theta.derivs = FALSE, optExpression = control$optExpression, interaction = (control$interaction == 1L), only.numeric = !.mixed, run.internal = TRUE, addProp = control$addProp) if (!is.null(.ret$model$inner)) { .atol <- c(.atol, rep(control$atolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.atol))) .rtol <- c(.rtol, rep(control$rtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.rtol))) .ret$control$rxControl$atol <- .atol .ret$control$rxControl$rtol <- .rtol .ssAtol <- c(.ssAtol, rep(control$ssAtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.ssAtol))) .ssRtol <- c(.ssRtol, rep(control$ssRtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.ssRtol))) .ret$control$rxControl$ssAtol <- .ssAtol .ret$control$rxControl$ssRtol <- .ssRtol } .covNames <- .parNames <- RxODE::rxParams(.ret$model$pred.only) .covNames <- .covNames[regexpr(rex::rex(start, or("THETA", "ETA"), "[", numbers, "]", end), .covNames) == -1] colnames(data) <- sapply(names(data), function(x) { if (any(x == .covNames)) { return(x) } else { return(toupper(x)) } }) .lhs <- c(names(RxODE::rxInits(.ret$model$pred.only)), RxODE::rxLhs(.ret$model$pred.only)) if (length(.lhs) > 0) { .covNames <- .covNames[regexpr(rex::rex(start, or(.lhs), end), .covNames) == -1] } if (length(.covNames) > 0) { if (!all(.covNames %in% names(data))) { message("Model:") RxODE::rxCat(.ret$model$pred.only) message("Needed Covariates:") nlmixrPrint(.covNames) stop("Not all the covariates are in the dataset.") } message("Needed Covariates:") print(.covNames) } .extraPars <- .ret$model$extra.pars } else { if (.ret$noLik) { .atol <- rep(control$atol, length(RxODE::rxModelVars(model)$state)) .rtol <- rep(control$rtol, length(RxODE::rxModelVars(model)$state)) .ret$model <- RxODE::rxSymPySetupPred(model, pred, PKpars, err, grad = FALSE, pred.minus.dv = TRUE, sum.prod = control$sumProd, theta.derivs = FALSE, optExpression = control$optExpression, run.internal = TRUE, only.numeric = TRUE, addProp = control$addProp) if (!is.null(.ret$model$inner)) { .atol <- c(.atol, rep(control$atolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.atol))) .rtol <- c(.rtol, rep(control$rtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.rtol))) .ret$control$rxControl$atol <- .atol .ret$control$rxControl$rtol <- .rtol } .covNames <- .parNames <- RxODE::rxParams(.ret$model$pred.only) .covNames <- .covNames[regexpr(rex::rex(start, or("THETA", "ETA"), "[", numbers, "]", end), .covNames) == -1] colnames(data) <- sapply(names(data), function(x) { if (any(x == .covNames)) { return(x) } else { return(toupper(x)) } }) .lhs <- c(names(RxODE::rxInits(.ret$model$pred.only)), RxODE::rxLhs(.ret$model$pred.only)) if (length(.lhs) > 0) { .covNames <- .covNames[regexpr(rex::rex(start, or(.lhs), end), .covNames) == -1] } if (length(.covNames) > 0) { if (!all(.covNames %in% names(data))) { message("Model:") RxODE::rxCat(.ret$model$pred.only) message("Needed Covariates:") nlmixrPrint(.covNames) stop("Not all the covariates are in the dataset.") } message("Needed Covariates:") print(.covNames) } .extraPars <- .ret$model$extra.pars } else { .extraPars <- NULL } } .ret$skipCov <- skipCov if (is.null(skipCov)) { if (is.null(fixed)) { .tmp <- rep(FALSE, length(inits$THTA)) } else { if (length(fixed) < length(inits$THTA)) { .tmp <- c(fixed, rep(FALSE, length(inits$THTA) - length(fixed))) } else { .tmp <- fixed[1:length(inits$THTA)] } } if (exists("uif", envir = .ret)) { .uifErr <- .ret$uif$ini$err[!is.na(.ret$uif$ini$ntheta)] .uifErr <- sapply(.uifErr, function(x) { if (is.na(x)) { return(FALSE) } return(!any(x == c("pow2", "tbs", "tbsYj"))) }) .tmp <- (.tmp | .uifErr) } .ret$skipCov <- c(.tmp, rep(TRUE, length(.extraPars))) .ret$control$focei.mu.ref <- .ret$uif$focei.mu.ref } if (is.null(.extraPars)) { .nms <- c(sprintf("THETA[%s]", seq_along(inits$THTA))) } else { .nms <- c(sprintf("THETA[%s]", seq_along(inits$THTA)), sprintf("ERR[%s]", seq_along(.extraPars))) } if (!is.null(thetaNames) && (length(inits$THTA) + length(.extraPars)) == length(thetaNames)) { .nms <- thetaNames } .ret$thetaNames <- .nms .thetaReset$thetaNames <- .nms if (length(lower) == 1) { lower <- rep(lower, length(inits$THTA)) } else if (length(lower) != length(inits$THTA)) { print(inits$THTA) print(lower) stop("Lower must be a single constant for all the THETA lower bounds, or match the dimension of THETA.") } if (length(upper) == 1) { upper <- rep(upper, length(inits$THTA)) } else if (length(lower) != length(inits$THTA)) { stop("Upper must be a single constant for all the THETA lower bounds, or match the dimension of THETA.") } if (!is.null(.extraPars)) { .ret$model$extra.pars <- eval(call(control$diagXform, .ret$model$extra.pars)) if (length(.ret$model$extra.pars) > 0) { inits$THTA <- c(inits$THTA, .ret$model$extra.pars) .lowerErr <- rep(control$atol[1] * 10, length(.ret$model$extra.pars)) .upperErr <- rep(Inf, length(.ret$model$extra.pars)) lower <- c(lower, .lowerErr) upper <- c(upper, .upperErr) } } if (is.null(data$ID)) stop("\"ID\" not found in data") if (is.null(data$DV)) stop("\"DV\" not found in data") if (is.null(data$EVID)) data$EVID <- 0 if (is.null(data$AMT)) data$AMT <- 0 for (.v in c("TIME", "AMT", "DV", .covNames)) { data[[.v]] <- as.double(data[[.v]]) } .ret$dataSav <- data .ds <- data[data$EVID != 0 & data$EVID != 2, c("ID", "TIME", "AMT", "EVID", .covNames)] .w <- which(tolower(names(data)) == "limit") .limitName <- NULL if (length(.w) == 1L) { .limitName <- names(data)[.w] } .censName <- NULL .w <- which(tolower(names(data)) == "cens") if (length(.w) == 1L) { .censName <- names(data[.w]) } data <- data[data$EVID == 0 | data$EVID == 2, c("ID", "TIME", "DV", "EVID", .covNames, .limitName, .censName)] .w <- which(!(names(.ret$dataSav) %in% c(.covNames, keep))) names(.ret$dataSav)[.w] <- tolower(names(.ret$dataSav[.w])) if (.mixed) { .lh <- .parseOM(inits$OMGA) .nlh <- sapply(.lh, length) .osplt <- rep(1:length(.lh), .nlh) .lini <- list(inits$THTA, unlist(.lh)) .nlini <- sapply(.lini, length) .nsplt <- rep(1:length(.lini), .nlini) .om0 <- .genOM(.lh) if (length(etaNames) == dim(.om0)[1]) { .ret$etaNames <- .ret$etaNames } else { .ret$etaNames <- sprintf("ETA[%d]", seq(1, dim(.om0)[1])) } .ret$rxInv <- RxODE::rxSymInvCholCreate(mat = .om0, diag.xform = control$diagXform) .ret$xType <- .ret$rxInv$xType .om0a <- .om0 .om0a <- .om0a/control$diagOmegaBoundLower .om0b <- .om0 .om0b <- .om0b * control$diagOmegaBoundUpper .om0a <- RxODE::rxSymInvCholCreate(mat = .om0a, diag.xform = control$diagXform) .om0b <- RxODE::rxSymInvCholCreate(mat = .om0b, diag.xform = control$diagXform) .omdf <- data.frame(a = .om0a$theta, m = .ret$rxInv$theta, b = .om0b$theta, diag = .om0a$theta.diag) .omdf$lower <- with(.omdf, ifelse(a > b, b, a)) .omdf$lower <- with(.omdf, ifelse(lower == m, -Inf, lower)) .omdf$lower <- with(.omdf, ifelse(!diag, -Inf, lower)) .omdf$upper <- with(.omdf, ifelse(a < b, b, a)) .omdf$upper <- with(.omdf, ifelse(upper == m, Inf, upper)) .omdf$upper <- with(.omdf, ifelse(!diag, Inf, upper)) .ret$control$nomega <- length(.omdf$lower) .ret$control$neta <- sum(.omdf$diag) .ret$control$ntheta <- length(lower) .ret$control$nfixed <- sum(fixed) lower <- c(lower, .omdf$lower) upper <- c(upper, .omdf$upper) } else { .ret$control$nomega <- 0 .ret$control$neta <- 0 .ret$xType <- -1 .ret$control$ntheta <- length(lower) .ret$control$nfixed <- sum(fixed) } .ret$lower <- lower .ret$upper <- upper .ret$thetaIni <- inits$THTA .scaleC <- double(length(lower)) if (is.null(control$scaleC)) { .scaleC <- rep(NA_real_, length(lower)) } else { .scaleC <- as.double(control$scaleC) if (length(lower) > length(.scaleC)) { .scaleC <- c(.scaleC, rep(NA_real_, length(lower) - length(.scaleC))) } else if (length(lower) < length(.scaleC)) { .scaleC <- .scaleC[seq(1, length(lower))] warning("scaleC control option has more options than estimated population parameters, please check.") } } .ret$scaleC <- .scaleC if (exists("uif", envir = .ret)) { .ini <- as.data.frame(.ret$uif$ini)[!is.na(.ret$uif$ini$err), c("est", "err", "ntheta")] for (.i in seq_along(.ini$err)) { if (is.na(.ret$scaleC[.ini$ntheta[.i]])) { if (any(.ini$err[.i] == c("boxCox", "yeoJohnson", "pow2", "tbs", "tbsYj"))) { .ret$scaleC[.ini$ntheta[.i]] <- 1 } else if (any(.ini$err[.i] == c("prop", "add", "norm", "dnorm", "logn", "dlogn", "lnorm", "dlnorm"))) { .ret$scaleC[.ini$ntheta[.i]] <- 0.5 * abs(.ini$est[.i]) } } } for (.i in .ini$model$extraProps$powTheta) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- 1 } .ini <- as.data.frame(.ret$uif$ini) for (.i in .ini$model$extraProps$factorial) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- abs(1/digamma(.ini$est[.i] + 1)) } for (.i in .ini$model$extraProps$gamma) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- abs(1/digamma(.ini$est[.i])) } for (.i in .ini$model$extraProps$log) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- log(abs(.ini$est[.i])) * abs(.ini$est[.i]) } for (.i in .ret$logitThetas) { .b <- .ret$logitThetasLow[.i] .c <- .ret$logitThetasHi[.i] .a <- .ini$est[.i] if (is.na(.ret$scaleC[.i])) { .ret$scaleC[.i] <- 1 * (-.b + .c) * exp(-.a)/((1 + exp(-.a))^2 * (.b + 1 * (-.b + .c)/(1 + exp(-.a)))) } } } names(.ret$thetaIni) <- sprintf("THETA[%d]", seq_along(.ret$thetaIni)) if (is.null(etaMat) & !is.null(control$etaMat)) { .ret$etaMat <- control$etaMat } else { .ret$etaMat <- etaMat } .ret$setupTime <- (proc.time() - .pt)["elapsed"] if (exists("uif", envir = .ret)) { .tmp <- .ret$uif$logThetasList .ret$logThetas <- .tmp[[1]] .ret$logThetasF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasList .ret$logitThetas <- .tmp[[1]] .ret$logitThetasF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasListLow .ret$logitThetasLow <- .tmp[[1]] .ret$logitThetasLowF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasListHi .ret$logitThetasHi <- .tmp[[1]] .ret$logitThetasHiF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasList .ret$probitThetas <- .tmp[[1]] .ret$probitThetasF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasListLow .ret$probitThetasLow <- .tmp[[1]] .ret$probitThetasLowF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasListHi .ret$probitThetasHi <- .tmp[[1]] .ret$probitThetasHiF <- .tmp[[2]] } else { .ret$logThetasF <- integer(0) .ret$logitThetasF <- integer(0) .ret$logitThetasHiF <- numeric(0) .ret$logitThetasLowF <- numeric(0) .ret$logitThetas <- integer(0) .ret$logitThetasHi <- numeric(0) .ret$logitThetasLow <- numeric(0) .ret$probitThetasF <- integer(0) .ret$probitThetasHiF <- numeric(0) .ret$probitThetasLowF <- numeric(0) .ret$probitThetas <- integer(0) .ret$probitThetasHi <- numeric(0) .ret$probitThetasLow <- numeric(0) } if (exists("noLik", envir = .ret)) { if (!.ret$noLik) { .ret$.params <- c(sprintf("THETA[%d]", seq_along(.ret$thetaIni)), sprintf("ETA[%d]", seq(1, dim(.om0)[1]))) .ret$.thetan <- length(.ret$thetaIni) .ret$nobs <- sum(data$EVID == 0) } } .ret$control$printTop <- TRUE .ret$control$nF <- 0 .est0 <- .ret$thetaIni if (!is.null(.ret$model$pred.nolhs)) { .ret$control$predNeq <- length(.ret$model$pred.nolhs$state) } else { .ret$control$predNeq <- 0L } .fitFun <- function(.ret) { this.env <- environment() assign("err", "theta reset", this.env) while (this.env$err == "theta reset") { assign("err", "", this.env) .ret0 <- tryCatch({ foceiFitCpp_(.ret) }, error = function(e) { if (regexpr("theta reset", e$message) != -1) { assign("zeroOuter", FALSE, this.env) assign("zeroGrad", FALSE, this.env) if (regexpr("theta reset0", e$message) != -1) { assign("zeroGrad", TRUE, this.env) } else if (regexpr("theta resetZ", e$message) != -1) { assign("zeroOuter", TRUE, this.env) } assign("err", "theta reset", this.env) } else { assign("err", e$message, this.env) } }) if (this.env$err == "theta reset") { .nm <- names(.ret$thetaIni) .ret$thetaIni <- setNames(.thetaReset$thetaIni + 0, .nm) .ret$rxInv$theta <- .thetaReset$omegaTheta .ret$control$printTop <- FALSE .ret$etaMat <- .thetaReset$etaMat .ret$control$etaMat <- .thetaReset$etaMat .ret$control$maxInnerIterations <- .thetaReset$maxInnerIterations .ret$control$nF <- .thetaReset$nF .ret$control$gillRetC <- .thetaReset$gillRetC .ret$control$gillRet <- .thetaReset$gillRet .ret$control$gillRet <- .thetaReset$gillRet .ret$control$gillDf <- .thetaReset$gillDf .ret$control$gillDf2 <- .thetaReset$gillDf2 .ret$control$gillErr <- .thetaReset$gillErr .ret$control$rEps <- .thetaReset$rEps .ret$control$aEps <- .thetaReset$aEps .ret$control$rEpsC <- .thetaReset$rEpsC .ret$control$aEpsC <- .thetaReset$aEpsC .ret$control$c1 <- .thetaReset$c1 .ret$control$c2 <- .thetaReset$c2 if (this.env$zeroOuter) { message("Posthoc reset") .ret$control$maxOuterIterations <- 0L } else if (this.env$zeroGrad) { message("Theta reset (zero gradient values); Switch to bobyqa") RxODE::rxReq("minqa") .ret$control$outerOptFun <- .bobyqa .ret$control$outerOpt <- -1L } else { message("Theta reset (ETA drift)") } } } if (this.env$err != "") { stop(this.env$err) } else { return(.ret0) } } .ret0 <- try(.fitFun(.ret)) .n <- 1 while (inherits(.ret0, "try-error") && control$maxOuterIterations != 0 && .n <= control$nRetries) { message(sprintf("Restart %s", .n)) .ret$control$nF <- 0 .estNew <- .est0 + 0.2 * .n * abs(.est0) * stats::runif(length(.est0)) - 0.1 * .n .estNew <- sapply(seq_along(.est0), function(.i) { if (.ret$thetaFixed[.i]) { return(.est0[.i]) } else if (.estNew[.i] < lower[.i]) { return(lower + (.Machine$double.eps)^(1/7)) } else if (.estNew[.i] > upper[.i]) { return(upper - (.Machine$double.eps)^(1/7)) } else { return(.estNew[.i]) } }) .ret$thetaIni <- .estNew .ret0 <- try(.fitFun(.ret)) .n <- .n + 1 } if (inherits(.ret0, "try-error")) stop("Could not fit data.") .ret <- .ret0 if (exists("parHistData", .ret)) { .tmp <- .ret$parHistData .tmp <- .tmp[.tmp$type == "Unscaled", names(.tmp) != "type"] .iter <- .tmp$iter .tmp <- .tmp[, names(.tmp) != "iter"] .ret$parHistStacked <- data.frame(stack(.tmp), iter = .iter) names(.ret$parHistStacked) <- c("val", "par", "iter") .ret$parHist <- data.frame(iter = .iter, .tmp) } if (.mixed) { .etas <- .ret$ranef .thetas <- .ret$fixef .pars <- .Call(`_nlmixr_nlmixrParameters`, .thetas, .etas) .ret$shrink <- .Call(`_nlmixr_calcShrinkOnly`, .ret$omega, .pars$eta.lst, length(.etas$ID)) .updateParFixed(.ret) } else { .updateParFixed(.ret) } if (!exists("table", .ret)) { .ret$table <- tableControl() } if (control$calcTables) { .ret <- addTable(.ret, updateObject = "no", keep = keep, drop = drop, table = .ret$table) } .ret})(data = dat, inits = .FoceiInits, PKpars = .pars, model = .mod, pred = function() { return(nlmixr_pred) }, err = uif$error, lower = uif$focei.lower, upper = uif$focei.upper, fixed = uif$focei.fixed, thetaNames = uif$focei.names, etaNames = uif$eta.names, control = control, env = env, keep = .keep, drop = .drop): Not all the covariates are in the dataset.</span></div><div class='output co'>#> <span class='message'>Timing stopped at: 6.853 0.393 7.242</span></div><div class='input'><span class='va'>f_nlmixr_dfop_sfo_focei_const</span> <span class='op'><-</span> <span class='fu'><a href='https://rdrr.io/pkg/nlmixr/man/nlmixr.html'>nlmixr</a></span><span class='op'>(</span><span class='va'>f_mmkin_const</span><span class='op'>[</span><span class='st'>"DFOP-SFO"</span>, <span class='op'>]</span>, est <span class='op'>=</span> <span class='st'>"focei"</span><span class='op'>)</span> +#> <span class='message'>dosenum=dosenum();</span></div><div class='output co'>#> <span class='message'>Needed Covariates:</span></div><div class='output co'>#> <span class='message'>[1] "f_parent_to_A1" "CMT" </span></div><div class='output co'>#> <span class='error'>Error in (function (data, inits, PKpars, model = NULL, pred = NULL, err = NULL, lower = -Inf, upper = Inf, fixed = NULL, skipCov = NULL, control = foceiControl(), thetaNames = NULL, etaNames = NULL, etaMat = NULL, ..., env = NULL, keep = NULL, drop = NULL) { set.seed(control$seed) .pt <- proc.time() RxODE::.setWarnIdSort(FALSE) on.exit(RxODE::.setWarnIdSort(TRUE)) loadNamespace("n1qn1") if (!RxODE::rxIs(control, "foceiControl")) { control <- do.call(foceiControl, control) } if (is.null(env)) { .ret <- new.env(parent = emptyenv()) } else { .ret <- env } .ret$origData <- data .ret$etaNames <- etaNames .ret$thetaFixed <- fixed .ret$control <- control .ret$control$focei.mu.ref <- integer(0) if (is(model, "RxODE") || is(model, "character")) { .ret$ODEmodel <- TRUE if (class(pred) != "function") { stop("pred must be a function specifying the prediction variables in this model.") } } else { .ret$ODEmodel <- TRUE model <- RxODE::rxGetLin(PKpars) pred <- eval(parse(text = "function(){return(Central);}")) } .square <- function(x) x * x .ret$diagXformInv <- c(sqrt = ".square", log = "exp", identity = "identity")[control$diagXform] if (is.null(err)) { err <- eval(parse(text = paste0("function(){err", paste(inits$ERROR[[1]], collapse = ""), "}"))) } .covNames <- .parNames <- c() .ret$adjLik <- control$adjLik .mixed <- !is.null(inits$OMGA) && length(inits$OMGA) > 0 if (!exists("noLik", envir = .ret)) { .atol <- rep(control$atol, length(RxODE::rxModelVars(model)$state)) .rtol <- rep(control$rtol, length(RxODE::rxModelVars(model)$state)) .ssAtol <- rep(control$ssAtol, length(RxODE::rxModelVars(model)$state)) .ssRtol <- rep(control$ssRtol, length(RxODE::rxModelVars(model)$state)) .ret$model <- RxODE::rxSymPySetupPred(model, pred, PKpars, err, grad = (control$derivMethod == 2L), pred.minus.dv = TRUE, sum.prod = control$sumProd, theta.derivs = FALSE, optExpression = control$optExpression, interaction = (control$interaction == 1L), only.numeric = !.mixed, run.internal = TRUE, addProp = control$addProp) if (!is.null(.ret$model$inner)) { .atol <- c(.atol, rep(control$atolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.atol))) .rtol <- c(.rtol, rep(control$rtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.rtol))) .ret$control$rxControl$atol <- .atol .ret$control$rxControl$rtol <- .rtol .ssAtol <- c(.ssAtol, rep(control$ssAtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.ssAtol))) .ssRtol <- c(.ssRtol, rep(control$ssRtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.ssRtol))) .ret$control$rxControl$ssAtol <- .ssAtol .ret$control$rxControl$ssRtol <- .ssRtol } .covNames <- .parNames <- RxODE::rxParams(.ret$model$pred.only) .covNames <- .covNames[regexpr(rex::rex(start, or("THETA", "ETA"), "[", numbers, "]", end), .covNames) == -1] colnames(data) <- sapply(names(data), function(x) { if (any(x == .covNames)) { return(x) } else { return(toupper(x)) } }) .lhs <- c(names(RxODE::rxInits(.ret$model$pred.only)), RxODE::rxLhs(.ret$model$pred.only)) if (length(.lhs) > 0) { .covNames <- .covNames[regexpr(rex::rex(start, or(.lhs), end), .covNames) == -1] } if (length(.covNames) > 0) { if (!all(.covNames %in% names(data))) { message("Model:") RxODE::rxCat(.ret$model$pred.only) message("Needed Covariates:") nlmixrPrint(.covNames) stop("Not all the covariates are in the dataset.") } message("Needed Covariates:") print(.covNames) } .extraPars <- .ret$model$extra.pars } else { if (.ret$noLik) { .atol <- rep(control$atol, length(RxODE::rxModelVars(model)$state)) .rtol <- rep(control$rtol, length(RxODE::rxModelVars(model)$state)) .ret$model <- RxODE::rxSymPySetupPred(model, pred, PKpars, err, grad = FALSE, pred.minus.dv = TRUE, sum.prod = control$sumProd, theta.derivs = FALSE, optExpression = control$optExpression, run.internal = TRUE, only.numeric = TRUE, addProp = control$addProp) if (!is.null(.ret$model$inner)) { .atol <- c(.atol, rep(control$atolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.atol))) .rtol <- c(.rtol, rep(control$rtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.rtol))) .ret$control$rxControl$atol <- .atol .ret$control$rxControl$rtol <- .rtol } .covNames <- .parNames <- RxODE::rxParams(.ret$model$pred.only) .covNames <- .covNames[regexpr(rex::rex(start, or("THETA", "ETA"), "[", numbers, "]", end), .covNames) == -1] colnames(data) <- sapply(names(data), function(x) { if (any(x == .covNames)) { return(x) } else { return(toupper(x)) } }) .lhs <- c(names(RxODE::rxInits(.ret$model$pred.only)), RxODE::rxLhs(.ret$model$pred.only)) if (length(.lhs) > 0) { .covNames <- .covNames[regexpr(rex::rex(start, or(.lhs), end), .covNames) == -1] } if (length(.covNames) > 0) { if (!all(.covNames %in% names(data))) { message("Model:") RxODE::rxCat(.ret$model$pred.only) message("Needed Covariates:") nlmixrPrint(.covNames) stop("Not all the covariates are in the dataset.") } message("Needed Covariates:") print(.covNames) } .extraPars <- .ret$model$extra.pars } else { .extraPars <- NULL } } .ret$skipCov <- skipCov if (is.null(skipCov)) { if (is.null(fixed)) { .tmp <- rep(FALSE, length(inits$THTA)) } else { if (length(fixed) < length(inits$THTA)) { .tmp <- c(fixed, rep(FALSE, length(inits$THTA) - length(fixed))) } else { .tmp <- fixed[1:length(inits$THTA)] } } if (exists("uif", envir = .ret)) { .uifErr <- .ret$uif$ini$err[!is.na(.ret$uif$ini$ntheta)] .uifErr <- sapply(.uifErr, function(x) { if (is.na(x)) { return(FALSE) } return(!any(x == c("pow2", "tbs", "tbsYj"))) }) .tmp <- (.tmp | .uifErr) } .ret$skipCov <- c(.tmp, rep(TRUE, length(.extraPars))) .ret$control$focei.mu.ref <- .ret$uif$focei.mu.ref } if (is.null(.extraPars)) { .nms <- c(sprintf("THETA[%s]", seq_along(inits$THTA))) } else { .nms <- c(sprintf("THETA[%s]", seq_along(inits$THTA)), sprintf("ERR[%s]", seq_along(.extraPars))) } if (!is.null(thetaNames) && (length(inits$THTA) + length(.extraPars)) == length(thetaNames)) { .nms <- thetaNames } .ret$thetaNames <- .nms .thetaReset$thetaNames <- .nms if (length(lower) == 1) { lower <- rep(lower, length(inits$THTA)) } else if (length(lower) != length(inits$THTA)) { print(inits$THTA) print(lower) stop("Lower must be a single constant for all the THETA lower bounds, or match the dimension of THETA.") } if (length(upper) == 1) { upper <- rep(upper, length(inits$THTA)) } else if (length(lower) != length(inits$THTA)) { stop("Upper must be a single constant for all the THETA lower bounds, or match the dimension of THETA.") } if (!is.null(.extraPars)) { .ret$model$extra.pars <- eval(call(control$diagXform, .ret$model$extra.pars)) if (length(.ret$model$extra.pars) > 0) { inits$THTA <- c(inits$THTA, .ret$model$extra.pars) .lowerErr <- rep(control$atol[1] * 10, length(.ret$model$extra.pars)) .upperErr <- rep(Inf, length(.ret$model$extra.pars)) lower <- c(lower, .lowerErr) upper <- c(upper, .upperErr) } } if (is.null(data$ID)) stop("\"ID\" not found in data") if (is.null(data$DV)) stop("\"DV\" not found in data") if (is.null(data$EVID)) data$EVID <- 0 if (is.null(data$AMT)) data$AMT <- 0 for (.v in c("TIME", "AMT", "DV", .covNames)) { data[[.v]] <- as.double(data[[.v]]) } .ret$dataSav <- data .ds <- data[data$EVID != 0 & data$EVID != 2, c("ID", "TIME", "AMT", "EVID", .covNames)] .w <- which(tolower(names(data)) == "limit") .limitName <- NULL if (length(.w) == 1L) { .limitName <- names(data)[.w] } .censName <- NULL .w <- which(tolower(names(data)) == "cens") if (length(.w) == 1L) { .censName <- names(data[.w]) } data <- data[data$EVID == 0 | data$EVID == 2, c("ID", "TIME", "DV", "EVID", .covNames, .limitName, .censName)] .w <- which(!(names(.ret$dataSav) %in% c(.covNames, keep))) names(.ret$dataSav)[.w] <- tolower(names(.ret$dataSav[.w])) if (.mixed) { .lh <- .parseOM(inits$OMGA) .nlh <- sapply(.lh, length) .osplt <- rep(1:length(.lh), .nlh) .lini <- list(inits$THTA, unlist(.lh)) .nlini <- sapply(.lini, length) .nsplt <- rep(1:length(.lini), .nlini) .om0 <- .genOM(.lh) if (length(etaNames) == dim(.om0)[1]) { .ret$etaNames <- .ret$etaNames } else { .ret$etaNames <- sprintf("ETA[%d]", seq(1, dim(.om0)[1])) } .ret$rxInv <- RxODE::rxSymInvCholCreate(mat = .om0, diag.xform = control$diagXform) .ret$xType <- .ret$rxInv$xType .om0a <- .om0 .om0a <- .om0a/control$diagOmegaBoundLower .om0b <- .om0 .om0b <- .om0b * control$diagOmegaBoundUpper .om0a <- RxODE::rxSymInvCholCreate(mat = .om0a, diag.xform = control$diagXform) .om0b <- RxODE::rxSymInvCholCreate(mat = .om0b, diag.xform = control$diagXform) .omdf <- data.frame(a = .om0a$theta, m = .ret$rxInv$theta, b = .om0b$theta, diag = .om0a$theta.diag) .omdf$lower <- with(.omdf, ifelse(a > b, b, a)) .omdf$lower <- with(.omdf, ifelse(lower == m, -Inf, lower)) .omdf$lower <- with(.omdf, ifelse(!diag, -Inf, lower)) .omdf$upper <- with(.omdf, ifelse(a < b, b, a)) .omdf$upper <- with(.omdf, ifelse(upper == m, Inf, upper)) .omdf$upper <- with(.omdf, ifelse(!diag, Inf, upper)) .ret$control$nomega <- length(.omdf$lower) .ret$control$neta <- sum(.omdf$diag) .ret$control$ntheta <- length(lower) .ret$control$nfixed <- sum(fixed) lower <- c(lower, .omdf$lower) upper <- c(upper, .omdf$upper) } else { .ret$control$nomega <- 0 .ret$control$neta <- 0 .ret$xType <- -1 .ret$control$ntheta <- length(lower) .ret$control$nfixed <- sum(fixed) } .ret$lower <- lower .ret$upper <- upper .ret$thetaIni <- inits$THTA .scaleC <- double(length(lower)) if (is.null(control$scaleC)) { .scaleC <- rep(NA_real_, length(lower)) } else { .scaleC <- as.double(control$scaleC) if (length(lower) > length(.scaleC)) { .scaleC <- c(.scaleC, rep(NA_real_, length(lower) - length(.scaleC))) } else if (length(lower) < length(.scaleC)) { .scaleC <- .scaleC[seq(1, length(lower))] warning("scaleC control option has more options than estimated population parameters, please check.") } } .ret$scaleC <- .scaleC if (exists("uif", envir = .ret)) { .ini <- as.data.frame(.ret$uif$ini)[!is.na(.ret$uif$ini$err), c("est", "err", "ntheta")] for (.i in seq_along(.ini$err)) { if (is.na(.ret$scaleC[.ini$ntheta[.i]])) { if (any(.ini$err[.i] == c("boxCox", "yeoJohnson", "pow2", "tbs", "tbsYj"))) { .ret$scaleC[.ini$ntheta[.i]] <- 1 } else if (any(.ini$err[.i] == c("prop", "add", "norm", "dnorm", "logn", "dlogn", "lnorm", "dlnorm"))) { .ret$scaleC[.ini$ntheta[.i]] <- 0.5 * abs(.ini$est[.i]) } } } for (.i in .ini$model$extraProps$powTheta) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- 1 } .ini <- as.data.frame(.ret$uif$ini) for (.i in .ini$model$extraProps$factorial) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- abs(1/digamma(.ini$est[.i] + 1)) } for (.i in .ini$model$extraProps$gamma) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- abs(1/digamma(.ini$est[.i])) } for (.i in .ini$model$extraProps$log) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- log(abs(.ini$est[.i])) * abs(.ini$est[.i]) } for (.i in .ret$logitThetas) { .b <- .ret$logitThetasLow[.i] .c <- .ret$logitThetasHi[.i] .a <- .ini$est[.i] if (is.na(.ret$scaleC[.i])) { .ret$scaleC[.i] <- 1 * (-.b + .c) * exp(-.a)/((1 + exp(-.a))^2 * (.b + 1 * (-.b + .c)/(1 + exp(-.a)))) } } } names(.ret$thetaIni) <- sprintf("THETA[%d]", seq_along(.ret$thetaIni)) if (is.null(etaMat) & !is.null(control$etaMat)) { .ret$etaMat <- control$etaMat } else { .ret$etaMat <- etaMat } .ret$setupTime <- (proc.time() - .pt)["elapsed"] if (exists("uif", envir = .ret)) { .tmp <- .ret$uif$logThetasList .ret$logThetas <- .tmp[[1]] .ret$logThetasF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasList .ret$logitThetas <- .tmp[[1]] .ret$logitThetasF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasListLow .ret$logitThetasLow <- .tmp[[1]] .ret$logitThetasLowF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasListHi .ret$logitThetasHi <- .tmp[[1]] .ret$logitThetasHiF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasList .ret$probitThetas <- .tmp[[1]] .ret$probitThetasF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasListLow .ret$probitThetasLow <- .tmp[[1]] .ret$probitThetasLowF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasListHi .ret$probitThetasHi <- .tmp[[1]] .ret$probitThetasHiF <- .tmp[[2]] } else { .ret$logThetasF <- integer(0) .ret$logitThetasF <- integer(0) .ret$logitThetasHiF <- numeric(0) .ret$logitThetasLowF <- numeric(0) .ret$logitThetas <- integer(0) .ret$logitThetasHi <- numeric(0) .ret$logitThetasLow <- numeric(0) .ret$probitThetasF <- integer(0) .ret$probitThetasHiF <- numeric(0) .ret$probitThetasLowF <- numeric(0) .ret$probitThetas <- integer(0) .ret$probitThetasHi <- numeric(0) .ret$probitThetasLow <- numeric(0) } if (exists("noLik", envir = .ret)) { if (!.ret$noLik) { .ret$.params <- c(sprintf("THETA[%d]", seq_along(.ret$thetaIni)), sprintf("ETA[%d]", seq(1, dim(.om0)[1]))) .ret$.thetan <- length(.ret$thetaIni) .ret$nobs <- sum(data$EVID == 0) } } .ret$control$printTop <- TRUE .ret$control$nF <- 0 .est0 <- .ret$thetaIni if (!is.null(.ret$model$pred.nolhs)) { .ret$control$predNeq <- length(.ret$model$pred.nolhs$state) } else { .ret$control$predNeq <- 0L } .fitFun <- function(.ret) { this.env <- environment() assign("err", "theta reset", this.env) while (this.env$err == "theta reset") { assign("err", "", this.env) .ret0 <- tryCatch({ foceiFitCpp_(.ret) }, error = function(e) { if (regexpr("theta reset", e$message) != -1) { assign("zeroOuter", FALSE, this.env) assign("zeroGrad", FALSE, this.env) if (regexpr("theta reset0", e$message) != -1) { assign("zeroGrad", TRUE, this.env) } else if (regexpr("theta resetZ", e$message) != -1) { assign("zeroOuter", TRUE, this.env) } assign("err", "theta reset", this.env) } else { assign("err", e$message, this.env) } }) if (this.env$err == "theta reset") { .nm <- names(.ret$thetaIni) .ret$thetaIni <- setNames(.thetaReset$thetaIni + 0, .nm) .ret$rxInv$theta <- .thetaReset$omegaTheta .ret$control$printTop <- FALSE .ret$etaMat <- .thetaReset$etaMat .ret$control$etaMat <- .thetaReset$etaMat .ret$control$maxInnerIterations <- .thetaReset$maxInnerIterations .ret$control$nF <- .thetaReset$nF .ret$control$gillRetC <- .thetaReset$gillRetC .ret$control$gillRet <- .thetaReset$gillRet .ret$control$gillRet <- .thetaReset$gillRet .ret$control$gillDf <- .thetaReset$gillDf .ret$control$gillDf2 <- .thetaReset$gillDf2 .ret$control$gillErr <- .thetaReset$gillErr .ret$control$rEps <- .thetaReset$rEps .ret$control$aEps <- .thetaReset$aEps .ret$control$rEpsC <- .thetaReset$rEpsC .ret$control$aEpsC <- .thetaReset$aEpsC .ret$control$c1 <- .thetaReset$c1 .ret$control$c2 <- .thetaReset$c2 if (this.env$zeroOuter) { message("Posthoc reset") .ret$control$maxOuterIterations <- 0L } else if (this.env$zeroGrad) { message("Theta reset (zero gradient values); Switch to bobyqa") RxODE::rxReq("minqa") .ret$control$outerOptFun <- .bobyqa .ret$control$outerOpt <- -1L } else { message("Theta reset (ETA drift)") } } } if (this.env$err != "") { stop(this.env$err) } else { return(.ret0) } } .ret0 <- try(.fitFun(.ret)) .n <- 1 while (inherits(.ret0, "try-error") && control$maxOuterIterations != 0 && .n <= control$nRetries) { message(sprintf("Restart %s", .n)) .ret$control$nF <- 0 .estNew <- .est0 + 0.2 * .n * abs(.est0) * stats::runif(length(.est0)) - 0.1 * .n .estNew <- sapply(seq_along(.est0), function(.i) { if (.ret$thetaFixed[.i]) { return(.est0[.i]) } else if (.estNew[.i] < lower[.i]) { return(lower + (.Machine$double.eps)^(1/7)) } else if (.estNew[.i] > upper[.i]) { return(upper - (.Machine$double.eps)^(1/7)) } else { return(.estNew[.i]) } }) .ret$thetaIni <- .estNew .ret0 <- try(.fitFun(.ret)) .n <- .n + 1 } if (inherits(.ret0, "try-error")) stop("Could not fit data.") .ret <- .ret0 if (exists("parHistData", .ret)) { .tmp <- .ret$parHistData .tmp <- .tmp[.tmp$type == "Unscaled", names(.tmp) != "type"] .iter <- .tmp$iter .tmp <- .tmp[, names(.tmp) != "iter"] .ret$parHistStacked <- data.frame(stack(.tmp), iter = .iter) names(.ret$parHistStacked) <- c("val", "par", "iter") .ret$parHist <- data.frame(iter = .iter, .tmp) } if (.mixed) { .etas <- .ret$ranef .thetas <- .ret$fixef .pars <- .Call(`_nlmixr_nlmixrParameters`, .thetas, .etas) .ret$shrink <- .Call(`_nlmixr_calcShrinkOnly`, .ret$omega, .pars$eta.lst, length(.etas$ID)) .updateParFixed(.ret) } else { .updateParFixed(.ret) } if (!exists("table", .ret)) { .ret$table <- tableControl() } if (control$calcTables) { .ret <- addTable(.ret, updateObject = "no", keep = keep, drop = drop, table = .ret$table) } .ret})(data = dat, inits = .FoceiInits, PKpars = .pars, model = .mod, pred = function() { return(nlmixr_pred) }, err = uif$error, lower = uif$focei.lower, upper = uif$focei.upper, fixed = uif$focei.fixed, thetaNames = uif$focei.names, etaNames = uif$eta.names, control = control, env = env, keep = .keep, drop = .drop): Not all the covariates are in the dataset.</span></div><div class='output co'>#> <span class='message'>Timing stopped at: 6.895 0.416 7.309</span></div><div class='input'><span class='va'>f_nlmixr_dfop_sfo_focei_const</span> <span class='op'><-</span> <span class='fu'><a href='https://rdrr.io/pkg/nlmixr/man/nlmixr.html'>nlmixr</a></span><span class='op'>(</span><span class='va'>f_mmkin_const</span><span class='op'>[</span><span class='st'>"DFOP-SFO"</span>, <span class='op'>]</span>, est <span class='op'>=</span> <span class='st'>"focei"</span><span class='op'>)</span> </div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> parameter labels from comments are typically ignored in non-interactive mode</span></div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> Need to run with the source intact to parse comments</span></div><div class='output co'>#> <span class='message'>→ creating full model...</span></div><div class='output co'>#> <span class='message'>→ pruning branches (<span style='color: #262626; background-color: #DADADA;'>`if`</span>/<span style='color: #262626; background-color: #DADADA;'>`else`</span>)...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ loading into <span style='color: #0000BB;'>symengine</span> environment...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ creating full model...</span></div><div class='output co'>#> <span class='message'>→ pruning branches (<span style='color: #262626; background-color: #DADADA;'>`if`</span>/<span style='color: #262626; background-color: #DADADA;'>`else`</span>)...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ loading into <span style='color: #0000BB;'>symengine</span> environment...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ calculate jacobian</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ calculate sensitivities</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ calculate ∂(f)/∂(η)</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ calculate ∂(R²)/∂(η)</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ finding duplicate expressions in inner model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ optimizing duplicate expressions in inner model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ finding duplicate expressions in EBE model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ optimizing duplicate expressions in EBE model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ compiling inner model...</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ finding duplicate expressions in FD model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ optimizing duplicate expressions in FD model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ compiling EBE model...</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ compiling events FD model...</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>Model:</span></div><div class='output co'>#> <span class='message'>cmt(parent);</span> #> <span class='message'>cmt(A1);</span> #> <span class='message'>rx_expr_6~ETA[1]+THETA[1];</span> @@ -4607,10 +4607,10 @@ obtained by fitting the same model to a list of datasets using <a href='mkinfit. #> <span class='message'>f_parent=1/(1+exp(-(ETA[3]+THETA[3])));</span> #> <span class='message'>g=1/(rx_expr_20);</span> #> <span class='message'>tad=tad();</span> -#> <span class='message'>dosenum=dosenum();</span></div><div class='output co'>#> <span class='message'>Needed Covariates:</span></div><div class='output co'>#> <span class='message'>[1] "f_parent_to_A1" "CMT" </span></div><div class='output co'>#> <span class='error'>Error in (function (data, inits, PKpars, model = NULL, pred = NULL, err = NULL, lower = -Inf, upper = Inf, fixed = NULL, skipCov = NULL, control = foceiControl(), thetaNames = NULL, etaNames = NULL, etaMat = NULL, ..., env = NULL, keep = NULL, drop = NULL) { set.seed(control$seed) .pt <- proc.time() RxODE::.setWarnIdSort(FALSE) on.exit(RxODE::.setWarnIdSort(TRUE)) loadNamespace("n1qn1") if (!RxODE::rxIs(control, "foceiControl")) { control <- do.call(foceiControl, control) } if (is.null(env)) { .ret <- new.env(parent = emptyenv()) } else { .ret <- env } .ret$origData <- data .ret$etaNames <- etaNames .ret$thetaFixed <- fixed .ret$control <- control .ret$control$focei.mu.ref <- integer(0) if (is(model, "RxODE") || is(model, "character")) { .ret$ODEmodel <- TRUE if (class(pred) != "function") { stop("pred must be a function specifying the prediction variables in this model.") } } else { .ret$ODEmodel <- TRUE model <- RxODE::rxGetLin(PKpars) pred <- eval(parse(text = "function(){return(Central);}")) } .square <- function(x) x * x .ret$diagXformInv <- c(sqrt = ".square", log = "exp", identity = "identity")[control$diagXform] if (is.null(err)) { err <- eval(parse(text = paste0("function(){err", paste(inits$ERROR[[1]], collapse = ""), "}"))) } .covNames <- .parNames <- c() .ret$adjLik <- control$adjLik .mixed <- !is.null(inits$OMGA) && length(inits$OMGA) > 0 if (!exists("noLik", envir = .ret)) { .atol <- rep(control$atol, length(RxODE::rxModelVars(model)$state)) .rtol <- rep(control$rtol, length(RxODE::rxModelVars(model)$state)) .ssAtol <- rep(control$ssAtol, length(RxODE::rxModelVars(model)$state)) .ssRtol <- rep(control$ssRtol, length(RxODE::rxModelVars(model)$state)) .ret$model <- RxODE::rxSymPySetupPred(model, pred, PKpars, err, grad = (control$derivMethod == 2L), pred.minus.dv = TRUE, sum.prod = control$sumProd, theta.derivs = FALSE, optExpression = control$optExpression, interaction = (control$interaction == 1L), only.numeric = !.mixed, run.internal = TRUE, addProp = control$addProp) if (!is.null(.ret$model$inner)) { .atol <- c(.atol, rep(control$atolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.atol))) .rtol <- c(.rtol, rep(control$rtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.rtol))) .ret$control$rxControl$atol <- .atol .ret$control$rxControl$rtol <- .rtol .ssAtol <- c(.ssAtol, rep(control$ssAtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.ssAtol))) .ssRtol <- c(.ssRtol, rep(control$ssRtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.ssRtol))) .ret$control$rxControl$ssAtol <- .ssAtol .ret$control$rxControl$ssRtol <- .ssRtol } .covNames <- .parNames <- RxODE::rxParams(.ret$model$pred.only) .covNames <- .covNames[regexpr(rex::rex(start, or("THETA", "ETA"), "[", numbers, "]", end), .covNames) == -1] colnames(data) <- sapply(names(data), function(x) { if (any(x == .covNames)) { return(x) } else { return(toupper(x)) } }) .lhs <- c(names(RxODE::rxInits(.ret$model$pred.only)), RxODE::rxLhs(.ret$model$pred.only)) if (length(.lhs) > 0) { .covNames <- .covNames[regexpr(rex::rex(start, or(.lhs), end), .covNames) == -1] } if (length(.covNames) > 0) { if (!all(.covNames %in% names(data))) { message("Model:") RxODE::rxCat(.ret$model$pred.only) message("Needed Covariates:") nlmixrPrint(.covNames) stop("Not all the covariates are in the dataset.") } message("Needed Covariates:") print(.covNames) } .extraPars <- .ret$model$extra.pars } else { if (.ret$noLik) { .atol <- rep(control$atol, length(RxODE::rxModelVars(model)$state)) .rtol <- rep(control$rtol, length(RxODE::rxModelVars(model)$state)) .ret$model <- RxODE::rxSymPySetupPred(model, pred, PKpars, err, grad = FALSE, pred.minus.dv = TRUE, sum.prod = control$sumProd, theta.derivs = FALSE, optExpression = control$optExpression, run.internal = TRUE, only.numeric = TRUE, addProp = control$addProp) if (!is.null(.ret$model$inner)) { .atol <- c(.atol, rep(control$atolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.atol))) .rtol <- c(.rtol, rep(control$rtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.rtol))) .ret$control$rxControl$atol <- .atol .ret$control$rxControl$rtol <- .rtol } .covNames <- .parNames <- RxODE::rxParams(.ret$model$pred.only) .covNames <- .covNames[regexpr(rex::rex(start, or("THETA", "ETA"), "[", numbers, "]", end), .covNames) == -1] colnames(data) <- sapply(names(data), function(x) { if (any(x == .covNames)) { return(x) } else { return(toupper(x)) } }) .lhs <- c(names(RxODE::rxInits(.ret$model$pred.only)), RxODE::rxLhs(.ret$model$pred.only)) if (length(.lhs) > 0) { .covNames <- .covNames[regexpr(rex::rex(start, or(.lhs), end), .covNames) == -1] } if (length(.covNames) > 0) { if (!all(.covNames %in% names(data))) { message("Model:") RxODE::rxCat(.ret$model$pred.only) message("Needed Covariates:") nlmixrPrint(.covNames) stop("Not all the covariates are in the dataset.") } message("Needed Covariates:") print(.covNames) } .extraPars <- .ret$model$extra.pars } else { .extraPars <- NULL } } .ret$skipCov <- skipCov if (is.null(skipCov)) { if (is.null(fixed)) { .tmp <- rep(FALSE, length(inits$THTA)) } else { if (length(fixed) < length(inits$THTA)) { .tmp <- c(fixed, rep(FALSE, length(inits$THTA) - length(fixed))) } else { .tmp <- fixed[1:length(inits$THTA)] } } if (exists("uif", envir = .ret)) { .uifErr <- .ret$uif$ini$err[!is.na(.ret$uif$ini$ntheta)] .uifErr <- sapply(.uifErr, function(x) { if (is.na(x)) { return(FALSE) } return(!any(x == c("pow2", "tbs", "tbsYj"))) }) .tmp <- (.tmp | .uifErr) } .ret$skipCov <- c(.tmp, rep(TRUE, length(.extraPars))) .ret$control$focei.mu.ref <- .ret$uif$focei.mu.ref } if (is.null(.extraPars)) { .nms <- c(sprintf("THETA[%s]", seq_along(inits$THTA))) } else { .nms <- c(sprintf("THETA[%s]", seq_along(inits$THTA)), sprintf("ERR[%s]", seq_along(.extraPars))) } if (!is.null(thetaNames) && (length(inits$THTA) + length(.extraPars)) == length(thetaNames)) { .nms <- thetaNames } .ret$thetaNames <- .nms .thetaReset$thetaNames <- .nms if (length(lower) == 1) { lower <- rep(lower, length(inits$THTA)) } else if (length(lower) != length(inits$THTA)) { print(inits$THTA) print(lower) stop("Lower must be a single constant for all the THETA lower bounds, or match the dimension of THETA.") } if (length(upper) == 1) { upper <- rep(upper, length(inits$THTA)) } else if (length(lower) != length(inits$THTA)) { stop("Upper must be a single constant for all the THETA lower bounds, or match the dimension of THETA.") } if (!is.null(.extraPars)) { .ret$model$extra.pars <- eval(call(control$diagXform, .ret$model$extra.pars)) if (length(.ret$model$extra.pars) > 0) { inits$THTA <- c(inits$THTA, .ret$model$extra.pars) .lowerErr <- rep(control$atol[1] * 10, length(.ret$model$extra.pars)) .upperErr <- rep(Inf, length(.ret$model$extra.pars)) lower <- c(lower, .lowerErr) upper <- c(upper, .upperErr) } } if (is.null(data$ID)) stop("\"ID\" not found in data") if (is.null(data$DV)) stop("\"DV\" not found in data") if (is.null(data$EVID)) data$EVID <- 0 if (is.null(data$AMT)) data$AMT <- 0 for (.v in c("TIME", "AMT", "DV", .covNames)) { data[[.v]] <- as.double(data[[.v]]) } .ret$dataSav <- data .ds <- data[data$EVID != 0 & data$EVID != 2, c("ID", "TIME", "AMT", "EVID", .covNames)] .w <- which(tolower(names(data)) == "limit") .limitName <- NULL if (length(.w) == 1L) { .limitName <- names(data)[.w] } .censName <- NULL .w <- which(tolower(names(data)) == "cens") if (length(.w) == 1L) { .censName <- names(data[.w]) } data <- data[data$EVID == 0 | data$EVID == 2, c("ID", "TIME", "DV", "EVID", .covNames, .limitName, .censName)] .w <- which(!(names(.ret$dataSav) %in% c(.covNames, keep))) names(.ret$dataSav)[.w] <- tolower(names(.ret$dataSav[.w])) if (.mixed) { .lh <- .parseOM(inits$OMGA) .nlh <- sapply(.lh, length) .osplt <- rep(1:length(.lh), .nlh) .lini <- list(inits$THTA, unlist(.lh)) .nlini <- sapply(.lini, length) .nsplt <- rep(1:length(.lini), .nlini) .om0 <- .genOM(.lh) if (length(etaNames) == dim(.om0)[1]) { .ret$etaNames <- .ret$etaNames } else { .ret$etaNames <- sprintf("ETA[%d]", seq(1, dim(.om0)[1])) } .ret$rxInv <- RxODE::rxSymInvCholCreate(mat = .om0, diag.xform = control$diagXform) .ret$xType <- .ret$rxInv$xType .om0a <- .om0 .om0a <- .om0a/control$diagOmegaBoundLower .om0b <- .om0 .om0b <- .om0b * control$diagOmegaBoundUpper .om0a <- RxODE::rxSymInvCholCreate(mat = .om0a, diag.xform = control$diagXform) .om0b <- RxODE::rxSymInvCholCreate(mat = .om0b, diag.xform = control$diagXform) .omdf <- data.frame(a = .om0a$theta, m = .ret$rxInv$theta, b = .om0b$theta, diag = .om0a$theta.diag) .omdf$lower <- with(.omdf, ifelse(a > b, b, a)) .omdf$lower <- with(.omdf, ifelse(lower == m, -Inf, lower)) .omdf$lower <- with(.omdf, ifelse(!diag, -Inf, lower)) .omdf$upper <- with(.omdf, ifelse(a < b, b, a)) .omdf$upper <- with(.omdf, ifelse(upper == m, Inf, upper)) .omdf$upper <- with(.omdf, ifelse(!diag, Inf, upper)) .ret$control$nomega <- length(.omdf$lower) .ret$control$neta <- sum(.omdf$diag) .ret$control$ntheta <- length(lower) .ret$control$nfixed <- sum(fixed) lower <- c(lower, .omdf$lower) upper <- c(upper, .omdf$upper) } else { .ret$control$nomega <- 0 .ret$control$neta <- 0 .ret$xType <- -1 .ret$control$ntheta <- length(lower) .ret$control$nfixed <- sum(fixed) } .ret$lower <- lower .ret$upper <- upper .ret$thetaIni <- inits$THTA .scaleC <- double(length(lower)) if (is.null(control$scaleC)) { .scaleC <- rep(NA_real_, length(lower)) } else { .scaleC <- as.double(control$scaleC) if (length(lower) > length(.scaleC)) { .scaleC <- c(.scaleC, rep(NA_real_, length(lower) - length(.scaleC))) } else if (length(lower) < length(.scaleC)) { .scaleC <- .scaleC[seq(1, length(lower))] warning("scaleC control option has more options than estimated population parameters, please check.") } } .ret$scaleC <- .scaleC if (exists("uif", envir = .ret)) { .ini <- as.data.frame(.ret$uif$ini)[!is.na(.ret$uif$ini$err), c("est", "err", "ntheta")] for (.i in seq_along(.ini$err)) { if (is.na(.ret$scaleC[.ini$ntheta[.i]])) { if (any(.ini$err[.i] == c("boxCox", "yeoJohnson", "pow2", "tbs", "tbsYj"))) { .ret$scaleC[.ini$ntheta[.i]] <- 1 } else if (any(.ini$err[.i] == c("prop", "add", "norm", "dnorm", "logn", "dlogn", "lnorm", "dlnorm"))) { .ret$scaleC[.ini$ntheta[.i]] <- 0.5 * abs(.ini$est[.i]) } } } for (.i in .ini$model$extraProps$powTheta) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- 1 } .ini <- as.data.frame(.ret$uif$ini) for (.i in .ini$model$extraProps$factorial) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- abs(1/digamma(.ini$est[.i] + 1)) } for (.i in .ini$model$extraProps$gamma) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- abs(1/digamma(.ini$est[.i])) } for (.i in .ini$model$extraProps$log) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- log(abs(.ini$est[.i])) * abs(.ini$est[.i]) } for (.i in .ret$logitThetas) { .b <- .ret$logitThetasLow[.i] .c <- .ret$logitThetasHi[.i] .a <- .ini$est[.i] if (is.na(.ret$scaleC[.i])) { .ret$scaleC[.i] <- 1 * (-.b + .c) * exp(-.a)/((1 + exp(-.a))^2 * (.b + 1 * (-.b + .c)/(1 + exp(-.a)))) } } } names(.ret$thetaIni) <- sprintf("THETA[%d]", seq_along(.ret$thetaIni)) if (is.null(etaMat) & !is.null(control$etaMat)) { .ret$etaMat <- control$etaMat } else { .ret$etaMat <- etaMat } .ret$setupTime <- (proc.time() - .pt)["elapsed"] if (exists("uif", envir = .ret)) { .tmp <- .ret$uif$logThetasList .ret$logThetas <- .tmp[[1]] .ret$logThetasF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasList .ret$logitThetas <- .tmp[[1]] .ret$logitThetasF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasListLow .ret$logitThetasLow <- .tmp[[1]] .ret$logitThetasLowF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasListHi .ret$logitThetasHi <- .tmp[[1]] .ret$logitThetasHiF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasList .ret$probitThetas <- .tmp[[1]] .ret$probitThetasF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasListLow .ret$probitThetasLow <- .tmp[[1]] .ret$probitThetasLowF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasListHi .ret$probitThetasHi <- .tmp[[1]] .ret$probitThetasHiF <- .tmp[[2]] } else { .ret$logThetasF <- integer(0) .ret$logitThetasF <- integer(0) .ret$logitThetasHiF <- numeric(0) .ret$logitThetasLowF <- numeric(0) .ret$logitThetas <- integer(0) .ret$logitThetasHi <- numeric(0) .ret$logitThetasLow <- numeric(0) .ret$probitThetasF <- integer(0) .ret$probitThetasHiF <- numeric(0) .ret$probitThetasLowF <- numeric(0) .ret$probitThetas <- integer(0) .ret$probitThetasHi <- numeric(0) .ret$probitThetasLow <- numeric(0) } if (exists("noLik", envir = .ret)) { if (!.ret$noLik) { .ret$.params <- c(sprintf("THETA[%d]", seq_along(.ret$thetaIni)), sprintf("ETA[%d]", seq(1, dim(.om0)[1]))) .ret$.thetan <- length(.ret$thetaIni) .ret$nobs <- sum(data$EVID == 0) } } .ret$control$printTop <- TRUE .ret$control$nF <- 0 .est0 <- .ret$thetaIni if (!is.null(.ret$model$pred.nolhs)) { .ret$control$predNeq <- length(.ret$model$pred.nolhs$state) } else { .ret$control$predNeq <- 0L } .fitFun <- function(.ret) { this.env <- environment() assign("err", "theta reset", this.env) while (this.env$err == "theta reset") { assign("err", "", this.env) .ret0 <- tryCatch({ foceiFitCpp_(.ret) }, error = function(e) { if (regexpr("theta reset", e$message) != -1) { assign("zeroOuter", FALSE, this.env) assign("zeroGrad", FALSE, this.env) if (regexpr("theta reset0", e$message) != -1) { assign("zeroGrad", TRUE, this.env) } else if (regexpr("theta resetZ", e$message) != -1) { assign("zeroOuter", TRUE, this.env) } assign("err", "theta reset", this.env) } else { assign("err", e$message, this.env) } }) if (this.env$err == "theta reset") { .nm <- names(.ret$thetaIni) .ret$thetaIni <- setNames(.thetaReset$thetaIni + 0, .nm) .ret$rxInv$theta <- .thetaReset$omegaTheta .ret$control$printTop <- FALSE .ret$etaMat <- .thetaReset$etaMat .ret$control$etaMat <- .thetaReset$etaMat .ret$control$maxInnerIterations <- .thetaReset$maxInnerIterations .ret$control$nF <- .thetaReset$nF .ret$control$gillRetC <- .thetaReset$gillRetC .ret$control$gillRet <- .thetaReset$gillRet .ret$control$gillRet <- .thetaReset$gillRet .ret$control$gillDf <- .thetaReset$gillDf .ret$control$gillDf2 <- .thetaReset$gillDf2 .ret$control$gillErr <- .thetaReset$gillErr .ret$control$rEps <- .thetaReset$rEps .ret$control$aEps <- .thetaReset$aEps .ret$control$rEpsC <- .thetaReset$rEpsC .ret$control$aEpsC <- .thetaReset$aEpsC .ret$control$c1 <- .thetaReset$c1 .ret$control$c2 <- .thetaReset$c2 if (this.env$zeroOuter) { message("Posthoc reset") .ret$control$maxOuterIterations <- 0L } else if (this.env$zeroGrad) { message("Theta reset (zero gradient values); Switch to bobyqa") RxODE::rxReq("minqa") .ret$control$outerOptFun <- .bobyqa .ret$control$outerOpt <- -1L } else { message("Theta reset (ETA drift)") } } } if (this.env$err != "") { stop(this.env$err) } else { return(.ret0) } } .ret0 <- try(.fitFun(.ret)) .n <- 1 while (inherits(.ret0, "try-error") && control$maxOuterIterations != 0 && .n <= control$nRetries) { message(sprintf("Restart %s", .n)) .ret$control$nF <- 0 .estNew <- .est0 + 0.2 * .n * abs(.est0) * stats::runif(length(.est0)) - 0.1 * .n .estNew <- sapply(seq_along(.est0), function(.i) { if (.ret$thetaFixed[.i]) { return(.est0[.i]) } else if (.estNew[.i] < lower[.i]) { return(lower + (.Machine$double.eps)^(1/7)) } else if (.estNew[.i] > upper[.i]) { return(upper - (.Machine$double.eps)^(1/7)) } else { return(.estNew[.i]) } }) .ret$thetaIni <- .estNew .ret0 <- try(.fitFun(.ret)) .n <- .n + 1 } if (inherits(.ret0, "try-error")) stop("Could not fit data.") .ret <- .ret0 if (exists("parHistData", .ret)) { .tmp <- .ret$parHistData .tmp <- .tmp[.tmp$type == "Unscaled", names(.tmp) != "type"] .iter <- .tmp$iter .tmp <- .tmp[, names(.tmp) != "iter"] .ret$parHistStacked <- data.frame(stack(.tmp), iter = .iter) names(.ret$parHistStacked) <- c("val", "par", "iter") .ret$parHist <- data.frame(iter = .iter, .tmp) } if (.mixed) { .etas <- .ret$ranef .thetas <- .ret$fixef .pars <- .Call(`_nlmixr_nlmixrParameters`, .thetas, .etas) .ret$shrink <- .Call(`_nlmixr_calcShrinkOnly`, .ret$omega, .pars$eta.lst, length(.etas$ID)) .updateParFixed(.ret) } else { .updateParFixed(.ret) } if (!exists("table", .ret)) { .ret$table <- tableControl() } if (control$calcTables) { .ret <- addTable(.ret, updateObject = "no", keep = keep, drop = drop, table = .ret$table) } .ret})(data = dat, inits = .FoceiInits, PKpars = .pars, model = .mod, pred = function() { return(nlmixr_pred) }, err = uif$error, lower = uif$focei.lower, upper = uif$focei.upper, fixed = uif$focei.fixed, thetaNames = uif$focei.names, etaNames = uif$eta.names, control = control, env = env, keep = .keep, drop = .drop): Not all the covariates are in the dataset.</span></div><div class='output co'>#> <span class='message'>Timing stopped at: 15.18 0.414 15.6</span></div><div class='input'> +#> <span class='message'>dosenum=dosenum();</span></div><div class='output co'>#> <span class='message'>Needed Covariates:</span></div><div class='output co'>#> <span class='message'>[1] "f_parent_to_A1" "CMT" </span></div><div class='output co'>#> <span class='error'>Error in (function (data, inits, PKpars, model = NULL, pred = NULL, err = NULL, lower = -Inf, upper = Inf, fixed = NULL, skipCov = NULL, control = foceiControl(), thetaNames = NULL, etaNames = NULL, etaMat = NULL, ..., env = NULL, keep = NULL, drop = NULL) { set.seed(control$seed) .pt <- proc.time() RxODE::.setWarnIdSort(FALSE) on.exit(RxODE::.setWarnIdSort(TRUE)) loadNamespace("n1qn1") if (!RxODE::rxIs(control, "foceiControl")) { control <- do.call(foceiControl, control) } if (is.null(env)) { .ret <- new.env(parent = emptyenv()) } else { .ret <- env } .ret$origData <- data .ret$etaNames <- etaNames .ret$thetaFixed <- fixed .ret$control <- control .ret$control$focei.mu.ref <- integer(0) if (is(model, "RxODE") || is(model, "character")) { .ret$ODEmodel <- TRUE if (class(pred) != "function") { stop("pred must be a function specifying the prediction variables in this model.") } } else { .ret$ODEmodel <- TRUE model <- RxODE::rxGetLin(PKpars) pred <- eval(parse(text = "function(){return(Central);}")) } .square <- function(x) x * x .ret$diagXformInv <- c(sqrt = ".square", log = "exp", identity = "identity")[control$diagXform] if (is.null(err)) { err <- eval(parse(text = paste0("function(){err", paste(inits$ERROR[[1]], collapse = ""), "}"))) } .covNames <- .parNames <- c() .ret$adjLik <- control$adjLik .mixed <- !is.null(inits$OMGA) && length(inits$OMGA) > 0 if (!exists("noLik", envir = .ret)) { .atol <- rep(control$atol, length(RxODE::rxModelVars(model)$state)) .rtol <- rep(control$rtol, length(RxODE::rxModelVars(model)$state)) .ssAtol <- rep(control$ssAtol, length(RxODE::rxModelVars(model)$state)) .ssRtol <- rep(control$ssRtol, length(RxODE::rxModelVars(model)$state)) .ret$model <- RxODE::rxSymPySetupPred(model, pred, PKpars, err, grad = (control$derivMethod == 2L), pred.minus.dv = TRUE, sum.prod = control$sumProd, theta.derivs = FALSE, optExpression = control$optExpression, interaction = (control$interaction == 1L), only.numeric = !.mixed, run.internal = TRUE, addProp = control$addProp) if (!is.null(.ret$model$inner)) { .atol <- c(.atol, rep(control$atolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.atol))) .rtol <- c(.rtol, rep(control$rtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.rtol))) .ret$control$rxControl$atol <- .atol .ret$control$rxControl$rtol <- .rtol .ssAtol <- c(.ssAtol, rep(control$ssAtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.ssAtol))) .ssRtol <- c(.ssRtol, rep(control$ssRtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.ssRtol))) .ret$control$rxControl$ssAtol <- .ssAtol .ret$control$rxControl$ssRtol <- .ssRtol } .covNames <- .parNames <- RxODE::rxParams(.ret$model$pred.only) .covNames <- .covNames[regexpr(rex::rex(start, or("THETA", "ETA"), "[", numbers, "]", end), .covNames) == -1] colnames(data) <- sapply(names(data), function(x) { if (any(x == .covNames)) { return(x) } else { return(toupper(x)) } }) .lhs <- c(names(RxODE::rxInits(.ret$model$pred.only)), RxODE::rxLhs(.ret$model$pred.only)) if (length(.lhs) > 0) { .covNames <- .covNames[regexpr(rex::rex(start, or(.lhs), end), .covNames) == -1] } if (length(.covNames) > 0) { if (!all(.covNames %in% names(data))) { message("Model:") RxODE::rxCat(.ret$model$pred.only) message("Needed Covariates:") nlmixrPrint(.covNames) stop("Not all the covariates are in the dataset.") } message("Needed Covariates:") print(.covNames) } .extraPars <- .ret$model$extra.pars } else { if (.ret$noLik) { .atol <- rep(control$atol, length(RxODE::rxModelVars(model)$state)) .rtol <- rep(control$rtol, length(RxODE::rxModelVars(model)$state)) .ret$model <- RxODE::rxSymPySetupPred(model, pred, PKpars, err, grad = FALSE, pred.minus.dv = TRUE, sum.prod = control$sumProd, theta.derivs = FALSE, optExpression = control$optExpression, run.internal = TRUE, only.numeric = TRUE, addProp = control$addProp) if (!is.null(.ret$model$inner)) { .atol <- c(.atol, rep(control$atolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.atol))) .rtol <- c(.rtol, rep(control$rtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.rtol))) .ret$control$rxControl$atol <- .atol .ret$control$rxControl$rtol <- .rtol } .covNames <- .parNames <- RxODE::rxParams(.ret$model$pred.only) .covNames <- .covNames[regexpr(rex::rex(start, or("THETA", "ETA"), "[", numbers, "]", end), .covNames) == -1] colnames(data) <- sapply(names(data), function(x) { if (any(x == .covNames)) { return(x) } else { return(toupper(x)) } }) .lhs <- c(names(RxODE::rxInits(.ret$model$pred.only)), RxODE::rxLhs(.ret$model$pred.only)) if (length(.lhs) > 0) { .covNames <- .covNames[regexpr(rex::rex(start, or(.lhs), end), .covNames) == -1] } if (length(.covNames) > 0) { if (!all(.covNames %in% names(data))) { message("Model:") RxODE::rxCat(.ret$model$pred.only) message("Needed Covariates:") nlmixrPrint(.covNames) stop("Not all the covariates are in the dataset.") } message("Needed Covariates:") print(.covNames) } .extraPars <- .ret$model$extra.pars } else { .extraPars <- NULL } } .ret$skipCov <- skipCov if (is.null(skipCov)) { if (is.null(fixed)) { .tmp <- rep(FALSE, length(inits$THTA)) } else { if (length(fixed) < length(inits$THTA)) { .tmp <- c(fixed, rep(FALSE, length(inits$THTA) - length(fixed))) } else { .tmp <- fixed[1:length(inits$THTA)] } } if (exists("uif", envir = .ret)) { .uifErr <- .ret$uif$ini$err[!is.na(.ret$uif$ini$ntheta)] .uifErr <- sapply(.uifErr, function(x) { if (is.na(x)) { return(FALSE) } return(!any(x == c("pow2", "tbs", "tbsYj"))) }) .tmp <- (.tmp | .uifErr) } .ret$skipCov <- c(.tmp, rep(TRUE, length(.extraPars))) .ret$control$focei.mu.ref <- .ret$uif$focei.mu.ref } if (is.null(.extraPars)) { .nms <- c(sprintf("THETA[%s]", seq_along(inits$THTA))) } else { .nms <- c(sprintf("THETA[%s]", seq_along(inits$THTA)), sprintf("ERR[%s]", seq_along(.extraPars))) } if (!is.null(thetaNames) && (length(inits$THTA) + length(.extraPars)) == length(thetaNames)) { .nms <- thetaNames } .ret$thetaNames <- .nms .thetaReset$thetaNames <- .nms if (length(lower) == 1) { lower <- rep(lower, length(inits$THTA)) } else if (length(lower) != length(inits$THTA)) { print(inits$THTA) print(lower) stop("Lower must be a single constant for all the THETA lower bounds, or match the dimension of THETA.") } if (length(upper) == 1) { upper <- rep(upper, length(inits$THTA)) } else if (length(lower) != length(inits$THTA)) { stop("Upper must be a single constant for all the THETA lower bounds, or match the dimension of THETA.") } if (!is.null(.extraPars)) { .ret$model$extra.pars <- eval(call(control$diagXform, .ret$model$extra.pars)) if (length(.ret$model$extra.pars) > 0) { inits$THTA <- c(inits$THTA, .ret$model$extra.pars) .lowerErr <- rep(control$atol[1] * 10, length(.ret$model$extra.pars)) .upperErr <- rep(Inf, length(.ret$model$extra.pars)) lower <- c(lower, .lowerErr) upper <- c(upper, .upperErr) } } if (is.null(data$ID)) stop("\"ID\" not found in data") if (is.null(data$DV)) stop("\"DV\" not found in data") if (is.null(data$EVID)) data$EVID <- 0 if (is.null(data$AMT)) data$AMT <- 0 for (.v in c("TIME", "AMT", "DV", .covNames)) { data[[.v]] <- as.double(data[[.v]]) } .ret$dataSav <- data .ds <- data[data$EVID != 0 & data$EVID != 2, c("ID", "TIME", "AMT", "EVID", .covNames)] .w <- which(tolower(names(data)) == "limit") .limitName <- NULL if (length(.w) == 1L) { .limitName <- names(data)[.w] } .censName <- NULL .w <- which(tolower(names(data)) == "cens") if (length(.w) == 1L) { .censName <- names(data[.w]) } data <- data[data$EVID == 0 | data$EVID == 2, c("ID", "TIME", "DV", "EVID", .covNames, .limitName, .censName)] .w <- which(!(names(.ret$dataSav) %in% c(.covNames, keep))) names(.ret$dataSav)[.w] <- tolower(names(.ret$dataSav[.w])) if (.mixed) { .lh <- .parseOM(inits$OMGA) .nlh <- sapply(.lh, length) .osplt <- rep(1:length(.lh), .nlh) .lini <- list(inits$THTA, unlist(.lh)) .nlini <- sapply(.lini, length) .nsplt <- rep(1:length(.lini), .nlini) .om0 <- .genOM(.lh) if (length(etaNames) == dim(.om0)[1]) { .ret$etaNames <- .ret$etaNames } else { .ret$etaNames <- sprintf("ETA[%d]", seq(1, dim(.om0)[1])) } .ret$rxInv <- RxODE::rxSymInvCholCreate(mat = .om0, diag.xform = control$diagXform) .ret$xType <- .ret$rxInv$xType .om0a <- .om0 .om0a <- .om0a/control$diagOmegaBoundLower .om0b <- .om0 .om0b <- .om0b * control$diagOmegaBoundUpper .om0a <- RxODE::rxSymInvCholCreate(mat = .om0a, diag.xform = control$diagXform) .om0b <- RxODE::rxSymInvCholCreate(mat = .om0b, diag.xform = control$diagXform) .omdf <- data.frame(a = .om0a$theta, m = .ret$rxInv$theta, b = .om0b$theta, diag = .om0a$theta.diag) .omdf$lower <- with(.omdf, ifelse(a > b, b, a)) .omdf$lower <- with(.omdf, ifelse(lower == m, -Inf, lower)) .omdf$lower <- with(.omdf, ifelse(!diag, -Inf, lower)) .omdf$upper <- with(.omdf, ifelse(a < b, b, a)) .omdf$upper <- with(.omdf, ifelse(upper == m, Inf, upper)) .omdf$upper <- with(.omdf, ifelse(!diag, Inf, upper)) .ret$control$nomega <- length(.omdf$lower) .ret$control$neta <- sum(.omdf$diag) .ret$control$ntheta <- length(lower) .ret$control$nfixed <- sum(fixed) lower <- c(lower, .omdf$lower) upper <- c(upper, .omdf$upper) } else { .ret$control$nomega <- 0 .ret$control$neta <- 0 .ret$xType <- -1 .ret$control$ntheta <- length(lower) .ret$control$nfixed <- sum(fixed) } .ret$lower <- lower .ret$upper <- upper .ret$thetaIni <- inits$THTA .scaleC <- double(length(lower)) if (is.null(control$scaleC)) { .scaleC <- rep(NA_real_, length(lower)) } else { .scaleC <- as.double(control$scaleC) if (length(lower) > length(.scaleC)) { .scaleC <- c(.scaleC, rep(NA_real_, length(lower) - length(.scaleC))) } else if (length(lower) < length(.scaleC)) { .scaleC <- .scaleC[seq(1, length(lower))] warning("scaleC control option has more options than estimated population parameters, please check.") } } .ret$scaleC <- .scaleC if (exists("uif", envir = .ret)) { .ini <- as.data.frame(.ret$uif$ini)[!is.na(.ret$uif$ini$err), c("est", "err", "ntheta")] for (.i in seq_along(.ini$err)) { if (is.na(.ret$scaleC[.ini$ntheta[.i]])) { if (any(.ini$err[.i] == c("boxCox", "yeoJohnson", "pow2", "tbs", "tbsYj"))) { .ret$scaleC[.ini$ntheta[.i]] <- 1 } else if (any(.ini$err[.i] == c("prop", "add", "norm", "dnorm", "logn", "dlogn", "lnorm", "dlnorm"))) { .ret$scaleC[.ini$ntheta[.i]] <- 0.5 * abs(.ini$est[.i]) } } } for (.i in .ini$model$extraProps$powTheta) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- 1 } .ini <- as.data.frame(.ret$uif$ini) for (.i in .ini$model$extraProps$factorial) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- abs(1/digamma(.ini$est[.i] + 1)) } for (.i in .ini$model$extraProps$gamma) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- abs(1/digamma(.ini$est[.i])) } for (.i in .ini$model$extraProps$log) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- log(abs(.ini$est[.i])) * abs(.ini$est[.i]) } for (.i in .ret$logitThetas) { .b <- .ret$logitThetasLow[.i] .c <- .ret$logitThetasHi[.i] .a <- .ini$est[.i] if (is.na(.ret$scaleC[.i])) { .ret$scaleC[.i] <- 1 * (-.b + .c) * exp(-.a)/((1 + exp(-.a))^2 * (.b + 1 * (-.b + .c)/(1 + exp(-.a)))) } } } names(.ret$thetaIni) <- sprintf("THETA[%d]", seq_along(.ret$thetaIni)) if (is.null(etaMat) & !is.null(control$etaMat)) { .ret$etaMat <- control$etaMat } else { .ret$etaMat <- etaMat } .ret$setupTime <- (proc.time() - .pt)["elapsed"] if (exists("uif", envir = .ret)) { .tmp <- .ret$uif$logThetasList .ret$logThetas <- .tmp[[1]] .ret$logThetasF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasList .ret$logitThetas <- .tmp[[1]] .ret$logitThetasF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasListLow .ret$logitThetasLow <- .tmp[[1]] .ret$logitThetasLowF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasListHi .ret$logitThetasHi <- .tmp[[1]] .ret$logitThetasHiF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasList .ret$probitThetas <- .tmp[[1]] .ret$probitThetasF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasListLow .ret$probitThetasLow <- .tmp[[1]] .ret$probitThetasLowF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasListHi .ret$probitThetasHi <- .tmp[[1]] .ret$probitThetasHiF <- .tmp[[2]] } else { .ret$logThetasF <- integer(0) .ret$logitThetasF <- integer(0) .ret$logitThetasHiF <- numeric(0) .ret$logitThetasLowF <- numeric(0) .ret$logitThetas <- integer(0) .ret$logitThetasHi <- numeric(0) .ret$logitThetasLow <- numeric(0) .ret$probitThetasF <- integer(0) .ret$probitThetasHiF <- numeric(0) .ret$probitThetasLowF <- numeric(0) .ret$probitThetas <- integer(0) .ret$probitThetasHi <- numeric(0) .ret$probitThetasLow <- numeric(0) } if (exists("noLik", envir = .ret)) { if (!.ret$noLik) { .ret$.params <- c(sprintf("THETA[%d]", seq_along(.ret$thetaIni)), sprintf("ETA[%d]", seq(1, dim(.om0)[1]))) .ret$.thetan <- length(.ret$thetaIni) .ret$nobs <- sum(data$EVID == 0) } } .ret$control$printTop <- TRUE .ret$control$nF <- 0 .est0 <- .ret$thetaIni if (!is.null(.ret$model$pred.nolhs)) { .ret$control$predNeq <- length(.ret$model$pred.nolhs$state) } else { .ret$control$predNeq <- 0L } .fitFun <- function(.ret) { this.env <- environment() assign("err", "theta reset", this.env) while (this.env$err == "theta reset") { assign("err", "", this.env) .ret0 <- tryCatch({ foceiFitCpp_(.ret) }, error = function(e) { if (regexpr("theta reset", e$message) != -1) { assign("zeroOuter", FALSE, this.env) assign("zeroGrad", FALSE, this.env) if (regexpr("theta reset0", e$message) != -1) { assign("zeroGrad", TRUE, this.env) } else if (regexpr("theta resetZ", e$message) != -1) { assign("zeroOuter", TRUE, this.env) } assign("err", "theta reset", this.env) } else { assign("err", e$message, this.env) } }) if (this.env$err == "theta reset") { .nm <- names(.ret$thetaIni) .ret$thetaIni <- setNames(.thetaReset$thetaIni + 0, .nm) .ret$rxInv$theta <- .thetaReset$omegaTheta .ret$control$printTop <- FALSE .ret$etaMat <- .thetaReset$etaMat .ret$control$etaMat <- .thetaReset$etaMat .ret$control$maxInnerIterations <- .thetaReset$maxInnerIterations .ret$control$nF <- .thetaReset$nF .ret$control$gillRetC <- .thetaReset$gillRetC .ret$control$gillRet <- .thetaReset$gillRet .ret$control$gillRet <- .thetaReset$gillRet .ret$control$gillDf <- .thetaReset$gillDf .ret$control$gillDf2 <- .thetaReset$gillDf2 .ret$control$gillErr <- .thetaReset$gillErr .ret$control$rEps <- .thetaReset$rEps .ret$control$aEps <- .thetaReset$aEps .ret$control$rEpsC <- .thetaReset$rEpsC .ret$control$aEpsC <- .thetaReset$aEpsC .ret$control$c1 <- .thetaReset$c1 .ret$control$c2 <- .thetaReset$c2 if (this.env$zeroOuter) { message("Posthoc reset") .ret$control$maxOuterIterations <- 0L } else if (this.env$zeroGrad) { message("Theta reset (zero gradient values); Switch to bobyqa") RxODE::rxReq("minqa") .ret$control$outerOptFun <- .bobyqa .ret$control$outerOpt <- -1L } else { message("Theta reset (ETA drift)") } } } if (this.env$err != "") { stop(this.env$err) } else { return(.ret0) } } .ret0 <- try(.fitFun(.ret)) .n <- 1 while (inherits(.ret0, "try-error") && control$maxOuterIterations != 0 && .n <= control$nRetries) { message(sprintf("Restart %s", .n)) .ret$control$nF <- 0 .estNew <- .est0 + 0.2 * .n * abs(.est0) * stats::runif(length(.est0)) - 0.1 * .n .estNew <- sapply(seq_along(.est0), function(.i) { if (.ret$thetaFixed[.i]) { return(.est0[.i]) } else if (.estNew[.i] < lower[.i]) { return(lower + (.Machine$double.eps)^(1/7)) } else if (.estNew[.i] > upper[.i]) { return(upper - (.Machine$double.eps)^(1/7)) } else { return(.estNew[.i]) } }) .ret$thetaIni <- .estNew .ret0 <- try(.fitFun(.ret)) .n <- .n + 1 } if (inherits(.ret0, "try-error")) stop("Could not fit data.") .ret <- .ret0 if (exists("parHistData", .ret)) { .tmp <- .ret$parHistData .tmp <- .tmp[.tmp$type == "Unscaled", names(.tmp) != "type"] .iter <- .tmp$iter .tmp <- .tmp[, names(.tmp) != "iter"] .ret$parHistStacked <- data.frame(stack(.tmp), iter = .iter) names(.ret$parHistStacked) <- c("val", "par", "iter") .ret$parHist <- data.frame(iter = .iter, .tmp) } if (.mixed) { .etas <- .ret$ranef .thetas <- .ret$fixef .pars <- .Call(`_nlmixr_nlmixrParameters`, .thetas, .etas) .ret$shrink <- .Call(`_nlmixr_calcShrinkOnly`, .ret$omega, .pars$eta.lst, length(.etas$ID)) .updateParFixed(.ret) } else { .updateParFixed(.ret) } if (!exists("table", .ret)) { .ret$table <- tableControl() } if (control$calcTables) { .ret <- addTable(.ret, updateObject = "no", keep = keep, drop = drop, table = .ret$table) } .ret})(data = dat, inits = .FoceiInits, PKpars = .pars, model = .mod, pred = function() { return(nlmixr_pred) }, err = uif$error, lower = uif$focei.lower, upper = uif$focei.upper, fixed = uif$focei.fixed, thetaNames = uif$focei.names, etaNames = uif$eta.names, control = control, env = env, keep = .keep, drop = .drop): Not all the covariates are in the dataset.</span></div><div class='output co'>#> <span class='message'>Timing stopped at: 15.03 0.478 15.51</span></div><div class='input'> <span class='co'># Variance by variable is supported by 'saem' and 'focei'</span> <span class='va'>f_nlmixr_fomc_sfo_saem_obs</span> <span class='op'><-</span> <span class='fu'><a href='https://rdrr.io/pkg/nlmixr/man/nlmixr.html'>nlmixr</a></span><span class='op'>(</span><span class='va'>f_mmkin_obs</span><span class='op'>[</span><span class='st'>"FOMC-SFO"</span>, <span class='op'>]</span>, est <span class='op'>=</span> <span class='st'>"saem"</span><span class='op'>)</span> -</div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> parameter labels from comments are typically ignored in non-interactive mode</span></div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> Need to run with the source intact to parse comments</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='message'>→ generate SAEM model</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='error'>Error in configsaem(model = model, data = dat, inits = inits, mcmc = .mcmc, ODEopt = .ODEopt, seed = .seed, distribution = .dist, DEBUG = .DEBUG, addProp = .addProp, tol = .tol, itmax = .itmax, type = .type, powRange = .powRange, lambdaRange = .lambdaRange): covariate(s) not found: f_parent_to_A1</span></div><div class='output co'>#> <span class='message'>Timing stopped at: 1.22 0.089 1.31</span></div><div class='input'><span class='va'>f_nlmixr_fomc_sfo_focei_obs</span> <span class='op'><-</span> <span class='fu'><a href='https://rdrr.io/pkg/nlmixr/man/nlmixr.html'>nlmixr</a></span><span class='op'>(</span><span class='va'>f_mmkin_obs</span><span class='op'>[</span><span class='st'>"FOMC-SFO"</span>, <span class='op'>]</span>, est <span class='op'>=</span> <span class='st'>"focei"</span><span class='op'>)</span> +</div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> parameter labels from comments are typically ignored in non-interactive mode</span></div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> Need to run with the source intact to parse comments</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='message'>→ generate SAEM model</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='error'>Error in configsaem(model = model, data = dat, inits = inits, mcmc = .mcmc, ODEopt = .ODEopt, seed = .seed, distribution = .dist, DEBUG = .DEBUG, addProp = .addProp, tol = .tol, itmax = .itmax, type = .type, powRange = .powRange, lambdaRange = .lambdaRange): covariate(s) not found: f_parent_to_A1</span></div><div class='output co'>#> <span class='message'>Timing stopped at: 1.294 0.134 1.427</span></div><div class='input'><span class='va'>f_nlmixr_fomc_sfo_focei_obs</span> <span class='op'><-</span> <span class='fu'><a href='https://rdrr.io/pkg/nlmixr/man/nlmixr.html'>nlmixr</a></span><span class='op'>(</span><span class='va'>f_mmkin_obs</span><span class='op'>[</span><span class='st'>"FOMC-SFO"</span>, <span class='op'>]</span>, est <span class='op'>=</span> <span class='st'>"focei"</span><span class='op'>)</span> </div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> parameter labels from comments are typically ignored in non-interactive mode</span></div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> Need to run with the source intact to parse comments</span></div><div class='output co'>#> <span class='message'>→ creating full model...</span></div><div class='output co'>#> <span class='message'>→ pruning branches (<span style='color: #262626; background-color: #DADADA;'>`if`</span>/<span style='color: #262626; background-color: #DADADA;'>`else`</span>)...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ loading into <span style='color: #0000BB;'>symengine</span> environment...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ creating full model...</span></div><div class='output co'>#> <span class='message'>→ pruning branches (<span style='color: #262626; background-color: #DADADA;'>`if`</span>/<span style='color: #262626; background-color: #DADADA;'>`else`</span>)...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ loading into <span style='color: #0000BB;'>symengine</span> environment...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ calculate jacobian</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ calculate sensitivities</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ calculate ∂(f)/∂(η)</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ calculate ∂(R²)/∂(η)</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ finding duplicate expressions in inner model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ optimizing duplicate expressions in inner model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ finding duplicate expressions in EBE model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ optimizing duplicate expressions in EBE model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ compiling inner model...</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ finding duplicate expressions in FD model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ optimizing duplicate expressions in FD model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ compiling EBE model...</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ compiling events FD model...</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>Model:</span></div><div class='output co'>#> <span class='message'>cmt(parent);</span> #> <span class='message'>cmt(A1);</span> #> <span class='message'>rx_expr_6~ETA[1]+THETA[1];</span> @@ -4659,8 +4659,8 @@ obtained by fitting the same model to a list of datasets using <a href='mkinfit. #> <span class='message'>beta=exp(rx_expr_8);</span> #> <span class='message'>f_parent=1/(1+exp(-(ETA[3]+THETA[3])));</span> #> <span class='message'>tad=tad();</span> -#> <span class='message'>dosenum=dosenum();</span></div><div class='output co'>#> <span class='message'>Needed Covariates:</span></div><div class='output co'>#> <span class='message'>[1] "f_parent_to_A1" "CMT" </span></div><div class='output co'>#> <span class='error'>Error in (function (data, inits, PKpars, model = NULL, pred = NULL, err = NULL, lower = -Inf, upper = Inf, fixed = NULL, skipCov = NULL, control = foceiControl(), thetaNames = NULL, etaNames = NULL, etaMat = NULL, ..., env = NULL, keep = NULL, drop = NULL) { set.seed(control$seed) .pt <- proc.time() RxODE::.setWarnIdSort(FALSE) on.exit(RxODE::.setWarnIdSort(TRUE)) loadNamespace("n1qn1") if (!RxODE::rxIs(control, "foceiControl")) { control <- do.call(foceiControl, control) } if (is.null(env)) { .ret <- new.env(parent = emptyenv()) } else { .ret <- env } .ret$origData <- data .ret$etaNames <- etaNames .ret$thetaFixed <- fixed .ret$control <- control .ret$control$focei.mu.ref <- integer(0) if (is(model, "RxODE") || is(model, "character")) { .ret$ODEmodel <- TRUE if (class(pred) != "function") { stop("pred must be a function specifying the prediction variables in this model.") } } else { .ret$ODEmodel <- TRUE model <- RxODE::rxGetLin(PKpars) pred <- eval(parse(text = "function(){return(Central);}")) } .square <- function(x) x * x .ret$diagXformInv <- c(sqrt = ".square", log = "exp", identity = "identity")[control$diagXform] if (is.null(err)) { err <- eval(parse(text = paste0("function(){err", paste(inits$ERROR[[1]], collapse = ""), "}"))) } .covNames <- .parNames <- c() .ret$adjLik <- control$adjLik .mixed <- !is.null(inits$OMGA) && length(inits$OMGA) > 0 if (!exists("noLik", envir = .ret)) { .atol <- rep(control$atol, length(RxODE::rxModelVars(model)$state)) .rtol <- rep(control$rtol, length(RxODE::rxModelVars(model)$state)) .ssAtol <- rep(control$ssAtol, length(RxODE::rxModelVars(model)$state)) .ssRtol <- rep(control$ssRtol, length(RxODE::rxModelVars(model)$state)) .ret$model <- RxODE::rxSymPySetupPred(model, pred, PKpars, err, grad = (control$derivMethod == 2L), pred.minus.dv = TRUE, sum.prod = control$sumProd, theta.derivs = FALSE, optExpression = control$optExpression, interaction = (control$interaction == 1L), only.numeric = !.mixed, run.internal = TRUE, addProp = control$addProp) if (!is.null(.ret$model$inner)) { .atol <- c(.atol, rep(control$atolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.atol))) .rtol <- c(.rtol, rep(control$rtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.rtol))) .ret$control$rxControl$atol <- .atol .ret$control$rxControl$rtol <- .rtol .ssAtol <- c(.ssAtol, rep(control$ssAtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.ssAtol))) .ssRtol <- c(.ssRtol, rep(control$ssRtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.ssRtol))) .ret$control$rxControl$ssAtol <- .ssAtol .ret$control$rxControl$ssRtol <- .ssRtol } .covNames <- .parNames <- RxODE::rxParams(.ret$model$pred.only) .covNames <- .covNames[regexpr(rex::rex(start, or("THETA", "ETA"), "[", numbers, "]", end), .covNames) == -1] colnames(data) <- sapply(names(data), function(x) { if (any(x == .covNames)) { return(x) } else { return(toupper(x)) } }) .lhs <- c(names(RxODE::rxInits(.ret$model$pred.only)), RxODE::rxLhs(.ret$model$pred.only)) if (length(.lhs) > 0) { .covNames <- .covNames[regexpr(rex::rex(start, or(.lhs), end), .covNames) == -1] } if (length(.covNames) > 0) { if (!all(.covNames %in% names(data))) { message("Model:") RxODE::rxCat(.ret$model$pred.only) message("Needed Covariates:") nlmixrPrint(.covNames) stop("Not all the covariates are in the dataset.") } message("Needed Covariates:") print(.covNames) } .extraPars <- .ret$model$extra.pars } else { if (.ret$noLik) { .atol <- rep(control$atol, length(RxODE::rxModelVars(model)$state)) .rtol <- rep(control$rtol, length(RxODE::rxModelVars(model)$state)) .ret$model <- RxODE::rxSymPySetupPred(model, pred, PKpars, err, grad = FALSE, pred.minus.dv = TRUE, sum.prod = control$sumProd, theta.derivs = FALSE, optExpression = control$optExpression, run.internal = TRUE, only.numeric = TRUE, addProp = control$addProp) if (!is.null(.ret$model$inner)) { .atol <- c(.atol, rep(control$atolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.atol))) .rtol <- c(.rtol, rep(control$rtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.rtol))) .ret$control$rxControl$atol <- .atol .ret$control$rxControl$rtol <- .rtol } .covNames <- .parNames <- RxODE::rxParams(.ret$model$pred.only) .covNames <- .covNames[regexpr(rex::rex(start, or("THETA", "ETA"), "[", numbers, "]", end), .covNames) == -1] colnames(data) <- sapply(names(data), function(x) { if (any(x == .covNames)) { return(x) } else { return(toupper(x)) } }) .lhs <- c(names(RxODE::rxInits(.ret$model$pred.only)), RxODE::rxLhs(.ret$model$pred.only)) if (length(.lhs) > 0) { .covNames <- .covNames[regexpr(rex::rex(start, or(.lhs), end), .covNames) == -1] } if (length(.covNames) > 0) { if (!all(.covNames %in% names(data))) { message("Model:") RxODE::rxCat(.ret$model$pred.only) message("Needed Covariates:") nlmixrPrint(.covNames) stop("Not all the covariates are in the dataset.") } message("Needed Covariates:") print(.covNames) } .extraPars <- .ret$model$extra.pars } else { .extraPars <- NULL } } .ret$skipCov <- skipCov if (is.null(skipCov)) { if (is.null(fixed)) { .tmp <- rep(FALSE, length(inits$THTA)) } else { if (length(fixed) < length(inits$THTA)) { .tmp <- c(fixed, rep(FALSE, length(inits$THTA) - length(fixed))) } else { .tmp <- fixed[1:length(inits$THTA)] } } if (exists("uif", envir = .ret)) { .uifErr <- .ret$uif$ini$err[!is.na(.ret$uif$ini$ntheta)] .uifErr <- sapply(.uifErr, function(x) { if (is.na(x)) { return(FALSE) } return(!any(x == c("pow2", "tbs", "tbsYj"))) }) .tmp <- (.tmp | .uifErr) } .ret$skipCov <- c(.tmp, rep(TRUE, length(.extraPars))) .ret$control$focei.mu.ref <- .ret$uif$focei.mu.ref } if (is.null(.extraPars)) { .nms <- c(sprintf("THETA[%s]", seq_along(inits$THTA))) } else { .nms <- c(sprintf("THETA[%s]", seq_along(inits$THTA)), sprintf("ERR[%s]", seq_along(.extraPars))) } if (!is.null(thetaNames) && (length(inits$THTA) + length(.extraPars)) == length(thetaNames)) { .nms <- thetaNames } .ret$thetaNames <- .nms .thetaReset$thetaNames <- .nms if (length(lower) == 1) { lower <- rep(lower, length(inits$THTA)) } else if (length(lower) != length(inits$THTA)) { print(inits$THTA) print(lower) stop("Lower must be a single constant for all the THETA lower bounds, or match the dimension of THETA.") } if (length(upper) == 1) { upper <- rep(upper, length(inits$THTA)) } else if (length(lower) != length(inits$THTA)) { stop("Upper must be a single constant for all the THETA lower bounds, or match the dimension of THETA.") } if (!is.null(.extraPars)) { .ret$model$extra.pars <- eval(call(control$diagXform, .ret$model$extra.pars)) if (length(.ret$model$extra.pars) > 0) { inits$THTA <- c(inits$THTA, .ret$model$extra.pars) .lowerErr <- rep(control$atol[1] * 10, length(.ret$model$extra.pars)) .upperErr <- rep(Inf, length(.ret$model$extra.pars)) lower <- c(lower, .lowerErr) upper <- c(upper, .upperErr) } } if (is.null(data$ID)) stop("\"ID\" not found in data") if (is.null(data$DV)) stop("\"DV\" not found in data") if (is.null(data$EVID)) data$EVID <- 0 if (is.null(data$AMT)) data$AMT <- 0 for (.v in c("TIME", "AMT", "DV", .covNames)) { data[[.v]] <- as.double(data[[.v]]) } .ret$dataSav <- data .ds <- data[data$EVID != 0 & data$EVID != 2, c("ID", "TIME", "AMT", "EVID", .covNames)] .w <- which(tolower(names(data)) == "limit") .limitName <- NULL if (length(.w) == 1L) { .limitName <- names(data)[.w] } .censName <- NULL .w <- which(tolower(names(data)) == "cens") if (length(.w) == 1L) { .censName <- names(data[.w]) } data <- data[data$EVID == 0 | data$EVID == 2, c("ID", "TIME", "DV", "EVID", .covNames, .limitName, .censName)] .w <- which(!(names(.ret$dataSav) %in% c(.covNames, keep))) names(.ret$dataSav)[.w] <- tolower(names(.ret$dataSav[.w])) if (.mixed) { .lh <- .parseOM(inits$OMGA) .nlh <- sapply(.lh, length) .osplt <- rep(1:length(.lh), .nlh) .lini <- list(inits$THTA, unlist(.lh)) .nlini <- sapply(.lini, length) .nsplt <- rep(1:length(.lini), .nlini) .om0 <- .genOM(.lh) if (length(etaNames) == dim(.om0)[1]) { .ret$etaNames <- .ret$etaNames } else { .ret$etaNames <- sprintf("ETA[%d]", seq(1, dim(.om0)[1])) } .ret$rxInv <- RxODE::rxSymInvCholCreate(mat = .om0, diag.xform = control$diagXform) .ret$xType <- .ret$rxInv$xType .om0a <- .om0 .om0a <- .om0a/control$diagOmegaBoundLower .om0b <- .om0 .om0b <- .om0b * control$diagOmegaBoundUpper .om0a <- RxODE::rxSymInvCholCreate(mat = .om0a, diag.xform = control$diagXform) .om0b <- RxODE::rxSymInvCholCreate(mat = .om0b, diag.xform = control$diagXform) .omdf <- data.frame(a = .om0a$theta, m = .ret$rxInv$theta, b = .om0b$theta, diag = .om0a$theta.diag) .omdf$lower <- with(.omdf, ifelse(a > b, b, a)) .omdf$lower <- with(.omdf, ifelse(lower == m, -Inf, lower)) .omdf$lower <- with(.omdf, ifelse(!diag, -Inf, lower)) .omdf$upper <- with(.omdf, ifelse(a < b, b, a)) .omdf$upper <- with(.omdf, ifelse(upper == m, Inf, upper)) .omdf$upper <- with(.omdf, ifelse(!diag, Inf, upper)) .ret$control$nomega <- length(.omdf$lower) .ret$control$neta <- sum(.omdf$diag) .ret$control$ntheta <- length(lower) .ret$control$nfixed <- sum(fixed) lower <- c(lower, .omdf$lower) upper <- c(upper, .omdf$upper) } else { .ret$control$nomega <- 0 .ret$control$neta <- 0 .ret$xType <- -1 .ret$control$ntheta <- length(lower) .ret$control$nfixed <- sum(fixed) } .ret$lower <- lower .ret$upper <- upper .ret$thetaIni <- inits$THTA .scaleC <- double(length(lower)) if (is.null(control$scaleC)) { .scaleC <- rep(NA_real_, length(lower)) } else { .scaleC <- as.double(control$scaleC) if (length(lower) > length(.scaleC)) { .scaleC <- c(.scaleC, rep(NA_real_, length(lower) - length(.scaleC))) } else if (length(lower) < length(.scaleC)) { .scaleC <- .scaleC[seq(1, length(lower))] warning("scaleC control option has more options than estimated population parameters, please check.") } } .ret$scaleC <- .scaleC if (exists("uif", envir = .ret)) { .ini <- as.data.frame(.ret$uif$ini)[!is.na(.ret$uif$ini$err), c("est", "err", "ntheta")] for (.i in seq_along(.ini$err)) { if (is.na(.ret$scaleC[.ini$ntheta[.i]])) { if (any(.ini$err[.i] == c("boxCox", "yeoJohnson", "pow2", "tbs", "tbsYj"))) { .ret$scaleC[.ini$ntheta[.i]] <- 1 } else if (any(.ini$err[.i] == c("prop", "add", "norm", "dnorm", "logn", "dlogn", "lnorm", "dlnorm"))) { .ret$scaleC[.ini$ntheta[.i]] <- 0.5 * abs(.ini$est[.i]) } } } for (.i in .ini$model$extraProps$powTheta) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- 1 } .ini <- as.data.frame(.ret$uif$ini) for (.i in .ini$model$extraProps$factorial) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- abs(1/digamma(.ini$est[.i] + 1)) } for (.i in .ini$model$extraProps$gamma) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- abs(1/digamma(.ini$est[.i])) } for (.i in .ini$model$extraProps$log) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- log(abs(.ini$est[.i])) * abs(.ini$est[.i]) } for (.i in .ret$logitThetas) { .b <- .ret$logitThetasLow[.i] .c <- .ret$logitThetasHi[.i] .a <- .ini$est[.i] if (is.na(.ret$scaleC[.i])) { .ret$scaleC[.i] <- 1 * (-.b + .c) * exp(-.a)/((1 + exp(-.a))^2 * (.b + 1 * (-.b + .c)/(1 + exp(-.a)))) } } } names(.ret$thetaIni) <- sprintf("THETA[%d]", seq_along(.ret$thetaIni)) if (is.null(etaMat) & !is.null(control$etaMat)) { .ret$etaMat <- control$etaMat } else { .ret$etaMat <- etaMat } .ret$setupTime <- (proc.time() - .pt)["elapsed"] if (exists("uif", envir = .ret)) { .tmp <- .ret$uif$logThetasList .ret$logThetas <- .tmp[[1]] .ret$logThetasF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasList .ret$logitThetas <- .tmp[[1]] .ret$logitThetasF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasListLow .ret$logitThetasLow <- .tmp[[1]] .ret$logitThetasLowF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasListHi .ret$logitThetasHi <- .tmp[[1]] .ret$logitThetasHiF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasList .ret$probitThetas <- .tmp[[1]] .ret$probitThetasF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasListLow .ret$probitThetasLow <- .tmp[[1]] .ret$probitThetasLowF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasListHi .ret$probitThetasHi <- .tmp[[1]] .ret$probitThetasHiF <- .tmp[[2]] } else { .ret$logThetasF <- integer(0) .ret$logitThetasF <- integer(0) .ret$logitThetasHiF <- numeric(0) .ret$logitThetasLowF <- numeric(0) .ret$logitThetas <- integer(0) .ret$logitThetasHi <- numeric(0) .ret$logitThetasLow <- numeric(0) .ret$probitThetasF <- integer(0) .ret$probitThetasHiF <- numeric(0) .ret$probitThetasLowF <- numeric(0) .ret$probitThetas <- integer(0) .ret$probitThetasHi <- numeric(0) .ret$probitThetasLow <- numeric(0) } if (exists("noLik", envir = .ret)) { if (!.ret$noLik) { .ret$.params <- c(sprintf("THETA[%d]", seq_along(.ret$thetaIni)), sprintf("ETA[%d]", seq(1, dim(.om0)[1]))) .ret$.thetan <- length(.ret$thetaIni) .ret$nobs <- sum(data$EVID == 0) } } .ret$control$printTop <- TRUE .ret$control$nF <- 0 .est0 <- .ret$thetaIni if (!is.null(.ret$model$pred.nolhs)) { .ret$control$predNeq <- length(.ret$model$pred.nolhs$state) } else { .ret$control$predNeq <- 0L } .fitFun <- function(.ret) { this.env <- environment() assign("err", "theta reset", this.env) while (this.env$err == "theta reset") { assign("err", "", this.env) .ret0 <- tryCatch({ foceiFitCpp_(.ret) }, error = function(e) { if (regexpr("theta reset", e$message) != -1) { assign("zeroOuter", FALSE, this.env) assign("zeroGrad", FALSE, this.env) if (regexpr("theta reset0", e$message) != -1) { assign("zeroGrad", TRUE, this.env) } else if (regexpr("theta resetZ", e$message) != -1) { assign("zeroOuter", TRUE, this.env) } assign("err", "theta reset", this.env) } else { assign("err", e$message, this.env) } }) if (this.env$err == "theta reset") { .nm <- names(.ret$thetaIni) .ret$thetaIni <- setNames(.thetaReset$thetaIni + 0, .nm) .ret$rxInv$theta <- .thetaReset$omegaTheta .ret$control$printTop <- FALSE .ret$etaMat <- .thetaReset$etaMat .ret$control$etaMat <- .thetaReset$etaMat .ret$control$maxInnerIterations <- .thetaReset$maxInnerIterations .ret$control$nF <- .thetaReset$nF .ret$control$gillRetC <- .thetaReset$gillRetC .ret$control$gillRet <- .thetaReset$gillRet .ret$control$gillRet <- .thetaReset$gillRet .ret$control$gillDf <- .thetaReset$gillDf .ret$control$gillDf2 <- .thetaReset$gillDf2 .ret$control$gillErr <- .thetaReset$gillErr .ret$control$rEps <- .thetaReset$rEps .ret$control$aEps <- .thetaReset$aEps .ret$control$rEpsC <- .thetaReset$rEpsC .ret$control$aEpsC <- .thetaReset$aEpsC .ret$control$c1 <- .thetaReset$c1 .ret$control$c2 <- .thetaReset$c2 if (this.env$zeroOuter) { message("Posthoc reset") .ret$control$maxOuterIterations <- 0L } else if (this.env$zeroGrad) { message("Theta reset (zero gradient values); Switch to bobyqa") RxODE::rxReq("minqa") .ret$control$outerOptFun <- .bobyqa .ret$control$outerOpt <- -1L } else { message("Theta reset (ETA drift)") } } } if (this.env$err != "") { stop(this.env$err) } else { return(.ret0) } } .ret0 <- try(.fitFun(.ret)) .n <- 1 while (inherits(.ret0, "try-error") && control$maxOuterIterations != 0 && .n <= control$nRetries) { message(sprintf("Restart %s", .n)) .ret$control$nF <- 0 .estNew <- .est0 + 0.2 * .n * abs(.est0) * stats::runif(length(.est0)) - 0.1 * .n .estNew <- sapply(seq_along(.est0), function(.i) { if (.ret$thetaFixed[.i]) { return(.est0[.i]) } else if (.estNew[.i] < lower[.i]) { return(lower + (.Machine$double.eps)^(1/7)) } else if (.estNew[.i] > upper[.i]) { return(upper - (.Machine$double.eps)^(1/7)) } else { return(.estNew[.i]) } }) .ret$thetaIni <- .estNew .ret0 <- try(.fitFun(.ret)) .n <- .n + 1 } if (inherits(.ret0, "try-error")) stop("Could not fit data.") .ret <- .ret0 if (exists("parHistData", .ret)) { .tmp <- .ret$parHistData .tmp <- .tmp[.tmp$type == "Unscaled", names(.tmp) != "type"] .iter <- .tmp$iter .tmp <- .tmp[, names(.tmp) != "iter"] .ret$parHistStacked <- data.frame(stack(.tmp), iter = .iter) names(.ret$parHistStacked) <- c("val", "par", "iter") .ret$parHist <- data.frame(iter = .iter, .tmp) } if (.mixed) { .etas <- .ret$ranef .thetas <- .ret$fixef .pars <- .Call(`_nlmixr_nlmixrParameters`, .thetas, .etas) .ret$shrink <- .Call(`_nlmixr_calcShrinkOnly`, .ret$omega, .pars$eta.lst, length(.etas$ID)) .updateParFixed(.ret) } else { .updateParFixed(.ret) } if (!exists("table", .ret)) { .ret$table <- tableControl() } if (control$calcTables) { .ret <- addTable(.ret, updateObject = "no", keep = keep, drop = drop, table = .ret$table) } .ret})(data = dat, inits = .FoceiInits, PKpars = .pars, model = .mod, pred = function() { return(nlmixr_pred) }, err = uif$error, lower = uif$focei.lower, upper = uif$focei.upper, fixed = uif$focei.fixed, thetaNames = uif$focei.names, etaNames = uif$eta.names, control = control, env = env, keep = .keep, drop = .drop): Not all the covariates are in the dataset.</span></div><div class='output co'>#> <span class='message'>Timing stopped at: 6.784 0.418 7.2</span></div><div class='input'><span class='va'>f_nlmixr_dfop_sfo_saem_obs</span> <span class='op'><-</span> <span class='fu'><a href='https://rdrr.io/pkg/nlmixr/man/nlmixr.html'>nlmixr</a></span><span class='op'>(</span><span class='va'>f_mmkin_obs</span><span class='op'>[</span><span class='st'>"DFOP-SFO"</span>, <span class='op'>]</span>, est <span class='op'>=</span> <span class='st'>"saem"</span><span class='op'>)</span> -</div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> parameter labels from comments are typically ignored in non-interactive mode</span></div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> Need to run with the source intact to parse comments</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='message'>→ generate SAEM model</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='error'>Error in configsaem(model = model, data = dat, inits = inits, mcmc = .mcmc, ODEopt = .ODEopt, seed = .seed, distribution = .dist, DEBUG = .DEBUG, addProp = .addProp, tol = .tol, itmax = .itmax, type = .type, powRange = .powRange, lambdaRange = .lambdaRange): covariate(s) not found: f_parent_to_A1</span></div><div class='output co'>#> <span class='message'>Timing stopped at: 1.357 0.096 1.452</span></div><div class='input'><span class='va'>f_nlmixr_dfop_sfo_focei_obs</span> <span class='op'><-</span> <span class='fu'><a href='https://rdrr.io/pkg/nlmixr/man/nlmixr.html'>nlmixr</a></span><span class='op'>(</span><span class='va'>f_mmkin_obs</span><span class='op'>[</span><span class='st'>"DFOP-SFO"</span>, <span class='op'>]</span>, est <span class='op'>=</span> <span class='st'>"focei"</span><span class='op'>)</span> +#> <span class='message'>dosenum=dosenum();</span></div><div class='output co'>#> <span class='message'>Needed Covariates:</span></div><div class='output co'>#> <span class='message'>[1] "f_parent_to_A1" "CMT" </span></div><div class='output co'>#> <span class='error'>Error in (function (data, inits, PKpars, model = NULL, pred = NULL, err = NULL, lower = -Inf, upper = Inf, fixed = NULL, skipCov = NULL, control = foceiControl(), thetaNames = NULL, etaNames = NULL, etaMat = NULL, ..., env = NULL, keep = NULL, drop = NULL) { set.seed(control$seed) .pt <- proc.time() RxODE::.setWarnIdSort(FALSE) on.exit(RxODE::.setWarnIdSort(TRUE)) loadNamespace("n1qn1") if (!RxODE::rxIs(control, "foceiControl")) { control <- do.call(foceiControl, control) } if (is.null(env)) { .ret <- new.env(parent = emptyenv()) } else { .ret <- env } .ret$origData <- data .ret$etaNames <- etaNames .ret$thetaFixed <- fixed .ret$control <- control .ret$control$focei.mu.ref <- integer(0) if (is(model, "RxODE") || is(model, "character")) { .ret$ODEmodel <- TRUE if (class(pred) != "function") { stop("pred must be a function specifying the prediction variables in this model.") } } else { .ret$ODEmodel <- TRUE model <- RxODE::rxGetLin(PKpars) pred <- eval(parse(text = "function(){return(Central);}")) } .square <- function(x) x * x .ret$diagXformInv <- c(sqrt = ".square", log = "exp", identity = "identity")[control$diagXform] if (is.null(err)) { err <- eval(parse(text = paste0("function(){err", paste(inits$ERROR[[1]], collapse = ""), "}"))) } .covNames <- .parNames <- c() .ret$adjLik <- control$adjLik .mixed <- !is.null(inits$OMGA) && length(inits$OMGA) > 0 if (!exists("noLik", envir = .ret)) { .atol <- rep(control$atol, length(RxODE::rxModelVars(model)$state)) .rtol <- rep(control$rtol, length(RxODE::rxModelVars(model)$state)) .ssAtol <- rep(control$ssAtol, length(RxODE::rxModelVars(model)$state)) .ssRtol <- rep(control$ssRtol, length(RxODE::rxModelVars(model)$state)) .ret$model <- RxODE::rxSymPySetupPred(model, pred, PKpars, err, grad = (control$derivMethod == 2L), pred.minus.dv = TRUE, sum.prod = control$sumProd, theta.derivs = FALSE, optExpression = control$optExpression, interaction = (control$interaction == 1L), only.numeric = !.mixed, run.internal = TRUE, addProp = control$addProp) if (!is.null(.ret$model$inner)) { .atol <- c(.atol, rep(control$atolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.atol))) .rtol <- c(.rtol, rep(control$rtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.rtol))) .ret$control$rxControl$atol <- .atol .ret$control$rxControl$rtol <- .rtol .ssAtol <- c(.ssAtol, rep(control$ssAtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.ssAtol))) .ssRtol <- c(.ssRtol, rep(control$ssRtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.ssRtol))) .ret$control$rxControl$ssAtol <- .ssAtol .ret$control$rxControl$ssRtol <- .ssRtol } .covNames <- .parNames <- RxODE::rxParams(.ret$model$pred.only) .covNames <- .covNames[regexpr(rex::rex(start, or("THETA", "ETA"), "[", numbers, "]", end), .covNames) == -1] colnames(data) <- sapply(names(data), function(x) { if (any(x == .covNames)) { return(x) } else { return(toupper(x)) } }) .lhs <- c(names(RxODE::rxInits(.ret$model$pred.only)), RxODE::rxLhs(.ret$model$pred.only)) if (length(.lhs) > 0) { .covNames <- .covNames[regexpr(rex::rex(start, or(.lhs), end), .covNames) == -1] } if (length(.covNames) > 0) { if (!all(.covNames %in% names(data))) { message("Model:") RxODE::rxCat(.ret$model$pred.only) message("Needed Covariates:") nlmixrPrint(.covNames) stop("Not all the covariates are in the dataset.") } message("Needed Covariates:") print(.covNames) } .extraPars <- .ret$model$extra.pars } else { if (.ret$noLik) { .atol <- rep(control$atol, length(RxODE::rxModelVars(model)$state)) .rtol <- rep(control$rtol, length(RxODE::rxModelVars(model)$state)) .ret$model <- RxODE::rxSymPySetupPred(model, pred, PKpars, err, grad = FALSE, pred.minus.dv = TRUE, sum.prod = control$sumProd, theta.derivs = FALSE, optExpression = control$optExpression, run.internal = TRUE, only.numeric = TRUE, addProp = control$addProp) if (!is.null(.ret$model$inner)) { .atol <- c(.atol, rep(control$atolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.atol))) .rtol <- c(.rtol, rep(control$rtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.rtol))) .ret$control$rxControl$atol <- .atol .ret$control$rxControl$rtol <- .rtol } .covNames <- .parNames <- RxODE::rxParams(.ret$model$pred.only) .covNames <- .covNames[regexpr(rex::rex(start, or("THETA", "ETA"), "[", numbers, "]", end), .covNames) == -1] colnames(data) <- sapply(names(data), function(x) { if (any(x == .covNames)) { return(x) } else { return(toupper(x)) } }) .lhs <- c(names(RxODE::rxInits(.ret$model$pred.only)), RxODE::rxLhs(.ret$model$pred.only)) if (length(.lhs) > 0) { .covNames <- .covNames[regexpr(rex::rex(start, or(.lhs), end), .covNames) == -1] } if (length(.covNames) > 0) { if (!all(.covNames %in% names(data))) { message("Model:") RxODE::rxCat(.ret$model$pred.only) message("Needed Covariates:") nlmixrPrint(.covNames) stop("Not all the covariates are in the dataset.") } message("Needed Covariates:") print(.covNames) } .extraPars <- .ret$model$extra.pars } else { .extraPars <- NULL } } .ret$skipCov <- skipCov if (is.null(skipCov)) { if (is.null(fixed)) { .tmp <- rep(FALSE, length(inits$THTA)) } else { if (length(fixed) < length(inits$THTA)) { .tmp <- c(fixed, rep(FALSE, length(inits$THTA) - length(fixed))) } else { .tmp <- fixed[1:length(inits$THTA)] } } if (exists("uif", envir = .ret)) { .uifErr <- .ret$uif$ini$err[!is.na(.ret$uif$ini$ntheta)] .uifErr <- sapply(.uifErr, function(x) { if (is.na(x)) { return(FALSE) } return(!any(x == c("pow2", "tbs", "tbsYj"))) }) .tmp <- (.tmp | .uifErr) } .ret$skipCov <- c(.tmp, rep(TRUE, length(.extraPars))) .ret$control$focei.mu.ref <- .ret$uif$focei.mu.ref } if (is.null(.extraPars)) { .nms <- c(sprintf("THETA[%s]", seq_along(inits$THTA))) } else { .nms <- c(sprintf("THETA[%s]", seq_along(inits$THTA)), sprintf("ERR[%s]", seq_along(.extraPars))) } if (!is.null(thetaNames) && (length(inits$THTA) + length(.extraPars)) == length(thetaNames)) { .nms <- thetaNames } .ret$thetaNames <- .nms .thetaReset$thetaNames <- .nms if (length(lower) == 1) { lower <- rep(lower, length(inits$THTA)) } else if (length(lower) != length(inits$THTA)) { print(inits$THTA) print(lower) stop("Lower must be a single constant for all the THETA lower bounds, or match the dimension of THETA.") } if (length(upper) == 1) { upper <- rep(upper, length(inits$THTA)) } else if (length(lower) != length(inits$THTA)) { stop("Upper must be a single constant for all the THETA lower bounds, or match the dimension of THETA.") } if (!is.null(.extraPars)) { .ret$model$extra.pars <- eval(call(control$diagXform, .ret$model$extra.pars)) if (length(.ret$model$extra.pars) > 0) { inits$THTA <- c(inits$THTA, .ret$model$extra.pars) .lowerErr <- rep(control$atol[1] * 10, length(.ret$model$extra.pars)) .upperErr <- rep(Inf, length(.ret$model$extra.pars)) lower <- c(lower, .lowerErr) upper <- c(upper, .upperErr) } } if (is.null(data$ID)) stop("\"ID\" not found in data") if (is.null(data$DV)) stop("\"DV\" not found in data") if (is.null(data$EVID)) data$EVID <- 0 if (is.null(data$AMT)) data$AMT <- 0 for (.v in c("TIME", "AMT", "DV", .covNames)) { data[[.v]] <- as.double(data[[.v]]) } .ret$dataSav <- data .ds <- data[data$EVID != 0 & data$EVID != 2, c("ID", "TIME", "AMT", "EVID", .covNames)] .w <- which(tolower(names(data)) == "limit") .limitName <- NULL if (length(.w) == 1L) { .limitName <- names(data)[.w] } .censName <- NULL .w <- which(tolower(names(data)) == "cens") if (length(.w) == 1L) { .censName <- names(data[.w]) } data <- data[data$EVID == 0 | data$EVID == 2, c("ID", "TIME", "DV", "EVID", .covNames, .limitName, .censName)] .w <- which(!(names(.ret$dataSav) %in% c(.covNames, keep))) names(.ret$dataSav)[.w] <- tolower(names(.ret$dataSav[.w])) if (.mixed) { .lh <- .parseOM(inits$OMGA) .nlh <- sapply(.lh, length) .osplt <- rep(1:length(.lh), .nlh) .lini <- list(inits$THTA, unlist(.lh)) .nlini <- sapply(.lini, length) .nsplt <- rep(1:length(.lini), .nlini) .om0 <- .genOM(.lh) if (length(etaNames) == dim(.om0)[1]) { .ret$etaNames <- .ret$etaNames } else { .ret$etaNames <- sprintf("ETA[%d]", seq(1, dim(.om0)[1])) } .ret$rxInv <- RxODE::rxSymInvCholCreate(mat = .om0, diag.xform = control$diagXform) .ret$xType <- .ret$rxInv$xType .om0a <- .om0 .om0a <- .om0a/control$diagOmegaBoundLower .om0b <- .om0 .om0b <- .om0b * control$diagOmegaBoundUpper .om0a <- RxODE::rxSymInvCholCreate(mat = .om0a, diag.xform = control$diagXform) .om0b <- RxODE::rxSymInvCholCreate(mat = .om0b, diag.xform = control$diagXform) .omdf <- data.frame(a = .om0a$theta, m = .ret$rxInv$theta, b = .om0b$theta, diag = .om0a$theta.diag) .omdf$lower <- with(.omdf, ifelse(a > b, b, a)) .omdf$lower <- with(.omdf, ifelse(lower == m, -Inf, lower)) .omdf$lower <- with(.omdf, ifelse(!diag, -Inf, lower)) .omdf$upper <- with(.omdf, ifelse(a < b, b, a)) .omdf$upper <- with(.omdf, ifelse(upper == m, Inf, upper)) .omdf$upper <- with(.omdf, ifelse(!diag, Inf, upper)) .ret$control$nomega <- length(.omdf$lower) .ret$control$neta <- sum(.omdf$diag) .ret$control$ntheta <- length(lower) .ret$control$nfixed <- sum(fixed) lower <- c(lower, .omdf$lower) upper <- c(upper, .omdf$upper) } else { .ret$control$nomega <- 0 .ret$control$neta <- 0 .ret$xType <- -1 .ret$control$ntheta <- length(lower) .ret$control$nfixed <- sum(fixed) } .ret$lower <- lower .ret$upper <- upper .ret$thetaIni <- inits$THTA .scaleC <- double(length(lower)) if (is.null(control$scaleC)) { .scaleC <- rep(NA_real_, length(lower)) } else { .scaleC <- as.double(control$scaleC) if (length(lower) > length(.scaleC)) { .scaleC <- c(.scaleC, rep(NA_real_, length(lower) - length(.scaleC))) } else if (length(lower) < length(.scaleC)) { .scaleC <- .scaleC[seq(1, length(lower))] warning("scaleC control option has more options than estimated population parameters, please check.") } } .ret$scaleC <- .scaleC if (exists("uif", envir = .ret)) { .ini <- as.data.frame(.ret$uif$ini)[!is.na(.ret$uif$ini$err), c("est", "err", "ntheta")] for (.i in seq_along(.ini$err)) { if (is.na(.ret$scaleC[.ini$ntheta[.i]])) { if (any(.ini$err[.i] == c("boxCox", "yeoJohnson", "pow2", "tbs", "tbsYj"))) { .ret$scaleC[.ini$ntheta[.i]] <- 1 } else if (any(.ini$err[.i] == c("prop", "add", "norm", "dnorm", "logn", "dlogn", "lnorm", "dlnorm"))) { .ret$scaleC[.ini$ntheta[.i]] <- 0.5 * abs(.ini$est[.i]) } } } for (.i in .ini$model$extraProps$powTheta) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- 1 } .ini <- as.data.frame(.ret$uif$ini) for (.i in .ini$model$extraProps$factorial) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- abs(1/digamma(.ini$est[.i] + 1)) } for (.i in .ini$model$extraProps$gamma) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- abs(1/digamma(.ini$est[.i])) } for (.i in .ini$model$extraProps$log) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- log(abs(.ini$est[.i])) * abs(.ini$est[.i]) } for (.i in .ret$logitThetas) { .b <- .ret$logitThetasLow[.i] .c <- .ret$logitThetasHi[.i] .a <- .ini$est[.i] if (is.na(.ret$scaleC[.i])) { .ret$scaleC[.i] <- 1 * (-.b + .c) * exp(-.a)/((1 + exp(-.a))^2 * (.b + 1 * (-.b + .c)/(1 + exp(-.a)))) } } } names(.ret$thetaIni) <- sprintf("THETA[%d]", seq_along(.ret$thetaIni)) if (is.null(etaMat) & !is.null(control$etaMat)) { .ret$etaMat <- control$etaMat } else { .ret$etaMat <- etaMat } .ret$setupTime <- (proc.time() - .pt)["elapsed"] if (exists("uif", envir = .ret)) { .tmp <- .ret$uif$logThetasList .ret$logThetas <- .tmp[[1]] .ret$logThetasF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasList .ret$logitThetas <- .tmp[[1]] .ret$logitThetasF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasListLow .ret$logitThetasLow <- .tmp[[1]] .ret$logitThetasLowF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasListHi .ret$logitThetasHi <- .tmp[[1]] .ret$logitThetasHiF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasList .ret$probitThetas <- .tmp[[1]] .ret$probitThetasF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasListLow .ret$probitThetasLow <- .tmp[[1]] .ret$probitThetasLowF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasListHi .ret$probitThetasHi <- .tmp[[1]] .ret$probitThetasHiF <- .tmp[[2]] } else { .ret$logThetasF <- integer(0) .ret$logitThetasF <- integer(0) .ret$logitThetasHiF <- numeric(0) .ret$logitThetasLowF <- numeric(0) .ret$logitThetas <- integer(0) .ret$logitThetasHi <- numeric(0) .ret$logitThetasLow <- numeric(0) .ret$probitThetasF <- integer(0) .ret$probitThetasHiF <- numeric(0) .ret$probitThetasLowF <- numeric(0) .ret$probitThetas <- integer(0) .ret$probitThetasHi <- numeric(0) .ret$probitThetasLow <- numeric(0) } if (exists("noLik", envir = .ret)) { if (!.ret$noLik) { .ret$.params <- c(sprintf("THETA[%d]", seq_along(.ret$thetaIni)), sprintf("ETA[%d]", seq(1, dim(.om0)[1]))) .ret$.thetan <- length(.ret$thetaIni) .ret$nobs <- sum(data$EVID == 0) } } .ret$control$printTop <- TRUE .ret$control$nF <- 0 .est0 <- .ret$thetaIni if (!is.null(.ret$model$pred.nolhs)) { .ret$control$predNeq <- length(.ret$model$pred.nolhs$state) } else { .ret$control$predNeq <- 0L } .fitFun <- function(.ret) { this.env <- environment() assign("err", "theta reset", this.env) while (this.env$err == "theta reset") { assign("err", "", this.env) .ret0 <- tryCatch({ foceiFitCpp_(.ret) }, error = function(e) { if (regexpr("theta reset", e$message) != -1) { assign("zeroOuter", FALSE, this.env) assign("zeroGrad", FALSE, this.env) if (regexpr("theta reset0", e$message) != -1) { assign("zeroGrad", TRUE, this.env) } else if (regexpr("theta resetZ", e$message) != -1) { assign("zeroOuter", TRUE, this.env) } assign("err", "theta reset", this.env) } else { assign("err", e$message, this.env) } }) if (this.env$err == "theta reset") { .nm <- names(.ret$thetaIni) .ret$thetaIni <- setNames(.thetaReset$thetaIni + 0, .nm) .ret$rxInv$theta <- .thetaReset$omegaTheta .ret$control$printTop <- FALSE .ret$etaMat <- .thetaReset$etaMat .ret$control$etaMat <- .thetaReset$etaMat .ret$control$maxInnerIterations <- .thetaReset$maxInnerIterations .ret$control$nF <- .thetaReset$nF .ret$control$gillRetC <- .thetaReset$gillRetC .ret$control$gillRet <- .thetaReset$gillRet .ret$control$gillRet <- .thetaReset$gillRet .ret$control$gillDf <- .thetaReset$gillDf .ret$control$gillDf2 <- .thetaReset$gillDf2 .ret$control$gillErr <- .thetaReset$gillErr .ret$control$rEps <- .thetaReset$rEps .ret$control$aEps <- .thetaReset$aEps .ret$control$rEpsC <- .thetaReset$rEpsC .ret$control$aEpsC <- .thetaReset$aEpsC .ret$control$c1 <- .thetaReset$c1 .ret$control$c2 <- .thetaReset$c2 if (this.env$zeroOuter) { message("Posthoc reset") .ret$control$maxOuterIterations <- 0L } else if (this.env$zeroGrad) { message("Theta reset (zero gradient values); Switch to bobyqa") RxODE::rxReq("minqa") .ret$control$outerOptFun <- .bobyqa .ret$control$outerOpt <- -1L } else { message("Theta reset (ETA drift)") } } } if (this.env$err != "") { stop(this.env$err) } else { return(.ret0) } } .ret0 <- try(.fitFun(.ret)) .n <- 1 while (inherits(.ret0, "try-error") && control$maxOuterIterations != 0 && .n <= control$nRetries) { message(sprintf("Restart %s", .n)) .ret$control$nF <- 0 .estNew <- .est0 + 0.2 * .n * abs(.est0) * stats::runif(length(.est0)) - 0.1 * .n .estNew <- sapply(seq_along(.est0), function(.i) { if (.ret$thetaFixed[.i]) { return(.est0[.i]) } else if (.estNew[.i] < lower[.i]) { return(lower + (.Machine$double.eps)^(1/7)) } else if (.estNew[.i] > upper[.i]) { return(upper - (.Machine$double.eps)^(1/7)) } else { return(.estNew[.i]) } }) .ret$thetaIni <- .estNew .ret0 <- try(.fitFun(.ret)) .n <- .n + 1 } if (inherits(.ret0, "try-error")) stop("Could not fit data.") .ret <- .ret0 if (exists("parHistData", .ret)) { .tmp <- .ret$parHistData .tmp <- .tmp[.tmp$type == "Unscaled", names(.tmp) != "type"] .iter <- .tmp$iter .tmp <- .tmp[, names(.tmp) != "iter"] .ret$parHistStacked <- data.frame(stack(.tmp), iter = .iter) names(.ret$parHistStacked) <- c("val", "par", "iter") .ret$parHist <- data.frame(iter = .iter, .tmp) } if (.mixed) { .etas <- .ret$ranef .thetas <- .ret$fixef .pars <- .Call(`_nlmixr_nlmixrParameters`, .thetas, .etas) .ret$shrink <- .Call(`_nlmixr_calcShrinkOnly`, .ret$omega, .pars$eta.lst, length(.etas$ID)) .updateParFixed(.ret) } else { .updateParFixed(.ret) } if (!exists("table", .ret)) { .ret$table <- tableControl() } if (control$calcTables) { .ret <- addTable(.ret, updateObject = "no", keep = keep, drop = drop, table = .ret$table) } .ret})(data = dat, inits = .FoceiInits, PKpars = .pars, model = .mod, pred = function() { return(nlmixr_pred) }, err = uif$error, lower = uif$focei.lower, upper = uif$focei.upper, fixed = uif$focei.fixed, thetaNames = uif$focei.names, etaNames = uif$eta.names, control = control, env = env, keep = .keep, drop = .drop): Not all the covariates are in the dataset.</span></div><div class='output co'>#> <span class='message'>Timing stopped at: 6.584 0.393 6.976</span></div><div class='input'><span class='va'>f_nlmixr_dfop_sfo_saem_obs</span> <span class='op'><-</span> <span class='fu'><a href='https://rdrr.io/pkg/nlmixr/man/nlmixr.html'>nlmixr</a></span><span class='op'>(</span><span class='va'>f_mmkin_obs</span><span class='op'>[</span><span class='st'>"DFOP-SFO"</span>, <span class='op'>]</span>, est <span class='op'>=</span> <span class='st'>"saem"</span><span class='op'>)</span> +</div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> parameter labels from comments are typically ignored in non-interactive mode</span></div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> Need to run with the source intact to parse comments</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='message'>→ generate SAEM model</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='error'>Error in configsaem(model = model, data = dat, inits = inits, mcmc = .mcmc, ODEopt = .ODEopt, seed = .seed, distribution = .dist, DEBUG = .DEBUG, addProp = .addProp, tol = .tol, itmax = .itmax, type = .type, powRange = .powRange, lambdaRange = .lambdaRange): covariate(s) not found: f_parent_to_A1</span></div><div class='output co'>#> <span class='message'>Timing stopped at: 1.302 0.142 1.443</span></div><div class='input'><span class='va'>f_nlmixr_dfop_sfo_focei_obs</span> <span class='op'><-</span> <span class='fu'><a href='https://rdrr.io/pkg/nlmixr/man/nlmixr.html'>nlmixr</a></span><span class='op'>(</span><span class='va'>f_mmkin_obs</span><span class='op'>[</span><span class='st'>"DFOP-SFO"</span>, <span class='op'>]</span>, est <span class='op'>=</span> <span class='st'>"focei"</span><span class='op'>)</span> </div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> parameter labels from comments are typically ignored in non-interactive mode</span></div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> Need to run with the source intact to parse comments</span></div><div class='output co'>#> <span class='message'>→ creating full model...</span></div><div class='output co'>#> <span class='message'>→ pruning branches (<span style='color: #262626; background-color: #DADADA;'>`if`</span>/<span style='color: #262626; background-color: #DADADA;'>`else`</span>)...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ loading into <span style='color: #0000BB;'>symengine</span> environment...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ creating full model...</span></div><div class='output co'>#> <span class='message'>→ pruning branches (<span style='color: #262626; background-color: #DADADA;'>`if`</span>/<span style='color: #262626; background-color: #DADADA;'>`else`</span>)...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ loading into <span style='color: #0000BB;'>symengine</span> environment...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ calculate jacobian</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ calculate sensitivities</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ calculate ∂(f)/∂(η)</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ calculate ∂(R²)/∂(η)</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ finding duplicate expressions in inner model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ optimizing duplicate expressions in inner model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ finding duplicate expressions in EBE model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ optimizing duplicate expressions in EBE model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ compiling inner model...</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ finding duplicate expressions in FD model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ optimizing duplicate expressions in FD model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ compiling EBE model...</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ compiling events FD model...</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>Model:</span></div><div class='output co'>#> <span class='message'>cmt(parent);</span> #> <span class='message'>cmt(A1);</span> #> <span class='message'>rx_expr_6~ETA[1]+THETA[1];</span> @@ -4717,7 +4717,7 @@ obtained by fitting the same model to a list of datasets using <a href='mkinfit. #> <span class='message'>f_parent=1/(1+exp(-(ETA[3]+THETA[3])));</span> #> <span class='message'>g=1/(rx_expr_19);</span> #> <span class='message'>tad=tad();</span> -#> <span class='message'>dosenum=dosenum();</span></div><div class='output co'>#> <span class='message'>Needed Covariates:</span></div><div class='output co'>#> <span class='message'>[1] "f_parent_to_A1" "CMT" </span></div><div class='output co'>#> <span class='error'>Error in (function (data, inits, PKpars, model = NULL, pred = NULL, err = NULL, lower = -Inf, upper = Inf, fixed = NULL, skipCov = NULL, control = foceiControl(), thetaNames = NULL, etaNames = NULL, etaMat = NULL, ..., env = NULL, keep = NULL, drop = NULL) { set.seed(control$seed) .pt <- proc.time() RxODE::.setWarnIdSort(FALSE) on.exit(RxODE::.setWarnIdSort(TRUE)) loadNamespace("n1qn1") if (!RxODE::rxIs(control, "foceiControl")) { control <- do.call(foceiControl, control) } if (is.null(env)) { .ret <- new.env(parent = emptyenv()) } else { .ret <- env } .ret$origData <- data .ret$etaNames <- etaNames .ret$thetaFixed <- fixed .ret$control <- control .ret$control$focei.mu.ref <- integer(0) if (is(model, "RxODE") || is(model, "character")) { .ret$ODEmodel <- TRUE if (class(pred) != "function") { stop("pred must be a function specifying the prediction variables in this model.") } } else { .ret$ODEmodel <- TRUE model <- RxODE::rxGetLin(PKpars) pred <- eval(parse(text = "function(){return(Central);}")) } .square <- function(x) x * x .ret$diagXformInv <- c(sqrt = ".square", log = "exp", identity = "identity")[control$diagXform] if (is.null(err)) { err <- eval(parse(text = paste0("function(){err", paste(inits$ERROR[[1]], collapse = ""), "}"))) } .covNames <- .parNames <- c() .ret$adjLik <- control$adjLik .mixed <- !is.null(inits$OMGA) && length(inits$OMGA) > 0 if (!exists("noLik", envir = .ret)) { .atol <- rep(control$atol, length(RxODE::rxModelVars(model)$state)) .rtol <- rep(control$rtol, length(RxODE::rxModelVars(model)$state)) .ssAtol <- rep(control$ssAtol, length(RxODE::rxModelVars(model)$state)) .ssRtol <- rep(control$ssRtol, length(RxODE::rxModelVars(model)$state)) .ret$model <- RxODE::rxSymPySetupPred(model, pred, PKpars, err, grad = (control$derivMethod == 2L), pred.minus.dv = TRUE, sum.prod = control$sumProd, theta.derivs = FALSE, optExpression = control$optExpression, interaction = (control$interaction == 1L), only.numeric = !.mixed, run.internal = TRUE, addProp = control$addProp) if (!is.null(.ret$model$inner)) { .atol <- c(.atol, rep(control$atolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.atol))) .rtol <- c(.rtol, rep(control$rtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.rtol))) .ret$control$rxControl$atol <- .atol .ret$control$rxControl$rtol <- .rtol .ssAtol <- c(.ssAtol, rep(control$ssAtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.ssAtol))) .ssRtol <- c(.ssRtol, rep(control$ssRtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.ssRtol))) .ret$control$rxControl$ssAtol <- .ssAtol .ret$control$rxControl$ssRtol <- .ssRtol } .covNames <- .parNames <- RxODE::rxParams(.ret$model$pred.only) .covNames <- .covNames[regexpr(rex::rex(start, or("THETA", "ETA"), "[", numbers, "]", end), .covNames) == -1] colnames(data) <- sapply(names(data), function(x) { if (any(x == .covNames)) { return(x) } else { return(toupper(x)) } }) .lhs <- c(names(RxODE::rxInits(.ret$model$pred.only)), RxODE::rxLhs(.ret$model$pred.only)) if (length(.lhs) > 0) { .covNames <- .covNames[regexpr(rex::rex(start, or(.lhs), end), .covNames) == -1] } if (length(.covNames) > 0) { if (!all(.covNames %in% names(data))) { message("Model:") RxODE::rxCat(.ret$model$pred.only) message("Needed Covariates:") nlmixrPrint(.covNames) stop("Not all the covariates are in the dataset.") } message("Needed Covariates:") print(.covNames) } .extraPars <- .ret$model$extra.pars } else { if (.ret$noLik) { .atol <- rep(control$atol, length(RxODE::rxModelVars(model)$state)) .rtol <- rep(control$rtol, length(RxODE::rxModelVars(model)$state)) .ret$model <- RxODE::rxSymPySetupPred(model, pred, PKpars, err, grad = FALSE, pred.minus.dv = TRUE, sum.prod = control$sumProd, theta.derivs = FALSE, optExpression = control$optExpression, run.internal = TRUE, only.numeric = TRUE, addProp = control$addProp) if (!is.null(.ret$model$inner)) { .atol <- c(.atol, rep(control$atolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.atol))) .rtol <- c(.rtol, rep(control$rtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.rtol))) .ret$control$rxControl$atol <- .atol .ret$control$rxControl$rtol <- .rtol } .covNames <- .parNames <- RxODE::rxParams(.ret$model$pred.only) .covNames <- .covNames[regexpr(rex::rex(start, or("THETA", "ETA"), "[", numbers, "]", end), .covNames) == -1] colnames(data) <- sapply(names(data), function(x) { if (any(x == .covNames)) { return(x) } else { return(toupper(x)) } }) .lhs <- c(names(RxODE::rxInits(.ret$model$pred.only)), RxODE::rxLhs(.ret$model$pred.only)) if (length(.lhs) > 0) { .covNames <- .covNames[regexpr(rex::rex(start, or(.lhs), end), .covNames) == -1] } if (length(.covNames) > 0) { if (!all(.covNames %in% names(data))) { message("Model:") RxODE::rxCat(.ret$model$pred.only) message("Needed Covariates:") nlmixrPrint(.covNames) stop("Not all the covariates are in the dataset.") } message("Needed Covariates:") print(.covNames) } .extraPars <- .ret$model$extra.pars } else { .extraPars <- NULL } } .ret$skipCov <- skipCov if (is.null(skipCov)) { if (is.null(fixed)) { .tmp <- rep(FALSE, length(inits$THTA)) } else { if (length(fixed) < length(inits$THTA)) { .tmp <- c(fixed, rep(FALSE, length(inits$THTA) - length(fixed))) } else { .tmp <- fixed[1:length(inits$THTA)] } } if (exists("uif", envir = .ret)) { .uifErr <- .ret$uif$ini$err[!is.na(.ret$uif$ini$ntheta)] .uifErr <- sapply(.uifErr, function(x) { if (is.na(x)) { return(FALSE) } return(!any(x == c("pow2", "tbs", "tbsYj"))) }) .tmp <- (.tmp | .uifErr) } .ret$skipCov <- c(.tmp, rep(TRUE, length(.extraPars))) .ret$control$focei.mu.ref <- .ret$uif$focei.mu.ref } if (is.null(.extraPars)) { .nms <- c(sprintf("THETA[%s]", seq_along(inits$THTA))) } else { .nms <- c(sprintf("THETA[%s]", seq_along(inits$THTA)), sprintf("ERR[%s]", seq_along(.extraPars))) } if (!is.null(thetaNames) && (length(inits$THTA) + length(.extraPars)) == length(thetaNames)) { .nms <- thetaNames } .ret$thetaNames <- .nms .thetaReset$thetaNames <- .nms if (length(lower) == 1) { lower <- rep(lower, length(inits$THTA)) } else if (length(lower) != length(inits$THTA)) { print(inits$THTA) print(lower) stop("Lower must be a single constant for all the THETA lower bounds, or match the dimension of THETA.") } if (length(upper) == 1) { upper <- rep(upper, length(inits$THTA)) } else if (length(lower) != length(inits$THTA)) { stop("Upper must be a single constant for all the THETA lower bounds, or match the dimension of THETA.") } if (!is.null(.extraPars)) { .ret$model$extra.pars <- eval(call(control$diagXform, .ret$model$extra.pars)) if (length(.ret$model$extra.pars) > 0) { inits$THTA <- c(inits$THTA, .ret$model$extra.pars) .lowerErr <- rep(control$atol[1] * 10, length(.ret$model$extra.pars)) .upperErr <- rep(Inf, length(.ret$model$extra.pars)) lower <- c(lower, .lowerErr) upper <- c(upper, .upperErr) } } if (is.null(data$ID)) stop("\"ID\" not found in data") if (is.null(data$DV)) stop("\"DV\" not found in data") if (is.null(data$EVID)) data$EVID <- 0 if (is.null(data$AMT)) data$AMT <- 0 for (.v in c("TIME", "AMT", "DV", .covNames)) { data[[.v]] <- as.double(data[[.v]]) } .ret$dataSav <- data .ds <- data[data$EVID != 0 & data$EVID != 2, c("ID", "TIME", "AMT", "EVID", .covNames)] .w <- which(tolower(names(data)) == "limit") .limitName <- NULL if (length(.w) == 1L) { .limitName <- names(data)[.w] } .censName <- NULL .w <- which(tolower(names(data)) == "cens") if (length(.w) == 1L) { .censName <- names(data[.w]) } data <- data[data$EVID == 0 | data$EVID == 2, c("ID", "TIME", "DV", "EVID", .covNames, .limitName, .censName)] .w <- which(!(names(.ret$dataSav) %in% c(.covNames, keep))) names(.ret$dataSav)[.w] <- tolower(names(.ret$dataSav[.w])) if (.mixed) { .lh <- .parseOM(inits$OMGA) .nlh <- sapply(.lh, length) .osplt <- rep(1:length(.lh), .nlh) .lini <- list(inits$THTA, unlist(.lh)) .nlini <- sapply(.lini, length) .nsplt <- rep(1:length(.lini), .nlini) .om0 <- .genOM(.lh) if (length(etaNames) == dim(.om0)[1]) { .ret$etaNames <- .ret$etaNames } else { .ret$etaNames <- sprintf("ETA[%d]", seq(1, dim(.om0)[1])) } .ret$rxInv <- RxODE::rxSymInvCholCreate(mat = .om0, diag.xform = control$diagXform) .ret$xType <- .ret$rxInv$xType .om0a <- .om0 .om0a <- .om0a/control$diagOmegaBoundLower .om0b <- .om0 .om0b <- .om0b * control$diagOmegaBoundUpper .om0a <- RxODE::rxSymInvCholCreate(mat = .om0a, diag.xform = control$diagXform) .om0b <- RxODE::rxSymInvCholCreate(mat = .om0b, diag.xform = control$diagXform) .omdf <- data.frame(a = .om0a$theta, m = .ret$rxInv$theta, b = .om0b$theta, diag = .om0a$theta.diag) .omdf$lower <- with(.omdf, ifelse(a > b, b, a)) .omdf$lower <- with(.omdf, ifelse(lower == m, -Inf, lower)) .omdf$lower <- with(.omdf, ifelse(!diag, -Inf, lower)) .omdf$upper <- with(.omdf, ifelse(a < b, b, a)) .omdf$upper <- with(.omdf, ifelse(upper == m, Inf, upper)) .omdf$upper <- with(.omdf, ifelse(!diag, Inf, upper)) .ret$control$nomega <- length(.omdf$lower) .ret$control$neta <- sum(.omdf$diag) .ret$control$ntheta <- length(lower) .ret$control$nfixed <- sum(fixed) lower <- c(lower, .omdf$lower) upper <- c(upper, .omdf$upper) } else { .ret$control$nomega <- 0 .ret$control$neta <- 0 .ret$xType <- -1 .ret$control$ntheta <- length(lower) .ret$control$nfixed <- sum(fixed) } .ret$lower <- lower .ret$upper <- upper .ret$thetaIni <- inits$THTA .scaleC <- double(length(lower)) if (is.null(control$scaleC)) { .scaleC <- rep(NA_real_, length(lower)) } else { .scaleC <- as.double(control$scaleC) if (length(lower) > length(.scaleC)) { .scaleC <- c(.scaleC, rep(NA_real_, length(lower) - length(.scaleC))) } else if (length(lower) < length(.scaleC)) { .scaleC <- .scaleC[seq(1, length(lower))] warning("scaleC control option has more options than estimated population parameters, please check.") } } .ret$scaleC <- .scaleC if (exists("uif", envir = .ret)) { .ini <- as.data.frame(.ret$uif$ini)[!is.na(.ret$uif$ini$err), c("est", "err", "ntheta")] for (.i in seq_along(.ini$err)) { if (is.na(.ret$scaleC[.ini$ntheta[.i]])) { if (any(.ini$err[.i] == c("boxCox", "yeoJohnson", "pow2", "tbs", "tbsYj"))) { .ret$scaleC[.ini$ntheta[.i]] <- 1 } else if (any(.ini$err[.i] == c("prop", "add", "norm", "dnorm", "logn", "dlogn", "lnorm", "dlnorm"))) { .ret$scaleC[.ini$ntheta[.i]] <- 0.5 * abs(.ini$est[.i]) } } } for (.i in .ini$model$extraProps$powTheta) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- 1 } .ini <- as.data.frame(.ret$uif$ini) for (.i in .ini$model$extraProps$factorial) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- abs(1/digamma(.ini$est[.i] + 1)) } for (.i in .ini$model$extraProps$gamma) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- abs(1/digamma(.ini$est[.i])) } for (.i in .ini$model$extraProps$log) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- log(abs(.ini$est[.i])) * abs(.ini$est[.i]) } for (.i in .ret$logitThetas) { .b <- .ret$logitThetasLow[.i] .c <- .ret$logitThetasHi[.i] .a <- .ini$est[.i] if (is.na(.ret$scaleC[.i])) { .ret$scaleC[.i] <- 1 * (-.b + .c) * exp(-.a)/((1 + exp(-.a))^2 * (.b + 1 * (-.b + .c)/(1 + exp(-.a)))) } } } names(.ret$thetaIni) <- sprintf("THETA[%d]", seq_along(.ret$thetaIni)) if (is.null(etaMat) & !is.null(control$etaMat)) { .ret$etaMat <- control$etaMat } else { .ret$etaMat <- etaMat } .ret$setupTime <- (proc.time() - .pt)["elapsed"] if (exists("uif", envir = .ret)) { .tmp <- .ret$uif$logThetasList .ret$logThetas <- .tmp[[1]] .ret$logThetasF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasList .ret$logitThetas <- .tmp[[1]] .ret$logitThetasF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasListLow .ret$logitThetasLow <- .tmp[[1]] .ret$logitThetasLowF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasListHi .ret$logitThetasHi <- .tmp[[1]] .ret$logitThetasHiF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasList .ret$probitThetas <- .tmp[[1]] .ret$probitThetasF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasListLow .ret$probitThetasLow <- .tmp[[1]] .ret$probitThetasLowF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasListHi .ret$probitThetasHi <- .tmp[[1]] .ret$probitThetasHiF <- .tmp[[2]] } else { .ret$logThetasF <- integer(0) .ret$logitThetasF <- integer(0) .ret$logitThetasHiF <- numeric(0) .ret$logitThetasLowF <- numeric(0) .ret$logitThetas <- integer(0) .ret$logitThetasHi <- numeric(0) .ret$logitThetasLow <- numeric(0) .ret$probitThetasF <- integer(0) .ret$probitThetasHiF <- numeric(0) .ret$probitThetasLowF <- numeric(0) .ret$probitThetas <- integer(0) .ret$probitThetasHi <- numeric(0) .ret$probitThetasLow <- numeric(0) } if (exists("noLik", envir = .ret)) { if (!.ret$noLik) { .ret$.params <- c(sprintf("THETA[%d]", seq_along(.ret$thetaIni)), sprintf("ETA[%d]", seq(1, dim(.om0)[1]))) .ret$.thetan <- length(.ret$thetaIni) .ret$nobs <- sum(data$EVID == 0) } } .ret$control$printTop <- TRUE .ret$control$nF <- 0 .est0 <- .ret$thetaIni if (!is.null(.ret$model$pred.nolhs)) { .ret$control$predNeq <- length(.ret$model$pred.nolhs$state) } else { .ret$control$predNeq <- 0L } .fitFun <- function(.ret) { this.env <- environment() assign("err", "theta reset", this.env) while (this.env$err == "theta reset") { assign("err", "", this.env) .ret0 <- tryCatch({ foceiFitCpp_(.ret) }, error = function(e) { if (regexpr("theta reset", e$message) != -1) { assign("zeroOuter", FALSE, this.env) assign("zeroGrad", FALSE, this.env) if (regexpr("theta reset0", e$message) != -1) { assign("zeroGrad", TRUE, this.env) } else if (regexpr("theta resetZ", e$message) != -1) { assign("zeroOuter", TRUE, this.env) } assign("err", "theta reset", this.env) } else { assign("err", e$message, this.env) } }) if (this.env$err == "theta reset") { .nm <- names(.ret$thetaIni) .ret$thetaIni <- setNames(.thetaReset$thetaIni + 0, .nm) .ret$rxInv$theta <- .thetaReset$omegaTheta .ret$control$printTop <- FALSE .ret$etaMat <- .thetaReset$etaMat .ret$control$etaMat <- .thetaReset$etaMat .ret$control$maxInnerIterations <- .thetaReset$maxInnerIterations .ret$control$nF <- .thetaReset$nF .ret$control$gillRetC <- .thetaReset$gillRetC .ret$control$gillRet <- .thetaReset$gillRet .ret$control$gillRet <- .thetaReset$gillRet .ret$control$gillDf <- .thetaReset$gillDf .ret$control$gillDf2 <- .thetaReset$gillDf2 .ret$control$gillErr <- .thetaReset$gillErr .ret$control$rEps <- .thetaReset$rEps .ret$control$aEps <- .thetaReset$aEps .ret$control$rEpsC <- .thetaReset$rEpsC .ret$control$aEpsC <- .thetaReset$aEpsC .ret$control$c1 <- .thetaReset$c1 .ret$control$c2 <- .thetaReset$c2 if (this.env$zeroOuter) { message("Posthoc reset") .ret$control$maxOuterIterations <- 0L } else if (this.env$zeroGrad) { message("Theta reset (zero gradient values); Switch to bobyqa") RxODE::rxReq("minqa") .ret$control$outerOptFun <- .bobyqa .ret$control$outerOpt <- -1L } else { message("Theta reset (ETA drift)") } } } if (this.env$err != "") { stop(this.env$err) } else { return(.ret0) } } .ret0 <- try(.fitFun(.ret)) .n <- 1 while (inherits(.ret0, "try-error") && control$maxOuterIterations != 0 && .n <= control$nRetries) { message(sprintf("Restart %s", .n)) .ret$control$nF <- 0 .estNew <- .est0 + 0.2 * .n * abs(.est0) * stats::runif(length(.est0)) - 0.1 * .n .estNew <- sapply(seq_along(.est0), function(.i) { if (.ret$thetaFixed[.i]) { return(.est0[.i]) } else if (.estNew[.i] < lower[.i]) { return(lower + (.Machine$double.eps)^(1/7)) } else if (.estNew[.i] > upper[.i]) { return(upper - (.Machine$double.eps)^(1/7)) } else { return(.estNew[.i]) } }) .ret$thetaIni <- .estNew .ret0 <- try(.fitFun(.ret)) .n <- .n + 1 } if (inherits(.ret0, "try-error")) stop("Could not fit data.") .ret <- .ret0 if (exists("parHistData", .ret)) { .tmp <- .ret$parHistData .tmp <- .tmp[.tmp$type == "Unscaled", names(.tmp) != "type"] .iter <- .tmp$iter .tmp <- .tmp[, names(.tmp) != "iter"] .ret$parHistStacked <- data.frame(stack(.tmp), iter = .iter) names(.ret$parHistStacked) <- c("val", "par", "iter") .ret$parHist <- data.frame(iter = .iter, .tmp) } if (.mixed) { .etas <- .ret$ranef .thetas <- .ret$fixef .pars <- .Call(`_nlmixr_nlmixrParameters`, .thetas, .etas) .ret$shrink <- .Call(`_nlmixr_calcShrinkOnly`, .ret$omega, .pars$eta.lst, length(.etas$ID)) .updateParFixed(.ret) } else { .updateParFixed(.ret) } if (!exists("table", .ret)) { .ret$table <- tableControl() } if (control$calcTables) { .ret <- addTable(.ret, updateObject = "no", keep = keep, drop = drop, table = .ret$table) } .ret})(data = dat, inits = .FoceiInits, PKpars = .pars, model = .mod, pred = function() { return(nlmixr_pred) }, err = uif$error, lower = uif$focei.lower, upper = uif$focei.upper, fixed = uif$focei.fixed, thetaNames = uif$focei.names, etaNames = uif$eta.names, control = control, env = env, keep = .keep, drop = .drop): Not all the covariates are in the dataset.</span></div><div class='output co'>#> <span class='message'>Timing stopped at: 15.17 0.353 15.52</span></div><div class='input'> +#> <span class='message'>dosenum=dosenum();</span></div><div class='output co'>#> <span class='message'>Needed Covariates:</span></div><div class='output co'>#> <span class='message'>[1] "f_parent_to_A1" "CMT" </span></div><div class='output co'>#> <span class='error'>Error in (function (data, inits, PKpars, model = NULL, pred = NULL, err = NULL, lower = -Inf, upper = Inf, fixed = NULL, skipCov = NULL, control = foceiControl(), thetaNames = NULL, etaNames = NULL, etaMat = NULL, ..., env = NULL, keep = NULL, drop = NULL) { set.seed(control$seed) .pt <- proc.time() RxODE::.setWarnIdSort(FALSE) on.exit(RxODE::.setWarnIdSort(TRUE)) loadNamespace("n1qn1") if (!RxODE::rxIs(control, "foceiControl")) { control <- do.call(foceiControl, control) } if (is.null(env)) { .ret <- new.env(parent = emptyenv()) } else { .ret <- env } .ret$origData <- data .ret$etaNames <- etaNames .ret$thetaFixed <- fixed .ret$control <- control .ret$control$focei.mu.ref <- integer(0) if (is(model, "RxODE") || is(model, "character")) { .ret$ODEmodel <- TRUE if (class(pred) != "function") { stop("pred must be a function specifying the prediction variables in this model.") } } else { .ret$ODEmodel <- TRUE model <- RxODE::rxGetLin(PKpars) pred <- eval(parse(text = "function(){return(Central);}")) } .square <- function(x) x * x .ret$diagXformInv <- c(sqrt = ".square", log = "exp", identity = "identity")[control$diagXform] if (is.null(err)) { err <- eval(parse(text = paste0("function(){err", paste(inits$ERROR[[1]], collapse = ""), "}"))) } .covNames <- .parNames <- c() .ret$adjLik <- control$adjLik .mixed <- !is.null(inits$OMGA) && length(inits$OMGA) > 0 if (!exists("noLik", envir = .ret)) { .atol <- rep(control$atol, length(RxODE::rxModelVars(model)$state)) .rtol <- rep(control$rtol, length(RxODE::rxModelVars(model)$state)) .ssAtol <- rep(control$ssAtol, length(RxODE::rxModelVars(model)$state)) .ssRtol <- rep(control$ssRtol, length(RxODE::rxModelVars(model)$state)) .ret$model <- RxODE::rxSymPySetupPred(model, pred, PKpars, err, grad = (control$derivMethod == 2L), pred.minus.dv = TRUE, sum.prod = control$sumProd, theta.derivs = FALSE, optExpression = control$optExpression, interaction = (control$interaction == 1L), only.numeric = !.mixed, run.internal = TRUE, addProp = control$addProp) if (!is.null(.ret$model$inner)) { .atol <- c(.atol, rep(control$atolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.atol))) .rtol <- c(.rtol, rep(control$rtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.rtol))) .ret$control$rxControl$atol <- .atol .ret$control$rxControl$rtol <- .rtol .ssAtol <- c(.ssAtol, rep(control$ssAtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.ssAtol))) .ssRtol <- c(.ssRtol, rep(control$ssRtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.ssRtol))) .ret$control$rxControl$ssAtol <- .ssAtol .ret$control$rxControl$ssRtol <- .ssRtol } .covNames <- .parNames <- RxODE::rxParams(.ret$model$pred.only) .covNames <- .covNames[regexpr(rex::rex(start, or("THETA", "ETA"), "[", numbers, "]", end), .covNames) == -1] colnames(data) <- sapply(names(data), function(x) { if (any(x == .covNames)) { return(x) } else { return(toupper(x)) } }) .lhs <- c(names(RxODE::rxInits(.ret$model$pred.only)), RxODE::rxLhs(.ret$model$pred.only)) if (length(.lhs) > 0) { .covNames <- .covNames[regexpr(rex::rex(start, or(.lhs), end), .covNames) == -1] } if (length(.covNames) > 0) { if (!all(.covNames %in% names(data))) { message("Model:") RxODE::rxCat(.ret$model$pred.only) message("Needed Covariates:") nlmixrPrint(.covNames) stop("Not all the covariates are in the dataset.") } message("Needed Covariates:") print(.covNames) } .extraPars <- .ret$model$extra.pars } else { if (.ret$noLik) { .atol <- rep(control$atol, length(RxODE::rxModelVars(model)$state)) .rtol <- rep(control$rtol, length(RxODE::rxModelVars(model)$state)) .ret$model <- RxODE::rxSymPySetupPred(model, pred, PKpars, err, grad = FALSE, pred.minus.dv = TRUE, sum.prod = control$sumProd, theta.derivs = FALSE, optExpression = control$optExpression, run.internal = TRUE, only.numeric = TRUE, addProp = control$addProp) if (!is.null(.ret$model$inner)) { .atol <- c(.atol, rep(control$atolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.atol))) .rtol <- c(.rtol, rep(control$rtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.rtol))) .ret$control$rxControl$atol <- .atol .ret$control$rxControl$rtol <- .rtol } .covNames <- .parNames <- RxODE::rxParams(.ret$model$pred.only) .covNames <- .covNames[regexpr(rex::rex(start, or("THETA", "ETA"), "[", numbers, "]", end), .covNames) == -1] colnames(data) <- sapply(names(data), function(x) { if (any(x == .covNames)) { return(x) } else { return(toupper(x)) } }) .lhs <- c(names(RxODE::rxInits(.ret$model$pred.only)), RxODE::rxLhs(.ret$model$pred.only)) if (length(.lhs) > 0) { .covNames <- .covNames[regexpr(rex::rex(start, or(.lhs), end), .covNames) == -1] } if (length(.covNames) > 0) { if (!all(.covNames %in% names(data))) { message("Model:") RxODE::rxCat(.ret$model$pred.only) message("Needed Covariates:") nlmixrPrint(.covNames) stop("Not all the covariates are in the dataset.") } message("Needed Covariates:") print(.covNames) } .extraPars <- .ret$model$extra.pars } else { .extraPars <- NULL } } .ret$skipCov <- skipCov if (is.null(skipCov)) { if (is.null(fixed)) { .tmp <- rep(FALSE, length(inits$THTA)) } else { if (length(fixed) < length(inits$THTA)) { .tmp <- c(fixed, rep(FALSE, length(inits$THTA) - length(fixed))) } else { .tmp <- fixed[1:length(inits$THTA)] } } if (exists("uif", envir = .ret)) { .uifErr <- .ret$uif$ini$err[!is.na(.ret$uif$ini$ntheta)] .uifErr <- sapply(.uifErr, function(x) { if (is.na(x)) { return(FALSE) } return(!any(x == c("pow2", "tbs", "tbsYj"))) }) .tmp <- (.tmp | .uifErr) } .ret$skipCov <- c(.tmp, rep(TRUE, length(.extraPars))) .ret$control$focei.mu.ref <- .ret$uif$focei.mu.ref } if (is.null(.extraPars)) { .nms <- c(sprintf("THETA[%s]", seq_along(inits$THTA))) } else { .nms <- c(sprintf("THETA[%s]", seq_along(inits$THTA)), sprintf("ERR[%s]", seq_along(.extraPars))) } if (!is.null(thetaNames) && (length(inits$THTA) + length(.extraPars)) == length(thetaNames)) { .nms <- thetaNames } .ret$thetaNames <- .nms .thetaReset$thetaNames <- .nms if (length(lower) == 1) { lower <- rep(lower, length(inits$THTA)) } else if (length(lower) != length(inits$THTA)) { print(inits$THTA) print(lower) stop("Lower must be a single constant for all the THETA lower bounds, or match the dimension of THETA.") } if (length(upper) == 1) { upper <- rep(upper, length(inits$THTA)) } else if (length(lower) != length(inits$THTA)) { stop("Upper must be a single constant for all the THETA lower bounds, or match the dimension of THETA.") } if (!is.null(.extraPars)) { .ret$model$extra.pars <- eval(call(control$diagXform, .ret$model$extra.pars)) if (length(.ret$model$extra.pars) > 0) { inits$THTA <- c(inits$THTA, .ret$model$extra.pars) .lowerErr <- rep(control$atol[1] * 10, length(.ret$model$extra.pars)) .upperErr <- rep(Inf, length(.ret$model$extra.pars)) lower <- c(lower, .lowerErr) upper <- c(upper, .upperErr) } } if (is.null(data$ID)) stop("\"ID\" not found in data") if (is.null(data$DV)) stop("\"DV\" not found in data") if (is.null(data$EVID)) data$EVID <- 0 if (is.null(data$AMT)) data$AMT <- 0 for (.v in c("TIME", "AMT", "DV", .covNames)) { data[[.v]] <- as.double(data[[.v]]) } .ret$dataSav <- data .ds <- data[data$EVID != 0 & data$EVID != 2, c("ID", "TIME", "AMT", "EVID", .covNames)] .w <- which(tolower(names(data)) == "limit") .limitName <- NULL if (length(.w) == 1L) { .limitName <- names(data)[.w] } .censName <- NULL .w <- which(tolower(names(data)) == "cens") if (length(.w) == 1L) { .censName <- names(data[.w]) } data <- data[data$EVID == 0 | data$EVID == 2, c("ID", "TIME", "DV", "EVID", .covNames, .limitName, .censName)] .w <- which(!(names(.ret$dataSav) %in% c(.covNames, keep))) names(.ret$dataSav)[.w] <- tolower(names(.ret$dataSav[.w])) if (.mixed) { .lh <- .parseOM(inits$OMGA) .nlh <- sapply(.lh, length) .osplt <- rep(1:length(.lh), .nlh) .lini <- list(inits$THTA, unlist(.lh)) .nlini <- sapply(.lini, length) .nsplt <- rep(1:length(.lini), .nlini) .om0 <- .genOM(.lh) if (length(etaNames) == dim(.om0)[1]) { .ret$etaNames <- .ret$etaNames } else { .ret$etaNames <- sprintf("ETA[%d]", seq(1, dim(.om0)[1])) } .ret$rxInv <- RxODE::rxSymInvCholCreate(mat = .om0, diag.xform = control$diagXform) .ret$xType <- .ret$rxInv$xType .om0a <- .om0 .om0a <- .om0a/control$diagOmegaBoundLower .om0b <- .om0 .om0b <- .om0b * control$diagOmegaBoundUpper .om0a <- RxODE::rxSymInvCholCreate(mat = .om0a, diag.xform = control$diagXform) .om0b <- RxODE::rxSymInvCholCreate(mat = .om0b, diag.xform = control$diagXform) .omdf <- data.frame(a = .om0a$theta, m = .ret$rxInv$theta, b = .om0b$theta, diag = .om0a$theta.diag) .omdf$lower <- with(.omdf, ifelse(a > b, b, a)) .omdf$lower <- with(.omdf, ifelse(lower == m, -Inf, lower)) .omdf$lower <- with(.omdf, ifelse(!diag, -Inf, lower)) .omdf$upper <- with(.omdf, ifelse(a < b, b, a)) .omdf$upper <- with(.omdf, ifelse(upper == m, Inf, upper)) .omdf$upper <- with(.omdf, ifelse(!diag, Inf, upper)) .ret$control$nomega <- length(.omdf$lower) .ret$control$neta <- sum(.omdf$diag) .ret$control$ntheta <- length(lower) .ret$control$nfixed <- sum(fixed) lower <- c(lower, .omdf$lower) upper <- c(upper, .omdf$upper) } else { .ret$control$nomega <- 0 .ret$control$neta <- 0 .ret$xType <- -1 .ret$control$ntheta <- length(lower) .ret$control$nfixed <- sum(fixed) } .ret$lower <- lower .ret$upper <- upper .ret$thetaIni <- inits$THTA .scaleC <- double(length(lower)) if (is.null(control$scaleC)) { .scaleC <- rep(NA_real_, length(lower)) } else { .scaleC <- as.double(control$scaleC) if (length(lower) > length(.scaleC)) { .scaleC <- c(.scaleC, rep(NA_real_, length(lower) - length(.scaleC))) } else if (length(lower) < length(.scaleC)) { .scaleC <- .scaleC[seq(1, length(lower))] warning("scaleC control option has more options than estimated population parameters, please check.") } } .ret$scaleC <- .scaleC if (exists("uif", envir = .ret)) { .ini <- as.data.frame(.ret$uif$ini)[!is.na(.ret$uif$ini$err), c("est", "err", "ntheta")] for (.i in seq_along(.ini$err)) { if (is.na(.ret$scaleC[.ini$ntheta[.i]])) { if (any(.ini$err[.i] == c("boxCox", "yeoJohnson", "pow2", "tbs", "tbsYj"))) { .ret$scaleC[.ini$ntheta[.i]] <- 1 } else if (any(.ini$err[.i] == c("prop", "add", "norm", "dnorm", "logn", "dlogn", "lnorm", "dlnorm"))) { .ret$scaleC[.ini$ntheta[.i]] <- 0.5 * abs(.ini$est[.i]) } } } for (.i in .ini$model$extraProps$powTheta) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- 1 } .ini <- as.data.frame(.ret$uif$ini) for (.i in .ini$model$extraProps$factorial) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- abs(1/digamma(.ini$est[.i] + 1)) } for (.i in .ini$model$extraProps$gamma) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- abs(1/digamma(.ini$est[.i])) } for (.i in .ini$model$extraProps$log) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- log(abs(.ini$est[.i])) * abs(.ini$est[.i]) } for (.i in .ret$logitThetas) { .b <- .ret$logitThetasLow[.i] .c <- .ret$logitThetasHi[.i] .a <- .ini$est[.i] if (is.na(.ret$scaleC[.i])) { .ret$scaleC[.i] <- 1 * (-.b + .c) * exp(-.a)/((1 + exp(-.a))^2 * (.b + 1 * (-.b + .c)/(1 + exp(-.a)))) } } } names(.ret$thetaIni) <- sprintf("THETA[%d]", seq_along(.ret$thetaIni)) if (is.null(etaMat) & !is.null(control$etaMat)) { .ret$etaMat <- control$etaMat } else { .ret$etaMat <- etaMat } .ret$setupTime <- (proc.time() - .pt)["elapsed"] if (exists("uif", envir = .ret)) { .tmp <- .ret$uif$logThetasList .ret$logThetas <- .tmp[[1]] .ret$logThetasF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasList .ret$logitThetas <- .tmp[[1]] .ret$logitThetasF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasListLow .ret$logitThetasLow <- .tmp[[1]] .ret$logitThetasLowF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasListHi .ret$logitThetasHi <- .tmp[[1]] .ret$logitThetasHiF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasList .ret$probitThetas <- .tmp[[1]] .ret$probitThetasF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasListLow .ret$probitThetasLow <- .tmp[[1]] .ret$probitThetasLowF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasListHi .ret$probitThetasHi <- .tmp[[1]] .ret$probitThetasHiF <- .tmp[[2]] } else { .ret$logThetasF <- integer(0) .ret$logitThetasF <- integer(0) .ret$logitThetasHiF <- numeric(0) .ret$logitThetasLowF <- numeric(0) .ret$logitThetas <- integer(0) .ret$logitThetasHi <- numeric(0) .ret$logitThetasLow <- numeric(0) .ret$probitThetasF <- integer(0) .ret$probitThetasHiF <- numeric(0) .ret$probitThetasLowF <- numeric(0) .ret$probitThetas <- integer(0) .ret$probitThetasHi <- numeric(0) .ret$probitThetasLow <- numeric(0) } if (exists("noLik", envir = .ret)) { if (!.ret$noLik) { .ret$.params <- c(sprintf("THETA[%d]", seq_along(.ret$thetaIni)), sprintf("ETA[%d]", seq(1, dim(.om0)[1]))) .ret$.thetan <- length(.ret$thetaIni) .ret$nobs <- sum(data$EVID == 0) } } .ret$control$printTop <- TRUE .ret$control$nF <- 0 .est0 <- .ret$thetaIni if (!is.null(.ret$model$pred.nolhs)) { .ret$control$predNeq <- length(.ret$model$pred.nolhs$state) } else { .ret$control$predNeq <- 0L } .fitFun <- function(.ret) { this.env <- environment() assign("err", "theta reset", this.env) while (this.env$err == "theta reset") { assign("err", "", this.env) .ret0 <- tryCatch({ foceiFitCpp_(.ret) }, error = function(e) { if (regexpr("theta reset", e$message) != -1) { assign("zeroOuter", FALSE, this.env) assign("zeroGrad", FALSE, this.env) if (regexpr("theta reset0", e$message) != -1) { assign("zeroGrad", TRUE, this.env) } else if (regexpr("theta resetZ", e$message) != -1) { assign("zeroOuter", TRUE, this.env) } assign("err", "theta reset", this.env) } else { assign("err", e$message, this.env) } }) if (this.env$err == "theta reset") { .nm <- names(.ret$thetaIni) .ret$thetaIni <- setNames(.thetaReset$thetaIni + 0, .nm) .ret$rxInv$theta <- .thetaReset$omegaTheta .ret$control$printTop <- FALSE .ret$etaMat <- .thetaReset$etaMat .ret$control$etaMat <- .thetaReset$etaMat .ret$control$maxInnerIterations <- .thetaReset$maxInnerIterations .ret$control$nF <- .thetaReset$nF .ret$control$gillRetC <- .thetaReset$gillRetC .ret$control$gillRet <- .thetaReset$gillRet .ret$control$gillRet <- .thetaReset$gillRet .ret$control$gillDf <- .thetaReset$gillDf .ret$control$gillDf2 <- .thetaReset$gillDf2 .ret$control$gillErr <- .thetaReset$gillErr .ret$control$rEps <- .thetaReset$rEps .ret$control$aEps <- .thetaReset$aEps .ret$control$rEpsC <- .thetaReset$rEpsC .ret$control$aEpsC <- .thetaReset$aEpsC .ret$control$c1 <- .thetaReset$c1 .ret$control$c2 <- .thetaReset$c2 if (this.env$zeroOuter) { message("Posthoc reset") .ret$control$maxOuterIterations <- 0L } else if (this.env$zeroGrad) { message("Theta reset (zero gradient values); Switch to bobyqa") RxODE::rxReq("minqa") .ret$control$outerOptFun <- .bobyqa .ret$control$outerOpt <- -1L } else { message("Theta reset (ETA drift)") } } } if (this.env$err != "") { stop(this.env$err) } else { return(.ret0) } } .ret0 <- try(.fitFun(.ret)) .n <- 1 while (inherits(.ret0, "try-error") && control$maxOuterIterations != 0 && .n <= control$nRetries) { message(sprintf("Restart %s", .n)) .ret$control$nF <- 0 .estNew <- .est0 + 0.2 * .n * abs(.est0) * stats::runif(length(.est0)) - 0.1 * .n .estNew <- sapply(seq_along(.est0), function(.i) { if (.ret$thetaFixed[.i]) { return(.est0[.i]) } else if (.estNew[.i] < lower[.i]) { return(lower + (.Machine$double.eps)^(1/7)) } else if (.estNew[.i] > upper[.i]) { return(upper - (.Machine$double.eps)^(1/7)) } else { return(.estNew[.i]) } }) .ret$thetaIni <- .estNew .ret0 <- try(.fitFun(.ret)) .n <- .n + 1 } if (inherits(.ret0, "try-error")) stop("Could not fit data.") .ret <- .ret0 if (exists("parHistData", .ret)) { .tmp <- .ret$parHistData .tmp <- .tmp[.tmp$type == "Unscaled", names(.tmp) != "type"] .iter <- .tmp$iter .tmp <- .tmp[, names(.tmp) != "iter"] .ret$parHistStacked <- data.frame(stack(.tmp), iter = .iter) names(.ret$parHistStacked) <- c("val", "par", "iter") .ret$parHist <- data.frame(iter = .iter, .tmp) } if (.mixed) { .etas <- .ret$ranef .thetas <- .ret$fixef .pars <- .Call(`_nlmixr_nlmixrParameters`, .thetas, .etas) .ret$shrink <- .Call(`_nlmixr_calcShrinkOnly`, .ret$omega, .pars$eta.lst, length(.etas$ID)) .updateParFixed(.ret) } else { .updateParFixed(.ret) } if (!exists("table", .ret)) { .ret$table <- tableControl() } if (control$calcTables) { .ret <- addTable(.ret, updateObject = "no", keep = keep, drop = drop, table = .ret$table) } .ret})(data = dat, inits = .FoceiInits, PKpars = .pars, model = .mod, pred = function() { return(nlmixr_pred) }, err = uif$error, lower = uif$focei.lower, upper = uif$focei.upper, fixed = uif$focei.fixed, thetaNames = uif$focei.names, etaNames = uif$eta.names, control = control, env = env, keep = .keep, drop = .drop): Not all the covariates are in the dataset.</span></div><div class='output co'>#> <span class='message'>Timing stopped at: 14.58 0.482 15.06</span></div><div class='input'> <span class='co'># Identical two-component error for all variables is only possible with</span> <span class='co'># est = 'focei' in nlmixr</span> <span class='va'>f_nlmixr_fomc_sfo_focei_tc</span> <span class='op'><-</span> <span class='fu'><a href='https://rdrr.io/pkg/nlmixr/man/nlmixr.html'>nlmixr</a></span><span class='op'>(</span><span class='va'>f_mmkin_tc</span><span class='op'>[</span><span class='st'>"FOMC-SFO"</span>, <span class='op'>]</span>, est <span class='op'>=</span> <span class='st'>"focei"</span><span class='op'>)</span> @@ -4771,7 +4771,7 @@ obtained by fitting the same model to a list of datasets using <a href='mkinfit. #> <span class='message'>beta=exp(rx_expr_8);</span> #> <span class='message'>f_parent=1/(1+exp(-(ETA[3]+THETA[3])));</span> #> <span class='message'>tad=tad();</span> -#> <span class='message'>dosenum=dosenum();</span></div><div class='output co'>#> <span class='message'>Needed Covariates:</span></div><div class='output co'>#> <span class='message'>[1] "f_parent_to_A1" "CMT" </span></div><div class='output co'>#> <span class='error'>Error in (function (data, inits, PKpars, model = NULL, pred = NULL, err = NULL, lower = -Inf, upper = Inf, fixed = NULL, skipCov = NULL, control = foceiControl(), thetaNames = NULL, etaNames = NULL, etaMat = NULL, ..., env = NULL, keep = NULL, drop = NULL) { set.seed(control$seed) .pt <- proc.time() RxODE::.setWarnIdSort(FALSE) on.exit(RxODE::.setWarnIdSort(TRUE)) loadNamespace("n1qn1") if (!RxODE::rxIs(control, "foceiControl")) { control <- do.call(foceiControl, control) } if (is.null(env)) { .ret <- new.env(parent = emptyenv()) } else { .ret <- env } .ret$origData <- data .ret$etaNames <- etaNames .ret$thetaFixed <- fixed .ret$control <- control .ret$control$focei.mu.ref <- integer(0) if (is(model, "RxODE") || is(model, "character")) { .ret$ODEmodel <- TRUE if (class(pred) != "function") { stop("pred must be a function specifying the prediction variables in this model.") } } else { .ret$ODEmodel <- TRUE model <- RxODE::rxGetLin(PKpars) pred <- eval(parse(text = "function(){return(Central);}")) } .square <- function(x) x * x .ret$diagXformInv <- c(sqrt = ".square", log = "exp", identity = "identity")[control$diagXform] if (is.null(err)) { err <- eval(parse(text = paste0("function(){err", paste(inits$ERROR[[1]], collapse = ""), "}"))) } .covNames <- .parNames <- c() .ret$adjLik <- control$adjLik .mixed <- !is.null(inits$OMGA) && length(inits$OMGA) > 0 if (!exists("noLik", envir = .ret)) { .atol <- rep(control$atol, length(RxODE::rxModelVars(model)$state)) .rtol <- rep(control$rtol, length(RxODE::rxModelVars(model)$state)) .ssAtol <- rep(control$ssAtol, length(RxODE::rxModelVars(model)$state)) .ssRtol <- rep(control$ssRtol, length(RxODE::rxModelVars(model)$state)) .ret$model <- RxODE::rxSymPySetupPred(model, pred, PKpars, err, grad = (control$derivMethod == 2L), pred.minus.dv = TRUE, sum.prod = control$sumProd, theta.derivs = FALSE, optExpression = control$optExpression, interaction = (control$interaction == 1L), only.numeric = !.mixed, run.internal = TRUE, addProp = control$addProp) if (!is.null(.ret$model$inner)) { .atol <- c(.atol, rep(control$atolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.atol))) .rtol <- c(.rtol, rep(control$rtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.rtol))) .ret$control$rxControl$atol <- .atol .ret$control$rxControl$rtol <- .rtol .ssAtol <- c(.ssAtol, rep(control$ssAtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.ssAtol))) .ssRtol <- c(.ssRtol, rep(control$ssRtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.ssRtol))) .ret$control$rxControl$ssAtol <- .ssAtol .ret$control$rxControl$ssRtol <- .ssRtol } .covNames <- .parNames <- RxODE::rxParams(.ret$model$pred.only) .covNames <- .covNames[regexpr(rex::rex(start, or("THETA", "ETA"), "[", numbers, "]", end), .covNames) == -1] colnames(data) <- sapply(names(data), function(x) { if (any(x == .covNames)) { return(x) } else { return(toupper(x)) } }) .lhs <- c(names(RxODE::rxInits(.ret$model$pred.only)), RxODE::rxLhs(.ret$model$pred.only)) if (length(.lhs) > 0) { .covNames <- .covNames[regexpr(rex::rex(start, or(.lhs), end), .covNames) == -1] } if (length(.covNames) > 0) { if (!all(.covNames %in% names(data))) { message("Model:") RxODE::rxCat(.ret$model$pred.only) message("Needed Covariates:") nlmixrPrint(.covNames) stop("Not all the covariates are in the dataset.") } message("Needed Covariates:") print(.covNames) } .extraPars <- .ret$model$extra.pars } else { if (.ret$noLik) { .atol <- rep(control$atol, length(RxODE::rxModelVars(model)$state)) .rtol <- rep(control$rtol, length(RxODE::rxModelVars(model)$state)) .ret$model <- RxODE::rxSymPySetupPred(model, pred, PKpars, err, grad = FALSE, pred.minus.dv = TRUE, sum.prod = control$sumProd, theta.derivs = FALSE, optExpression = control$optExpression, run.internal = TRUE, only.numeric = TRUE, addProp = control$addProp) if (!is.null(.ret$model$inner)) { .atol <- c(.atol, rep(control$atolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.atol))) .rtol <- c(.rtol, rep(control$rtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.rtol))) .ret$control$rxControl$atol <- .atol .ret$control$rxControl$rtol <- .rtol } .covNames <- .parNames <- RxODE::rxParams(.ret$model$pred.only) .covNames <- .covNames[regexpr(rex::rex(start, or("THETA", "ETA"), "[", numbers, "]", end), .covNames) == -1] colnames(data) <- sapply(names(data), function(x) { if (any(x == .covNames)) { return(x) } else { return(toupper(x)) } }) .lhs <- c(names(RxODE::rxInits(.ret$model$pred.only)), RxODE::rxLhs(.ret$model$pred.only)) if (length(.lhs) > 0) { .covNames <- .covNames[regexpr(rex::rex(start, or(.lhs), end), .covNames) == -1] } if (length(.covNames) > 0) { if (!all(.covNames %in% names(data))) { message("Model:") RxODE::rxCat(.ret$model$pred.only) message("Needed Covariates:") nlmixrPrint(.covNames) stop("Not all the covariates are in the dataset.") } message("Needed Covariates:") print(.covNames) } .extraPars <- .ret$model$extra.pars } else { .extraPars <- NULL } } .ret$skipCov <- skipCov if (is.null(skipCov)) { if (is.null(fixed)) { .tmp <- rep(FALSE, length(inits$THTA)) } else { if (length(fixed) < length(inits$THTA)) { .tmp <- c(fixed, rep(FALSE, length(inits$THTA) - length(fixed))) } else { .tmp <- fixed[1:length(inits$THTA)] } } if (exists("uif", envir = .ret)) { .uifErr <- .ret$uif$ini$err[!is.na(.ret$uif$ini$ntheta)] .uifErr <- sapply(.uifErr, function(x) { if (is.na(x)) { return(FALSE) } return(!any(x == c("pow2", "tbs", "tbsYj"))) }) .tmp <- (.tmp | .uifErr) } .ret$skipCov <- c(.tmp, rep(TRUE, length(.extraPars))) .ret$control$focei.mu.ref <- .ret$uif$focei.mu.ref } if (is.null(.extraPars)) { .nms <- c(sprintf("THETA[%s]", seq_along(inits$THTA))) } else { .nms <- c(sprintf("THETA[%s]", seq_along(inits$THTA)), sprintf("ERR[%s]", seq_along(.extraPars))) } if (!is.null(thetaNames) && (length(inits$THTA) + length(.extraPars)) == length(thetaNames)) { .nms <- thetaNames } .ret$thetaNames <- .nms .thetaReset$thetaNames <- .nms if (length(lower) == 1) { lower <- rep(lower, length(inits$THTA)) } else if (length(lower) != length(inits$THTA)) { print(inits$THTA) print(lower) stop("Lower must be a single constant for all the THETA lower bounds, or match the dimension of THETA.") } if (length(upper) == 1) { upper <- rep(upper, length(inits$THTA)) } else if (length(lower) != length(inits$THTA)) { stop("Upper must be a single constant for all the THETA lower bounds, or match the dimension of THETA.") } if (!is.null(.extraPars)) { .ret$model$extra.pars <- eval(call(control$diagXform, .ret$model$extra.pars)) if (length(.ret$model$extra.pars) > 0) { inits$THTA <- c(inits$THTA, .ret$model$extra.pars) .lowerErr <- rep(control$atol[1] * 10, length(.ret$model$extra.pars)) .upperErr <- rep(Inf, length(.ret$model$extra.pars)) lower <- c(lower, .lowerErr) upper <- c(upper, .upperErr) } } if (is.null(data$ID)) stop("\"ID\" not found in data") if (is.null(data$DV)) stop("\"DV\" not found in data") if (is.null(data$EVID)) data$EVID <- 0 if (is.null(data$AMT)) data$AMT <- 0 for (.v in c("TIME", "AMT", "DV", .covNames)) { data[[.v]] <- as.double(data[[.v]]) } .ret$dataSav <- data .ds <- data[data$EVID != 0 & data$EVID != 2, c("ID", "TIME", "AMT", "EVID", .covNames)] .w <- which(tolower(names(data)) == "limit") .limitName <- NULL if (length(.w) == 1L) { .limitName <- names(data)[.w] } .censName <- NULL .w <- which(tolower(names(data)) == "cens") if (length(.w) == 1L) { .censName <- names(data[.w]) } data <- data[data$EVID == 0 | data$EVID == 2, c("ID", "TIME", "DV", "EVID", .covNames, .limitName, .censName)] .w <- which(!(names(.ret$dataSav) %in% c(.covNames, keep))) names(.ret$dataSav)[.w] <- tolower(names(.ret$dataSav[.w])) if (.mixed) { .lh <- .parseOM(inits$OMGA) .nlh <- sapply(.lh, length) .osplt <- rep(1:length(.lh), .nlh) .lini <- list(inits$THTA, unlist(.lh)) .nlini <- sapply(.lini, length) .nsplt <- rep(1:length(.lini), .nlini) .om0 <- .genOM(.lh) if (length(etaNames) == dim(.om0)[1]) { .ret$etaNames <- .ret$etaNames } else { .ret$etaNames <- sprintf("ETA[%d]", seq(1, dim(.om0)[1])) } .ret$rxInv <- RxODE::rxSymInvCholCreate(mat = .om0, diag.xform = control$diagXform) .ret$xType <- .ret$rxInv$xType .om0a <- .om0 .om0a <- .om0a/control$diagOmegaBoundLower .om0b <- .om0 .om0b <- .om0b * control$diagOmegaBoundUpper .om0a <- RxODE::rxSymInvCholCreate(mat = .om0a, diag.xform = control$diagXform) .om0b <- RxODE::rxSymInvCholCreate(mat = .om0b, diag.xform = control$diagXform) .omdf <- data.frame(a = .om0a$theta, m = .ret$rxInv$theta, b = .om0b$theta, diag = .om0a$theta.diag) .omdf$lower <- with(.omdf, ifelse(a > b, b, a)) .omdf$lower <- with(.omdf, ifelse(lower == m, -Inf, lower)) .omdf$lower <- with(.omdf, ifelse(!diag, -Inf, lower)) .omdf$upper <- with(.omdf, ifelse(a < b, b, a)) .omdf$upper <- with(.omdf, ifelse(upper == m, Inf, upper)) .omdf$upper <- with(.omdf, ifelse(!diag, Inf, upper)) .ret$control$nomega <- length(.omdf$lower) .ret$control$neta <- sum(.omdf$diag) .ret$control$ntheta <- length(lower) .ret$control$nfixed <- sum(fixed) lower <- c(lower, .omdf$lower) upper <- c(upper, .omdf$upper) } else { .ret$control$nomega <- 0 .ret$control$neta <- 0 .ret$xType <- -1 .ret$control$ntheta <- length(lower) .ret$control$nfixed <- sum(fixed) } .ret$lower <- lower .ret$upper <- upper .ret$thetaIni <- inits$THTA .scaleC <- double(length(lower)) if (is.null(control$scaleC)) { .scaleC <- rep(NA_real_, length(lower)) } else { .scaleC <- as.double(control$scaleC) if (length(lower) > length(.scaleC)) { .scaleC <- c(.scaleC, rep(NA_real_, length(lower) - length(.scaleC))) } else if (length(lower) < length(.scaleC)) { .scaleC <- .scaleC[seq(1, length(lower))] warning("scaleC control option has more options than estimated population parameters, please check.") } } .ret$scaleC <- .scaleC if (exists("uif", envir = .ret)) { .ini <- as.data.frame(.ret$uif$ini)[!is.na(.ret$uif$ini$err), c("est", "err", "ntheta")] for (.i in seq_along(.ini$err)) { if (is.na(.ret$scaleC[.ini$ntheta[.i]])) { if (any(.ini$err[.i] == c("boxCox", "yeoJohnson", "pow2", "tbs", "tbsYj"))) { .ret$scaleC[.ini$ntheta[.i]] <- 1 } else if (any(.ini$err[.i] == c("prop", "add", "norm", "dnorm", "logn", "dlogn", "lnorm", "dlnorm"))) { .ret$scaleC[.ini$ntheta[.i]] <- 0.5 * abs(.ini$est[.i]) } } } for (.i in .ini$model$extraProps$powTheta) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- 1 } .ini <- as.data.frame(.ret$uif$ini) for (.i in .ini$model$extraProps$factorial) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- abs(1/digamma(.ini$est[.i] + 1)) } for (.i in .ini$model$extraProps$gamma) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- abs(1/digamma(.ini$est[.i])) } for (.i in .ini$model$extraProps$log) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- log(abs(.ini$est[.i])) * abs(.ini$est[.i]) } for (.i in .ret$logitThetas) { .b <- .ret$logitThetasLow[.i] .c <- .ret$logitThetasHi[.i] .a <- .ini$est[.i] if (is.na(.ret$scaleC[.i])) { .ret$scaleC[.i] <- 1 * (-.b + .c) * exp(-.a)/((1 + exp(-.a))^2 * (.b + 1 * (-.b + .c)/(1 + exp(-.a)))) } } } names(.ret$thetaIni) <- sprintf("THETA[%d]", seq_along(.ret$thetaIni)) if (is.null(etaMat) & !is.null(control$etaMat)) { .ret$etaMat <- control$etaMat } else { .ret$etaMat <- etaMat } .ret$setupTime <- (proc.time() - .pt)["elapsed"] if (exists("uif", envir = .ret)) { .tmp <- .ret$uif$logThetasList .ret$logThetas <- .tmp[[1]] .ret$logThetasF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasList .ret$logitThetas <- .tmp[[1]] .ret$logitThetasF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasListLow .ret$logitThetasLow <- .tmp[[1]] .ret$logitThetasLowF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasListHi .ret$logitThetasHi <- .tmp[[1]] .ret$logitThetasHiF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasList .ret$probitThetas <- .tmp[[1]] .ret$probitThetasF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasListLow .ret$probitThetasLow <- .tmp[[1]] .ret$probitThetasLowF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasListHi .ret$probitThetasHi <- .tmp[[1]] .ret$probitThetasHiF <- .tmp[[2]] } else { .ret$logThetasF <- integer(0) .ret$logitThetasF <- integer(0) .ret$logitThetasHiF <- numeric(0) .ret$logitThetasLowF <- numeric(0) .ret$logitThetas <- integer(0) .ret$logitThetasHi <- numeric(0) .ret$logitThetasLow <- numeric(0) .ret$probitThetasF <- integer(0) .ret$probitThetasHiF <- numeric(0) .ret$probitThetasLowF <- numeric(0) .ret$probitThetas <- integer(0) .ret$probitThetasHi <- numeric(0) .ret$probitThetasLow <- numeric(0) } if (exists("noLik", envir = .ret)) { if (!.ret$noLik) { .ret$.params <- c(sprintf("THETA[%d]", seq_along(.ret$thetaIni)), sprintf("ETA[%d]", seq(1, dim(.om0)[1]))) .ret$.thetan <- length(.ret$thetaIni) .ret$nobs <- sum(data$EVID == 0) } } .ret$control$printTop <- TRUE .ret$control$nF <- 0 .est0 <- .ret$thetaIni if (!is.null(.ret$model$pred.nolhs)) { .ret$control$predNeq <- length(.ret$model$pred.nolhs$state) } else { .ret$control$predNeq <- 0L } .fitFun <- function(.ret) { this.env <- environment() assign("err", "theta reset", this.env) while (this.env$err == "theta reset") { assign("err", "", this.env) .ret0 <- tryCatch({ foceiFitCpp_(.ret) }, error = function(e) { if (regexpr("theta reset", e$message) != -1) { assign("zeroOuter", FALSE, this.env) assign("zeroGrad", FALSE, this.env) if (regexpr("theta reset0", e$message) != -1) { assign("zeroGrad", TRUE, this.env) } else if (regexpr("theta resetZ", e$message) != -1) { assign("zeroOuter", TRUE, this.env) } assign("err", "theta reset", this.env) } else { assign("err", e$message, this.env) } }) if (this.env$err == "theta reset") { .nm <- names(.ret$thetaIni) .ret$thetaIni <- setNames(.thetaReset$thetaIni + 0, .nm) .ret$rxInv$theta <- .thetaReset$omegaTheta .ret$control$printTop <- FALSE .ret$etaMat <- .thetaReset$etaMat .ret$control$etaMat <- .thetaReset$etaMat .ret$control$maxInnerIterations <- .thetaReset$maxInnerIterations .ret$control$nF <- .thetaReset$nF .ret$control$gillRetC <- .thetaReset$gillRetC .ret$control$gillRet <- .thetaReset$gillRet .ret$control$gillRet <- .thetaReset$gillRet .ret$control$gillDf <- .thetaReset$gillDf .ret$control$gillDf2 <- .thetaReset$gillDf2 .ret$control$gillErr <- .thetaReset$gillErr .ret$control$rEps <- .thetaReset$rEps .ret$control$aEps <- .thetaReset$aEps .ret$control$rEpsC <- .thetaReset$rEpsC .ret$control$aEpsC <- .thetaReset$aEpsC .ret$control$c1 <- .thetaReset$c1 .ret$control$c2 <- .thetaReset$c2 if (this.env$zeroOuter) { message("Posthoc reset") .ret$control$maxOuterIterations <- 0L } else if (this.env$zeroGrad) { message("Theta reset (zero gradient values); Switch to bobyqa") RxODE::rxReq("minqa") .ret$control$outerOptFun <- .bobyqa .ret$control$outerOpt <- -1L } else { message("Theta reset (ETA drift)") } } } if (this.env$err != "") { stop(this.env$err) } else { return(.ret0) } } .ret0 <- try(.fitFun(.ret)) .n <- 1 while (inherits(.ret0, "try-error") && control$maxOuterIterations != 0 && .n <= control$nRetries) { message(sprintf("Restart %s", .n)) .ret$control$nF <- 0 .estNew <- .est0 + 0.2 * .n * abs(.est0) * stats::runif(length(.est0)) - 0.1 * .n .estNew <- sapply(seq_along(.est0), function(.i) { if (.ret$thetaFixed[.i]) { return(.est0[.i]) } else if (.estNew[.i] < lower[.i]) { return(lower + (.Machine$double.eps)^(1/7)) } else if (.estNew[.i] > upper[.i]) { return(upper - (.Machine$double.eps)^(1/7)) } else { return(.estNew[.i]) } }) .ret$thetaIni <- .estNew .ret0 <- try(.fitFun(.ret)) .n <- .n + 1 } if (inherits(.ret0, "try-error")) stop("Could not fit data.") .ret <- .ret0 if (exists("parHistData", .ret)) { .tmp <- .ret$parHistData .tmp <- .tmp[.tmp$type == "Unscaled", names(.tmp) != "type"] .iter <- .tmp$iter .tmp <- .tmp[, names(.tmp) != "iter"] .ret$parHistStacked <- data.frame(stack(.tmp), iter = .iter) names(.ret$parHistStacked) <- c("val", "par", "iter") .ret$parHist <- data.frame(iter = .iter, .tmp) } if (.mixed) { .etas <- .ret$ranef .thetas <- .ret$fixef .pars <- .Call(`_nlmixr_nlmixrParameters`, .thetas, .etas) .ret$shrink <- .Call(`_nlmixr_calcShrinkOnly`, .ret$omega, .pars$eta.lst, length(.etas$ID)) .updateParFixed(.ret) } else { .updateParFixed(.ret) } if (!exists("table", .ret)) { .ret$table <- tableControl() } if (control$calcTables) { .ret <- addTable(.ret, updateObject = "no", keep = keep, drop = drop, table = .ret$table) } .ret})(data = dat, inits = .FoceiInits, PKpars = .pars, model = .mod, pred = function() { return(nlmixr_pred) }, err = uif$error, lower = uif$focei.lower, upper = uif$focei.upper, fixed = uif$focei.fixed, thetaNames = uif$focei.names, etaNames = uif$eta.names, control = control, env = env, keep = .keep, drop = .drop): Not all the covariates are in the dataset.</span></div><div class='output co'>#> <span class='message'>Timing stopped at: 8.708 0.429 9.135</span></div><div class='input'><span class='va'>f_nlmixr_dfop_sfo_focei_tc</span> <span class='op'><-</span> <span class='fu'><a href='https://rdrr.io/pkg/nlmixr/man/nlmixr.html'>nlmixr</a></span><span class='op'>(</span><span class='va'>f_mmkin_tc</span><span class='op'>[</span><span class='st'>"DFOP-SFO"</span>, <span class='op'>]</span>, est <span class='op'>=</span> <span class='st'>"focei"</span><span class='op'>)</span> +#> <span class='message'>dosenum=dosenum();</span></div><div class='output co'>#> <span class='message'>Needed Covariates:</span></div><div class='output co'>#> <span class='message'>[1] "f_parent_to_A1" "CMT" </span></div><div class='output co'>#> <span class='error'>Error in (function (data, inits, PKpars, model = NULL, pred = NULL, err = NULL, lower = -Inf, upper = Inf, fixed = NULL, skipCov = NULL, control = foceiControl(), thetaNames = NULL, etaNames = NULL, etaMat = NULL, ..., env = NULL, keep = NULL, drop = NULL) { set.seed(control$seed) .pt <- proc.time() RxODE::.setWarnIdSort(FALSE) on.exit(RxODE::.setWarnIdSort(TRUE)) loadNamespace("n1qn1") if (!RxODE::rxIs(control, "foceiControl")) { control <- do.call(foceiControl, control) } if (is.null(env)) { .ret <- new.env(parent = emptyenv()) } else { .ret <- env } .ret$origData <- data .ret$etaNames <- etaNames .ret$thetaFixed <- fixed .ret$control <- control .ret$control$focei.mu.ref <- integer(0) if (is(model, "RxODE") || is(model, "character")) { .ret$ODEmodel <- TRUE if (class(pred) != "function") { stop("pred must be a function specifying the prediction variables in this model.") } } else { .ret$ODEmodel <- TRUE model <- RxODE::rxGetLin(PKpars) pred <- eval(parse(text = "function(){return(Central);}")) } .square <- function(x) x * x .ret$diagXformInv <- c(sqrt = ".square", log = "exp", identity = "identity")[control$diagXform] if (is.null(err)) { err <- eval(parse(text = paste0("function(){err", paste(inits$ERROR[[1]], collapse = ""), "}"))) } .covNames <- .parNames <- c() .ret$adjLik <- control$adjLik .mixed <- !is.null(inits$OMGA) && length(inits$OMGA) > 0 if (!exists("noLik", envir = .ret)) { .atol <- rep(control$atol, length(RxODE::rxModelVars(model)$state)) .rtol <- rep(control$rtol, length(RxODE::rxModelVars(model)$state)) .ssAtol <- rep(control$ssAtol, length(RxODE::rxModelVars(model)$state)) .ssRtol <- rep(control$ssRtol, length(RxODE::rxModelVars(model)$state)) .ret$model <- RxODE::rxSymPySetupPred(model, pred, PKpars, err, grad = (control$derivMethod == 2L), pred.minus.dv = TRUE, sum.prod = control$sumProd, theta.derivs = FALSE, optExpression = control$optExpression, interaction = (control$interaction == 1L), only.numeric = !.mixed, run.internal = TRUE, addProp = control$addProp) if (!is.null(.ret$model$inner)) { .atol <- c(.atol, rep(control$atolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.atol))) .rtol <- c(.rtol, rep(control$rtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.rtol))) .ret$control$rxControl$atol <- .atol .ret$control$rxControl$rtol <- .rtol .ssAtol <- c(.ssAtol, rep(control$ssAtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.ssAtol))) .ssRtol <- c(.ssRtol, rep(control$ssRtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.ssRtol))) .ret$control$rxControl$ssAtol <- .ssAtol .ret$control$rxControl$ssRtol <- .ssRtol } .covNames <- .parNames <- RxODE::rxParams(.ret$model$pred.only) .covNames <- .covNames[regexpr(rex::rex(start, or("THETA", "ETA"), "[", numbers, "]", end), .covNames) == -1] colnames(data) <- sapply(names(data), function(x) { if (any(x == .covNames)) { return(x) } else { return(toupper(x)) } }) .lhs <- c(names(RxODE::rxInits(.ret$model$pred.only)), RxODE::rxLhs(.ret$model$pred.only)) if (length(.lhs) > 0) { .covNames <- .covNames[regexpr(rex::rex(start, or(.lhs), end), .covNames) == -1] } if (length(.covNames) > 0) { if (!all(.covNames %in% names(data))) { message("Model:") RxODE::rxCat(.ret$model$pred.only) message("Needed Covariates:") nlmixrPrint(.covNames) stop("Not all the covariates are in the dataset.") } message("Needed Covariates:") print(.covNames) } .extraPars <- .ret$model$extra.pars } else { if (.ret$noLik) { .atol <- rep(control$atol, length(RxODE::rxModelVars(model)$state)) .rtol <- rep(control$rtol, length(RxODE::rxModelVars(model)$state)) .ret$model <- RxODE::rxSymPySetupPred(model, pred, PKpars, err, grad = FALSE, pred.minus.dv = TRUE, sum.prod = control$sumProd, theta.derivs = FALSE, optExpression = control$optExpression, run.internal = TRUE, only.numeric = TRUE, addProp = control$addProp) if (!is.null(.ret$model$inner)) { .atol <- c(.atol, rep(control$atolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.atol))) .rtol <- c(.rtol, rep(control$rtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.rtol))) .ret$control$rxControl$atol <- .atol .ret$control$rxControl$rtol <- .rtol } .covNames <- .parNames <- RxODE::rxParams(.ret$model$pred.only) .covNames <- .covNames[regexpr(rex::rex(start, or("THETA", "ETA"), "[", numbers, "]", end), .covNames) == -1] colnames(data) <- sapply(names(data), function(x) { if (any(x == .covNames)) { return(x) } else { return(toupper(x)) } }) .lhs <- c(names(RxODE::rxInits(.ret$model$pred.only)), RxODE::rxLhs(.ret$model$pred.only)) if (length(.lhs) > 0) { .covNames <- .covNames[regexpr(rex::rex(start, or(.lhs), end), .covNames) == -1] } if (length(.covNames) > 0) { if (!all(.covNames %in% names(data))) { message("Model:") RxODE::rxCat(.ret$model$pred.only) message("Needed Covariates:") nlmixrPrint(.covNames) stop("Not all the covariates are in the dataset.") } message("Needed Covariates:") print(.covNames) } .extraPars <- .ret$model$extra.pars } else { .extraPars <- NULL } } .ret$skipCov <- skipCov if (is.null(skipCov)) { if (is.null(fixed)) { .tmp <- rep(FALSE, length(inits$THTA)) } else { if (length(fixed) < length(inits$THTA)) { .tmp <- c(fixed, rep(FALSE, length(inits$THTA) - length(fixed))) } else { .tmp <- fixed[1:length(inits$THTA)] } } if (exists("uif", envir = .ret)) { .uifErr <- .ret$uif$ini$err[!is.na(.ret$uif$ini$ntheta)] .uifErr <- sapply(.uifErr, function(x) { if (is.na(x)) { return(FALSE) } return(!any(x == c("pow2", "tbs", "tbsYj"))) }) .tmp <- (.tmp | .uifErr) } .ret$skipCov <- c(.tmp, rep(TRUE, length(.extraPars))) .ret$control$focei.mu.ref <- .ret$uif$focei.mu.ref } if (is.null(.extraPars)) { .nms <- c(sprintf("THETA[%s]", seq_along(inits$THTA))) } else { .nms <- c(sprintf("THETA[%s]", seq_along(inits$THTA)), sprintf("ERR[%s]", seq_along(.extraPars))) } if (!is.null(thetaNames) && (length(inits$THTA) + length(.extraPars)) == length(thetaNames)) { .nms <- thetaNames } .ret$thetaNames <- .nms .thetaReset$thetaNames <- .nms if (length(lower) == 1) { lower <- rep(lower, length(inits$THTA)) } else if (length(lower) != length(inits$THTA)) { print(inits$THTA) print(lower) stop("Lower must be a single constant for all the THETA lower bounds, or match the dimension of THETA.") } if (length(upper) == 1) { upper <- rep(upper, length(inits$THTA)) } else if (length(lower) != length(inits$THTA)) { stop("Upper must be a single constant for all the THETA lower bounds, or match the dimension of THETA.") } if (!is.null(.extraPars)) { .ret$model$extra.pars <- eval(call(control$diagXform, .ret$model$extra.pars)) if (length(.ret$model$extra.pars) > 0) { inits$THTA <- c(inits$THTA, .ret$model$extra.pars) .lowerErr <- rep(control$atol[1] * 10, length(.ret$model$extra.pars)) .upperErr <- rep(Inf, length(.ret$model$extra.pars)) lower <- c(lower, .lowerErr) upper <- c(upper, .upperErr) } } if (is.null(data$ID)) stop("\"ID\" not found in data") if (is.null(data$DV)) stop("\"DV\" not found in data") if (is.null(data$EVID)) data$EVID <- 0 if (is.null(data$AMT)) data$AMT <- 0 for (.v in c("TIME", "AMT", "DV", .covNames)) { data[[.v]] <- as.double(data[[.v]]) } .ret$dataSav <- data .ds <- data[data$EVID != 0 & data$EVID != 2, c("ID", "TIME", "AMT", "EVID", .covNames)] .w <- which(tolower(names(data)) == "limit") .limitName <- NULL if (length(.w) == 1L) { .limitName <- names(data)[.w] } .censName <- NULL .w <- which(tolower(names(data)) == "cens") if (length(.w) == 1L) { .censName <- names(data[.w]) } data <- data[data$EVID == 0 | data$EVID == 2, c("ID", "TIME", "DV", "EVID", .covNames, .limitName, .censName)] .w <- which(!(names(.ret$dataSav) %in% c(.covNames, keep))) names(.ret$dataSav)[.w] <- tolower(names(.ret$dataSav[.w])) if (.mixed) { .lh <- .parseOM(inits$OMGA) .nlh <- sapply(.lh, length) .osplt <- rep(1:length(.lh), .nlh) .lini <- list(inits$THTA, unlist(.lh)) .nlini <- sapply(.lini, length) .nsplt <- rep(1:length(.lini), .nlini) .om0 <- .genOM(.lh) if (length(etaNames) == dim(.om0)[1]) { .ret$etaNames <- .ret$etaNames } else { .ret$etaNames <- sprintf("ETA[%d]", seq(1, dim(.om0)[1])) } .ret$rxInv <- RxODE::rxSymInvCholCreate(mat = .om0, diag.xform = control$diagXform) .ret$xType <- .ret$rxInv$xType .om0a <- .om0 .om0a <- .om0a/control$diagOmegaBoundLower .om0b <- .om0 .om0b <- .om0b * control$diagOmegaBoundUpper .om0a <- RxODE::rxSymInvCholCreate(mat = .om0a, diag.xform = control$diagXform) .om0b <- RxODE::rxSymInvCholCreate(mat = .om0b, diag.xform = control$diagXform) .omdf <- data.frame(a = .om0a$theta, m = .ret$rxInv$theta, b = .om0b$theta, diag = .om0a$theta.diag) .omdf$lower <- with(.omdf, ifelse(a > b, b, a)) .omdf$lower <- with(.omdf, ifelse(lower == m, -Inf, lower)) .omdf$lower <- with(.omdf, ifelse(!diag, -Inf, lower)) .omdf$upper <- with(.omdf, ifelse(a < b, b, a)) .omdf$upper <- with(.omdf, ifelse(upper == m, Inf, upper)) .omdf$upper <- with(.omdf, ifelse(!diag, Inf, upper)) .ret$control$nomega <- length(.omdf$lower) .ret$control$neta <- sum(.omdf$diag) .ret$control$ntheta <- length(lower) .ret$control$nfixed <- sum(fixed) lower <- c(lower, .omdf$lower) upper <- c(upper, .omdf$upper) } else { .ret$control$nomega <- 0 .ret$control$neta <- 0 .ret$xType <- -1 .ret$control$ntheta <- length(lower) .ret$control$nfixed <- sum(fixed) } .ret$lower <- lower .ret$upper <- upper .ret$thetaIni <- inits$THTA .scaleC <- double(length(lower)) if (is.null(control$scaleC)) { .scaleC <- rep(NA_real_, length(lower)) } else { .scaleC <- as.double(control$scaleC) if (length(lower) > length(.scaleC)) { .scaleC <- c(.scaleC, rep(NA_real_, length(lower) - length(.scaleC))) } else if (length(lower) < length(.scaleC)) { .scaleC <- .scaleC[seq(1, length(lower))] warning("scaleC control option has more options than estimated population parameters, please check.") } } .ret$scaleC <- .scaleC if (exists("uif", envir = .ret)) { .ini <- as.data.frame(.ret$uif$ini)[!is.na(.ret$uif$ini$err), c("est", "err", "ntheta")] for (.i in seq_along(.ini$err)) { if (is.na(.ret$scaleC[.ini$ntheta[.i]])) { if (any(.ini$err[.i] == c("boxCox", "yeoJohnson", "pow2", "tbs", "tbsYj"))) { .ret$scaleC[.ini$ntheta[.i]] <- 1 } else if (any(.ini$err[.i] == c("prop", "add", "norm", "dnorm", "logn", "dlogn", "lnorm", "dlnorm"))) { .ret$scaleC[.ini$ntheta[.i]] <- 0.5 * abs(.ini$est[.i]) } } } for (.i in .ini$model$extraProps$powTheta) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- 1 } .ini <- as.data.frame(.ret$uif$ini) for (.i in .ini$model$extraProps$factorial) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- abs(1/digamma(.ini$est[.i] + 1)) } for (.i in .ini$model$extraProps$gamma) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- abs(1/digamma(.ini$est[.i])) } for (.i in .ini$model$extraProps$log) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- log(abs(.ini$est[.i])) * abs(.ini$est[.i]) } for (.i in .ret$logitThetas) { .b <- .ret$logitThetasLow[.i] .c <- .ret$logitThetasHi[.i] .a <- .ini$est[.i] if (is.na(.ret$scaleC[.i])) { .ret$scaleC[.i] <- 1 * (-.b + .c) * exp(-.a)/((1 + exp(-.a))^2 * (.b + 1 * (-.b + .c)/(1 + exp(-.a)))) } } } names(.ret$thetaIni) <- sprintf("THETA[%d]", seq_along(.ret$thetaIni)) if (is.null(etaMat) & !is.null(control$etaMat)) { .ret$etaMat <- control$etaMat } else { .ret$etaMat <- etaMat } .ret$setupTime <- (proc.time() - .pt)["elapsed"] if (exists("uif", envir = .ret)) { .tmp <- .ret$uif$logThetasList .ret$logThetas <- .tmp[[1]] .ret$logThetasF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasList .ret$logitThetas <- .tmp[[1]] .ret$logitThetasF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasListLow .ret$logitThetasLow <- .tmp[[1]] .ret$logitThetasLowF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasListHi .ret$logitThetasHi <- .tmp[[1]] .ret$logitThetasHiF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasList .ret$probitThetas <- .tmp[[1]] .ret$probitThetasF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasListLow .ret$probitThetasLow <- .tmp[[1]] .ret$probitThetasLowF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasListHi .ret$probitThetasHi <- .tmp[[1]] .ret$probitThetasHiF <- .tmp[[2]] } else { .ret$logThetasF <- integer(0) .ret$logitThetasF <- integer(0) .ret$logitThetasHiF <- numeric(0) .ret$logitThetasLowF <- numeric(0) .ret$logitThetas <- integer(0) .ret$logitThetasHi <- numeric(0) .ret$logitThetasLow <- numeric(0) .ret$probitThetasF <- integer(0) .ret$probitThetasHiF <- numeric(0) .ret$probitThetasLowF <- numeric(0) .ret$probitThetas <- integer(0) .ret$probitThetasHi <- numeric(0) .ret$probitThetasLow <- numeric(0) } if (exists("noLik", envir = .ret)) { if (!.ret$noLik) { .ret$.params <- c(sprintf("THETA[%d]", seq_along(.ret$thetaIni)), sprintf("ETA[%d]", seq(1, dim(.om0)[1]))) .ret$.thetan <- length(.ret$thetaIni) .ret$nobs <- sum(data$EVID == 0) } } .ret$control$printTop <- TRUE .ret$control$nF <- 0 .est0 <- .ret$thetaIni if (!is.null(.ret$model$pred.nolhs)) { .ret$control$predNeq <- length(.ret$model$pred.nolhs$state) } else { .ret$control$predNeq <- 0L } .fitFun <- function(.ret) { this.env <- environment() assign("err", "theta reset", this.env) while (this.env$err == "theta reset") { assign("err", "", this.env) .ret0 <- tryCatch({ foceiFitCpp_(.ret) }, error = function(e) { if (regexpr("theta reset", e$message) != -1) { assign("zeroOuter", FALSE, this.env) assign("zeroGrad", FALSE, this.env) if (regexpr("theta reset0", e$message) != -1) { assign("zeroGrad", TRUE, this.env) } else if (regexpr("theta resetZ", e$message) != -1) { assign("zeroOuter", TRUE, this.env) } assign("err", "theta reset", this.env) } else { assign("err", e$message, this.env) } }) if (this.env$err == "theta reset") { .nm <- names(.ret$thetaIni) .ret$thetaIni <- setNames(.thetaReset$thetaIni + 0, .nm) .ret$rxInv$theta <- .thetaReset$omegaTheta .ret$control$printTop <- FALSE .ret$etaMat <- .thetaReset$etaMat .ret$control$etaMat <- .thetaReset$etaMat .ret$control$maxInnerIterations <- .thetaReset$maxInnerIterations .ret$control$nF <- .thetaReset$nF .ret$control$gillRetC <- .thetaReset$gillRetC .ret$control$gillRet <- .thetaReset$gillRet .ret$control$gillRet <- .thetaReset$gillRet .ret$control$gillDf <- .thetaReset$gillDf .ret$control$gillDf2 <- .thetaReset$gillDf2 .ret$control$gillErr <- .thetaReset$gillErr .ret$control$rEps <- .thetaReset$rEps .ret$control$aEps <- .thetaReset$aEps .ret$control$rEpsC <- .thetaReset$rEpsC .ret$control$aEpsC <- .thetaReset$aEpsC .ret$control$c1 <- .thetaReset$c1 .ret$control$c2 <- .thetaReset$c2 if (this.env$zeroOuter) { message("Posthoc reset") .ret$control$maxOuterIterations <- 0L } else if (this.env$zeroGrad) { message("Theta reset (zero gradient values); Switch to bobyqa") RxODE::rxReq("minqa") .ret$control$outerOptFun <- .bobyqa .ret$control$outerOpt <- -1L } else { message("Theta reset (ETA drift)") } } } if (this.env$err != "") { stop(this.env$err) } else { return(.ret0) } } .ret0 <- try(.fitFun(.ret)) .n <- 1 while (inherits(.ret0, "try-error") && control$maxOuterIterations != 0 && .n <= control$nRetries) { message(sprintf("Restart %s", .n)) .ret$control$nF <- 0 .estNew <- .est0 + 0.2 * .n * abs(.est0) * stats::runif(length(.est0)) - 0.1 * .n .estNew <- sapply(seq_along(.est0), function(.i) { if (.ret$thetaFixed[.i]) { return(.est0[.i]) } else if (.estNew[.i] < lower[.i]) { return(lower + (.Machine$double.eps)^(1/7)) } else if (.estNew[.i] > upper[.i]) { return(upper - (.Machine$double.eps)^(1/7)) } else { return(.estNew[.i]) } }) .ret$thetaIni <- .estNew .ret0 <- try(.fitFun(.ret)) .n <- .n + 1 } if (inherits(.ret0, "try-error")) stop("Could not fit data.") .ret <- .ret0 if (exists("parHistData", .ret)) { .tmp <- .ret$parHistData .tmp <- .tmp[.tmp$type == "Unscaled", names(.tmp) != "type"] .iter <- .tmp$iter .tmp <- .tmp[, names(.tmp) != "iter"] .ret$parHistStacked <- data.frame(stack(.tmp), iter = .iter) names(.ret$parHistStacked) <- c("val", "par", "iter") .ret$parHist <- data.frame(iter = .iter, .tmp) } if (.mixed) { .etas <- .ret$ranef .thetas <- .ret$fixef .pars <- .Call(`_nlmixr_nlmixrParameters`, .thetas, .etas) .ret$shrink <- .Call(`_nlmixr_calcShrinkOnly`, .ret$omega, .pars$eta.lst, length(.etas$ID)) .updateParFixed(.ret) } else { .updateParFixed(.ret) } if (!exists("table", .ret)) { .ret$table <- tableControl() } if (control$calcTables) { .ret <- addTable(.ret, updateObject = "no", keep = keep, drop = drop, table = .ret$table) } .ret})(data = dat, inits = .FoceiInits, PKpars = .pars, model = .mod, pred = function() { return(nlmixr_pred) }, err = uif$error, lower = uif$focei.lower, upper = uif$focei.upper, fixed = uif$focei.fixed, thetaNames = uif$focei.names, etaNames = uif$eta.names, control = control, env = env, keep = .keep, drop = .drop): Not all the covariates are in the dataset.</span></div><div class='output co'>#> <span class='message'>Timing stopped at: 8.484 0.401 8.883</span></div><div class='input'><span class='va'>f_nlmixr_dfop_sfo_focei_tc</span> <span class='op'><-</span> <span class='fu'><a href='https://rdrr.io/pkg/nlmixr/man/nlmixr.html'>nlmixr</a></span><span class='op'>(</span><span class='va'>f_mmkin_tc</span><span class='op'>[</span><span class='st'>"DFOP-SFO"</span>, <span class='op'>]</span>, est <span class='op'>=</span> <span class='st'>"focei"</span><span class='op'>)</span> </div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> parameter labels from comments are typically ignored in non-interactive mode</span></div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> Need to run with the source intact to parse comments</span></div><div class='output co'>#> <span class='message'>→ creating full model...</span></div><div class='output co'>#> <span class='message'>→ pruning branches (<span style='color: #262626; background-color: #DADADA;'>`if`</span>/<span style='color: #262626; background-color: #DADADA;'>`else`</span>)...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ loading into <span style='color: #0000BB;'>symengine</span> environment...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ creating full model...</span></div><div class='output co'>#> <span class='message'>→ pruning branches (<span style='color: #262626; background-color: #DADADA;'>`if`</span>/<span style='color: #262626; background-color: #DADADA;'>`else`</span>)...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ loading into <span style='color: #0000BB;'>symengine</span> environment...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ calculate jacobian</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ calculate sensitivities</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ calculate ∂(f)/∂(η)</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ calculate ∂(R²)/∂(η)</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ finding duplicate expressions in inner model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ optimizing duplicate expressions in inner model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ finding duplicate expressions in EBE model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ optimizing duplicate expressions in EBE model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ compiling inner model...</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ finding duplicate expressions in FD model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ optimizing duplicate expressions in FD model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ compiling EBE model...</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ compiling events FD model...</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>Model:</span></div><div class='output co'>#> <span class='message'>cmt(parent);</span> #> <span class='message'>cmt(A1);</span> #> <span class='message'>rx_expr_6~ETA[1]+THETA[1];</span> @@ -4830,12 +4830,12 @@ obtained by fitting the same model to a list of datasets using <a href='mkinfit. #> <span class='message'>f_parent=1/(1+exp(-(ETA[3]+THETA[3])));</span> #> <span class='message'>g=1/(rx_expr_21);</span> #> <span class='message'>tad=tad();</span> -#> <span class='message'>dosenum=dosenum();</span></div><div class='output co'>#> <span class='message'>Needed Covariates:</span></div><div class='output co'>#> <span class='message'>[1] "f_parent_to_A1" "CMT" </span></div><div class='output co'>#> <span class='error'>Error in (function (data, inits, PKpars, model = NULL, pred = NULL, err = NULL, lower = -Inf, upper = Inf, fixed = NULL, skipCov = NULL, control = foceiControl(), thetaNames = NULL, etaNames = NULL, etaMat = NULL, ..., env = NULL, keep = NULL, drop = NULL) { set.seed(control$seed) .pt <- proc.time() RxODE::.setWarnIdSort(FALSE) on.exit(RxODE::.setWarnIdSort(TRUE)) loadNamespace("n1qn1") if (!RxODE::rxIs(control, "foceiControl")) { control <- do.call(foceiControl, control) } if (is.null(env)) { .ret <- new.env(parent = emptyenv()) } else { .ret <- env } .ret$origData <- data .ret$etaNames <- etaNames .ret$thetaFixed <- fixed .ret$control <- control .ret$control$focei.mu.ref <- integer(0) if (is(model, "RxODE") || is(model, "character")) { .ret$ODEmodel <- TRUE if (class(pred) != "function") { stop("pred must be a function specifying the prediction variables in this model.") } } else { .ret$ODEmodel <- TRUE model <- RxODE::rxGetLin(PKpars) pred <- eval(parse(text = "function(){return(Central);}")) } .square <- function(x) x * x .ret$diagXformInv <- c(sqrt = ".square", log = "exp", identity = "identity")[control$diagXform] if (is.null(err)) { err <- eval(parse(text = paste0("function(){err", paste(inits$ERROR[[1]], collapse = ""), "}"))) } .covNames <- .parNames <- c() .ret$adjLik <- control$adjLik .mixed <- !is.null(inits$OMGA) && length(inits$OMGA) > 0 if (!exists("noLik", envir = .ret)) { .atol <- rep(control$atol, length(RxODE::rxModelVars(model)$state)) .rtol <- rep(control$rtol, length(RxODE::rxModelVars(model)$state)) .ssAtol <- rep(control$ssAtol, length(RxODE::rxModelVars(model)$state)) .ssRtol <- rep(control$ssRtol, length(RxODE::rxModelVars(model)$state)) .ret$model <- RxODE::rxSymPySetupPred(model, pred, PKpars, err, grad = (control$derivMethod == 2L), pred.minus.dv = TRUE, sum.prod = control$sumProd, theta.derivs = FALSE, optExpression = control$optExpression, interaction = (control$interaction == 1L), only.numeric = !.mixed, run.internal = TRUE, addProp = control$addProp) if (!is.null(.ret$model$inner)) { .atol <- c(.atol, rep(control$atolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.atol))) .rtol <- c(.rtol, rep(control$rtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.rtol))) .ret$control$rxControl$atol <- .atol .ret$control$rxControl$rtol <- .rtol .ssAtol <- c(.ssAtol, rep(control$ssAtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.ssAtol))) .ssRtol <- c(.ssRtol, rep(control$ssRtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.ssRtol))) .ret$control$rxControl$ssAtol <- .ssAtol .ret$control$rxControl$ssRtol <- .ssRtol } .covNames <- .parNames <- RxODE::rxParams(.ret$model$pred.only) .covNames <- .covNames[regexpr(rex::rex(start, or("THETA", "ETA"), "[", numbers, "]", end), .covNames) == -1] colnames(data) <- sapply(names(data), function(x) { if (any(x == .covNames)) { return(x) } else { return(toupper(x)) } }) .lhs <- c(names(RxODE::rxInits(.ret$model$pred.only)), RxODE::rxLhs(.ret$model$pred.only)) if (length(.lhs) > 0) { .covNames <- .covNames[regexpr(rex::rex(start, or(.lhs), end), .covNames) == -1] } if (length(.covNames) > 0) { if (!all(.covNames %in% names(data))) { message("Model:") RxODE::rxCat(.ret$model$pred.only) message("Needed Covariates:") nlmixrPrint(.covNames) stop("Not all the covariates are in the dataset.") } message("Needed Covariates:") print(.covNames) } .extraPars <- .ret$model$extra.pars } else { if (.ret$noLik) { .atol <- rep(control$atol, length(RxODE::rxModelVars(model)$state)) .rtol <- rep(control$rtol, length(RxODE::rxModelVars(model)$state)) .ret$model <- RxODE::rxSymPySetupPred(model, pred, PKpars, err, grad = FALSE, pred.minus.dv = TRUE, sum.prod = control$sumProd, theta.derivs = FALSE, optExpression = control$optExpression, run.internal = TRUE, only.numeric = TRUE, addProp = control$addProp) if (!is.null(.ret$model$inner)) { .atol <- c(.atol, rep(control$atolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.atol))) .rtol <- c(.rtol, rep(control$rtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.rtol))) .ret$control$rxControl$atol <- .atol .ret$control$rxControl$rtol <- .rtol } .covNames <- .parNames <- RxODE::rxParams(.ret$model$pred.only) .covNames <- .covNames[regexpr(rex::rex(start, or("THETA", "ETA"), "[", numbers, "]", end), .covNames) == -1] colnames(data) <- sapply(names(data), function(x) { if (any(x == .covNames)) { return(x) } else { return(toupper(x)) } }) .lhs <- c(names(RxODE::rxInits(.ret$model$pred.only)), RxODE::rxLhs(.ret$model$pred.only)) if (length(.lhs) > 0) { .covNames <- .covNames[regexpr(rex::rex(start, or(.lhs), end), .covNames) == -1] } if (length(.covNames) > 0) { if (!all(.covNames %in% names(data))) { message("Model:") RxODE::rxCat(.ret$model$pred.only) message("Needed Covariates:") nlmixrPrint(.covNames) stop("Not all the covariates are in the dataset.") } message("Needed Covariates:") print(.covNames) } .extraPars <- .ret$model$extra.pars } else { .extraPars <- NULL } } .ret$skipCov <- skipCov if (is.null(skipCov)) { if (is.null(fixed)) { .tmp <- rep(FALSE, length(inits$THTA)) } else { if (length(fixed) < length(inits$THTA)) { .tmp <- c(fixed, rep(FALSE, length(inits$THTA) - length(fixed))) } else { .tmp <- fixed[1:length(inits$THTA)] } } if (exists("uif", envir = .ret)) { .uifErr <- .ret$uif$ini$err[!is.na(.ret$uif$ini$ntheta)] .uifErr <- sapply(.uifErr, function(x) { if (is.na(x)) { return(FALSE) } return(!any(x == c("pow2", "tbs", "tbsYj"))) }) .tmp <- (.tmp | .uifErr) } .ret$skipCov <- c(.tmp, rep(TRUE, length(.extraPars))) .ret$control$focei.mu.ref <- .ret$uif$focei.mu.ref } if (is.null(.extraPars)) { .nms <- c(sprintf("THETA[%s]", seq_along(inits$THTA))) } else { .nms <- c(sprintf("THETA[%s]", seq_along(inits$THTA)), sprintf("ERR[%s]", seq_along(.extraPars))) } if (!is.null(thetaNames) && (length(inits$THTA) + length(.extraPars)) == length(thetaNames)) { .nms <- thetaNames } .ret$thetaNames <- .nms .thetaReset$thetaNames <- .nms if (length(lower) == 1) { lower <- rep(lower, length(inits$THTA)) } else if (length(lower) != length(inits$THTA)) { print(inits$THTA) print(lower) stop("Lower must be a single constant for all the THETA lower bounds, or match the dimension of THETA.") } if (length(upper) == 1) { upper <- rep(upper, length(inits$THTA)) } else if (length(lower) != length(inits$THTA)) { stop("Upper must be a single constant for all the THETA lower bounds, or match the dimension of THETA.") } if (!is.null(.extraPars)) { .ret$model$extra.pars <- eval(call(control$diagXform, .ret$model$extra.pars)) if (length(.ret$model$extra.pars) > 0) { inits$THTA <- c(inits$THTA, .ret$model$extra.pars) .lowerErr <- rep(control$atol[1] * 10, length(.ret$model$extra.pars)) .upperErr <- rep(Inf, length(.ret$model$extra.pars)) lower <- c(lower, .lowerErr) upper <- c(upper, .upperErr) } } if (is.null(data$ID)) stop("\"ID\" not found in data") if (is.null(data$DV)) stop("\"DV\" not found in data") if (is.null(data$EVID)) data$EVID <- 0 if (is.null(data$AMT)) data$AMT <- 0 for (.v in c("TIME", "AMT", "DV", .covNames)) { data[[.v]] <- as.double(data[[.v]]) } .ret$dataSav <- data .ds <- data[data$EVID != 0 & data$EVID != 2, c("ID", "TIME", "AMT", "EVID", .covNames)] .w <- which(tolower(names(data)) == "limit") .limitName <- NULL if (length(.w) == 1L) { .limitName <- names(data)[.w] } .censName <- NULL .w <- which(tolower(names(data)) == "cens") if (length(.w) == 1L) { .censName <- names(data[.w]) } data <- data[data$EVID == 0 | data$EVID == 2, c("ID", "TIME", "DV", "EVID", .covNames, .limitName, .censName)] .w <- which(!(names(.ret$dataSav) %in% c(.covNames, keep))) names(.ret$dataSav)[.w] <- tolower(names(.ret$dataSav[.w])) if (.mixed) { .lh <- .parseOM(inits$OMGA) .nlh <- sapply(.lh, length) .osplt <- rep(1:length(.lh), .nlh) .lini <- list(inits$THTA, unlist(.lh)) .nlini <- sapply(.lini, length) .nsplt <- rep(1:length(.lini), .nlini) .om0 <- .genOM(.lh) if (length(etaNames) == dim(.om0)[1]) { .ret$etaNames <- .ret$etaNames } else { .ret$etaNames <- sprintf("ETA[%d]", seq(1, dim(.om0)[1])) } .ret$rxInv <- RxODE::rxSymInvCholCreate(mat = .om0, diag.xform = control$diagXform) .ret$xType <- .ret$rxInv$xType .om0a <- .om0 .om0a <- .om0a/control$diagOmegaBoundLower .om0b <- .om0 .om0b <- .om0b * control$diagOmegaBoundUpper .om0a <- RxODE::rxSymInvCholCreate(mat = .om0a, diag.xform = control$diagXform) .om0b <- RxODE::rxSymInvCholCreate(mat = .om0b, diag.xform = control$diagXform) .omdf <- data.frame(a = .om0a$theta, m = .ret$rxInv$theta, b = .om0b$theta, diag = .om0a$theta.diag) .omdf$lower <- with(.omdf, ifelse(a > b, b, a)) .omdf$lower <- with(.omdf, ifelse(lower == m, -Inf, lower)) .omdf$lower <- with(.omdf, ifelse(!diag, -Inf, lower)) .omdf$upper <- with(.omdf, ifelse(a < b, b, a)) .omdf$upper <- with(.omdf, ifelse(upper == m, Inf, upper)) .omdf$upper <- with(.omdf, ifelse(!diag, Inf, upper)) .ret$control$nomega <- length(.omdf$lower) .ret$control$neta <- sum(.omdf$diag) .ret$control$ntheta <- length(lower) .ret$control$nfixed <- sum(fixed) lower <- c(lower, .omdf$lower) upper <- c(upper, .omdf$upper) } else { .ret$control$nomega <- 0 .ret$control$neta <- 0 .ret$xType <- -1 .ret$control$ntheta <- length(lower) .ret$control$nfixed <- sum(fixed) } .ret$lower <- lower .ret$upper <- upper .ret$thetaIni <- inits$THTA .scaleC <- double(length(lower)) if (is.null(control$scaleC)) { .scaleC <- rep(NA_real_, length(lower)) } else { .scaleC <- as.double(control$scaleC) if (length(lower) > length(.scaleC)) { .scaleC <- c(.scaleC, rep(NA_real_, length(lower) - length(.scaleC))) } else if (length(lower) < length(.scaleC)) { .scaleC <- .scaleC[seq(1, length(lower))] warning("scaleC control option has more options than estimated population parameters, please check.") } } .ret$scaleC <- .scaleC if (exists("uif", envir = .ret)) { .ini <- as.data.frame(.ret$uif$ini)[!is.na(.ret$uif$ini$err), c("est", "err", "ntheta")] for (.i in seq_along(.ini$err)) { if (is.na(.ret$scaleC[.ini$ntheta[.i]])) { if (any(.ini$err[.i] == c("boxCox", "yeoJohnson", "pow2", "tbs", "tbsYj"))) { .ret$scaleC[.ini$ntheta[.i]] <- 1 } else if (any(.ini$err[.i] == c("prop", "add", "norm", "dnorm", "logn", "dlogn", "lnorm", "dlnorm"))) { .ret$scaleC[.ini$ntheta[.i]] <- 0.5 * abs(.ini$est[.i]) } } } for (.i in .ini$model$extraProps$powTheta) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- 1 } .ini <- as.data.frame(.ret$uif$ini) for (.i in .ini$model$extraProps$factorial) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- abs(1/digamma(.ini$est[.i] + 1)) } for (.i in .ini$model$extraProps$gamma) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- abs(1/digamma(.ini$est[.i])) } for (.i in .ini$model$extraProps$log) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- log(abs(.ini$est[.i])) * abs(.ini$est[.i]) } for (.i in .ret$logitThetas) { .b <- .ret$logitThetasLow[.i] .c <- .ret$logitThetasHi[.i] .a <- .ini$est[.i] if (is.na(.ret$scaleC[.i])) { .ret$scaleC[.i] <- 1 * (-.b + .c) * exp(-.a)/((1 + exp(-.a))^2 * (.b + 1 * (-.b + .c)/(1 + exp(-.a)))) } } } names(.ret$thetaIni) <- sprintf("THETA[%d]", seq_along(.ret$thetaIni)) if (is.null(etaMat) & !is.null(control$etaMat)) { .ret$etaMat <- control$etaMat } else { .ret$etaMat <- etaMat } .ret$setupTime <- (proc.time() - .pt)["elapsed"] if (exists("uif", envir = .ret)) { .tmp <- .ret$uif$logThetasList .ret$logThetas <- .tmp[[1]] .ret$logThetasF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasList .ret$logitThetas <- .tmp[[1]] .ret$logitThetasF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasListLow .ret$logitThetasLow <- .tmp[[1]] .ret$logitThetasLowF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasListHi .ret$logitThetasHi <- .tmp[[1]] .ret$logitThetasHiF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasList .ret$probitThetas <- .tmp[[1]] .ret$probitThetasF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasListLow .ret$probitThetasLow <- .tmp[[1]] .ret$probitThetasLowF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasListHi .ret$probitThetasHi <- .tmp[[1]] .ret$probitThetasHiF <- .tmp[[2]] } else { .ret$logThetasF <- integer(0) .ret$logitThetasF <- integer(0) .ret$logitThetasHiF <- numeric(0) .ret$logitThetasLowF <- numeric(0) .ret$logitThetas <- integer(0) .ret$logitThetasHi <- numeric(0) .ret$logitThetasLow <- numeric(0) .ret$probitThetasF <- integer(0) .ret$probitThetasHiF <- numeric(0) .ret$probitThetasLowF <- numeric(0) .ret$probitThetas <- integer(0) .ret$probitThetasHi <- numeric(0) .ret$probitThetasLow <- numeric(0) } if (exists("noLik", envir = .ret)) { if (!.ret$noLik) { .ret$.params <- c(sprintf("THETA[%d]", seq_along(.ret$thetaIni)), sprintf("ETA[%d]", seq(1, dim(.om0)[1]))) .ret$.thetan <- length(.ret$thetaIni) .ret$nobs <- sum(data$EVID == 0) } } .ret$control$printTop <- TRUE .ret$control$nF <- 0 .est0 <- .ret$thetaIni if (!is.null(.ret$model$pred.nolhs)) { .ret$control$predNeq <- length(.ret$model$pred.nolhs$state) } else { .ret$control$predNeq <- 0L } .fitFun <- function(.ret) { this.env <- environment() assign("err", "theta reset", this.env) while (this.env$err == "theta reset") { assign("err", "", this.env) .ret0 <- tryCatch({ foceiFitCpp_(.ret) }, error = function(e) { if (regexpr("theta reset", e$message) != -1) { assign("zeroOuter", FALSE, this.env) assign("zeroGrad", FALSE, this.env) if (regexpr("theta reset0", e$message) != -1) { assign("zeroGrad", TRUE, this.env) } else if (regexpr("theta resetZ", e$message) != -1) { assign("zeroOuter", TRUE, this.env) } assign("err", "theta reset", this.env) } else { assign("err", e$message, this.env) } }) if (this.env$err == "theta reset") { .nm <- names(.ret$thetaIni) .ret$thetaIni <- setNames(.thetaReset$thetaIni + 0, .nm) .ret$rxInv$theta <- .thetaReset$omegaTheta .ret$control$printTop <- FALSE .ret$etaMat <- .thetaReset$etaMat .ret$control$etaMat <- .thetaReset$etaMat .ret$control$maxInnerIterations <- .thetaReset$maxInnerIterations .ret$control$nF <- .thetaReset$nF .ret$control$gillRetC <- .thetaReset$gillRetC .ret$control$gillRet <- .thetaReset$gillRet .ret$control$gillRet <- .thetaReset$gillRet .ret$control$gillDf <- .thetaReset$gillDf .ret$control$gillDf2 <- .thetaReset$gillDf2 .ret$control$gillErr <- .thetaReset$gillErr .ret$control$rEps <- .thetaReset$rEps .ret$control$aEps <- .thetaReset$aEps .ret$control$rEpsC <- .thetaReset$rEpsC .ret$control$aEpsC <- .thetaReset$aEpsC .ret$control$c1 <- .thetaReset$c1 .ret$control$c2 <- .thetaReset$c2 if (this.env$zeroOuter) { message("Posthoc reset") .ret$control$maxOuterIterations <- 0L } else if (this.env$zeroGrad) { message("Theta reset (zero gradient values); Switch to bobyqa") RxODE::rxReq("minqa") .ret$control$outerOptFun <- .bobyqa .ret$control$outerOpt <- -1L } else { message("Theta reset (ETA drift)") } } } if (this.env$err != "") { stop(this.env$err) } else { return(.ret0) } } .ret0 <- try(.fitFun(.ret)) .n <- 1 while (inherits(.ret0, "try-error") && control$maxOuterIterations != 0 && .n <= control$nRetries) { message(sprintf("Restart %s", .n)) .ret$control$nF <- 0 .estNew <- .est0 + 0.2 * .n * abs(.est0) * stats::runif(length(.est0)) - 0.1 * .n .estNew <- sapply(seq_along(.est0), function(.i) { if (.ret$thetaFixed[.i]) { return(.est0[.i]) } else if (.estNew[.i] < lower[.i]) { return(lower + (.Machine$double.eps)^(1/7)) } else if (.estNew[.i] > upper[.i]) { return(upper - (.Machine$double.eps)^(1/7)) } else { return(.estNew[.i]) } }) .ret$thetaIni <- .estNew .ret0 <- try(.fitFun(.ret)) .n <- .n + 1 } if (inherits(.ret0, "try-error")) stop("Could not fit data.") .ret <- .ret0 if (exists("parHistData", .ret)) { .tmp <- .ret$parHistData .tmp <- .tmp[.tmp$type == "Unscaled", names(.tmp) != "type"] .iter <- .tmp$iter .tmp <- .tmp[, names(.tmp) != "iter"] .ret$parHistStacked <- data.frame(stack(.tmp), iter = .iter) names(.ret$parHistStacked) <- c("val", "par", "iter") .ret$parHist <- data.frame(iter = .iter, .tmp) } if (.mixed) { .etas <- .ret$ranef .thetas <- .ret$fixef .pars <- .Call(`_nlmixr_nlmixrParameters`, .thetas, .etas) .ret$shrink <- .Call(`_nlmixr_calcShrinkOnly`, .ret$omega, .pars$eta.lst, length(.etas$ID)) .updateParFixed(.ret) } else { .updateParFixed(.ret) } if (!exists("table", .ret)) { .ret$table <- tableControl() } if (control$calcTables) { .ret <- addTable(.ret, updateObject = "no", keep = keep, drop = drop, table = .ret$table) } .ret})(data = dat, inits = .FoceiInits, PKpars = .pars, model = .mod, pred = function() { return(nlmixr_pred) }, err = uif$error, lower = uif$focei.lower, upper = uif$focei.upper, fixed = uif$focei.fixed, thetaNames = uif$focei.names, etaNames = uif$eta.names, control = control, env = env, keep = .keep, drop = .drop): Not all the covariates are in the dataset.</span></div><div class='output co'>#> <span class='message'>Timing stopped at: 18.05 0.446 18.5</span></div><div class='input'> +#> <span class='message'>dosenum=dosenum();</span></div><div class='output co'>#> <span class='message'>Needed Covariates:</span></div><div class='output co'>#> <span class='message'>[1] "f_parent_to_A1" "CMT" </span></div><div class='output co'>#> <span class='error'>Error in (function (data, inits, PKpars, model = NULL, pred = NULL, err = NULL, lower = -Inf, upper = Inf, fixed = NULL, skipCov = NULL, control = foceiControl(), thetaNames = NULL, etaNames = NULL, etaMat = NULL, ..., env = NULL, keep = NULL, drop = NULL) { set.seed(control$seed) .pt <- proc.time() RxODE::.setWarnIdSort(FALSE) on.exit(RxODE::.setWarnIdSort(TRUE)) loadNamespace("n1qn1") if (!RxODE::rxIs(control, "foceiControl")) { control <- do.call(foceiControl, control) } if (is.null(env)) { .ret <- new.env(parent = emptyenv()) } else { .ret <- env } .ret$origData <- data .ret$etaNames <- etaNames .ret$thetaFixed <- fixed .ret$control <- control .ret$control$focei.mu.ref <- integer(0) if (is(model, "RxODE") || is(model, "character")) { .ret$ODEmodel <- TRUE if (class(pred) != "function") { stop("pred must be a function specifying the prediction variables in this model.") } } else { .ret$ODEmodel <- TRUE model <- RxODE::rxGetLin(PKpars) pred <- eval(parse(text = "function(){return(Central);}")) } .square <- function(x) x * x .ret$diagXformInv <- c(sqrt = ".square", log = "exp", identity = "identity")[control$diagXform] if (is.null(err)) { err <- eval(parse(text = paste0("function(){err", paste(inits$ERROR[[1]], collapse = ""), "}"))) } .covNames <- .parNames <- c() .ret$adjLik <- control$adjLik .mixed <- !is.null(inits$OMGA) && length(inits$OMGA) > 0 if (!exists("noLik", envir = .ret)) { .atol <- rep(control$atol, length(RxODE::rxModelVars(model)$state)) .rtol <- rep(control$rtol, length(RxODE::rxModelVars(model)$state)) .ssAtol <- rep(control$ssAtol, length(RxODE::rxModelVars(model)$state)) .ssRtol <- rep(control$ssRtol, length(RxODE::rxModelVars(model)$state)) .ret$model <- RxODE::rxSymPySetupPred(model, pred, PKpars, err, grad = (control$derivMethod == 2L), pred.minus.dv = TRUE, sum.prod = control$sumProd, theta.derivs = FALSE, optExpression = control$optExpression, interaction = (control$interaction == 1L), only.numeric = !.mixed, run.internal = TRUE, addProp = control$addProp) if (!is.null(.ret$model$inner)) { .atol <- c(.atol, rep(control$atolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.atol))) .rtol <- c(.rtol, rep(control$rtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.rtol))) .ret$control$rxControl$atol <- .atol .ret$control$rxControl$rtol <- .rtol .ssAtol <- c(.ssAtol, rep(control$ssAtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.ssAtol))) .ssRtol <- c(.ssRtol, rep(control$ssRtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.ssRtol))) .ret$control$rxControl$ssAtol <- .ssAtol .ret$control$rxControl$ssRtol <- .ssRtol } .covNames <- .parNames <- RxODE::rxParams(.ret$model$pred.only) .covNames <- .covNames[regexpr(rex::rex(start, or("THETA", "ETA"), "[", numbers, "]", end), .covNames) == -1] colnames(data) <- sapply(names(data), function(x) { if (any(x == .covNames)) { return(x) } else { return(toupper(x)) } }) .lhs <- c(names(RxODE::rxInits(.ret$model$pred.only)), RxODE::rxLhs(.ret$model$pred.only)) if (length(.lhs) > 0) { .covNames <- .covNames[regexpr(rex::rex(start, or(.lhs), end), .covNames) == -1] } if (length(.covNames) > 0) { if (!all(.covNames %in% names(data))) { message("Model:") RxODE::rxCat(.ret$model$pred.only) message("Needed Covariates:") nlmixrPrint(.covNames) stop("Not all the covariates are in the dataset.") } message("Needed Covariates:") print(.covNames) } .extraPars <- .ret$model$extra.pars } else { if (.ret$noLik) { .atol <- rep(control$atol, length(RxODE::rxModelVars(model)$state)) .rtol <- rep(control$rtol, length(RxODE::rxModelVars(model)$state)) .ret$model <- RxODE::rxSymPySetupPred(model, pred, PKpars, err, grad = FALSE, pred.minus.dv = TRUE, sum.prod = control$sumProd, theta.derivs = FALSE, optExpression = control$optExpression, run.internal = TRUE, only.numeric = TRUE, addProp = control$addProp) if (!is.null(.ret$model$inner)) { .atol <- c(.atol, rep(control$atolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.atol))) .rtol <- c(.rtol, rep(control$rtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.rtol))) .ret$control$rxControl$atol <- .atol .ret$control$rxControl$rtol <- .rtol } .covNames <- .parNames <- RxODE::rxParams(.ret$model$pred.only) .covNames <- .covNames[regexpr(rex::rex(start, or("THETA", "ETA"), "[", numbers, "]", end), .covNames) == -1] colnames(data) <- sapply(names(data), function(x) { if (any(x == .covNames)) { return(x) } else { return(toupper(x)) } }) .lhs <- c(names(RxODE::rxInits(.ret$model$pred.only)), RxODE::rxLhs(.ret$model$pred.only)) if (length(.lhs) > 0) { .covNames <- .covNames[regexpr(rex::rex(start, or(.lhs), end), .covNames) == -1] } if (length(.covNames) > 0) { if (!all(.covNames %in% names(data))) { message("Model:") RxODE::rxCat(.ret$model$pred.only) message("Needed Covariates:") nlmixrPrint(.covNames) stop("Not all the covariates are in the dataset.") } message("Needed Covariates:") print(.covNames) } .extraPars <- .ret$model$extra.pars } else { .extraPars <- NULL } } .ret$skipCov <- skipCov if (is.null(skipCov)) { if (is.null(fixed)) { .tmp <- rep(FALSE, length(inits$THTA)) } else { if (length(fixed) < length(inits$THTA)) { .tmp <- c(fixed, rep(FALSE, length(inits$THTA) - length(fixed))) } else { .tmp <- fixed[1:length(inits$THTA)] } } if (exists("uif", envir = .ret)) { .uifErr <- .ret$uif$ini$err[!is.na(.ret$uif$ini$ntheta)] .uifErr <- sapply(.uifErr, function(x) { if (is.na(x)) { return(FALSE) } return(!any(x == c("pow2", "tbs", "tbsYj"))) }) .tmp <- (.tmp | .uifErr) } .ret$skipCov <- c(.tmp, rep(TRUE, length(.extraPars))) .ret$control$focei.mu.ref <- .ret$uif$focei.mu.ref } if (is.null(.extraPars)) { .nms <- c(sprintf("THETA[%s]", seq_along(inits$THTA))) } else { .nms <- c(sprintf("THETA[%s]", seq_along(inits$THTA)), sprintf("ERR[%s]", seq_along(.extraPars))) } if (!is.null(thetaNames) && (length(inits$THTA) + length(.extraPars)) == length(thetaNames)) { .nms <- thetaNames } .ret$thetaNames <- .nms .thetaReset$thetaNames <- .nms if (length(lower) == 1) { lower <- rep(lower, length(inits$THTA)) } else if (length(lower) != length(inits$THTA)) { print(inits$THTA) print(lower) stop("Lower must be a single constant for all the THETA lower bounds, or match the dimension of THETA.") } if (length(upper) == 1) { upper <- rep(upper, length(inits$THTA)) } else if (length(lower) != length(inits$THTA)) { stop("Upper must be a single constant for all the THETA lower bounds, or match the dimension of THETA.") } if (!is.null(.extraPars)) { .ret$model$extra.pars <- eval(call(control$diagXform, .ret$model$extra.pars)) if (length(.ret$model$extra.pars) > 0) { inits$THTA <- c(inits$THTA, .ret$model$extra.pars) .lowerErr <- rep(control$atol[1] * 10, length(.ret$model$extra.pars)) .upperErr <- rep(Inf, length(.ret$model$extra.pars)) lower <- c(lower, .lowerErr) upper <- c(upper, .upperErr) } } if (is.null(data$ID)) stop("\"ID\" not found in data") if (is.null(data$DV)) stop("\"DV\" not found in data") if (is.null(data$EVID)) data$EVID <- 0 if (is.null(data$AMT)) data$AMT <- 0 for (.v in c("TIME", "AMT", "DV", .covNames)) { data[[.v]] <- as.double(data[[.v]]) } .ret$dataSav <- data .ds <- data[data$EVID != 0 & data$EVID != 2, c("ID", "TIME", "AMT", "EVID", .covNames)] .w <- which(tolower(names(data)) == "limit") .limitName <- NULL if (length(.w) == 1L) { .limitName <- names(data)[.w] } .censName <- NULL .w <- which(tolower(names(data)) == "cens") if (length(.w) == 1L) { .censName <- names(data[.w]) } data <- data[data$EVID == 0 | data$EVID == 2, c("ID", "TIME", "DV", "EVID", .covNames, .limitName, .censName)] .w <- which(!(names(.ret$dataSav) %in% c(.covNames, keep))) names(.ret$dataSav)[.w] <- tolower(names(.ret$dataSav[.w])) if (.mixed) { .lh <- .parseOM(inits$OMGA) .nlh <- sapply(.lh, length) .osplt <- rep(1:length(.lh), .nlh) .lini <- list(inits$THTA, unlist(.lh)) .nlini <- sapply(.lini, length) .nsplt <- rep(1:length(.lini), .nlini) .om0 <- .genOM(.lh) if (length(etaNames) == dim(.om0)[1]) { .ret$etaNames <- .ret$etaNames } else { .ret$etaNames <- sprintf("ETA[%d]", seq(1, dim(.om0)[1])) } .ret$rxInv <- RxODE::rxSymInvCholCreate(mat = .om0, diag.xform = control$diagXform) .ret$xType <- .ret$rxInv$xType .om0a <- .om0 .om0a <- .om0a/control$diagOmegaBoundLower .om0b <- .om0 .om0b <- .om0b * control$diagOmegaBoundUpper .om0a <- RxODE::rxSymInvCholCreate(mat = .om0a, diag.xform = control$diagXform) .om0b <- RxODE::rxSymInvCholCreate(mat = .om0b, diag.xform = control$diagXform) .omdf <- data.frame(a = .om0a$theta, m = .ret$rxInv$theta, b = .om0b$theta, diag = .om0a$theta.diag) .omdf$lower <- with(.omdf, ifelse(a > b, b, a)) .omdf$lower <- with(.omdf, ifelse(lower == m, -Inf, lower)) .omdf$lower <- with(.omdf, ifelse(!diag, -Inf, lower)) .omdf$upper <- with(.omdf, ifelse(a < b, b, a)) .omdf$upper <- with(.omdf, ifelse(upper == m, Inf, upper)) .omdf$upper <- with(.omdf, ifelse(!diag, Inf, upper)) .ret$control$nomega <- length(.omdf$lower) .ret$control$neta <- sum(.omdf$diag) .ret$control$ntheta <- length(lower) .ret$control$nfixed <- sum(fixed) lower <- c(lower, .omdf$lower) upper <- c(upper, .omdf$upper) } else { .ret$control$nomega <- 0 .ret$control$neta <- 0 .ret$xType <- -1 .ret$control$ntheta <- length(lower) .ret$control$nfixed <- sum(fixed) } .ret$lower <- lower .ret$upper <- upper .ret$thetaIni <- inits$THTA .scaleC <- double(length(lower)) if (is.null(control$scaleC)) { .scaleC <- rep(NA_real_, length(lower)) } else { .scaleC <- as.double(control$scaleC) if (length(lower) > length(.scaleC)) { .scaleC <- c(.scaleC, rep(NA_real_, length(lower) - length(.scaleC))) } else if (length(lower) < length(.scaleC)) { .scaleC <- .scaleC[seq(1, length(lower))] warning("scaleC control option has more options than estimated population parameters, please check.") } } .ret$scaleC <- .scaleC if (exists("uif", envir = .ret)) { .ini <- as.data.frame(.ret$uif$ini)[!is.na(.ret$uif$ini$err), c("est", "err", "ntheta")] for (.i in seq_along(.ini$err)) { if (is.na(.ret$scaleC[.ini$ntheta[.i]])) { if (any(.ini$err[.i] == c("boxCox", "yeoJohnson", "pow2", "tbs", "tbsYj"))) { .ret$scaleC[.ini$ntheta[.i]] <- 1 } else if (any(.ini$err[.i] == c("prop", "add", "norm", "dnorm", "logn", "dlogn", "lnorm", "dlnorm"))) { .ret$scaleC[.ini$ntheta[.i]] <- 0.5 * abs(.ini$est[.i]) } } } for (.i in .ini$model$extraProps$powTheta) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- 1 } .ini <- as.data.frame(.ret$uif$ini) for (.i in .ini$model$extraProps$factorial) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- abs(1/digamma(.ini$est[.i] + 1)) } for (.i in .ini$model$extraProps$gamma) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- abs(1/digamma(.ini$est[.i])) } for (.i in .ini$model$extraProps$log) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- log(abs(.ini$est[.i])) * abs(.ini$est[.i]) } for (.i in .ret$logitThetas) { .b <- .ret$logitThetasLow[.i] .c <- .ret$logitThetasHi[.i] .a <- .ini$est[.i] if (is.na(.ret$scaleC[.i])) { .ret$scaleC[.i] <- 1 * (-.b + .c) * exp(-.a)/((1 + exp(-.a))^2 * (.b + 1 * (-.b + .c)/(1 + exp(-.a)))) } } } names(.ret$thetaIni) <- sprintf("THETA[%d]", seq_along(.ret$thetaIni)) if (is.null(etaMat) & !is.null(control$etaMat)) { .ret$etaMat <- control$etaMat } else { .ret$etaMat <- etaMat } .ret$setupTime <- (proc.time() - .pt)["elapsed"] if (exists("uif", envir = .ret)) { .tmp <- .ret$uif$logThetasList .ret$logThetas <- .tmp[[1]] .ret$logThetasF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasList .ret$logitThetas <- .tmp[[1]] .ret$logitThetasF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasListLow .ret$logitThetasLow <- .tmp[[1]] .ret$logitThetasLowF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasListHi .ret$logitThetasHi <- .tmp[[1]] .ret$logitThetasHiF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasList .ret$probitThetas <- .tmp[[1]] .ret$probitThetasF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasListLow .ret$probitThetasLow <- .tmp[[1]] .ret$probitThetasLowF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasListHi .ret$probitThetasHi <- .tmp[[1]] .ret$probitThetasHiF <- .tmp[[2]] } else { .ret$logThetasF <- integer(0) .ret$logitThetasF <- integer(0) .ret$logitThetasHiF <- numeric(0) .ret$logitThetasLowF <- numeric(0) .ret$logitThetas <- integer(0) .ret$logitThetasHi <- numeric(0) .ret$logitThetasLow <- numeric(0) .ret$probitThetasF <- integer(0) .ret$probitThetasHiF <- numeric(0) .ret$probitThetasLowF <- numeric(0) .ret$probitThetas <- integer(0) .ret$probitThetasHi <- numeric(0) .ret$probitThetasLow <- numeric(0) } if (exists("noLik", envir = .ret)) { if (!.ret$noLik) { .ret$.params <- c(sprintf("THETA[%d]", seq_along(.ret$thetaIni)), sprintf("ETA[%d]", seq(1, dim(.om0)[1]))) .ret$.thetan <- length(.ret$thetaIni) .ret$nobs <- sum(data$EVID == 0) } } .ret$control$printTop <- TRUE .ret$control$nF <- 0 .est0 <- .ret$thetaIni if (!is.null(.ret$model$pred.nolhs)) { .ret$control$predNeq <- length(.ret$model$pred.nolhs$state) } else { .ret$control$predNeq <- 0L } .fitFun <- function(.ret) { this.env <- environment() assign("err", "theta reset", this.env) while (this.env$err == "theta reset") { assign("err", "", this.env) .ret0 <- tryCatch({ foceiFitCpp_(.ret) }, error = function(e) { if (regexpr("theta reset", e$message) != -1) { assign("zeroOuter", FALSE, this.env) assign("zeroGrad", FALSE, this.env) if (regexpr("theta reset0", e$message) != -1) { assign("zeroGrad", TRUE, this.env) } else if (regexpr("theta resetZ", e$message) != -1) { assign("zeroOuter", TRUE, this.env) } assign("err", "theta reset", this.env) } else { assign("err", e$message, this.env) } }) if (this.env$err == "theta reset") { .nm <- names(.ret$thetaIni) .ret$thetaIni <- setNames(.thetaReset$thetaIni + 0, .nm) .ret$rxInv$theta <- .thetaReset$omegaTheta .ret$control$printTop <- FALSE .ret$etaMat <- .thetaReset$etaMat .ret$control$etaMat <- .thetaReset$etaMat .ret$control$maxInnerIterations <- .thetaReset$maxInnerIterations .ret$control$nF <- .thetaReset$nF .ret$control$gillRetC <- .thetaReset$gillRetC .ret$control$gillRet <- .thetaReset$gillRet .ret$control$gillRet <- .thetaReset$gillRet .ret$control$gillDf <- .thetaReset$gillDf .ret$control$gillDf2 <- .thetaReset$gillDf2 .ret$control$gillErr <- .thetaReset$gillErr .ret$control$rEps <- .thetaReset$rEps .ret$control$aEps <- .thetaReset$aEps .ret$control$rEpsC <- .thetaReset$rEpsC .ret$control$aEpsC <- .thetaReset$aEpsC .ret$control$c1 <- .thetaReset$c1 .ret$control$c2 <- .thetaReset$c2 if (this.env$zeroOuter) { message("Posthoc reset") .ret$control$maxOuterIterations <- 0L } else if (this.env$zeroGrad) { message("Theta reset (zero gradient values); Switch to bobyqa") RxODE::rxReq("minqa") .ret$control$outerOptFun <- .bobyqa .ret$control$outerOpt <- -1L } else { message("Theta reset (ETA drift)") } } } if (this.env$err != "") { stop(this.env$err) } else { return(.ret0) } } .ret0 <- try(.fitFun(.ret)) .n <- 1 while (inherits(.ret0, "try-error") && control$maxOuterIterations != 0 && .n <= control$nRetries) { message(sprintf("Restart %s", .n)) .ret$control$nF <- 0 .estNew <- .est0 + 0.2 * .n * abs(.est0) * stats::runif(length(.est0)) - 0.1 * .n .estNew <- sapply(seq_along(.est0), function(.i) { if (.ret$thetaFixed[.i]) { return(.est0[.i]) } else if (.estNew[.i] < lower[.i]) { return(lower + (.Machine$double.eps)^(1/7)) } else if (.estNew[.i] > upper[.i]) { return(upper - (.Machine$double.eps)^(1/7)) } else { return(.estNew[.i]) } }) .ret$thetaIni <- .estNew .ret0 <- try(.fitFun(.ret)) .n <- .n + 1 } if (inherits(.ret0, "try-error")) stop("Could not fit data.") .ret <- .ret0 if (exists("parHistData", .ret)) { .tmp <- .ret$parHistData .tmp <- .tmp[.tmp$type == "Unscaled", names(.tmp) != "type"] .iter <- .tmp$iter .tmp <- .tmp[, names(.tmp) != "iter"] .ret$parHistStacked <- data.frame(stack(.tmp), iter = .iter) names(.ret$parHistStacked) <- c("val", "par", "iter") .ret$parHist <- data.frame(iter = .iter, .tmp) } if (.mixed) { .etas <- .ret$ranef .thetas <- .ret$fixef .pars <- .Call(`_nlmixr_nlmixrParameters`, .thetas, .etas) .ret$shrink <- .Call(`_nlmixr_calcShrinkOnly`, .ret$omega, .pars$eta.lst, length(.etas$ID)) .updateParFixed(.ret) } else { .updateParFixed(.ret) } if (!exists("table", .ret)) { .ret$table <- tableControl() } if (control$calcTables) { .ret <- addTable(.ret, updateObject = "no", keep = keep, drop = drop, table = .ret$table) } .ret})(data = dat, inits = .FoceiInits, PKpars = .pars, model = .mod, pred = function() { return(nlmixr_pred) }, err = uif$error, lower = uif$focei.lower, upper = uif$focei.upper, fixed = uif$focei.fixed, thetaNames = uif$focei.names, etaNames = uif$eta.names, control = control, env = env, keep = .keep, drop = .drop): Not all the covariates are in the dataset.</span></div><div class='output co'>#> <span class='message'>Timing stopped at: 18.44 0.438 18.87</span></div><div class='input'> <span class='co'># Two-component error by variable is possible with both estimation methods</span> <span class='co'># Variance by variable is supported by 'saem' and 'focei'</span> <span class='va'>f_nlmixr_fomc_sfo_saem_obs_tc</span> <span class='op'><-</span> <span class='fu'><a href='https://rdrr.io/pkg/nlmixr/man/nlmixr.html'>nlmixr</a></span><span class='op'>(</span><span class='va'>f_mmkin_tc</span><span class='op'>[</span><span class='st'>"FOMC-SFO"</span>, <span class='op'>]</span>, est <span class='op'>=</span> <span class='st'>"saem"</span>, error_model <span class='op'>=</span> <span class='st'>"obs_tc"</span><span class='op'>)</span> -</div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> parameter labels from comments are typically ignored in non-interactive mode</span></div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> Need to run with the source intact to parse comments</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='error'>Error in configsaem(model = model, data = dat, inits = inits, mcmc = .mcmc, ODEopt = .ODEopt, seed = .seed, distribution = .dist, DEBUG = .DEBUG, addProp = .addProp, tol = .tol, itmax = .itmax, type = .type, powRange = .powRange, lambdaRange = .lambdaRange): covariate(s) not found: f_parent_to_A1</span></div><div class='output co'>#> <span class='message'>Timing stopped at: 0.763 0.036 0.799</span></div><div class='input'><span class='va'>f_nlmixr_fomc_sfo_focei_obs_tc</span> <span class='op'><-</span> <span class='fu'><a href='https://rdrr.io/pkg/nlmixr/man/nlmixr.html'>nlmixr</a></span><span class='op'>(</span><span class='va'>f_mmkin_tc</span><span class='op'>[</span><span class='st'>"FOMC-SFO"</span>, <span class='op'>]</span>, est <span class='op'>=</span> <span class='st'>"focei"</span>, +</div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> parameter labels from comments are typically ignored in non-interactive mode</span></div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> Need to run with the source intact to parse comments</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='error'>Error in configsaem(model = model, data = dat, inits = inits, mcmc = .mcmc, ODEopt = .ODEopt, seed = .seed, distribution = .dist, DEBUG = .DEBUG, addProp = .addProp, tol = .tol, itmax = .itmax, type = .type, powRange = .powRange, lambdaRange = .lambdaRange): covariate(s) not found: f_parent_to_A1</span></div><div class='output co'>#> <span class='message'>Timing stopped at: 0.784 0.028 0.812</span></div><div class='input'><span class='va'>f_nlmixr_fomc_sfo_focei_obs_tc</span> <span class='op'><-</span> <span class='fu'><a href='https://rdrr.io/pkg/nlmixr/man/nlmixr.html'>nlmixr</a></span><span class='op'>(</span><span class='va'>f_mmkin_tc</span><span class='op'>[</span><span class='st'>"FOMC-SFO"</span>, <span class='op'>]</span>, est <span class='op'>=</span> <span class='st'>"focei"</span>, error_model <span class='op'>=</span> <span class='st'>"obs_tc"</span><span class='op'>)</span> </div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> parameter labels from comments are typically ignored in non-interactive mode</span></div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> Need to run with the source intact to parse comments</span></div><div class='output co'>#> <span class='message'>→ creating full model...</span></div><div class='output co'>#> <span class='message'>→ pruning branches (<span style='color: #262626; background-color: #DADADA;'>`if`</span>/<span style='color: #262626; background-color: #DADADA;'>`else`</span>)...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ loading into <span style='color: #0000BB;'>symengine</span> environment...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ creating full model...</span></div><div class='output co'>#> <span class='message'>→ pruning branches (<span style='color: #262626; background-color: #DADADA;'>`if`</span>/<span style='color: #262626; background-color: #DADADA;'>`else`</span>)...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ loading into <span style='color: #0000BB;'>symengine</span> environment...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ calculate jacobian</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ calculate sensitivities</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ calculate ∂(f)/∂(η)</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ calculate ∂(R²)/∂(η)</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ finding duplicate expressions in inner model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ optimizing duplicate expressions in inner model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ finding duplicate expressions in EBE model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ optimizing duplicate expressions in EBE model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ compiling inner model...</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ finding duplicate expressions in FD model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ optimizing duplicate expressions in FD model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ compiling EBE model...</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ compiling events FD model...</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>Model:</span></div><div class='output co'>#> <span class='message'>cmt(parent);</span> #> <span class='message'>cmt(A1);</span> @@ -4887,9 +4887,9 @@ obtained by fitting the same model to a list of datasets using <a href='mkinfit. #> <span class='message'>beta=exp(rx_expr_8);</span> #> <span class='message'>f_parent=1/(1+exp(-(ETA[3]+THETA[3])));</span> #> <span class='message'>tad=tad();</span> -#> <span class='message'>dosenum=dosenum();</span></div><div class='output co'>#> <span class='message'>Needed Covariates:</span></div><div class='output co'>#> <span class='message'>[1] "f_parent_to_A1" "CMT" </span></div><div class='output co'>#> <span class='error'>Error in (function (data, inits, PKpars, model = NULL, pred = NULL, err = NULL, lower = -Inf, upper = Inf, fixed = NULL, skipCov = NULL, control = foceiControl(), thetaNames = NULL, etaNames = NULL, etaMat = NULL, ..., env = NULL, keep = NULL, drop = NULL) { set.seed(control$seed) .pt <- proc.time() RxODE::.setWarnIdSort(FALSE) on.exit(RxODE::.setWarnIdSort(TRUE)) loadNamespace("n1qn1") if (!RxODE::rxIs(control, "foceiControl")) { control <- do.call(foceiControl, control) } if (is.null(env)) { .ret <- new.env(parent = emptyenv()) } else { .ret <- env } .ret$origData <- data .ret$etaNames <- etaNames .ret$thetaFixed <- fixed .ret$control <- control .ret$control$focei.mu.ref <- integer(0) if (is(model, "RxODE") || is(model, "character")) { .ret$ODEmodel <- TRUE if (class(pred) != "function") { stop("pred must be a function specifying the prediction variables in this model.") } } else { .ret$ODEmodel <- TRUE model <- RxODE::rxGetLin(PKpars) pred <- eval(parse(text = "function(){return(Central);}")) } .square <- function(x) x * x .ret$diagXformInv <- c(sqrt = ".square", log = "exp", identity = "identity")[control$diagXform] if (is.null(err)) { err <- eval(parse(text = paste0("function(){err", paste(inits$ERROR[[1]], collapse = ""), "}"))) } .covNames <- .parNames <- c() .ret$adjLik <- control$adjLik .mixed <- !is.null(inits$OMGA) && length(inits$OMGA) > 0 if (!exists("noLik", envir = .ret)) { .atol <- rep(control$atol, length(RxODE::rxModelVars(model)$state)) .rtol <- rep(control$rtol, length(RxODE::rxModelVars(model)$state)) .ssAtol <- rep(control$ssAtol, length(RxODE::rxModelVars(model)$state)) .ssRtol <- rep(control$ssRtol, length(RxODE::rxModelVars(model)$state)) .ret$model <- RxODE::rxSymPySetupPred(model, pred, PKpars, err, grad = (control$derivMethod == 2L), pred.minus.dv = TRUE, sum.prod = control$sumProd, theta.derivs = FALSE, optExpression = control$optExpression, interaction = (control$interaction == 1L), only.numeric = !.mixed, run.internal = TRUE, addProp = control$addProp) if (!is.null(.ret$model$inner)) { .atol <- c(.atol, rep(control$atolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.atol))) .rtol <- c(.rtol, rep(control$rtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.rtol))) .ret$control$rxControl$atol <- .atol .ret$control$rxControl$rtol <- .rtol .ssAtol <- c(.ssAtol, rep(control$ssAtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.ssAtol))) .ssRtol <- c(.ssRtol, rep(control$ssRtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.ssRtol))) .ret$control$rxControl$ssAtol <- .ssAtol .ret$control$rxControl$ssRtol <- .ssRtol } .covNames <- .parNames <- RxODE::rxParams(.ret$model$pred.only) .covNames <- .covNames[regexpr(rex::rex(start, or("THETA", "ETA"), "[", numbers, "]", end), .covNames) == -1] colnames(data) <- sapply(names(data), function(x) { if (any(x == .covNames)) { return(x) } else { return(toupper(x)) } }) .lhs <- c(names(RxODE::rxInits(.ret$model$pred.only)), RxODE::rxLhs(.ret$model$pred.only)) if (length(.lhs) > 0) { .covNames <- .covNames[regexpr(rex::rex(start, or(.lhs), end), .covNames) == -1] } if (length(.covNames) > 0) { if (!all(.covNames %in% names(data))) { message("Model:") RxODE::rxCat(.ret$model$pred.only) message("Needed Covariates:") nlmixrPrint(.covNames) stop("Not all the covariates are in the dataset.") } message("Needed Covariates:") print(.covNames) } .extraPars <- .ret$model$extra.pars } else { if (.ret$noLik) { .atol <- rep(control$atol, length(RxODE::rxModelVars(model)$state)) .rtol <- rep(control$rtol, length(RxODE::rxModelVars(model)$state)) .ret$model <- RxODE::rxSymPySetupPred(model, pred, PKpars, err, grad = FALSE, pred.minus.dv = TRUE, sum.prod = control$sumProd, theta.derivs = FALSE, optExpression = control$optExpression, run.internal = TRUE, only.numeric = TRUE, addProp = control$addProp) if (!is.null(.ret$model$inner)) { .atol <- c(.atol, rep(control$atolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.atol))) .rtol <- c(.rtol, rep(control$rtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.rtol))) .ret$control$rxControl$atol <- .atol .ret$control$rxControl$rtol <- .rtol } .covNames <- .parNames <- RxODE::rxParams(.ret$model$pred.only) .covNames <- .covNames[regexpr(rex::rex(start, or("THETA", "ETA"), "[", numbers, "]", end), .covNames) == -1] colnames(data) <- sapply(names(data), function(x) { if (any(x == .covNames)) { return(x) } else { return(toupper(x)) } }) .lhs <- c(names(RxODE::rxInits(.ret$model$pred.only)), RxODE::rxLhs(.ret$model$pred.only)) if (length(.lhs) > 0) { .covNames <- .covNames[regexpr(rex::rex(start, or(.lhs), end), .covNames) == -1] } if (length(.covNames) > 0) { if (!all(.covNames %in% names(data))) { message("Model:") RxODE::rxCat(.ret$model$pred.only) message("Needed Covariates:") nlmixrPrint(.covNames) stop("Not all the covariates are in the dataset.") } message("Needed Covariates:") print(.covNames) } .extraPars <- .ret$model$extra.pars } else { .extraPars <- NULL } } .ret$skipCov <- skipCov if (is.null(skipCov)) { if (is.null(fixed)) { .tmp <- rep(FALSE, length(inits$THTA)) } else { if (length(fixed) < length(inits$THTA)) { .tmp <- c(fixed, rep(FALSE, length(inits$THTA) - length(fixed))) } else { .tmp <- fixed[1:length(inits$THTA)] } } if (exists("uif", envir = .ret)) { .uifErr <- .ret$uif$ini$err[!is.na(.ret$uif$ini$ntheta)] .uifErr <- sapply(.uifErr, function(x) { if (is.na(x)) { return(FALSE) } return(!any(x == c("pow2", "tbs", "tbsYj"))) }) .tmp <- (.tmp | .uifErr) } .ret$skipCov <- c(.tmp, rep(TRUE, length(.extraPars))) .ret$control$focei.mu.ref <- .ret$uif$focei.mu.ref } if (is.null(.extraPars)) { .nms <- c(sprintf("THETA[%s]", seq_along(inits$THTA))) } else { .nms <- c(sprintf("THETA[%s]", seq_along(inits$THTA)), sprintf("ERR[%s]", seq_along(.extraPars))) } if (!is.null(thetaNames) && (length(inits$THTA) + length(.extraPars)) == length(thetaNames)) { .nms <- thetaNames } .ret$thetaNames <- .nms .thetaReset$thetaNames <- .nms if (length(lower) == 1) { lower <- rep(lower, length(inits$THTA)) } else if (length(lower) != length(inits$THTA)) { print(inits$THTA) print(lower) stop("Lower must be a single constant for all the THETA lower bounds, or match the dimension of THETA.") } if (length(upper) == 1) { upper <- rep(upper, length(inits$THTA)) } else if (length(lower) != length(inits$THTA)) { stop("Upper must be a single constant for all the THETA lower bounds, or match the dimension of THETA.") } if (!is.null(.extraPars)) { .ret$model$extra.pars <- eval(call(control$diagXform, .ret$model$extra.pars)) if (length(.ret$model$extra.pars) > 0) { inits$THTA <- c(inits$THTA, .ret$model$extra.pars) .lowerErr <- rep(control$atol[1] * 10, length(.ret$model$extra.pars)) .upperErr <- rep(Inf, length(.ret$model$extra.pars)) lower <- c(lower, .lowerErr) upper <- c(upper, .upperErr) } } if (is.null(data$ID)) stop("\"ID\" not found in data") if (is.null(data$DV)) stop("\"DV\" not found in data") if (is.null(data$EVID)) data$EVID <- 0 if (is.null(data$AMT)) data$AMT <- 0 for (.v in c("TIME", "AMT", "DV", .covNames)) { data[[.v]] <- as.double(data[[.v]]) } .ret$dataSav <- data .ds <- data[data$EVID != 0 & data$EVID != 2, c("ID", "TIME", "AMT", "EVID", .covNames)] .w <- which(tolower(names(data)) == "limit") .limitName <- NULL if (length(.w) == 1L) { .limitName <- names(data)[.w] } .censName <- NULL .w <- which(tolower(names(data)) == "cens") if (length(.w) == 1L) { .censName <- names(data[.w]) } data <- data[data$EVID == 0 | data$EVID == 2, c("ID", "TIME", "DV", "EVID", .covNames, .limitName, .censName)] .w <- which(!(names(.ret$dataSav) %in% c(.covNames, keep))) names(.ret$dataSav)[.w] <- tolower(names(.ret$dataSav[.w])) if (.mixed) { .lh <- .parseOM(inits$OMGA) .nlh <- sapply(.lh, length) .osplt <- rep(1:length(.lh), .nlh) .lini <- list(inits$THTA, unlist(.lh)) .nlini <- sapply(.lini, length) .nsplt <- rep(1:length(.lini), .nlini) .om0 <- .genOM(.lh) if (length(etaNames) == dim(.om0)[1]) { .ret$etaNames <- .ret$etaNames } else { .ret$etaNames <- sprintf("ETA[%d]", seq(1, dim(.om0)[1])) } .ret$rxInv <- RxODE::rxSymInvCholCreate(mat = .om0, diag.xform = control$diagXform) .ret$xType <- .ret$rxInv$xType .om0a <- .om0 .om0a <- .om0a/control$diagOmegaBoundLower .om0b <- .om0 .om0b <- .om0b * control$diagOmegaBoundUpper .om0a <- RxODE::rxSymInvCholCreate(mat = .om0a, diag.xform = control$diagXform) .om0b <- RxODE::rxSymInvCholCreate(mat = .om0b, diag.xform = control$diagXform) .omdf <- data.frame(a = .om0a$theta, m = .ret$rxInv$theta, b = .om0b$theta, diag = .om0a$theta.diag) .omdf$lower <- with(.omdf, ifelse(a > b, b, a)) .omdf$lower <- with(.omdf, ifelse(lower == m, -Inf, lower)) .omdf$lower <- with(.omdf, ifelse(!diag, -Inf, lower)) .omdf$upper <- with(.omdf, ifelse(a < b, b, a)) .omdf$upper <- with(.omdf, ifelse(upper == m, Inf, upper)) .omdf$upper <- with(.omdf, ifelse(!diag, Inf, upper)) .ret$control$nomega <- length(.omdf$lower) .ret$control$neta <- sum(.omdf$diag) .ret$control$ntheta <- length(lower) .ret$control$nfixed <- sum(fixed) lower <- c(lower, .omdf$lower) upper <- c(upper, .omdf$upper) } else { .ret$control$nomega <- 0 .ret$control$neta <- 0 .ret$xType <- -1 .ret$control$ntheta <- length(lower) .ret$control$nfixed <- sum(fixed) } .ret$lower <- lower .ret$upper <- upper .ret$thetaIni <- inits$THTA .scaleC <- double(length(lower)) if (is.null(control$scaleC)) { .scaleC <- rep(NA_real_, length(lower)) } else { .scaleC <- as.double(control$scaleC) if (length(lower) > length(.scaleC)) { .scaleC <- c(.scaleC, rep(NA_real_, length(lower) - length(.scaleC))) } else if (length(lower) < length(.scaleC)) { .scaleC <- .scaleC[seq(1, length(lower))] warning("scaleC control option has more options than estimated population parameters, please check.") } } .ret$scaleC <- .scaleC if (exists("uif", envir = .ret)) { .ini <- as.data.frame(.ret$uif$ini)[!is.na(.ret$uif$ini$err), c("est", "err", "ntheta")] for (.i in seq_along(.ini$err)) { if (is.na(.ret$scaleC[.ini$ntheta[.i]])) { if (any(.ini$err[.i] == c("boxCox", "yeoJohnson", "pow2", "tbs", "tbsYj"))) { .ret$scaleC[.ini$ntheta[.i]] <- 1 } else if (any(.ini$err[.i] == c("prop", "add", "norm", "dnorm", "logn", "dlogn", "lnorm", "dlnorm"))) { .ret$scaleC[.ini$ntheta[.i]] <- 0.5 * abs(.ini$est[.i]) } } } for (.i in .ini$model$extraProps$powTheta) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- 1 } .ini <- as.data.frame(.ret$uif$ini) for (.i in .ini$model$extraProps$factorial) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- abs(1/digamma(.ini$est[.i] + 1)) } for (.i in .ini$model$extraProps$gamma) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- abs(1/digamma(.ini$est[.i])) } for (.i in .ini$model$extraProps$log) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- log(abs(.ini$est[.i])) * abs(.ini$est[.i]) } for (.i in .ret$logitThetas) { .b <- .ret$logitThetasLow[.i] .c <- .ret$logitThetasHi[.i] .a <- .ini$est[.i] if (is.na(.ret$scaleC[.i])) { .ret$scaleC[.i] <- 1 * (-.b + .c) * exp(-.a)/((1 + exp(-.a))^2 * (.b + 1 * (-.b + .c)/(1 + exp(-.a)))) } } } names(.ret$thetaIni) <- sprintf("THETA[%d]", seq_along(.ret$thetaIni)) if (is.null(etaMat) & !is.null(control$etaMat)) { .ret$etaMat <- control$etaMat } else { .ret$etaMat <- etaMat } .ret$setupTime <- (proc.time() - .pt)["elapsed"] if (exists("uif", envir = .ret)) { .tmp <- .ret$uif$logThetasList .ret$logThetas <- .tmp[[1]] .ret$logThetasF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasList .ret$logitThetas <- .tmp[[1]] .ret$logitThetasF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasListLow .ret$logitThetasLow <- .tmp[[1]] .ret$logitThetasLowF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasListHi .ret$logitThetasHi <- .tmp[[1]] .ret$logitThetasHiF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasList .ret$probitThetas <- .tmp[[1]] .ret$probitThetasF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasListLow .ret$probitThetasLow <- .tmp[[1]] .ret$probitThetasLowF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasListHi .ret$probitThetasHi <- .tmp[[1]] .ret$probitThetasHiF <- .tmp[[2]] } else { .ret$logThetasF <- integer(0) .ret$logitThetasF <- integer(0) .ret$logitThetasHiF <- numeric(0) .ret$logitThetasLowF <- numeric(0) .ret$logitThetas <- integer(0) .ret$logitThetasHi <- numeric(0) .ret$logitThetasLow <- numeric(0) .ret$probitThetasF <- integer(0) .ret$probitThetasHiF <- numeric(0) .ret$probitThetasLowF <- numeric(0) .ret$probitThetas <- integer(0) .ret$probitThetasHi <- numeric(0) .ret$probitThetasLow <- numeric(0) } if (exists("noLik", envir = .ret)) { if (!.ret$noLik) { .ret$.params <- c(sprintf("THETA[%d]", seq_along(.ret$thetaIni)), sprintf("ETA[%d]", seq(1, dim(.om0)[1]))) .ret$.thetan <- length(.ret$thetaIni) .ret$nobs <- sum(data$EVID == 0) } } .ret$control$printTop <- TRUE .ret$control$nF <- 0 .est0 <- .ret$thetaIni if (!is.null(.ret$model$pred.nolhs)) { .ret$control$predNeq <- length(.ret$model$pred.nolhs$state) } else { .ret$control$predNeq <- 0L } .fitFun <- function(.ret) { this.env <- environment() assign("err", "theta reset", this.env) while (this.env$err == "theta reset") { assign("err", "", this.env) .ret0 <- tryCatch({ foceiFitCpp_(.ret) }, error = function(e) { if (regexpr("theta reset", e$message) != -1) { assign("zeroOuter", FALSE, this.env) assign("zeroGrad", FALSE, this.env) if (regexpr("theta reset0", e$message) != -1) { assign("zeroGrad", TRUE, this.env) } else if (regexpr("theta resetZ", e$message) != -1) { assign("zeroOuter", TRUE, this.env) } assign("err", "theta reset", this.env) } else { assign("err", e$message, this.env) } }) if (this.env$err == "theta reset") { .nm <- names(.ret$thetaIni) .ret$thetaIni <- setNames(.thetaReset$thetaIni + 0, .nm) .ret$rxInv$theta <- .thetaReset$omegaTheta .ret$control$printTop <- FALSE .ret$etaMat <- .thetaReset$etaMat .ret$control$etaMat <- .thetaReset$etaMat .ret$control$maxInnerIterations <- .thetaReset$maxInnerIterations .ret$control$nF <- .thetaReset$nF .ret$control$gillRetC <- .thetaReset$gillRetC .ret$control$gillRet <- .thetaReset$gillRet .ret$control$gillRet <- .thetaReset$gillRet .ret$control$gillDf <- .thetaReset$gillDf .ret$control$gillDf2 <- .thetaReset$gillDf2 .ret$control$gillErr <- .thetaReset$gillErr .ret$control$rEps <- .thetaReset$rEps .ret$control$aEps <- .thetaReset$aEps .ret$control$rEpsC <- .thetaReset$rEpsC .ret$control$aEpsC <- .thetaReset$aEpsC .ret$control$c1 <- .thetaReset$c1 .ret$control$c2 <- .thetaReset$c2 if (this.env$zeroOuter) { message("Posthoc reset") .ret$control$maxOuterIterations <- 0L } else if (this.env$zeroGrad) { message("Theta reset (zero gradient values); Switch to bobyqa") RxODE::rxReq("minqa") .ret$control$outerOptFun <- .bobyqa .ret$control$outerOpt <- -1L } else { message("Theta reset (ETA drift)") } } } if (this.env$err != "") { stop(this.env$err) } else { return(.ret0) } } .ret0 <- try(.fitFun(.ret)) .n <- 1 while (inherits(.ret0, "try-error") && control$maxOuterIterations != 0 && .n <= control$nRetries) { message(sprintf("Restart %s", .n)) .ret$control$nF <- 0 .estNew <- .est0 + 0.2 * .n * abs(.est0) * stats::runif(length(.est0)) - 0.1 * .n .estNew <- sapply(seq_along(.est0), function(.i) { if (.ret$thetaFixed[.i]) { return(.est0[.i]) } else if (.estNew[.i] < lower[.i]) { return(lower + (.Machine$double.eps)^(1/7)) } else if (.estNew[.i] > upper[.i]) { return(upper - (.Machine$double.eps)^(1/7)) } else { return(.estNew[.i]) } }) .ret$thetaIni <- .estNew .ret0 <- try(.fitFun(.ret)) .n <- .n + 1 } if (inherits(.ret0, "try-error")) stop("Could not fit data.") .ret <- .ret0 if (exists("parHistData", .ret)) { .tmp <- .ret$parHistData .tmp <- .tmp[.tmp$type == "Unscaled", names(.tmp) != "type"] .iter <- .tmp$iter .tmp <- .tmp[, names(.tmp) != "iter"] .ret$parHistStacked <- data.frame(stack(.tmp), iter = .iter) names(.ret$parHistStacked) <- c("val", "par", "iter") .ret$parHist <- data.frame(iter = .iter, .tmp) } if (.mixed) { .etas <- .ret$ranef .thetas <- .ret$fixef .pars <- .Call(`_nlmixr_nlmixrParameters`, .thetas, .etas) .ret$shrink <- .Call(`_nlmixr_calcShrinkOnly`, .ret$omega, .pars$eta.lst, length(.etas$ID)) .updateParFixed(.ret) } else { .updateParFixed(.ret) } if (!exists("table", .ret)) { .ret$table <- tableControl() } if (control$calcTables) { .ret <- addTable(.ret, updateObject = "no", keep = keep, drop = drop, table = .ret$table) } .ret})(data = dat, inits = .FoceiInits, PKpars = .pars, model = .mod, pred = function() { return(nlmixr_pred) }, err = uif$error, lower = uif$focei.lower, upper = uif$focei.upper, fixed = uif$focei.fixed, thetaNames = uif$focei.names, etaNames = uif$eta.names, control = control, env = env, keep = .keep, drop = .drop): Not all the covariates are in the dataset.</span></div><div class='output co'>#> <span class='message'>Timing stopped at: 8.196 0.388 8.584</span></div><div class='input'><span class='va'>f_nlmixr_dfop_sfo_saem_obs_tc</span> <span class='op'><-</span> <span class='fu'><a href='https://rdrr.io/pkg/nlmixr/man/nlmixr.html'>nlmixr</a></span><span class='op'>(</span><span class='va'>f_mmkin_tc</span><span class='op'>[</span><span class='st'>"DFOP-SFO"</span>, <span class='op'>]</span>, est <span class='op'>=</span> <span class='st'>"saem"</span>, +#> <span class='message'>dosenum=dosenum();</span></div><div class='output co'>#> <span class='message'>Needed Covariates:</span></div><div class='output co'>#> <span class='message'>[1] "f_parent_to_A1" "CMT" </span></div><div class='output co'>#> <span class='error'>Error in (function (data, inits, PKpars, model = NULL, pred = NULL, err = NULL, lower = -Inf, upper = Inf, fixed = NULL, skipCov = NULL, control = foceiControl(), thetaNames = NULL, etaNames = NULL, etaMat = NULL, ..., env = NULL, keep = NULL, drop = NULL) { set.seed(control$seed) .pt <- proc.time() RxODE::.setWarnIdSort(FALSE) on.exit(RxODE::.setWarnIdSort(TRUE)) loadNamespace("n1qn1") if (!RxODE::rxIs(control, "foceiControl")) { control <- do.call(foceiControl, control) } if (is.null(env)) { .ret <- new.env(parent = emptyenv()) } else { .ret <- env } .ret$origData <- data .ret$etaNames <- etaNames .ret$thetaFixed <- fixed .ret$control <- control .ret$control$focei.mu.ref <- integer(0) if (is(model, "RxODE") || is(model, "character")) { .ret$ODEmodel <- TRUE if (class(pred) != "function") { stop("pred must be a function specifying the prediction variables in this model.") } } else { .ret$ODEmodel <- TRUE model <- RxODE::rxGetLin(PKpars) pred <- eval(parse(text = "function(){return(Central);}")) } .square <- function(x) x * x .ret$diagXformInv <- c(sqrt = ".square", log = "exp", identity = "identity")[control$diagXform] if (is.null(err)) { err <- eval(parse(text = paste0("function(){err", paste(inits$ERROR[[1]], collapse = ""), "}"))) } .covNames <- .parNames <- c() .ret$adjLik <- control$adjLik .mixed <- !is.null(inits$OMGA) && length(inits$OMGA) > 0 if (!exists("noLik", envir = .ret)) { .atol <- rep(control$atol, length(RxODE::rxModelVars(model)$state)) .rtol <- rep(control$rtol, length(RxODE::rxModelVars(model)$state)) .ssAtol <- rep(control$ssAtol, length(RxODE::rxModelVars(model)$state)) .ssRtol <- rep(control$ssRtol, length(RxODE::rxModelVars(model)$state)) .ret$model <- RxODE::rxSymPySetupPred(model, pred, PKpars, err, grad = (control$derivMethod == 2L), pred.minus.dv = TRUE, sum.prod = control$sumProd, theta.derivs = FALSE, optExpression = control$optExpression, interaction = (control$interaction == 1L), only.numeric = !.mixed, run.internal = TRUE, addProp = control$addProp) if (!is.null(.ret$model$inner)) { .atol <- c(.atol, rep(control$atolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.atol))) .rtol <- c(.rtol, rep(control$rtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.rtol))) .ret$control$rxControl$atol <- .atol .ret$control$rxControl$rtol <- .rtol .ssAtol <- c(.ssAtol, rep(control$ssAtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.ssAtol))) .ssRtol <- c(.ssRtol, rep(control$ssRtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.ssRtol))) .ret$control$rxControl$ssAtol <- .ssAtol .ret$control$rxControl$ssRtol <- .ssRtol } .covNames <- .parNames <- RxODE::rxParams(.ret$model$pred.only) .covNames <- .covNames[regexpr(rex::rex(start, or("THETA", "ETA"), "[", numbers, "]", end), .covNames) == -1] colnames(data) <- sapply(names(data), function(x) { if (any(x == .covNames)) { return(x) } else { return(toupper(x)) } }) .lhs <- c(names(RxODE::rxInits(.ret$model$pred.only)), RxODE::rxLhs(.ret$model$pred.only)) if (length(.lhs) > 0) { .covNames <- .covNames[regexpr(rex::rex(start, or(.lhs), end), .covNames) == -1] } if (length(.covNames) > 0) { if (!all(.covNames %in% names(data))) { message("Model:") RxODE::rxCat(.ret$model$pred.only) message("Needed Covariates:") nlmixrPrint(.covNames) stop("Not all the covariates are in the dataset.") } message("Needed Covariates:") print(.covNames) } .extraPars <- .ret$model$extra.pars } else { if (.ret$noLik) { .atol <- rep(control$atol, length(RxODE::rxModelVars(model)$state)) .rtol <- rep(control$rtol, length(RxODE::rxModelVars(model)$state)) .ret$model <- RxODE::rxSymPySetupPred(model, pred, PKpars, err, grad = FALSE, pred.minus.dv = TRUE, sum.prod = control$sumProd, theta.derivs = FALSE, optExpression = control$optExpression, run.internal = TRUE, only.numeric = TRUE, addProp = control$addProp) if (!is.null(.ret$model$inner)) { .atol <- c(.atol, rep(control$atolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.atol))) .rtol <- c(.rtol, rep(control$rtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.rtol))) .ret$control$rxControl$atol <- .atol .ret$control$rxControl$rtol <- .rtol } .covNames <- .parNames <- RxODE::rxParams(.ret$model$pred.only) .covNames <- .covNames[regexpr(rex::rex(start, or("THETA", "ETA"), "[", numbers, "]", end), .covNames) == -1] colnames(data) <- sapply(names(data), function(x) { if (any(x == .covNames)) { return(x) } else { return(toupper(x)) } }) .lhs <- c(names(RxODE::rxInits(.ret$model$pred.only)), RxODE::rxLhs(.ret$model$pred.only)) if (length(.lhs) > 0) { .covNames <- .covNames[regexpr(rex::rex(start, or(.lhs), end), .covNames) == -1] } if (length(.covNames) > 0) { if (!all(.covNames %in% names(data))) { message("Model:") RxODE::rxCat(.ret$model$pred.only) message("Needed Covariates:") nlmixrPrint(.covNames) stop("Not all the covariates are in the dataset.") } message("Needed Covariates:") print(.covNames) } .extraPars <- .ret$model$extra.pars } else { .extraPars <- NULL } } .ret$skipCov <- skipCov if (is.null(skipCov)) { if (is.null(fixed)) { .tmp <- rep(FALSE, length(inits$THTA)) } else { if (length(fixed) < length(inits$THTA)) { .tmp <- c(fixed, rep(FALSE, length(inits$THTA) - length(fixed))) } else { .tmp <- fixed[1:length(inits$THTA)] } } if (exists("uif", envir = .ret)) { .uifErr <- .ret$uif$ini$err[!is.na(.ret$uif$ini$ntheta)] .uifErr <- sapply(.uifErr, function(x) { if (is.na(x)) { return(FALSE) } return(!any(x == c("pow2", "tbs", "tbsYj"))) }) .tmp <- (.tmp | .uifErr) } .ret$skipCov <- c(.tmp, rep(TRUE, length(.extraPars))) .ret$control$focei.mu.ref <- .ret$uif$focei.mu.ref } if (is.null(.extraPars)) { .nms <- c(sprintf("THETA[%s]", seq_along(inits$THTA))) } else { .nms <- c(sprintf("THETA[%s]", seq_along(inits$THTA)), sprintf("ERR[%s]", seq_along(.extraPars))) } if (!is.null(thetaNames) && (length(inits$THTA) + length(.extraPars)) == length(thetaNames)) { .nms <- thetaNames } .ret$thetaNames <- .nms .thetaReset$thetaNames <- .nms if (length(lower) == 1) { lower <- rep(lower, length(inits$THTA)) } else if (length(lower) != length(inits$THTA)) { print(inits$THTA) print(lower) stop("Lower must be a single constant for all the THETA lower bounds, or match the dimension of THETA.") } if (length(upper) == 1) { upper <- rep(upper, length(inits$THTA)) } else if (length(lower) != length(inits$THTA)) { stop("Upper must be a single constant for all the THETA lower bounds, or match the dimension of THETA.") } if (!is.null(.extraPars)) { .ret$model$extra.pars <- eval(call(control$diagXform, .ret$model$extra.pars)) if (length(.ret$model$extra.pars) > 0) { inits$THTA <- c(inits$THTA, .ret$model$extra.pars) .lowerErr <- rep(control$atol[1] * 10, length(.ret$model$extra.pars)) .upperErr <- rep(Inf, length(.ret$model$extra.pars)) lower <- c(lower, .lowerErr) upper <- c(upper, .upperErr) } } if (is.null(data$ID)) stop("\"ID\" not found in data") if (is.null(data$DV)) stop("\"DV\" not found in data") if (is.null(data$EVID)) data$EVID <- 0 if (is.null(data$AMT)) data$AMT <- 0 for (.v in c("TIME", "AMT", "DV", .covNames)) { data[[.v]] <- as.double(data[[.v]]) } .ret$dataSav <- data .ds <- data[data$EVID != 0 & data$EVID != 2, c("ID", "TIME", "AMT", "EVID", .covNames)] .w <- which(tolower(names(data)) == "limit") .limitName <- NULL if (length(.w) == 1L) { .limitName <- names(data)[.w] } .censName <- NULL .w <- which(tolower(names(data)) == "cens") if (length(.w) == 1L) { .censName <- names(data[.w]) } data <- data[data$EVID == 0 | data$EVID == 2, c("ID", "TIME", "DV", "EVID", .covNames, .limitName, .censName)] .w <- which(!(names(.ret$dataSav) %in% c(.covNames, keep))) names(.ret$dataSav)[.w] <- tolower(names(.ret$dataSav[.w])) if (.mixed) { .lh <- .parseOM(inits$OMGA) .nlh <- sapply(.lh, length) .osplt <- rep(1:length(.lh), .nlh) .lini <- list(inits$THTA, unlist(.lh)) .nlini <- sapply(.lini, length) .nsplt <- rep(1:length(.lini), .nlini) .om0 <- .genOM(.lh) if (length(etaNames) == dim(.om0)[1]) { .ret$etaNames <- .ret$etaNames } else { .ret$etaNames <- sprintf("ETA[%d]", seq(1, dim(.om0)[1])) } .ret$rxInv <- RxODE::rxSymInvCholCreate(mat = .om0, diag.xform = control$diagXform) .ret$xType <- .ret$rxInv$xType .om0a <- .om0 .om0a <- .om0a/control$diagOmegaBoundLower .om0b <- .om0 .om0b <- .om0b * control$diagOmegaBoundUpper .om0a <- RxODE::rxSymInvCholCreate(mat = .om0a, diag.xform = control$diagXform) .om0b <- RxODE::rxSymInvCholCreate(mat = .om0b, diag.xform = control$diagXform) .omdf <- data.frame(a = .om0a$theta, m = .ret$rxInv$theta, b = .om0b$theta, diag = .om0a$theta.diag) .omdf$lower <- with(.omdf, ifelse(a > b, b, a)) .omdf$lower <- with(.omdf, ifelse(lower == m, -Inf, lower)) .omdf$lower <- with(.omdf, ifelse(!diag, -Inf, lower)) .omdf$upper <- with(.omdf, ifelse(a < b, b, a)) .omdf$upper <- with(.omdf, ifelse(upper == m, Inf, upper)) .omdf$upper <- with(.omdf, ifelse(!diag, Inf, upper)) .ret$control$nomega <- length(.omdf$lower) .ret$control$neta <- sum(.omdf$diag) .ret$control$ntheta <- length(lower) .ret$control$nfixed <- sum(fixed) lower <- c(lower, .omdf$lower) upper <- c(upper, .omdf$upper) } else { .ret$control$nomega <- 0 .ret$control$neta <- 0 .ret$xType <- -1 .ret$control$ntheta <- length(lower) .ret$control$nfixed <- sum(fixed) } .ret$lower <- lower .ret$upper <- upper .ret$thetaIni <- inits$THTA .scaleC <- double(length(lower)) if (is.null(control$scaleC)) { .scaleC <- rep(NA_real_, length(lower)) } else { .scaleC <- as.double(control$scaleC) if (length(lower) > length(.scaleC)) { .scaleC <- c(.scaleC, rep(NA_real_, length(lower) - length(.scaleC))) } else if (length(lower) < length(.scaleC)) { .scaleC <- .scaleC[seq(1, length(lower))] warning("scaleC control option has more options than estimated population parameters, please check.") } } .ret$scaleC <- .scaleC if (exists("uif", envir = .ret)) { .ini <- as.data.frame(.ret$uif$ini)[!is.na(.ret$uif$ini$err), c("est", "err", "ntheta")] for (.i in seq_along(.ini$err)) { if (is.na(.ret$scaleC[.ini$ntheta[.i]])) { if (any(.ini$err[.i] == c("boxCox", "yeoJohnson", "pow2", "tbs", "tbsYj"))) { .ret$scaleC[.ini$ntheta[.i]] <- 1 } else if (any(.ini$err[.i] == c("prop", "add", "norm", "dnorm", "logn", "dlogn", "lnorm", "dlnorm"))) { .ret$scaleC[.ini$ntheta[.i]] <- 0.5 * abs(.ini$est[.i]) } } } for (.i in .ini$model$extraProps$powTheta) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- 1 } .ini <- as.data.frame(.ret$uif$ini) for (.i in .ini$model$extraProps$factorial) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- abs(1/digamma(.ini$est[.i] + 1)) } for (.i in .ini$model$extraProps$gamma) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- abs(1/digamma(.ini$est[.i])) } for (.i in .ini$model$extraProps$log) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- log(abs(.ini$est[.i])) * abs(.ini$est[.i]) } for (.i in .ret$logitThetas) { .b <- .ret$logitThetasLow[.i] .c <- .ret$logitThetasHi[.i] .a <- .ini$est[.i] if (is.na(.ret$scaleC[.i])) { .ret$scaleC[.i] <- 1 * (-.b + .c) * exp(-.a)/((1 + exp(-.a))^2 * (.b + 1 * (-.b + .c)/(1 + exp(-.a)))) } } } names(.ret$thetaIni) <- sprintf("THETA[%d]", seq_along(.ret$thetaIni)) if (is.null(etaMat) & !is.null(control$etaMat)) { .ret$etaMat <- control$etaMat } else { .ret$etaMat <- etaMat } .ret$setupTime <- (proc.time() - .pt)["elapsed"] if (exists("uif", envir = .ret)) { .tmp <- .ret$uif$logThetasList .ret$logThetas <- .tmp[[1]] .ret$logThetasF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasList .ret$logitThetas <- .tmp[[1]] .ret$logitThetasF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasListLow .ret$logitThetasLow <- .tmp[[1]] .ret$logitThetasLowF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasListHi .ret$logitThetasHi <- .tmp[[1]] .ret$logitThetasHiF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasList .ret$probitThetas <- .tmp[[1]] .ret$probitThetasF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasListLow .ret$probitThetasLow <- .tmp[[1]] .ret$probitThetasLowF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasListHi .ret$probitThetasHi <- .tmp[[1]] .ret$probitThetasHiF <- .tmp[[2]] } else { .ret$logThetasF <- integer(0) .ret$logitThetasF <- integer(0) .ret$logitThetasHiF <- numeric(0) .ret$logitThetasLowF <- numeric(0) .ret$logitThetas <- integer(0) .ret$logitThetasHi <- numeric(0) .ret$logitThetasLow <- numeric(0) .ret$probitThetasF <- integer(0) .ret$probitThetasHiF <- numeric(0) .ret$probitThetasLowF <- numeric(0) .ret$probitThetas <- integer(0) .ret$probitThetasHi <- numeric(0) .ret$probitThetasLow <- numeric(0) } if (exists("noLik", envir = .ret)) { if (!.ret$noLik) { .ret$.params <- c(sprintf("THETA[%d]", seq_along(.ret$thetaIni)), sprintf("ETA[%d]", seq(1, dim(.om0)[1]))) .ret$.thetan <- length(.ret$thetaIni) .ret$nobs <- sum(data$EVID == 0) } } .ret$control$printTop <- TRUE .ret$control$nF <- 0 .est0 <- .ret$thetaIni if (!is.null(.ret$model$pred.nolhs)) { .ret$control$predNeq <- length(.ret$model$pred.nolhs$state) } else { .ret$control$predNeq <- 0L } .fitFun <- function(.ret) { this.env <- environment() assign("err", "theta reset", this.env) while (this.env$err == "theta reset") { assign("err", "", this.env) .ret0 <- tryCatch({ foceiFitCpp_(.ret) }, error = function(e) { if (regexpr("theta reset", e$message) != -1) { assign("zeroOuter", FALSE, this.env) assign("zeroGrad", FALSE, this.env) if (regexpr("theta reset0", e$message) != -1) { assign("zeroGrad", TRUE, this.env) } else if (regexpr("theta resetZ", e$message) != -1) { assign("zeroOuter", TRUE, this.env) } assign("err", "theta reset", this.env) } else { assign("err", e$message, this.env) } }) if (this.env$err == "theta reset") { .nm <- names(.ret$thetaIni) .ret$thetaIni <- setNames(.thetaReset$thetaIni + 0, .nm) .ret$rxInv$theta <- .thetaReset$omegaTheta .ret$control$printTop <- FALSE .ret$etaMat <- .thetaReset$etaMat .ret$control$etaMat <- .thetaReset$etaMat .ret$control$maxInnerIterations <- .thetaReset$maxInnerIterations .ret$control$nF <- .thetaReset$nF .ret$control$gillRetC <- .thetaReset$gillRetC .ret$control$gillRet <- .thetaReset$gillRet .ret$control$gillRet <- .thetaReset$gillRet .ret$control$gillDf <- .thetaReset$gillDf .ret$control$gillDf2 <- .thetaReset$gillDf2 .ret$control$gillErr <- .thetaReset$gillErr .ret$control$rEps <- .thetaReset$rEps .ret$control$aEps <- .thetaReset$aEps .ret$control$rEpsC <- .thetaReset$rEpsC .ret$control$aEpsC <- .thetaReset$aEpsC .ret$control$c1 <- .thetaReset$c1 .ret$control$c2 <- .thetaReset$c2 if (this.env$zeroOuter) { message("Posthoc reset") .ret$control$maxOuterIterations <- 0L } else if (this.env$zeroGrad) { message("Theta reset (zero gradient values); Switch to bobyqa") RxODE::rxReq("minqa") .ret$control$outerOptFun <- .bobyqa .ret$control$outerOpt <- -1L } else { message("Theta reset (ETA drift)") } } } if (this.env$err != "") { stop(this.env$err) } else { return(.ret0) } } .ret0 <- try(.fitFun(.ret)) .n <- 1 while (inherits(.ret0, "try-error") && control$maxOuterIterations != 0 && .n <= control$nRetries) { message(sprintf("Restart %s", .n)) .ret$control$nF <- 0 .estNew <- .est0 + 0.2 * .n * abs(.est0) * stats::runif(length(.est0)) - 0.1 * .n .estNew <- sapply(seq_along(.est0), function(.i) { if (.ret$thetaFixed[.i]) { return(.est0[.i]) } else if (.estNew[.i] < lower[.i]) { return(lower + (.Machine$double.eps)^(1/7)) } else if (.estNew[.i] > upper[.i]) { return(upper - (.Machine$double.eps)^(1/7)) } else { return(.estNew[.i]) } }) .ret$thetaIni <- .estNew .ret0 <- try(.fitFun(.ret)) .n <- .n + 1 } if (inherits(.ret0, "try-error")) stop("Could not fit data.") .ret <- .ret0 if (exists("parHistData", .ret)) { .tmp <- .ret$parHistData .tmp <- .tmp[.tmp$type == "Unscaled", names(.tmp) != "type"] .iter <- .tmp$iter .tmp <- .tmp[, names(.tmp) != "iter"] .ret$parHistStacked <- data.frame(stack(.tmp), iter = .iter) names(.ret$parHistStacked) <- c("val", "par", "iter") .ret$parHist <- data.frame(iter = .iter, .tmp) } if (.mixed) { .etas <- .ret$ranef .thetas <- .ret$fixef .pars <- .Call(`_nlmixr_nlmixrParameters`, .thetas, .etas) .ret$shrink <- .Call(`_nlmixr_calcShrinkOnly`, .ret$omega, .pars$eta.lst, length(.etas$ID)) .updateParFixed(.ret) } else { .updateParFixed(.ret) } if (!exists("table", .ret)) { .ret$table <- tableControl() } if (control$calcTables) { .ret <- addTable(.ret, updateObject = "no", keep = keep, drop = drop, table = .ret$table) } .ret})(data = dat, inits = .FoceiInits, PKpars = .pars, model = .mod, pred = function() { return(nlmixr_pred) }, err = uif$error, lower = uif$focei.lower, upper = uif$focei.upper, fixed = uif$focei.fixed, thetaNames = uif$focei.names, etaNames = uif$eta.names, control = control, env = env, keep = .keep, drop = .drop): Not all the covariates are in the dataset.</span></div><div class='output co'>#> <span class='message'>Timing stopped at: 8.157 0.51 8.664</span></div><div class='input'><span class='va'>f_nlmixr_dfop_sfo_saem_obs_tc</span> <span class='op'><-</span> <span class='fu'><a href='https://rdrr.io/pkg/nlmixr/man/nlmixr.html'>nlmixr</a></span><span class='op'>(</span><span class='va'>f_mmkin_tc</span><span class='op'>[</span><span class='st'>"DFOP-SFO"</span>, <span class='op'>]</span>, est <span class='op'>=</span> <span class='st'>"saem"</span>, error_model <span class='op'>=</span> <span class='st'>"obs_tc"</span><span class='op'>)</span> -</div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> parameter labels from comments are typically ignored in non-interactive mode</span></div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> Need to run with the source intact to parse comments</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='error'>Error in configsaem(model = model, data = dat, inits = inits, mcmc = .mcmc, ODEopt = .ODEopt, seed = .seed, distribution = .dist, DEBUG = .DEBUG, addProp = .addProp, tol = .tol, itmax = .itmax, type = .type, powRange = .powRange, lambdaRange = .lambdaRange): covariate(s) not found: f_parent_to_A1</span></div><div class='output co'>#> <span class='message'>Timing stopped at: 0.843 0.028 0.871</span></div><div class='input'><span class='va'>f_nlmixr_dfop_sfo_focei_obs_tc</span> <span class='op'><-</span> <span class='fu'><a href='https://rdrr.io/pkg/nlmixr/man/nlmixr.html'>nlmixr</a></span><span class='op'>(</span><span class='va'>f_mmkin_tc</span><span class='op'>[</span><span class='st'>"DFOP-SFO"</span>, <span class='op'>]</span>, est <span class='op'>=</span> <span class='st'>"focei"</span>, +</div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> parameter labels from comments are typically ignored in non-interactive mode</span></div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> Need to run with the source intact to parse comments</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='error'>Error in configsaem(model = model, data = dat, inits = inits, mcmc = .mcmc, ODEopt = .ODEopt, seed = .seed, distribution = .dist, DEBUG = .DEBUG, addProp = .addProp, tol = .tol, itmax = .itmax, type = .type, powRange = .powRange, lambdaRange = .lambdaRange): covariate(s) not found: f_parent_to_A1</span></div><div class='output co'>#> <span class='message'>Timing stopped at: 0.81 0.045 0.854</span></div><div class='input'><span class='va'>f_nlmixr_dfop_sfo_focei_obs_tc</span> <span class='op'><-</span> <span class='fu'><a href='https://rdrr.io/pkg/nlmixr/man/nlmixr.html'>nlmixr</a></span><span class='op'>(</span><span class='va'>f_mmkin_tc</span><span class='op'>[</span><span class='st'>"DFOP-SFO"</span>, <span class='op'>]</span>, est <span class='op'>=</span> <span class='st'>"focei"</span>, error_model <span class='op'>=</span> <span class='st'>"obs_tc"</span><span class='op'>)</span> </div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> parameter labels from comments are typically ignored in non-interactive mode</span></div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> Need to run with the source intact to parse comments</span></div><div class='output co'>#> <span class='message'>→ creating full model...</span></div><div class='output co'>#> <span class='message'>→ pruning branches (<span style='color: #262626; background-color: #DADADA;'>`if`</span>/<span style='color: #262626; background-color: #DADADA;'>`else`</span>)...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ loading into <span style='color: #0000BB;'>symengine</span> environment...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ creating full model...</span></div><div class='output co'>#> <span class='message'>→ pruning branches (<span style='color: #262626; background-color: #DADADA;'>`if`</span>/<span style='color: #262626; background-color: #DADADA;'>`else`</span>)...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ loading into <span style='color: #0000BB;'>symengine</span> environment...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ calculate jacobian</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ calculate sensitivities</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ calculate ∂(f)/∂(η)</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ calculate ∂(R²)/∂(η)</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ finding duplicate expressions in inner model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ optimizing duplicate expressions in inner model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ finding duplicate expressions in EBE model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ optimizing duplicate expressions in EBE model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ compiling inner model...</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ finding duplicate expressions in FD model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ optimizing duplicate expressions in FD model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ compiling EBE model...</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ compiling events FD model...</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>Model:</span></div><div class='output co'>#> <span class='message'>cmt(parent);</span> #> <span class='message'>cmt(A1);</span> @@ -4949,7 +4949,7 @@ obtained by fitting the same model to a list of datasets using <a href='mkinfit. #> <span class='message'>f_parent=1/(1+exp(-(ETA[3]+THETA[3])));</span> #> <span class='message'>g=1/(rx_expr_19);</span> #> <span class='message'>tad=tad();</span> -#> <span class='message'>dosenum=dosenum();</span></div><div class='output co'>#> <span class='message'>Needed Covariates:</span></div><div class='output co'>#> <span class='message'>[1] "f_parent_to_A1" "CMT" </span></div><div class='output co'>#> <span class='error'>Error in (function (data, inits, PKpars, model = NULL, pred = NULL, err = NULL, lower = -Inf, upper = Inf, fixed = NULL, skipCov = NULL, control = foceiControl(), thetaNames = NULL, etaNames = NULL, etaMat = NULL, ..., env = NULL, keep = NULL, drop = NULL) { set.seed(control$seed) .pt <- proc.time() RxODE::.setWarnIdSort(FALSE) on.exit(RxODE::.setWarnIdSort(TRUE)) loadNamespace("n1qn1") if (!RxODE::rxIs(control, "foceiControl")) { control <- do.call(foceiControl, control) } if (is.null(env)) { .ret <- new.env(parent = emptyenv()) } else { .ret <- env } .ret$origData <- data .ret$etaNames <- etaNames .ret$thetaFixed <- fixed .ret$control <- control .ret$control$focei.mu.ref <- integer(0) if (is(model, "RxODE") || is(model, "character")) { .ret$ODEmodel <- TRUE if (class(pred) != "function") { stop("pred must be a function specifying the prediction variables in this model.") } } else { .ret$ODEmodel <- TRUE model <- RxODE::rxGetLin(PKpars) pred <- eval(parse(text = "function(){return(Central);}")) } .square <- function(x) x * x .ret$diagXformInv <- c(sqrt = ".square", log = "exp", identity = "identity")[control$diagXform] if (is.null(err)) { err <- eval(parse(text = paste0("function(){err", paste(inits$ERROR[[1]], collapse = ""), "}"))) } .covNames <- .parNames <- c() .ret$adjLik <- control$adjLik .mixed <- !is.null(inits$OMGA) && length(inits$OMGA) > 0 if (!exists("noLik", envir = .ret)) { .atol <- rep(control$atol, length(RxODE::rxModelVars(model)$state)) .rtol <- rep(control$rtol, length(RxODE::rxModelVars(model)$state)) .ssAtol <- rep(control$ssAtol, length(RxODE::rxModelVars(model)$state)) .ssRtol <- rep(control$ssRtol, length(RxODE::rxModelVars(model)$state)) .ret$model <- RxODE::rxSymPySetupPred(model, pred, PKpars, err, grad = (control$derivMethod == 2L), pred.minus.dv = TRUE, sum.prod = control$sumProd, theta.derivs = FALSE, optExpression = control$optExpression, interaction = (control$interaction == 1L), only.numeric = !.mixed, run.internal = TRUE, addProp = control$addProp) if (!is.null(.ret$model$inner)) { .atol <- c(.atol, rep(control$atolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.atol))) .rtol <- c(.rtol, rep(control$rtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.rtol))) .ret$control$rxControl$atol <- .atol .ret$control$rxControl$rtol <- .rtol .ssAtol <- c(.ssAtol, rep(control$ssAtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.ssAtol))) .ssRtol <- c(.ssRtol, rep(control$ssRtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.ssRtol))) .ret$control$rxControl$ssAtol <- .ssAtol .ret$control$rxControl$ssRtol <- .ssRtol } .covNames <- .parNames <- RxODE::rxParams(.ret$model$pred.only) .covNames <- .covNames[regexpr(rex::rex(start, or("THETA", "ETA"), "[", numbers, "]", end), .covNames) == -1] colnames(data) <- sapply(names(data), function(x) { if (any(x == .covNames)) { return(x) } else { return(toupper(x)) } }) .lhs <- c(names(RxODE::rxInits(.ret$model$pred.only)), RxODE::rxLhs(.ret$model$pred.only)) if (length(.lhs) > 0) { .covNames <- .covNames[regexpr(rex::rex(start, or(.lhs), end), .covNames) == -1] } if (length(.covNames) > 0) { if (!all(.covNames %in% names(data))) { message("Model:") RxODE::rxCat(.ret$model$pred.only) message("Needed Covariates:") nlmixrPrint(.covNames) stop("Not all the covariates are in the dataset.") } message("Needed Covariates:") print(.covNames) } .extraPars <- .ret$model$extra.pars } else { if (.ret$noLik) { .atol <- rep(control$atol, length(RxODE::rxModelVars(model)$state)) .rtol <- rep(control$rtol, length(RxODE::rxModelVars(model)$state)) .ret$model <- RxODE::rxSymPySetupPred(model, pred, PKpars, err, grad = FALSE, pred.minus.dv = TRUE, sum.prod = control$sumProd, theta.derivs = FALSE, optExpression = control$optExpression, run.internal = TRUE, only.numeric = TRUE, addProp = control$addProp) if (!is.null(.ret$model$inner)) { .atol <- c(.atol, rep(control$atolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.atol))) .rtol <- c(.rtol, rep(control$rtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.rtol))) .ret$control$rxControl$atol <- .atol .ret$control$rxControl$rtol <- .rtol } .covNames <- .parNames <- RxODE::rxParams(.ret$model$pred.only) .covNames <- .covNames[regexpr(rex::rex(start, or("THETA", "ETA"), "[", numbers, "]", end), .covNames) == -1] colnames(data) <- sapply(names(data), function(x) { if (any(x == .covNames)) { return(x) } else { return(toupper(x)) } }) .lhs <- c(names(RxODE::rxInits(.ret$model$pred.only)), RxODE::rxLhs(.ret$model$pred.only)) if (length(.lhs) > 0) { .covNames <- .covNames[regexpr(rex::rex(start, or(.lhs), end), .covNames) == -1] } if (length(.covNames) > 0) { if (!all(.covNames %in% names(data))) { message("Model:") RxODE::rxCat(.ret$model$pred.only) message("Needed Covariates:") nlmixrPrint(.covNames) stop("Not all the covariates are in the dataset.") } message("Needed Covariates:") print(.covNames) } .extraPars <- .ret$model$extra.pars } else { .extraPars <- NULL } } .ret$skipCov <- skipCov if (is.null(skipCov)) { if (is.null(fixed)) { .tmp <- rep(FALSE, length(inits$THTA)) } else { if (length(fixed) < length(inits$THTA)) { .tmp <- c(fixed, rep(FALSE, length(inits$THTA) - length(fixed))) } else { .tmp <- fixed[1:length(inits$THTA)] } } if (exists("uif", envir = .ret)) { .uifErr <- .ret$uif$ini$err[!is.na(.ret$uif$ini$ntheta)] .uifErr <- sapply(.uifErr, function(x) { if (is.na(x)) { return(FALSE) } return(!any(x == c("pow2", "tbs", "tbsYj"))) }) .tmp <- (.tmp | .uifErr) } .ret$skipCov <- c(.tmp, rep(TRUE, length(.extraPars))) .ret$control$focei.mu.ref <- .ret$uif$focei.mu.ref } if (is.null(.extraPars)) { .nms <- c(sprintf("THETA[%s]", seq_along(inits$THTA))) } else { .nms <- c(sprintf("THETA[%s]", seq_along(inits$THTA)), sprintf("ERR[%s]", seq_along(.extraPars))) } if (!is.null(thetaNames) && (length(inits$THTA) + length(.extraPars)) == length(thetaNames)) { .nms <- thetaNames } .ret$thetaNames <- .nms .thetaReset$thetaNames <- .nms if (length(lower) == 1) { lower <- rep(lower, length(inits$THTA)) } else if (length(lower) != length(inits$THTA)) { print(inits$THTA) print(lower) stop("Lower must be a single constant for all the THETA lower bounds, or match the dimension of THETA.") } if (length(upper) == 1) { upper <- rep(upper, length(inits$THTA)) } else if (length(lower) != length(inits$THTA)) { stop("Upper must be a single constant for all the THETA lower bounds, or match the dimension of THETA.") } if (!is.null(.extraPars)) { .ret$model$extra.pars <- eval(call(control$diagXform, .ret$model$extra.pars)) if (length(.ret$model$extra.pars) > 0) { inits$THTA <- c(inits$THTA, .ret$model$extra.pars) .lowerErr <- rep(control$atol[1] * 10, length(.ret$model$extra.pars)) .upperErr <- rep(Inf, length(.ret$model$extra.pars)) lower <- c(lower, .lowerErr) upper <- c(upper, .upperErr) } } if (is.null(data$ID)) stop("\"ID\" not found in data") if (is.null(data$DV)) stop("\"DV\" not found in data") if (is.null(data$EVID)) data$EVID <- 0 if (is.null(data$AMT)) data$AMT <- 0 for (.v in c("TIME", "AMT", "DV", .covNames)) { data[[.v]] <- as.double(data[[.v]]) } .ret$dataSav <- data .ds <- data[data$EVID != 0 & data$EVID != 2, c("ID", "TIME", "AMT", "EVID", .covNames)] .w <- which(tolower(names(data)) == "limit") .limitName <- NULL if (length(.w) == 1L) { .limitName <- names(data)[.w] } .censName <- NULL .w <- which(tolower(names(data)) == "cens") if (length(.w) == 1L) { .censName <- names(data[.w]) } data <- data[data$EVID == 0 | data$EVID == 2, c("ID", "TIME", "DV", "EVID", .covNames, .limitName, .censName)] .w <- which(!(names(.ret$dataSav) %in% c(.covNames, keep))) names(.ret$dataSav)[.w] <- tolower(names(.ret$dataSav[.w])) if (.mixed) { .lh <- .parseOM(inits$OMGA) .nlh <- sapply(.lh, length) .osplt <- rep(1:length(.lh), .nlh) .lini <- list(inits$THTA, unlist(.lh)) .nlini <- sapply(.lini, length) .nsplt <- rep(1:length(.lini), .nlini) .om0 <- .genOM(.lh) if (length(etaNames) == dim(.om0)[1]) { .ret$etaNames <- .ret$etaNames } else { .ret$etaNames <- sprintf("ETA[%d]", seq(1, dim(.om0)[1])) } .ret$rxInv <- RxODE::rxSymInvCholCreate(mat = .om0, diag.xform = control$diagXform) .ret$xType <- .ret$rxInv$xType .om0a <- .om0 .om0a <- .om0a/control$diagOmegaBoundLower .om0b <- .om0 .om0b <- .om0b * control$diagOmegaBoundUpper .om0a <- RxODE::rxSymInvCholCreate(mat = .om0a, diag.xform = control$diagXform) .om0b <- RxODE::rxSymInvCholCreate(mat = .om0b, diag.xform = control$diagXform) .omdf <- data.frame(a = .om0a$theta, m = .ret$rxInv$theta, b = .om0b$theta, diag = .om0a$theta.diag) .omdf$lower <- with(.omdf, ifelse(a > b, b, a)) .omdf$lower <- with(.omdf, ifelse(lower == m, -Inf, lower)) .omdf$lower <- with(.omdf, ifelse(!diag, -Inf, lower)) .omdf$upper <- with(.omdf, ifelse(a < b, b, a)) .omdf$upper <- with(.omdf, ifelse(upper == m, Inf, upper)) .omdf$upper <- with(.omdf, ifelse(!diag, Inf, upper)) .ret$control$nomega <- length(.omdf$lower) .ret$control$neta <- sum(.omdf$diag) .ret$control$ntheta <- length(lower) .ret$control$nfixed <- sum(fixed) lower <- c(lower, .omdf$lower) upper <- c(upper, .omdf$upper) } else { .ret$control$nomega <- 0 .ret$control$neta <- 0 .ret$xType <- -1 .ret$control$ntheta <- length(lower) .ret$control$nfixed <- sum(fixed) } .ret$lower <- lower .ret$upper <- upper .ret$thetaIni <- inits$THTA .scaleC <- double(length(lower)) if (is.null(control$scaleC)) { .scaleC <- rep(NA_real_, length(lower)) } else { .scaleC <- as.double(control$scaleC) if (length(lower) > length(.scaleC)) { .scaleC <- c(.scaleC, rep(NA_real_, length(lower) - length(.scaleC))) } else if (length(lower) < length(.scaleC)) { .scaleC <- .scaleC[seq(1, length(lower))] warning("scaleC control option has more options than estimated population parameters, please check.") } } .ret$scaleC <- .scaleC if (exists("uif", envir = .ret)) { .ini <- as.data.frame(.ret$uif$ini)[!is.na(.ret$uif$ini$err), c("est", "err", "ntheta")] for (.i in seq_along(.ini$err)) { if (is.na(.ret$scaleC[.ini$ntheta[.i]])) { if (any(.ini$err[.i] == c("boxCox", "yeoJohnson", "pow2", "tbs", "tbsYj"))) { .ret$scaleC[.ini$ntheta[.i]] <- 1 } else if (any(.ini$err[.i] == c("prop", "add", "norm", "dnorm", "logn", "dlogn", "lnorm", "dlnorm"))) { .ret$scaleC[.ini$ntheta[.i]] <- 0.5 * abs(.ini$est[.i]) } } } for (.i in .ini$model$extraProps$powTheta) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- 1 } .ini <- as.data.frame(.ret$uif$ini) for (.i in .ini$model$extraProps$factorial) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- abs(1/digamma(.ini$est[.i] + 1)) } for (.i in .ini$model$extraProps$gamma) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- abs(1/digamma(.ini$est[.i])) } for (.i in .ini$model$extraProps$log) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- log(abs(.ini$est[.i])) * abs(.ini$est[.i]) } for (.i in .ret$logitThetas) { .b <- .ret$logitThetasLow[.i] .c <- .ret$logitThetasHi[.i] .a <- .ini$est[.i] if (is.na(.ret$scaleC[.i])) { .ret$scaleC[.i] <- 1 * (-.b + .c) * exp(-.a)/((1 + exp(-.a))^2 * (.b + 1 * (-.b + .c)/(1 + exp(-.a)))) } } } names(.ret$thetaIni) <- sprintf("THETA[%d]", seq_along(.ret$thetaIni)) if (is.null(etaMat) & !is.null(control$etaMat)) { .ret$etaMat <- control$etaMat } else { .ret$etaMat <- etaMat } .ret$setupTime <- (proc.time() - .pt)["elapsed"] if (exists("uif", envir = .ret)) { .tmp <- .ret$uif$logThetasList .ret$logThetas <- .tmp[[1]] .ret$logThetasF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasList .ret$logitThetas <- .tmp[[1]] .ret$logitThetasF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasListLow .ret$logitThetasLow <- .tmp[[1]] .ret$logitThetasLowF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasListHi .ret$logitThetasHi <- .tmp[[1]] .ret$logitThetasHiF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasList .ret$probitThetas <- .tmp[[1]] .ret$probitThetasF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasListLow .ret$probitThetasLow <- .tmp[[1]] .ret$probitThetasLowF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasListHi .ret$probitThetasHi <- .tmp[[1]] .ret$probitThetasHiF <- .tmp[[2]] } else { .ret$logThetasF <- integer(0) .ret$logitThetasF <- integer(0) .ret$logitThetasHiF <- numeric(0) .ret$logitThetasLowF <- numeric(0) .ret$logitThetas <- integer(0) .ret$logitThetasHi <- numeric(0) .ret$logitThetasLow <- numeric(0) .ret$probitThetasF <- integer(0) .ret$probitThetasHiF <- numeric(0) .ret$probitThetasLowF <- numeric(0) .ret$probitThetas <- integer(0) .ret$probitThetasHi <- numeric(0) .ret$probitThetasLow <- numeric(0) } if (exists("noLik", envir = .ret)) { if (!.ret$noLik) { .ret$.params <- c(sprintf("THETA[%d]", seq_along(.ret$thetaIni)), sprintf("ETA[%d]", seq(1, dim(.om0)[1]))) .ret$.thetan <- length(.ret$thetaIni) .ret$nobs <- sum(data$EVID == 0) } } .ret$control$printTop <- TRUE .ret$control$nF <- 0 .est0 <- .ret$thetaIni if (!is.null(.ret$model$pred.nolhs)) { .ret$control$predNeq <- length(.ret$model$pred.nolhs$state) } else { .ret$control$predNeq <- 0L } .fitFun <- function(.ret) { this.env <- environment() assign("err", "theta reset", this.env) while (this.env$err == "theta reset") { assign("err", "", this.env) .ret0 <- tryCatch({ foceiFitCpp_(.ret) }, error = function(e) { if (regexpr("theta reset", e$message) != -1) { assign("zeroOuter", FALSE, this.env) assign("zeroGrad", FALSE, this.env) if (regexpr("theta reset0", e$message) != -1) { assign("zeroGrad", TRUE, this.env) } else if (regexpr("theta resetZ", e$message) != -1) { assign("zeroOuter", TRUE, this.env) } assign("err", "theta reset", this.env) } else { assign("err", e$message, this.env) } }) if (this.env$err == "theta reset") { .nm <- names(.ret$thetaIni) .ret$thetaIni <- setNames(.thetaReset$thetaIni + 0, .nm) .ret$rxInv$theta <- .thetaReset$omegaTheta .ret$control$printTop <- FALSE .ret$etaMat <- .thetaReset$etaMat .ret$control$etaMat <- .thetaReset$etaMat .ret$control$maxInnerIterations <- .thetaReset$maxInnerIterations .ret$control$nF <- .thetaReset$nF .ret$control$gillRetC <- .thetaReset$gillRetC .ret$control$gillRet <- .thetaReset$gillRet .ret$control$gillRet <- .thetaReset$gillRet .ret$control$gillDf <- .thetaReset$gillDf .ret$control$gillDf2 <- .thetaReset$gillDf2 .ret$control$gillErr <- .thetaReset$gillErr .ret$control$rEps <- .thetaReset$rEps .ret$control$aEps <- .thetaReset$aEps .ret$control$rEpsC <- .thetaReset$rEpsC .ret$control$aEpsC <- .thetaReset$aEpsC .ret$control$c1 <- .thetaReset$c1 .ret$control$c2 <- .thetaReset$c2 if (this.env$zeroOuter) { message("Posthoc reset") .ret$control$maxOuterIterations <- 0L } else if (this.env$zeroGrad) { message("Theta reset (zero gradient values); Switch to bobyqa") RxODE::rxReq("minqa") .ret$control$outerOptFun <- .bobyqa .ret$control$outerOpt <- -1L } else { message("Theta reset (ETA drift)") } } } if (this.env$err != "") { stop(this.env$err) } else { return(.ret0) } } .ret0 <- try(.fitFun(.ret)) .n <- 1 while (inherits(.ret0, "try-error") && control$maxOuterIterations != 0 && .n <= control$nRetries) { message(sprintf("Restart %s", .n)) .ret$control$nF <- 0 .estNew <- .est0 + 0.2 * .n * abs(.est0) * stats::runif(length(.est0)) - 0.1 * .n .estNew <- sapply(seq_along(.est0), function(.i) { if (.ret$thetaFixed[.i]) { return(.est0[.i]) } else if (.estNew[.i] < lower[.i]) { return(lower + (.Machine$double.eps)^(1/7)) } else if (.estNew[.i] > upper[.i]) { return(upper - (.Machine$double.eps)^(1/7)) } else { return(.estNew[.i]) } }) .ret$thetaIni <- .estNew .ret0 <- try(.fitFun(.ret)) .n <- .n + 1 } if (inherits(.ret0, "try-error")) stop("Could not fit data.") .ret <- .ret0 if (exists("parHistData", .ret)) { .tmp <- .ret$parHistData .tmp <- .tmp[.tmp$type == "Unscaled", names(.tmp) != "type"] .iter <- .tmp$iter .tmp <- .tmp[, names(.tmp) != "iter"] .ret$parHistStacked <- data.frame(stack(.tmp), iter = .iter) names(.ret$parHistStacked) <- c("val", "par", "iter") .ret$parHist <- data.frame(iter = .iter, .tmp) } if (.mixed) { .etas <- .ret$ranef .thetas <- .ret$fixef .pars <- .Call(`_nlmixr_nlmixrParameters`, .thetas, .etas) .ret$shrink <- .Call(`_nlmixr_calcShrinkOnly`, .ret$omega, .pars$eta.lst, length(.etas$ID)) .updateParFixed(.ret) } else { .updateParFixed(.ret) } if (!exists("table", .ret)) { .ret$table <- tableControl() } if (control$calcTables) { .ret <- addTable(.ret, updateObject = "no", keep = keep, drop = drop, table = .ret$table) } .ret})(data = dat, inits = .FoceiInits, PKpars = .pars, model = .mod, pred = function() { return(nlmixr_pred) }, err = uif$error, lower = uif$focei.lower, upper = uif$focei.upper, fixed = uif$focei.fixed, thetaNames = uif$focei.names, etaNames = uif$eta.names, control = control, env = env, keep = .keep, drop = .drop): Not all the covariates are in the dataset.</span></div><div class='output co'>#> <span class='message'>Timing stopped at: 17.73 0.411 18.14</span></div><div class='input'> +#> <span class='message'>dosenum=dosenum();</span></div><div class='output co'>#> <span class='message'>Needed Covariates:</span></div><div class='output co'>#> <span class='message'>[1] "f_parent_to_A1" "CMT" </span></div><div class='output co'>#> <span class='error'>Error in (function (data, inits, PKpars, model = NULL, pred = NULL, err = NULL, lower = -Inf, upper = Inf, fixed = NULL, skipCov = NULL, control = foceiControl(), thetaNames = NULL, etaNames = NULL, etaMat = NULL, ..., env = NULL, keep = NULL, drop = NULL) { set.seed(control$seed) .pt <- proc.time() RxODE::.setWarnIdSort(FALSE) on.exit(RxODE::.setWarnIdSort(TRUE)) loadNamespace("n1qn1") if (!RxODE::rxIs(control, "foceiControl")) { control <- do.call(foceiControl, control) } if (is.null(env)) { .ret <- new.env(parent = emptyenv()) } else { .ret <- env } .ret$origData <- data .ret$etaNames <- etaNames .ret$thetaFixed <- fixed .ret$control <- control .ret$control$focei.mu.ref <- integer(0) if (is(model, "RxODE") || is(model, "character")) { .ret$ODEmodel <- TRUE if (class(pred) != "function") { stop("pred must be a function specifying the prediction variables in this model.") } } else { .ret$ODEmodel <- TRUE model <- RxODE::rxGetLin(PKpars) pred <- eval(parse(text = "function(){return(Central);}")) } .square <- function(x) x * x .ret$diagXformInv <- c(sqrt = ".square", log = "exp", identity = "identity")[control$diagXform] if (is.null(err)) { err <- eval(parse(text = paste0("function(){err", paste(inits$ERROR[[1]], collapse = ""), "}"))) } .covNames <- .parNames <- c() .ret$adjLik <- control$adjLik .mixed <- !is.null(inits$OMGA) && length(inits$OMGA) > 0 if (!exists("noLik", envir = .ret)) { .atol <- rep(control$atol, length(RxODE::rxModelVars(model)$state)) .rtol <- rep(control$rtol, length(RxODE::rxModelVars(model)$state)) .ssAtol <- rep(control$ssAtol, length(RxODE::rxModelVars(model)$state)) .ssRtol <- rep(control$ssRtol, length(RxODE::rxModelVars(model)$state)) .ret$model <- RxODE::rxSymPySetupPred(model, pred, PKpars, err, grad = (control$derivMethod == 2L), pred.minus.dv = TRUE, sum.prod = control$sumProd, theta.derivs = FALSE, optExpression = control$optExpression, interaction = (control$interaction == 1L), only.numeric = !.mixed, run.internal = TRUE, addProp = control$addProp) if (!is.null(.ret$model$inner)) { .atol <- c(.atol, rep(control$atolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.atol))) .rtol <- c(.rtol, rep(control$rtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.rtol))) .ret$control$rxControl$atol <- .atol .ret$control$rxControl$rtol <- .rtol .ssAtol <- c(.ssAtol, rep(control$ssAtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.ssAtol))) .ssRtol <- c(.ssRtol, rep(control$ssRtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.ssRtol))) .ret$control$rxControl$ssAtol <- .ssAtol .ret$control$rxControl$ssRtol <- .ssRtol } .covNames <- .parNames <- RxODE::rxParams(.ret$model$pred.only) .covNames <- .covNames[regexpr(rex::rex(start, or("THETA", "ETA"), "[", numbers, "]", end), .covNames) == -1] colnames(data) <- sapply(names(data), function(x) { if (any(x == .covNames)) { return(x) } else { return(toupper(x)) } }) .lhs <- c(names(RxODE::rxInits(.ret$model$pred.only)), RxODE::rxLhs(.ret$model$pred.only)) if (length(.lhs) > 0) { .covNames <- .covNames[regexpr(rex::rex(start, or(.lhs), end), .covNames) == -1] } if (length(.covNames) > 0) { if (!all(.covNames %in% names(data))) { message("Model:") RxODE::rxCat(.ret$model$pred.only) message("Needed Covariates:") nlmixrPrint(.covNames) stop("Not all the covariates are in the dataset.") } message("Needed Covariates:") print(.covNames) } .extraPars <- .ret$model$extra.pars } else { if (.ret$noLik) { .atol <- rep(control$atol, length(RxODE::rxModelVars(model)$state)) .rtol <- rep(control$rtol, length(RxODE::rxModelVars(model)$state)) .ret$model <- RxODE::rxSymPySetupPred(model, pred, PKpars, err, grad = FALSE, pred.minus.dv = TRUE, sum.prod = control$sumProd, theta.derivs = FALSE, optExpression = control$optExpression, run.internal = TRUE, only.numeric = TRUE, addProp = control$addProp) if (!is.null(.ret$model$inner)) { .atol <- c(.atol, rep(control$atolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.atol))) .rtol <- c(.rtol, rep(control$rtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.rtol))) .ret$control$rxControl$atol <- .atol .ret$control$rxControl$rtol <- .rtol } .covNames <- .parNames <- RxODE::rxParams(.ret$model$pred.only) .covNames <- .covNames[regexpr(rex::rex(start, or("THETA", "ETA"), "[", numbers, "]", end), .covNames) == -1] colnames(data) <- sapply(names(data), function(x) { if (any(x == .covNames)) { return(x) } else { return(toupper(x)) } }) .lhs <- c(names(RxODE::rxInits(.ret$model$pred.only)), RxODE::rxLhs(.ret$model$pred.only)) if (length(.lhs) > 0) { .covNames <- .covNames[regexpr(rex::rex(start, or(.lhs), end), .covNames) == -1] } if (length(.covNames) > 0) { if (!all(.covNames %in% names(data))) { message("Model:") RxODE::rxCat(.ret$model$pred.only) message("Needed Covariates:") nlmixrPrint(.covNames) stop("Not all the covariates are in the dataset.") } message("Needed Covariates:") print(.covNames) } .extraPars <- .ret$model$extra.pars } else { .extraPars <- NULL } } .ret$skipCov <- skipCov if (is.null(skipCov)) { if (is.null(fixed)) { .tmp <- rep(FALSE, length(inits$THTA)) } else { if (length(fixed) < length(inits$THTA)) { .tmp <- c(fixed, rep(FALSE, length(inits$THTA) - length(fixed))) } else { .tmp <- fixed[1:length(inits$THTA)] } } if (exists("uif", envir = .ret)) { .uifErr <- .ret$uif$ini$err[!is.na(.ret$uif$ini$ntheta)] .uifErr <- sapply(.uifErr, function(x) { if (is.na(x)) { return(FALSE) } return(!any(x == c("pow2", "tbs", "tbsYj"))) }) .tmp <- (.tmp | .uifErr) } .ret$skipCov <- c(.tmp, rep(TRUE, length(.extraPars))) .ret$control$focei.mu.ref <- .ret$uif$focei.mu.ref } if (is.null(.extraPars)) { .nms <- c(sprintf("THETA[%s]", seq_along(inits$THTA))) } else { .nms <- c(sprintf("THETA[%s]", seq_along(inits$THTA)), sprintf("ERR[%s]", seq_along(.extraPars))) } if (!is.null(thetaNames) && (length(inits$THTA) + length(.extraPars)) == length(thetaNames)) { .nms <- thetaNames } .ret$thetaNames <- .nms .thetaReset$thetaNames <- .nms if (length(lower) == 1) { lower <- rep(lower, length(inits$THTA)) } else if (length(lower) != length(inits$THTA)) { print(inits$THTA) print(lower) stop("Lower must be a single constant for all the THETA lower bounds, or match the dimension of THETA.") } if (length(upper) == 1) { upper <- rep(upper, length(inits$THTA)) } else if (length(lower) != length(inits$THTA)) { stop("Upper must be a single constant for all the THETA lower bounds, or match the dimension of THETA.") } if (!is.null(.extraPars)) { .ret$model$extra.pars <- eval(call(control$diagXform, .ret$model$extra.pars)) if (length(.ret$model$extra.pars) > 0) { inits$THTA <- c(inits$THTA, .ret$model$extra.pars) .lowerErr <- rep(control$atol[1] * 10, length(.ret$model$extra.pars)) .upperErr <- rep(Inf, length(.ret$model$extra.pars)) lower <- c(lower, .lowerErr) upper <- c(upper, .upperErr) } } if (is.null(data$ID)) stop("\"ID\" not found in data") if (is.null(data$DV)) stop("\"DV\" not found in data") if (is.null(data$EVID)) data$EVID <- 0 if (is.null(data$AMT)) data$AMT <- 0 for (.v in c("TIME", "AMT", "DV", .covNames)) { data[[.v]] <- as.double(data[[.v]]) } .ret$dataSav <- data .ds <- data[data$EVID != 0 & data$EVID != 2, c("ID", "TIME", "AMT", "EVID", .covNames)] .w <- which(tolower(names(data)) == "limit") .limitName <- NULL if (length(.w) == 1L) { .limitName <- names(data)[.w] } .censName <- NULL .w <- which(tolower(names(data)) == "cens") if (length(.w) == 1L) { .censName <- names(data[.w]) } data <- data[data$EVID == 0 | data$EVID == 2, c("ID", "TIME", "DV", "EVID", .covNames, .limitName, .censName)] .w <- which(!(names(.ret$dataSav) %in% c(.covNames, keep))) names(.ret$dataSav)[.w] <- tolower(names(.ret$dataSav[.w])) if (.mixed) { .lh <- .parseOM(inits$OMGA) .nlh <- sapply(.lh, length) .osplt <- rep(1:length(.lh), .nlh) .lini <- list(inits$THTA, unlist(.lh)) .nlini <- sapply(.lini, length) .nsplt <- rep(1:length(.lini), .nlini) .om0 <- .genOM(.lh) if (length(etaNames) == dim(.om0)[1]) { .ret$etaNames <- .ret$etaNames } else { .ret$etaNames <- sprintf("ETA[%d]", seq(1, dim(.om0)[1])) } .ret$rxInv <- RxODE::rxSymInvCholCreate(mat = .om0, diag.xform = control$diagXform) .ret$xType <- .ret$rxInv$xType .om0a <- .om0 .om0a <- .om0a/control$diagOmegaBoundLower .om0b <- .om0 .om0b <- .om0b * control$diagOmegaBoundUpper .om0a <- RxODE::rxSymInvCholCreate(mat = .om0a, diag.xform = control$diagXform) .om0b <- RxODE::rxSymInvCholCreate(mat = .om0b, diag.xform = control$diagXform) .omdf <- data.frame(a = .om0a$theta, m = .ret$rxInv$theta, b = .om0b$theta, diag = .om0a$theta.diag) .omdf$lower <- with(.omdf, ifelse(a > b, b, a)) .omdf$lower <- with(.omdf, ifelse(lower == m, -Inf, lower)) .omdf$lower <- with(.omdf, ifelse(!diag, -Inf, lower)) .omdf$upper <- with(.omdf, ifelse(a < b, b, a)) .omdf$upper <- with(.omdf, ifelse(upper == m, Inf, upper)) .omdf$upper <- with(.omdf, ifelse(!diag, Inf, upper)) .ret$control$nomega <- length(.omdf$lower) .ret$control$neta <- sum(.omdf$diag) .ret$control$ntheta <- length(lower) .ret$control$nfixed <- sum(fixed) lower <- c(lower, .omdf$lower) upper <- c(upper, .omdf$upper) } else { .ret$control$nomega <- 0 .ret$control$neta <- 0 .ret$xType <- -1 .ret$control$ntheta <- length(lower) .ret$control$nfixed <- sum(fixed) } .ret$lower <- lower .ret$upper <- upper .ret$thetaIni <- inits$THTA .scaleC <- double(length(lower)) if (is.null(control$scaleC)) { .scaleC <- rep(NA_real_, length(lower)) } else { .scaleC <- as.double(control$scaleC) if (length(lower) > length(.scaleC)) { .scaleC <- c(.scaleC, rep(NA_real_, length(lower) - length(.scaleC))) } else if (length(lower) < length(.scaleC)) { .scaleC <- .scaleC[seq(1, length(lower))] warning("scaleC control option has more options than estimated population parameters, please check.") } } .ret$scaleC <- .scaleC if (exists("uif", envir = .ret)) { .ini <- as.data.frame(.ret$uif$ini)[!is.na(.ret$uif$ini$err), c("est", "err", "ntheta")] for (.i in seq_along(.ini$err)) { if (is.na(.ret$scaleC[.ini$ntheta[.i]])) { if (any(.ini$err[.i] == c("boxCox", "yeoJohnson", "pow2", "tbs", "tbsYj"))) { .ret$scaleC[.ini$ntheta[.i]] <- 1 } else if (any(.ini$err[.i] == c("prop", "add", "norm", "dnorm", "logn", "dlogn", "lnorm", "dlnorm"))) { .ret$scaleC[.ini$ntheta[.i]] <- 0.5 * abs(.ini$est[.i]) } } } for (.i in .ini$model$extraProps$powTheta) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- 1 } .ini <- as.data.frame(.ret$uif$ini) for (.i in .ini$model$extraProps$factorial) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- abs(1/digamma(.ini$est[.i] + 1)) } for (.i in .ini$model$extraProps$gamma) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- abs(1/digamma(.ini$est[.i])) } for (.i in .ini$model$extraProps$log) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- log(abs(.ini$est[.i])) * abs(.ini$est[.i]) } for (.i in .ret$logitThetas) { .b <- .ret$logitThetasLow[.i] .c <- .ret$logitThetasHi[.i] .a <- .ini$est[.i] if (is.na(.ret$scaleC[.i])) { .ret$scaleC[.i] <- 1 * (-.b + .c) * exp(-.a)/((1 + exp(-.a))^2 * (.b + 1 * (-.b + .c)/(1 + exp(-.a)))) } } } names(.ret$thetaIni) <- sprintf("THETA[%d]", seq_along(.ret$thetaIni)) if (is.null(etaMat) & !is.null(control$etaMat)) { .ret$etaMat <- control$etaMat } else { .ret$etaMat <- etaMat } .ret$setupTime <- (proc.time() - .pt)["elapsed"] if (exists("uif", envir = .ret)) { .tmp <- .ret$uif$logThetasList .ret$logThetas <- .tmp[[1]] .ret$logThetasF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasList .ret$logitThetas <- .tmp[[1]] .ret$logitThetasF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasListLow .ret$logitThetasLow <- .tmp[[1]] .ret$logitThetasLowF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasListHi .ret$logitThetasHi <- .tmp[[1]] .ret$logitThetasHiF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasList .ret$probitThetas <- .tmp[[1]] .ret$probitThetasF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasListLow .ret$probitThetasLow <- .tmp[[1]] .ret$probitThetasLowF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasListHi .ret$probitThetasHi <- .tmp[[1]] .ret$probitThetasHiF <- .tmp[[2]] } else { .ret$logThetasF <- integer(0) .ret$logitThetasF <- integer(0) .ret$logitThetasHiF <- numeric(0) .ret$logitThetasLowF <- numeric(0) .ret$logitThetas <- integer(0) .ret$logitThetasHi <- numeric(0) .ret$logitThetasLow <- numeric(0) .ret$probitThetasF <- integer(0) .ret$probitThetasHiF <- numeric(0) .ret$probitThetasLowF <- numeric(0) .ret$probitThetas <- integer(0) .ret$probitThetasHi <- numeric(0) .ret$probitThetasLow <- numeric(0) } if (exists("noLik", envir = .ret)) { if (!.ret$noLik) { .ret$.params <- c(sprintf("THETA[%d]", seq_along(.ret$thetaIni)), sprintf("ETA[%d]", seq(1, dim(.om0)[1]))) .ret$.thetan <- length(.ret$thetaIni) .ret$nobs <- sum(data$EVID == 0) } } .ret$control$printTop <- TRUE .ret$control$nF <- 0 .est0 <- .ret$thetaIni if (!is.null(.ret$model$pred.nolhs)) { .ret$control$predNeq <- length(.ret$model$pred.nolhs$state) } else { .ret$control$predNeq <- 0L } .fitFun <- function(.ret) { this.env <- environment() assign("err", "theta reset", this.env) while (this.env$err == "theta reset") { assign("err", "", this.env) .ret0 <- tryCatch({ foceiFitCpp_(.ret) }, error = function(e) { if (regexpr("theta reset", e$message) != -1) { assign("zeroOuter", FALSE, this.env) assign("zeroGrad", FALSE, this.env) if (regexpr("theta reset0", e$message) != -1) { assign("zeroGrad", TRUE, this.env) } else if (regexpr("theta resetZ", e$message) != -1) { assign("zeroOuter", TRUE, this.env) } assign("err", "theta reset", this.env) } else { assign("err", e$message, this.env) } }) if (this.env$err == "theta reset") { .nm <- names(.ret$thetaIni) .ret$thetaIni <- setNames(.thetaReset$thetaIni + 0, .nm) .ret$rxInv$theta <- .thetaReset$omegaTheta .ret$control$printTop <- FALSE .ret$etaMat <- .thetaReset$etaMat .ret$control$etaMat <- .thetaReset$etaMat .ret$control$maxInnerIterations <- .thetaReset$maxInnerIterations .ret$control$nF <- .thetaReset$nF .ret$control$gillRetC <- .thetaReset$gillRetC .ret$control$gillRet <- .thetaReset$gillRet .ret$control$gillRet <- .thetaReset$gillRet .ret$control$gillDf <- .thetaReset$gillDf .ret$control$gillDf2 <- .thetaReset$gillDf2 .ret$control$gillErr <- .thetaReset$gillErr .ret$control$rEps <- .thetaReset$rEps .ret$control$aEps <- .thetaReset$aEps .ret$control$rEpsC <- .thetaReset$rEpsC .ret$control$aEpsC <- .thetaReset$aEpsC .ret$control$c1 <- .thetaReset$c1 .ret$control$c2 <- .thetaReset$c2 if (this.env$zeroOuter) { message("Posthoc reset") .ret$control$maxOuterIterations <- 0L } else if (this.env$zeroGrad) { message("Theta reset (zero gradient values); Switch to bobyqa") RxODE::rxReq("minqa") .ret$control$outerOptFun <- .bobyqa .ret$control$outerOpt <- -1L } else { message("Theta reset (ETA drift)") } } } if (this.env$err != "") { stop(this.env$err) } else { return(.ret0) } } .ret0 <- try(.fitFun(.ret)) .n <- 1 while (inherits(.ret0, "try-error") && control$maxOuterIterations != 0 && .n <= control$nRetries) { message(sprintf("Restart %s", .n)) .ret$control$nF <- 0 .estNew <- .est0 + 0.2 * .n * abs(.est0) * stats::runif(length(.est0)) - 0.1 * .n .estNew <- sapply(seq_along(.est0), function(.i) { if (.ret$thetaFixed[.i]) { return(.est0[.i]) } else if (.estNew[.i] < lower[.i]) { return(lower + (.Machine$double.eps)^(1/7)) } else if (.estNew[.i] > upper[.i]) { return(upper - (.Machine$double.eps)^(1/7)) } else { return(.estNew[.i]) } }) .ret$thetaIni <- .estNew .ret0 <- try(.fitFun(.ret)) .n <- .n + 1 } if (inherits(.ret0, "try-error")) stop("Could not fit data.") .ret <- .ret0 if (exists("parHistData", .ret)) { .tmp <- .ret$parHistData .tmp <- .tmp[.tmp$type == "Unscaled", names(.tmp) != "type"] .iter <- .tmp$iter .tmp <- .tmp[, names(.tmp) != "iter"] .ret$parHistStacked <- data.frame(stack(.tmp), iter = .iter) names(.ret$parHistStacked) <- c("val", "par", "iter") .ret$parHist <- data.frame(iter = .iter, .tmp) } if (.mixed) { .etas <- .ret$ranef .thetas <- .ret$fixef .pars <- .Call(`_nlmixr_nlmixrParameters`, .thetas, .etas) .ret$shrink <- .Call(`_nlmixr_calcShrinkOnly`, .ret$omega, .pars$eta.lst, length(.etas$ID)) .updateParFixed(.ret) } else { .updateParFixed(.ret) } if (!exists("table", .ret)) { .ret$table <- tableControl() } if (control$calcTables) { .ret <- addTable(.ret, updateObject = "no", keep = keep, drop = drop, table = .ret$table) } .ret})(data = dat, inits = .FoceiInits, PKpars = .pars, model = .mod, pred = function() { return(nlmixr_pred) }, err = uif$error, lower = uif$focei.lower, upper = uif$focei.upper, fixed = uif$focei.fixed, thetaNames = uif$focei.names, etaNames = uif$eta.names, control = control, env = env, keep = .keep, drop = .drop): Not all the covariates are in the dataset.</span></div><div class='output co'>#> <span class='message'>Timing stopped at: 17.34 0.397 17.73</span></div><div class='input'> <span class='fu'><a href='https://rdrr.io/r/stats/AIC.html'>AIC</a></span><span class='op'>(</span> <span class='va'>f_nlmixr_sfo_sfo_focei_const</span><span class='op'>$</span><span class='va'>nm</span>, <span class='va'>f_nlmixr_fomc_sfo_focei_const</span><span class='op'>$</span><span class='va'>nm</span>, diff --git a/docs/dev/reference/plot.mixed.mmkin-3.png b/docs/dev/reference/plot.mixed.mmkin-3.png Binary files differindex a9b96726..7e2876b3 100644 --- a/docs/dev/reference/plot.mixed.mmkin-3.png +++ b/docs/dev/reference/plot.mixed.mmkin-3.png diff --git a/docs/dev/reference/plot.mixed.mmkin-4.png b/docs/dev/reference/plot.mixed.mmkin-4.png Binary files differindex 22219e5e..945c4d41 100644 --- a/docs/dev/reference/plot.mixed.mmkin-4.png +++ b/docs/dev/reference/plot.mixed.mmkin-4.png diff --git a/docs/dev/reference/plot.mixed.mmkin.html b/docs/dev/reference/plot.mixed.mmkin.html index a4222991..7f3faa90 100644 --- a/docs/dev/reference/plot.mixed.mmkin.html +++ b/docs/dev/reference/plot.mixed.mmkin.html @@ -72,7 +72,7 @@ </button> <span class="navbar-brand"> <a class="navbar-link" href="../index.html">mkin</a> - <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.0.5</span> + <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.1.0</span> </span> </div> @@ -296,10 +296,10 @@ corresponding model prediction lines for the different datasets.</p></td> </div><div class='img'><img src='plot.mixed.mmkin-2.png' alt='' width='700' height='433' /></div><div class='input'> <span class='va'>f_saem</span> <span class='op'><-</span> <span class='fu'><a href='saem.html'>saem</a></span><span class='op'>(</span><span class='va'>f</span>, transformations <span class='op'>=</span> <span class='st'>"saemix"</span><span class='op'>)</span> </div><div class='output co'>#> Running main SAEM algorithm -#> [1] "Fri Jun 11 10:56:37 2021" +#> [1] "Tue Jul 27 16:30:50 2021" #> .... #> Minimisation finished -#> [1] "Fri Jun 11 10:56:44 2021"</div><div class='input'><span class='fu'><a href='https://rdrr.io/r/graphics/plot.default.html'>plot</a></span><span class='op'>(</span><span class='va'>f_saem</span><span class='op'>)</span> +#> [1] "Tue Jul 27 16:30:58 2021"</div><div class='input'><span class='fu'><a href='https://rdrr.io/r/graphics/plot.default.html'>plot</a></span><span class='op'>(</span><span class='va'>f_saem</span><span class='op'>)</span> </div><div class='img'><img src='plot.mixed.mmkin-3.png' alt='' width='700' height='433' /></div><div class='input'> <span class='va'>f_obs</span> <span class='op'><-</span> <span class='fu'><a href='mmkin.html'>mmkin</a></span><span class='op'>(</span><span class='fu'><a href='https://rdrr.io/r/base/list.html'>list</a></span><span class='op'>(</span><span class='st'>"DFOP-SFO"</span> <span class='op'>=</span> <span class='va'>dfop_sfo</span><span class='op'>)</span>, <span class='va'>ds</span>, quiet <span class='op'>=</span> <span class='cn'>TRUE</span>, error_model <span class='op'>=</span> <span class='st'>"obs"</span><span class='op'>)</span> <span class='va'>f_nlmix</span> <span class='op'><-</span> <span class='fu'>nlmix</span><span class='op'>(</span><span class='va'>f_obs</span><span class='op'>)</span> diff --git a/docs/dev/reference/reexports.html b/docs/dev/reference/reexports.html index f5ace044..ac4fa4d9 100644 --- a/docs/dev/reference/reexports.html +++ b/docs/dev/reference/reexports.html @@ -81,7 +81,7 @@ below to see their documentation. </button> <span class="navbar-brand"> <a class="navbar-link" href="../index.html">mkin</a> - <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.0.5</span> + <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.1.0</span> </span> </div> diff --git a/docs/dev/reference/saem-5.png b/docs/dev/reference/saem-5.png Binary files differindex 8212ec67..d22e7285 100644 --- a/docs/dev/reference/saem-5.png +++ b/docs/dev/reference/saem-5.png diff --git a/docs/dev/reference/saem.html b/docs/dev/reference/saem.html index 98faad6f..15271c8a 100644 --- a/docs/dev/reference/saem.html +++ b/docs/dev/reference/saem.html @@ -74,7 +74,7 @@ Expectation Maximisation algorithm (SAEM)." /> </button> <span class="navbar-brand"> <a class="navbar-link" href="../index.html">mkin</a> - <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.0.5</span> + <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.1.0</span> </span> </div> @@ -158,7 +158,7 @@ Expectation Maximisation algorithm (SAEM).</p> <span class='va'>object</span>, transformations <span class='op'>=</span> <span class='fu'><a href='https://rdrr.io/r/base/c.html'>c</a></span><span class='op'>(</span><span class='st'>"mkin"</span>, <span class='st'>"saemix"</span><span class='op'>)</span>, degparms_start <span class='op'>=</span> <span class='fu'><a href='https://rdrr.io/r/base/numeric.html'>numeric</a></span><span class='op'>(</span><span class='op'>)</span>, - test_log_parms <span class='op'>=</span> <span class='cn'>FALSE</span>, + test_log_parms <span class='op'>=</span> <span class='cn'>TRUE</span>, conf.level <span class='op'>=</span> <span class='fl'>0.6</span>, solution_type <span class='op'>=</span> <span class='st'>"auto"</span>, nbiter.saemix <span class='op'>=</span> <span class='fu'><a href='https://rdrr.io/r/base/c.html'>c</a></span><span class='op'>(</span><span class='fl'>300</span>, <span class='fl'>100</span><span class='op'>)</span>, @@ -288,27 +288,27 @@ using <a href='mmkin.html'>mmkin</a>.</p> state.ini <span class='op'>=</span> <span class='fu'><a href='https://rdrr.io/r/base/c.html'>c</a></span><span class='op'>(</span>parent <span class='op'>=</span> <span class='fl'>100</span><span class='op'>)</span>, fixed_initials <span class='op'>=</span> <span class='st'>"parent"</span>, quiet <span class='op'>=</span> <span class='cn'>TRUE</span><span class='op'>)</span> <span class='va'>f_saem_p0_fixed</span> <span class='op'><-</span> <span class='fu'>saem</span><span class='op'>(</span><span class='va'>f_mmkin_parent_p0_fixed</span><span class='op'>)</span> </div><div class='output co'>#> Running main SAEM algorithm -#> [1] "Fri Jun 11 10:56:49 2021" +#> [1] "Tue Jul 27 16:31:02 2021" #> .... #> Minimisation finished -#> [1] "Fri Jun 11 10:56:51 2021"</div><div class='input'> +#> [1] "Tue Jul 27 16:31:04 2021"</div><div class='input'> <span class='va'>f_mmkin_parent</span> <span class='op'><-</span> <span class='fu'><a href='mmkin.html'>mmkin</a></span><span class='op'>(</span><span class='fu'><a href='https://rdrr.io/r/base/c.html'>c</a></span><span class='op'>(</span><span class='st'>"SFO"</span>, <span class='st'>"FOMC"</span>, <span class='st'>"DFOP"</span><span class='op'>)</span>, <span class='va'>ds</span>, quiet <span class='op'>=</span> <span class='cn'>TRUE</span><span class='op'>)</span> <span class='va'>f_saem_sfo</span> <span class='op'><-</span> <span class='fu'>saem</span><span class='op'>(</span><span class='va'>f_mmkin_parent</span><span class='op'>[</span><span class='st'>"SFO"</span>, <span class='op'>]</span><span class='op'>)</span> </div><div class='output co'>#> Running main SAEM algorithm -#> [1] "Fri Jun 11 10:56:53 2021" +#> [1] "Tue Jul 27 16:31:06 2021" #> .... #> Minimisation finished -#> [1] "Fri Jun 11 10:56:54 2021"</div><div class='input'><span class='va'>f_saem_fomc</span> <span class='op'><-</span> <span class='fu'>saem</span><span class='op'>(</span><span class='va'>f_mmkin_parent</span><span class='op'>[</span><span class='st'>"FOMC"</span>, <span class='op'>]</span><span class='op'>)</span> +#> [1] "Tue Jul 27 16:31:07 2021"</div><div class='input'><span class='va'>f_saem_fomc</span> <span class='op'><-</span> <span class='fu'>saem</span><span class='op'>(</span><span class='va'>f_mmkin_parent</span><span class='op'>[</span><span class='st'>"FOMC"</span>, <span class='op'>]</span><span class='op'>)</span> </div><div class='output co'>#> Running main SAEM algorithm -#> [1] "Fri Jun 11 10:56:54 2021" +#> [1] "Tue Jul 27 16:31:07 2021" #> .... #> Minimisation finished -#> [1] "Fri Jun 11 10:56:57 2021"</div><div class='input'><span class='va'>f_saem_dfop</span> <span class='op'><-</span> <span class='fu'>saem</span><span class='op'>(</span><span class='va'>f_mmkin_parent</span><span class='op'>[</span><span class='st'>"DFOP"</span>, <span class='op'>]</span><span class='op'>)</span> +#> [1] "Tue Jul 27 16:31:09 2021"</div><div class='input'><span class='va'>f_saem_dfop</span> <span class='op'><-</span> <span class='fu'>saem</span><span class='op'>(</span><span class='va'>f_mmkin_parent</span><span class='op'>[</span><span class='st'>"DFOP"</span>, <span class='op'>]</span><span class='op'>)</span> </div><div class='output co'>#> Running main SAEM algorithm -#> [1] "Fri Jun 11 10:56:57 2021" +#> [1] "Tue Jul 27 16:31:10 2021" #> .... #> Minimisation finished -#> [1] "Fri Jun 11 10:57:00 2021"</div><div class='input'> +#> [1] "Tue Jul 27 16:31:12 2021"</div><div class='input'> <span class='co'># The returned saem.mmkin object contains an SaemixObject, therefore we can use</span> <span class='co'># functions from saemix</span> <span class='kw'><a href='https://rdrr.io/r/base/library.html'>library</a></span><span class='op'>(</span><span class='va'>saemix</span><span class='op'>)</span> @@ -357,10 +357,10 @@ using <a href='mmkin.html'>mmkin</a>.</p> <span class='va'>f_mmkin_parent_tc</span> <span class='op'><-</span> <span class='fu'><a href='https://rdrr.io/r/stats/update.html'>update</a></span><span class='op'>(</span><span class='va'>f_mmkin_parent</span>, error_model <span class='op'>=</span> <span class='st'>"tc"</span><span class='op'>)</span> <span class='va'>f_saem_fomc_tc</span> <span class='op'><-</span> <span class='fu'>saem</span><span class='op'>(</span><span class='va'>f_mmkin_parent_tc</span><span class='op'>[</span><span class='st'>"FOMC"</span>, <span class='op'>]</span><span class='op'>)</span> </div><div class='output co'>#> Running main SAEM algorithm -#> [1] "Fri Jun 11 10:57:03 2021" +#> [1] "Tue Jul 27 16:31:16 2021" #> .... #> Minimisation finished -#> [1] "Fri Jun 11 10:57:09 2021"</div><div class='input'><span class='fu'><a href='https://rdrr.io/pkg/saemix/man/compare.saemix.html'>compare.saemix</a></span><span class='op'>(</span><span class='va'>f_saem_fomc</span><span class='op'>$</span><span class='va'>so</span>, <span class='va'>f_saem_fomc_tc</span><span class='op'>$</span><span class='va'>so</span><span class='op'>)</span> +#> [1] "Tue Jul 27 16:31:20 2021"</div><div class='input'><span class='fu'><a href='https://rdrr.io/pkg/saemix/man/compare.saemix.html'>compare.saemix</a></span><span class='op'>(</span><span class='va'>f_saem_fomc</span><span class='op'>$</span><span class='va'>so</span>, <span class='va'>f_saem_fomc_tc</span><span class='op'>$</span><span class='va'>so</span><span class='op'>)</span> </div><div class='output co'>#> <span class='message'>Likelihoods calculated by importance sampling</span></div><div class='output co'>#> AIC BIC #> 1 467.7096 464.9757 #> 2 469.6831 466.5586</div><div class='input'> @@ -381,15 +381,15 @@ using <a href='mmkin.html'>mmkin</a>.</p> <span class='co'># four minutes</span> <span class='va'>f_saem_sfo_sfo</span> <span class='op'><-</span> <span class='fu'>saem</span><span class='op'>(</span><span class='va'>f_mmkin</span><span class='op'>[</span><span class='st'>"SFO-SFO"</span>, <span class='op'>]</span><span class='op'>)</span> </div><div class='output co'>#> Running main SAEM algorithm -#> [1] "Fri Jun 11 10:57:12 2021" +#> [1] "Tue Jul 27 16:31:24 2021" #> .... #> Minimisation finished -#> [1] "Fri Jun 11 10:57:17 2021"</div><div class='input'><span class='va'>f_saem_dfop_sfo</span> <span class='op'><-</span> <span class='fu'>saem</span><span class='op'>(</span><span class='va'>f_mmkin</span><span class='op'>[</span><span class='st'>"DFOP-SFO"</span>, <span class='op'>]</span><span class='op'>)</span> +#> [1] "Tue Jul 27 16:31:29 2021"</div><div class='input'><span class='va'>f_saem_dfop_sfo</span> <span class='op'><-</span> <span class='fu'>saem</span><span class='op'>(</span><span class='va'>f_mmkin</span><span class='op'>[</span><span class='st'>"DFOP-SFO"</span>, <span class='op'>]</span><span class='op'>)</span> </div><div class='output co'>#> Running main SAEM algorithm -#> [1] "Fri Jun 11 10:57:17 2021" +#> [1] "Tue Jul 27 16:31:30 2021" #> .... #> Minimisation finished -#> [1] "Fri Jun 11 10:57:26 2021"</div><div class='input'><span class='co'># We can use print, plot and summary methods to check the results</span> +#> [1] "Tue Jul 27 16:31:38 2021"</div><div class='input'><span class='co'># We can use print, plot and summary methods to check the results</span> <span class='fu'><a href='https://rdrr.io/r/base/print.html'>print</a></span><span class='op'>(</span><span class='va'>f_saem_dfop_sfo</span><span class='op'>)</span> </div><div class='output co'>#> Kinetic nonlinear mixed-effects model fit by SAEM #> Structural model: @@ -405,35 +405,35 @@ using <a href='mmkin.html'>mmkin</a>.</p> #> #> Likelihood computed by importance sampling #> AIC BIC logLik -#> 841.6 836.5 -407.8 +#> 839.6 834.6 -406.8 #> #> Fitted parameters: #> estimate lower upper -#> parent_0 93.76647 91.15312 96.3798 -#> log_k_A1 -6.13235 -8.45788 -3.8068 -#> f_parent_qlogis -0.97364 -1.36940 -0.5779 -#> log_k1 -2.53176 -3.80372 -1.2598 -#> log_k2 -3.58667 -5.29524 -1.8781 -#> g_qlogis 0.01238 -1.07968 1.1044 -#> Var.parent_0 7.61106 -3.34955 18.5717 -#> Var.log_k_A1 4.64679 -2.73133 12.0249 -#> Var.f_parent_qlogis 0.19693 -0.05498 0.4488 -#> Var.log_k1 2.01717 -0.51980 4.5542 -#> Var.log_k2 3.63412 -0.92964 8.1979 -#> Var.g_qlogis 0.20045 -0.97425 1.3751 -#> a.1 1.88335 1.66636 2.1004 -#> SD.parent_0 2.75881 0.77234 4.7453 -#> SD.log_k_A1 2.15564 0.44429 3.8670 -#> SD.f_parent_qlogis 0.44377 0.15994 0.7276 -#> SD.log_k1 1.42027 0.52714 2.3134 -#> SD.log_k2 1.90634 0.70934 3.1033 -#> SD.g_qlogis 0.44771 -0.86417 1.7596</div><div class='input'><span class='fu'><a href='https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html'>plot</a></span><span class='op'>(</span><span class='va'>f_saem_dfop_sfo</span><span class='op'>)</span> +#> parent_0 93.80521 91.22487 96.3856 +#> log_k_A1 -6.06244 -8.26517 -3.8597 +#> f_parent_qlogis -0.97319 -1.37024 -0.5761 +#> log_k1 -2.55394 -4.00815 -1.0997 +#> log_k2 -3.47160 -5.18763 -1.7556 +#> g_qlogis -0.09324 -1.42737 1.2409 +#> Var.parent_0 7.42157 -3.25683 18.1000 +#> Var.log_k_A1 4.22850 -2.46339 10.9204 +#> Var.f_parent_qlogis 0.19803 -0.05541 0.4515 +#> Var.log_k1 2.28644 -0.86079 5.4337 +#> Var.log_k2 3.35626 -1.14639 7.8589 +#> Var.g_qlogis 0.20084 -1.32516 1.7268 +#> a.1 1.88399 1.66794 2.1000 +#> SD.parent_0 2.72425 0.76438 4.6841 +#> SD.log_k_A1 2.05633 0.42919 3.6835 +#> SD.f_parent_qlogis 0.44501 0.16025 0.7298 +#> SD.log_k1 1.51210 0.47142 2.5528 +#> SD.log_k2 1.83201 0.60313 3.0609 +#> SD.g_qlogis 0.44816 -1.25437 2.1507</div><div class='input'><span class='fu'><a href='https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html'>plot</a></span><span class='op'>(</span><span class='va'>f_saem_dfop_sfo</span><span class='op'>)</span> </div><div class='img'><img src='saem-5.png' alt='' width='700' height='433' /></div><div class='input'><span class='fu'><a href='https://rdrr.io/pkg/saemix/man/summary-methods.html'>summary</a></span><span class='op'>(</span><span class='va'>f_saem_dfop_sfo</span>, data <span class='op'>=</span> <span class='cn'>TRUE</span><span class='op'>)</span> </div><div class='output co'>#> saemix version used for fitting: 3.1.9000 -#> mkin version used for pre-fitting: 1.0.5 +#> mkin version used for pre-fitting: 1.1.0 #> R version used for fitting: 4.1.0 -#> Date of fit: Fri Jun 11 10:57:27 2021 -#> Date of summary: Fri Jun 11 10:57:27 2021 +#> Date of fit: Tue Jul 27 16:31:39 2021 +#> Date of summary: Tue Jul 27 16:31:39 2021 #> #> Equations: #> d_parent/dt = - ((k1 * g * exp(-k1 * time) + k2 * (1 - g) * exp(-k2 * @@ -448,13 +448,13 @@ using <a href='mmkin.html'>mmkin</a>.</p> #> #> Model predictions using solution type analytical #> -#> Fitted in 9.712 s using 300, 100 iterations +#> Fitted in 9.479 s using 300, 100 iterations #> #> Variance model: Constant variance #> #> Mean of starting values for individual parameters: #> parent_0 log_k_A1 f_parent_qlogis log_k1 log_k2 -#> 93.8102 -9.7647 -0.9711 -1.8799 -4.2708 +#> 93.8102 -5.3734 -0.9711 -1.8799 -4.2708 #> g_qlogis #> 0.1356 #> @@ -465,46 +465,46 @@ using <a href='mmkin.html'>mmkin</a>.</p> #> #> Likelihood computed by importance sampling #> AIC BIC logLik -#> 841.6 836.5 -407.8 +#> 839.6 834.6 -406.8 #> #> Optimised parameters: #> est. lower upper -#> parent_0 93.76647 91.153 96.3798 -#> log_k_A1 -6.13235 -8.458 -3.8068 -#> f_parent_qlogis -0.97364 -1.369 -0.5779 -#> log_k1 -2.53176 -3.804 -1.2598 -#> log_k2 -3.58667 -5.295 -1.8781 -#> g_qlogis 0.01238 -1.080 1.1044 +#> parent_0 93.80521 91.225 96.3856 +#> log_k_A1 -6.06244 -8.265 -3.8597 +#> f_parent_qlogis -0.97319 -1.370 -0.5761 +#> log_k1 -2.55394 -4.008 -1.0997 +#> log_k2 -3.47160 -5.188 -1.7556 +#> g_qlogis -0.09324 -1.427 1.2409 #> #> Correlation: #> prnt_0 lg__A1 f_prn_ log_k1 log_k2 -#> log_k_A1 -0.013 -#> f_parent_qlogis -0.025 0.050 -#> log_k1 0.030 0.000 -0.005 -#> log_k2 0.010 0.005 -0.003 0.032 -#> g_qlogis -0.063 -0.015 0.010 -0.167 -0.177 +#> log_k_A1 -0.014 +#> f_parent_qlogis -0.025 0.054 +#> log_k1 0.027 -0.003 -0.005 +#> log_k2 0.011 0.005 -0.002 -0.070 +#> g_qlogis -0.067 -0.009 0.011 -0.189 -0.171 #> #> Random effects: #> est. lower upper -#> SD.parent_0 2.7588 0.7723 4.7453 -#> SD.log_k_A1 2.1556 0.4443 3.8670 -#> SD.f_parent_qlogis 0.4438 0.1599 0.7276 -#> SD.log_k1 1.4203 0.5271 2.3134 -#> SD.log_k2 1.9063 0.7093 3.1033 -#> SD.g_qlogis 0.4477 -0.8642 1.7596 +#> SD.parent_0 2.7243 0.7644 4.6841 +#> SD.log_k_A1 2.0563 0.4292 3.6835 +#> SD.f_parent_qlogis 0.4450 0.1602 0.7298 +#> SD.log_k1 1.5121 0.4714 2.5528 +#> SD.log_k2 1.8320 0.6031 3.0609 +#> SD.g_qlogis 0.4482 -1.2544 2.1507 #> #> Variance model: #> est. lower upper -#> a.1 1.883 1.666 2.1 +#> a.1 1.884 1.668 2.1 #> #> Backtransformed parameters: #> est. lower upper -#> parent_0 93.766473 9.115e+01 96.37983 -#> k_A1 0.002171 2.122e-04 0.02222 -#> f_parent_to_A1 0.274156 2.027e-01 0.35942 -#> k1 0.079519 2.229e-02 0.28371 -#> k2 0.027691 5.015e-03 0.15288 -#> g 0.503095 2.536e-01 0.75109 +#> parent_0 93.805214 9.122e+01 96.38556 +#> k_A1 0.002329 2.573e-04 0.02107 +#> f_parent_to_A1 0.274245 2.026e-01 0.35982 +#> k1 0.077775 1.817e-02 0.33296 +#> k2 0.031067 5.585e-03 0.17281 +#> g 0.476707 1.935e-01 0.77572 #> #> Resulting formation fractions: #> ff @@ -512,182 +512,182 @@ using <a href='mmkin.html'>mmkin</a>.</p> #> parent_sink 0.7258 #> #> Estimated disappearance times: -#> DT50 DT90 DT50back DT50_k1 DT50_k2 -#> parent 14.11 59.53 17.92 8.717 25.03 -#> A1 319.21 1060.38 NA NA NA +#> DT50 DT90 DT50back DT50_k1 DT50_k2 +#> parent 13.96 55.4 16.68 8.912 22.31 +#> A1 297.65 988.8 NA NA NA #> #> Data: -#> ds name time observed predicted residual std standardized -#> Dataset 6 parent 0 97.2 95.79523 1.40477 1.883 0.745888 -#> Dataset 6 parent 0 96.4 95.79523 0.60477 1.883 0.321114 -#> Dataset 6 parent 3 71.1 71.32042 -0.22042 1.883 -0.117035 -#> Dataset 6 parent 3 69.2 71.32042 -2.12042 1.883 -1.125873 -#> Dataset 6 parent 6 58.1 56.45256 1.64744 1.883 0.874739 -#> Dataset 6 parent 6 56.6 56.45256 0.14744 1.883 0.078288 -#> Dataset 6 parent 10 44.4 44.48523 -0.08523 1.883 -0.045257 -#> Dataset 6 parent 10 43.4 44.48523 -1.08523 1.883 -0.576224 -#> Dataset 6 parent 20 33.3 29.75774 3.54226 1.883 1.880826 -#> Dataset 6 parent 20 29.2 29.75774 -0.55774 1.883 -0.296141 -#> Dataset 6 parent 34 17.6 19.35710 -1.75710 1.883 -0.932966 -#> Dataset 6 parent 34 18.0 19.35710 -1.35710 1.883 -0.720579 -#> Dataset 6 parent 55 10.5 10.48443 0.01557 1.883 0.008266 -#> Dataset 6 parent 55 9.3 10.48443 -1.18443 1.883 -0.628895 -#> Dataset 6 parent 90 4.5 3.78622 0.71378 1.883 0.378995 -#> Dataset 6 parent 90 4.7 3.78622 0.91378 1.883 0.485188 -#> Dataset 6 parent 112 3.0 1.99608 1.00392 1.883 0.533048 -#> Dataset 6 parent 112 3.4 1.99608 1.40392 1.883 0.745435 -#> Dataset 6 parent 132 2.3 1.11539 1.18461 1.883 0.628990 -#> Dataset 6 parent 132 2.7 1.11539 1.58461 1.883 0.841377 -#> Dataset 6 A1 3 4.3 4.66132 -0.36132 1.883 -0.191849 -#> Dataset 6 A1 3 4.6 4.66132 -0.06132 1.883 -0.032559 -#> Dataset 6 A1 6 7.0 7.41087 -0.41087 1.883 -0.218157 -#> Dataset 6 A1 6 7.2 7.41087 -0.21087 1.883 -0.111964 -#> Dataset 6 A1 10 8.2 9.50878 -1.30878 1.883 -0.694921 -#> Dataset 6 A1 10 8.0 9.50878 -1.50878 1.883 -0.801114 -#> Dataset 6 A1 20 11.0 11.69902 -0.69902 1.883 -0.371157 -#> Dataset 6 A1 20 13.7 11.69902 2.00098 1.883 1.062455 -#> Dataset 6 A1 34 11.5 12.67784 -1.17784 1.883 -0.625396 -#> Dataset 6 A1 34 12.7 12.67784 0.02216 1.883 0.011765 -#> Dataset 6 A1 55 14.9 12.78556 2.11444 1.883 1.122701 -#> Dataset 6 A1 55 14.5 12.78556 1.71444 1.883 0.910314 -#> Dataset 6 A1 90 12.1 11.52954 0.57046 1.883 0.302898 -#> Dataset 6 A1 90 12.3 11.52954 0.77046 1.883 0.409092 -#> Dataset 6 A1 112 9.9 10.43825 -0.53825 1.883 -0.285793 -#> Dataset 6 A1 112 10.2 10.43825 -0.23825 1.883 -0.126503 -#> Dataset 6 A1 132 8.8 9.42830 -0.62830 1.883 -0.333609 -#> Dataset 6 A1 132 7.8 9.42830 -1.62830 1.883 -0.864577 -#> Dataset 7 parent 0 93.6 90.91477 2.68523 1.883 1.425772 -#> Dataset 7 parent 0 92.3 90.91477 1.38523 1.883 0.735514 -#> Dataset 7 parent 3 87.0 84.76874 2.23126 1.883 1.184726 -#> Dataset 7 parent 3 82.2 84.76874 -2.56874 1.883 -1.363919 -#> Dataset 7 parent 7 74.0 77.62735 -3.62735 1.883 -1.926003 -#> Dataset 7 parent 7 73.9 77.62735 -3.72735 1.883 -1.979100 -#> Dataset 7 parent 14 64.2 67.52266 -3.32266 1.883 -1.764224 -#> Dataset 7 parent 14 69.5 67.52266 1.97734 1.883 1.049904 -#> Dataset 7 parent 30 54.0 52.41949 1.58051 1.883 0.839202 -#> Dataset 7 parent 30 54.6 52.41949 2.18051 1.883 1.157783 -#> Dataset 7 parent 60 41.1 39.36582 1.73418 1.883 0.920794 -#> Dataset 7 parent 60 38.4 39.36582 -0.96582 1.883 -0.512818 -#> Dataset 7 parent 90 32.5 33.75388 -1.25388 1.883 -0.665771 -#> Dataset 7 parent 90 35.5 33.75388 1.74612 1.883 0.927132 -#> Dataset 7 parent 120 28.1 30.41716 -2.31716 1.883 -1.230335 -#> Dataset 7 parent 120 29.0 30.41716 -1.41716 1.883 -0.752464 -#> Dataset 7 parent 180 26.5 25.66046 0.83954 1.883 0.445767 -#> Dataset 7 parent 180 27.6 25.66046 1.93954 1.883 1.029832 -#> Dataset 7 A1 3 3.9 2.69355 1.20645 1.883 0.640585 -#> Dataset 7 A1 3 3.1 2.69355 0.40645 1.883 0.215811 -#> Dataset 7 A1 7 6.9 5.81807 1.08193 1.883 0.574470 -#> Dataset 7 A1 7 6.6 5.81807 0.78193 1.883 0.415180 -#> Dataset 7 A1 14 10.4 10.22529 0.17471 1.883 0.092767 -#> Dataset 7 A1 14 8.3 10.22529 -1.92529 1.883 -1.022265 -#> Dataset 7 A1 30 14.4 16.75484 -2.35484 1.883 -1.250345 -#> Dataset 7 A1 30 13.7 16.75484 -3.05484 1.883 -1.622022 -#> Dataset 7 A1 60 22.1 22.22540 -0.12540 1.883 -0.066583 -#> Dataset 7 A1 60 22.3 22.22540 0.07460 1.883 0.039610 -#> Dataset 7 A1 90 27.5 24.38799 3.11201 1.883 1.652376 -#> Dataset 7 A1 90 25.4 24.38799 1.01201 1.883 0.537344 -#> Dataset 7 A1 120 28.0 25.53294 2.46706 1.883 1.309927 -#> Dataset 7 A1 120 26.6 25.53294 1.06706 1.883 0.566572 -#> Dataset 7 A1 180 25.8 26.94943 -1.14943 1.883 -0.610309 -#> Dataset 7 A1 180 25.3 26.94943 -1.64943 1.883 -0.875793 -#> Dataset 8 parent 0 91.9 91.53246 0.36754 1.883 0.195151 -#> Dataset 8 parent 0 90.8 91.53246 -0.73246 1.883 -0.388914 -#> Dataset 8 parent 1 64.9 67.73197 -2.83197 1.883 -1.503686 -#> Dataset 8 parent 1 66.2 67.73197 -1.53197 1.883 -0.813428 -#> Dataset 8 parent 3 43.5 41.58448 1.91552 1.883 1.017081 -#> Dataset 8 parent 3 44.1 41.58448 2.51552 1.883 1.335662 -#> Dataset 8 parent 8 18.3 19.62286 -1.32286 1.883 -0.702395 -#> Dataset 8 parent 8 18.1 19.62286 -1.52286 1.883 -0.808588 -#> Dataset 8 parent 14 10.2 10.77819 -0.57819 1.883 -0.306999 -#> Dataset 8 parent 14 10.8 10.77819 0.02181 1.883 0.011582 -#> Dataset 8 parent 27 4.9 3.26977 1.63023 1.883 0.865599 -#> Dataset 8 parent 27 3.3 3.26977 0.03023 1.883 0.016051 -#> Dataset 8 parent 48 1.6 0.48024 1.11976 1.883 0.594557 -#> Dataset 8 parent 48 1.5 0.48024 1.01976 1.883 0.541460 -#> Dataset 8 parent 70 1.1 0.06438 1.03562 1.883 0.549881 -#> Dataset 8 parent 70 0.9 0.06438 0.83562 1.883 0.443688 -#> Dataset 8 A1 1 9.6 7.61539 1.98461 1.883 1.053761 -#> Dataset 8 A1 1 7.7 7.61539 0.08461 1.883 0.044923 -#> Dataset 8 A1 3 15.0 15.47954 -0.47954 1.883 -0.254622 -#> Dataset 8 A1 3 15.1 15.47954 -0.37954 1.883 -0.201525 -#> Dataset 8 A1 8 21.2 20.22616 0.97384 1.883 0.517075 -#> Dataset 8 A1 8 21.1 20.22616 0.87384 1.883 0.463979 -#> Dataset 8 A1 14 19.7 20.00067 -0.30067 1.883 -0.159645 -#> Dataset 8 A1 14 18.9 20.00067 -1.10067 1.883 -0.584419 -#> Dataset 8 A1 27 17.5 16.38142 1.11858 1.883 0.593928 -#> Dataset 8 A1 27 15.9 16.38142 -0.48142 1.883 -0.255620 -#> Dataset 8 A1 48 9.5 10.25357 -0.75357 1.883 -0.400124 -#> Dataset 8 A1 48 9.8 10.25357 -0.45357 1.883 -0.240833 -#> Dataset 8 A1 70 6.2 5.95728 0.24272 1.883 0.128878 -#> Dataset 8 A1 70 6.1 5.95728 0.14272 1.883 0.075781 -#> Dataset 9 parent 0 99.8 97.47274 2.32726 1.883 1.235697 -#> Dataset 9 parent 0 98.3 97.47274 0.82726 1.883 0.439246 -#> Dataset 9 parent 1 77.1 79.72257 -2.62257 1.883 -1.392500 -#> Dataset 9 parent 1 77.2 79.72257 -2.52257 1.883 -1.339404 -#> Dataset 9 parent 3 59.0 56.26497 2.73503 1.883 1.452212 -#> Dataset 9 parent 3 58.1 56.26497 1.83503 1.883 0.974342 -#> Dataset 9 parent 8 27.4 31.66985 -4.26985 1.883 -2.267151 -#> Dataset 9 parent 8 29.2 31.66985 -2.46985 1.883 -1.311410 -#> Dataset 9 parent 14 19.1 22.39789 -3.29789 1.883 -1.751071 -#> Dataset 9 parent 14 29.6 22.39789 7.20211 1.883 3.824090 -#> Dataset 9 parent 27 10.1 14.21758 -4.11758 1.883 -2.186301 -#> Dataset 9 parent 27 18.2 14.21758 3.98242 1.883 2.114537 -#> Dataset 9 parent 48 4.5 7.27921 -2.77921 1.883 -1.475671 -#> Dataset 9 parent 48 9.1 7.27921 1.82079 1.883 0.966780 -#> Dataset 9 parent 70 2.3 3.61470 -1.31470 1.883 -0.698065 -#> Dataset 9 parent 70 2.9 3.61470 -0.71470 1.883 -0.379485 -#> Dataset 9 parent 91 2.0 1.85303 0.14697 1.883 0.078038 -#> Dataset 9 parent 91 1.8 1.85303 -0.05303 1.883 -0.028155 -#> Dataset 9 parent 120 2.0 0.73645 1.26355 1.883 0.670906 -#> Dataset 9 parent 120 2.2 0.73645 1.46355 1.883 0.777099 -#> Dataset 9 A1 1 4.2 3.87843 0.32157 1.883 0.170743 -#> Dataset 9 A1 1 3.9 3.87843 0.02157 1.883 0.011453 -#> Dataset 9 A1 3 7.4 8.90535 -1.50535 1.883 -0.799291 -#> Dataset 9 A1 3 7.9 8.90535 -1.00535 1.883 -0.533807 -#> Dataset 9 A1 8 14.5 13.75172 0.74828 1.883 0.397312 -#> Dataset 9 A1 8 13.7 13.75172 -0.05172 1.883 -0.027462 -#> Dataset 9 A1 14 14.2 14.97541 -0.77541 1.883 -0.411715 -#> Dataset 9 A1 14 12.2 14.97541 -2.77541 1.883 -1.473650 -#> Dataset 9 A1 27 13.7 14.94728 -1.24728 1.883 -0.662266 -#> Dataset 9 A1 27 13.2 14.94728 -1.74728 1.883 -0.927750 -#> Dataset 9 A1 48 13.6 13.66078 -0.06078 1.883 -0.032272 -#> Dataset 9 A1 48 15.4 13.66078 1.73922 1.883 0.923470 -#> Dataset 9 A1 70 10.4 11.84899 -1.44899 1.883 -0.769365 -#> Dataset 9 A1 70 11.6 11.84899 -0.24899 1.883 -0.132204 -#> Dataset 9 A1 91 10.0 10.09177 -0.09177 1.883 -0.048727 -#> Dataset 9 A1 91 9.5 10.09177 -0.59177 1.883 -0.314211 -#> Dataset 9 A1 120 9.1 7.91379 1.18621 1.883 0.629841 -#> Dataset 9 A1 120 9.0 7.91379 1.08621 1.883 0.576744 -#> Dataset 10 parent 0 96.1 93.65257 2.44743 1.883 1.299505 -#> Dataset 10 parent 0 94.3 93.65257 0.64743 1.883 0.343763 -#> Dataset 10 parent 8 73.9 77.85906 -3.95906 1.883 -2.102132 -#> Dataset 10 parent 8 73.9 77.85906 -3.95906 1.883 -2.102132 -#> Dataset 10 parent 14 69.4 70.17143 -0.77143 1.883 -0.409606 -#> Dataset 10 parent 14 73.1 70.17143 2.92857 1.883 1.554974 -#> Dataset 10 parent 21 65.6 63.99188 1.60812 1.883 0.853862 -#> Dataset 10 parent 21 65.3 63.99188 1.30812 1.883 0.694572 -#> Dataset 10 parent 41 55.9 54.64292 1.25708 1.883 0.667467 -#> Dataset 10 parent 41 54.4 54.64292 -0.24292 1.883 -0.128985 -#> Dataset 10 parent 63 47.0 49.61303 -2.61303 1.883 -1.387433 -#> Dataset 10 parent 63 49.3 49.61303 -0.31303 1.883 -0.166207 -#> Dataset 10 parent 91 44.7 45.17807 -0.47807 1.883 -0.253839 -#> Dataset 10 parent 91 46.7 45.17807 1.52193 1.883 0.808096 -#> Dataset 10 parent 120 42.1 41.27970 0.82030 1.883 0.435552 -#> Dataset 10 parent 120 41.3 41.27970 0.02030 1.883 0.010778 -#> Dataset 10 A1 8 3.3 3.99294 -0.69294 1.883 -0.367929 -#> Dataset 10 A1 8 3.4 3.99294 -0.59294 1.883 -0.314832 -#> Dataset 10 A1 14 3.9 5.92756 -2.02756 1.883 -1.076570 -#> Dataset 10 A1 14 2.9 5.92756 -3.02756 1.883 -1.607538 -#> Dataset 10 A1 21 6.4 7.47313 -1.07313 1.883 -0.569799 -#> Dataset 10 A1 21 7.2 7.47313 -0.27313 1.883 -0.145025 -#> Dataset 10 A1 41 9.1 9.76819 -0.66819 1.883 -0.354786 -#> Dataset 10 A1 41 8.5 9.76819 -1.26819 1.883 -0.673367 -#> Dataset 10 A1 63 11.7 10.94733 0.75267 1.883 0.399643 -#> Dataset 10 A1 63 12.0 10.94733 1.05267 1.883 0.558933 -#> Dataset 10 A1 91 13.3 11.93773 1.36227 1.883 0.723321 -#> Dataset 10 A1 91 13.2 11.93773 1.26227 1.883 0.670224 -#> Dataset 10 A1 120 14.3 12.77666 1.52334 1.883 0.808847 -#> Dataset 10 A1 120 12.1 12.77666 -0.67666 1.883 -0.359282</div><div class='input'> +#> ds name time observed predicted residual std standardized +#> Dataset 6 parent 0 97.2 95.75408 1.445920 1.884 0.767479 +#> Dataset 6 parent 0 96.4 95.75408 0.645920 1.884 0.342847 +#> Dataset 6 parent 3 71.1 71.22466 -0.124662 1.884 -0.066169 +#> Dataset 6 parent 3 69.2 71.22466 -2.024662 1.884 -1.074669 +#> Dataset 6 parent 6 58.1 56.42290 1.677100 1.884 0.890187 +#> Dataset 6 parent 6 56.6 56.42290 0.177100 1.884 0.094003 +#> Dataset 6 parent 10 44.4 44.55255 -0.152554 1.884 -0.080974 +#> Dataset 6 parent 10 43.4 44.55255 -1.152554 1.884 -0.611763 +#> Dataset 6 parent 20 33.3 29.88846 3.411537 1.884 1.810807 +#> Dataset 6 parent 20 29.2 29.88846 -0.688463 1.884 -0.365429 +#> Dataset 6 parent 34 17.6 19.40826 -1.808260 1.884 -0.959805 +#> Dataset 6 parent 34 18.0 19.40826 -1.408260 1.884 -0.747489 +#> Dataset 6 parent 55 10.5 10.45560 0.044398 1.884 0.023566 +#> Dataset 6 parent 55 9.3 10.45560 -1.155602 1.884 -0.613381 +#> Dataset 6 parent 90 4.5 3.74026 0.759744 1.884 0.403264 +#> Dataset 6 parent 90 4.7 3.74026 0.959744 1.884 0.509421 +#> Dataset 6 parent 112 3.0 1.96015 1.039853 1.884 0.551943 +#> Dataset 6 parent 112 3.4 1.96015 1.439853 1.884 0.764258 +#> Dataset 6 parent 132 2.3 1.08940 1.210603 1.884 0.642575 +#> Dataset 6 parent 132 2.7 1.08940 1.610603 1.884 0.854890 +#> Dataset 6 A1 3 4.3 4.75601 -0.456009 1.884 -0.242045 +#> Dataset 6 A1 3 4.6 4.75601 -0.156009 1.884 -0.082808 +#> Dataset 6 A1 6 7.0 7.53839 -0.538391 1.884 -0.285772 +#> Dataset 6 A1 6 7.2 7.53839 -0.338391 1.884 -0.179614 +#> Dataset 6 A1 10 8.2 9.64728 -1.447276 1.884 -0.768198 +#> Dataset 6 A1 10 8.0 9.64728 -1.647276 1.884 -0.874356 +#> Dataset 6 A1 20 11.0 11.83954 -0.839545 1.884 -0.445621 +#> Dataset 6 A1 20 13.7 11.83954 1.860455 1.884 0.987509 +#> Dataset 6 A1 34 11.5 12.81233 -1.312327 1.884 -0.696569 +#> Dataset 6 A1 34 12.7 12.81233 -0.112327 1.884 -0.059622 +#> Dataset 6 A1 55 14.9 12.87919 2.020809 1.884 1.072624 +#> Dataset 6 A1 55 14.5 12.87919 1.620809 1.884 0.860308 +#> Dataset 6 A1 90 12.1 11.52464 0.575364 1.884 0.305397 +#> Dataset 6 A1 90 12.3 11.52464 0.775364 1.884 0.411555 +#> Dataset 6 A1 112 9.9 10.37694 -0.476938 1.884 -0.253153 +#> Dataset 6 A1 112 10.2 10.37694 -0.176938 1.884 -0.093917 +#> Dataset 6 A1 132 8.8 9.32474 -0.524742 1.884 -0.278528 +#> Dataset 6 A1 132 7.8 9.32474 -1.524742 1.884 -0.809317 +#> Dataset 7 parent 0 93.6 90.16918 3.430816 1.884 1.821040 +#> Dataset 7 parent 0 92.3 90.16918 2.130816 1.884 1.131014 +#> Dataset 7 parent 3 87.0 84.05442 2.945583 1.884 1.563483 +#> Dataset 7 parent 3 82.2 84.05442 -1.854417 1.884 -0.984304 +#> Dataset 7 parent 7 74.0 77.00960 -3.009596 1.884 -1.597461 +#> Dataset 7 parent 7 73.9 77.00960 -3.109596 1.884 -1.650540 +#> Dataset 7 parent 14 64.2 67.15684 -2.956840 1.884 -1.569459 +#> Dataset 7 parent 14 69.5 67.15684 2.343160 1.884 1.243724 +#> Dataset 7 parent 30 54.0 52.66290 1.337101 1.884 0.709719 +#> Dataset 7 parent 30 54.6 52.66290 1.937101 1.884 1.028192 +#> Dataset 7 parent 60 41.1 40.04995 1.050050 1.884 0.557355 +#> Dataset 7 parent 60 38.4 40.04995 -1.649950 1.884 -0.875775 +#> Dataset 7 parent 90 32.5 34.09675 -1.596746 1.884 -0.847535 +#> Dataset 7 parent 90 35.5 34.09675 1.403254 1.884 0.744832 +#> Dataset 7 parent 120 28.1 30.12281 -2.022814 1.884 -1.073688 +#> Dataset 7 parent 120 29.0 30.12281 -1.122814 1.884 -0.595977 +#> Dataset 7 parent 180 26.5 24.10888 2.391123 1.884 1.269182 +#> Dataset 7 parent 180 27.6 24.10888 3.491123 1.884 1.853050 +#> Dataset 7 A1 3 3.9 2.77684 1.123161 1.884 0.596161 +#> Dataset 7 A1 3 3.1 2.77684 0.323161 1.884 0.171530 +#> Dataset 7 A1 7 6.9 5.96705 0.932950 1.884 0.495200 +#> Dataset 7 A1 7 6.6 5.96705 0.632950 1.884 0.335963 +#> Dataset 7 A1 14 10.4 10.40535 -0.005348 1.884 -0.002839 +#> Dataset 7 A1 14 8.3 10.40535 -2.105348 1.884 -1.117496 +#> Dataset 7 A1 30 14.4 16.83722 -2.437216 1.884 -1.293648 +#> Dataset 7 A1 30 13.7 16.83722 -3.137216 1.884 -1.665200 +#> Dataset 7 A1 60 22.1 22.15018 -0.050179 1.884 -0.026635 +#> Dataset 7 A1 60 22.3 22.15018 0.149821 1.884 0.079523 +#> Dataset 7 A1 90 27.5 24.36286 3.137143 1.884 1.665161 +#> Dataset 7 A1 90 25.4 24.36286 1.037143 1.884 0.550504 +#> Dataset 7 A1 120 28.0 25.64064 2.359361 1.884 1.252323 +#> Dataset 7 A1 120 26.6 25.64064 0.959361 1.884 0.509218 +#> Dataset 7 A1 180 25.8 27.25486 -1.454858 1.884 -0.772223 +#> Dataset 7 A1 180 25.3 27.25486 -1.954858 1.884 -1.037617 +#> Dataset 8 parent 0 91.9 91.72652 0.173479 1.884 0.092081 +#> Dataset 8 parent 0 90.8 91.72652 -0.926521 1.884 -0.491787 +#> Dataset 8 parent 1 64.9 67.22810 -2.328104 1.884 -1.235732 +#> Dataset 8 parent 1 66.2 67.22810 -1.028104 1.884 -0.545706 +#> Dataset 8 parent 3 43.5 41.46375 2.036251 1.884 1.080820 +#> Dataset 8 parent 3 44.1 41.46375 2.636251 1.884 1.399293 +#> Dataset 8 parent 8 18.3 19.83597 -1.535968 1.884 -0.815275 +#> Dataset 8 parent 8 18.1 19.83597 -1.735968 1.884 -0.921433 +#> Dataset 8 parent 14 10.2 10.34793 -0.147927 1.884 -0.078518 +#> Dataset 8 parent 14 10.8 10.34793 0.452073 1.884 0.239956 +#> Dataset 8 parent 27 4.9 2.67641 2.223595 1.884 1.180260 +#> Dataset 8 parent 27 3.3 2.67641 0.623595 1.884 0.330997 +#> Dataset 8 parent 48 1.6 0.30218 1.297822 1.884 0.688870 +#> Dataset 8 parent 48 1.5 0.30218 1.197822 1.884 0.635791 +#> Dataset 8 parent 70 1.1 0.03075 1.069248 1.884 0.567545 +#> Dataset 8 parent 70 0.9 0.03075 0.869248 1.884 0.461388 +#> Dataset 8 A1 1 9.6 7.74066 1.859342 1.884 0.986918 +#> Dataset 8 A1 1 7.7 7.74066 -0.040658 1.884 -0.021581 +#> Dataset 8 A1 3 15.0 15.37549 -0.375495 1.884 -0.199309 +#> Dataset 8 A1 3 15.1 15.37549 -0.275495 1.884 -0.146230 +#> Dataset 8 A1 8 21.2 19.95900 1.241003 1.884 0.658711 +#> Dataset 8 A1 8 21.1 19.95900 1.141003 1.884 0.605632 +#> Dataset 8 A1 14 19.7 19.92898 -0.228978 1.884 -0.121539 +#> Dataset 8 A1 14 18.9 19.92898 -1.028978 1.884 -0.546170 +#> Dataset 8 A1 27 17.5 16.34046 1.159536 1.884 0.615469 +#> Dataset 8 A1 27 15.9 16.34046 -0.440464 1.884 -0.233793 +#> Dataset 8 A1 48 9.5 10.12131 -0.621313 1.884 -0.329786 +#> Dataset 8 A1 48 9.8 10.12131 -0.321313 1.884 -0.170550 +#> Dataset 8 A1 70 6.2 5.84753 0.352469 1.884 0.187087 +#> Dataset 8 A1 70 6.1 5.84753 0.252469 1.884 0.134008 +#> Dataset 9 parent 0 99.8 98.23600 1.564002 1.884 0.830155 +#> Dataset 9 parent 0 98.3 98.23600 0.064002 1.884 0.033972 +#> Dataset 9 parent 1 77.1 79.68007 -2.580074 1.884 -1.369475 +#> Dataset 9 parent 1 77.2 79.68007 -2.480074 1.884 -1.316396 +#> Dataset 9 parent 3 59.0 55.81142 3.188584 1.884 1.692465 +#> Dataset 9 parent 3 58.1 55.81142 2.288584 1.884 1.214755 +#> Dataset 9 parent 8 27.4 31.81995 -4.419948 1.884 -2.346060 +#> Dataset 9 parent 8 29.2 31.81995 -2.619948 1.884 -1.390640 +#> Dataset 9 parent 14 19.1 22.78328 -3.683282 1.884 -1.955046 +#> Dataset 9 parent 14 29.6 22.78328 6.816718 1.884 3.618240 +#> Dataset 9 parent 27 10.1 14.15172 -4.051720 1.884 -2.150609 +#> Dataset 9 parent 27 18.2 14.15172 4.048280 1.884 2.148783 +#> Dataset 9 parent 48 4.5 6.86094 -2.360941 1.884 -1.253162 +#> Dataset 9 parent 48 9.1 6.86094 2.239059 1.884 1.188468 +#> Dataset 9 parent 70 2.3 3.21580 -0.915798 1.884 -0.486096 +#> Dataset 9 parent 70 2.9 3.21580 -0.315798 1.884 -0.167622 +#> Dataset 9 parent 91 2.0 1.56010 0.439897 1.884 0.233492 +#> Dataset 9 parent 91 1.8 1.56010 0.239897 1.884 0.127335 +#> Dataset 9 parent 120 2.0 0.57458 1.425424 1.884 0.756600 +#> Dataset 9 parent 120 2.2 0.57458 1.625424 1.884 0.862757 +#> Dataset 9 A1 1 4.2 4.01796 0.182037 1.884 0.096623 +#> Dataset 9 A1 1 3.9 4.01796 -0.117963 1.884 -0.062613 +#> Dataset 9 A1 3 7.4 9.08527 -1.685270 1.884 -0.894523 +#> Dataset 9 A1 3 7.9 9.08527 -1.185270 1.884 -0.629129 +#> Dataset 9 A1 8 14.5 13.75054 0.749457 1.884 0.397804 +#> Dataset 9 A1 8 13.7 13.75054 -0.050543 1.884 -0.026827 +#> Dataset 9 A1 14 14.2 14.91180 -0.711804 1.884 -0.377818 +#> Dataset 9 A1 14 12.2 14.91180 -2.711804 1.884 -1.439396 +#> Dataset 9 A1 27 13.7 14.97813 -1.278129 1.884 -0.678417 +#> Dataset 9 A1 27 13.2 14.97813 -1.778129 1.884 -0.943812 +#> Dataset 9 A1 48 13.6 13.75574 -0.155745 1.884 -0.082668 +#> Dataset 9 A1 48 15.4 13.75574 1.644255 1.884 0.872753 +#> Dataset 9 A1 70 10.4 11.92861 -1.528608 1.884 -0.811369 +#> Dataset 9 A1 70 11.6 11.92861 -0.328608 1.884 -0.174422 +#> Dataset 9 A1 91 10.0 10.14395 -0.143947 1.884 -0.076405 +#> Dataset 9 A1 91 9.5 10.14395 -0.643947 1.884 -0.341800 +#> Dataset 9 A1 120 9.1 7.93869 1.161307 1.884 0.616409 +#> Dataset 9 A1 120 9.0 7.93869 1.061307 1.884 0.563330 +#> Dataset 10 parent 0 96.1 93.65914 2.440862 1.884 1.295583 +#> Dataset 10 parent 0 94.3 93.65914 0.640862 1.884 0.340163 +#> Dataset 10 parent 8 73.9 77.83065 -3.930647 1.884 -2.086344 +#> Dataset 10 parent 8 73.9 77.83065 -3.930647 1.884 -2.086344 +#> Dataset 10 parent 14 69.4 70.15862 -0.758619 1.884 -0.402667 +#> Dataset 10 parent 14 73.1 70.15862 2.941381 1.884 1.561253 +#> Dataset 10 parent 21 65.6 64.00840 1.591600 1.884 0.844804 +#> Dataset 10 parent 21 65.3 64.00840 1.291600 1.884 0.685567 +#> Dataset 10 parent 41 55.9 54.71192 1.188076 1.884 0.630618 +#> Dataset 10 parent 41 54.4 54.71192 -0.311924 1.884 -0.165566 +#> Dataset 10 parent 63 47.0 49.66775 -2.667747 1.884 -1.416011 +#> Dataset 10 parent 63 49.3 49.66775 -0.367747 1.884 -0.195196 +#> Dataset 10 parent 91 44.7 45.17119 -0.471186 1.884 -0.250101 +#> Dataset 10 parent 91 46.7 45.17119 1.528814 1.884 0.811478 +#> Dataset 10 parent 120 42.1 41.20430 0.895699 1.884 0.475427 +#> Dataset 10 parent 120 41.3 41.20430 0.095699 1.884 0.050796 +#> Dataset 10 A1 8 3.3 4.00920 -0.709204 1.884 -0.376438 +#> Dataset 10 A1 8 3.4 4.00920 -0.609204 1.884 -0.323359 +#> Dataset 10 A1 14 3.9 5.94267 -2.042668 1.884 -1.084226 +#> Dataset 10 A1 14 2.9 5.94267 -3.042668 1.884 -1.615015 +#> Dataset 10 A1 21 6.4 7.48222 -1.082219 1.884 -0.574430 +#> Dataset 10 A1 21 7.2 7.48222 -0.282219 1.884 -0.149799 +#> Dataset 10 A1 41 9.1 9.76246 -0.662460 1.884 -0.351626 +#> Dataset 10 A1 41 8.5 9.76246 -1.262460 1.884 -0.670100 +#> Dataset 10 A1 63 11.7 10.93972 0.760278 1.884 0.403547 +#> Dataset 10 A1 63 12.0 10.93972 1.060278 1.884 0.562784 +#> Dataset 10 A1 91 13.3 11.93666 1.363337 1.884 0.723645 +#> Dataset 10 A1 91 13.2 11.93666 1.263337 1.884 0.670566 +#> Dataset 10 A1 120 14.3 12.78218 1.517817 1.884 0.805641 +#> Dataset 10 A1 120 12.1 12.78218 -0.682183 1.884 -0.362095</div><div class='input'> <span class='co'># The following takes about 6 minutes</span> <span class='co'>#f_saem_dfop_sfo_deSolve <- saem(f_mmkin["DFOP-SFO", ], solution_type = "deSolve",</span> <span class='co'># control = list(nbiter.saemix = c(200, 80), nbdisplay = 10))</span> diff --git a/docs/dev/reference/summary.nlmixr.mmkin.html b/docs/dev/reference/summary.nlmixr.mmkin.html index 0fead0df..373ce75f 100644 --- a/docs/dev/reference/summary.nlmixr.mmkin.html +++ b/docs/dev/reference/summary.nlmixr.mmkin.html @@ -76,7 +76,7 @@ endpoints such as formation fractions and DT50 values. Optionally </button> <span class="navbar-brand"> <a class="navbar-link" href="../index.html">mkin</a> - <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.0.5</span> + <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.1.0</span> </span> </div> @@ -258,737 +258,73 @@ nlmixr authors for the parts inherited from nlmixr.</p> quiet <span class='op'>=</span> <span class='cn'>TRUE</span>, error_model <span class='op'>=</span> <span class='st'>"tc"</span>, cores <span class='op'>=</span> <span class='fl'>5</span><span class='op'>)</span> <span class='va'>f_saemix_dfop_sfo</span> <span class='op'><-</span> <span class='fu'>mkin</span><span class='fu'>::</span><span class='fu'><a href='saem.html'>saem</a></span><span class='op'>(</span><span class='va'>f_mmkin_dfop_sfo</span><span class='op'>)</span> </div><div class='output co'>#> Running main SAEM algorithm -#> [1] "Fri Jun 11 10:57:31 2021" +#> [1] "Tue Jul 27 16:31:43 2021" #> .... #> Minimisation finished -#> [1] "Fri Jun 11 10:57:43 2021"</div><div class='input'><span class='va'>f_nlme_dfop_sfo</span> <span class='op'><-</span> <span class='fu'>mkin</span><span class='fu'>::</span><span class='fu'><a href='https://rdrr.io/pkg/nlme/man/nlme.html'>nlme</a></span><span class='op'>(</span><span class='va'>f_mmkin_dfop_sfo</span><span class='op'>)</span> +#> [1] "Tue Jul 27 16:31:55 2021"</div><div class='input'><span class='va'>f_nlme_dfop_sfo</span> <span class='op'><-</span> <span class='fu'>mkin</span><span class='fu'>::</span><span class='fu'><a href='https://rdrr.io/pkg/nlme/man/nlme.html'>nlme</a></span><span class='op'>(</span><span class='va'>f_mmkin_dfop_sfo</span><span class='op'>)</span> </div><div class='output co'>#> <span class='warning'>Warning: Iteration 4, LME step: nlminb() did not converge (code = 1). PORT message: false convergence (8)</span></div><div class='output co'>#> <span class='warning'>Warning: Iteration 6, LME step: nlminb() did not converge (code = 1). PORT message: false convergence (8)</span></div><div class='input'><span class='va'>f_nlmixr_dfop_sfo_saem</span> <span class='op'><-</span> <span class='fu'><a href='https://rdrr.io/pkg/nlmixr/man/nlmixr.html'>nlmixr</a></span><span class='op'>(</span><span class='va'>f_mmkin_dfop_sfo</span>, est <span class='op'>=</span> <span class='st'>"saem"</span><span class='op'>)</span> -</div><div class='output co'>#> <span class='message'>With est = 'saem', a different error model is required for each observed variableChanging the error model to 'obs_tc' (Two-component error for each observed variable)</span></div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> parameter labels from comments are typically ignored in non-interactive mode</span></div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> Need to run with the source intact to parse comments</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='message'>→ generate SAEM model</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> 1: 1.0127e+02 -3.8515e+00 -2.0719e+00 -3.7271e+00 -1.9335e+00 4.0311e-01 6.9594e+00 1.5021e-01 5.3947e-01 1.9686e-01 3.7429e-01 5.4209e-01 8.4121e+00 7.3391e-02 7.1185e+00 2.5869e-01 -#> 2: 1.0136e+02 -3.8005e+00 -2.3424e+00 -4.0759e+00 -1.6475e+00 1.1598e-01 6.6115e+00 1.4406e-01 5.1249e-01 1.8701e-01 3.5786e-01 5.1499e-01 4.9102e+00 6.2829e-02 4.7230e+00 7.8901e-02 -#> 3: 1.0126e+02 -4.0285e+00 -2.3629e+00 -4.1271e+00 -1.1733e+00 1.7634e-02 6.2809e+00 1.6892e-01 4.8687e-01 1.7766e-01 3.3997e-01 4.8924e-01 3.2256e+00 6.6693e-02 3.3261e+00 8.7190e-02 -#> 4: 1.0105e+02 -4.0894e+00 -2.5516e+00 -4.1037e+00 -1.0816e+00 4.5377e-02 5.9668e+00 1.6048e-01 4.6252e-01 1.6878e-01 3.2297e-01 4.6478e-01 2.4343e+00 7.0557e-02 2.2610e+00 9.2498e-02 -#> 5: 1.0101e+02 -4.1364e+00 -2.4605e+00 -4.0737e+00 -1.0920e+00 -4.7953e-03 5.9593e+00 1.5245e-01 4.3940e-01 1.8078e-01 3.0682e-01 5.4688e-01 1.7424e+00 7.4776e-02 1.5144e+00 1.0787e-01 -#> 6: 1.0042e+02 -4.0933e+00 -2.4472e+00 -4.1090e+00 -9.7996e-01 -9.0472e-02 6.0175e+00 1.4483e-01 4.1743e-01 1.8824e-01 2.9148e-01 5.3033e-01 1.5545e+00 6.8588e-02 1.3401e+00 9.8865e-02 -#> 7: 1.0078e+02 -4.0911e+00 -2.4335e+00 -4.0758e+00 -9.9422e-01 -7.8849e-02 6.6318e+00 1.3759e-01 3.9656e-01 1.7882e-01 2.7691e-01 5.0381e-01 1.3780e+00 6.9978e-02 1.1346e+00 9.6162e-02 -#> 8: 1.0077e+02 -4.0196e+00 -2.4345e+00 -4.0444e+00 -9.3483e-01 -1.1032e-01 6.3002e+00 1.3071e-01 3.7673e-01 1.6988e-01 2.6306e-01 4.8191e-01 1.1774e+00 7.4232e-02 1.0270e+00 9.5616e-02 -#> 9: 1.0118e+02 -4.0436e+00 -2.4649e+00 -4.0207e+00 -8.9829e-01 -1.7784e-01 5.9852e+00 1.2417e-01 3.5789e-01 1.6139e-01 2.4991e-01 5.5466e-01 1.1040e+00 7.1515e-02 1.0342e+00 9.3972e-02 -#> 10: 1.0143e+02 -4.0523e+00 -2.3737e+00 -4.0184e+00 -9.1167e-01 -2.3828e-01 5.8520e+00 1.1797e-01 3.4196e-01 1.5332e-01 2.3741e-01 5.2849e-01 1.0510e+00 7.5719e-02 1.0638e+00 9.3973e-02 -#> 11: 1.0119e+02 -4.0699e+00 -2.3680e+00 -4.0191e+00 -9.4858e-01 -1.7310e-01 6.9958e+00 1.1207e-01 3.6891e-01 1.4565e-01 2.2554e-01 5.0206e-01 1.0247e+00 7.5497e-02 1.0292e+00 9.3707e-02 -#> 12: 1.0121e+02 -4.0189e+00 -2.4198e+00 -4.0139e+00 -9.1693e-01 -2.0613e-01 6.6460e+00 1.0646e-01 3.5046e-01 1.3837e-01 2.1427e-01 5.7696e-01 1.1046e+00 7.6090e-02 9.3689e-01 9.4115e-02 -#> 13: 1.0083e+02 -4.0451e+00 -2.4395e+00 -4.0235e+00 -9.4535e-01 -1.4723e-01 6.3137e+00 1.0114e-01 3.3294e-01 1.3145e-01 2.0355e-01 5.4811e-01 1.0360e+00 7.3381e-02 9.7078e-01 9.1659e-02 -#> 14: 1.0056e+02 -4.0401e+00 -2.4045e+00 -4.0054e+00 -9.4191e-01 -1.3928e-01 5.9980e+00 9.6084e-02 3.4934e-01 1.2488e-01 1.9338e-01 5.2071e-01 1.0303e+00 7.7118e-02 8.8372e-01 9.0469e-02 -#> 15: 1.0070e+02 -4.0388e+00 -2.4210e+00 -4.0113e+00 -9.1136e-01 -1.2702e-01 5.6981e+00 9.1279e-02 3.3187e-01 1.1864e-01 1.8371e-01 4.9467e-01 1.0486e+00 7.2427e-02 7.8179e-01 9.1572e-02 -#> 16: 1.0078e+02 -4.0175e+00 -2.4766e+00 -4.0191e+00 -9.0733e-01 -1.1952e-01 5.4132e+00 8.6716e-02 3.1528e-01 1.1270e-01 1.7452e-01 4.8928e-01 9.7799e-01 8.1464e-02 8.2935e-01 8.6520e-02 -#> 17: 1.0069e+02 -4.0533e+00 -2.5110e+00 -4.0294e+00 -9.1841e-01 -6.8363e-03 5.1426e+00 8.2380e-02 2.9952e-01 1.0707e-01 1.6580e-01 4.6482e-01 9.1609e-01 8.1008e-02 8.1783e-01 8.8818e-02 -#> 18: 99.9647 -4.0672 -2.5327 -4.0416 -0.9273 0.0097 4.8854 0.0783 0.2970 0.1280 0.1941 0.5053 0.9306 0.0764 0.8097 0.0881 -#> 19: 1.0027e+02 -4.0667e+00 -2.4653e+00 -4.0579e+00 -9.2776e-01 3.0417e-02 4.6412e+00 7.4348e-02 3.3694e-01 1.2164e-01 1.8435e-01 5.1797e-01 9.7386e-01 7.4954e-02 7.9297e-01 8.9915e-02 -#> 20: 1.0006e+02 -4.0935e+00 -2.4804e+00 -4.0721e+00 -9.3737e-01 1.9496e-02 4.4091e+00 7.0630e-02 3.3728e-01 1.2544e-01 1.7513e-01 6.0925e-01 1.0232e+00 7.4618e-02 7.9988e-01 8.9642e-02 -#> 21: 1.0043e+02 -4.0542e+00 -2.5168e+00 -4.0623e+00 -9.1553e-01 3.9474e-02 4.1887e+00 6.7099e-02 3.4553e-01 1.1917e-01 1.6638e-01 6.0827e-01 1.0155e+00 8.0771e-02 7.8424e-01 8.6213e-02 -#> 22: 1.0049e+02 -4.0449e+00 -2.5082e+00 -4.0849e+00 -9.2553e-01 4.5424e-02 3.9792e+00 6.3744e-02 3.2825e-01 1.2365e-01 1.5806e-01 5.8922e-01 8.2860e-01 8.3384e-02 8.2525e-01 8.9218e-02 -#> 23: 1.0067e+02 -4.0411e+00 -2.5460e+00 -4.0736e+00 -9.2578e-01 5.2422e-02 3.7803e+00 6.0557e-02 3.1661e-01 1.2306e-01 1.5016e-01 5.8274e-01 9.3412e-01 8.0508e-02 8.1829e-01 8.6377e-02 -#> 24: 1.0091e+02 -4.0314e+00 -2.5298e+00 -4.0566e+00 -8.9743e-01 3.7634e-02 3.5913e+00 5.7529e-02 3.5267e-01 1.2194e-01 1.4265e-01 5.5360e-01 9.6271e-01 7.6960e-02 8.8466e-01 8.5693e-02 -#> 25: 1.0100e+02 -4.0442e+00 -2.5399e+00 -4.0568e+00 -8.9494e-01 1.7415e-02 3.4117e+00 5.4652e-02 3.3504e-01 1.2781e-01 1.3552e-01 5.2592e-01 9.6040e-01 7.7299e-02 8.9561e-01 8.6893e-02 -#> 26: 1.0111e+02 -4.0354e+00 -2.5182e+00 -4.0899e+00 -9.0799e-01 7.6464e-02 4.8614e+00 5.1920e-02 3.1829e-01 1.2142e-01 1.3110e-01 4.9963e-01 9.6997e-01 7.4932e-02 8.2521e-01 9.3659e-02 -#> 27: 1.0159e+02 -4.0653e+00 -2.4934e+00 -4.0803e+00 -9.5632e-01 2.8659e-03 4.6184e+00 4.9324e-02 3.0237e-01 1.1535e-01 1.4743e-01 4.7465e-01 9.4314e-01 7.7860e-02 8.9820e-01 8.8210e-02 -#> 28: 1.0154e+02 -4.0487e+00 -2.4844e+00 -4.0511e+00 -9.6473e-01 -4.7382e-02 4.3874e+00 4.6858e-02 3.2049e-01 1.0958e-01 1.5243e-01 4.5091e-01 9.8808e-01 7.4786e-02 8.6833e-01 8.8720e-02 -#> 29: 1.0144e+02 -4.0414e+00 -2.4105e+00 -4.0504e+00 -9.4039e-01 -3.6753e-02 4.1681e+00 4.4515e-02 3.2754e-01 1.0410e-01 1.4940e-01 4.2837e-01 9.5520e-01 7.8507e-02 8.2408e-01 8.5998e-02 -#> 30: 1.0137e+02 -4.0292e+00 -2.4174e+00 -4.0382e+00 -9.3180e-01 -7.1482e-02 5.4636e+00 4.2289e-02 3.2074e-01 9.8896e-02 1.6877e-01 4.0695e-01 8.8153e-01 7.5106e-02 8.5239e-01 8.8266e-02 -#> 31: 1.0105e+02 -4.0387e+00 -2.4368e+00 -4.0346e+00 -9.1098e-01 -5.4730e-02 5.1904e+00 4.0175e-02 3.0470e-01 9.3951e-02 1.6034e-01 3.8660e-01 8.7853e-01 8.0278e-02 8.7981e-01 8.6404e-02 -#> 32: 1.0147e+02 -4.0435e+00 -2.4530e+00 -4.0365e+00 -9.1241e-01 -7.1281e-02 4.9309e+00 3.8166e-02 2.8947e-01 9.4694e-02 1.7475e-01 3.6727e-01 8.7005e-01 8.1398e-02 8.7784e-01 8.8976e-02 -#> 33: 1.0144e+02 -4.0092e+00 -2.4279e+00 -4.0090e+00 -8.8656e-01 -1.4017e-01 5.2945e+00 3.6258e-02 2.9770e-01 1.0169e-01 1.6601e-01 3.4891e-01 9.2202e-01 7.8841e-02 8.7551e-01 8.4011e-02 -#> 34: 1.0157e+02 -3.9839e+00 -2.4469e+00 -4.0180e+00 -8.3877e-01 -1.4664e-01 6.3506e+00 3.4445e-02 2.8282e-01 1.0831e-01 1.6850e-01 3.3146e-01 8.4403e-01 7.9056e-02 8.4620e-01 8.6363e-02 -#> 35: 1.0149e+02 -3.9928e+00 -2.4771e+00 -4.0106e+00 -8.6974e-01 -1.4219e-01 6.2039e+00 3.2722e-02 2.8123e-01 1.1283e-01 1.6008e-01 3.1489e-01 9.1308e-01 7.8685e-02 7.8939e-01 8.7289e-02 -#> 36: 1.0162e+02 -4.0099e+00 -2.4822e+00 -3.9880e+00 -8.7959e-01 -1.3237e-01 5.8937e+00 3.1086e-02 3.2200e-01 1.0719e-01 1.6077e-01 2.9914e-01 9.0821e-01 8.4066e-02 7.5559e-01 8.4838e-02 -#> 37: 1.0102e+02 -3.9962e+00 -2.4852e+00 -3.9954e+00 -8.8307e-01 -9.2070e-02 5.5991e+00 2.9532e-02 3.3713e-01 1.0183e-01 1.5333e-01 2.8419e-01 8.3918e-01 8.5231e-02 7.6007e-01 8.9541e-02 -#> 38: 1.0102e+02 -3.9987e+00 -2.5129e+00 -3.9833e+00 -8.7454e-01 -1.6469e-01 5.3191e+00 2.8055e-02 3.2027e-01 1.0792e-01 1.4707e-01 2.6998e-01 9.1490e-01 8.4715e-02 7.6778e-01 8.9241e-02 -#> 39: 1.0054e+02 -3.9875e+00 -2.4301e+00 -3.9797e+00 -8.7222e-01 -1.9597e-01 7.3800e+00 2.6653e-02 3.0426e-01 1.0801e-01 1.4393e-01 2.5648e-01 9.5901e-01 7.8320e-02 8.1559e-01 9.2429e-02 -#> 40: 1.0077e+02 -4.0057e+00 -2.4630e+00 -3.9849e+00 -8.6788e-01 -1.9606e-01 7.0110e+00 2.5320e-02 3.0385e-01 1.3164e-01 1.4567e-01 3.0284e-01 9.7123e-01 7.6328e-02 8.3681e-01 8.9349e-02 -#> 41: 1.0069e+02 -4.0143e+00 -2.3805e+00 -3.9962e+00 -8.7503e-01 -1.8532e-01 6.6604e+00 2.4054e-02 3.0707e-01 1.4668e-01 1.5021e-01 3.0404e-01 1.0072e+00 7.3629e-02 9.4494e-01 8.4745e-02 -#> 42: 1.0073e+02 -3.9861e+00 -2.4464e+00 -3.9919e+00 -8.7912e-01 -1.8435e-01 6.3274e+00 2.2851e-02 2.9171e-01 1.3935e-01 1.5080e-01 2.8883e-01 9.6502e-01 7.7470e-02 9.4221e-01 8.2459e-02 -#> 43: 1.0104e+02 -3.9881e+00 -2.4156e+00 -3.9688e+00 -8.9448e-01 -2.3739e-01 6.0110e+00 2.1709e-02 2.7713e-01 1.3238e-01 1.5603e-01 2.7439e-01 9.7714e-01 7.1720e-02 8.5890e-01 8.6635e-02 -#> 44: 1.0084e+02 -4.0117e+00 -2.4455e+00 -3.9753e+00 -8.8716e-01 -2.0112e-01 5.7105e+00 2.0623e-02 2.6327e-01 1.2741e-01 1.5200e-01 2.6067e-01 9.3289e-01 8.0543e-02 8.5055e-01 8.2921e-02 -#> 45: 1.0071e+02 -3.9996e+00 -2.4359e+00 -3.9764e+00 -9.1082e-01 -2.4578e-01 5.4250e+00 1.9592e-02 2.5011e-01 1.3254e-01 1.6132e-01 2.8273e-01 9.5805e-01 7.7734e-02 7.8171e-01 8.4571e-02 -#> 46: 1.0018e+02 -4.0077e+00 -2.4835e+00 -3.9739e+00 -8.6079e-01 -1.6592e-01 5.1537e+00 1.8613e-02 2.3760e-01 1.3830e-01 1.5392e-01 3.0295e-01 1.0931e+00 7.3274e-02 8.9544e-01 8.8388e-02 -#> 47: 99.9834 -3.9991 -2.5292 -3.9863 -0.8820 -0.0796 4.8960 0.0177 0.2348 0.1376 0.1639 0.2878 0.9864 0.0837 0.9094 0.0832 -#> 48: 99.9155 -4.0224 -2.5422 -3.9854 -0.8719 -0.0750 4.6512 0.0184 0.2251 0.1307 0.1596 0.2734 0.9841 0.0835 0.8696 0.0843 -#> 49: 99.6136 -4.0397 -2.5172 -4.0115 -0.8774 -0.0922 5.2402 0.0175 0.2558 0.1242 0.1551 0.2597 0.9060 0.0816 0.8365 0.0869 -#> 50: 99.4747 -4.0542 -2.4192 -3.9834 -0.9041 -0.1798 4.9782 0.0219 0.2695 0.1234 0.1474 0.2468 0.9269 0.0783 0.8593 0.0854 -#> 51: 99.3401 -4.0386 -2.3951 -3.9661 -0.9181 -0.1887 4.7574 0.0213 0.2746 0.1522 0.1400 0.2344 0.9901 0.0781 0.8863 0.0928 -#> 52: 99.7109 -4.0509 -2.4227 -3.9770 -0.9247 -0.1431 4.9004 0.0203 0.2688 0.1446 0.1330 0.2227 0.8999 0.0791 1.0265 0.0890 -#> 53: 99.6496 -4.0397 -2.4398 -3.9752 -0.9193 -0.2119 5.1106 0.0193 0.2795 0.1527 0.1325 0.2116 0.8949 0.0788 0.9447 0.0872 -#> 54: 99.9071 -4.0211 -2.3887 -3.9812 -0.9233 -0.1946 5.0887 0.0183 0.2763 0.1450 0.1365 0.2010 0.8793 0.0875 0.8643 0.0903 -#> 55: 1.0012e+02 -4.0401e+00 -2.4203e+00 -3.9511e+00 -9.0712e-01 -2.5566e-01 5.7301e+00 1.7375e-02 2.7324e-01 1.3780e-01 1.6204e-01 1.9094e-01 9.7803e-01 7.6146e-02 9.0756e-01 8.7636e-02 -#> 56: 1.0032e+02 -4.0207e+00 -2.4263e+00 -3.9533e+00 -8.7574e-01 -2.3076e-01 6.5321e+00 1.6507e-02 3.0821e-01 1.3091e-01 1.5394e-01 1.8139e-01 8.8520e-01 7.6350e-02 9.2796e-01 8.5283e-02 -#> 57: 1.0028e+02 -4.0037e+00 -2.4301e+00 -3.9655e+00 -8.8472e-01 -1.8969e-01 9.8969e+00 1.5681e-02 2.9280e-01 1.2436e-01 1.4624e-01 1.7232e-01 9.2902e-01 7.4974e-02 8.9204e-01 8.4563e-02 -#> 58: 1.0048e+02 -3.9928e+00 -2.4961e+00 -3.9709e+00 -9.0263e-01 -1.4516e-01 9.4021e+00 1.6151e-02 2.7816e-01 1.1814e-01 1.4165e-01 1.6370e-01 9.5145e-01 8.0233e-02 8.2896e-01 8.3498e-02 -#> 59: 1.0060e+02 -4.0181e+00 -2.4963e+00 -3.9751e+00 -9.0684e-01 -1.1186e-01 8.9320e+00 1.9914e-02 3.0097e-01 1.1224e-01 1.4109e-01 1.5552e-01 9.9121e-01 7.3120e-02 8.6454e-01 8.2239e-02 -#> 60: 1.0047e+02 -3.9976e+00 -2.4797e+00 -3.9780e+00 -8.9328e-01 -1.0814e-01 8.4854e+00 1.8918e-02 3.2275e-01 1.1591e-01 1.3404e-01 1.4774e-01 9.6968e-01 7.4984e-02 8.9831e-01 8.1655e-02 -#> 61: 1.0040e+02 -4.0068e+00 -2.5217e+00 -3.9844e+00 -8.6447e-01 -1.0567e-01 8.0611e+00 1.7972e-02 3.1372e-01 1.1011e-01 1.2973e-01 1.4036e-01 9.1698e-01 7.8118e-02 9.1811e-01 8.4420e-02 -#> 62: 1.0076e+02 -4.0080e+00 -2.4931e+00 -3.9623e+00 -8.9789e-01 -8.3896e-02 7.6580e+00 1.7073e-02 3.0460e-01 1.1254e-01 1.2324e-01 1.3334e-01 9.9032e-01 7.7618e-02 8.3808e-01 8.5031e-02 -#> 63: 1.0064e+02 -4.0129e+00 -2.4731e+00 -3.9561e+00 -8.9103e-01 -8.8987e-02 7.2751e+00 1.6220e-02 2.8944e-01 1.1647e-01 1.4845e-01 1.2667e-01 1.0745e+00 7.6375e-02 8.4316e-01 8.6681e-02 -#> 64: 1.0098e+02 -4.0094e+00 -2.4541e+00 -3.9604e+00 -9.1524e-01 -9.3413e-02 6.9114e+00 1.5409e-02 2.7497e-01 1.2065e-01 1.7095e-01 1.2034e-01 1.0963e+00 7.8304e-02 8.7104e-01 8.5727e-02 -#> 65: 1.0070e+02 -4.0433e+00 -2.4793e+00 -3.9722e+00 -9.3012e-01 -6.5917e-02 6.5658e+00 1.4638e-02 2.7040e-01 1.1462e-01 1.9067e-01 1.1432e-01 9.7444e-01 8.4510e-02 8.7028e-01 8.6292e-02 -#> 66: 1.0049e+02 -4.0656e+00 -2.4659e+00 -3.9898e+00 -9.4278e-01 -7.5929e-02 6.2375e+00 1.3906e-02 2.9347e-01 1.1997e-01 1.8114e-01 1.0860e-01 9.9830e-01 8.0902e-02 9.3551e-01 8.5261e-02 -#> 67: 1.0046e+02 -4.0477e+00 -2.4685e+00 -3.9907e+00 -9.1503e-01 -9.8019e-02 5.9256e+00 1.3211e-02 3.2166e-01 1.1506e-01 1.7208e-01 1.0317e-01 8.6453e-01 9.0533e-02 8.3598e-01 8.6343e-02 -#> 68: 1.0077e+02 -4.0575e+00 -2.4709e+00 -3.9523e+00 -9.2903e-01 -8.1099e-02 5.6294e+00 1.2818e-02 3.1005e-01 1.3665e-01 1.6347e-01 9.8015e-02 9.0181e-01 8.7058e-02 8.4937e-01 8.3248e-02 -#> 69: 1.0086e+02 -4.0626e+00 -2.3922e+00 -3.9557e+00 -9.6741e-01 -3.5986e-02 5.3479e+00 1.2844e-02 3.3024e-01 1.2982e-01 1.5530e-01 9.3115e-02 9.8180e-01 8.3132e-02 8.6549e-01 8.8939e-02 -#> 70: 1.0082e+02 -4.0640e+00 -2.4449e+00 -3.9787e+00 -9.5159e-01 -3.2904e-02 5.0805e+00 1.4346e-02 3.1373e-01 1.2333e-01 1.4754e-01 8.8459e-02 1.0129e+00 7.4856e-02 8.6688e-01 8.4769e-02 -#> 71: 1.0072e+02 -4.0642e+00 -2.5069e+00 -3.9493e+00 -9.3453e-01 -4.4116e-02 4.8265e+00 1.3628e-02 3.0428e-01 1.2122e-01 1.4091e-01 8.4036e-02 1.0454e+00 7.7023e-02 8.9566e-01 8.1639e-02 -#> 72: 1.0049e+02 -4.0609e+00 -2.4472e+00 -3.9669e+00 -9.3972e-01 -7.7498e-02 4.5852e+00 1.4441e-02 3.2552e-01 1.3911e-01 1.4144e-01 8.1899e-02 1.0114e+00 7.7019e-02 8.2312e-01 8.2494e-02 -#> 73: 1.0022e+02 -4.0598e+00 -2.4410e+00 -3.9952e+00 -9.2810e-01 -1.1309e-01 4.3559e+00 1.3719e-02 3.3556e-01 1.3303e-01 1.4990e-01 1.1303e-01 9.6726e-01 7.6776e-02 8.6331e-01 8.3048e-02 -#> 74: 1.0024e+02 -4.0628e+00 -2.4358e+00 -3.9977e+00 -9.1347e-01 -9.1966e-02 4.1381e+00 1.3033e-02 3.4332e-01 1.3418e-01 1.8099e-01 1.0738e-01 1.0158e+00 7.4697e-02 8.6366e-01 8.4370e-02 -#> 75: 99.7847 -4.0500 -2.4401 -4.0018 -0.9252 -0.1013 4.4651 0.0124 0.3365 0.1399 0.1817 0.1020 1.0278 0.0779 0.9008 0.0841 -#> 76: 99.9526 -4.0482 -2.4819 -3.9947 -0.9049 -0.0557 4.2419 0.0126 0.3248 0.1494 0.1726 0.1135 1.0493 0.0778 0.9341 0.0804 -#> 77: 99.9982 -4.0184 -2.4951 -4.0043 -0.8927 -0.0688 5.2538 0.0120 0.3696 0.1419 0.1817 0.1078 1.0402 0.0839 0.9605 0.0848 -#> 78: 1.0007e+02 -4.0210e+00 -2.4725e+00 -4.0040e+00 -8.9827e-01 2.3164e-03 6.4464e+00 1.1395e-02 3.7410e-01 1.3481e-01 2.0294e-01 1.0879e-01 9.7822e-01 8.7445e-02 9.9990e-01 8.2845e-02 -#> 79: 99.3513 -4.0171 -2.5065 -4.0078 -0.8962 -0.0029 7.7527 0.0108 0.3554 0.1281 0.1928 0.1069 1.0455 0.0866 0.9982 0.0870 -#> 80: 98.9945 -4.0172 -2.5412 -4.0341 -0.8891 -0.0187 9.8218 0.0103 0.3376 0.1217 0.1831 0.1457 0.9733 0.0894 1.0164 0.0832 -#> 81: 99.0936 -4.0275 -2.5134 -4.0127 -0.8552 -0.0614 12.1567 0.0098 0.3494 0.1156 0.1740 0.1384 0.9509 0.0843 1.0171 0.0855 -#> 82: 99.2481 -3.9996 -2.4945 -4.0011 -0.8914 -0.0492 11.5489 0.0128 0.3792 0.1098 0.1653 0.1315 0.9915 0.0818 1.0405 0.0928 -#> 83: 99.6941 -3.9998 -2.4851 -3.9845 -0.8802 -0.0560 10.9714 0.0146 0.3602 0.1043 0.1570 0.1249 0.9934 0.0852 0.9707 0.0866 -#> 84: 99.2185 -3.9920 -2.4843 -4.0051 -0.8546 -0.0642 10.4228 0.0153 0.3422 0.0991 0.1492 0.1187 0.9923 0.0833 0.9799 0.0873 -#> 85: 98.8470 -3.9956 -2.4652 -4.0201 -0.8483 -0.0414 9.9017 0.0146 0.3251 0.0941 0.1417 0.1128 0.9732 0.0901 0.9035 0.0858 -#> 86: 98.5012 -3.9841 -2.5148 -4.0250 -0.8408 -0.0551 9.4066 0.0148 0.3088 0.0962 0.1346 0.1071 0.8570 0.0932 0.8532 0.0896 -#> 87: 99.0868 -4.0055 -2.5058 -4.0249 -0.8522 -0.0311 10.3528 0.0175 0.2934 0.1013 0.1411 0.1018 0.8802 0.0838 0.8849 0.0862 -#> 88: 99.5158 -4.0031 -2.4437 -3.9866 -0.8894 -0.0963 9.9832 0.0167 0.3049 0.1030 0.1447 0.0967 0.9955 0.0834 0.8861 0.0893 -#> 89: 99.5538 -4.0347 -2.4494 -4.0213 -0.8695 -0.0494 9.4841 0.0158 0.2897 0.0978 0.1543 0.0918 0.8597 0.0904 0.8959 0.0880 -#> 90: 99.4422 -4.0453 -2.4398 -4.0114 -0.9279 -0.0745 9.8221 0.0150 0.2842 0.0929 0.1466 0.0944 0.9009 0.0871 0.8696 0.0924 -#> 91: 98.8721 -4.0328 -2.4996 -4.0041 -0.8832 -0.0689 9.3310 0.0143 0.2700 0.0896 0.1444 0.1137 0.9567 0.0904 0.8680 0.0891 -#> 92: 99.8390 -4.0418 -2.4914 -4.0182 -0.9279 -0.0460 10.9801 0.0136 0.2585 0.0949 0.1461 0.1210 1.0043 0.0908 0.8310 0.0939 -#> 93: 1.0029e+02 -4.0313e+00 -2.4620e+00 -4.0187e+00 -8.9083e-01 -1.0908e-01 1.0431e+01 1.2890e-02 2.4559e-01 9.5757e-02 1.3878e-01 1.1565e-01 9.9174e-01 9.0056e-02 8.9538e-01 8.8925e-02 -#> 94: 99.3285 -4.0295 -2.4523 -4.0235 -0.8828 -0.1190 10.9003 0.0137 0.2333 0.0915 0.1318 0.1212 1.0729 0.0779 0.9543 0.0907 -#> 95: 99.4117 -4.0422 -2.3807 -4.0870 -0.8960 -0.0889 10.3553 0.0130 0.2216 0.0870 0.1253 0.1366 0.9127 0.0864 0.8901 0.0911 -#> 96: 99.3348 -4.0401 -2.4009 -4.0698 -0.8730 -0.0622 9.8375 0.0123 0.2106 0.0826 0.1241 0.1297 0.8504 0.0836 0.9140 0.0881 -#> 97: 99.4898 -4.0419 -2.4310 -4.0589 -0.8932 -0.0634 9.3456 0.0132 0.2000 0.0785 0.1224 0.1233 0.8770 0.0836 0.8715 0.0837 -#> 98: 99.3750 -4.0704 -2.4353 -4.0616 -0.9333 -0.0846 8.8783 0.0136 0.1900 0.0746 0.1245 0.1171 0.8907 0.0838 0.9066 0.0832 -#> 99: 99.6234 -4.0366 -2.3740 -4.0657 -0.9242 -0.0675 8.4344 0.0129 0.1805 0.0708 0.1182 0.1112 0.8814 0.0808 0.9511 0.0863 -#> 100: 1.0025e+02 -4.0420e+00 -2.3557e+00 -4.0579e+00 -9.5051e-01 -6.3418e-02 8.0319e+00 1.2286e-02 1.7150e-01 6.7291e-02 1.1232e-01 1.0568e-01 8.5851e-01 8.7881e-02 8.9363e-01 8.5897e-02 -#> 101: 1.0041e+02 -4.0461e+00 -2.3840e+00 -4.0384e+00 -9.3752e-01 -7.7594e-02 9.5649e+00 1.1672e-02 1.7509e-01 6.3926e-02 1.2760e-01 1.0039e-01 8.6733e-01 8.2748e-02 9.6277e-01 8.4274e-02 -#> 102: 1.0095e+02 -4.0372e+00 -2.3633e+00 -4.0286e+00 -9.1961e-01 -6.5350e-02 1.1428e+01 1.1088e-02 1.8557e-01 6.0730e-02 1.3211e-01 9.5374e-02 9.3928e-01 8.0161e-02 9.7913e-01 8.4081e-02 -#> 103: 1.0019e+02 -4.0236e+00 -2.4105e+00 -4.0337e+00 -9.1362e-01 -7.3859e-02 1.0856e+01 1.0534e-02 1.7629e-01 5.7693e-02 1.2695e-01 9.1362e-02 9.8491e-01 8.1430e-02 9.7682e-01 8.2250e-02 -#> 104: 99.7755 -4.0280 -2.4452 -4.0197 -0.9112 -0.0810 11.0317 0.0100 0.1796 0.0548 0.1301 0.0868 0.9418 0.0816 0.9170 0.0806 -#> 105: 1.0010e+02 -4.0418e+00 -2.4294e+00 -4.0225e+00 -9.1111e-01 -8.9920e-02 1.0480e+01 9.5070e-03 1.7060e-01 5.2068e-02 1.3987e-01 8.2454e-02 9.1944e-01 7.8110e-02 8.9266e-01 8.7228e-02 -#> 106: 1.0025e+02 -4.0507e+00 -2.4134e+00 -4.0343e+00 -9.0244e-01 -8.4683e-02 1.3506e+01 9.0316e-03 1.6207e-01 4.9465e-02 1.5337e-01 7.8331e-02 9.9609e-01 8.4473e-02 8.7046e-01 8.5479e-02 -#> 107: 1.0014e+02 -4.0468e+00 -2.3972e+00 -4.0196e+00 -9.3650e-01 -2.4087e-02 1.2830e+01 8.5801e-03 1.6027e-01 4.6992e-02 1.5429e-01 8.2493e-02 9.8959e-01 8.2626e-02 8.3427e-01 8.8197e-02 -#> 108: 1.0114e+02 -4.0338e+00 -2.4307e+00 -4.0724e+00 -9.1363e-01 1.1952e-02 1.2189e+01 8.1511e-03 1.5563e-01 4.4854e-02 1.7315e-01 7.8368e-02 9.8589e-01 7.8130e-02 9.0460e-01 8.2870e-02 -#> 109: 1.0066e+02 -4.0550e+00 -2.4094e+00 -4.0641e+00 -9.0945e-01 -1.5401e-03 1.3149e+01 7.7435e-03 1.4785e-01 4.2612e-02 1.7232e-01 7.4450e-02 1.0942e+00 7.4816e-02 9.1706e-01 8.5333e-02 -#> 110: 1.0111e+02 -4.0266e+00 -2.4047e+00 -4.0646e+00 -9.0541e-01 -1.7212e-02 1.2492e+01 7.3563e-03 1.4046e-01 4.0481e-02 1.8132e-01 7.0727e-02 1.0508e+00 7.9457e-02 9.8990e-01 8.2975e-02 -#> 111: 1.0155e+02 -4.0274e+00 -2.3645e+00 -4.0663e+00 -9.4902e-01 -1.8882e-02 1.1867e+01 8.7757e-03 1.4436e-01 3.8457e-02 1.7225e-01 6.7191e-02 1.0217e+00 7.7437e-02 9.9196e-01 8.1580e-02 -#> 112: 1.0209e+02 -4.0230e+00 -2.3938e+00 -4.0375e+00 -9.5447e-01 -5.0888e-02 1.4321e+01 8.3370e-03 1.4863e-01 3.6534e-02 1.6778e-01 8.2186e-02 9.3085e-01 8.3291e-02 9.8775e-01 7.9492e-02 -#> 113: 1.0188e+02 -4.0173e+00 -2.3804e+00 -4.0403e+00 -9.6152e-01 -7.7453e-02 1.3605e+01 7.9201e-03 1.5060e-01 3.4708e-02 1.7341e-01 8.4506e-02 9.0783e-01 8.7383e-02 9.4854e-01 8.2648e-02 -#> 114: 1.0239e+02 -4.0081e+00 -2.3724e+00 -4.0332e+00 -9.4315e-01 -7.4933e-02 1.2925e+01 7.5241e-03 1.4307e-01 3.2972e-02 1.6695e-01 8.0281e-02 9.2775e-01 8.4314e-02 9.6195e-01 7.9448e-02 -#> 115: 1.0199e+02 -4.0127e+00 -2.3773e+00 -4.0472e+00 -9.5157e-01 -2.0947e-02 1.2279e+01 7.4483e-03 1.3592e-01 3.1324e-02 1.6705e-01 7.6267e-02 9.4956e-01 7.6989e-02 1.0340e+00 8.5564e-02 -#> 116: 1.0122e+02 -4.0264e+00 -2.4014e+00 -4.0509e+00 -9.1462e-01 -2.3511e-02 1.1665e+01 7.0759e-03 1.2912e-01 2.9757e-02 1.5870e-01 7.2453e-02 9.3580e-01 8.2952e-02 9.3341e-01 8.3302e-02 -#> 117: 1.0112e+02 -4.0326e+00 -2.4093e+00 -4.0559e+00 -8.9743e-01 -2.0572e-02 1.1082e+01 6.7221e-03 1.2266e-01 2.8269e-02 1.5339e-01 6.8831e-02 9.0879e-01 8.4441e-02 9.1432e-01 8.0538e-02 -#> 118: 1.0123e+02 -4.0411e+00 -2.4077e+00 -4.0556e+00 -9.2971e-01 -2.1885e-02 1.0528e+01 6.3860e-03 1.1653e-01 3.3123e-02 1.6947e-01 6.5389e-02 9.7140e-01 8.6671e-02 8.9874e-01 8.1670e-02 -#> 119: 1.0098e+02 -4.0538e+00 -2.3515e+00 -4.0607e+00 -9.5433e-01 -7.5743e-02 1.0001e+01 6.0667e-03 1.1070e-01 3.1467e-02 1.8338e-01 6.2120e-02 9.1537e-01 8.4827e-02 9.2420e-01 8.2769e-02 -#> 120: 1.0076e+02 -4.0573e+00 -2.3627e+00 -4.0329e+00 -9.3251e-01 -6.7669e-02 9.5011e+00 5.7634e-03 1.0517e-01 3.2868e-02 1.7422e-01 6.6096e-02 9.5247e-01 8.5343e-02 9.4678e-01 8.5335e-02 -#> 121: 1.0085e+02 -4.0450e+00 -2.3478e+00 -4.0692e+00 -9.2333e-01 -9.8005e-03 9.0261e+00 5.4752e-03 9.9911e-02 3.1225e-02 1.6550e-01 7.1593e-02 8.5572e-01 8.8654e-02 1.0248e+00 8.0646e-02 -#> 122: 1.0164e+02 -4.0325e+00 -2.3562e+00 -4.0680e+00 -9.4287e-01 -1.2103e-02 8.5748e+00 5.3493e-03 9.4915e-02 2.9663e-02 1.6347e-01 6.8014e-02 8.4872e-01 8.6803e-02 1.0282e+00 8.0381e-02 -#> 123: 1.0184e+02 -4.0521e+00 -2.3504e+00 -4.0714e+00 -9.5966e-01 -9.1996e-05 8.1460e+00 5.0818e-03 9.8247e-02 3.0007e-02 1.7746e-01 6.4613e-02 9.7181e-01 8.0986e-02 9.8860e-01 8.0317e-02 -#> 124: 1.0235e+02 -4.0674e+00 -2.3315e+00 -4.0874e+00 -9.9802e-01 3.8818e-02 7.7387e+00 4.8277e-03 9.3335e-02 2.8506e-02 1.7611e-01 6.8940e-02 9.7376e-01 7.6658e-02 9.9156e-01 8.4407e-02 -#> 125: 1.0257e+02 -4.0718e+00 -2.3604e+00 -4.0627e+00 -1.0591e+00 2.4685e-02 7.3518e+00 4.5863e-03 8.8668e-02 3.0650e-02 1.8671e-01 6.5493e-02 1.0275e+00 8.2278e-02 1.0896e+00 8.0976e-02 -#> 126: 1.0287e+02 -4.0691e+00 -2.3103e+00 -4.0552e+00 -1.0174e+00 2.1863e-02 7.5644e+00 4.3570e-03 1.0937e-01 2.9117e-02 1.7738e-01 6.2218e-02 9.2668e-01 7.9560e-02 9.5409e-01 8.4671e-02 -#> 127: 1.0327e+02 -4.0528e+00 -2.3141e+00 -4.0522e+00 -1.0108e+00 4.4779e-03 7.1862e+00 4.1392e-03 1.2239e-01 2.7661e-02 1.6925e-01 5.9107e-02 9.1372e-01 7.9536e-02 9.9164e-01 8.2999e-02 -#> 128: 1.0352e+02 -4.0496e+00 -2.2880e+00 -4.0496e+00 -1.0063e+00 -1.3248e-02 7.6721e+00 3.9613e-03 1.1627e-01 2.6278e-02 1.7517e-01 8.0231e-02 8.4407e-01 8.5078e-02 9.4382e-01 8.7530e-02 -#> 129: 1.0345e+02 -4.0715e+00 -2.3090e+00 -4.0400e+00 -1.0276e+00 -1.8301e-02 8.2197e+00 3.7633e-03 1.1046e-01 2.7141e-02 1.9366e-01 7.6220e-02 9.3357e-01 8.2674e-02 9.7064e-01 8.6011e-02 -#> 130: 1.0245e+02 -4.0787e+00 -2.3263e+00 -4.0106e+00 -1.0200e+00 -8.5976e-02 7.8087e+00 4.0830e-03 1.3607e-01 2.6631e-02 2.2700e-01 7.2409e-02 9.8233e-01 7.9348e-02 9.6780e-01 8.2658e-02 -#> 131: 1.0217e+02 -4.0760e+00 -2.2525e+00 -4.0082e+00 -1.0099e+00 -1.6111e-01 7.4183e+00 3.8789e-03 1.3972e-01 2.5299e-02 2.2508e-01 6.8788e-02 1.0066e+00 7.8692e-02 9.4684e-01 8.4349e-02 -#> 132: 1.0185e+02 -4.0792e+00 -2.2309e+00 -3.9996e+00 -9.8302e-01 -2.2504e-01 7.0474e+00 4.0356e-03 1.3743e-01 2.4034e-02 2.1383e-01 7.7346e-02 9.4225e-01 7.9110e-02 9.5160e-01 8.4398e-02 -#> 133: 1.0135e+02 -4.0818e+00 -2.2219e+00 -4.0054e+00 -9.7264e-01 -1.8912e-01 7.1932e+00 3.8338e-03 1.3056e-01 2.2833e-02 2.0314e-01 7.6769e-02 1.0031e+00 8.5400e-02 1.0034e+00 8.4805e-02 -#> 134: 1.0148e+02 -4.0782e+00 -2.2492e+00 -3.9886e+00 -9.5184e-01 -1.5049e-01 6.8336e+00 3.6422e-03 1.2403e-01 2.3398e-02 1.9298e-01 7.2931e-02 9.3696e-01 8.3566e-02 9.4742e-01 8.9137e-02 -#> 135: 1.0145e+02 -4.0852e+00 -2.3062e+00 -4.0011e+00 -9.4444e-01 -1.6803e-01 6.4919e+00 3.4600e-03 1.1783e-01 2.2228e-02 1.8333e-01 6.9284e-02 9.4846e-01 8.3087e-02 9.7774e-01 8.2610e-02 -#> 136: 1.0177e+02 -4.0861e+00 -2.2785e+00 -3.9890e+00 -9.9625e-01 -1.8938e-01 6.1673e+00 3.2870e-03 1.1752e-01 2.1116e-02 1.8815e-01 6.5820e-02 9.3634e-01 8.5255e-02 1.1001e+00 8.5332e-02 -#> 137: 1.0200e+02 -4.0928e+00 -2.1946e+00 -3.9974e+00 -1.0098e+00 -1.8810e-01 5.8589e+00 3.1227e-03 1.2394e-01 2.1203e-02 1.7874e-01 7.2232e-02 1.0048e+00 7.3422e-02 1.0222e+00 8.3484e-02 -#> 138: 1.0214e+02 -4.0820e+00 -2.2052e+00 -3.9737e+00 -1.0420e+00 -2.0594e-01 5.5660e+00 3.8937e-03 1.9164e-01 2.0143e-02 1.6980e-01 6.8621e-02 1.0126e+00 7.6106e-02 1.0780e+00 8.2960e-02 -#> 139: 1.0249e+02 -4.0785e+00 -2.1649e+00 -3.9567e+00 -1.0095e+00 -2.8807e-01 5.2877e+00 3.6990e-03 1.8647e-01 1.9135e-02 1.6131e-01 6.5190e-02 1.0030e+00 7.9858e-02 1.0611e+00 8.4109e-02 -#> 140: 1.0184e+02 -4.0847e+00 -2.1800e+00 -3.9565e+00 -9.9415e-01 -2.8869e-01 5.0233e+00 4.0857e-03 1.9502e-01 1.8179e-02 1.6676e-01 6.2879e-02 9.5962e-01 7.8117e-02 9.9649e-01 8.4914e-02 -#> 141: 1.0195e+02 -4.1012e+00 -2.1831e+00 -3.9488e+00 -9.9515e-01 -3.1864e-01 4.7721e+00 3.8814e-03 1.8527e-01 1.7270e-02 1.6797e-01 6.1084e-02 9.0969e-01 8.2722e-02 1.0122e+00 8.2518e-02 -#> 142: 1.0233e+02 -4.1139e+00 -2.1692e+00 -3.9542e+00 -1.0023e+00 -3.3242e-01 4.5335e+00 3.6873e-03 2.0662e-01 1.6406e-02 1.5957e-01 5.8030e-02 9.4761e-01 8.4629e-02 1.0342e+00 8.3954e-02 -#> 143: 1.0217e+02 -4.1103e+00 -2.1380e+00 -3.9511e+00 -1.0300e+00 -2.5992e-01 5.2035e+00 4.7053e-03 1.9629e-01 1.5586e-02 1.5979e-01 5.5128e-02 8.9255e-01 7.9042e-02 1.0461e+00 8.6952e-02 -#> 144: 1.0185e+02 -4.1335e+00 -2.1911e+00 -3.9650e+00 -1.0440e+00 -2.4451e-01 5.0998e+00 4.4700e-03 1.8648e-01 1.9590e-02 1.5534e-01 5.2372e-02 9.7863e-01 8.3932e-02 1.0197e+00 8.7673e-02 -#> 145: 1.0242e+02 -4.1445e+00 -2.1203e+00 -3.9616e+00 -1.0426e+00 -2.7120e-01 4.8448e+00 4.2465e-03 1.7715e-01 1.8611e-02 1.4757e-01 4.9753e-02 1.0024e+00 8.4131e-02 1.0768e+00 8.5388e-02 -#> 146: 1.0236e+02 -4.1519e+00 -2.1958e+00 -3.9779e+00 -9.8615e-01 -2.5863e-01 4.6026e+00 4.0718e-03 1.6829e-01 1.7680e-02 1.6407e-01 4.7266e-02 1.0740e+00 8.2413e-02 1.0706e+00 8.3410e-02 -#> 147: 1.0251e+02 -4.1465e+00 -2.2042e+00 -3.9775e+00 -1.0317e+00 -2.2757e-01 4.3725e+00 3.8682e-03 1.5988e-01 1.6796e-02 1.7016e-01 4.4902e-02 9.7748e-01 8.3376e-02 1.0880e+00 8.1968e-02 -#> 148: 1.0244e+02 -4.1432e+00 -2.1786e+00 -3.9792e+00 -1.0442e+00 -2.2002e-01 4.9671e+00 3.6748e-03 1.5189e-01 1.5956e-02 2.2196e-01 4.2657e-02 1.0412e+00 7.8051e-02 1.1051e+00 8.1618e-02 -#> 149: 1.0219e+02 -4.1384e+00 -2.2318e+00 -3.9757e+00 -1.0438e+00 -2.4124e-01 4.7187e+00 3.4910e-03 1.4429e-01 1.6061e-02 2.1086e-01 4.0524e-02 1.0082e+00 8.0377e-02 1.1455e+00 8.0545e-02 -#> 150: 1.0264e+02 -4.1498e+00 -2.2352e+00 -3.9915e+00 -1.0669e+00 -2.1255e-01 4.4828e+00 3.3165e-03 1.3708e-01 1.7218e-02 2.0032e-01 3.8498e-02 9.5031e-01 8.7248e-02 9.8770e-01 8.3250e-02 -#> 151: 1.0250e+02 -4.1365e+00 -2.1876e+00 -3.9939e+00 -1.0568e+00 -1.8159e-01 4.2587e+00 3.1507e-03 1.3022e-01 1.7383e-02 1.9030e-01 3.6573e-02 9.6938e-01 8.0203e-02 1.0578e+00 8.3430e-02 -#> 152: 1.0256e+02 -4.1370e+00 -2.2238e+00 -4.0047e+00 -1.0406e+00 -1.8764e-01 1.9609e+00 1.4191e-03 1.1882e-01 1.7924e-02 1.6889e-01 4.1216e-02 9.1972e-01 7.8573e-02 1.0717e+00 8.0882e-02 -#> 153: 1.0219e+02 -4.1299e+00 -2.2139e+00 -3.9917e+00 -9.9964e-01 -2.0505e-01 1.8258e+00 1.0432e-03 8.4660e-02 2.1446e-02 1.7634e-01 3.5573e-02 9.3702e-01 8.4860e-02 1.0145e+00 8.3329e-02 -#> 154: 1.0199e+02 -4.1354e+00 -2.2231e+00 -3.9779e+00 -1.0155e+00 -2.2573e-01 2.6463e+00 5.8153e-04 8.8101e-02 2.3167e-02 1.6103e-01 3.3874e-02 9.5360e-01 8.6215e-02 9.5723e-01 8.4603e-02 -#> 155: 1.0234e+02 -4.1239e+00 -2.2137e+00 -3.9802e+00 -1.0070e+00 -2.3158e-01 2.9697e+00 6.6709e-04 1.1190e-01 2.0949e-02 1.8298e-01 3.1557e-02 9.2910e-01 8.2509e-02 9.8680e-01 8.5206e-02 -#> 156: 1.0253e+02 -4.1269e+00 -2.2370e+00 -3.9682e+00 -1.0420e+00 -2.1219e-01 2.7267e+00 6.8451e-04 8.9651e-02 2.4380e-02 1.6613e-01 3.4846e-02 9.3608e-01 8.7506e-02 9.0446e-01 8.1755e-02 -#> 157: 1.0265e+02 -4.1241e+00 -2.2179e+00 -3.9676e+00 -1.0308e+00 -2.2480e-01 2.1278e+00 4.9811e-04 6.7161e-02 1.9758e-02 1.5607e-01 4.4198e-02 9.4162e-01 8.7311e-02 9.9147e-01 7.9857e-02 -#> 158: 1.0239e+02 -4.1219e+00 -2.1615e+00 -3.9781e+00 -1.0384e+00 -2.6750e-01 2.5310e+00 4.8270e-04 6.5662e-02 1.8085e-02 1.7665e-01 4.4020e-02 8.8632e-01 8.6004e-02 1.0425e+00 8.2894e-02 -#> 159: 1.0270e+02 -4.1204e+00 -2.1837e+00 -3.9530e+00 -1.0587e+00 -2.5809e-01 3.4348e+00 5.6788e-04 6.5500e-02 1.9540e-02 1.8629e-01 4.0730e-02 9.5079e-01 8.2399e-02 9.9316e-01 8.3381e-02 -#> 160: 1.0282e+02 -4.1223e+00 -2.1325e+00 -3.9734e+00 -1.0068e+00 -2.8751e-01 3.9652e+00 7.6565e-04 8.5246e-02 1.7068e-02 1.7587e-01 3.0778e-02 9.1802e-01 8.0158e-02 9.9642e-01 8.1564e-02 -#> 161: 1.0330e+02 -4.1180e+00 -2.1879e+00 -3.9743e+00 -1.0268e+00 -2.8812e-01 4.9153e+00 5.8033e-04 8.0457e-02 1.8555e-02 1.7312e-01 3.3941e-02 8.6920e-01 8.2509e-02 9.5632e-01 8.1798e-02 -#> 162: 1.0335e+02 -4.1182e+00 -2.2089e+00 -3.9566e+00 -1.0409e+00 -2.7390e-01 3.6169e+00 2.8392e-04 1.0776e-01 1.9589e-02 1.6479e-01 2.8481e-02 8.8603e-01 8.7799e-02 9.5197e-01 7.9563e-02 -#> 163: 1.0294e+02 -4.1181e+00 -2.2025e+00 -3.9462e+00 -9.9783e-01 -3.0753e-01 3.7234e+00 1.6293e-04 9.6922e-02 2.4842e-02 1.9367e-01 3.1473e-02 9.0380e-01 9.1697e-02 9.4394e-01 8.2786e-02 -#> 164: 1.0246e+02 -4.1155e+00 -2.2157e+00 -3.9736e+00 -9.9866e-01 -2.9356e-01 3.9439e+00 1.9405e-04 1.0404e-01 2.8435e-02 1.9043e-01 3.1239e-02 8.9853e-01 8.9427e-02 9.2586e-01 8.3170e-02 -#> 165: 1.0204e+02 -4.1117e+00 -2.2133e+00 -3.9674e+00 -1.0079e+00 -2.6996e-01 3.0774e+00 1.6591e-04 7.0005e-02 2.8285e-02 2.0813e-01 2.4574e-02 8.9719e-01 9.1629e-02 9.8242e-01 8.3692e-02 -#> 166: 1.0207e+02 -4.1164e+00 -2.2192e+00 -3.9893e+00 -1.0354e+00 -2.7396e-01 1.8145e+00 8.4168e-05 9.0739e-02 2.7410e-02 2.1403e-01 2.4311e-02 8.9386e-01 9.2727e-02 9.4636e-01 8.4238e-02 -#> 167: 1.0187e+02 -4.1149e+00 -2.2185e+00 -3.9708e+00 -1.0036e+00 -2.5751e-01 1.5355e+00 4.0974e-05 9.9346e-02 2.2030e-02 2.1916e-01 2.6726e-02 9.1055e-01 8.1030e-02 1.0098e+00 7.9180e-02 -#> 168: 1.0172e+02 -4.1167e+00 -2.2673e+00 -3.9702e+00 -9.8388e-01 -2.1404e-01 1.4836e+00 2.7779e-05 7.7509e-02 2.9513e-02 1.9543e-01 3.4526e-02 1.0152e+00 8.1248e-02 9.7482e-01 8.0746e-02 -#> 169: 1.0175e+02 -4.1171e+00 -2.2634e+00 -3.9701e+00 -9.5962e-01 -2.4130e-01 1.4263e+00 4.7370e-05 5.0986e-02 2.8211e-02 2.2554e-01 3.9909e-02 9.8519e-01 7.8842e-02 1.0023e+00 8.5684e-02 -#> 170: 1.0177e+02 -4.1189e+00 -2.2417e+00 -3.9834e+00 -1.0059e+00 -2.6551e-01 9.9010e-01 3.7247e-05 4.2517e-02 2.9791e-02 1.8705e-01 4.2435e-02 9.6604e-01 8.8427e-02 9.6699e-01 8.3986e-02 -#> 171: 1.0182e+02 -4.1187e+00 -2.2464e+00 -3.9953e+00 -9.8154e-01 -2.5146e-01 7.4179e-01 3.2420e-05 5.0690e-02 3.0483e-02 1.7888e-01 6.3177e-02 9.2784e-01 8.4814e-02 1.0018e+00 8.4070e-02 -#> 172: 1.0184e+02 -4.1178e+00 -2.2483e+00 -4.0009e+00 -1.0096e+00 -2.2636e-01 9.6710e-01 2.6981e-05 3.1321e-02 2.7772e-02 1.9767e-01 7.4969e-02 9.9720e-01 8.1434e-02 9.5483e-01 8.3419e-02 -#> 173: 1.0160e+02 -4.1183e+00 -2.2513e+00 -3.9920e+00 -9.8456e-01 -2.0144e-01 4.9964e-01 2.1222e-05 4.1909e-02 2.8101e-02 2.1163e-01 1.2811e-01 9.6384e-01 8.0352e-02 9.2496e-01 8.2328e-02 -#> 174: 1.0159e+02 -4.1179e+00 -2.2334e+00 -4.0068e+00 -1.0316e+00 -2.0656e-01 4.6608e-01 1.8044e-05 4.4647e-02 2.8273e-02 2.0083e-01 1.2780e-01 9.4612e-01 8.3630e-02 8.9385e-01 8.3930e-02 -#> 175: 1.0159e+02 -4.1182e+00 -2.2567e+00 -3.9972e+00 -1.0299e+00 -1.6534e-01 4.5228e-01 2.0060e-05 8.5751e-02 2.5343e-02 1.7864e-01 8.6977e-02 9.5795e-01 7.8867e-02 8.9213e-01 8.4362e-02 -#> 176: 1.0159e+02 -4.1183e+00 -2.2109e+00 -3.9983e+00 -1.0210e+00 -2.0879e-01 5.3694e-01 2.0264e-05 1.2835e-01 2.5563e-02 1.9469e-01 6.0808e-02 9.1537e-01 7.8520e-02 9.3355e-01 8.3608e-02 -#> 177: 1.0155e+02 -4.1193e+00 -2.2587e+00 -3.9825e+00 -1.0180e+00 -1.6859e-01 4.4935e-01 3.0321e-05 1.3509e-01 2.4979e-02 2.0113e-01 6.3617e-02 9.7277e-01 7.8515e-02 9.2667e-01 8.5309e-02 -#> 178: 1.0158e+02 -4.1196e+00 -2.2679e+00 -4.0231e+00 -1.0143e+00 -1.6084e-01 6.7629e-01 3.2855e-05 6.8816e-02 2.7808e-02 1.8944e-01 8.1814e-02 8.8319e-01 8.0114e-02 9.5183e-01 8.2195e-02 -#> 179: 1.0166e+02 -4.1190e+00 -2.2764e+00 -3.9875e+00 -1.0061e+00 -1.8260e-01 7.1129e-01 3.8250e-05 7.5489e-02 2.4148e-02 1.8082e-01 7.1172e-02 9.1387e-01 8.0813e-02 9.6660e-01 8.2457e-02 -#> 180: 1.0179e+02 -4.1202e+00 -2.2848e+00 -3.9974e+00 -9.9825e-01 -2.0277e-01 5.5755e-01 2.8041e-05 8.6779e-02 2.7193e-02 1.8826e-01 6.5133e-02 8.8812e-01 8.2655e-02 9.2100e-01 7.9919e-02 -#> 181: 1.0176e+02 -4.1200e+00 -2.2704e+00 -3.9954e+00 -1.0194e+00 -1.6896e-01 4.3842e-01 2.2428e-05 7.4093e-02 3.0526e-02 2.3473e-01 1.0537e-01 9.2303e-01 8.2141e-02 9.2941e-01 8.4699e-02 -#> 182: 1.0182e+02 -4.1211e+00 -2.3159e+00 -4.0259e+00 -1.0162e+00 -1.2876e-01 3.4993e-01 1.5716e-05 5.9887e-02 2.6422e-02 2.1757e-01 1.0488e-01 9.1725e-01 9.4143e-02 9.7674e-01 8.8668e-02 -#> 183: 1.0184e+02 -4.1216e+00 -2.2985e+00 -4.0278e+00 -1.0136e+00 -1.3154e-01 2.6456e-01 1.2552e-05 5.7149e-02 3.2712e-02 2.0632e-01 1.5501e-01 9.2464e-01 8.5394e-02 8.8699e-01 8.4279e-02 -#> 184: 1.0172e+02 -4.1212e+00 -2.2726e+00 -4.0189e+00 -1.0280e+00 -1.2967e-01 3.0582e-01 7.5239e-06 8.2812e-02 2.9556e-02 1.9725e-01 1.3753e-01 9.0862e-01 8.1319e-02 9.0031e-01 8.3491e-02 -#> 185: 1.0178e+02 -4.1208e+00 -2.2858e+00 -4.0272e+00 -1.0063e+00 -1.6155e-01 3.0856e-01 4.5894e-06 8.8870e-02 2.5817e-02 1.9251e-01 1.0670e-01 9.1157e-01 7.7834e-02 9.6258e-01 7.8990e-02 -#> 186: 1.0198e+02 -4.1208e+00 -2.2682e+00 -4.0401e+00 -9.8523e-01 -1.1556e-01 2.4761e-01 3.2640e-06 7.5614e-02 2.1067e-02 1.9085e-01 9.0045e-02 8.5090e-01 8.6621e-02 1.0145e+00 8.1864e-02 -#> 187: 1.0197e+02 -4.1208e+00 -2.2788e+00 -4.0281e+00 -1.0066e+00 -1.0149e-01 2.0460e-01 4.5073e-06 7.8797e-02 2.3861e-02 2.0725e-01 7.9771e-02 9.6253e-01 8.2363e-02 9.3855e-01 8.3939e-02 -#> 188: 1.0196e+02 -4.1207e+00 -2.3105e+00 -4.0149e+00 -1.0217e+00 -9.0603e-02 2.2178e-01 3.6903e-06 8.9793e-02 2.1775e-02 1.9248e-01 8.2415e-02 9.4078e-01 8.1247e-02 9.1756e-01 8.2786e-02 -#> 189: 1.0202e+02 -4.1204e+00 -2.2702e+00 -4.0430e+00 -1.0032e+00 -1.1308e-01 2.2944e-01 3.5141e-06 7.8575e-02 2.4885e-02 2.0968e-01 8.2380e-02 9.5115e-01 8.1619e-02 9.2134e-01 8.9958e-02 -#> 190: 1.0195e+02 -4.1207e+00 -2.3126e+00 -4.0312e+00 -1.0154e+00 -6.3842e-02 2.5129e-01 2.6517e-06 4.2267e-02 2.2084e-02 1.9361e-01 7.0492e-02 9.3985e-01 8.5817e-02 9.3893e-01 8.7011e-02 -#> 191: 1.0203e+02 -4.1206e+00 -2.2758e+00 -4.0290e+00 -1.0102e+00 -3.1042e-02 1.7935e-01 3.4489e-06 5.7444e-02 2.3544e-02 1.9651e-01 7.9509e-02 9.5213e-01 8.2030e-02 1.0054e+00 8.7523e-02 -#> 192: 1.0199e+02 -4.1205e+00 -2.2969e+00 -4.0329e+00 -1.0364e+00 -8.3705e-02 1.5785e-01 3.5081e-06 7.4305e-02 2.2992e-02 1.9662e-01 7.7684e-02 9.2601e-01 8.3027e-02 9.8642e-01 8.3428e-02 -#> 193: 1.0196e+02 -4.1205e+00 -2.2661e+00 -4.0513e+00 -9.9271e-01 -4.6516e-02 1.2084e-01 2.6911e-06 6.8360e-02 3.5444e-02 1.9649e-01 7.5188e-02 9.1949e-01 7.9194e-02 1.0046e+00 8.5964e-02 -#> 194: 1.0198e+02 -4.1207e+00 -2.2817e+00 -4.0520e+00 -9.9852e-01 -8.4466e-02 1.3596e-01 1.5511e-06 6.5142e-02 4.1562e-02 1.9137e-01 9.6992e-02 9.6709e-01 7.6757e-02 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-2.3365e-02 4.5888e-02 5.0564e-07 5.9894e-02 3.5053e-02 2.0322e-01 5.4423e-02 9.0925e-01 8.5899e-02 9.8418e-01 8.3421e-02 -#> 206: 1.0192e+02 -4.1205e+00 -2.3095e+00 -4.0715e+00 -9.9721e-01 -2.6262e-02 4.3985e-02 5.1954e-07 5.8681e-02 3.4539e-02 2.0202e-01 5.8248e-02 9.1301e-01 8.5459e-02 9.8621e-01 8.3465e-02 -#> 207: 1.0192e+02 -4.1205e+00 -2.3179e+00 -4.0731e+00 -9.9906e-01 -2.3191e-02 4.3649e-02 5.3824e-07 5.7537e-02 3.4790e-02 2.0220e-01 6.0242e-02 9.1783e-01 8.5307e-02 9.8436e-01 8.3111e-02 -#> 208: 1.0191e+02 -4.1205e+00 -2.3238e+00 -4.0734e+00 -9.9920e-01 -1.9434e-02 4.3223e-02 5.3831e-07 5.7908e-02 3.4909e-02 2.0126e-01 6.0353e-02 9.2010e-01 8.5244e-02 9.8002e-01 8.2975e-02 -#> 209: 1.0191e+02 -4.1205e+00 -2.3279e+00 -4.0726e+00 -1.0053e+00 -1.5390e-02 4.1064e-02 5.3171e-07 5.8749e-02 3.4510e-02 1.9942e-01 6.3063e-02 9.3192e-01 8.4436e-02 9.8298e-01 8.3187e-02 -#> 210: 1.0191e+02 -4.1205e+00 -2.3310e+00 -4.0705e+00 -1.0061e+00 -1.3507e-02 3.8265e-02 5.2762e-07 5.9344e-02 3.3374e-02 1.9612e-01 6.7006e-02 9.3199e-01 8.4573e-02 9.8382e-01 8.3227e-02 -#> 211: 1.0191e+02 -4.1205e+00 -2.3383e+00 -4.0683e+00 -1.0043e+00 -1.3973e-02 3.6076e-02 5.2584e-07 6.1568e-02 3.2369e-02 1.9504e-01 6.9982e-02 9.4179e-01 8.4625e-02 9.9145e-01 8.3067e-02 -#> 212: 1.0192e+02 -4.1204e+00 -2.3396e+00 -4.0662e+00 -1.0055e+00 -1.8011e-02 3.4746e-02 5.4375e-07 6.2747e-02 3.1588e-02 1.9405e-01 7.2360e-02 9.4525e-01 8.4466e-02 9.9581e-01 8.2952e-02 -#> 213: 1.0192e+02 -4.1204e+00 -2.3407e+00 -4.0649e+00 -1.0066e+00 -2.1077e-02 3.4708e-02 5.5843e-07 6.1940e-02 3.0715e-02 1.9382e-01 7.4602e-02 9.4611e-01 8.4322e-02 9.9397e-01 8.2717e-02 -#> 214: 1.0192e+02 -4.1204e+00 -2.3392e+00 -4.0648e+00 -1.0076e+00 -2.3417e-02 3.4282e-02 5.8157e-07 6.1893e-02 3.0158e-02 1.9322e-01 7.8942e-02 9.5250e-01 8.3922e-02 9.9723e-01 8.2793e-02 -#> 215: 1.0192e+02 -4.1204e+00 -2.3410e+00 -4.0645e+00 -1.0087e+00 -2.1950e-02 3.5820e-02 6.0691e-07 6.2032e-02 2.9890e-02 1.9172e-01 8.3774e-02 9.5617e-01 8.3280e-02 1.0003e+00 8.2881e-02 -#> 216: 1.0192e+02 -4.1203e+00 -2.3425e+00 -4.0628e+00 -1.0069e+00 -2.4268e-02 3.7597e-02 6.4187e-07 6.1733e-02 2.9353e-02 1.9092e-01 8.8150e-02 9.5834e-01 8.3091e-02 1.0027e+00 8.2753e-02 -#> 217: 1.0192e+02 -4.1203e+00 -2.3439e+00 -4.0613e+00 -1.0064e+00 -2.4197e-02 3.9291e-02 6.5775e-07 6.2318e-02 2.8903e-02 1.8958e-01 9.0470e-02 9.5766e-01 8.3234e-02 1.0020e+00 8.2707e-02 -#> 218: 1.0191e+02 -4.1203e+00 -2.3441e+00 -4.0619e+00 -1.0065e+00 -2.2460e-02 4.0043e-02 6.4921e-07 6.2280e-02 2.8349e-02 1.8800e-01 9.4476e-02 9.5499e-01 8.3416e-02 1.0036e+00 8.2628e-02 -#> 219: 1.0191e+02 -4.1203e+00 -2.3437e+00 -4.0624e+00 -1.0066e+00 -1.9698e-02 3.9735e-02 6.3365e-07 6.2264e-02 2.7720e-02 1.8768e-01 9.7275e-02 9.4994e-01 8.3350e-02 1.0047e+00 8.2572e-02 -#> 220: 1.0191e+02 -4.1203e+00 -2.3447e+00 -4.0630e+00 -1.0070e+00 -1.5871e-02 4.0198e-02 6.3507e-07 6.1981e-02 2.7259e-02 1.8786e-01 9.9168e-02 9.4781e-01 8.3355e-02 1.0046e+00 8.2752e-02 -#> 221: 1.0191e+02 -4.1203e+00 -2.3459e+00 -4.0638e+00 -1.0069e+00 -1.4298e-02 4.0161e-02 6.2865e-07 6.2113e-02 2.7201e-02 1.8810e-01 1.0163e-01 9.4863e-01 8.3154e-02 1.0042e+00 8.2670e-02 -#> 222: 1.0191e+02 -4.1203e+00 -2.3472e+00 -4.0646e+00 -1.0064e+00 -1.0921e-02 4.0310e-02 6.2450e-07 6.2436e-02 2.6979e-02 1.8736e-01 1.0306e-01 9.4914e-01 8.3081e-02 1.0050e+00 8.2757e-02 -#> 223: 1.0191e+02 -4.1203e+00 -2.3478e+00 -4.0650e+00 -1.0063e+00 -1.1053e-02 3.9741e-02 6.1973e-07 6.2918e-02 2.6636e-02 1.8806e-01 1.0506e-01 9.4996e-01 8.2927e-02 1.0054e+00 8.2579e-02 -#> 224: 1.0191e+02 -4.1203e+00 -2.3478e+00 -4.0653e+00 -1.0061e+00 -1.0324e-02 3.9480e-02 6.1421e-07 6.4180e-02 2.6403e-02 1.8833e-01 1.0733e-01 9.4750e-01 8.2697e-02 1.0033e+00 8.2517e-02 -#> 225: 1.0191e+02 -4.1203e+00 -2.3479e+00 -4.0654e+00 -1.0060e+00 -1.0650e-02 3.9188e-02 6.0959e-07 6.3862e-02 2.6122e-02 1.8815e-01 1.0786e-01 9.4504e-01 8.2833e-02 1.0002e+00 8.2398e-02 -#> 226: 1.0192e+02 -4.1204e+00 -2.3469e+00 -4.0657e+00 -1.0052e+00 -1.0205e-02 3.9129e-02 6.0577e-07 6.4045e-02 2.5875e-02 1.8762e-01 1.0921e-01 9.4663e-01 8.2599e-02 9.9857e-01 8.2472e-02 -#> 227: 1.0192e+02 -4.1203e+00 -2.3467e+00 -4.0658e+00 -1.0053e+00 -1.0189e-02 3.8797e-02 6.0837e-07 6.5125e-02 2.5679e-02 1.8721e-01 1.1060e-01 9.4729e-01 8.2470e-02 9.9802e-01 8.2753e-02 -#> 228: 1.0192e+02 -4.1204e+00 -2.3469e+00 -4.0657e+00 -1.0054e+00 -1.0575e-02 3.8741e-02 6.0738e-07 6.5467e-02 2.5448e-02 1.8548e-01 1.1134e-01 9.4840e-01 8.2580e-02 9.9829e-01 8.2888e-02 -#> 229: 1.0192e+02 -4.1204e+00 -2.3479e+00 -4.0650e+00 -1.0056e+00 -1.1215e-02 3.9360e-02 6.0182e-07 6.4817e-02 2.5237e-02 1.8448e-01 1.1090e-01 9.5039e-01 8.2625e-02 9.9900e-01 8.2896e-02 -#> 230: 1.0192e+02 -4.1204e+00 -2.3482e+00 -4.0652e+00 -1.0060e+00 -9.9775e-03 3.9501e-02 5.9385e-07 6.4132e-02 2.5093e-02 1.8510e-01 1.1122e-01 9.4938e-01 8.2763e-02 9.9961e-01 8.2886e-02 -#> 231: 1.0192e+02 -4.1204e+00 -2.3479e+00 -4.0654e+00 -1.0070e+00 -8.9509e-03 3.9907e-02 5.9290e-07 6.3744e-02 2.4829e-02 1.8560e-01 1.1062e-01 9.4790e-01 8.2872e-02 1.0022e+00 8.2955e-02 -#> 232: 1.0192e+02 -4.1204e+00 -2.3484e+00 -4.0657e+00 -1.0081e+00 -6.9066e-03 4.0738e-02 5.7862e-07 6.3242e-02 2.4729e-02 1.8626e-01 1.0975e-01 9.4866e-01 8.2846e-02 1.0036e+00 8.3065e-02 -#> 233: 1.0191e+02 -4.1204e+00 -2.3487e+00 -4.0660e+00 -1.0080e+00 -5.1163e-03 4.0708e-02 5.7326e-07 6.2392e-02 2.4475e-02 1.8701e-01 1.0932e-01 9.4816e-01 8.2933e-02 1.0059e+00 8.3155e-02 -#> 234: 1.0191e+02 -4.1204e+00 -2.3500e+00 -4.0660e+00 -1.0077e+00 -4.0637e-03 4.1065e-02 5.6885e-07 6.1938e-02 2.4418e-02 1.8673e-01 1.0923e-01 9.5001e-01 8.3005e-02 1.0080e+00 8.3207e-02 -#> 235: 1.0191e+02 -4.1204e+00 -2.3526e+00 -4.0653e+00 -1.0074e+00 -3.6541e-03 4.1151e-02 5.6498e-07 6.2228e-02 2.4447e-02 1.8667e-01 1.0995e-01 9.5059e-01 8.3101e-02 1.0055e+00 8.3101e-02 -#> 236: 1.0191e+02 -4.1204e+00 -2.3540e+00 -4.0648e+00 -1.0078e+00 -4.0127e-03 4.0966e-02 5.7047e-07 6.1779e-02 2.4457e-02 1.8777e-01 1.0971e-01 9.4919e-01 8.3203e-02 1.0044e+00 8.3078e-02 -#> 237: 1.0191e+02 -4.1204e+00 -2.3528e+00 -4.0645e+00 -1.0078e+00 -4.4251e-03 4.0491e-02 5.6811e-07 6.1507e-02 2.4421e-02 1.8827e-01 1.1047e-01 9.4870e-01 8.3149e-02 1.0031e+00 8.3008e-02 -#> 238: 1.0190e+02 -4.1204e+00 -2.3517e+00 -4.0647e+00 -1.0076e+00 -5.2540e-03 3.9988e-02 5.6832e-07 6.1612e-02 2.4262e-02 1.8801e-01 1.1019e-01 9.4737e-01 8.3172e-02 1.0037e+00 8.2959e-02 -#> 239: 1.0190e+02 -4.1204e+00 -2.3509e+00 -4.0650e+00 -1.0089e+00 -5.1598e-03 3.9373e-02 5.6396e-07 6.1635e-02 2.4040e-02 1.8812e-01 1.1055e-01 9.4885e-01 8.3140e-02 1.0053e+00 8.2956e-02 -#> 240: 1.0190e+02 -4.1204e+00 -2.3515e+00 -4.0643e+00 -1.0095e+00 -4.5817e-03 3.9031e-02 5.5929e-07 6.2233e-02 2.3840e-02 1.8766e-01 1.1014e-01 9.5018e-01 8.3172e-02 1.0066e+00 8.2937e-02 -#> 241: 1.0190e+02 -4.1204e+00 -2.3524e+00 -4.0642e+00 -1.0097e+00 -3.9061e-03 3.8686e-02 5.5496e-07 6.3349e-02 2.3663e-02 1.8759e-01 1.1046e-01 9.4922e-01 8.3162e-02 1.0064e+00 8.2940e-02 -#> 242: 1.0190e+02 -4.1204e+00 -2.3535e+00 -4.0642e+00 -1.0092e+00 -2.9411e-03 3.8674e-02 5.5359e-07 6.3930e-02 2.3604e-02 1.8742e-01 1.1027e-01 9.4748e-01 8.3177e-02 1.0052e+00 8.2955e-02 -#> 243: 1.0190e+02 -4.1204e+00 -2.3551e+00 -4.0642e+00 -1.0089e+00 -1.6071e-03 3.8635e-02 5.4669e-07 6.4141e-02 2.3570e-02 1.8666e-01 1.1022e-01 9.4770e-01 8.3208e-02 1.0048e+00 8.2962e-02 -#> 244: 1.0190e+02 -4.1204e+00 -2.3566e+00 -4.0645e+00 -1.0093e+00 -7.0474e-04 3.8502e-02 5.4194e-07 6.4399e-02 2.3591e-02 1.8627e-01 1.0938e-01 9.4615e-01 8.3402e-02 1.0043e+00 8.2891e-02 -#> 245: 1.0189e+02 -4.1204e+00 -2.3575e+00 -4.0649e+00 -1.0093e+00 1.3351e-03 3.8372e-02 5.4266e-07 6.4935e-02 2.3511e-02 1.8609e-01 1.0840e-01 9.4586e-01 8.3393e-02 1.0041e+00 8.2835e-02 -#> 246: 1.0189e+02 -4.1204e+00 -2.3595e+00 -4.0655e+00 -1.0085e+00 4.2316e-03 3.8487e-02 5.4393e-07 6.5284e-02 2.3457e-02 1.8581e-01 1.0811e-01 9.4656e-01 8.3372e-02 1.0036e+00 8.2746e-02 -#> 247: 1.0189e+02 -4.1204e+00 -2.3608e+00 -4.0659e+00 -1.0081e+00 6.1314e-03 3.8249e-02 5.4752e-07 6.5440e-02 2.3455e-02 1.8584e-01 1.0706e-01 9.4795e-01 8.3330e-02 1.0025e+00 8.2710e-02 -#> 248: 1.0189e+02 -4.1204e+00 -2.3617e+00 -4.0662e+00 -1.0084e+00 8.1978e-03 3.8017e-02 5.4713e-07 6.5853e-02 2.3439e-02 1.8637e-01 1.0634e-01 9.4748e-01 8.3377e-02 1.0016e+00 8.2677e-02 -#> 249: 1.0189e+02 -4.1204e+00 -2.3633e+00 -4.0667e+00 -1.0085e+00 9.8011e-03 3.7934e-02 5.5069e-07 6.6442e-02 2.3533e-02 1.8652e-01 1.0606e-01 9.4761e-01 8.3449e-02 1.0009e+00 8.2712e-02 -#> 250: 1.0189e+02 -4.1204e+00 -2.3644e+00 -4.0668e+00 -1.0087e+00 1.0992e-02 3.8199e-02 5.5486e-07 6.6746e-02 2.3638e-02 1.8739e-01 1.0611e-01 9.4838e-01 8.3442e-02 9.9958e-01 8.2692e-02 -#> 251: 1.0189e+02 -4.1204e+00 -2.3644e+00 -4.0671e+00 -1.0097e+00 1.2215e-02 3.8648e-02 5.5448e-07 6.6916e-02 2.3592e-02 1.8753e-01 1.0607e-01 9.4773e-01 8.3511e-02 9.9919e-01 8.2701e-02 -#> 252: 1.0189e+02 -4.1204e+00 -2.3645e+00 -4.0671e+00 -1.0100e+00 1.2881e-02 3.8792e-02 5.5615e-07 6.7323e-02 2.3559e-02 1.8811e-01 1.0641e-01 9.4665e-01 8.3575e-02 9.9809e-01 8.2743e-02 -#> 253: 1.0189e+02 -4.1204e+00 -2.3646e+00 -4.0675e+00 -1.0100e+00 1.3605e-02 3.9013e-02 5.5568e-07 6.7625e-02 2.3432e-02 1.8825e-01 1.0688e-01 9.4424e-01 8.3598e-02 9.9825e-01 8.2702e-02 -#> 254: 1.0189e+02 -4.1204e+00 -2.3642e+00 -4.0677e+00 -1.0101e+00 1.3119e-02 3.8838e-02 5.5231e-07 6.7802e-02 2.3429e-02 1.8849e-01 1.0680e-01 9.4281e-01 8.3706e-02 9.9829e-01 8.2631e-02 -#> 255: 1.0189e+02 -4.1204e+00 -2.3627e+00 -4.0679e+00 -1.0104e+00 1.2490e-02 3.8574e-02 5.4955e-07 6.8395e-02 2.3368e-02 1.8890e-01 1.0661e-01 9.4101e-01 8.3756e-02 9.9798e-01 8.2674e-02 -#> 256: 1.0189e+02 -4.1204e+00 -2.3615e+00 -4.0677e+00 -1.0102e+00 1.1525e-02 3.8502e-02 5.4764e-07 6.8824e-02 2.3405e-02 1.8912e-01 1.0649e-01 9.4109e-01 8.3709e-02 9.9811e-01 8.2698e-02 -#> 257: 1.0189e+02 -4.1204e+00 -2.3604e+00 -4.0673e+00 -1.0104e+00 1.0381e-02 3.8286e-02 5.4694e-07 6.9020e-02 2.3338e-02 1.8925e-01 1.0614e-01 9.4075e-01 8.3695e-02 9.9738e-01 8.2689e-02 -#> 258: 1.0189e+02 -4.1204e+00 -2.3591e+00 -4.0670e+00 -1.0103e+00 8.9559e-03 3.7972e-02 5.4665e-07 6.9077e-02 2.3267e-02 1.8919e-01 1.0590e-01 9.4089e-01 8.3618e-02 9.9742e-01 8.2681e-02 -#> 259: 1.0189e+02 -4.1204e+00 -2.3585e+00 -4.0669e+00 -1.0099e+00 8.6011e-03 3.7874e-02 5.4788e-07 6.9455e-02 2.3264e-02 1.8885e-01 1.0519e-01 9.3952e-01 8.3583e-02 9.9610e-01 8.2650e-02 -#> 260: 1.0189e+02 -4.1204e+00 -2.3584e+00 -4.0666e+00 -1.0098e+00 8.0471e-03 3.7771e-02 5.5294e-07 7.0269e-02 2.3292e-02 1.8877e-01 1.0442e-01 9.3898e-01 8.3519e-02 9.9504e-01 8.2641e-02 -#> 261: 1.0189e+02 -4.1204e+00 -2.3583e+00 -4.0664e+00 -1.0100e+00 7.9344e-03 3.7597e-02 5.5650e-07 7.1087e-02 2.3370e-02 1.8867e-01 1.0399e-01 9.3810e-01 8.3488e-02 9.9419e-01 8.2673e-02 -#> 262: 1.0189e+02 -4.1204e+00 -2.3575e+00 -4.0662e+00 -1.0106e+00 7.2123e-03 3.7203e-02 5.5375e-07 7.1794e-02 2.3393e-02 1.8855e-01 1.0356e-01 9.3773e-01 8.3458e-02 9.9406e-01 8.2739e-02 -#> 263: 1.0189e+02 -4.1204e+00 -2.3564e+00 -4.0659e+00 -1.0112e+00 6.6044e-03 3.6977e-02 5.5306e-07 7.2290e-02 2.3475e-02 1.8847e-01 1.0316e-01 9.3744e-01 8.3383e-02 9.9341e-01 8.2818e-02 -#> 264: 1.0189e+02 -4.1204e+00 -2.3549e+00 -4.0657e+00 -1.0118e+00 6.0119e-03 3.6749e-02 5.5152e-07 7.2896e-02 2.3530e-02 1.8849e-01 1.0277e-01 9.3658e-01 8.3443e-02 9.9248e-01 8.2877e-02 -#> 265: 1.0189e+02 -4.1204e+00 -2.3545e+00 -4.0655e+00 -1.0121e+00 5.6547e-03 3.6562e-02 5.4816e-07 7.3238e-02 2.3560e-02 1.8863e-01 1.0269e-01 9.3597e-01 8.3434e-02 9.9139e-01 8.2879e-02 -#> 266: 1.0189e+02 -4.1204e+00 -2.3545e+00 -4.0651e+00 -1.0121e+00 5.0995e-03 3.6357e-02 5.4458e-07 7.3522e-02 2.3561e-02 1.8883e-01 1.0270e-01 9.3607e-01 8.3407e-02 9.9133e-01 8.2857e-02 -#> 267: 1.0189e+02 -4.1204e+00 -2.3541e+00 -4.0648e+00 -1.0122e+00 4.0105e-03 3.6306e-02 5.4160e-07 7.3833e-02 2.3499e-02 1.8889e-01 1.0317e-01 9.3624e-01 8.3359e-02 9.9151e-01 8.2865e-02 -#> 268: 1.0189e+02 -4.1204e+00 -2.3530e+00 -4.0646e+00 -1.0122e+00 3.0925e-03 3.6248e-02 5.3845e-07 7.4663e-02 2.3413e-02 1.8895e-01 1.0371e-01 9.3624e-01 8.3277e-02 9.9210e-01 8.2909e-02 -#> 269: 1.0189e+02 -4.1204e+00 -2.3518e+00 -4.0643e+00 -1.0123e+00 2.0507e-03 3.6181e-02 5.3602e-07 7.5442e-02 2.3291e-02 1.8886e-01 1.0397e-01 9.3581e-01 8.3260e-02 9.9238e-01 8.2898e-02 -#> 270: 1.0189e+02 -4.1204e+00 -2.3513e+00 -4.0640e+00 -1.0127e+00 1.3309e-03 3.5900e-02 5.3234e-07 7.6677e-02 2.3220e-02 1.8860e-01 1.0367e-01 9.3573e-01 8.3250e-02 9.9169e-01 8.2904e-02 -#> 271: 1.0189e+02 -4.1204e+00 -2.3514e+00 -4.0637e+00 -1.0129e+00 1.1237e-03 3.5608e-02 5.3092e-07 7.7065e-02 2.3102e-02 1.8826e-01 1.0384e-01 9.3645e-01 8.3228e-02 9.9173e-01 8.2896e-02 -#> 272: 1.0189e+02 -4.1204e+00 -2.3510e+00 -4.0639e+00 -1.0134e+00 9.7855e-04 3.5328e-02 5.3100e-07 7.7173e-02 2.3014e-02 1.8817e-01 1.0367e-01 9.3538e-01 8.3266e-02 9.9139e-01 8.2943e-02 -#> 273: 1.0189e+02 -4.1204e+00 -2.3501e+00 -4.0643e+00 -1.0133e+00 1.1275e-03 3.5187e-02 5.3298e-07 7.7467e-02 2.2923e-02 1.8793e-01 1.0344e-01 9.3474e-01 8.3194e-02 9.9249e-01 8.2973e-02 -#> 274: 1.0189e+02 -4.1204e+00 -2.3498e+00 -4.0643e+00 -1.0134e+00 1.4524e-03 3.4996e-02 5.3407e-07 7.7929e-02 2.2819e-02 1.8837e-01 1.0316e-01 9.3399e-01 8.3168e-02 9.9307e-01 8.2981e-02 -#> 275: 1.0189e+02 -4.1204e+00 -2.3500e+00 -4.0641e+00 -1.0136e+00 1.3605e-03 3.4786e-02 5.3269e-07 7.8177e-02 2.2747e-02 1.8855e-01 1.0305e-01 9.3319e-01 8.3205e-02 9.9277e-01 8.2938e-02 -#> 276: 1.0189e+02 -4.1204e+00 -2.3504e+00 -4.0641e+00 -1.0136e+00 1.5273e-03 3.4581e-02 5.3172e-07 7.8495e-02 2.2764e-02 1.8824e-01 1.0297e-01 9.3267e-01 8.3223e-02 9.9204e-01 8.2884e-02 -#> 277: 1.0189e+02 -4.1204e+00 -2.3506e+00 -4.0643e+00 -1.0133e+00 1.2961e-03 3.4373e-02 5.2917e-07 7.8721e-02 2.2791e-02 1.8801e-01 1.0288e-01 9.3253e-01 8.3185e-02 9.9192e-01 8.2854e-02 -#> 278: 1.0189e+02 -4.1204e+00 -2.3508e+00 -4.0643e+00 -1.0129e+00 1.1750e-03 3.4396e-02 5.2693e-07 7.8999e-02 2.2787e-02 1.8793e-01 1.0278e-01 9.3279e-01 8.3113e-02 9.9144e-01 8.2856e-02 -#> 279: 1.0189e+02 -4.1204e+00 -2.3507e+00 -4.0642e+00 -1.0126e+00 1.2755e-03 3.4381e-02 5.2405e-07 7.9351e-02 2.2804e-02 1.8779e-01 1.0255e-01 9.3319e-01 8.3049e-02 9.9099e-01 8.2875e-02 -#> 280: 1.0189e+02 -4.1204e+00 -2.3507e+00 -4.0641e+00 -1.0127e+00 6.3408e-04 3.4519e-02 5.2180e-07 7.9825e-02 2.2801e-02 1.8775e-01 1.0292e-01 9.3349e-01 8.2970e-02 9.9076e-01 8.2918e-02 -#> 281: 1.0189e+02 -4.1204e+00 -2.3508e+00 -4.0639e+00 -1.0124e+00 6.2438e-04 3.4782e-02 5.1859e-07 8.0328e-02 2.2816e-02 1.8757e-01 1.0299e-01 9.3299e-01 8.3025e-02 9.9050e-01 8.2897e-02 -#> 282: 1.0189e+02 -4.1205e+00 -2.3511e+00 -4.0641e+00 -1.0122e+00 1.1770e-03 3.4754e-02 5.1798e-07 8.0649e-02 2.2836e-02 1.8766e-01 1.0297e-01 9.3351e-01 8.2989e-02 9.9171e-01 8.2893e-02 -#> 283: 1.0189e+02 -4.1205e+00 -2.3519e+00 -4.0644e+00 -1.0120e+00 2.1716e-03 3.4711e-02 5.1567e-07 8.0910e-02 2.2836e-02 1.8774e-01 1.0270e-01 9.3288e-01 8.3029e-02 9.9246e-01 8.2853e-02 -#> 284: 1.0189e+02 -4.1205e+00 -2.3524e+00 -4.0647e+00 -1.0115e+00 2.6623e-03 3.4646e-02 5.1350e-07 8.1153e-02 2.2950e-02 1.8775e-01 1.0277e-01 9.3238e-01 8.2990e-02 9.9212e-01 8.2836e-02 -#> 285: 1.0189e+02 -4.1205e+00 -2.3531e+00 -4.0649e+00 -1.0116e+00 3.7830e-03 3.4626e-02 5.1216e-07 8.1058e-02 2.3007e-02 1.8782e-01 1.0270e-01 9.3232e-01 8.3017e-02 9.9094e-01 8.2829e-02 -#> 286: 1.0189e+02 -4.1205e+00 -2.3539e+00 -4.0651e+00 -1.0111e+00 5.1752e-03 3.4599e-02 5.0989e-07 8.0970e-02 2.3004e-02 1.8757e-01 1.0254e-01 9.3280e-01 8.3006e-02 9.9130e-01 8.2818e-02 -#> 287: 1.0189e+02 -4.1205e+00 -2.3541e+00 -4.0654e+00 -1.0112e+00 6.3747e-03 3.4592e-02 5.0930e-07 8.1117e-02 2.2959e-02 1.8756e-01 1.0222e-01 9.3212e-01 8.3146e-02 9.9183e-01 8.2863e-02 -#> 288: 1.0189e+02 -4.1205e+00 -2.3540e+00 -4.0656e+00 -1.0115e+00 6.5668e-03 3.4598e-02 5.0976e-07 8.1125e-02 2.2895e-02 1.8782e-01 1.0183e-01 9.3310e-01 8.3169e-02 9.9404e-01 8.2836e-02 -#> 289: 1.0189e+02 -4.1205e+00 -2.3539e+00 -4.0658e+00 -1.0119e+00 7.3521e-03 3.4525e-02 5.1097e-07 8.1097e-02 2.2869e-02 1.8753e-01 1.0126e-01 9.3336e-01 8.3244e-02 9.9435e-01 8.2833e-02 -#> 290: 1.0189e+02 -4.1205e+00 -2.3539e+00 -4.0659e+00 -1.0122e+00 7.5226e-03 3.4377e-02 5.0846e-07 8.1212e-02 2.2831e-02 1.8724e-01 1.0073e-01 9.3292e-01 8.3261e-02 9.9415e-01 8.2837e-02 -#> 291: 1.0189e+02 -4.1205e+00 -2.3536e+00 -4.0659e+00 -1.0122e+00 7.2889e-03 3.4263e-02 5.0823e-07 8.1182e-02 2.2801e-02 1.8711e-01 1.0056e-01 9.3309e-01 8.3300e-02 9.9427e-01 8.2805e-02 -#> 292: 1.0189e+02 -4.1205e+00 -2.3531e+00 -4.0659e+00 -1.0123e+00 7.1827e-03 3.4146e-02 5.0825e-07 8.1696e-02 2.2760e-02 1.8703e-01 1.0039e-01 9.3324e-01 8.3306e-02 9.9379e-01 8.2784e-02 -#> 293: 1.0189e+02 -4.1205e+00 -2.3528e+00 -4.0660e+00 -1.0125e+00 7.7142e-03 3.4126e-02 5.0971e-07 8.2026e-02 2.2705e-02 1.8721e-01 1.0036e-01 9.3316e-01 8.3316e-02 9.9357e-01 8.2756e-02 -#> 294: 1.0188e+02 -4.1204e+00 -2.3529e+00 -4.0663e+00 -1.0126e+00 8.5146e-03 3.4314e-02 5.0823e-07 8.2197e-02 2.2608e-02 1.8743e-01 1.0009e-01 9.3356e-01 8.3308e-02 9.9367e-01 8.2719e-02 -#> 295: 1.0188e+02 -4.1204e+00 -2.3532e+00 -4.0666e+00 -1.0123e+00 9.2199e-03 3.4472e-02 5.0839e-07 8.2550e-02 2.2529e-02 1.8745e-01 9.9731e-02 9.3393e-01 8.3255e-02 9.9373e-01 8.2686e-02 -#> 296: 1.0188e+02 -4.1204e+00 -2.3537e+00 -4.0667e+00 -1.0121e+00 9.7869e-03 3.4678e-02 5.0983e-07 8.3059e-02 2.2497e-02 1.8729e-01 9.9260e-02 9.3395e-01 8.3198e-02 9.9300e-01 8.2681e-02 -#> 297: 1.0188e+02 -4.1204e+00 -2.3540e+00 -4.0670e+00 -1.0118e+00 1.0166e-02 3.4957e-02 5.1049e-07 8.3080e-02 2.2448e-02 1.8710e-01 9.8969e-02 9.3321e-01 8.3178e-02 9.9255e-01 8.2663e-02 -#> 298: 1.0188e+02 -4.1204e+00 -2.3544e+00 -4.0673e+00 -1.0117e+00 1.0649e-02 3.5259e-02 5.1103e-07 8.3179e-02 2.2383e-02 1.8704e-01 9.8442e-02 9.3227e-01 8.3199e-02 9.9266e-01 8.2646e-02 -#> 299: 1.0188e+02 -4.1204e+00 -2.3542e+00 -4.0676e+00 -1.0117e+00 1.0927e-02 3.5438e-02 5.1128e-07 8.3068e-02 2.2378e-02 1.8699e-01 9.8203e-02 9.3263e-01 8.3138e-02 9.9353e-01 8.2671e-02 -#> 300: 1.0188e+02 -4.1204e+00 -2.3544e+00 -4.0678e+00 -1.0116e+00 1.1083e-02 3.5694e-02 5.1107e-07 8.2896e-02 2.2344e-02 1.8733e-01 9.7775e-02 9.3179e-01 8.3124e-02 9.9379e-01 8.2657e-02 -#> 301: 1.0188e+02 -4.1204e+00 -2.3542e+00 -4.0680e+00 -1.0115e+00 1.0992e-02 3.5896e-02 5.1262e-07 8.2816e-02 2.2349e-02 1.8753e-01 9.7431e-02 9.3209e-01 8.3086e-02 9.9388e-01 8.2674e-02 -#> 302: 1.0188e+02 -4.1204e+00 -2.3540e+00 -4.0681e+00 -1.0113e+00 1.0410e-02 3.6050e-02 5.1256e-07 8.2817e-02 2.2308e-02 1.8734e-01 9.7153e-02 9.3221e-01 8.3073e-02 9.9402e-01 8.2670e-02 -#> 303: 1.0188e+02 -4.1204e+00 -2.3540e+00 -4.0681e+00 -1.0112e+00 1.0301e-02 3.6150e-02 5.1127e-07 8.2826e-02 2.2325e-02 1.8730e-01 9.6656e-02 9.3192e-01 8.3040e-02 9.9393e-01 8.2665e-02 -#> 304: 1.0188e+02 -4.1204e+00 -2.3536e+00 -4.0681e+00 -1.0113e+00 1.0235e-02 3.6393e-02 5.1176e-07 8.2606e-02 2.2353e-02 1.8724e-01 9.6171e-02 9.3161e-01 8.3068e-02 9.9361e-01 8.2698e-02 -#> 305: 1.0188e+02 -4.1204e+00 -2.3533e+00 -4.0683e+00 -1.0112e+00 9.9655e-03 3.6369e-02 5.1442e-07 8.2520e-02 2.2378e-02 1.8707e-01 9.5656e-02 9.3113e-01 8.3109e-02 9.9338e-01 8.2731e-02 -#> 306: 1.0188e+02 -4.1204e+00 -2.3531e+00 -4.0684e+00 -1.0110e+00 9.9701e-03 3.6346e-02 5.1546e-07 8.2789e-02 2.2360e-02 1.8702e-01 9.5116e-02 9.3102e-01 8.3065e-02 9.9405e-01 8.2761e-02 -#> 307: 1.0188e+02 -4.1204e+00 -2.3530e+00 -4.0684e+00 -1.0112e+00 1.0194e-02 3.6300e-02 5.1196e-07 8.3035e-02 2.2381e-02 1.8704e-01 9.4760e-02 9.3082e-01 8.3003e-02 9.9410e-01 8.2779e-02 -#> 308: 1.0189e+02 -4.1204e+00 -2.3530e+00 -4.0685e+00 -1.0109e+00 9.9531e-03 3.6400e-02 5.1140e-07 8.3511e-02 2.2334e-02 1.8726e-01 9.4494e-02 9.3151e-01 8.2910e-02 9.9484e-01 8.2760e-02 -#> 309: 1.0188e+02 -4.1204e+00 -2.3530e+00 -4.0685e+00 -1.0107e+00 1.0089e-02 3.6382e-02 5.1081e-07 8.3917e-02 2.2276e-02 1.8728e-01 9.4285e-02 9.3133e-01 8.2875e-02 9.9545e-01 8.2757e-02 -#> 310: 1.0188e+02 -4.1204e+00 -2.3533e+00 -4.0685e+00 -1.0105e+00 1.0805e-02 3.6375e-02 5.1041e-07 8.4245e-02 2.2246e-02 1.8753e-01 9.3894e-02 9.3052e-01 8.2899e-02 9.9500e-01 8.2743e-02 -#> 311: 1.0188e+02 -4.1204e+00 -2.3534e+00 -4.0685e+00 -1.0103e+00 1.1449e-02 3.6311e-02 5.0884e-07 8.4434e-02 2.2231e-02 1.8783e-01 9.3542e-02 9.3039e-01 8.2864e-02 9.9458e-01 8.2733e-02 -#> 312: 1.0188e+02 -4.1204e+00 -2.3535e+00 -4.0685e+00 -1.0102e+00 1.2173e-02 3.6373e-02 5.0821e-07 8.4730e-02 2.2176e-02 1.8769e-01 9.3317e-02 9.2982e-01 8.2916e-02 9.9438e-01 8.2740e-02 -#> 313: 1.0188e+02 -4.1204e+00 -2.3533e+00 -4.0688e+00 -1.0103e+00 1.2812e-02 3.6558e-02 5.0751e-07 8.5211e-02 2.2131e-02 1.8754e-01 9.3387e-02 9.2962e-01 8.2892e-02 9.9458e-01 8.2741e-02 -#> 314: 1.0188e+02 -4.1204e+00 -2.3534e+00 -4.0690e+00 -1.0103e+00 1.3241e-02 3.6680e-02 5.0887e-07 8.5667e-02 2.2079e-02 1.8772e-01 9.3442e-02 9.2941e-01 8.2947e-02 9.9511e-01 8.2743e-02 -#> 315: 1.0188e+02 -4.1204e+00 -2.3534e+00 -4.0691e+00 -1.0104e+00 1.3699e-02 3.6924e-02 5.0965e-07 8.5865e-02 2.2028e-02 1.8766e-01 9.3264e-02 9.2904e-01 8.2986e-02 9.9543e-01 8.2763e-02 -#> 316: 1.0188e+02 -4.1204e+00 -2.3533e+00 -4.0693e+00 -1.0103e+00 1.4121e-02 3.7218e-02 5.1041e-07 8.6216e-02 2.2076e-02 1.8773e-01 9.3035e-02 9.2917e-01 8.3013e-02 9.9486e-01 8.2782e-02 -#> 317: 1.0188e+02 -4.1204e+00 -2.3533e+00 -4.0694e+00 -1.0102e+00 1.4588e-02 3.7304e-02 5.0994e-07 8.6513e-02 2.2128e-02 1.8773e-01 9.2766e-02 9.2943e-01 8.3025e-02 9.9441e-01 8.2779e-02 -#> 318: 1.0188e+02 -4.1204e+00 -2.3534e+00 -4.0693e+00 -1.0101e+00 1.4714e-02 3.7538e-02 5.0773e-07 8.6801e-02 2.2128e-02 1.8767e-01 9.2698e-02 9.2907e-01 8.3052e-02 9.9378e-01 8.2780e-02 -#> 319: 1.0187e+02 -4.1204e+00 -2.3533e+00 -4.0692e+00 -1.0099e+00 1.4582e-02 3.7563e-02 5.0550e-07 8.6669e-02 2.2135e-02 1.8775e-01 9.2604e-02 9.2925e-01 8.3042e-02 9.9356e-01 8.2773e-02 -#> 320: 1.0187e+02 -4.1204e+00 -2.3535e+00 -4.0690e+00 -1.0102e+00 1.4511e-02 3.7580e-02 5.0281e-07 8.6617e-02 2.2121e-02 1.8780e-01 9.2508e-02 9.3001e-01 8.3032e-02 9.9322e-01 8.2780e-02 -#> 321: 1.0187e+02 -4.1204e+00 -2.3534e+00 -4.0688e+00 -1.0100e+00 1.4288e-02 3.7624e-02 5.0172e-07 8.6311e-02 2.2115e-02 1.8783e-01 9.2445e-02 9.3011e-01 8.3054e-02 9.9288e-01 8.2772e-02 -#> 322: 1.0187e+02 -4.1204e+00 -2.3532e+00 -4.0687e+00 -1.0098e+00 1.3834e-02 3.7497e-02 5.0086e-07 8.6187e-02 2.2111e-02 1.8791e-01 9.2699e-02 9.3037e-01 8.3069e-02 9.9284e-01 8.2773e-02 -#> 323: 1.0187e+02 -4.1204e+00 -2.3524e+00 -4.0683e+00 -1.0097e+00 1.2977e-02 3.7420e-02 4.9925e-07 8.6082e-02 2.2084e-02 1.8818e-01 9.3123e-02 9.3036e-01 8.3012e-02 9.9265e-01 8.2813e-02 -#> 324: 1.0187e+02 -4.1204e+00 -2.3523e+00 -4.0682e+00 -1.0096e+00 1.2679e-02 3.7420e-02 4.9836e-07 8.5721e-02 2.2071e-02 1.8829e-01 9.3535e-02 9.3062e-01 8.3011e-02 9.9241e-01 8.2827e-02 -#> 325: 1.0187e+02 -4.1204e+00 -2.3520e+00 -4.0680e+00 -1.0094e+00 1.2196e-02 3.7298e-02 4.9735e-07 8.5411e-02 2.2028e-02 1.8848e-01 9.3706e-02 9.3043e-01 8.3020e-02 9.9256e-01 8.2826e-02 -#> 326: 1.0187e+02 -4.1204e+00 -2.3517e+00 -4.0678e+00 -1.0091e+00 1.1924e-02 3.7185e-02 4.9661e-07 8.5453e-02 2.1983e-02 1.8830e-01 9.3688e-02 9.3050e-01 8.2996e-02 9.9284e-01 8.2806e-02 -#> 327: 1.0187e+02 -4.1204e+00 -2.3516e+00 -4.0677e+00 -1.0090e+00 1.1449e-02 3.7155e-02 4.9755e-07 8.5761e-02 2.1967e-02 1.8819e-01 9.3936e-02 9.3052e-01 8.2912e-02 9.9245e-01 8.2806e-02 -#> 328: 1.0187e+02 -4.1204e+00 -2.3514e+00 -4.0675e+00 -1.0089e+00 1.0758e-02 3.7146e-02 4.9892e-07 8.6019e-02 2.1971e-02 1.8806e-01 9.4361e-02 9.3070e-01 8.2833e-02 9.9182e-01 8.2840e-02 -#> 329: 1.0187e+02 -4.1204e+00 -2.3515e+00 -4.0672e+00 -1.0087e+00 1.0256e-02 3.7342e-02 5.0019e-07 8.5965e-02 2.1989e-02 1.8796e-01 9.4614e-02 9.3067e-01 8.2818e-02 9.9159e-01 8.2858e-02 -#> 330: 1.0187e+02 -4.1204e+00 -2.3520e+00 -4.0670e+00 -1.0086e+00 1.0021e-02 3.7376e-02 4.9911e-07 8.6124e-02 2.1978e-02 1.8796e-01 9.4836e-02 9.3036e-01 8.2819e-02 9.9148e-01 8.2866e-02 -#> 331: 1.0187e+02 -4.1204e+00 -2.3521e+00 -4.0668e+00 -1.0086e+00 9.5790e-03 3.7296e-02 4.9753e-07 8.6122e-02 2.1951e-02 1.8782e-01 9.5042e-02 9.3064e-01 8.2783e-02 9.9196e-01 8.2863e-02 -#> 332: 1.0187e+02 -4.1204e+00 -2.3523e+00 -4.0667e+00 -1.0085e+00 9.2971e-03 3.7221e-02 4.9729e-07 8.6215e-02 2.1952e-02 1.8787e-01 9.5082e-02 9.3103e-01 8.2782e-02 9.9224e-01 8.2861e-02 -#> 333: 1.0187e+02 -4.1204e+00 -2.3524e+00 -4.0667e+00 -1.0084e+00 9.2591e-03 3.7097e-02 4.9556e-07 8.6302e-02 2.1922e-02 1.8792e-01 9.5155e-02 9.3058e-01 8.2798e-02 9.9202e-01 8.2831e-02 -#> 334: 1.0187e+02 -4.1204e+00 -2.3528e+00 -4.0667e+00 -1.0082e+00 9.5799e-03 3.6997e-02 4.9398e-07 8.6409e-02 2.1911e-02 1.8792e-01 9.5231e-02 9.3035e-01 8.2810e-02 9.9157e-01 8.2803e-02 -#> 335: 1.0187e+02 -4.1204e+00 -2.3529e+00 -4.0667e+00 -1.0080e+00 9.5724e-03 3.6912e-02 4.9206e-07 8.6310e-02 2.1923e-02 1.8791e-01 9.5379e-02 9.3054e-01 8.2759e-02 9.9143e-01 8.2776e-02 -#> 336: 1.0187e+02 -4.1204e+00 -2.3525e+00 -4.0667e+00 -1.0082e+00 9.5794e-03 3.6983e-02 4.9255e-07 8.6282e-02 2.1882e-02 1.8789e-01 9.5422e-02 9.3064e-01 8.2705e-02 9.9138e-01 8.2778e-02 -#> 337: 1.0187e+02 -4.1204e+00 -2.3525e+00 -4.0669e+00 -1.0083e+00 1.0008e-02 3.6943e-02 4.9278e-07 8.6483e-02 2.1844e-02 1.8794e-01 9.5240e-02 9.2981e-01 8.2753e-02 9.9100e-01 8.2774e-02 -#> 338: 1.0187e+02 -4.1204e+00 -2.3525e+00 -4.0669e+00 -1.0084e+00 1.0297e-02 3.6869e-02 4.9309e-07 8.6547e-02 2.1803e-02 1.8808e-01 9.5094e-02 9.2978e-01 8.2764e-02 9.9113e-01 8.2759e-02 -#> 339: 1.0187e+02 -4.1204e+00 -2.3528e+00 -4.0669e+00 -1.0083e+00 1.0465e-02 3.6822e-02 4.9257e-07 8.6779e-02 2.1769e-02 1.8813e-01 9.5062e-02 9.3020e-01 8.2702e-02 9.9135e-01 8.2750e-02 -#> 340: 1.0187e+02 -4.1204e+00 -2.3531e+00 -4.0668e+00 -1.0083e+00 1.0321e-02 3.6733e-02 4.9228e-07 8.7033e-02 2.1721e-02 1.8827e-01 9.4862e-02 9.3062e-01 8.2698e-02 9.9195e-01 8.2729e-02 -#> 341: 1.0187e+02 -4.1204e+00 -2.3531e+00 -4.0670e+00 -1.0085e+00 1.0501e-02 3.6671e-02 4.9236e-07 8.7297e-02 2.1733e-02 1.8820e-01 9.4558e-02 9.3121e-01 8.2677e-02 9.9238e-01 8.2713e-02 -#> 342: 1.0187e+02 -4.1204e+00 -2.3534e+00 -4.0670e+00 -1.0085e+00 1.0818e-02 3.6715e-02 4.9084e-07 8.7450e-02 2.1726e-02 1.8801e-01 9.4252e-02 9.3160e-01 8.2657e-02 9.9232e-01 8.2708e-02 -#> 343: 1.0187e+02 -4.1204e+00 -2.3535e+00 -4.0670e+00 -1.0087e+00 1.1046e-02 3.6784e-02 4.8872e-07 8.7718e-02 2.1718e-02 1.8799e-01 9.3887e-02 9.3187e-01 8.2645e-02 9.9225e-01 8.2722e-02 -#> 344: 1.0187e+02 -4.1204e+00 -2.3535e+00 -4.0670e+00 -1.0087e+00 1.0652e-02 3.6736e-02 4.8852e-07 8.7725e-02 2.1730e-02 1.8792e-01 9.3731e-02 9.3202e-01 8.2618e-02 9.9218e-01 8.2712e-02 -#> 345: 1.0187e+02 -4.1204e+00 -2.3536e+00 -4.0669e+00 -1.0090e+00 1.0445e-02 3.6714e-02 4.8690e-07 8.7782e-02 2.1751e-02 1.8798e-01 9.3450e-02 9.3223e-01 8.2582e-02 9.9239e-01 8.2706e-02 -#> 346: 1.0187e+02 -4.1204e+00 -2.3536e+00 -4.0668e+00 -1.0089e+00 1.0173e-02 3.6743e-02 4.8656e-07 8.7733e-02 2.1810e-02 1.8814e-01 9.3151e-02 9.3257e-01 8.2575e-02 9.9181e-01 8.2708e-02 -#> 347: 1.0187e+02 -4.1205e+00 -2.3532e+00 -4.0668e+00 -1.0089e+00 9.9457e-03 3.6808e-02 4.8756e-07 8.7948e-02 2.1819e-02 1.8813e-01 9.3040e-02 9.3255e-01 8.2599e-02 9.9124e-01 8.2727e-02 -#> 348: 1.0187e+02 -4.1205e+00 -2.3534e+00 -4.0667e+00 -1.0090e+00 9.8498e-03 3.6967e-02 4.8883e-07 8.7998e-02 2.1841e-02 1.8820e-01 9.3180e-02 9.3259e-01 8.2612e-02 9.9148e-01 8.2750e-02 -#> 349: 1.0187e+02 -4.1205e+00 -2.3535e+00 -4.0668e+00 -1.0091e+00 9.6211e-03 3.6891e-02 4.8867e-07 8.8006e-02 2.1930e-02 1.8819e-01 9.3390e-02 9.3232e-01 8.2612e-02 9.9073e-01 8.2738e-02 -#> 350: 1.0187e+02 -4.1205e+00 -2.3534e+00 -4.0669e+00 -1.0090e+00 9.7176e-03 3.6813e-02 4.8925e-07 8.7923e-02 2.1964e-02 1.8820e-01 9.3434e-02 9.3224e-01 8.2600e-02 9.9031e-01 8.2734e-02 -#> 351: 1.0187e+02 -4.1204e+00 -2.3535e+00 -4.0669e+00 -1.0090e+00 9.6652e-03 3.6769e-02 4.8873e-07 8.7985e-02 2.2046e-02 1.8814e-01 9.3529e-02 9.3220e-01 8.2558e-02 9.8978e-01 8.2728e-02 -#> 352: 1.0187e+02 -4.1204e+00 -2.3536e+00 -4.0669e+00 -1.0089e+00 9.8745e-03 3.6732e-02 4.8969e-07 8.8016e-02 2.2094e-02 1.8799e-01 9.3644e-02 9.3168e-01 8.2577e-02 9.8913e-01 8.2722e-02 -#> 353: 1.0187e+02 -4.1204e+00 -2.3537e+00 -4.0669e+00 -1.0088e+00 9.7530e-03 3.6700e-02 4.9008e-07 8.7949e-02 2.2116e-02 1.8798e-01 9.3769e-02 9.3165e-01 8.2559e-02 9.8871e-01 8.2711e-02 -#> 354: 1.0187e+02 -4.1204e+00 -2.3538e+00 -4.0667e+00 -1.0089e+00 9.4103e-03 3.6653e-02 4.9045e-07 8.7894e-02 2.2118e-02 1.8793e-01 9.3872e-02 9.3188e-01 8.2551e-02 9.8887e-01 8.2692e-02 -#> 355: 1.0187e+02 -4.1204e+00 -2.3540e+00 -4.0666e+00 -1.0088e+00 9.1684e-03 3.6536e-02 4.9125e-07 8.7920e-02 2.2107e-02 1.8812e-01 9.4123e-02 9.3223e-01 8.2517e-02 9.8893e-01 8.2687e-02 -#> 356: 1.0187e+02 -4.1204e+00 -2.3542e+00 -4.0664e+00 -1.0086e+00 8.9025e-03 3.6431e-02 4.9325e-07 8.7949e-02 2.2110e-02 1.8827e-01 9.4135e-02 9.3252e-01 8.2503e-02 9.8907e-01 8.2649e-02 -#> 357: 1.0187e+02 -4.1204e+00 -2.3542e+00 -4.0663e+00 -1.0085e+00 8.6757e-03 3.6417e-02 4.9505e-07 8.8052e-02 2.2096e-02 1.8848e-01 9.4192e-02 9.3281e-01 8.2490e-02 9.8957e-01 8.2624e-02 -#> 358: 1.0187e+02 -4.1204e+00 -2.3542e+00 -4.0661e+00 -1.0084e+00 8.1812e-03 3.6349e-02 4.9610e-07 8.8344e-02 2.2104e-02 1.8844e-01 9.4129e-02 9.3294e-01 8.2493e-02 9.8977e-01 8.2614e-02 -#> 359: 1.0187e+02 -4.1204e+00 -2.3541e+00 -4.0659e+00 -1.0083e+00 8.0905e-03 3.6475e-02 4.9675e-07 8.8647e-02 2.2116e-02 1.8831e-01 9.4146e-02 9.3322e-01 8.2473e-02 9.8978e-01 8.2622e-02 -#> 360: 1.0187e+02 -4.1204e+00 -2.3542e+00 -4.0657e+00 -1.0082e+00 7.8390e-03 3.6468e-02 4.9649e-07 8.8981e-02 2.2120e-02 1.8815e-01 9.4249e-02 9.3361e-01 8.2430e-02 9.8997e-01 8.2616e-02 -#> 361: 1.0187e+02 -4.1204e+00 -2.3545e+00 -4.0656e+00 -1.0083e+00 7.9104e-03 3.6434e-02 4.9737e-07 8.9447e-02 2.2133e-02 1.8808e-01 9.4085e-02 9.3387e-01 8.2426e-02 9.9025e-01 8.2616e-02 -#> 362: 1.0187e+02 -4.1204e+00 -2.3547e+00 -4.0655e+00 -1.0087e+00 7.6341e-03 3.6428e-02 4.9748e-07 8.9872e-02 2.2148e-02 1.8805e-01 9.4025e-02 9.3407e-01 8.2456e-02 9.9070e-01 8.2609e-02 -#> 363: 1.0187e+02 -4.1204e+00 -2.3546e+00 -4.0653e+00 -1.0087e+00 7.2351e-03 3.6392e-02 4.9842e-07 9.0125e-02 2.2179e-02 1.8818e-01 9.4157e-02 9.3437e-01 8.2439e-02 9.9051e-01 8.2626e-02 -#> 364: 1.0187e+02 -4.1204e+00 -2.3543e+00 -4.0651e+00 -1.0089e+00 6.7851e-03 3.6303e-02 4.9890e-07 9.0448e-02 2.2189e-02 1.8831e-01 9.4432e-02 9.3513e-01 8.2433e-02 9.9051e-01 8.2655e-02 -#> 365: 1.0187e+02 -4.1204e+00 -2.3538e+00 -4.0650e+00 -1.0089e+00 6.2935e-03 3.6267e-02 4.9829e-07 9.0718e-02 2.2204e-02 1.8818e-01 9.4507e-02 9.3580e-01 8.2387e-02 9.9049e-01 8.2678e-02 -#> 366: 1.0187e+02 -4.1204e+00 -2.3535e+00 -4.0649e+00 -1.0088e+00 5.8910e-03 3.6339e-02 4.9911e-07 9.0727e-02 2.2231e-02 1.8801e-01 9.4683e-02 9.3567e-01 8.2359e-02 9.8997e-01 8.2681e-02 -#> 367: 1.0187e+02 -4.1204e+00 -2.3533e+00 -4.0649e+00 -1.0088e+00 5.8610e-03 3.6366e-02 5.0123e-07 9.0732e-02 2.2245e-02 1.8793e-01 9.4666e-02 9.3556e-01 8.2339e-02 9.8945e-01 8.2691e-02 -#> 368: 1.0187e+02 -4.1204e+00 -2.3531e+00 -4.0650e+00 -1.0088e+00 6.1043e-03 3.6424e-02 5.0107e-07 9.0729e-02 2.2248e-02 1.8780e-01 9.4599e-02 9.3554e-01 8.2315e-02 9.8903e-01 8.2705e-02 -#> 369: 1.0187e+02 -4.1204e+00 -2.3530e+00 -4.0650e+00 -1.0088e+00 6.1767e-03 3.6436e-02 5.0046e-07 9.0617e-02 2.2226e-02 1.8787e-01 9.4410e-02 9.3504e-01 8.2361e-02 9.8843e-01 8.2694e-02 -#> 370: 1.0187e+02 -4.1204e+00 -2.3528e+00 -4.0651e+00 -1.0088e+00 6.2532e-03 3.6467e-02 5.0024e-07 9.0741e-02 2.2223e-02 1.8794e-01 9.4288e-02 9.3472e-01 8.2374e-02 9.8781e-01 8.2703e-02 -#> 371: 1.0186e+02 -4.1204e+00 -2.3525e+00 -4.0652e+00 -1.0088e+00 6.2117e-03 3.6465e-02 4.9964e-07 9.0904e-02 2.2220e-02 1.8788e-01 9.4310e-02 9.3470e-01 8.2367e-02 9.8730e-01 8.2731e-02 -#> 372: 1.0186e+02 -4.1204e+00 -2.3524e+00 -4.0651e+00 -1.0089e+00 6.1363e-03 3.6367e-02 5.0037e-07 9.1177e-02 2.2230e-02 1.8783e-01 9.4288e-02 9.3496e-01 8.2365e-02 9.8699e-01 8.2729e-02 -#> 373: 1.0186e+02 -4.1204e+00 -2.3523e+00 -4.0650e+00 -1.0089e+00 6.0384e-03 3.6353e-02 5.0195e-07 9.1402e-02 2.2219e-02 1.8764e-01 9.4343e-02 9.3478e-01 8.2430e-02 9.8641e-01 8.2747e-02 -#> 374: 1.0186e+02 -4.1204e+00 -2.3523e+00 -4.0650e+00 -1.0091e+00 5.9821e-03 3.6377e-02 5.0424e-07 9.1532e-02 2.2243e-02 1.8761e-01 9.4219e-02 9.3466e-01 8.2418e-02 9.8614e-01 8.2735e-02 -#> 375: 1.0186e+02 -4.1204e+00 -2.3524e+00 -4.0649e+00 -1.0091e+00 5.8843e-03 3.6358e-02 5.0568e-07 9.1556e-02 2.2250e-02 1.8768e-01 9.4173e-02 9.3432e-01 8.2413e-02 9.8592e-01 8.2728e-02 -#> 376: 1.0186e+02 -4.1204e+00 -2.3526e+00 -4.0649e+00 -1.0090e+00 5.7256e-03 3.6406e-02 5.0673e-07 9.1590e-02 2.2260e-02 1.8765e-01 9.4159e-02 9.3417e-01 8.2400e-02 9.8565e-01 8.2701e-02 -#> 377: 1.0186e+02 -4.1204e+00 -2.3527e+00 -4.0647e+00 -1.0091e+00 5.2782e-03 3.6397e-02 5.0740e-07 9.1564e-02 2.2263e-02 1.8765e-01 9.4084e-02 9.3434e-01 8.2395e-02 9.8563e-01 8.2680e-02 -#> 378: 1.0186e+02 -4.1204e+00 -2.3524e+00 -4.0646e+00 -1.0091e+00 4.8184e-03 3.6478e-02 5.0759e-07 9.1590e-02 2.2213e-02 1.8766e-01 9.4162e-02 9.3432e-01 8.2353e-02 9.8595e-01 8.2681e-02 -#> 379: 1.0186e+02 -4.1204e+00 -2.3521e+00 -4.0646e+00 -1.0089e+00 4.4861e-03 3.6557e-02 5.0710e-07 9.1595e-02 2.2159e-02 1.8767e-01 9.3894e-02 9.3395e-01 8.2341e-02 9.8636e-01 8.2671e-02 -#> 380: 1.0186e+02 -4.1204e+00 -2.3517e+00 -4.0644e+00 -1.0089e+00 3.9799e-03 3.6543e-02 5.0682e-07 9.1532e-02 2.2143e-02 1.8768e-01 9.3854e-02 9.3372e-01 8.2331e-02 9.8640e-01 8.2678e-02 -#> 381: 1.0186e+02 -4.1204e+00 -2.3515e+00 -4.0643e+00 -1.0089e+00 3.6269e-03 3.6531e-02 5.0770e-07 9.1364e-02 2.2157e-02 1.8768e-01 9.3897e-02 9.3383e-01 8.2326e-02 9.8630e-01 8.2675e-02 -#> 382: 1.0186e+02 -4.1204e+00 -2.3513e+00 -4.0643e+00 -1.0090e+00 3.1691e-03 3.6469e-02 5.0860e-07 9.1318e-02 2.2188e-02 1.8767e-01 9.3787e-02 9.3433e-01 8.2306e-02 9.8643e-01 8.2670e-02 -#> 383: 1.0186e+02 -4.1204e+00 -2.3508e+00 -4.0642e+00 -1.0090e+00 2.6209e-03 3.6416e-02 5.0893e-07 9.1374e-02 2.2165e-02 1.8759e-01 9.3654e-02 9.3443e-01 8.2289e-02 9.8663e-01 8.2672e-02 -#> 384: 1.0186e+02 -4.1204e+00 -2.3505e+00 -4.0640e+00 -1.0090e+00 2.1556e-03 3.6403e-02 5.0834e-07 9.1550e-02 2.2148e-02 1.8750e-01 9.3422e-02 9.3444e-01 8.2277e-02 9.8639e-01 8.2670e-02 -#> 385: 1.0186e+02 -4.1204e+00 -2.3505e+00 -4.0638e+00 -1.0089e+00 1.7048e-03 3.6391e-02 5.0788e-07 9.1717e-02 2.2160e-02 1.8746e-01 9.3178e-02 9.3457e-01 8.2261e-02 9.8616e-01 8.2636e-02 -#> 386: 1.0186e+02 -4.1204e+00 -2.3504e+00 -4.0637e+00 -1.0089e+00 1.4309e-03 3.6372e-02 5.0847e-07 9.1895e-02 2.2157e-02 1.8754e-01 9.2918e-02 9.3439e-01 8.2246e-02 9.8601e-01 8.2617e-02 -#> 387: 1.0186e+02 -4.1204e+00 -2.3505e+00 -4.0636e+00 -1.0089e+00 1.3524e-03 3.6446e-02 5.0896e-07 9.2022e-02 2.2182e-02 1.8768e-01 9.2684e-02 9.3470e-01 8.2216e-02 9.8593e-01 8.2620e-02 -#> 388: 1.0186e+02 -4.1204e+00 -2.3506e+00 -4.0635e+00 -1.0089e+00 1.2887e-03 3.6478e-02 5.0904e-07 9.2117e-02 2.2174e-02 1.8761e-01 9.2506e-02 9.3463e-01 8.2221e-02 9.8563e-01 8.2609e-02 -#> 389: 1.0186e+02 -4.1204e+00 -2.3505e+00 -4.0635e+00 -1.0089e+00 1.2044e-03 3.6479e-02 5.0969e-07 9.2068e-02 2.2180e-02 1.8751e-01 9.2308e-02 9.3438e-01 8.2241e-02 9.8516e-01 8.2592e-02 -#> 390: 1.0186e+02 -4.1204e+00 -2.3506e+00 -4.0635e+00 -1.0087e+00 1.1442e-03 3.6497e-02 5.0878e-07 9.1995e-02 2.2156e-02 1.8744e-01 9.2169e-02 9.3410e-01 8.2257e-02 9.8511e-01 8.2581e-02 -#> 391: 1.0186e+02 -4.1204e+00 -2.3508e+00 -4.0635e+00 -1.0089e+00 1.0925e-03 3.6454e-02 5.0876e-07 9.1945e-02 2.2177e-02 1.8739e-01 9.1989e-02 9.3439e-01 8.2254e-02 9.8472e-01 8.2579e-02 -#> 392: 1.0186e+02 -4.1204e+00 -2.3506e+00 -4.0633e+00 -1.0091e+00 7.9940e-04 3.6417e-02 5.0874e-07 9.1956e-02 2.2185e-02 1.8730e-01 9.1977e-02 9.3422e-01 8.2244e-02 9.8463e-01 8.2589e-02 -#> 393: 1.0186e+02 -4.1204e+00 -2.3504e+00 -4.0632e+00 -1.0093e+00 4.2112e-04 3.6433e-02 5.0843e-07 9.1868e-02 2.2211e-02 1.8739e-01 9.2106e-02 9.3464e-01 8.2217e-02 9.8458e-01 8.2594e-02 -#> 394: 1.0186e+02 -4.1204e+00 -2.3502e+00 -4.0631e+00 -1.0093e+00 1.4926e-04 3.6534e-02 5.0862e-07 9.1713e-02 2.2244e-02 1.8735e-01 9.2105e-02 9.3454e-01 8.2239e-02 9.8410e-01 8.2601e-02 -#> 395: 1.0186e+02 -4.1204e+00 -2.3499e+00 -4.0630e+00 -1.0095e+00 5.2506e-05 3.6667e-02 5.0955e-07 9.1548e-02 2.2269e-02 1.8733e-01 9.2151e-02 9.3450e-01 8.2256e-02 9.8389e-01 8.2612e-02 -#> 396: 1.0186e+02 -4.1204e+00 -2.3497e+00 -4.0630e+00 -1.0097e+00 1.6581e-05 3.6789e-02 5.1002e-07 9.1431e-02 2.2299e-02 1.8742e-01 9.2120e-02 9.3450e-01 8.2252e-02 9.8367e-01 8.2620e-02 -#> 397: 1.0186e+02 -4.1205e+00 -2.3495e+00 -4.0629e+00 -1.0098e+00 -5.0310e-05 3.6860e-02 5.0949e-07 9.1311e-02 2.2323e-02 1.8738e-01 9.2130e-02 9.3467e-01 8.2250e-02 9.8388e-01 8.2628e-02 -#> 398: 1.0186e+02 -4.1205e+00 -2.3494e+00 -4.0629e+00 -1.0097e+00 -1.4918e-04 3.6902e-02 5.0935e-07 9.1211e-02 2.2330e-02 1.8747e-01 9.2144e-02 9.3478e-01 8.2260e-02 9.8420e-01 8.2632e-02 -#> 399: 1.0186e+02 -4.1205e+00 -2.3497e+00 -4.0628e+00 -1.0097e+00 -2.2152e-04 3.6932e-02 5.0927e-07 9.1209e-02 2.2377e-02 1.8750e-01 9.2136e-02 9.3481e-01 8.2286e-02 9.8431e-01 8.2622e-02 -#> 400: 1.0186e+02 -4.1205e+00 -2.3499e+00 -4.0629e+00 -1.0097e+00 3.2878e-05 3.6943e-02 5.0892e-07 9.1092e-02 2.2388e-02 1.8752e-01 9.2072e-02 9.3534e-01 8.2276e-02 9.8472e-01 8.2615e-02 -#> 401: 1.0186e+02 -4.1205e+00 -2.3501e+00 -4.0630e+00 -1.0097e+00 2.6776e-04 3.6950e-02 5.0860e-07 9.1038e-02 2.2395e-02 1.8740e-01 9.1911e-02 9.3515e-01 8.2331e-02 9.8459e-01 8.2615e-02 -#> 402: 1.0186e+02 -4.1205e+00 -2.3502e+00 -4.0632e+00 -1.0097e+00 3.9988e-04 3.6912e-02 5.0849e-07 9.0944e-02 2.2401e-02 1.8737e-01 9.1701e-02 9.3494e-01 8.2353e-02 9.8479e-01 8.2609e-02 -#> 403: 1.0186e+02 -4.1205e+00 -2.3503e+00 -4.0633e+00 -1.0098e+00 4.9714e-04 3.6935e-02 5.0805e-07 9.0895e-02 2.2404e-02 1.8741e-01 9.1609e-02 9.3444e-01 8.2372e-02 9.8505e-01 8.2638e-02 -#> 404: 1.0186e+02 -4.1205e+00 -2.3504e+00 -4.0633e+00 -1.0100e+00 5.8465e-04 3.6978e-02 5.0889e-07 9.0862e-02 2.2453e-02 1.8746e-01 9.1650e-02 9.3491e-01 8.2364e-02 9.8484e-01 8.2653e-02 -#> 405: 1.0186e+02 -4.1205e+00 -2.3505e+00 -4.0634e+00 -1.0099e+00 5.5970e-04 3.6999e-02 5.0964e-07 9.0930e-02 2.2480e-02 1.8742e-01 9.1823e-02 9.3458e-01 8.2371e-02 9.8465e-01 8.2670e-02 -#> 406: 1.0186e+02 -4.1205e+00 -2.3507e+00 -4.0634e+00 -1.0098e+00 5.4464e-04 3.7123e-02 5.1046e-07 9.1008e-02 2.2478e-02 1.8749e-01 9.1930e-02 9.3449e-01 8.2361e-02 9.8440e-01 8.2666e-02 -#> 407: 1.0186e+02 -4.1205e+00 -2.3506e+00 -4.0634e+00 -1.0097e+00 3.5564e-04 3.7226e-02 5.0978e-07 9.0891e-02 2.2469e-02 1.8751e-01 9.2130e-02 9.3444e-01 8.2380e-02 9.8462e-01 8.2660e-02 -#> 408: 1.0186e+02 -4.1205e+00 -2.3506e+00 -4.0635e+00 -1.0097e+00 3.8362e-04 3.7354e-02 5.0967e-07 9.0892e-02 2.2461e-02 1.8747e-01 9.2230e-02 9.3453e-01 8.2363e-02 9.8466e-01 8.2661e-02 -#> 409: 1.0186e+02 -4.1205e+00 -2.3505e+00 -4.0635e+00 -1.0097e+00 2.6671e-04 3.7473e-02 5.0928e-07 9.0894e-02 2.2519e-02 1.8751e-01 9.2243e-02 9.3447e-01 8.2347e-02 9.8449e-01 8.2667e-02 -#> 410: 1.0186e+02 -4.1205e+00 -2.3506e+00 -4.0634e+00 -1.0098e+00 1.7963e-04 3.7438e-02 5.0981e-07 9.0898e-02 2.2600e-02 1.8764e-01 9.2237e-02 9.3502e-01 8.2320e-02 9.8430e-01 8.2663e-02 -#> 411: 1.0186e+02 -4.1205e+00 -2.3506e+00 -4.0634e+00 -1.0098e+00 1.0085e-04 3.7381e-02 5.0970e-07 9.0820e-02 2.2618e-02 1.8767e-01 9.2103e-02 9.3480e-01 8.2324e-02 9.8427e-01 8.2652e-02 -#> 412: 1.0186e+02 -4.1205e+00 -2.3508e+00 -4.0633e+00 -1.0097e+00 1.9452e-04 3.7315e-02 5.0984e-07 9.0784e-02 2.2605e-02 1.8772e-01 9.2118e-02 9.3504e-01 8.2314e-02 9.8431e-01 8.2636e-02 -#> 413: 1.0186e+02 -4.1205e+00 -2.3508e+00 -4.0632e+00 -1.0097e+00 1.8432e-04 3.7243e-02 5.0946e-07 9.0798e-02 2.2604e-02 1.8765e-01 9.2206e-02 9.3499e-01 8.2299e-02 9.8426e-01 8.2636e-02 -#> 414: 1.0186e+02 -4.1205e+00 -2.3505e+00 -4.0632e+00 -1.0097e+00 2.1744e-04 3.7203e-02 5.0880e-07 9.0769e-02 2.2604e-02 1.8757e-01 9.2403e-02 9.3516e-01 8.2279e-02 9.8414e-01 8.2659e-02 -#> 415: 1.0186e+02 -4.1205e+00 -2.3505e+00 -4.0633e+00 -1.0097e+00 1.9330e-04 3.7197e-02 5.0896e-07 9.0657e-02 2.2618e-02 1.8764e-01 9.2565e-02 9.3514e-01 8.2264e-02 9.8435e-01 8.2655e-02 -#> 416: 1.0186e+02 -4.1205e+00 -2.3501e+00 -4.0634e+00 -1.0097e+00 2.1450e-04 3.7144e-02 5.0882e-07 9.0762e-02 2.2645e-02 1.8761e-01 9.2614e-02 9.3511e-01 8.2277e-02 9.8415e-01 8.2669e-02 -#> 417: 1.0186e+02 -4.1205e+00 -2.3498e+00 -4.0634e+00 -1.0099e+00 1.0737e-04 3.7092e-02 5.0932e-07 9.0804e-02 2.2631e-02 1.8754e-01 9.2581e-02 9.3509e-01 8.2284e-02 9.8430e-01 8.2667e-02 -#> 418: 1.0186e+02 -4.1205e+00 -2.3495e+00 -4.0633e+00 -1.0099e+00 2.4734e-05 3.7061e-02 5.0972e-07 9.0913e-02 2.2624e-02 1.8736e-01 9.2572e-02 9.3482e-01 8.2275e-02 9.8413e-01 8.2682e-02 -#> 419: 1.0186e+02 -4.1205e+00 -2.3495e+00 -4.0633e+00 -1.0099e+00 -3.9197e-05 3.7070e-02 5.1000e-07 9.1084e-02 2.2644e-02 1.8727e-01 9.2636e-02 9.3494e-01 8.2259e-02 9.8382e-01 8.2673e-02 -#> 420: 1.0186e+02 -4.1205e+00 -2.3494e+00 -4.0633e+00 -1.0098e+00 -1.2434e-04 3.7103e-02 5.1037e-07 9.1152e-02 2.2631e-02 1.8733e-01 9.2862e-02 9.3515e-01 8.2244e-02 9.8388e-01 8.2656e-02 -#> 421: 1.0186e+02 -4.1205e+00 -2.3494e+00 -4.0632e+00 -1.0097e+00 -1.5440e-04 3.7123e-02 5.1205e-07 9.1233e-02 2.2626e-02 1.8744e-01 9.2935e-02 9.3523e-01 8.2241e-02 9.8360e-01 8.2652e-02 -#> 422: 1.0186e+02 -4.1205e+00 -2.3495e+00 -4.0633e+00 -1.0095e+00 -8.9184e-05 3.7182e-02 5.1296e-07 9.1123e-02 2.2617e-02 1.8749e-01 9.2915e-02 9.3509e-01 8.2276e-02 9.8367e-01 8.2637e-02 -#> 423: 1.0186e+02 -4.1205e+00 -2.3497e+00 -4.0634e+00 -1.0095e+00 6.7469e-05 3.7194e-02 5.1323e-07 9.1083e-02 2.2642e-02 1.8739e-01 9.3097e-02 9.3529e-01 8.2270e-02 9.8367e-01 8.2642e-02 -#> 424: 1.0186e+02 -4.1205e+00 -2.3498e+00 -4.0635e+00 -1.0094e+00 1.5970e-04 3.7258e-02 5.1292e-07 9.0998e-02 2.2667e-02 1.8730e-01 9.3311e-02 9.3525e-01 8.2262e-02 9.8362e-01 8.2648e-02 -#> 425: 1.0186e+02 -4.1205e+00 -2.3499e+00 -4.0636e+00 -1.0095e+00 2.7004e-04 3.7298e-02 5.1307e-07 9.0839e-02 2.2665e-02 1.8744e-01 9.3429e-02 9.3497e-01 8.2282e-02 9.8395e-01 8.2657e-02 -#> 426: 1.0186e+02 -4.1205e+00 -2.3499e+00 -4.0636e+00 -1.0094e+00 3.9201e-04 3.7303e-02 5.1305e-07 9.0647e-02 2.2675e-02 1.8743e-01 9.3523e-02 9.3477e-01 8.2314e-02 9.8371e-01 8.2655e-02 -#> 427: 1.0186e+02 -4.1205e+00 -2.3496e+00 -4.0636e+00 -1.0093e+00 2.9359e-04 3.7366e-02 5.1245e-07 9.0630e-02 2.2673e-02 1.8738e-01 9.3813e-02 9.3495e-01 8.2291e-02 9.8368e-01 8.2653e-02 -#> 428: 1.0186e+02 -4.1204e+00 -2.3496e+00 -4.0635e+00 -1.0094e+00 2.5099e-04 3.7411e-02 5.1144e-07 9.0647e-02 2.2674e-02 1.8732e-01 9.3993e-02 9.3493e-01 8.2273e-02 9.8373e-01 8.2652e-02 -#> 429: 1.0186e+02 -4.1204e+00 -2.3495e+00 -4.0635e+00 -1.0095e+00 2.4723e-04 3.7543e-02 5.1084e-07 9.0600e-02 2.2677e-02 1.8723e-01 9.4269e-02 9.3518e-01 8.2286e-02 9.8396e-01 8.2659e-02 -#> 430: 1.0186e+02 -4.1204e+00 -2.3494e+00 -4.0635e+00 -1.0096e+00 2.7711e-04 3.7579e-02 5.1022e-07 9.0496e-02 2.2679e-02 1.8708e-01 9.4484e-02 9.3525e-01 8.2309e-02 9.8433e-01 8.2672e-02 -#> 431: 1.0186e+02 -4.1204e+00 -2.3494e+00 -4.0634e+00 -1.0095e+00 1.3934e-05 3.7631e-02 5.0908e-07 9.0378e-02 2.2671e-02 1.8708e-01 9.4770e-02 9.3528e-01 8.2302e-02 9.8470e-01 8.2682e-02 -#> 432: 1.0186e+02 -4.1204e+00 -2.3495e+00 -4.0633e+00 -1.0096e+00 -8.9401e-05 3.7677e-02 5.0861e-07 9.0278e-02 2.2654e-02 1.8702e-01 9.4882e-02 9.3518e-01 8.2318e-02 9.8488e-01 8.2667e-02 -#> 433: 1.0186e+02 -4.1205e+00 -2.3495e+00 -4.0633e+00 -1.0096e+00 -3.6841e-04 3.7706e-02 5.0854e-07 9.0108e-02 2.2652e-02 1.8703e-01 9.5039e-02 9.3487e-01 8.2331e-02 9.8494e-01 8.2669e-02 -#> 434: 1.0186e+02 -4.1205e+00 -2.3493e+00 -4.0632e+00 -1.0096e+00 -4.3399e-04 3.7671e-02 5.0796e-07 9.0036e-02 2.2661e-02 1.8701e-01 9.5122e-02 9.3474e-01 8.2331e-02 9.8474e-01 8.2675e-02 -#> 435: 1.0186e+02 -4.1205e+00 -2.3491e+00 -4.0632e+00 -1.0096e+00 -6.1398e-04 3.7654e-02 5.0727e-07 8.9940e-02 2.2664e-02 1.8691e-01 9.5242e-02 9.3451e-01 8.2346e-02 9.8466e-01 8.2677e-02 -#> 436: 1.0186e+02 -4.1205e+00 -2.3487e+00 -4.0632e+00 -1.0094e+00 -7.2148e-04 3.7647e-02 5.0649e-07 8.9838e-02 2.2661e-02 1.8694e-01 9.5465e-02 9.3429e-01 8.2365e-02 9.8475e-01 8.2683e-02 -#> 437: 1.0186e+02 -4.1205e+00 -2.3484e+00 -4.0632e+00 -1.0093e+00 -1.1480e-03 3.7613e-02 5.0662e-07 8.9719e-02 2.2674e-02 1.8698e-01 9.5631e-02 9.3419e-01 8.2380e-02 9.8490e-01 8.2684e-02 -#> 438: 1.0186e+02 -4.1204e+00 -2.3482e+00 -4.0631e+00 -1.0092e+00 -1.5547e-03 3.7583e-02 5.0753e-07 8.9612e-02 2.2680e-02 1.8703e-01 9.5913e-02 9.3413e-01 8.2394e-02 9.8523e-01 8.2678e-02 -#> 439: 1.0186e+02 -4.1205e+00 -2.3483e+00 -4.0630e+00 -1.0093e+00 -1.9392e-03 3.7463e-02 5.0769e-07 8.9410e-02 2.2706e-02 1.8706e-01 9.6149e-02 9.3392e-01 8.2425e-02 9.8512e-01 8.2670e-02 -#> 440: 1.0186e+02 -4.1205e+00 -2.3482e+00 -4.0629e+00 -1.0094e+00 -2.1940e-03 3.7360e-02 5.0743e-07 8.9245e-02 2.2742e-02 1.8710e-01 9.6213e-02 9.3400e-01 8.2445e-02 9.8490e-01 8.2676e-02 -#> 441: 1.0186e+02 -4.1205e+00 -2.3481e+00 -4.0629e+00 -1.0095e+00 -2.3414e-03 3.7297e-02 5.0838e-07 8.9137e-02 2.2806e-02 1.8721e-01 9.6155e-02 9.3405e-01 8.2450e-02 9.8470e-01 8.2684e-02 -#> 442: 1.0186e+02 -4.1205e+00 -2.3481e+00 -4.0628e+00 -1.0095e+00 -2.6378e-03 3.7241e-02 5.0923e-07 8.9066e-02 2.2846e-02 1.8727e-01 9.6135e-02 9.3389e-01 8.2465e-02 9.8454e-01 8.2686e-02 -#> 443: 1.0186e+02 -4.1205e+00 -2.3482e+00 -4.0627e+00 -1.0094e+00 -2.8716e-03 3.7214e-02 5.1026e-07 8.9128e-02 2.2901e-02 1.8740e-01 9.6077e-02 9.3386e-01 8.2444e-02 9.8421e-01 8.2692e-02 -#> 444: 1.0186e+02 -4.1205e+00 -2.3483e+00 -4.0627e+00 -1.0092e+00 -2.9147e-03 3.7196e-02 5.1104e-07 8.9190e-02 2.2985e-02 1.8744e-01 9.5999e-02 9.3390e-01 8.2424e-02 9.8381e-01 8.2696e-02 -#> 445: 1.0186e+02 -4.1205e+00 -2.3484e+00 -4.0626e+00 -1.0090e+00 -2.9638e-03 3.7251e-02 5.1283e-07 8.9335e-02 2.3004e-02 1.8756e-01 9.5788e-02 9.3382e-01 8.2416e-02 9.8347e-01 8.2683e-02 -#> 446: 1.0186e+02 -4.1205e+00 -2.3485e+00 -4.0627e+00 -1.0090e+00 -2.8796e-03 3.7331e-02 5.1479e-07 8.9470e-02 2.3017e-02 1.8762e-01 9.5656e-02 9.3368e-01 8.2405e-02 9.8325e-01 8.2680e-02 -#> 447: 1.0186e+02 -4.1205e+00 -2.3485e+00 -4.0628e+00 -1.0091e+00 -2.7695e-03 3.7473e-02 5.1656e-07 8.9568e-02 2.3030e-02 1.8757e-01 9.5575e-02 9.3379e-01 8.2386e-02 9.8306e-01 8.2690e-02 -#> 448: 1.0186e+02 -4.1205e+00 -2.3485e+00 -4.0629e+00 -1.0091e+00 -2.6293e-03 3.7498e-02 5.1814e-07 8.9776e-02 2.3052e-02 1.8762e-01 9.5422e-02 9.3373e-01 8.2372e-02 9.8274e-01 8.2685e-02 -#> 449: 1.0186e+02 -4.1205e+00 -2.3485e+00 -4.0628e+00 -1.0092e+00 -2.5640e-03 3.7542e-02 5.1867e-07 8.9888e-02 2.3056e-02 1.8763e-01 9.5364e-02 9.3400e-01 8.2365e-02 9.8239e-01 8.2691e-02 -#> 450: 1.0186e+02 -4.1205e+00 -2.3483e+00 -4.0628e+00 -1.0093e+00 -2.5816e-03 3.7622e-02 5.1849e-07 9.0050e-02 2.3061e-02 1.8765e-01 9.5274e-02 9.3435e-01 8.2341e-02 9.8235e-01 8.2699e-02 -#> 451: 1.0186e+02 -4.1205e+00 -2.3483e+00 -4.0627e+00 -1.0094e+00 -2.4837e-03 3.7631e-02 5.1931e-07 9.0177e-02 2.3053e-02 1.8766e-01 9.5103e-02 9.3459e-01 8.2322e-02 9.8226e-01 8.2715e-02 -#> 452: 1.0186e+02 -4.1205e+00 -2.3482e+00 -4.0627e+00 -1.0094e+00 -2.4156e-03 3.7606e-02 5.1901e-07 9.0333e-02 2.3047e-02 1.8763e-01 9.4959e-02 9.3485e-01 8.2289e-02 9.8210e-01 8.2713e-02 -#> 453: 1.0186e+02 -4.1205e+00 -2.3484e+00 -4.0627e+00 -1.0093e+00 -2.4619e-03 3.7552e-02 5.1874e-07 9.0495e-02 2.3066e-02 1.8761e-01 9.4960e-02 9.3485e-01 8.2293e-02 9.8178e-01 8.2703e-02 -#> 454: 1.0186e+02 -4.1205e+00 -2.3485e+00 -4.0627e+00 -1.0092e+00 -2.4816e-03 3.7514e-02 5.1835e-07 9.0606e-02 2.3073e-02 1.8754e-01 9.4896e-02 9.3491e-01 8.2277e-02 9.8154e-01 8.2696e-02 -#> 455: 1.0186e+02 -4.1205e+00 -2.3484e+00 -4.0627e+00 -1.0092e+00 -2.3708e-03 3.7457e-02 5.1742e-07 9.0715e-02 2.3099e-02 1.8756e-01 9.4804e-02 9.3481e-01 8.2272e-02 9.8122e-01 8.2688e-02 -#> 456: 1.0186e+02 -4.1205e+00 -2.3484e+00 -4.0627e+00 -1.0093e+00 -2.2313e-03 3.7409e-02 5.1680e-07 9.0906e-02 2.3131e-02 1.8743e-01 9.4814e-02 9.3476e-01 8.2261e-02 9.8108e-01 8.2694e-02 -#> 457: 1.0186e+02 -4.1205e+00 -2.3483e+00 -4.0628e+00 -1.0095e+00 -2.1182e-03 3.7342e-02 5.1630e-07 9.0986e-02 2.3158e-02 1.8733e-01 9.4843e-02 9.3488e-01 8.2244e-02 9.8094e-01 8.2700e-02 -#> 458: 1.0186e+02 -4.1205e+00 -2.3483e+00 -4.0628e+00 -1.0095e+00 -1.9242e-03 3.7244e-02 5.1605e-07 9.1085e-02 2.3168e-02 1.8720e-01 9.4820e-02 9.3509e-01 8.2228e-02 9.8093e-01 8.2703e-02 -#> 459: 1.0186e+02 -4.1205e+00 -2.3484e+00 -4.0629e+00 -1.0095e+00 -1.7643e-03 3.7203e-02 5.1566e-07 9.1179e-02 2.3175e-02 1.8715e-01 9.4809e-02 9.3516e-01 8.2216e-02 9.8087e-01 8.2690e-02 -#> 460: 1.0186e+02 -4.1205e+00 -2.3485e+00 -4.0629e+00 -1.0094e+00 -1.5479e-03 3.7151e-02 5.1547e-07 9.1211e-02 2.3155e-02 1.8712e-01 9.4703e-02 9.3539e-01 8.2201e-02 9.8100e-01 8.2683e-02 -#> 461: 1.0186e+02 -4.1205e+00 -2.3484e+00 -4.0630e+00 -1.0095e+00 -1.4993e-03 3.7111e-02 5.1446e-07 9.1225e-02 2.3159e-02 1.8705e-01 9.4569e-02 9.3555e-01 8.2183e-02 9.8078e-01 8.2680e-02 -#> 462: 1.0186e+02 -4.1205e+00 -2.3485e+00 -4.0629e+00 -1.0094e+00 -1.4890e-03 3.7056e-02 5.1361e-07 9.1446e-02 2.3158e-02 1.8694e-01 9.4494e-02 9.3557e-01 8.2171e-02 9.8058e-01 8.2688e-02 -#> 463: 1.0186e+02 -4.1205e+00 -2.3485e+00 -4.0629e+00 -1.0094e+00 -1.3999e-03 3.6996e-02 5.1319e-07 9.1659e-02 2.3176e-02 1.8695e-01 9.4436e-02 9.3570e-01 8.2153e-02 9.8053e-01 8.2686e-02 -#> 464: 1.0186e+02 -4.1205e+00 -2.3484e+00 -4.0630e+00 -1.0095e+00 -1.1544e-03 3.6949e-02 5.1300e-07 9.1885e-02 2.3162e-02 1.8688e-01 9.4378e-02 9.3599e-01 8.2134e-02 9.8051e-01 8.2694e-02 -#> 465: 1.0186e+02 -4.1205e+00 -2.3485e+00 -4.0630e+00 -1.0097e+00 -9.7372e-04 3.6943e-02 5.1235e-07 9.2014e-02 2.3136e-02 1.8692e-01 9.4288e-02 9.3605e-01 8.2141e-02 9.8053e-01 8.2693e-02 -#> 466: 1.0186e+02 -4.1205e+00 -2.3485e+00 -4.0630e+00 -1.0097e+00 -9.2442e-04 3.6916e-02 5.1246e-07 9.2074e-02 2.3132e-02 1.8688e-01 9.4254e-02 9.3590e-01 8.2131e-02 9.8016e-01 8.2691e-02 -#> 467: 1.0186e+02 -4.1205e+00 -2.3485e+00 -4.0631e+00 -1.0098e+00 -8.2540e-04 3.6928e-02 5.1340e-07 9.2164e-02 2.3141e-02 1.8690e-01 9.4382e-02 9.3620e-01 8.2106e-02 9.7996e-01 8.2705e-02 -#> 468: 1.0186e+02 -4.1205e+00 -2.3484e+00 -4.0631e+00 -1.0097e+00 -7.3368e-04 3.6925e-02 5.1395e-07 9.2218e-02 2.3136e-02 1.8695e-01 9.4504e-02 9.3629e-01 8.2094e-02 9.7985e-01 8.2716e-02 -#> 469: 1.0186e+02 -4.1205e+00 -2.3483e+00 -4.0630e+00 -1.0096e+00 -7.4343e-04 3.6891e-02 5.1401e-07 9.2204e-02 2.3114e-02 1.8700e-01 9.4639e-02 9.3643e-01 8.2078e-02 9.7996e-01 8.2709e-02 -#> 470: 1.0186e+02 -4.1205e+00 -2.3482e+00 -4.0630e+00 -1.0096e+00 -7.8250e-04 3.6874e-02 5.1370e-07 9.2209e-02 2.3083e-02 1.8702e-01 9.4728e-02 9.3646e-01 8.2073e-02 9.7989e-01 8.2703e-02 -#> 471: 1.0186e+02 -4.1205e+00 -2.3480e+00 -4.0629e+00 -1.0095e+00 -1.0440e-03 3.6843e-02 5.1358e-07 9.2194e-02 2.3062e-02 1.8710e-01 9.4741e-02 9.3649e-01 8.2082e-02 9.8003e-01 8.2701e-02 -#> 472: 1.0186e+02 -4.1205e+00 -2.3481e+00 -4.0629e+00 -1.0096e+00 -9.5438e-04 3.6869e-02 5.1330e-07 9.2176e-02 2.3050e-02 1.8712e-01 9.4766e-02 9.3666e-01 8.2080e-02 9.7996e-01 8.2691e-02 -#> 473: 1.0186e+02 -4.1205e+00 -2.3481e+00 -4.0630e+00 -1.0096e+00 -8.2178e-04 3.6877e-02 5.1283e-07 9.2191e-02 2.3021e-02 1.8703e-01 9.4747e-02 9.3670e-01 8.2072e-02 9.8007e-01 8.2693e-02 -#> 474: 1.0186e+02 -4.1205e+00 -2.3481e+00 -4.0630e+00 -1.0096e+00 -7.0189e-04 3.6927e-02 5.1196e-07 9.2195e-02 2.2989e-02 1.8702e-01 9.4746e-02 9.3669e-01 8.2054e-02 9.8029e-01 8.2689e-02 -#> 475: 1.0186e+02 -4.1205e+00 -2.3481e+00 -4.0630e+00 -1.0095e+00 -7.1989e-04 3.6993e-02 5.1125e-07 9.2159e-02 2.2963e-02 1.8700e-01 9.4813e-02 9.3681e-01 8.2051e-02 9.8027e-01 8.2680e-02 -#> 476: 1.0186e+02 -4.1205e+00 -2.3481e+00 -4.0629e+00 -1.0096e+00 -7.1806e-04 3.7018e-02 5.1105e-07 9.2091e-02 2.2933e-02 1.8696e-01 9.4837e-02 9.3713e-01 8.2067e-02 9.8033e-01 8.2674e-02 -#> 477: 1.0186e+02 -4.1205e+00 -2.3479e+00 -4.0630e+00 -1.0097e+00 -7.3438e-04 3.6986e-02 5.1121e-07 9.2046e-02 2.2909e-02 1.8698e-01 9.4809e-02 9.3743e-01 8.2059e-02 9.8045e-01 8.2693e-02 -#> 478: 1.0186e+02 -4.1205e+00 -2.3478e+00 -4.0630e+00 -1.0096e+00 -7.9338e-04 3.6912e-02 5.1224e-07 9.2056e-02 2.2881e-02 1.8698e-01 9.4791e-02 9.3757e-01 8.2042e-02 9.8072e-01 8.2682e-02 -#> 479: 1.0186e+02 -4.1205e+00 -2.3476e+00 -4.0629e+00 -1.0096e+00 -8.6158e-04 3.6882e-02 5.1284e-07 9.2159e-02 2.2867e-02 1.8694e-01 9.4774e-02 9.3749e-01 8.2051e-02 9.8088e-01 8.2679e-02 -#> 480: 1.0186e+02 -4.1205e+00 -2.3474e+00 -4.0629e+00 -1.0096e+00 -1.1334e-03 3.6851e-02 5.1423e-07 9.2253e-02 2.2869e-02 1.8696e-01 9.4820e-02 9.3751e-01 8.2063e-02 9.8097e-01 8.2693e-02 -#> 481: 1.0186e+02 -4.1205e+00 -2.3470e+00 -4.0629e+00 -1.0096e+00 -1.2444e-03 3.6785e-02 5.1490e-07 9.2397e-02 2.2853e-02 1.8694e-01 9.4838e-02 9.3770e-01 8.2031e-02 9.8124e-01 8.2707e-02 -#> 482: 1.0186e+02 -4.1205e+00 -2.3467e+00 -4.0629e+00 -1.0095e+00 -1.3612e-03 3.6750e-02 5.1658e-07 9.2440e-02 2.2842e-02 1.8683e-01 9.4800e-02 9.3786e-01 8.2041e-02 9.8107e-01 8.2719e-02 -#> 483: 1.0186e+02 -4.1205e+00 -2.3467e+00 -4.0628e+00 -1.0096e+00 -1.5168e-03 3.6783e-02 5.1708e-07 9.2590e-02 2.2804e-02 1.8674e-01 9.4804e-02 9.3790e-01 8.2042e-02 9.8116e-01 8.2719e-02 -#> 484: 1.0186e+02 -4.1205e+00 -2.3466e+00 -4.0628e+00 -1.0097e+00 -1.5218e-03 3.6848e-02 5.1669e-07 9.2717e-02 2.2775e-02 1.8670e-01 9.4940e-02 9.3798e-01 8.2028e-02 9.8106e-01 8.2719e-02 -#> 485: 1.0186e+02 -4.1205e+00 -2.3464e+00 -4.0628e+00 -1.0097e+00 -1.4177e-03 3.6867e-02 5.1615e-07 9.2806e-02 2.2765e-02 1.8669e-01 9.5018e-02 9.3816e-01 8.2020e-02 9.8090e-01 8.2721e-02 -#> 486: 1.0186e+02 -4.1205e+00 -2.3462e+00 -4.0628e+00 -1.0098e+00 -1.5257e-03 3.6968e-02 5.1513e-07 9.3019e-02 2.2762e-02 1.8663e-01 9.5111e-02 9.3816e-01 8.2013e-02 9.8071e-01 8.2732e-02 -#> 487: 1.0186e+02 -4.1205e+00 -2.3460e+00 -4.0628e+00 -1.0097e+00 -1.7055e-03 3.7021e-02 5.1446e-07 9.3161e-02 2.2732e-02 1.8652e-01 9.5373e-02 9.3832e-01 8.1997e-02 9.8078e-01 8.2737e-02 -#> 488: 1.0186e+02 -4.1205e+00 -2.3459e+00 -4.0628e+00 -1.0097e+00 -1.8502e-03 3.7069e-02 5.1391e-07 9.3282e-02 2.2741e-02 1.8641e-01 9.5414e-02 9.3818e-01 8.2001e-02 9.8064e-01 8.2738e-02 -#> 489: 1.0186e+02 -4.1205e+00 -2.3458e+00 -4.0628e+00 -1.0097e+00 -1.9091e-03 3.7017e-02 5.1291e-07 9.3286e-02 2.2738e-02 1.8639e-01 9.5453e-02 9.3808e-01 8.1991e-02 9.8047e-01 8.2728e-02 -#> 490: 1.0186e+02 -4.1205e+00 -2.3456e+00 -4.0628e+00 -1.0097e+00 -1.8766e-03 3.6969e-02 5.1220e-07 9.3297e-02 2.2728e-02 1.8635e-01 9.5468e-02 9.3793e-01 8.1988e-02 9.8034e-01 8.2726e-02 -#> 491: 1.0186e+02 -4.1205e+00 -2.3457e+00 -4.0627e+00 -1.0097e+00 -1.7736e-03 3.6915e-02 5.1153e-07 9.3298e-02 2.2716e-02 1.8634e-01 9.5548e-02 9.3772e-01 8.2005e-02 9.8025e-01 8.2722e-02 -#> 492: 1.0186e+02 -4.1205e+00 -2.3457e+00 -4.0627e+00 -1.0097e+00 -1.7747e-03 3.6877e-02 5.1077e-07 9.3336e-02 2.2697e-02 1.8635e-01 9.5593e-02 9.3778e-01 8.2001e-02 9.8013e-01 8.2725e-02 -#> 493: 1.0186e+02 -4.1205e+00 -2.3456e+00 -4.0628e+00 -1.0094e+00 -1.6324e-03 3.6857e-02 5.1020e-07 9.3348e-02 2.2668e-02 1.8636e-01 9.5735e-02 9.3764e-01 8.1984e-02 9.8019e-01 8.2723e-02 -#> 494: 1.0186e+02 -4.1205e+00 -2.3456e+00 -4.0629e+00 -1.0094e+00 -1.5393e-03 3.6842e-02 5.1022e-07 9.3359e-02 2.2649e-02 1.8637e-01 9.5812e-02 9.3739e-01 8.1982e-02 9.8033e-01 8.2708e-02 -#> 495: 1.0186e+02 -4.1205e+00 -2.3456e+00 -4.0629e+00 -1.0094e+00 -1.5166e-03 3.6841e-02 5.1004e-07 9.3321e-02 2.2642e-02 1.8640e-01 9.5849e-02 9.3716e-01 8.1979e-02 9.8016e-01 8.2700e-02 -#> 496: 1.0186e+02 -4.1205e+00 -2.3456e+00 -4.0630e+00 -1.0095e+00 -1.4947e-03 3.6841e-02 5.0969e-07 9.3236e-02 2.2646e-02 1.8640e-01 9.5916e-02 9.3719e-01 8.1963e-02 9.8028e-01 8.2702e-02 -#> 497: 1.0186e+02 -4.1205e+00 -2.3457e+00 -4.0629e+00 -1.0094e+00 -1.4507e-03 3.6827e-02 5.0937e-07 9.3185e-02 2.2663e-02 1.8638e-01 9.5991e-02 9.3707e-01 8.1954e-02 9.8047e-01 8.2718e-02 -#> 498: 1.0186e+02 -4.1205e+00 -2.3459e+00 -4.0630e+00 -1.0094e+00 -1.2569e-03 3.6805e-02 5.0854e-07 9.3089e-02 2.2677e-02 1.8634e-01 9.5931e-02 9.3719e-01 8.1952e-02 9.8051e-01 8.2718e-02 -#> 499: 1.0186e+02 -4.1205e+00 -2.3460e+00 -4.0630e+00 -1.0093e+00 -1.0466e-03 3.6769e-02 5.0789e-07 9.3029e-02 2.2690e-02 1.8631e-01 9.5862e-02 9.3729e-01 8.1956e-02 9.8046e-01 8.2731e-02 -#> 500: 1.0186e+02 -4.1205e+00 -2.3464e+00 -4.0630e+00 -1.0093e+00 -7.3346e-04 3.6766e-02 5.0769e-07 9.3093e-02 2.2701e-02 1.8633e-01 9.5687e-02 9.3739e-01 8.1977e-02 9.8039e-01 8.2728e-02</div><div class='output co'>#> <span class='message'>Calculating covariance matrix</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ creating full model...</span></div><div class='output co'>#> <span class='message'>→ pruning branches (<span style='color: #262626; background-color: #DADADA;'>`if`</span>/<span style='color: #262626; background-color: #DADADA;'>`else`</span>)...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ loading into <span style='color: #0000BB;'>symengine</span> environment...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ compiling EBE model...</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>Needed Covariates:</span></div><div class='output co'>#> [1] "CMT"</div><div class='output co'>#> <span class='message'>Calculating residuals/tables</span></div><div class='output co'>#> <span class='message'>done</span></div><div class='input'><span class='co'># The following takes a very long time but gives</span> +</div><div class='output co'>#> <span class='message'>With est = 'saem', a different error model is required for each observed variableChanging the error model to 'obs_tc' (Two-component error for each observed variable)</span></div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> parameter labels from comments are typically ignored in non-interactive mode</span></div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> Need to run with the source intact to parse comments</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='message'>→ generate SAEM model</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='error'>Error in configsaem(model = model, data = dat, inits = inits, mcmc = .mcmc, ODEopt = .ODEopt, seed = .seed, distribution = .dist, DEBUG = .DEBUG, addProp = .addProp, tol = .tol, itmax = .itmax, type = .type, powRange = .powRange, lambdaRange = .lambdaRange): covariate(s) not found: f_parent_to_m1</span></div><div class='output co'>#> <span class='message'>Timing stopped at: 1.281 0.142 1.422</span></div><div class='input'><span class='co'># The following takes a very long time but gives</span> <span class='va'>f_nlmixr_dfop_sfo_focei</span> <span class='op'><-</span> <span class='fu'><a href='https://rdrr.io/pkg/nlmixr/man/nlmixr.html'>nlmixr</a></span><span class='op'>(</span><span class='va'>f_mmkin_dfop_sfo</span>, est <span class='op'>=</span> <span class='st'>"focei"</span><span class='op'>)</span> -</div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> parameter labels from comments are typically ignored in non-interactive mode</span></div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> Need to run with the source intact to parse comments</span></div><div class='output co'>#> <span class='message'>→ creating full model...</span></div><div class='output co'>#> <span class='message'>→ pruning branches (<span style='color: #262626; background-color: #DADADA;'>`if`</span>/<span style='color: #262626; background-color: #DADADA;'>`else`</span>)...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ loading into <span style='color: #0000BB;'>symengine</span> environment...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ creating full model...</span></div><div class='output co'>#> <span class='message'>→ pruning branches (<span style='color: #262626; background-color: #DADADA;'>`if`</span>/<span style='color: #262626; background-color: #DADADA;'>`else`</span>)...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ loading into <span style='color: #0000BB;'>symengine</span> environment...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ calculate jacobian</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ calculate sensitivities</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ calculate ∂(f)/∂(η)</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ calculate ∂(R²)/∂(η)</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ finding duplicate expressions in inner model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ optimizing duplicate expressions in inner model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ finding duplicate expressions in EBE model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ optimizing duplicate expressions in EBE model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ compiling inner model...</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ finding duplicate expressions in FD model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ optimizing duplicate expressions in FD model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ compiling EBE model...</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ compiling events FD model...</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>Needed Covariates:</span></div><div class='output co'>#> [1] "CMT" -#> <span style='font-weight: bold;'>Key:</span> U: Unscaled Parameters; X: Back-transformed parameters; G: Gill difference gradient approximation -#> F: Forward difference gradient approximation -#> C: Central difference gradient approximation -#> M: Mixed forward and central difference gradient approximation -#> Unscaled parameters for Omegas=chol(solve(omega)); -#> Diagonals are transformed, as specified by foceiControl(diagXform=) -#> |-----+---------------+-----------+-----------+-----------+-----------| -#> | #| Objective Fun | parent_0 | log_k_m1 |f_parent_qlogis | log_k1 | -#> |.....................| log_k2 | g_qlogis | sigma_low | rsd_high | -#> |.....................| o1 | o2 | o3 | o4 | -#> <span style='text-decoration: underline;'>|.....................| o5 | o6 |...........|...........|</span> -#> |<span style='font-weight: bold;'> 1</span>| 496.98032 | 1.000 | -0.9997 | -0.9408 | -0.9676 | -#> |.....................| -1.000 | -0.9232 | -0.9092 | -0.9217 | -#> |.....................| -0.9102 | -0.8930 | -0.8991 | -0.9012 | -#> <span style='text-decoration: underline;'>|.....................| -0.8950 | -0.9012 |...........|...........|</span> -#> | U| 496.98032 | 101.7 | -4.054 | -0.9431 | -2.359 | -#> |.....................| -4.070 | -0.01132 | 0.7275 | 0.06652 | -#> |.....................| 0.6768 | 1.586 | 1.262 | 1.152 | -#> <span style='text-decoration: underline;'>|.....................| 1.482 | 1.151 |...........|...........|</span> -#> | X|<span style='font-weight: bold;'> 496.98032</span> | 101.7 | 0.01736 | 0.2803 | 0.09447 | -#> |.....................| 0.01708 | 0.4972 | 0.7275 | 0.06652 | -#> |.....................| 0.6768 | 1.586 | 1.262 | 1.152 | -#> <span style='text-decoration: underline;'>|.....................| 1.482 | 1.151 |...........|...........|</span> -#> | G| Gill Diff. | 57.10 | -0.1453 | -0.1275 | 0.2854 | -#> |.....................| -0.6156 | 0.007043 | -23.49 | -32.87 | -#> |.....................| 3.669 | -17.46 | -13.05 | -13.08 | -#> <span style='text-decoration: underline;'>|.....................| -16.16 | -9.766 |...........|...........|</span> -#> |<span style='font-weight: bold;'> 2</span>| 3094.8373 | 0.2572 | -0.9978 | -0.9392 | -0.9714 | -#> |.....................| -0.9920 | -0.9233 | -0.6037 | -0.4942 | -#> |.....................| -0.9579 | -0.6658 | -0.7293 | -0.7310 | -#> <span style='text-decoration: underline;'>|.....................| -0.6848 | -0.7742 |...........|...........|</span> -#> | U| 3094.8373 | 26.15 | -4.052 | -0.9415 | -2.363 | -#> |.....................| -4.062 | -0.01133 | 0.8386 | 0.08074 | -#> |.....................| 0.6445 | 1.946 | 1.477 | 1.348 | -#> <span style='text-decoration: underline;'>|.....................| 1.794 | 1.297 |...........|...........|</span> -#> | X|<span style='font-weight: bold;'> 3094.8373</span> | 26.15 | 0.01739 | 0.2806 | 0.09412 | -#> |.....................| 0.01721 | 0.4972 | 0.8386 | 0.08074 | -#> |.....................| 0.6445 | 1.946 | 1.477 | 1.348 | -#> <span style='text-decoration: underline;'>|.....................| 1.794 | 1.297 |...........|...........|</span> -#> |<span style='font-weight: bold;'> 3</span>| 557.60681 | 0.9257 | -0.9995 | -0.9407 | -0.9680 | -#> |.....................| -0.9992 | -0.9232 | -0.8787 | -0.8790 | -#> |.....................| -0.9150 | -0.8703 | -0.8821 | -0.8842 | -#> <span style='text-decoration: underline;'>|.....................| -0.8739 | -0.8885 |...........|...........|</span> -#> | U| 557.60681 | 94.11 | -4.053 | -0.9430 | -2.360 | -#> |.....................| -4.069 | -0.01133 | 0.7386 | 0.06794 | -#> |.....................| 0.6735 | 1.622 | 1.284 | 1.172 | -#> <span style='text-decoration: underline;'>|.....................| 1.513 | 1.165 |...........|...........|</span> -#> | X|<span style='font-weight: bold;'> 557.60681</span> | 94.11 | 0.01736 | 0.2803 | 0.09444 | -#> |.....................| 0.01709 | 0.4972 | 0.7386 | 0.06794 | -#> |.....................| 0.6735 | 1.622 | 1.284 | 1.172 | -#> <span style='text-decoration: underline;'>|.....................| 1.513 | 1.165 |...........|...........|</span> -#> |<span style='font-weight: bold;'> 4</span>| 543.47785 | 0.9926 | -0.9997 | -0.9408 | -0.9677 | -#> |.....................| -0.9999 | -0.9232 | -0.9062 | -0.9175 | -#> |.....................| -0.9107 | -0.8907 | -0.8974 | -0.8995 | -#> <span style='text-decoration: underline;'>|.....................| -0.8929 | -0.9000 |...........|...........|</span> -#> | U| 543.47785 | 100.9 | -4.054 | -0.9431 | -2.359 | -#> |.....................| -4.070 | -0.01132 | 0.7286 | 0.06666 | -#> |.....................| 0.6764 | 1.589 | 1.264 | 1.154 | -#> <span style='text-decoration: underline;'>|.....................| 1.485 | 1.152 |...........|...........|</span> -#> | X|<span style='font-weight: bold;'> 543.47785</span> | 100.9 | 0.01736 | 0.2803 | 0.09447 | -#> |.....................| 0.01708 | 0.4972 | 0.7286 | 0.06666 | -#> |.....................| 0.6764 | 1.589 | 1.264 | 1.154 | -#> <span style='text-decoration: underline;'>|.....................| 1.485 | 1.152 |...........|...........|</span> -#> |<span style='font-weight: bold;'> 5</span>| 544.09017 | 0.9993 | -0.9997 | -0.9408 | -0.9676 | -#> |.....................| -1.000 | -0.9232 | -0.9089 | -0.9213 | -#> |.....................| -0.9103 | -0.8928 | -0.8990 | -0.9010 | -#> <span style='text-decoration: underline;'>|.....................| -0.8948 | -0.9011 |...........|...........|</span> -#> | U| 544.09017 | 101.6 | -4.054 | -0.9431 | -2.359 | -#> |.....................| -4.070 | -0.01132 | 0.7276 | 0.06654 | -#> |.....................| 0.6767 | 1.586 | 1.262 | 1.152 | -#> <span style='text-decoration: underline;'>|.....................| 1.482 | 1.151 |...........|...........|</span> -#> | X|<span style='font-weight: bold;'> 544.09017</span> | 101.6 | 0.01736 | 0.2803 | 0.09447 | -#> |.....................| 0.01708 | 0.4972 | 0.7276 | 0.06654 | -#> |.....................| 0.6767 | 1.586 | 1.262 | 1.152 | -#> <span style='text-decoration: underline;'>|.....................| 1.482 | 1.151 |...........|...........|</span> -#> |<span style='font-weight: bold;'> 6</span>| 544.17109 | 0.9999 | -0.9997 | -0.9408 | -0.9676 | -#> |.....................| -1.000 | -0.9232 | -0.9092 | -0.9217 | -#> |.....................| -0.9102 | -0.8930 | -0.8991 | -0.9012 | -#> <span style='text-decoration: underline;'>|.....................| -0.8949 | -0.9012 |...........|...........|</span> -#> | U| 544.17109 | 101.6 | -4.054 | -0.9431 | -2.359 | -#> |.....................| -4.070 | -0.01132 | 0.7275 | 0.06652 | -#> |.....................| 0.6768 | 1.586 | 1.262 | 1.152 | -#> <span style='text-decoration: underline;'>|.....................| 1.482 | 1.151 |...........|...........|</span> -#> | X|<span style='font-weight: bold;'> 544.17109</span> | 101.6 | 0.01736 | 0.2803 | 0.09447 | -#> |.....................| 0.01708 | 0.4972 | 0.7275 | 0.06652 | -#> |.....................| 0.6768 | 1.586 | 1.262 | 1.152 | -#> <span style='text-decoration: underline;'>|.....................| 1.482 | 1.151 |...........|...........|</span> -#> |<span style='font-weight: bold;'> 7</span>| 544.17937 | 1.000 | -0.9997 | -0.9408 | -0.9676 | -#> |.....................| -1.000 | -0.9232 | -0.9092 | -0.9217 | -#> |.....................| -0.9102 | -0.8930 | -0.8991 | -0.9012 | -#> <span style='text-decoration: underline;'>|.....................| -0.8950 | -0.9012 |...........|...........|</span> -#> | U| 544.17937 | 101.7 | -4.054 | -0.9431 | -2.359 | -#> |.....................| -4.070 | -0.01132 | 0.7275 | 0.06652 | -#> |.....................| 0.6768 | 1.586 | 1.262 | 1.152 | -#> <span style='text-decoration: underline;'>|.....................| 1.482 | 1.151 |...........|...........|</span> -#> | X|<span style='font-weight: bold;'> 544.17937</span> | 101.7 | 0.01736 | 0.2803 | 0.09447 | -#> |.....................| 0.01708 | 0.4972 | 0.7275 | 0.06652 | -#> |.....................| 0.6768 | 1.586 | 1.262 | 1.152 | -#> <span style='text-decoration: underline;'>|.....................| 1.482 | 1.151 |...........|...........|</span> -#> |<span style='font-weight: bold;'> 8</span>| 544.18025 | 1.000 | -0.9997 | -0.9408 | -0.9676 | -#> |.....................| -1.000 | -0.9232 | -0.9092 | -0.9217 | -#> |.....................| -0.9102 | -0.8930 | -0.8991 | -0.9012 | -#> <span style='text-decoration: underline;'>|.....................| -0.8950 | -0.9012 |...........|...........|</span> -#> | U| 544.18025 | 101.7 | -4.054 | -0.9431 | -2.359 | -#> |.....................| -4.070 | -0.01132 | 0.7275 | 0.06652 | -#> |.....................| 0.6768 | 1.586 | 1.262 | 1.152 | -#> <span style='text-decoration: underline;'>|.....................| 1.482 | 1.151 |...........|...........|</span> -#> | X|<span style='font-weight: bold;'> 544.18025</span> | 101.7 | 0.01736 | 0.2803 | 0.09447 | -#> |.....................| 0.01708 | 0.4972 | 0.7275 | 0.06652 | -#> |.....................| 0.6768 | 1.586 | 1.262 | 1.152 | -#> <span style='text-decoration: underline;'>|.....................| 1.482 | 1.151 |...........|...........|</span> -#> |<span style='font-weight: bold;'> 9</span>| 544.18033 | 1.000 | -0.9997 | -0.9408 | -0.9676 | -#> |.....................| -1.000 | -0.9232 | -0.9092 | -0.9217 | -#> |.....................| -0.9102 | -0.8930 | -0.8991 | -0.9012 | -#> <span style='text-decoration: underline;'>|.....................| -0.8950 | -0.9012 |...........|...........|</span> -#> | U| 544.18033 | 101.7 | -4.054 | -0.9431 | -2.359 | -#> |.....................| -4.070 | -0.01132 | 0.7275 | 0.06652 | -#> |.....................| 0.6768 | 1.586 | 1.262 | 1.152 | -#> <span style='text-decoration: underline;'>|.....................| 1.482 | 1.151 |...........|...........|</span> -#> | X|<span style='font-weight: bold;'> 544.18033</span> | 101.7 | 0.01736 | 0.2803 | 0.09447 | -#> |.....................| 0.01708 | 0.4972 | 0.7275 | 0.06652 | -#> |.....................| 0.6768 | 1.586 | 1.262 | 1.152 | -#> <span style='text-decoration: underline;'>|.....................| 1.482 | 1.151 |...........|...........|</span> -#> |<span style='font-weight: bold;'> 10</span>| 544.18034 | 1.000 | -0.9997 | -0.9408 | -0.9676 | -#> |.....................| -1.000 | -0.9232 | -0.9092 | -0.9217 | -#> |.....................| -0.9102 | -0.8930 | -0.8991 | -0.9012 | -#> <span style='text-decoration: underline;'>|.....................| -0.8950 | -0.9012 |...........|...........|</span> -#> | U| 544.18034 | 101.7 | -4.054 | -0.9431 | -2.359 | -#> |.....................| -4.070 | -0.01132 | 0.7275 | 0.06652 | -#> |.....................| 0.6768 | 1.586 | 1.262 | 1.152 | -#> <span style='text-decoration: underline;'>|.....................| 1.482 | 1.151 |...........|...........|</span> -#> | X|<span style='font-weight: bold;'> 544.18034</span> | 101.7 | 0.01736 | 0.2803 | 0.09447 | -#> |.....................| 0.01708 | 0.4972 | 0.7275 | 0.06652 | -#> |.....................| 0.6768 | 1.586 | 1.262 | 1.152 | -#> <span style='text-decoration: underline;'>|.....................| 1.482 | 1.151 |...........|...........|</span> -#> |<span style='font-weight: bold;'> 11</span>| 544.18036 | 1.000 | -0.9997 | -0.9408 | -0.9676 | -#> |.....................| -1.000 | -0.9232 | -0.9092 | -0.9217 | -#> |.....................| -0.9102 | -0.8930 | -0.8991 | -0.9012 | -#> <span style='text-decoration: underline;'>|.....................| -0.8950 | -0.9012 |...........|...........|</span> -#> | U| 544.18036 | 101.7 | -4.054 | -0.9431 | -2.359 | -#> |.....................| -4.070 | -0.01132 | 0.7275 | 0.06652 | -#> |.....................| 0.6768 | 1.586 | 1.262 | 1.152 | -#> <span style='text-decoration: underline;'>|.....................| 1.482 | 1.151 |...........|...........|</span> -#> | X|<span style='font-weight: bold;'> 544.18036</span> | 101.7 | 0.01736 | 0.2803 | 0.09447 | -#> |.....................| 0.01708 | 0.4972 | 0.7275 | 0.06652 | -#> |.....................| 0.6768 | 1.586 | 1.262 | 1.152 | -#> <span style='text-decoration: underline;'>|.....................| 1.482 | 1.151 |...........|...........|</span> -#> |<span style='font-weight: bold;'> 12</span>| 544.18036 | 1.000 | -0.9997 | -0.9408 | -0.9676 | -#> |.....................| -1.000 | -0.9232 | -0.9092 | -0.9217 | -#> |.....................| -0.9102 | -0.8930 | -0.8991 | -0.9012 | -#> <span style='text-decoration: underline;'>|.....................| -0.8950 | -0.9012 |...........|...........|</span> -#> | U| 544.18036 | 101.7 | -4.054 | -0.9431 | -2.359 | -#> |.....................| -4.070 | -0.01132 | 0.7275 | 0.06652 | -#> |.....................| 0.6768 | 1.586 | 1.262 | 1.152 | -#> <span style='text-decoration: underline;'>|.....................| 1.482 | 1.151 |...........|...........|</span> -#> | X|<span style='font-weight: bold;'> 544.18036</span> | 101.7 | 0.01736 | 0.2803 | 0.09447 | -#> |.....................| 0.01708 | 0.4972 | 0.7275 | 0.06652 | -#> |.....................| 0.6768 | 1.586 | 1.262 | 1.152 | -#> <span style='text-decoration: underline;'>|.....................| 1.482 | 1.151 |...........|...........|</span> -#> |<span style='font-weight: bold;'> 13</span>| 544.18036 | 1.000 | -0.9997 | -0.9408 | -0.9676 | -#> |.....................| -1.000 | -0.9232 | -0.9092 | -0.9217 | -#> |.....................| -0.9102 | -0.8930 | -0.8991 | -0.9012 | -#> <span style='text-decoration: underline;'>|.....................| -0.8950 | -0.9012 |...........|...........|</span> -#> | U| 544.18036 | 101.7 | -4.054 | -0.9431 | -2.359 | -#> |.....................| -4.070 | -0.01132 | 0.7275 | 0.06652 | -#> |.....................| 0.6768 | 1.586 | 1.262 | 1.152 | -#> <span style='text-decoration: underline;'>|.....................| 1.482 | 1.151 |...........|...........|</span> -#> | X|<span style='font-weight: bold;'> 544.18036</span> | 101.7 | 0.01736 | 0.2803 | 0.09447 | -#> |.....................| 0.01708 | 0.4972 | 0.7275 | 0.06652 | -#> |.....................| 0.6768 | 1.586 | 1.262 | 1.152 | -#> <span style='text-decoration: underline;'>|.....................| 1.482 | 1.151 |...........|...........|</span> -#> |<span style='font-weight: bold;'> 14</span>| 544.18036 | 1.000 | -0.9997 | -0.9408 | -0.9676 | -#> |.....................| -1.000 | -0.9232 | -0.9092 | -0.9217 | -#> |.....................| -0.9102 | -0.8930 | -0.8991 | -0.9012 | -#> <span style='text-decoration: underline;'>|.....................| -0.8950 | -0.9012 |...........|...........|</span> -#> | U| 544.18036 | 101.7 | -4.054 | -0.9431 | -2.359 | -#> |.....................| -4.070 | -0.01132 | 0.7275 | 0.06652 | -#> |.....................| 0.6768 | 1.586 | 1.262 | 1.152 | -#> <span style='text-decoration: underline;'>|.....................| 1.482 | 1.151 |...........|...........|</span> -#> | X|<span style='font-weight: bold;'> 544.18036</span> | 101.7 | 0.01736 | 0.2803 | 0.09447 | -#> |.....................| 0.01708 | 0.4972 | 0.7275 | 0.06652 | -#> |.....................| 0.6768 | 1.586 | 1.262 | 1.152 | -#> <span style='text-decoration: underline;'>|.....................| 1.482 | 1.151 |...........|...........|</span> -#> |<span style='font-weight: bold;'> 15</span>| 544.18036 | 1.000 | -0.9997 | -0.9408 | -0.9676 | -#> |.....................| -1.000 | -0.9232 | -0.9092 | -0.9217 | -#> |.....................| -0.9102 | -0.8930 | -0.8991 | -0.9012 | -#> <span style='text-decoration: underline;'>|.....................| -0.8950 | -0.9012 |...........|...........|</span> -#> | U| 544.18036 | 101.7 | -4.054 | -0.9431 | -2.359 | -#> |.....................| -4.070 | -0.01132 | 0.7275 | 0.06652 | -#> |.....................| 0.6768 | 1.586 | 1.262 | 1.152 | -#> <span style='text-decoration: underline;'>|.....................| 1.482 | 1.151 |...........|...........|</span> -#> | X|<span style='font-weight: bold;'> 544.18036</span> | 101.7 | 0.01736 | 0.2803 | 0.09447 | -#> |.....................| 0.01708 | 0.4972 | 0.7275 | 0.06652 | -#> |.....................| 0.6768 | 1.586 | 1.262 | 1.152 | -#> <span style='text-decoration: underline;'>|.....................| 1.482 | 1.151 |...........|...........|</span> -#> |<span style='font-weight: bold;'> 16</span>| 544.18036 | 1.000 | -0.9997 | -0.9408 | -0.9676 | -#> |.....................| -1.000 | -0.9232 | -0.9092 | -0.9217 | -#> |.....................| -0.9102 | -0.8930 | -0.8991 | -0.9012 | -#> <span style='text-decoration: underline;'>|.....................| -0.8950 | -0.9012 |...........|...........|</span> -#> | U| 544.18036 | 101.7 | -4.054 | -0.9431 | -2.359 | -#> |.....................| -4.070 | -0.01132 | 0.7275 | 0.06652 | -#> |.....................| 0.6768 | 1.586 | 1.262 | 1.152 | -#> <span style='text-decoration: underline;'>|.....................| 1.482 | 1.151 |...........|...........|</span> -#> | X|<span style='font-weight: bold;'> 544.18036</span> | 101.7 | 0.01736 | 0.2803 | 0.09447 | -#> |.....................| 0.01708 | 0.4972 | 0.7275 | 0.06652 | -#> |.....................| 0.6768 | 1.586 | 1.262 | 1.152 | -#> <span style='text-decoration: underline;'>|.....................| 1.482 | 1.151 |...........|...........|</span> -#> |<span style='font-weight: bold;'> 17</span>| 544.18036 | 1.000 | -0.9997 | -0.9408 | -0.9676 | -#> |.....................| -1.000 | -0.9232 | -0.9092 | -0.9217 | -#> |.....................| -0.9102 | -0.8930 | -0.8991 | -0.9012 | -#> <span style='text-decoration: underline;'>|.....................| -0.8950 | -0.9012 |...........|...........|</span> -#> | U| 544.18036 | 101.7 | -4.054 | -0.9431 | -2.359 | -#> |.....................| -4.070 | -0.01132 | 0.7275 | 0.06652 | -#> |.....................| 0.6768 | 1.586 | 1.262 | 1.152 | -#> <span style='text-decoration: underline;'>|.....................| 1.482 | 1.151 |...........|...........|</span> -#> | X|<span style='font-weight: bold;'> 544.18036</span> | 101.7 | 0.01736 | 0.2803 | 0.09447 | -#> |.....................| 0.01708 | 0.4972 | 0.7275 | 0.06652 | -#> |.....................| 0.6768 | 1.586 | 1.262 | 1.152 | -#> <span style='text-decoration: underline;'>|.....................| 1.482 | 1.151 |...........|...........|</span> -#> calculating covariance matrix -#> done</div><div class='output co'>#> <span class='message'>Calculating residuals/tables</span></div><div class='output co'>#> <span class='message'>done</span></div><div class='output co'>#> <span class='warning'>Warning: initial ETAs were nudged; (can control by foceiControl(etaNudge=., etaNudge2=))</span></div><div class='output co'>#> <span class='warning'>Warning: last objective function was not at minimum, possible problems in optimization</span></div><div class='output co'>#> <span class='warning'>Warning: using R matrix to calculate covariance, can check sandwich or S matrix with $covRS and $covS</span></div><div class='output co'>#> <span class='warning'>Warning: gradient problems with initial estimate and covariance; see $scaleInfo</span></div><div class='input'><span class='fu'><a href='https://rdrr.io/r/stats/AIC.html'>AIC</a></span><span class='op'>(</span><span class='va'>f_nlmixr_dfop_sfo_saem</span><span class='op'>$</span><span class='va'>nm</span>, <span class='va'>f_nlmixr_dfop_sfo_focei</span><span class='op'>$</span><span class='va'>nm</span><span class='op'>)</span> -</div><div class='output co'>#> <span class='message'>Calculating -2LL by Gaussian quadrature (nnodes=3,nsd=1.6)</span></div><div class='output co'>#> </div><div class='output co'>#> df AIC -#> f_nlmixr_dfop_sfo_saem$nm 16 Inf -#> f_nlmixr_dfop_sfo_focei$nm 14 886.4573</div><div class='input'><span class='fu'><a href='https://rdrr.io/pkg/saemix/man/summary-methods.html'>summary</a></span><span class='op'>(</span><span class='va'>f_nlmixr_dfop_sfo_sfo</span>, data <span class='op'>=</span> <span class='cn'>TRUE</span><span class='op'>)</span> +</div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> parameter labels from comments are typically ignored in non-interactive mode</span></div><div class='output co'>#> <span class='message'><span style='color: #00BBBB;'>ℹ</span> Need to run with the source intact to parse comments</span></div><div class='output co'>#> <span class='message'>→ creating full model...</span></div><div class='output co'>#> <span class='message'>→ pruning branches (<span style='color: #262626; background-color: #DADADA;'>`if`</span>/<span style='color: #262626; background-color: #DADADA;'>`else`</span>)...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ loading into <span style='color: #0000BB;'>symengine</span> environment...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ creating full model...</span></div><div class='output co'>#> <span class='message'>→ pruning branches (<span style='color: #262626; background-color: #DADADA;'>`if`</span>/<span style='color: #262626; background-color: #DADADA;'>`else`</span>)...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ loading into <span style='color: #0000BB;'>symengine</span> environment...</span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ calculate jacobian</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ calculate sensitivities</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ calculate ∂(f)/∂(η)</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ calculate ∂(R²)/∂(η)</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ finding duplicate expressions in inner model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ optimizing duplicate expressions in inner model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ finding duplicate expressions in EBE model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ optimizing duplicate expressions in EBE model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ compiling inner model...</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ finding duplicate expressions in FD model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ optimizing duplicate expressions in FD model...</span></div><div class='output co'>#> </div><div class='output co'>#> <span class='message'>→ compiling EBE model...</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>→ compiling events FD model...</span></div><div class='output co'>#> <span class='message'> </span></div><div class='output co'>#> <span class='message'><span style='color: #00BB00;'>✔</span> done</span></div><div class='output co'>#> <span class='message'>Model:</span></div><div class='output co'>#> <span class='message'>cmt(parent);</span> +#> <span class='message'>cmt(m1);</span> +#> <span class='message'>rx_expr_6~ETA[1]+THETA[1];</span> +#> <span class='message'>parent(0)=rx_expr_6;</span> +#> <span class='message'>rx_expr_7~ETA[4]+THETA[4];</span> +#> <span class='message'>rx_expr_8~ETA[6]+THETA[6];</span> +#> <span class='message'>rx_expr_9~ETA[5]+THETA[5];</span> +#> <span class='message'>rx_expr_12~exp(rx_expr_7);</span> +#> <span class='message'>rx_expr_13~exp(rx_expr_9);</span> +#> <span class='message'>rx_expr_15~t*rx_expr_12;</span> +#> <span class='message'>rx_expr_16~t*rx_expr_13;</span> +#> <span class='message'>rx_expr_19~exp(-(rx_expr_8));</span> +#> <span class='message'>rx_expr_21~1+rx_expr_19;</span> +#> <span class='message'>rx_expr_26~1/(rx_expr_21);</span> +#> <span class='message'>rx_expr_28~(rx_expr_26);</span> +#> <span class='message'>rx_expr_29~1-rx_expr_28;</span> +#> <span class='message'>d/dt(parent)=-parent*(exp(rx_expr_7-rx_expr_15)/(rx_expr_21)+exp(rx_expr_9-rx_expr_16)*(rx_expr_29))/(exp(-t*rx_expr_12)/(rx_expr_21)+exp(-t*rx_expr_13)*(rx_expr_29));</span> +#> <span class='message'>rx_expr_10~ETA[2]+THETA[2];</span> +#> <span class='message'>rx_expr_14~exp(rx_expr_10);</span> +#> <span class='message'>d/dt(m1)=-rx_expr_14*m1+parent*f_parent_to_m1*(exp(rx_expr_7-rx_expr_15)/(rx_expr_21)+exp(rx_expr_9-rx_expr_16)*(rx_expr_29))/(exp(-t*rx_expr_12)/(rx_expr_21)+exp(-t*rx_expr_13)*(rx_expr_29));</span> +#> <span class='message'>rx_expr_0~CMT==2;</span> +#> <span class='message'>rx_expr_1~CMT==1;</span> +#> <span class='message'>rx_expr_2~1-(rx_expr_0);</span> +#> <span class='message'>rx_yj_~2*(rx_expr_2)*(rx_expr_1)+2*(rx_expr_0);</span> +#> <span class='message'>rx_expr_3~(rx_expr_0);</span> +#> <span class='message'>rx_expr_5~(rx_expr_2);</span> +#> <span class='message'>rx_expr_20~rx_expr_5*(rx_expr_1);</span> +#> <span class='message'>rx_lambda_~rx_expr_20+rx_expr_3;</span> +#> <span class='message'>rx_hi_~rx_expr_20+rx_expr_3;</span> +#> <span class='message'>rx_low_~0;</span> +#> <span class='message'>rx_expr_4~m1*(rx_expr_0);</span> +#> <span class='message'>rx_expr_11~parent*(rx_expr_2);</span> +#> <span class='message'>rx_expr_24~rx_expr_11*(rx_expr_1);</span> +#> <span class='message'>rx_pred_=(rx_expr_4+rx_expr_24)*(rx_expr_0)+(rx_expr_4+rx_expr_24)*(rx_expr_2)*(rx_expr_1);</span> +#> <span class='message'>rx_expr_17~Rx_pow_di(THETA[8],2);</span> +#> <span class='message'>rx_expr_18~Rx_pow_di(THETA[7],2);</span> +#> <span class='message'>rx_r_=(Rx_pow_di(((rx_expr_4+rx_expr_24)*(rx_expr_0)+(rx_expr_4+rx_expr_24)*(rx_expr_2)*(rx_expr_1)),2)*rx_expr_17+rx_expr_18)*(rx_expr_0)+(Rx_pow_di(((rx_expr_4+rx_expr_24)*(rx_expr_1)),2)*rx_expr_17+rx_expr_18)*(rx_expr_2)*(rx_expr_1);</span> +#> <span class='message'>parent_0=THETA[1];</span> +#> <span class='message'>log_k_m1=THETA[2];</span> +#> <span class='message'>f_parent_qlogis=THETA[3];</span> +#> <span class='message'>log_k1=THETA[4];</span> +#> <span class='message'>log_k2=THETA[5];</span> +#> <span class='message'>g_qlogis=THETA[6];</span> +#> <span class='message'>sigma_low=THETA[7];</span> +#> <span class='message'>rsd_high=THETA[8];</span> +#> <span class='message'>eta.parent_0=ETA[1];</span> +#> <span class='message'>eta.log_k_m1=ETA[2];</span> +#> <span class='message'>eta.f_parent_qlogis=ETA[3];</span> +#> <span class='message'>eta.log_k1=ETA[4];</span> +#> <span class='message'>eta.log_k2=ETA[5];</span> +#> <span class='message'>eta.g_qlogis=ETA[6];</span> +#> <span class='message'>parent_0_model=rx_expr_6;</span> +#> <span class='message'>k_m1=rx_expr_14;</span> +#> <span class='message'>k1=rx_expr_12;</span> +#> <span class='message'>k2=rx_expr_13;</span> +#> <span class='message'>f_parent=1/(1+exp(-(ETA[3]+THETA[3])));</span> +#> <span class='message'>g=1/(rx_expr_21);</span> +#> <span class='message'>tad=tad();</span> +#> <span class='message'>dosenum=dosenum();</span></div><div class='output co'>#> <span class='message'>Needed Covariates:</span></div><div class='output co'>#> <span class='message'>[1] "f_parent_to_m1" "CMT" </span></div><div class='output co'>#> <span class='error'>Error in (function (data, inits, PKpars, model = NULL, pred = NULL, err = NULL, lower = -Inf, upper = Inf, fixed = NULL, skipCov = NULL, control = foceiControl(), thetaNames = NULL, etaNames = NULL, etaMat = NULL, ..., env = NULL, keep = NULL, drop = NULL) { set.seed(control$seed) .pt <- proc.time() RxODE::.setWarnIdSort(FALSE) on.exit(RxODE::.setWarnIdSort(TRUE)) loadNamespace("n1qn1") if (!RxODE::rxIs(control, "foceiControl")) { control <- do.call(foceiControl, control) } if (is.null(env)) { .ret <- new.env(parent = emptyenv()) } else { .ret <- env } .ret$origData <- data .ret$etaNames <- etaNames .ret$thetaFixed <- fixed .ret$control <- control .ret$control$focei.mu.ref <- integer(0) if (is(model, "RxODE") || is(model, "character")) { .ret$ODEmodel <- TRUE if (class(pred) != "function") { stop("pred must be a function specifying the prediction variables in this model.") } } else { .ret$ODEmodel <- TRUE model <- RxODE::rxGetLin(PKpars) pred <- eval(parse(text = "function(){return(Central);}")) } .square <- function(x) x * x .ret$diagXformInv <- c(sqrt = ".square", log = "exp", identity = "identity")[control$diagXform] if (is.null(err)) { err <- eval(parse(text = paste0("function(){err", paste(inits$ERROR[[1]], collapse = ""), "}"))) } .covNames <- .parNames <- c() .ret$adjLik <- control$adjLik .mixed <- !is.null(inits$OMGA) && length(inits$OMGA) > 0 if (!exists("noLik", envir = .ret)) { .atol <- rep(control$atol, length(RxODE::rxModelVars(model)$state)) .rtol <- rep(control$rtol, length(RxODE::rxModelVars(model)$state)) .ssAtol <- rep(control$ssAtol, length(RxODE::rxModelVars(model)$state)) .ssRtol <- rep(control$ssRtol, length(RxODE::rxModelVars(model)$state)) .ret$model <- RxODE::rxSymPySetupPred(model, pred, PKpars, err, grad = (control$derivMethod == 2L), pred.minus.dv = TRUE, sum.prod = control$sumProd, theta.derivs = FALSE, optExpression = control$optExpression, interaction = (control$interaction == 1L), only.numeric = !.mixed, run.internal = TRUE, addProp = control$addProp) if (!is.null(.ret$model$inner)) { .atol <- c(.atol, rep(control$atolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.atol))) .rtol <- c(.rtol, rep(control$rtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.rtol))) .ret$control$rxControl$atol <- .atol .ret$control$rxControl$rtol <- .rtol .ssAtol <- c(.ssAtol, rep(control$ssAtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.ssAtol))) .ssRtol <- c(.ssRtol, rep(control$ssRtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.ssRtol))) .ret$control$rxControl$ssAtol <- .ssAtol .ret$control$rxControl$ssRtol <- .ssRtol } .covNames <- .parNames <- RxODE::rxParams(.ret$model$pred.only) .covNames <- .covNames[regexpr(rex::rex(start, or("THETA", "ETA"), "[", numbers, "]", end), .covNames) == -1] colnames(data) <- sapply(names(data), function(x) { if (any(x == .covNames)) { return(x) } else { return(toupper(x)) } }) .lhs <- c(names(RxODE::rxInits(.ret$model$pred.only)), RxODE::rxLhs(.ret$model$pred.only)) if (length(.lhs) > 0) { .covNames <- .covNames[regexpr(rex::rex(start, or(.lhs), end), .covNames) == -1] } if (length(.covNames) > 0) { if (!all(.covNames %in% names(data))) { message("Model:") RxODE::rxCat(.ret$model$pred.only) message("Needed Covariates:") nlmixrPrint(.covNames) stop("Not all the covariates are in the dataset.") } message("Needed Covariates:") print(.covNames) } .extraPars <- .ret$model$extra.pars } else { if (.ret$noLik) { .atol <- rep(control$atol, length(RxODE::rxModelVars(model)$state)) .rtol <- rep(control$rtol, length(RxODE::rxModelVars(model)$state)) .ret$model <- RxODE::rxSymPySetupPred(model, pred, PKpars, err, grad = FALSE, pred.minus.dv = TRUE, sum.prod = control$sumProd, theta.derivs = FALSE, optExpression = control$optExpression, run.internal = TRUE, only.numeric = TRUE, addProp = control$addProp) if (!is.null(.ret$model$inner)) { .atol <- c(.atol, rep(control$atolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.atol))) .rtol <- c(.rtol, rep(control$rtolSens, length(RxODE::rxModelVars(.ret$model$inner)$state) - length(.rtol))) .ret$control$rxControl$atol <- .atol .ret$control$rxControl$rtol <- .rtol } .covNames <- .parNames <- RxODE::rxParams(.ret$model$pred.only) .covNames <- .covNames[regexpr(rex::rex(start, or("THETA", "ETA"), "[", numbers, "]", end), .covNames) == -1] colnames(data) <- sapply(names(data), function(x) { if (any(x == .covNames)) { return(x) } else { return(toupper(x)) } }) .lhs <- c(names(RxODE::rxInits(.ret$model$pred.only)), RxODE::rxLhs(.ret$model$pred.only)) if (length(.lhs) > 0) { .covNames <- .covNames[regexpr(rex::rex(start, or(.lhs), end), .covNames) == -1] } if (length(.covNames) > 0) { if (!all(.covNames %in% names(data))) { message("Model:") RxODE::rxCat(.ret$model$pred.only) message("Needed Covariates:") nlmixrPrint(.covNames) stop("Not all the covariates are in the dataset.") } message("Needed Covariates:") print(.covNames) } .extraPars <- .ret$model$extra.pars } else { .extraPars <- NULL } } .ret$skipCov <- skipCov if (is.null(skipCov)) { if (is.null(fixed)) { .tmp <- rep(FALSE, length(inits$THTA)) } else { if (length(fixed) < length(inits$THTA)) { .tmp <- c(fixed, rep(FALSE, length(inits$THTA) - length(fixed))) } else { .tmp <- fixed[1:length(inits$THTA)] } } if (exists("uif", envir = .ret)) { .uifErr <- .ret$uif$ini$err[!is.na(.ret$uif$ini$ntheta)] .uifErr <- sapply(.uifErr, function(x) { if (is.na(x)) { return(FALSE) } return(!any(x == c("pow2", "tbs", "tbsYj"))) }) .tmp <- (.tmp | .uifErr) } .ret$skipCov <- c(.tmp, rep(TRUE, length(.extraPars))) .ret$control$focei.mu.ref <- .ret$uif$focei.mu.ref } if (is.null(.extraPars)) { .nms <- c(sprintf("THETA[%s]", seq_along(inits$THTA))) } else { .nms <- c(sprintf("THETA[%s]", seq_along(inits$THTA)), sprintf("ERR[%s]", seq_along(.extraPars))) } if (!is.null(thetaNames) && (length(inits$THTA) + length(.extraPars)) == length(thetaNames)) { .nms <- thetaNames } .ret$thetaNames <- .nms .thetaReset$thetaNames <- .nms if (length(lower) == 1) { lower <- rep(lower, length(inits$THTA)) } else if (length(lower) != length(inits$THTA)) { print(inits$THTA) print(lower) stop("Lower must be a single constant for all the THETA lower bounds, or match the dimension of THETA.") } if (length(upper) == 1) { upper <- rep(upper, length(inits$THTA)) } else if (length(lower) != length(inits$THTA)) { stop("Upper must be a single constant for all the THETA lower bounds, or match the dimension of THETA.") } if (!is.null(.extraPars)) { .ret$model$extra.pars <- eval(call(control$diagXform, .ret$model$extra.pars)) if (length(.ret$model$extra.pars) > 0) { inits$THTA <- c(inits$THTA, .ret$model$extra.pars) .lowerErr <- rep(control$atol[1] * 10, length(.ret$model$extra.pars)) .upperErr <- rep(Inf, length(.ret$model$extra.pars)) lower <- c(lower, .lowerErr) upper <- c(upper, .upperErr) } } if (is.null(data$ID)) stop("\"ID\" not found in data") if (is.null(data$DV)) stop("\"DV\" not found in data") if (is.null(data$EVID)) data$EVID <- 0 if (is.null(data$AMT)) data$AMT <- 0 for (.v in c("TIME", "AMT", "DV", .covNames)) { data[[.v]] <- as.double(data[[.v]]) } .ret$dataSav <- data .ds <- data[data$EVID != 0 & data$EVID != 2, c("ID", "TIME", "AMT", "EVID", .covNames)] .w <- which(tolower(names(data)) == "limit") .limitName <- NULL if (length(.w) == 1L) { .limitName <- names(data)[.w] } .censName <- NULL .w <- which(tolower(names(data)) == "cens") if (length(.w) == 1L) { .censName <- names(data[.w]) } data <- data[data$EVID == 0 | data$EVID == 2, c("ID", "TIME", "DV", "EVID", .covNames, .limitName, .censName)] .w <- which(!(names(.ret$dataSav) %in% c(.covNames, keep))) names(.ret$dataSav)[.w] <- tolower(names(.ret$dataSav[.w])) if (.mixed) { .lh <- .parseOM(inits$OMGA) .nlh <- sapply(.lh, length) .osplt <- rep(1:length(.lh), .nlh) .lini <- list(inits$THTA, unlist(.lh)) .nlini <- sapply(.lini, length) .nsplt <- rep(1:length(.lini), .nlini) .om0 <- .genOM(.lh) if (length(etaNames) == dim(.om0)[1]) { .ret$etaNames <- .ret$etaNames } else { .ret$etaNames <- sprintf("ETA[%d]", seq(1, dim(.om0)[1])) } .ret$rxInv <- RxODE::rxSymInvCholCreate(mat = .om0, diag.xform = control$diagXform) .ret$xType <- .ret$rxInv$xType .om0a <- .om0 .om0a <- .om0a/control$diagOmegaBoundLower .om0b <- .om0 .om0b <- .om0b * control$diagOmegaBoundUpper .om0a <- RxODE::rxSymInvCholCreate(mat = .om0a, diag.xform = control$diagXform) .om0b <- RxODE::rxSymInvCholCreate(mat = .om0b, diag.xform = control$diagXform) .omdf <- data.frame(a = .om0a$theta, m = .ret$rxInv$theta, b = .om0b$theta, diag = .om0a$theta.diag) .omdf$lower <- with(.omdf, ifelse(a > b, b, a)) .omdf$lower <- with(.omdf, ifelse(lower == m, -Inf, lower)) .omdf$lower <- with(.omdf, ifelse(!diag, -Inf, lower)) .omdf$upper <- with(.omdf, ifelse(a < b, b, a)) .omdf$upper <- with(.omdf, ifelse(upper == m, Inf, upper)) .omdf$upper <- with(.omdf, ifelse(!diag, Inf, upper)) .ret$control$nomega <- length(.omdf$lower) .ret$control$neta <- sum(.omdf$diag) .ret$control$ntheta <- length(lower) .ret$control$nfixed <- sum(fixed) lower <- c(lower, .omdf$lower) upper <- c(upper, .omdf$upper) } else { .ret$control$nomega <- 0 .ret$control$neta <- 0 .ret$xType <- -1 .ret$control$ntheta <- length(lower) .ret$control$nfixed <- sum(fixed) } .ret$lower <- lower .ret$upper <- upper .ret$thetaIni <- inits$THTA .scaleC <- double(length(lower)) if (is.null(control$scaleC)) { .scaleC <- rep(NA_real_, length(lower)) } else { .scaleC <- as.double(control$scaleC) if (length(lower) > length(.scaleC)) { .scaleC <- c(.scaleC, rep(NA_real_, length(lower) - length(.scaleC))) } else if (length(lower) < length(.scaleC)) { .scaleC <- .scaleC[seq(1, length(lower))] warning("scaleC control option has more options than estimated population parameters, please check.") } } .ret$scaleC <- .scaleC if (exists("uif", envir = .ret)) { .ini <- as.data.frame(.ret$uif$ini)[!is.na(.ret$uif$ini$err), c("est", "err", "ntheta")] for (.i in seq_along(.ini$err)) { if (is.na(.ret$scaleC[.ini$ntheta[.i]])) { if (any(.ini$err[.i] == c("boxCox", "yeoJohnson", "pow2", "tbs", "tbsYj"))) { .ret$scaleC[.ini$ntheta[.i]] <- 1 } else if (any(.ini$err[.i] == c("prop", "add", "norm", "dnorm", "logn", "dlogn", "lnorm", "dlnorm"))) { .ret$scaleC[.ini$ntheta[.i]] <- 0.5 * abs(.ini$est[.i]) } } } for (.i in .ini$model$extraProps$powTheta) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- 1 } .ini <- as.data.frame(.ret$uif$ini) for (.i in .ini$model$extraProps$factorial) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- abs(1/digamma(.ini$est[.i] + 1)) } for (.i in .ini$model$extraProps$gamma) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- abs(1/digamma(.ini$est[.i])) } for (.i in .ini$model$extraProps$log) { if (is.na(.ret$scaleC[.i])) .ret$scaleC[.i] <- log(abs(.ini$est[.i])) * abs(.ini$est[.i]) } for (.i in .ret$logitThetas) { .b <- .ret$logitThetasLow[.i] .c <- .ret$logitThetasHi[.i] .a <- .ini$est[.i] if (is.na(.ret$scaleC[.i])) { .ret$scaleC[.i] <- 1 * (-.b + .c) * exp(-.a)/((1 + exp(-.a))^2 * (.b + 1 * (-.b + .c)/(1 + exp(-.a)))) } } } names(.ret$thetaIni) <- sprintf("THETA[%d]", seq_along(.ret$thetaIni)) if (is.null(etaMat) & !is.null(control$etaMat)) { .ret$etaMat <- control$etaMat } else { .ret$etaMat <- etaMat } .ret$setupTime <- (proc.time() - .pt)["elapsed"] if (exists("uif", envir = .ret)) { .tmp <- .ret$uif$logThetasList .ret$logThetas <- .tmp[[1]] .ret$logThetasF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasList .ret$logitThetas <- .tmp[[1]] .ret$logitThetasF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasListLow .ret$logitThetasLow <- .tmp[[1]] .ret$logitThetasLowF <- .tmp[[2]] .tmp <- .ret$uif$logitThetasListHi .ret$logitThetasHi <- .tmp[[1]] .ret$logitThetasHiF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasList .ret$probitThetas <- .tmp[[1]] .ret$probitThetasF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasListLow .ret$probitThetasLow <- .tmp[[1]] .ret$probitThetasLowF <- .tmp[[2]] .tmp <- .ret$uif$probitThetasListHi .ret$probitThetasHi <- .tmp[[1]] .ret$probitThetasHiF <- .tmp[[2]] } else { .ret$logThetasF <- integer(0) .ret$logitThetasF <- integer(0) .ret$logitThetasHiF <- numeric(0) .ret$logitThetasLowF <- numeric(0) .ret$logitThetas <- integer(0) .ret$logitThetasHi <- numeric(0) .ret$logitThetasLow <- numeric(0) .ret$probitThetasF <- integer(0) .ret$probitThetasHiF <- numeric(0) .ret$probitThetasLowF <- numeric(0) .ret$probitThetas <- integer(0) .ret$probitThetasHi <- numeric(0) .ret$probitThetasLow <- numeric(0) } if (exists("noLik", envir = .ret)) { if (!.ret$noLik) { .ret$.params <- c(sprintf("THETA[%d]", seq_along(.ret$thetaIni)), sprintf("ETA[%d]", seq(1, dim(.om0)[1]))) .ret$.thetan <- length(.ret$thetaIni) .ret$nobs <- sum(data$EVID == 0) } } .ret$control$printTop <- TRUE .ret$control$nF <- 0 .est0 <- .ret$thetaIni if (!is.null(.ret$model$pred.nolhs)) { .ret$control$predNeq <- length(.ret$model$pred.nolhs$state) } else { .ret$control$predNeq <- 0L } .fitFun <- function(.ret) { this.env <- environment() assign("err", "theta reset", this.env) while (this.env$err == "theta reset") { assign("err", "", this.env) .ret0 <- tryCatch({ foceiFitCpp_(.ret) }, error = function(e) { if (regexpr("theta reset", e$message) != -1) { assign("zeroOuter", FALSE, this.env) assign("zeroGrad", FALSE, this.env) if (regexpr("theta reset0", e$message) != -1) { assign("zeroGrad", TRUE, this.env) } else if (regexpr("theta resetZ", e$message) != -1) { assign("zeroOuter", TRUE, this.env) } assign("err", "theta reset", this.env) } else { assign("err", e$message, this.env) } }) if (this.env$err == "theta reset") { .nm <- names(.ret$thetaIni) .ret$thetaIni <- setNames(.thetaReset$thetaIni + 0, .nm) .ret$rxInv$theta <- .thetaReset$omegaTheta .ret$control$printTop <- FALSE .ret$etaMat <- .thetaReset$etaMat .ret$control$etaMat <- .thetaReset$etaMat .ret$control$maxInnerIterations <- .thetaReset$maxInnerIterations .ret$control$nF <- .thetaReset$nF .ret$control$gillRetC <- .thetaReset$gillRetC .ret$control$gillRet <- .thetaReset$gillRet .ret$control$gillRet <- .thetaReset$gillRet .ret$control$gillDf <- .thetaReset$gillDf .ret$control$gillDf2 <- .thetaReset$gillDf2 .ret$control$gillErr <- .thetaReset$gillErr .ret$control$rEps <- .thetaReset$rEps .ret$control$aEps <- .thetaReset$aEps .ret$control$rEpsC <- .thetaReset$rEpsC .ret$control$aEpsC <- .thetaReset$aEpsC .ret$control$c1 <- .thetaReset$c1 .ret$control$c2 <- .thetaReset$c2 if (this.env$zeroOuter) { message("Posthoc reset") .ret$control$maxOuterIterations <- 0L } else if (this.env$zeroGrad) { message("Theta reset (zero gradient values); Switch to bobyqa") RxODE::rxReq("minqa") .ret$control$outerOptFun <- .bobyqa .ret$control$outerOpt <- -1L } else { message("Theta reset (ETA drift)") } } } if (this.env$err != "") { stop(this.env$err) } else { return(.ret0) } } .ret0 <- try(.fitFun(.ret)) .n <- 1 while (inherits(.ret0, "try-error") && control$maxOuterIterations != 0 && .n <= control$nRetries) { message(sprintf("Restart %s", .n)) .ret$control$nF <- 0 .estNew <- .est0 + 0.2 * .n * abs(.est0) * stats::runif(length(.est0)) - 0.1 * .n .estNew <- sapply(seq_along(.est0), function(.i) { if (.ret$thetaFixed[.i]) { return(.est0[.i]) } else if (.estNew[.i] < lower[.i]) { return(lower + (.Machine$double.eps)^(1/7)) } else if (.estNew[.i] > upper[.i]) { return(upper - (.Machine$double.eps)^(1/7)) } else { return(.estNew[.i]) } }) .ret$thetaIni <- .estNew .ret0 <- try(.fitFun(.ret)) .n <- .n + 1 } if (inherits(.ret0, "try-error")) stop("Could not fit data.") .ret <- .ret0 if (exists("parHistData", .ret)) { .tmp <- .ret$parHistData .tmp <- .tmp[.tmp$type == "Unscaled", names(.tmp) != "type"] .iter <- .tmp$iter .tmp <- .tmp[, names(.tmp) != "iter"] .ret$parHistStacked <- data.frame(stack(.tmp), iter = .iter) names(.ret$parHistStacked) <- c("val", "par", "iter") .ret$parHist <- data.frame(iter = .iter, .tmp) } if (.mixed) { .etas <- .ret$ranef .thetas <- .ret$fixef .pars <- .Call(`_nlmixr_nlmixrParameters`, .thetas, .etas) .ret$shrink <- .Call(`_nlmixr_calcShrinkOnly`, .ret$omega, .pars$eta.lst, length(.etas$ID)) .updateParFixed(.ret) } else { .updateParFixed(.ret) } if (!exists("table", .ret)) { .ret$table <- tableControl() } if (control$calcTables) { .ret <- addTable(.ret, updateObject = "no", keep = keep, drop = drop, table = .ret$table) } .ret})(data = dat, inits = .FoceiInits, PKpars = .pars, model = .mod, pred = function() { return(nlmixr_pred) }, err = uif$error, lower = uif$focei.lower, upper = uif$focei.upper, fixed = uif$focei.fixed, thetaNames = uif$focei.names, etaNames = uif$eta.names, control = control, env = env, keep = .keep, drop = .drop): Not all the covariates are in the dataset.</span></div><div class='output co'>#> <span class='message'>Timing stopped at: 19.01 0.403 19.42</span></div><div class='input'><span class='fu'><a href='https://rdrr.io/r/stats/AIC.html'>AIC</a></span><span class='op'>(</span><span class='va'>f_nlmixr_dfop_sfo_saem</span><span class='op'>$</span><span class='va'>nm</span>, <span class='va'>f_nlmixr_dfop_sfo_focei</span><span class='op'>$</span><span class='va'>nm</span><span class='op'>)</span> +</div><div class='output co'>#> <span class='error'>Error in AIC(f_nlmixr_dfop_sfo_saem$nm, f_nlmixr_dfop_sfo_focei$nm): object 'f_nlmixr_dfop_sfo_saem' not found</span></div><div class='input'><span class='fu'><a href='https://rdrr.io/pkg/saemix/man/summary-methods.html'>summary</a></span><span class='op'>(</span><span class='va'>f_nlmixr_dfop_sfo_sfo</span>, data <span class='op'>=</span> <span class='cn'>TRUE</span><span class='op'>)</span> </div><div class='output co'>#> <span class='error'>Error in h(simpleError(msg, call)): error in evaluating the argument 'object' in selecting a method for function 'summary': object 'f_nlmixr_dfop_sfo_sfo' not found</span></div><div class='input'><span class='co'># }</span> </div></pre> diff --git a/docs/dev/reference/tffm0.html b/docs/dev/reference/tffm0.html index d993e8ff..67f26b85 100644 --- a/docs/dev/reference/tffm0.html +++ b/docs/dev/reference/tffm0.html @@ -81,7 +81,7 @@ from RxODE." /> </button> <span class="navbar-brand"> <a class="navbar-link" href="../index.html">mkin</a> - <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.0.5</span> + <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.1.0</span> </span> </div> diff --git a/docs/dev/sitemap.xml b/docs/dev/sitemap.xml index 150840e1..b5e83f34 100644 --- a/docs/dev/sitemap.xml +++ b/docs/dev/sitemap.xml @@ -246,4 +246,7 @@ <url> <loc>https://pkgdown.jrwb.de/mkin/articles/web_only/compiled_models.html</loc> </url> + <url> + <loc>https://pkgdown.jrwb.de/mkin/articles/web_only/dimethenamid_2018.html</loc> + </url> </urlset> 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