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+</li> + </ul> +</div> +<!--/.nav-collapse --> + </div> +<!--/.container --> +</div> +<!--/.navbar --> + + + + </header><div class="row"> + <div class="col-md-9 contents"> + <div class="page-header toc-ignore"> + <h1 data-toc-skip>Testing hierarchical pathway kinetics with +residue data on dimethenamid and dimethenamid-P</h1> + <h4 data-toc-skip class="author">Johannes +Ranke</h4> + + <h4 data-toc-skip class="date">Last change on 20 April 2023, +last compiled on 20 April 2023</h4> + + <small class="dont-index">Source: <a href="https://github.com/jranke/mkin/blob/HEAD/vignettes/prebuilt/2022_dmta_pathway.rmd" class="external-link"><code>vignettes/prebuilt/2022_dmta_pathway.rmd</code></a></small> + <div class="hidden name"><code>2022_dmta_pathway.rmd</code></div> + + </div> + + + +<div class="section level2"> +<h2 id="introduction">Introduction<a class="anchor" aria-label="anchor" href="#introduction"></a> +</h2> +<p>The purpose of this document is to test demonstrate how nonlinear +hierarchical models (NLHM) based on the parent degradation models SFO, +FOMC, DFOP and HS, with parallel formation of two or more metabolites +can be fitted with the mkin package.</p> +<p>It was assembled in the course of work package 1.2 of Project Number +173340 (Application of nonlinear hierarchical models to the kinetic +evaluation of chemical degradation data) of the German Environment +Agency carried out in 2022 and 2023.</p> +<p>The mkin package is used in version 1.2.3, which is currently under +development. It contains the test data, and the functions used in the +evaluations. The <code>saemix</code> package is used as a backend for +fitting the NLHM, but is also loaded to make the convergence plot +function available.</p> +<p>This document is processed with the <code>knitr</code> package, which +also provides the <code>kable</code> function that is used to improve +the display of tabular data in R markdown documents. For parallel +processing, the <code>parallel</code> package is used.</p> +<div class="sourceCode" id="cb1"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span><span class="kw"><a href="https://rdrr.io/r/base/library.html" class="external-link">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> +<span><span class="kw"><a href="https://rdrr.io/r/base/library.html" class="external-link">library</a></span><span class="op">(</span><span class="va"><a href="https://yihui.org/knitr/" class="external-link">knitr</a></span><span class="op">)</span></span> +<span><span class="kw"><a href="https://rdrr.io/r/base/library.html" class="external-link">library</a></span><span class="op">(</span><span class="va">saemix</span><span class="op">)</span></span> +<span><span class="kw"><a href="https://rdrr.io/r/base/library.html" class="external-link">library</a></span><span class="op">(</span><span class="va">parallel</span><span class="op">)</span></span> +<span><span class="va">n_cores</span> <span class="op"><-</span> <span class="fu"><a href="https://rdrr.io/r/parallel/detectCores.html" class="external-link">detectCores</a></span><span class="op">(</span><span class="op">)</span></span> +<span></span> +<span><span class="co"># We need to start a new cluster after defining a compiled model that is</span></span> +<span><span class="co"># saved as a DLL to the user directory, therefore we define a function</span></span> +<span><span class="co"># This is used again after defining the pathway model</span></span> +<span><span class="va">start_cluster</span> <span class="op"><-</span> <span class="kw">function</span><span class="op">(</span><span class="va">n_cores</span><span class="op">)</span> <span class="op">{</span></span> +<span> <span class="kw">if</span> <span class="op">(</span><span class="fu"><a href="https://rdrr.io/r/base/Sys.info.html" class="external-link">Sys.info</a></span><span class="op">(</span><span class="op">)</span><span class="op">[</span><span class="st">"sysname"</span><span class="op">]</span> <span class="op">==</span> <span class="st">"Windows"</span><span class="op">)</span> <span class="op">{</span></span> +<span> <span class="va">ret</span> <span class="op"><-</span> <span class="fu"><a href="https://rdrr.io/r/parallel/makeCluster.html" class="external-link">makePSOCKcluster</a></span><span class="op">(</span><span class="va">n_cores</span><span class="op">)</span></span> +<span> <span class="op">}</span> <span class="kw">else</span> <span class="op">{</span></span> +<span> <span class="va">ret</span> <span class="op"><-</span> <span class="fu"><a href="https://rdrr.io/r/parallel/makeCluster.html" class="external-link">makeForkCluster</a></span><span class="op">(</span><span class="va">n_cores</span><span class="op">)</span></span> +<span> <span class="op">}</span></span> +<span> <span class="kw"><a href="https://rdrr.io/r/base/function.html" class="external-link">return</a></span><span class="op">(</span><span class="va">ret</span><span class="op">)</span></span> +<span><span class="op">}</span></span></code></pre></div> +</div> +<div class="section level2"> +<h2 id="data">Data<a class="anchor" aria-label="anchor" href="#data"></a> +</h2> +<p>The test data are available in the mkin package as an object of class +<code>mkindsg</code> (mkin dataset group) under the identifier +<code>dimethenamid_2018</code>. The following preprocessing steps are +done in this document.</p> +<ul> +<li>The data available for the enantiomer dimethenamid-P (DMTAP) are +renamed to have the same substance name as the data for the racemic +mixture dimethenamid (DMTA). The reason for this is that no difference +between their degradation behaviour was identified in the EU risk +assessment.</li> +<li>Unnecessary columns are discarded</li> +<li>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 that are independent of temperature</li> +<li>Finally, datasets observed in the same soil (<code>Elliot 1</code> +and <code>Elliot 2</code>) are combined, resulting in dimethenamid +(DMTA) data from six soils.</li> +</ul> +<p>The following commented R code performs this preprocessing.</p> +<div class="sourceCode" id="cb2"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span><span class="co"># Apply a function to each of the seven datasets in the mkindsg object to create a list</span></span> +<span><span class="va">dmta_ds</span> <span class="op"><-</span> <span class="fu"><a href="https://rdrr.io/r/base/lapply.html" class="external-link">lapply</a></span><span class="op">(</span><span class="fl">1</span><span class="op">:</span><span class="fl">7</span>, <span class="kw">function</span><span class="op">(</span><span class="va">i</span><span class="op">)</span> <span class="op">{</span></span> +<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="co"># Get a dataset</span></span> +<span> <span class="va">ds_i</span><span class="op">[</span><span class="va">ds_i</span><span class="op">$</span><span class="va">name</span> <span class="op">==</span> <span class="st">"DMTAP"</span>, <span class="st">"name"</span><span class="op">]</span> <span class="op"><-</span> <span class="st">"DMTA"</span> <span class="co"># Rename DMTAP to DMTA</span></span> +<span> <span class="va">ds_i</span> <span class="op"><-</span> <span class="fu"><a href="https://rdrr.io/r/base/subset.html" class="external-link">subset</a></span><span class="op">(</span><span class="va">ds_i</span>, select <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/c.html" class="external-link">c</a></span><span class="op">(</span><span class="st">"name"</span>, <span class="st">"time"</span>, <span class="st">"value"</span><span class="op">)</span><span class="op">)</span> <span class="co"># Select data</span></span> +<span> <span class="va">ds_i</span><span class="op">$</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="co"># Normalise time</span></span> +<span> <span class="va">ds_i</span> <span class="co"># Return the dataset</span></span> +<span><span class="op">}</span><span class="op">)</span></span> +<span></span> +<span><span class="co"># Use dataset titles as names for the list elements</span></span> +<span><span class="fu"><a href="https://rdrr.io/r/base/names.html" class="external-link">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" class="external-link">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> +<span></span> +<span><span class="co"># Combine data for Elliot soil to obtain a named list with six elements</span></span> +<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" class="external-link">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="co">#</span></span> +<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> +<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></span></code></pre></div> +<p>The following tables show the 6 datasets.</p> +<div class="sourceCode" id="cb3"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span><span class="kw">for</span> <span class="op">(</span><span class="va">ds_name</span> <span class="kw">in</span> <span class="fu"><a href="https://rdrr.io/r/base/names.html" class="external-link">names</a></span><span class="op">(</span><span class="va">dmta_ds</span><span class="op">)</span><span class="op">)</span> <span class="op">{</span></span> +<span> <span class="fu"><a href="https://rdrr.io/r/base/print.html" class="external-link">print</a></span><span class="op">(</span></span> +<span> <span class="fu"><a href="https://rdrr.io/pkg/knitr/man/kable.html" class="external-link">kable</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mkin_long_to_wide.html">mkin_long_to_wide</a></span><span class="op">(</span><span class="va">dmta_ds</span><span class="op">[[</span><span class="va">ds_name</span><span class="op">]</span><span class="op">]</span><span class="op">)</span>,</span> +<span> caption <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/paste.html" class="external-link">paste</a></span><span class="op">(</span><span class="st">"Dataset"</span>, <span class="va">ds_name</span><span class="op">)</span>,</span> +<span> booktabs <span class="op">=</span> <span class="cn">TRUE</span>, row.names <span class="op">=</span> <span class="cn">FALSE</span><span class="op">)</span><span class="op">)</span></span> +<span> <span class="fu"><a href="https://rdrr.io/r/base/cat.html" class="external-link">cat</a></span><span class="op">(</span><span class="st">"\n\\clearpage\n"</span><span class="op">)</span></span> +<span><span class="op">}</span></span></code></pre></div> +<table class="table"> +<caption>Dataset Calke</caption> +<thead><tr class="header"> +<th align="right">time</th> +<th align="right">DMTA</th> +<th align="right">M23</th> +<th align="right">M27</th> +<th align="right">M31</th> +</tr></thead> +<tbody> +<tr class="odd"> +<td align="right">0</td> +<td align="right">95.8</td> +<td align="right">NA</td> +<td align="right">NA</td> +<td align="right">NA</td> +</tr> +<tr class="even"> +<td align="right">0</td> +<td align="right">98.7</td> +<td align="right">NA</td> +<td align="right">NA</td> +<td align="right">NA</td> +</tr> +<tr class="odd"> +<td align="right">14</td> +<td align="right">60.5</td> +<td align="right">4.1</td> +<td align="right">1.5</td> +<td align="right">2.0</td> +</tr> +<tr class="even"> +<td align="right">30</td> +<td align="right">39.1</td> +<td align="right">5.3</td> +<td align="right">2.4</td> +<td align="right">2.1</td> +</tr> +<tr class="odd"> +<td align="right">59</td> +<td align="right">15.2</td> +<td align="right">6.0</td> +<td align="right">3.2</td> +<td align="right">2.2</td> +</tr> +<tr class="even"> +<td align="right">120</td> +<td align="right">4.8</td> +<td align="right">4.3</td> +<td align="right">3.8</td> +<td align="right">1.8</td> +</tr> +<tr class="odd"> +<td align="right">120</td> +<td align="right">4.6</td> +<td align="right">4.1</td> +<td align="right">3.7</td> +<td align="right">2.1</td> +</tr> +</tbody> +</table> +<table class="table"> +<caption>Dataset Borstel</caption> +<thead><tr class="header"> +<th align="right">time</th> +<th align="right">DMTA</th> +<th align="right">M23</th> +<th align="right">M27</th> +<th align="right">M31</th> +</tr></thead> +<tbody> +<tr class="odd"> +<td align="right">0.000000</td> +<td align="right">100.5</td> +<td align="right">NA</td> +<td align="right">NA</td> +<td align="right">NA</td> +</tr> +<tr class="even"> +<td align="right">0.000000</td> +<td align="right">99.6</td> +<td align="right">NA</td> +<td align="right">NA</td> +<td align="right">NA</td> +</tr> +<tr class="odd"> +<td align="right">1.941295</td> +<td align="right">91.9</td> +<td align="right">0.4</td> +<td align="right">NA</td> +<td align="right">NA</td> +</tr> +<tr class="even"> +<td align="right">1.941295</td> +<td align="right">91.3</td> +<td align="right">0.5</td> +<td align="right">0.3</td> +<td align="right">0.1</td> +</tr> +<tr class="odd"> +<td align="right">6.794534</td> +<td align="right">81.8</td> +<td align="right">1.2</td> +<td align="right">0.8</td> +<td align="right">1.0</td> +</tr> +<tr class="even"> +<td align="right">6.794534</td> +<td align="right">82.1</td> +<td align="right">1.3</td> +<td align="right">0.9</td> +<td align="right">0.9</td> +</tr> +<tr class="odd"> +<td align="right">13.589067</td> +<td align="right">69.1</td> +<td align="right">2.8</td> +<td align="right">1.4</td> +<td align="right">2.0</td> +</tr> +<tr class="even"> +<td align="right">13.589067</td> +<td align="right">68.0</td> +<td align="right">2.0</td> +<td align="right">1.4</td> +<td align="right">2.5</td> +</tr> +<tr class="odd"> +<td align="right">27.178135</td> +<td align="right">51.4</td> +<td align="right">2.9</td> +<td align="right">2.7</td> +<td align="right">4.3</td> +</tr> +<tr class="even"> +<td align="right">27.178135</td> +<td align="right">51.4</td> +<td align="right">4.9</td> +<td align="right">2.6</td> +<td align="right">3.2</td> +</tr> +<tr class="odd"> +<td align="right">56.297565</td> +<td align="right">27.6</td> +<td align="right">12.2</td> +<td align="right">4.4</td> +<td align="right">4.3</td> +</tr> +<tr class="even"> +<td align="right">56.297565</td> +<td align="right">26.8</td> +<td align="right">12.2</td> +<td align="right">4.7</td> +<td align="right">4.8</td> +</tr> +<tr class="odd"> +<td align="right">86.387643</td> +<td align="right">15.7</td> +<td align="right">12.2</td> +<td align="right">5.4</td> +<td align="right">5.0</td> +</tr> +<tr class="even"> +<td align="right">86.387643</td> +<td align="right">15.3</td> +<td align="right">12.0</td> +<td align="right">5.2</td> +<td align="right">5.1</td> +</tr> +<tr class="odd"> +<td align="right">115.507073</td> +<td align="right">7.9</td> +<td align="right">10.4</td> +<td align="right">5.4</td> +<td align="right">4.3</td> +</tr> +<tr class="even"> +<td align="right">115.507073</td> +<td align="right">8.1</td> +<td align="right">11.6</td> +<td align="right">5.4</td> +<td align="right">4.4</td> +</tr> +</tbody> +</table> +<table class="table"> +<caption>Dataset Flaach</caption> +<thead><tr class="header"> +<th align="right">time</th> +<th align="right">DMTA</th> +<th align="right">M23</th> +<th align="right">M27</th> +<th align="right">M31</th> +</tr></thead> +<tbody> +<tr class="odd"> +<td align="right">0.0000000</td> +<td align="right">96.5</td> +<td align="right">NA</td> +<td align="right">NA</td> +<td align="right">NA</td> +</tr> +<tr class="even"> +<td align="right">0.0000000</td> +<td align="right">96.8</td> +<td align="right">NA</td> +<td align="right">NA</td> +<td align="right">NA</td> +</tr> +<tr class="odd"> +<td align="right">0.0000000</td> +<td align="right">97.0</td> +<td align="right">NA</td> +<td align="right">NA</td> +<td align="right">NA</td> +</tr> +<tr class="even"> +<td align="right">0.6233856</td> +<td align="right">82.9</td> +<td align="right">0.7</td> +<td align="right">1.1</td> +<td align="right">0.3</td> +</tr> +<tr class="odd"> +<td align="right">0.6233856</td> +<td align="right">86.7</td> +<td align="right">0.7</td> +<td align="right">1.1</td> +<td align="right">0.3</td> +</tr> +<tr class="even"> +<td align="right">0.6233856</td> +<td align="right">87.4</td> +<td align="right">0.2</td> +<td align="right">0.3</td> +<td align="right">0.1</td> +</tr> +<tr class="odd"> +<td align="right">1.8701567</td> +<td align="right">72.8</td> +<td align="right">2.2</td> +<td align="right">2.6</td> +<td align="right">0.7</td> +</tr> +<tr class="even"> +<td align="right">1.8701567</td> +<td align="right">69.9</td> +<td align="right">1.8</td> +<td align="right">2.4</td> +<td align="right">0.6</td> +</tr> +<tr class="odd"> +<td align="right">1.8701567</td> +<td align="right">71.9</td> +<td align="right">1.6</td> +<td align="right">2.3</td> +<td align="right">0.7</td> +</tr> +<tr class="even"> +<td align="right">4.3636989</td> +<td align="right">51.4</td> +<td align="right">4.1</td> +<td align="right">5.0</td> +<td align="right">1.3</td> +</tr> +<tr class="odd"> +<td align="right">4.3636989</td> +<td align="right">52.9</td> +<td align="right">4.2</td> +<td align="right">5.9</td> +<td align="right">1.2</td> +</tr> +<tr class="even"> +<td align="right">4.3636989</td> +<td align="right">48.6</td> +<td align="right">4.2</td> +<td align="right">4.8</td> +<td align="right">1.4</td> +</tr> +<tr class="odd"> +<td align="right">8.7273979</td> +<td align="right">28.5</td> +<td align="right">7.5</td> +<td align="right">8.5</td> +<td align="right">2.4</td> +</tr> +<tr class="even"> +<td align="right">8.7273979</td> +<td align="right">27.3</td> +<td align="right">7.1</td> +<td align="right">8.5</td> +<td align="right">2.1</td> +</tr> +<tr class="odd"> +<td align="right">8.7273979</td> +<td align="right">27.5</td> +<td align="right">7.5</td> +<td align="right">8.3</td> +<td align="right">2.3</td> +</tr> +<tr class="even"> +<td align="right">13.0910968</td> +<td align="right">14.8</td> +<td align="right">8.4</td> +<td align="right">9.3</td> +<td align="right">3.3</td> +</tr> +<tr class="odd"> +<td align="right">13.0910968</td> +<td align="right">13.4</td> +<td align="right">6.8</td> +<td align="right">8.7</td> +<td align="right">2.4</td> +</tr> +<tr class="even"> +<td align="right">13.0910968</td> +<td align="right">14.4</td> +<td align="right">8.0</td> +<td align="right">9.1</td> +<td align="right">2.6</td> +</tr> +<tr class="odd"> +<td align="right">17.4547957</td> +<td align="right">7.7</td> +<td align="right">7.2</td> +<td align="right">8.6</td> +<td align="right">4.0</td> +</tr> +<tr class="even"> +<td align="right">17.4547957</td> +<td align="right">7.3</td> +<td align="right">7.2</td> +<td align="right">8.5</td> +<td align="right">3.6</td> +</tr> +<tr class="odd"> +<td align="right">17.4547957</td> +<td align="right">8.1</td> +<td align="right">6.9</td> +<td align="right">8.9</td> +<td align="right">3.3</td> +</tr> +<tr class="even"> +<td align="right">26.1821936</td> +<td align="right">2.0</td> +<td align="right">4.9</td> +<td align="right">8.1</td> +<td align="right">2.1</td> +</tr> +<tr class="odd"> +<td align="right">26.1821936</td> +<td align="right">1.5</td> +<td align="right">4.3</td> +<td align="right">7.7</td> +<td align="right">1.7</td> +</tr> +<tr class="even"> +<td align="right">26.1821936</td> +<td align="right">1.9</td> +<td align="right">4.5</td> +<td align="right">7.4</td> +<td align="right">1.8</td> +</tr> +<tr class="odd"> +<td align="right">34.9095915</td> +<td align="right">1.3</td> +<td align="right">3.8</td> +<td align="right">5.9</td> +<td align="right">1.6</td> +</tr> +<tr class="even"> +<td align="right">34.9095915</td> +<td align="right">1.0</td> +<td align="right">3.1</td> +<td align="right">6.0</td> +<td align="right">1.6</td> +</tr> +<tr class="odd"> +<td align="right">34.9095915</td> +<td align="right">1.1</td> +<td align="right">3.1</td> +<td align="right">5.9</td> +<td align="right">1.4</td> +</tr> +<tr class="even"> +<td align="right">43.6369893</td> +<td align="right">0.9</td> +<td align="right">2.7</td> +<td align="right">5.6</td> +<td align="right">1.8</td> +</tr> +<tr class="odd"> +<td align="right">43.6369893</td> +<td align="right">0.7</td> +<td align="right">2.3</td> +<td align="right">5.2</td> +<td align="right">1.5</td> +</tr> +<tr class="even"> +<td align="right">43.6369893</td> +<td align="right">0.7</td> +<td align="right">2.1</td> +<td align="right">5.6</td> +<td align="right">1.3</td> +</tr> +<tr class="odd"> +<td align="right">52.3643872</td> +<td align="right">0.6</td> +<td align="right">1.6</td> +<td align="right">4.3</td> +<td align="right">1.2</td> +</tr> +<tr class="even"> +<td align="right">52.3643872</td> +<td align="right">0.4</td> +<td align="right">1.1</td> +<td align="right">3.7</td> +<td align="right">0.9</td> +</tr> +<tr class="odd"> +<td align="right">52.3643872</td> +<td align="right">0.5</td> +<td align="right">1.3</td> +<td align="right">3.9</td> +<td align="right">1.1</td> +</tr> +<tr class="even"> +<td align="right">74.8062674</td> +<td align="right">0.4</td> +<td align="right">0.4</td> +<td align="right">2.5</td> +<td align="right">0.5</td> +</tr> +<tr class="odd"> +<td align="right">74.8062674</td> +<td align="right">0.3</td> +<td align="right">0.4</td> +<td align="right">2.4</td> +<td align="right">0.5</td> +</tr> +<tr class="even"> +<td align="right">74.8062674</td> +<td align="right">0.3</td> +<td align="right">0.3</td> +<td align="right">2.2</td> +<td align="right">0.3</td> +</tr> +</tbody> +</table> +<table class="table"> +<caption>Dataset BBA 2.2</caption> +<thead><tr class="header"> +<th align="right">time</th> +<th align="right">DMTA</th> +<th align="right">M23</th> +<th align="right">M27</th> +<th align="right">M31</th> +</tr></thead> +<tbody> +<tr class="odd"> +<td align="right">0.0000000</td> +<td align="right">98.09</td> +<td align="right">NA</td> +<td align="right">NA</td> +<td align="right">NA</td> +</tr> +<tr class="even"> +<td align="right">0.0000000</td> +<td align="right">98.77</td> +<td align="right">NA</td> +<td align="right">NA</td> +<td align="right">NA</td> +</tr> +<tr class="odd"> +<td align="right">0.7678922</td> +<td align="right">93.52</td> +<td align="right">0.36</td> +<td align="right">0.42</td> +<td align="right">0.36</td> +</tr> +<tr class="even"> +<td align="right">0.7678922</td> +<td align="right">92.03</td> +<td align="right">0.40</td> +<td align="right">0.47</td> +<td align="right">0.33</td> +</tr> +<tr class="odd"> +<td align="right">2.3036765</td> +<td align="right">88.39</td> +<td align="right">1.03</td> +<td align="right">0.71</td> +<td align="right">0.55</td> +</tr> +<tr class="even"> +<td align="right">2.3036765</td> +<td align="right">87.18</td> +<td align="right">1.07</td> +<td align="right">0.82</td> +<td align="right">0.64</td> +</tr> +<tr class="odd"> +<td align="right">5.3752452</td> +<td align="right">69.38</td> +<td align="right">3.60</td> +<td align="right">2.19</td> +<td align="right">1.94</td> +</tr> +<tr class="even"> +<td align="right">5.3752452</td> +<td align="right">71.06</td> +<td align="right">3.66</td> +<td align="right">2.28</td> +<td align="right">1.62</td> +</tr> +<tr class="odd"> +<td align="right">10.7504904</td> +<td align="right">45.21</td> +<td align="right">6.97</td> +<td align="right">5.45</td> +<td align="right">4.22</td> +</tr> +<tr class="even"> +<td align="right">10.7504904</td> +<td align="right">46.81</td> +<td align="right">7.22</td> +<td align="right">5.19</td> +<td align="right">4.37</td> +</tr> +<tr class="odd"> +<td align="right">16.1257355</td> +<td align="right">30.54</td> +<td align="right">8.65</td> +<td align="right">8.81</td> +<td align="right">6.31</td> +</tr> +<tr class="even"> +<td align="right">16.1257355</td> +<td align="right">30.07</td> +<td align="right">8.38</td> +<td align="right">7.93</td> +<td align="right">6.85</td> +</tr> +<tr class="odd"> +<td align="right">21.5009807</td> +<td align="right">21.60</td> +<td align="right">9.10</td> +<td align="right">10.25</td> +<td align="right">7.05</td> +</tr> +<tr class="even"> +<td align="right">21.5009807</td> +<td align="right">20.41</td> +<td align="right">8.63</td> +<td align="right">10.77</td> +<td align="right">6.84</td> +</tr> +<tr class="odd"> +<td align="right">32.2514711</td> +<td align="right">9.10</td> +<td align="right">7.63</td> +<td align="right">10.89</td> +<td align="right">6.53</td> +</tr> +<tr class="even"> +<td align="right">32.2514711</td> +<td align="right">9.70</td> +<td align="right">8.01</td> +<td align="right">10.85</td> +<td align="right">7.11</td> +</tr> +<tr class="odd"> +<td align="right">43.0019614</td> +<td align="right">6.58</td> +<td align="right">6.40</td> +<td align="right">10.41</td> +<td align="right">6.06</td> +</tr> +<tr class="even"> +<td align="right">43.0019614</td> +<td align="right">6.31</td> +<td align="right">6.35</td> +<td align="right">10.35</td> +<td align="right">6.05</td> +</tr> +<tr class="odd"> +<td align="right">53.7524518</td> +<td align="right">3.47</td> +<td align="right">5.35</td> +<td align="right">9.92</td> +<td align="right">5.50</td> +</tr> +<tr class="even"> +<td align="right">53.7524518</td> +<td align="right">3.52</td> +<td align="right">5.06</td> +<td align="right">9.42</td> +<td align="right">5.07</td> +</tr> +<tr class="odd"> +<td align="right">64.5029421</td> +<td align="right">3.40</td> +<td align="right">5.14</td> +<td align="right">9.15</td> +<td align="right">4.94</td> +</tr> +<tr class="even"> +<td align="right">64.5029421</td> +<td align="right">3.67</td> +<td align="right">5.91</td> +<td align="right">9.25</td> +<td align="right">4.39</td> +</tr> +<tr class="odd"> +<td align="right">91.3791680</td> +<td align="right">1.62</td> +<td align="right">3.35</td> +<td align="right">7.14</td> +<td align="right">3.64</td> +</tr> +<tr class="even"> +<td align="right">91.3791680</td> +<td align="right">1.62</td> +<td align="right">2.87</td> +<td align="right">7.13</td> +<td align="right">3.55</td> +</tr> +</tbody> +</table> +<table class="table"> +<caption>Dataset BBA 2.3</caption> +<thead><tr class="header"> +<th align="right">time</th> +<th align="right">DMTA</th> +<th align="right">M23</th> +<th align="right">M27</th> +<th align="right">M31</th> +</tr></thead> +<tbody> +<tr class="odd"> +<td align="right">0.0000000</td> +<td align="right">99.33</td> +<td align="right">NA</td> +<td align="right">NA</td> +<td align="right">NA</td> +</tr> +<tr class="even"> +<td align="right">0.0000000</td> +<td align="right">97.44</td> +<td align="right">NA</td> +<td align="right">NA</td> +<td align="right">NA</td> +</tr> +<tr class="odd"> +<td align="right">0.6733938</td> +<td align="right">93.73</td> +<td align="right">0.18</td> +<td align="right">0.50</td> +<td align="right">0.47</td> +</tr> +<tr class="even"> +<td align="right">0.6733938</td> +<td align="right">93.77</td> +<td align="right">0.18</td> +<td align="right">0.83</td> +<td align="right">0.34</td> +</tr> +<tr class="odd"> +<td align="right">2.0201814</td> +<td align="right">87.84</td> +<td align="right">0.52</td> +<td align="right">1.25</td> +<td align="right">1.00</td> +</tr> +<tr class="even"> +<td align="right">2.0201814</td> +<td align="right">89.82</td> +<td align="right">0.43</td> +<td align="right">1.09</td> +<td align="right">0.89</td> +</tr> +<tr class="odd"> +<td align="right">4.7137565</td> +<td align="right">71.61</td> +<td align="right">1.19</td> +<td align="right">3.28</td> +<td align="right">3.58</td> +</tr> +<tr class="even"> +<td align="right">4.7137565</td> +<td align="right">71.42</td> +<td align="right">1.11</td> +<td align="right">3.24</td> +<td align="right">3.41</td> +</tr> +<tr class="odd"> +<td align="right">9.4275131</td> +<td align="right">45.60</td> +<td align="right">2.26</td> +<td align="right">7.17</td> +<td align="right">8.74</td> +</tr> +<tr class="even"> +<td align="right">9.4275131</td> +<td align="right">45.42</td> +<td align="right">1.99</td> +<td align="right">7.91</td> +<td align="right">8.28</td> +</tr> +<tr class="odd"> +<td align="right">14.1412696</td> +<td align="right">31.12</td> +<td align="right">2.81</td> +<td align="right">10.15</td> +<td align="right">9.67</td> +</tr> +<tr class="even"> +<td align="right">14.1412696</td> +<td align="right">31.68</td> +<td align="right">2.83</td> +<td align="right">9.55</td> +<td align="right">8.95</td> +</tr> +<tr class="odd"> +<td align="right">18.8550262</td> +<td align="right">23.20</td> +<td align="right">3.39</td> +<td align="right">12.09</td> +<td align="right">10.34</td> +</tr> +<tr class="even"> +<td align="right">18.8550262</td> +<td align="right">24.13</td> +<td align="right">3.56</td> +<td align="right">11.89</td> +<td align="right">10.00</td> +</tr> +<tr class="odd"> +<td align="right">28.2825393</td> +<td align="right">9.43</td> +<td align="right">3.49</td> +<td align="right">13.32</td> +<td align="right">7.89</td> +</tr> +<tr class="even"> +<td align="right">28.2825393</td> +<td align="right">9.82</td> +<td align="right">3.28</td> +<td align="right">12.05</td> +<td align="right">8.13</td> +</tr> +<tr class="odd"> +<td align="right">37.7100523</td> +<td align="right">7.08</td> +<td align="right">2.80</td> +<td align="right">10.04</td> +<td align="right">5.06</td> +</tr> +<tr class="even"> +<td align="right">37.7100523</td> +<td align="right">8.64</td> +<td align="right">2.97</td> +<td align="right">10.78</td> +<td align="right">5.54</td> +</tr> +<tr class="odd"> +<td align="right">47.1375654</td> +<td align="right">4.41</td> +<td align="right">2.42</td> +<td align="right">9.32</td> +<td align="right">3.79</td> +</tr> +<tr class="even"> +<td align="right">47.1375654</td> +<td align="right">4.78</td> +<td align="right">2.51</td> +<td align="right">9.62</td> +<td align="right">4.11</td> +</tr> +<tr class="odd"> +<td align="right">56.5650785</td> +<td align="right">4.92</td> +<td align="right">2.22</td> +<td align="right">8.00</td> +<td align="right">3.11</td> +</tr> +<tr class="even"> +<td align="right">56.5650785</td> +<td align="right">5.08</td> +<td align="right">1.95</td> +<td align="right">8.45</td> +<td align="right">2.98</td> +</tr> +<tr class="odd"> +<td align="right">80.1338612</td> +<td align="right">2.13</td> +<td align="right">1.28</td> +<td align="right">5.71</td> +<td align="right">1.78</td> +</tr> +<tr class="even"> +<td align="right">80.1338612</td> +<td align="right">2.23</td> +<td align="right">0.99</td> +<td align="right">3.33</td> +<td align="right">1.55</td> +</tr> +</tbody> +</table> +<table class="table"> +<caption>Dataset Elliot</caption> +<thead><tr class="header"> +<th align="right">time</th> +<th align="right">DMTA</th> +<th align="right">M23</th> +<th align="right">M27</th> +<th align="right">M31</th> +</tr></thead> +<tbody> +<tr class="odd"> +<td align="right">0.000000</td> +<td align="right">97.5</td> +<td align="right">NA</td> +<td align="right">NA</td> +<td align="right">NA</td> +</tr> +<tr class="even"> +<td align="right">0.000000</td> +<td align="right">100.7</td> +<td align="right">NA</td> +<td align="right">NA</td> +<td align="right">NA</td> +</tr> +<tr class="odd"> +<td align="right">1.228478</td> +<td align="right">86.4</td> +<td align="right">NA</td> +<td align="right">NA</td> +<td align="right">NA</td> +</tr> +<tr class="even"> +<td align="right">1.228478</td> +<td align="right">88.5</td> +<td align="right">NA</td> +<td align="right">NA</td> +<td align="right">1.5</td> +</tr> +<tr class="odd"> +<td align="right">3.685435</td> +<td align="right">69.8</td> +<td align="right">2.8</td> +<td align="right">2.3</td> +<td align="right">5.0</td> +</tr> +<tr class="even"> +<td align="right">3.685435</td> +<td align="right">77.1</td> +<td align="right">1.7</td> +<td align="right">2.1</td> +<td align="right">2.4</td> +</tr> +<tr class="odd"> +<td align="right">8.599349</td> +<td align="right">59.0</td> +<td align="right">4.3</td> +<td align="right">4.0</td> +<td align="right">4.3</td> +</tr> +<tr class="even"> +<td align="right">8.599349</td> +<td align="right">54.2</td> +<td align="right">5.8</td> +<td align="right">3.4</td> +<td align="right">5.0</td> +</tr> +<tr class="odd"> +<td align="right">17.198697</td> +<td align="right">31.3</td> +<td align="right">8.2</td> +<td align="right">6.6</td> +<td align="right">8.0</td> +</tr> +<tr class="even"> +<td align="right">17.198697</td> +<td align="right">33.5</td> +<td align="right">5.2</td> +<td align="right">6.9</td> +<td align="right">7.7</td> +</tr> +<tr class="odd"> +<td align="right">25.798046</td> +<td align="right">19.6</td> +<td align="right">5.1</td> +<td align="right">8.2</td> +<td align="right">7.8</td> +</tr> +<tr class="even"> +<td align="right">25.798046</td> +<td align="right">20.9</td> +<td align="right">6.1</td> +<td align="right">8.8</td> +<td align="right">6.5</td> +</tr> +<tr class="odd"> +<td align="right">34.397395</td> +<td align="right">13.3</td> +<td align="right">6.0</td> +<td align="right">9.7</td> +<td align="right">8.0</td> +</tr> +<tr class="even"> +<td align="right">34.397395</td> +<td align="right">15.8</td> +<td align="right">6.0</td> +<td align="right">8.8</td> +<td align="right">7.4</td> +</tr> +<tr class="odd"> +<td align="right">51.596092</td> +<td align="right">6.7</td> +<td align="right">5.0</td> +<td align="right">8.3</td> +<td align="right">6.9</td> +</tr> +<tr class="even"> +<td align="right">51.596092</td> +<td align="right">8.7</td> +<td align="right">4.2</td> +<td align="right">9.2</td> +<td align="right">9.0</td> +</tr> +<tr class="odd"> +<td align="right">68.794789</td> +<td align="right">8.8</td> +<td align="right">3.9</td> +<td align="right">9.3</td> +<td align="right">5.5</td> +</tr> +<tr class="even"> +<td align="right">68.794789</td> +<td align="right">8.7</td> +<td align="right">2.9</td> +<td align="right">8.5</td> +<td align="right">6.1</td> +</tr> +<tr class="odd"> +<td align="right">103.192184</td> +<td align="right">6.0</td> +<td align="right">1.9</td> +<td align="right">8.6</td> +<td align="right">6.1</td> +</tr> +<tr class="even"> +<td align="right">103.192184</td> +<td align="right">4.4</td> +<td align="right">1.5</td> +<td align="right">6.0</td> +<td align="right">4.0</td> +</tr> +<tr class="odd"> +<td align="right">146.188928</td> +<td align="right">3.3</td> +<td align="right">2.0</td> +<td align="right">5.6</td> +<td align="right">3.1</td> +</tr> +<tr class="even"> +<td align="right">146.188928</td> +<td align="right">2.8</td> +<td align="right">2.3</td> +<td align="right">4.5</td> +<td align="right">2.9</td> +</tr> +<tr class="odd"> +<td align="right">223.583066</td> +<td align="right">1.4</td> +<td align="right">1.2</td> +<td align="right">4.1</td> +<td align="right">1.8</td> +</tr> +<tr class="even"> +<td align="right">223.583066</td> +<td align="right">1.8</td> +<td align="right">1.9</td> +<td align="right">3.9</td> +<td align="right">2.6</td> +</tr> +<tr class="odd"> +<td align="right">0.000000</td> +<td align="right">93.4</td> +<td align="right">NA</td> +<td align="right">NA</td> +<td align="right">NA</td> +</tr> +<tr class="even"> +<td align="right">0.000000</td> +<td align="right">103.2</td> +<td align="right">NA</td> +<td align="right">NA</td> +<td align="right">NA</td> +</tr> +<tr class="odd"> +<td align="right">1.228478</td> +<td align="right">89.2</td> +<td align="right">NA</td> +<td align="right">NA</td> +<td align="right">1.3</td> +</tr> +<tr class="even"> +<td align="right">1.228478</td> +<td align="right">86.6</td> +<td align="right">NA</td> +<td align="right">NA</td> +<td align="right">NA</td> +</tr> +<tr class="odd"> +<td align="right">3.685435</td> +<td align="right">78.2</td> +<td align="right">2.6</td> +<td align="right">1.0</td> +<td align="right">3.1</td> +</tr> +<tr class="even"> +<td align="right">3.685435</td> +<td align="right">78.1</td> +<td align="right">2.4</td> +<td align="right">2.6</td> +<td align="right">2.3</td> +</tr> +<tr class="odd"> +<td align="right">8.599349</td> +<td align="right">55.6</td> +<td align="right">5.5</td> +<td align="right">4.5</td> +<td align="right">3.4</td> +</tr> +<tr class="even"> +<td align="right">8.599349</td> +<td align="right">53.0</td> +<td align="right">5.6</td> +<td align="right">4.6</td> +<td align="right">4.3</td> +</tr> +<tr class="odd"> +<td align="right">17.198697</td> +<td align="right">33.7</td> +<td align="right">7.3</td> +<td align="right">7.6</td> +<td align="right">7.8</td> +</tr> +<tr class="even"> +<td align="right">17.198697</td> +<td align="right">33.2</td> +<td align="right">6.5</td> +<td align="right">6.7</td> +<td align="right">8.7</td> +</tr> +<tr class="odd"> +<td align="right">25.798046</td> +<td align="right">20.9</td> +<td align="right">5.8</td> +<td align="right">8.7</td> +<td align="right">7.7</td> +</tr> +<tr class="even"> +<td align="right">25.798046</td> +<td align="right">19.9</td> +<td align="right">7.7</td> +<td align="right">7.6</td> +<td align="right">6.5</td> +</tr> +<tr class="odd"> +<td align="right">34.397395</td> +<td align="right">18.2</td> +<td align="right">7.8</td> +<td align="right">8.0</td> +<td align="right">6.3</td> +</tr> +<tr class="even"> +<td align="right">34.397395</td> +<td align="right">12.7</td> +<td align="right">7.3</td> +<td align="right">8.6</td> +<td align="right">8.7</td> +</tr> +<tr class="odd"> +<td align="right">51.596092</td> +<td align="right">7.8</td> +<td align="right">7.0</td> +<td align="right">7.4</td> +<td align="right">5.7</td> +</tr> +<tr class="even"> +<td align="right">51.596092</td> +<td align="right">9.0</td> +<td align="right">6.3</td> +<td align="right">7.2</td> +<td align="right">4.2</td> +</tr> +<tr class="odd"> +<td align="right">68.794789</td> +<td align="right">11.4</td> +<td align="right">4.3</td> +<td align="right">10.3</td> +<td align="right">3.2</td> +</tr> +<tr class="even"> +<td align="right">68.794789</td> +<td align="right">9.0</td> +<td align="right">3.8</td> +<td align="right">9.4</td> +<td align="right">4.2</td> +</tr> +<tr class="odd"> +<td align="right">103.192184</td> +<td align="right">3.9</td> +<td align="right">2.6</td> +<td align="right">6.5</td> +<td align="right">3.8</td> +</tr> +<tr class="even"> +<td align="right">103.192184</td> +<td align="right">4.4</td> +<td align="right">2.8</td> +<td align="right">6.9</td> +<td align="right">4.0</td> +</tr> +<tr class="odd"> +<td align="right">146.188928</td> +<td align="right">2.6</td> +<td align="right">1.6</td> +<td align="right">4.6</td> +<td align="right">4.5</td> +</tr> +<tr class="even"> +<td align="right">146.188928</td> +<td align="right">3.4</td> +<td align="right">1.1</td> +<td align="right">4.5</td> +<td align="right">4.5</td> +</tr> +<tr class="odd"> +<td align="right">223.583066</td> +<td align="right">2.0</td> +<td align="right">1.4</td> +<td align="right">4.3</td> +<td align="right">3.8</td> +</tr> +<tr class="even"> +<td align="right">223.583066</td> +<td align="right">1.7</td> +<td align="right">1.3</td> +<td align="right">4.2</td> +<td align="right">2.3</td> +</tr> +</tbody> +</table> +</div> +<div class="section level2"> +<h2 id="separate-evaluations">Separate evaluations<a class="anchor" aria-label="anchor" href="#separate-evaluations"></a> +</h2> +<p>As a first step to obtain suitable starting parameters for the NLHM +fits, we do separate fits of several variants of the pathway model used +previously <span class="citation">(Ranke et al. 2021)</span>, varying +the kinetic model for the parent compound. Because the SFORB model often +provides faster convergence than the DFOP model, and can sometimes be +fitted where the DFOP model results in errors, it is included in the set +of parent models tested here.</p> +<div class="sourceCode" id="cb4"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span><span class="kw">if</span> <span class="op">(</span><span class="op">!</span><span class="fu"><a href="https://rdrr.io/r/base/files2.html" class="external-link">dir.exists</a></span><span class="op">(</span><span class="st">"dmta_dlls"</span><span class="op">)</span><span class="op">)</span> <span class="fu"><a href="https://rdrr.io/r/base/files2.html" class="external-link">dir.create</a></span><span class="op">(</span><span class="st">"dmta_dlls"</span><span class="op">)</span></span> +<span><span class="va">m_sfo_path_1</span> <span class="op"><-</span> <span class="fu"><a href="../../reference/mkinmod.html">mkinmod</a></span><span class="op">(</span></span> +<span> DMTA <span class="op">=</span> <span class="fu"><a href="../../reference/mkinmod.html">mkinsub</a></span><span class="op">(</span><span class="st">"SFO"</span>, <span class="fu"><a href="https://rdrr.io/r/base/c.html" class="external-link">c</a></span><span class="op">(</span><span class="st">"M23"</span>, <span class="st">"M27"</span>, <span class="st">"M31"</span><span class="op">)</span><span class="op">)</span>,</span> +<span> M23 <span class="op">=</span> <span class="fu"><a href="../../reference/mkinmod.html">mkinsub</a></span><span class="op">(</span><span class="st">"SFO"</span><span class="op">)</span>,</span> +<span> M27 <span class="op">=</span> <span class="fu"><a href="../../reference/mkinmod.html">mkinsub</a></span><span class="op">(</span><span class="st">"SFO"</span><span class="op">)</span>,</span> +<span> M31 <span class="op">=</span> <span class="fu"><a href="../../reference/mkinmod.html">mkinsub</a></span><span class="op">(</span><span class="st">"SFO"</span>, <span class="st">"M27"</span>, sink <span class="op">=</span> <span class="cn">FALSE</span><span class="op">)</span>,</span> +<span> name <span class="op">=</span> <span class="st">"m_sfo_path"</span>, dll_dir <span class="op">=</span> <span class="st">"dmta_dlls"</span>,</span> +<span> unload <span class="op">=</span> <span class="cn">TRUE</span>, overwrite <span class="op">=</span> <span class="cn">TRUE</span>,</span> +<span> quiet <span class="op">=</span> <span class="cn">TRUE</span></span> +<span><span class="op">)</span></span> +<span><span class="va">m_fomc_path_1</span> <span class="op"><-</span> <span class="fu"><a href="../../reference/mkinmod.html">mkinmod</a></span><span class="op">(</span></span> +<span> DMTA <span class="op">=</span> <span class="fu"><a href="../../reference/mkinmod.html">mkinsub</a></span><span class="op">(</span><span class="st">"FOMC"</span>, <span class="fu"><a href="https://rdrr.io/r/base/c.html" class="external-link">c</a></span><span class="op">(</span><span class="st">"M23"</span>, <span class="st">"M27"</span>, <span class="st">"M31"</span><span class="op">)</span><span class="op">)</span>,</span> +<span> M23 <span class="op">=</span> <span class="fu"><a href="../../reference/mkinmod.html">mkinsub</a></span><span class="op">(</span><span class="st">"SFO"</span><span class="op">)</span>,</span> +<span> M27 <span class="op">=</span> <span class="fu"><a href="../../reference/mkinmod.html">mkinsub</a></span><span class="op">(</span><span class="st">"SFO"</span><span class="op">)</span>,</span> +<span> M31 <span class="op">=</span> <span class="fu"><a href="../../reference/mkinmod.html">mkinsub</a></span><span class="op">(</span><span class="st">"SFO"</span>, <span class="st">"M27"</span>, sink <span class="op">=</span> <span class="cn">FALSE</span><span class="op">)</span>,</span> +<span> name <span class="op">=</span> <span class="st">"m_fomc_path"</span>, dll_dir <span class="op">=</span> <span class="st">"dmta_dlls"</span>,</span> +<span> unload <span class="op">=</span> <span class="cn">TRUE</span>, overwrite <span class="op">=</span> <span class="cn">TRUE</span>,</span> +<span> quiet <span class="op">=</span> <span class="cn">TRUE</span></span> +<span><span class="op">)</span></span> +<span><span class="va">m_dfop_path_1</span> <span class="op"><-</span> <span class="fu"><a href="../../reference/mkinmod.html">mkinmod</a></span><span class="op">(</span></span> +<span> DMTA <span class="op">=</span> <span class="fu"><a href="../../reference/mkinmod.html">mkinsub</a></span><span class="op">(</span><span class="st">"DFOP"</span>, <span class="fu"><a href="https://rdrr.io/r/base/c.html" class="external-link">c</a></span><span class="op">(</span><span class="st">"M23"</span>, <span class="st">"M27"</span>, <span class="st">"M31"</span><span class="op">)</span><span class="op">)</span>,</span> +<span> M23 <span class="op">=</span> <span class="fu"><a href="../../reference/mkinmod.html">mkinsub</a></span><span class="op">(</span><span class="st">"SFO"</span><span class="op">)</span>,</span> +<span> M27 <span class="op">=</span> <span class="fu"><a href="../../reference/mkinmod.html">mkinsub</a></span><span class="op">(</span><span class="st">"SFO"</span><span class="op">)</span>,</span> +<span> M31 <span class="op">=</span> <span class="fu"><a href="../../reference/mkinmod.html">mkinsub</a></span><span class="op">(</span><span class="st">"SFO"</span>, <span class="st">"M27"</span>, sink <span class="op">=</span> <span class="cn">FALSE</span><span class="op">)</span>,</span> +<span> name <span class="op">=</span> <span class="st">"m_dfop_path"</span>, dll_dir <span class="op">=</span> <span class="st">"dmta_dlls"</span>,</span> +<span> unload <span class="op">=</span> <span class="cn">TRUE</span>, overwrite <span class="op">=</span> <span class="cn">TRUE</span>,</span> +<span> quiet <span class="op">=</span> <span class="cn">TRUE</span></span> +<span><span class="op">)</span></span> +<span><span class="va">m_sforb_path_1</span> <span class="op"><-</span> <span class="fu"><a href="../../reference/mkinmod.html">mkinmod</a></span><span class="op">(</span></span> +<span> DMTA <span class="op">=</span> <span class="fu"><a href="../../reference/mkinmod.html">mkinsub</a></span><span class="op">(</span><span class="st">"SFORB"</span>, <span class="fu"><a href="https://rdrr.io/r/base/c.html" class="external-link">c</a></span><span class="op">(</span><span class="st">"M23"</span>, <span class="st">"M27"</span>, <span class="st">"M31"</span><span class="op">)</span><span class="op">)</span>,</span> +<span> M23 <span class="op">=</span> <span class="fu"><a href="../../reference/mkinmod.html">mkinsub</a></span><span class="op">(</span><span class="st">"SFO"</span><span class="op">)</span>,</span> +<span> M27 <span class="op">=</span> <span class="fu"><a href="../../reference/mkinmod.html">mkinsub</a></span><span class="op">(</span><span class="st">"SFO"</span><span class="op">)</span>,</span> +<span> M31 <span class="op">=</span> <span class="fu"><a href="../../reference/mkinmod.html">mkinsub</a></span><span class="op">(</span><span class="st">"SFO"</span>, <span class="st">"M27"</span>, sink <span class="op">=</span> <span class="cn">FALSE</span><span class="op">)</span>,</span> +<span> name <span class="op">=</span> <span class="st">"m_sforb_path"</span>, dll_dir <span class="op">=</span> <span class="st">"dmta_dlls"</span>,</span> +<span> unload <span class="op">=</span> <span class="cn">TRUE</span>, overwrite <span class="op">=</span> <span class="cn">TRUE</span>,</span> +<span> quiet <span class="op">=</span> <span class="cn">TRUE</span></span> +<span><span class="op">)</span></span> +<span><span class="va">m_hs_path_1</span> <span class="op"><-</span> <span class="fu"><a href="../../reference/mkinmod.html">mkinmod</a></span><span class="op">(</span></span> +<span> DMTA <span class="op">=</span> <span class="fu"><a href="../../reference/mkinmod.html">mkinsub</a></span><span class="op">(</span><span class="st">"HS"</span>, <span class="fu"><a href="https://rdrr.io/r/base/c.html" class="external-link">c</a></span><span class="op">(</span><span class="st">"M23"</span>, <span class="st">"M27"</span>, <span class="st">"M31"</span><span class="op">)</span><span class="op">)</span>,</span> +<span> M23 <span class="op">=</span> <span class="fu"><a href="../../reference/mkinmod.html">mkinsub</a></span><span class="op">(</span><span class="st">"SFO"</span><span class="op">)</span>,</span> +<span> M27 <span class="op">=</span> <span class="fu"><a href="../../reference/mkinmod.html">mkinsub</a></span><span class="op">(</span><span class="st">"SFO"</span><span class="op">)</span>,</span> +<span> M31 <span class="op">=</span> <span class="fu"><a href="../../reference/mkinmod.html">mkinsub</a></span><span class="op">(</span><span class="st">"SFO"</span>, <span class="st">"M27"</span>, sink <span class="op">=</span> <span class="cn">FALSE</span><span class="op">)</span>,</span> +<span> name <span class="op">=</span> <span class="st">"m_hs_path"</span>, dll_dir <span class="op">=</span> <span class="st">"dmta_dlls"</span>,</span> +<span> unload <span class="op">=</span> <span class="cn">TRUE</span>, overwrite <span class="op">=</span> <span class="cn">TRUE</span>,</span> +<span> quiet <span class="op">=</span> <span class="cn">TRUE</span></span> +<span><span class="op">)</span></span> +<span><span class="va">cl</span> <span class="op"><-</span> <span class="fu">start_cluster</span><span class="op">(</span><span class="va">n_cores</span><span class="op">)</span></span> +<span></span> +<span><span class="va">deg_mods_1</span> <span class="op"><-</span> <span class="fu"><a href="https://rdrr.io/r/base/list.html" class="external-link">list</a></span><span class="op">(</span></span> +<span> sfo_path_1 <span class="op">=</span> <span class="va">m_sfo_path_1</span>,</span> +<span> fomc_path_1 <span class="op">=</span> <span class="va">m_fomc_path_1</span>,</span> +<span> dfop_path_1 <span class="op">=</span> <span class="va">m_dfop_path_1</span>,</span> +<span> sforb_path_1 <span class="op">=</span> <span class="va">m_sforb_path_1</span>,</span> +<span> hs_path_1 <span class="op">=</span> <span class="va">m_hs_path_1</span><span class="op">)</span></span> +<span></span> +<span><span class="va">sep_1_const</span> <span class="op"><-</span> <span class="fu"><a href="../../reference/mmkin.html">mmkin</a></span><span class="op">(</span></span> +<span> <span class="va">deg_mods_1</span>,</span> +<span> <span class="va">dmta_ds</span>,</span> +<span> error_model <span class="op">=</span> <span class="st">"const"</span>,</span> +<span> quiet <span class="op">=</span> <span class="cn">TRUE</span><span class="op">)</span></span> +<span></span> +<span><span class="fu"><a href="../../reference/status.html">status</a></span><span class="op">(</span><span class="va">sep_1_const</span><span class="op">)</span> <span class="op">|></span> <span class="fu"><a href="https://rdrr.io/pkg/knitr/man/kable.html" class="external-link">kable</a></span><span class="op">(</span><span class="op">)</span></span></code></pre></div> +<table class="table"> +<thead><tr class="header"> +<th align="left"></th> +<th align="left">Calke</th> +<th align="left">Borstel</th> +<th align="left">Flaach</th> +<th align="left">BBA 2.2</th> +<th align="left">BBA 2.3</th> +<th align="left">Elliot</th> +</tr></thead> +<tbody> +<tr class="odd"> +<td align="left">sfo_path_1</td> +<td align="left">OK</td> +<td align="left">OK</td> +<td align="left">OK</td> +<td align="left">OK</td> +<td align="left">OK</td> +<td align="left">OK</td> +</tr> +<tr class="even"> +<td align="left">fomc_path_1</td> +<td align="left">OK</td> +<td align="left">OK</td> +<td align="left">OK</td> +<td align="left">OK</td> +<td align="left">OK</td> +<td align="left">OK</td> +</tr> +<tr class="odd"> +<td align="left">dfop_path_1</td> +<td align="left">OK</td> +<td align="left">OK</td> +<td align="left">C</td> +<td align="left">OK</td> +<td align="left">OK</td> +<td align="left">OK</td> +</tr> +<tr class="even"> +<td align="left">sforb_path_1</td> +<td align="left">OK</td> +<td align="left">OK</td> +<td align="left">C</td> +<td align="left">OK</td> +<td align="left">OK</td> +<td align="left">OK</td> +</tr> +<tr class="odd"> +<td align="left">hs_path_1</td> +<td align="left">C</td> +<td align="left">C</td> +<td align="left">C</td> +<td align="left">C</td> +<td align="left">C</td> +<td align="left">C</td> +</tr> +</tbody> +</table> +<p>All separate pathway fits with SFO or FOMC for the parent and +constant variance converged (status OK). Most fits with DFOP or SFORB +for the parent converged as well. The fits with HS for the parent did +not converge with default settings.</p> +<div class="sourceCode" id="cb5"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span><span class="va">sep_1_tc</span> <span class="op"><-</span> <span class="fu"><a href="https://rdrr.io/r/stats/update.html" class="external-link">update</a></span><span class="op">(</span><span class="va">sep_1_const</span>, error_model <span class="op">=</span> <span class="st">"tc"</span><span class="op">)</span></span> +<span><span class="fu"><a href="../../reference/status.html">status</a></span><span class="op">(</span><span class="va">sep_1_tc</span><span class="op">)</span> <span class="op">|></span> <span class="fu"><a href="https://rdrr.io/pkg/knitr/man/kable.html" class="external-link">kable</a></span><span class="op">(</span><span class="op">)</span></span></code></pre></div> +<table class="table"> +<thead><tr class="header"> +<th align="left"></th> +<th align="left">Calke</th> +<th align="left">Borstel</th> +<th align="left">Flaach</th> +<th align="left">BBA 2.2</th> +<th align="left">BBA 2.3</th> +<th align="left">Elliot</th> +</tr></thead> +<tbody> +<tr class="odd"> +<td align="left">sfo_path_1</td> +<td align="left">OK</td> +<td align="left">OK</td> +<td align="left">OK</td> +<td align="left">OK</td> +<td align="left">OK</td> +<td align="left">OK</td> +</tr> +<tr class="even"> +<td align="left">fomc_path_1</td> +<td align="left">OK</td> +<td align="left">OK</td> +<td align="left">C</td> +<td align="left">OK</td> +<td align="left">OK</td> +<td align="left">C</td> +</tr> +<tr class="odd"> +<td align="left">dfop_path_1</td> +<td align="left">OK</td> +<td align="left">C</td> +<td align="left">OK</td> +<td align="left">OK</td> +<td align="left">OK</td> +<td align="left">OK</td> +</tr> +<tr class="even"> +<td align="left">sforb_path_1</td> +<td align="left">OK</td> +<td align="left">C</td> +<td align="left">OK</td> +<td align="left">OK</td> +<td align="left">OK</td> +<td align="left">OK</td> +</tr> +<tr class="odd"> +<td align="left">hs_path_1</td> +<td align="left">C</td> +<td align="left">C</td> +<td align="left">C</td> +<td align="left">C</td> +<td align="left">C</td> +<td align="left">OK</td> +</tr> +</tbody> +</table> +<p>With the two-component error model, the set of fits with convergence +problems is slightly different, with convergence problems appearing for +different data sets when applying the DFOP and SFORB model and some +additional convergence problems when using the FOMC model for the +parent.</p> +</div> +<div class="section level2"> +<h2 id="hierarchichal-model-fits">Hierarchichal model fits<a class="anchor" aria-label="anchor" href="#hierarchichal-model-fits"></a> +</h2> +<p>The following code fits two sets of the corresponding hierarchical +models to the data, one assuming constant variance, and one assuming +two-component error.</p> +<div class="sourceCode" id="cb6"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span><span class="va">saem_1</span> <span class="op"><-</span> <span class="fu"><a href="../../reference/mhmkin.html">mhmkin</a></span><span class="op">(</span><span class="fu"><a href="https://rdrr.io/r/base/list.html" class="external-link">list</a></span><span class="op">(</span><span class="va">sep_1_const</span>, <span class="va">sep_1_tc</span><span class="op">)</span><span class="op">)</span></span></code></pre></div> +<p>The run time for these fits was around two hours on five year old +hardware. After a recent hardware upgrade these fits complete in less +than twenty minutes.</p> +<div class="sourceCode" id="cb7"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span><span class="fu"><a href="../../reference/status.html">status</a></span><span class="op">(</span><span class="va">saem_1</span><span class="op">)</span> <span class="op">|></span> <span class="fu"><a href="https://rdrr.io/pkg/knitr/man/kable.html" class="external-link">kable</a></span><span class="op">(</span><span class="op">)</span></span></code></pre></div> +<table class="table"> +<thead><tr class="header"> +<th align="left"></th> +<th align="left">const</th> +<th align="left">tc</th> +</tr></thead> +<tbody> +<tr class="odd"> +<td align="left">sfo_path_1</td> +<td align="left">OK</td> +<td align="left">OK</td> +</tr> +<tr class="even"> +<td align="left">fomc_path_1</td> +<td align="left">OK</td> +<td align="left">OK</td> +</tr> +<tr class="odd"> +<td align="left">dfop_path_1</td> +<td align="left">OK</td> +<td align="left">OK</td> +</tr> +<tr class="even"> +<td align="left">sforb_path_1</td> +<td align="left">OK</td> +<td align="left">OK</td> +</tr> +<tr class="odd"> +<td align="left">hs_path_1</td> +<td align="left">OK</td> +<td align="left">OK</td> +</tr> +</tbody> +</table> +<p>According to the <code>status</code> function, all fits terminated +successfully.</p> +<div class="sourceCode" id="cb8"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span><span class="fu"><a href="https://rdrr.io/r/stats/anova.html" class="external-link">anova</a></span><span class="op">(</span><span class="va">saem_1</span><span class="op">)</span> <span class="op">|></span> <span class="fu"><a href="https://rdrr.io/pkg/knitr/man/kable.html" class="external-link">kable</a></span><span class="op">(</span>digits <span class="op">=</span> <span class="fl">1</span><span class="op">)</span></span></code></pre></div> +<pre><code>Warning in FUN(X[[i]], ...): Could not obtain log likelihood with 'is' method +for sforb_path_1 const</code></pre> +<table class="table"> +<thead><tr class="header"> +<th align="left"></th> +<th align="right">npar</th> +<th align="right">AIC</th> +<th align="right">BIC</th> +<th align="right">Lik</th> +</tr></thead> +<tbody> +<tr class="odd"> +<td align="left">sfo_path_1 const</td> +<td align="right">17</td> +<td align="right">2291.8</td> +<td align="right">2288.3</td> +<td align="right">-1128.9</td> +</tr> +<tr class="even"> +<td align="left">sfo_path_1 tc</td> +<td align="right">18</td> +<td align="right">2276.3</td> +<td align="right">2272.5</td> +<td align="right">-1120.1</td> +</tr> +<tr class="odd"> +<td align="left">fomc_path_1 const</td> +<td align="right">19</td> +<td align="right">2099.0</td> +<td align="right">2095.0</td> +<td align="right">-1030.5</td> +</tr> +<tr class="even"> +<td align="left">fomc_path_1 tc</td> +<td align="right">20</td> +<td align="right">1939.6</td> +<td align="right">1935.5</td> +<td align="right">-949.8</td> +</tr> +<tr class="odd"> +<td align="left">dfop_path_1 const</td> +<td align="right">21</td> +<td align="right">2038.8</td> +<td align="right">2034.4</td> +<td align="right">-998.4</td> +</tr> +<tr class="even"> +<td align="left">hs_path_1 const</td> +<td align="right">21</td> +<td align="right">2024.2</td> +<td align="right">2019.8</td> +<td align="right">-991.1</td> +</tr> +<tr class="odd"> +<td align="left">dfop_path_1 tc</td> +<td align="right">22</td> +<td align="right">1879.8</td> +<td align="right">1875.2</td> +<td align="right">-917.9</td> +</tr> +<tr class="even"> +<td align="left">sforb_path_1 tc</td> +<td align="right">22</td> +<td align="right">1832.9</td> +<td align="right">1828.3</td> +<td align="right">-894.4</td> +</tr> +<tr class="odd"> +<td align="left">hs_path_1 tc</td> +<td align="right">22</td> +<td align="right">1831.4</td> +<td align="right">1826.8</td> +<td align="right">-893.7</td> +</tr> +</tbody> +</table> +<p>When the goodness-of-fit of the models is compared, a warning is +obtained, indicating that the likelihood of the pathway fit with SFORB +for the parent compound and constant variance could not be calculated +with importance sampling (method ‘is’). As this is the default method on +which all AIC and BIC comparisons are based, this variant is not +included in the model comparison table. Comparing the goodness-of-fit of +the remaining models, HS model model with two-component error provides +the best fit. However, for batch experiments performed with constant +conditions such as the experiments evaluated here, there is no reason to +assume a discontinuity, so the SFORB model is preferable from a +mechanistic viewpoint. In addition, the information criteria AIC and BIC +are very similar for HS and SFORB. Therefore, the SFORB model is +selected here for further refinements.</p> +<div class="section level3"> +<h3 id="parameter-identifiability-based-on-the-fisher-information-matrix">Parameter identifiability based on the Fisher Information +Matrix<a class="anchor" aria-label="anchor" href="#parameter-identifiability-based-on-the-fisher-information-matrix"></a> +</h3> +<p>Using the <code>illparms</code> function, ill-defined statistical +model parameters such as standard deviations of the degradation +parameters in the population and error model parameters can be +found.</p> +<div class="sourceCode" id="cb10"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span><span class="fu"><a href="../../reference/illparms.html">illparms</a></span><span class="op">(</span><span class="va">saem_1</span><span class="op">)</span> <span class="op">|></span> <span class="fu"><a href="https://rdrr.io/pkg/knitr/man/kable.html" class="external-link">kable</a></span><span class="op">(</span><span class="op">)</span></span></code></pre></div> +<table class="table"> +<thead><tr class="header"> +<th align="left"></th> +<th align="left">const</th> +<th align="left">tc</th> +</tr></thead> +<tbody> +<tr class="odd"> +<td align="left">sfo_path_1</td> +<td align="left"></td> +<td align="left">sd(DMTA_0)</td> +</tr> +<tr class="even"> +<td align="left">fomc_path_1</td> +<td align="left"></td> +<td align="left">sd(DMTA_0)</td> +</tr> +<tr class="odd"> +<td align="left">dfop_path_1</td> +<td align="left"></td> +<td align="left"></td> +</tr> +<tr class="even"> +<td align="left">sforb_path_1</td> +<td align="left"></td> +<td align="left">sd(log_k_DMTA_bound_free)</td> +</tr> +<tr class="odd"> +<td align="left">hs_path_1</td> +<td align="left"></td> +<td align="left">sd(log_tb)</td> +</tr> +</tbody> +</table> +<p>When using constant variance, no ill-defined variance parameters are +identified with the <code>illparms</code> function in any of the +degradation models. When using the two-component error model, there is +one ill-defined variance parameter in all variants except for the +variant using DFOP for the parent compound.</p> +<p>For the selected combination of the SFORB pathway model with +two-component error, the random effect for the rate constant from +reversibly bound DMTA to the free DMTA (<code>k_DMTA_bound_free</code>) +is not well-defined. Therefore, the fit is updated without assuming a +random effect for this parameter.</p> +<div class="sourceCode" id="cb11"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span><span class="va">saem_sforb_path_1_tc_reduced</span> <span class="op"><-</span> <span class="fu"><a href="https://rdrr.io/r/stats/update.html" class="external-link">update</a></span><span class="op">(</span><span class="va">saem_1</span><span class="op">[[</span><span class="st">"sforb_path_1"</span>, <span class="st">"tc"</span><span class="op">]</span><span class="op">]</span>,</span> +<span> no_random_effect <span class="op">=</span> <span class="st">"log_k_DMTA_bound_free"</span><span class="op">)</span></span> +<span><span class="fu"><a href="../../reference/illparms.html">illparms</a></span><span class="op">(</span><span class="va">saem_sforb_path_1_tc_reduced</span><span class="op">)</span></span></code></pre></div> +<p>As expected, no ill-defined parameters remain. The model comparison +below shows that the reduced model is preferable.</p> +<div class="sourceCode" id="cb12"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span><span class="fu"><a href="https://rdrr.io/r/stats/anova.html" class="external-link">anova</a></span><span class="op">(</span><span class="va">saem_1</span><span class="op">[[</span><span class="st">"sforb_path_1"</span>, <span class="st">"tc"</span><span class="op">]</span><span class="op">]</span>, <span class="va">saem_sforb_path_1_tc_reduced</span><span class="op">)</span> <span class="op">|></span> <span class="fu"><a href="https://rdrr.io/pkg/knitr/man/kable.html" class="external-link">kable</a></span><span class="op">(</span>digits <span class="op">=</span> <span class="fl">1</span><span class="op">)</span></span></code></pre></div> +<table class="table"> +<thead><tr class="header"> +<th align="left"></th> +<th align="right">npar</th> +<th align="right">AIC</th> +<th align="right">BIC</th> +<th align="right">Lik</th> +</tr></thead> +<tbody> +<tr class="odd"> +<td align="left">saem_sforb_path_1_tc_reduced</td> +<td align="right">21</td> +<td align="right">1830.3</td> +<td align="right">1825.9</td> +<td align="right">-894.2</td> +</tr> +<tr class="even"> +<td align="left">saem_1[[“sforb_path_1”, “tc”]]</td> +<td align="right">22</td> +<td align="right">1832.9</td> +<td align="right">1828.3</td> +<td align="right">-894.4</td> +</tr> +</tbody> +</table> +<p>The convergence plot of the refined fit is shown below.</p> +<div class="sourceCode" id="cb13"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span><span class="fu"><a href="https://rdrr.io/r/base/plot.html" class="external-link">plot</a></span><span class="op">(</span><span class="va">saem_sforb_path_1_tc_reduced</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></span></code></pre></div> +<p><img src="2022_dmta_pathway_files/figure-html/saem-sforb-path-1-tc-reduced-convergence-1.png" width="700" style="display: block; margin: auto;"></p> +<p>For some parameters, for example for <code>f_DMTA_ilr_1</code> and +<code>f_DMTA_ilr_2</code>, i.e. for two of the parameters determining +the formation fractions of the parallel formation of the three +metabolites, some movement of the parameters is still visible in the +second phase of the algorithm. However, the amplitude of this movement +is in the range of the amplitude towards the end of the first phase. +Therefore, it is likely that an increase in iterations would not improve +the parameter estimates very much, and it is proposed that the fit is +acceptable. No numeric convergence criterion is implemented in +saemix.</p> +</div> +<div class="section level3"> +<h3 id="alternative-check-of-parameter-identifiability">Alternative check of parameter identifiability<a class="anchor" aria-label="anchor" href="#alternative-check-of-parameter-identifiability"></a> +</h3> +<p>As an alternative check of parameter identifiability <span class="citation">(Duchesne et al. 2021)</span>, multistart runs were +performed on the basis of the refined fit shown above.</p> +<div class="sourceCode" id="cb14"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span><span class="va">saem_sforb_path_1_tc_reduced_multi</span> <span class="op"><-</span> <span class="fu"><a href="../../reference/multistart.html">multistart</a></span><span class="op">(</span><span class="va">saem_sforb_path_1_tc_reduced</span>,</span> +<span> n <span class="op">=</span> <span class="fl">32</span>, cores <span class="op">=</span> <span class="fl">10</span><span class="op">)</span></span></code></pre></div> +<div class="sourceCode" id="cb15"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span><span class="fu"><a href="https://rdrr.io/r/base/print.html" class="external-link">print</a></span><span class="op">(</span><span class="va">saem_sforb_path_1_tc_reduced_multi</span><span class="op">)</span></span></code></pre></div> +<pre><code><multistart> object with 32 fits: + E OK +15 17 +OK: Fit terminated successfully +E: Error</code></pre> +<p>Out of the 32 fits that were initiated, only 17 terminated without an +error. The reason for this is that the wide variation of starting +parameters in combination with the parameter variation that is used in +the SAEM algorithm leads to parameter combinations for the degradation +model that the numerical integration routine cannot cope with. Because +of this variation of initial parameters, some of the model fits take up +to two times more time than the original fit.</p> +<div class="sourceCode" id="cb17"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span><span class="fu"><a href="https://rdrr.io/r/graphics/par.html" class="external-link">par</a></span><span class="op">(</span>mar <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/c.html" class="external-link">c</a></span><span class="op">(</span><span class="fl">12.1</span>, <span class="fl">4.1</span>, <span class="fl">2.1</span>, <span class="fl">2.1</span><span class="op">)</span><span class="op">)</span></span> +<span><span class="fu"><a href="../../reference/parplot.html">parplot</a></span><span class="op">(</span><span class="va">saem_sforb_path_1_tc_reduced_multi</span>, ylim <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/c.html" class="external-link">c</a></span><span class="op">(</span><span class="fl">0.5</span>, <span class="fl">2</span><span class="op">)</span>, las <span class="op">=</span> <span class="fl">2</span><span class="op">)</span></span></code></pre></div> +<div class="figure" style="text-align: center"> +<img src="2022_dmta_pathway_files/figure-html/unnamed-chunk-2-1.png" alt="Parameter boxplots for the multistart runs that succeeded" width="960"><p class="caption"> +Parameter boxplots for the multistart runs that succeeded +</p> +</div> +<p>However, visual analysis of the boxplot of the parameters obtained in +the successful fits confirms that the results are sufficiently +independent of the starting parameters, and there are no remaining +ill-defined parameters.</p> +</div> +</div> +<div class="section level2"> +<h2 id="plots-of-selected-fits">Plots of selected fits<a class="anchor" aria-label="anchor" href="#plots-of-selected-fits"></a> +</h2> +<p>The SFORB pathway fits with full and reduced parameter distribution +model are shown below.</p> +<div class="sourceCode" id="cb18"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span><span class="fu"><a href="https://rdrr.io/r/base/plot.html" class="external-link">plot</a></span><span class="op">(</span><span class="va">saem_1</span><span class="op">[[</span><span class="st">"sforb_path_1"</span>, <span class="st">"tc"</span><span class="op">]</span><span class="op">]</span><span class="op">)</span></span></code></pre></div> +<div class="figure" style="text-align: center"> +<img src="2022_dmta_pathway_files/figure-html/unnamed-chunk-3-1.png" alt="SFORB pathway fit with two-component error" width="700"><p class="caption"> +SFORB pathway fit with two-component error +</p> +</div> +<div class="sourceCode" id="cb19"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span><span class="fu"><a href="https://rdrr.io/r/base/plot.html" class="external-link">plot</a></span><span class="op">(</span><span class="va">saem_sforb_path_1_tc_reduced</span><span class="op">)</span></span></code></pre></div> +<div class="figure" style="text-align: center"> +<img src="2022_dmta_pathway_files/figure-html/unnamed-chunk-4-1.png" alt="SFORB pathway fit with two-component error, reduced parameter model" width="700"><p class="caption"> +SFORB pathway fit with two-component error, reduced parameter model +</p> +</div> +<p>Plots of the remaining fits and listings for all successful fits are +shown in the Appendix.</p> +<div class="sourceCode" id="cb20"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span><span class="fu"><a href="https://rdrr.io/r/parallel/makeCluster.html" class="external-link">stopCluster</a></span><span class="op">(</span><span class="va">cl</span><span class="op">)</span></span></code></pre></div> +</div> +<div class="section level2"> +<h2 id="conclusions">Conclusions<a class="anchor" aria-label="anchor" href="#conclusions"></a> +</h2> +<p>Pathway fits with SFO, FOMC, DFOP, SFORB and HS models for the parent +compound could be successfully performed.</p> +</div> +<div class="section level2"> +<h2 id="acknowledgements">Acknowledgements<a class="anchor" aria-label="anchor" href="#acknowledgements"></a> +</h2> +<p>The helpful comments by Janina Wöltjen of the German Environment +Agency on earlier versions of this document are gratefully +acknowledged.</p> +</div> +<div class="section level2"> +<h2 id="references">References<a class="anchor" aria-label="anchor" href="#references"></a> +</h2> +<div id="refs" class="references csl-bib-body hanging-indent"> +<div id="ref-duchesne_2021" class="csl-entry"> +Duchesne, Ronan, Anissa Guillemin, Olivier Gandrillon, and Fabien +Crauste. 2021. <span>“Practical Identifiability in the Frame of +Nonlinear Mixed Effects Models: The Example of the in Vitro +Erythropoiesis.”</span> <em>BMC Bioinformatics</em> 22 (478). <a href="https://doi.org/10.1186/s12859-021-04373-4" class="external-link">https://doi.org/10.1186/s12859-021-04373-4</a>. +</div> +<div id="ref-ranke2021" class="csl-entry"> +Ranke, Johannes, Janina Wöltjen, Jana Schmidt, and Emmanuelle Comets. +2021. <span>“Taking Kinetic Evaluations of Degradation Data to the Next +Level with Nonlinear Mixed-Effects Models.”</span> <em>Environments</em> +8 (8). <a href="https://doi.org/10.3390/environments8080071" class="external-link">https://doi.org/10.3390/environments8080071</a>. +</div> +</div> +</div> +<div class="section level2"> +<h2 id="appendix">Appendix<a class="anchor" aria-label="anchor" href="#appendix"></a> +</h2> +<div class="section level3"> +<h3 id="plots-of-hierarchical-fits-not-selected-for-refinement">Plots of hierarchical fits not selected for refinement<a class="anchor" aria-label="anchor" href="#plots-of-hierarchical-fits-not-selected-for-refinement"></a> +</h3> +<div class="sourceCode" id="cb21"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span><span class="fu"><a href="https://rdrr.io/r/base/plot.html" class="external-link">plot</a></span><span class="op">(</span><span class="va">saem_1</span><span class="op">[[</span><span class="st">"sfo_path_1"</span>, <span class="st">"tc"</span><span class="op">]</span><span class="op">]</span><span class="op">)</span></span></code></pre></div> +<div class="figure" style="text-align: center"> +<img src="2022_dmta_pathway_files/figure-html/unnamed-chunk-6-1.png" alt="SFO pathway fit with two-component error" width="700"><p class="caption"> +SFO pathway fit with two-component error +</p> +</div> +<div class="sourceCode" id="cb22"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span><span class="fu"><a href="https://rdrr.io/r/base/plot.html" class="external-link">plot</a></span><span class="op">(</span><span class="va">saem_1</span><span class="op">[[</span><span class="st">"fomc_path_1"</span>, <span class="st">"tc"</span><span class="op">]</span><span class="op">]</span><span class="op">)</span></span></code></pre></div> +<div class="figure" style="text-align: center"> +<img src="2022_dmta_pathway_files/figure-html/unnamed-chunk-7-1.png" alt="FOMC pathway fit with two-component error" width="700"><p class="caption"> +FOMC pathway fit with two-component error +</p> +</div> +<div class="sourceCode" id="cb23"><pre class="downlit sourceCode r"> +<code class="sourceCode R"><span><span class="fu"><a href="https://rdrr.io/r/base/plot.html" class="external-link">plot</a></span><span class="op">(</span><span class="va">saem_1</span><span class="op">[[</span><span class="st">"sforb_path_1"</span>, <span class="st">"tc"</span><span class="op">]</span><span class="op">]</span><span class="op">)</span></span></code></pre></div> +<div class="figure" style="text-align: center"> +<img src="2022_dmta_pathway_files/figure-html/unnamed-chunk-8-1.png" alt="HS pathway fit with two-component error" width="700"><p class="caption"> +HS pathway fit with two-component error +</p> +</div> +</div> +<div class="section level3"> +<h3 id="hierarchical-model-fit-listings">Hierarchical model fit listings<a class="anchor" aria-label="anchor" href="#hierarchical-model-fit-listings"></a> +</h3> +<div class="section level4"> +<h4 id="fits-with-random-effects-for-all-degradation-parameters">Fits with random effects for all degradation parameters<a class="anchor" aria-label="anchor" href="#fits-with-random-effects-for-all-degradation-parameters"></a> +</h4> + +</div> +<div class="section level4"> +<h4 id="improved-fit-of-the-sforb-pathway-model-with-two-component-error">Improved fit of the SFORB pathway model with two-component +error<a class="anchor" aria-label="anchor" href="#improved-fit-of-the-sforb-pathway-model-with-two-component-error"></a> +</h4> + +</div> +</div> +<div class="section level3"> +<h3 id="session-info">Session info<a class="anchor" aria-label="anchor" href="#session-info"></a> +</h3> +<pre><code>R version 4.2.3 (2023-03-15) +Platform: x86_64-pc-linux-gnu (64-bit) +Running under: Debian GNU/Linux 12 (bookworm) + +Matrix products: default +BLAS: /usr/lib/x86_64-linux-gnu/openblas-serial/libblas.so.3 +LAPACK: /usr/lib/x86_64-linux-gnu/openblas-serial/libopenblas-r0.3.21.so + +locale: + [1] LC_CTYPE=de_DE.UTF-8 LC_NUMERIC=C + [3] LC_TIME=de_DE.UTF-8 LC_COLLATE=de_DE.UTF-8 + [5] LC_MONETARY=de_DE.UTF-8 LC_MESSAGES=de_DE.UTF-8 + [7] LC_PAPER=de_DE.UTF-8 LC_NAME=C + [9] LC_ADDRESS=C LC_TELEPHONE=C +[11] LC_MEASUREMENT=de_DE.UTF-8 LC_IDENTIFICATION=C + +attached base packages: +[1] parallel stats graphics grDevices utils datasets methods +[8] base + +other attached packages: +[1] saemix_3.2 npde_3.3 knitr_1.42 mkin_1.2.3 + +loaded via a namespace (and not attached): + [1] deSolve_1.35 zoo_1.8-12 tidyselect_1.2.0 xfun_0.38 + [5] bslib_0.4.2 purrr_1.0.1 lattice_0.21-8 colorspace_2.1-0 + [9] vctrs_0.6.1 generics_0.1.3 htmltools_0.5.5 yaml_2.3.7 +[13] utf8_1.2.3 rlang_1.1.0 pkgbuild_1.4.0 pkgdown_2.0.7 +[17] jquerylib_0.1.4 pillar_1.9.0 glue_1.6.2 DBI_1.1.3 +[21] lifecycle_1.0.3 stringr_1.5.0 munsell_0.5.0 gtable_0.3.3 +[25] ragg_1.2.5 codetools_0.2-19 memoise_2.0.1 evaluate_0.20 +[29] inline_0.3.19 callr_3.7.3 fastmap_1.1.1 ps_1.7.4 +[33] lmtest_0.9-40 fansi_1.0.4 highr_0.10 scales_1.2.1 +[37] cachem_1.0.7 desc_1.4.2 jsonlite_1.8.4 systemfonts_1.0.4 +[41] fs_1.6.1 textshaping_0.3.6 gridExtra_2.3 ggplot2_3.4.2 +[45] digest_0.6.31 stringi_1.7.12 processx_3.8.0 dplyr_1.1.1 +[49] grid_4.2.3 rprojroot_2.0.3 cli_3.6.1 tools_4.2.3 +[53] magrittr_2.0.3 sass_0.4.5 tibble_3.2.1 crayon_1.5.2 +[57] pkgconfig_2.0.3 prettyunits_1.1.1 rmarkdown_2.21 R6_2.5.1 +[61] mclust_6.0.0 nlme_3.1-162 compiler_4.2.3 </code></pre> +</div> +<div class="section level3"> +<h3 id="hardware-info">Hardware info<a class="anchor" aria-label="anchor" href="#hardware-info"></a> +</h3> +<pre><code>CPU model: AMD Ryzen 9 7950X 16-Core Processor</code></pre> +<pre><code>MemTotal: 64936316 kB</code></pre> +</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></p> +<p>Developed by Johannes Ranke.</p> +</div> + +<div class="pkgdown"> + <p></p> +<p>Site built with <a href="https://pkgdown.r-lib.org/" class="external-link">pkgdown</a> 2.0.7.</p> +</div> + + </footer> +</div> + + + + + + + </body> +</html> |