From 40b78bed232798ecbeb72759cdf8d400ea35b31f Mon Sep 17 00:00:00 2001 From: Johannes Ranke Date: Fri, 23 Jul 2021 13:55:34 +0200 Subject: Some example evaluations of dimethenamid data Evaluations with nlme, saemix and nlmixr are included --- .../figure-html/f_parent_mkin_dfop_const-1.png | Bin 0 -> 60693 bytes .../figure-html/f_parent_mkin_dfop_const_test-1.png | Bin 0 -> 60929 bytes .../figure-html/f_parent_mkin_dfop_tc_test-1.png | Bin 0 -> 62234 bytes .../figure-html/f_parent_mkin_sfo_const-1.png | Bin 0 -> 58445 bytes .../figure-html/f_parent_nlmixr_saem_dfop_const-1.png | Bin 0 -> 92167 bytes .../figure-html/f_parent_nlmixr_saem_dfop_tc-1.png | Bin 0 -> 76934 bytes .../figure-html/f_parent_nlmixr_saem_sfo_const-1.png | Bin 0 -> 62426 bytes .../figure-html/f_parent_nlmixr_saem_sfo_tc-1.png | Bin 0 -> 70230 bytes .../figure-html/f_parent_saemix_dfop_const-1.png | Bin 0 -> 41208 bytes .../f_parent_saemix_dfop_const_moreiter-1.png | Bin 0 -> 39456 bytes 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OK * checking if there is a namespace ... OK * checking for executable files ... OK -* checking for hidden files and directories ... NOTE -Found the following hidden files and directories: - vignettes/web_only/.build.timestamp -These were most likely included in error. See section ‘Package -structure’ in the ‘Writing R Extensions’ manual. - -CRAN-pack does not know about - vignettes/web_only/.build.timestamp +* checking for hidden files and directories ... OK * checking for portable file names ... OK * checking for sufficient/correct file permissions ... OK * checking serialization versions ... OK @@ -75,9 +68,5 @@ CRAN-pack does not know about * checking for detritus in the temp directory ... OK * DONE -Status: 1 NOTE -See - ‘/home/jranke/git/mkin/mkin.Rcheck/00check.log’ -for details. - +Status: OK 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 @@ mkin - 1.0.5 + 1.1.0 diff --git a/docs/dev/articles/index.html b/docs/dev/articles/index.html index 99ce950b..c0338df8 100644 --- a/docs/dev/articles/index.html +++ b/docs/dev/articles/index.html @@ -71,7 +71,7 @@ mkin - 1.0.5 + 1.1.0 diff --git a/docs/dev/articles/web_only/dimethenamid_2018.html b/docs/dev/articles/web_only/dimethenamid_2018.html index 9a6d8388..b35d8210 100644 --- a/docs/dev/articles/web_only/dimethenamid_2018.html +++ b/docs/dev/articles/web_only/dimethenamid_2018.html @@ -32,7 +32,7 @@ mkin - 1.0.5 + 1.1.0 @@ -95,13 +95,13 @@ -
+

Example evaluations of the dimethenamid data from 2018

Johannes Ranke

-

Last change 4 August 2021, built on 04 Aug 2021

+

Last change 16 September 2021, built on 16 Sep 2021

Source: vignettes/web_only/dimethenamid_2018.rmd @@ -110,31 +110,28 @@ -

Wissenschaftlicher Berater, Kronacher Str. 12, 79639 Grenzach-Wyhlen, Germany
Privatdozent at the University of Bremen

+

Wissenschaftlicher Berater, Kronacher Str. 12, 79639 Grenzach-Wyhlen, Germany

Introduction

-

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.

+

During the preparation of the journal article on nonlinear mixed-effects models in degradation kinetics (Ranke et al. 2021) 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.

This vignette is an attempt to satisfy this need.

Data

-

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 (EFSA 2018) were transcribed from the risk assessment report (Rapporteur Member State Germany, Co-Rapporteur Member State Bulgaria 2018) which can be downloaded from the EFSA register of questions.

+

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 (EFSA 2018) were transcribed from the risk assessment report (Rapporteur Member State Germany, Co-Rapporteur Member State Bulgaria 2018) which can be downloaded from the Open EFSA repository https://open.efsa.europa.eu/study-inventory/EFSA-Q-2014-00716.

The data are available in the mkin package. 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.

Also, datasets observed in the same soil are merged, resulting in dimethenamid (DMTA) data from six soils.

 library(mkin)
-dmta_ds <- lapply(1:8, function(i) {
+dmta_ds <- lapply(1:7, function(i) {
   ds_i <- dimethenamid_2018$ds[[i]]$data
   ds_i[ds_i$name == "DMTAP", "name"] <-  "DMTA"
   ds_i$time <- ds_i$time * dimethenamid_2018$f_time_norm[i]
   ds_i
 })
 names(dmta_ds) <- sapply(dimethenamid_2018$ds, function(ds) ds$title)
-dmta_ds[["Borstel"]] <- rbind(dmta_ds[["Borstel 1"]], dmta_ds[["Borstel 2"]])
-dmta_ds[["Borstel 1"]] <- NULL
-dmta_ds[["Borstel 2"]] <- NULL
 dmta_ds[["Elliot"]] <- rbind(dmta_ds[["Elliot 1"]], dmta_ds[["Elliot 2"]])
 dmta_ds[["Elliot 1"]] <- NULL
 dmta_ds[["Elliot 2"]] <- NULL
@@ -154,20 +151,20 @@ error_model = "tc", quiet = TRUE)

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):

-plot(mixed(f_parent_mkin_const["SFO", ]))
+plot(mixed(f_parent_mkin_const["SFO", ]))

Using biexponential decline (DFOP) results in a slightly more random scatter of the residuals:

-plot(mixed(f_parent_mkin_const["DFOP", ]))
+plot(mixed(f_parent_mkin_const["DFOP", ]))

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:

-plot(mixed(f_parent_mkin_const["DFOP", ]), test_log_parms = TRUE)
+plot(mixed(f_parent_mkin_const["DFOP", ]), test_log_parms = TRUE)

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).

The remaining trend of the residuals to be higher for higher predicted residues is reduced by using the two-component error model:

-plot(mixed(f_parent_mkin_tc["DFOP", ]), test_log_parms = TRUE)
+plot(mixed(f_parent_mkin_tc["DFOP", ]), test_log_parms = TRUE)

@@ -177,175 +174,184 @@

nlme

-

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.

+

The nlme package was the first R extension providing facilities to fit nonlinear mixed-effects models. We 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.

 library(nlme)
 f_parent_nlme_sfo_const <- nlme(f_parent_mkin_const["SFO", ])
-#f_parent_nlme_dfop_const <- nlme(f_parent_mkin_const["DFOP", ])
-# maxIter = 50 reached
+# f_parent_nlme_dfop_const <- nlme(f_parent_mkin_const["DFOP", ])
 f_parent_nlme_sfo_tc <- nlme(f_parent_mkin_tc["SFO", ])
 f_parent_nlme_dfop_tc <- nlme(f_parent_mkin_tc["DFOP", ])
-

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.

+

Note that a certain degree of overparameterisation is also indicated by a warning obtained when fitting DFOP with the two-component error model (‘false convergence’ in the ‘LME step’ in iteration 3). However, as this warning does not occur in later iterations, and specifically not in the last of the 6 iterations, we can ignore this warning.

+

The model comparison function of the nlme package can directly be applied to these fits showing 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.

-f_parent_nlme_sfo_const_logchol <- nlme(f_parent_mkin_const["SFO", ],
-  random = pdLogChol(list(DMTA_0 ~ 1, log_k_DMTA ~ 1)))
-anova(f_parent_nlme_sfo_const, f_parent_nlme_sfo_const_logchol) # not better
-#f_parent_nlme_dfop_tc_logchol <- update(f_parent_nlme_dfop_tc,
-#  random = pdLogChol(list(DMTA_0 ~ 1, log_k1 ~ 1, log_k2 ~ 1, g_qlogis ~ 1)))
-# using log Cholesky parameterisation for random effects (nlme default) does
-# not converge here and gives lots of warnings about the LME step not converging
-

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.

-
 anova(
   f_parent_nlme_sfo_const, f_parent_nlme_sfo_tc, f_parent_nlme_dfop_tc
 )
                        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
+f_parent_nlme_sfo_const 1 5 796.60 811.82 -393.30 +f_parent_nlme_sfo_tc 2 6 798.60 816.86 -393.30 1 vs 2 0.00 0.998 +f_parent_nlme_dfop_tc 3 10 671.91 702.34 -325.96 2 vs 3 134.69 <.0001 +

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.

+
+f_parent_nlme_sfo_const_logchol <- nlme(f_parent_mkin_const["SFO", ],
+  random = nlme::pdLogChol(list(DMTA_0 ~ 1, log_k_DMTA ~ 1)))
+anova(f_parent_nlme_sfo_const, f_parent_nlme_sfo_const_logchol)
+f_parent_nlme_sfo_tc_logchol <- nlme(f_parent_mkin_tc["SFO", ],
+  random = nlme::pdLogChol(list(DMTA_0 ~ 1, log_k_DMTA ~ 1)))
+anova(f_parent_nlme_sfo_tc, f_parent_nlme_sfo_tc_logchol)
+f_parent_nlme_dfop_tc_logchol <- nlme(f_parent_mkin_const["DFOP", ],
+  random = nlme::pdLogChol(list(DMTA_0 ~ 1, log_k1 ~ 1, log_k2 ~ 1, g_qlogis ~ 1)))
+anova(f_parent_nlme_dfop_tc, f_parent_nlme_dfop_tc_logchol)
+

While the SFO variants converge fast, the additional parameters introduced by this lead to convergence warnings for the DFOP model. The model comparison clearly show that adding correlations between random effects does not improve the fits.

The selected model (DFOP with two-component error) fitted to the data assuming no correlations between random effects is shown below.

-plot(f_parent_nlme_dfop_tc)
+plot(f_parent_nlme_dfop_tc)

saemix

-

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.

-

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.

-

The convergence plot for the SFO model using constant variance is shown below.

+

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 conveniently performed using an interface to the saemix package available in current development versions of the mkin package.

+

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. As we will compare the SAEM implementation of saemix to the results obtained using the nlmixr package later, we define control settings that work well for all the parent data fits shown in this vignette.

 library(saemix)
-f_parent_saemix_sfo_const <- mkin::saem(f_parent_mkin_const["SFO", ], quiet = TRUE,
-  transformations = "saemix")
+saemix_control <- saemixControl(nbiter.saemix = c(800, 300), nb.chains = 15,
+    print = FALSE, save = FALSE, save.graphs = FALSE, displayProgress = FALSE)
+

The convergence plot for the SFO model using constant variance is shown below.

+
+f_parent_saemix_sfo_const <- mkin::saem(f_parent_mkin_const["SFO", ], quiet = TRUE,
+  control = saemix_control, transformations = "saemix")
 plot(f_parent_saemix_sfo_const$so, plot.type = "convergence")

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.

-
+
 f_parent_saemix_sfo_tc <- mkin::saem(f_parent_mkin_tc["SFO", ], quiet = TRUE,
-  transformations = "saemix")
+  control = saemix_control, transformations = "saemix")
 plot(f_parent_saemix_sfo_tc$so, plot.type = "convergence")

 

 
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.

-
+
 f_parent_saemix_dfop_const <- mkin::saem(f_parent_mkin_const["DFOP", ], quiet = TRUE,
-  control = saemixControl(nbiter.saemix = c(800, 200), print = FALSE,
-    save = FALSE, save.graphs = FALSE, displayProgress = FALSE),
-  transformations = "saemix")
+  control = saemix_control, transformations = "saemix")
 plot(f_parent_saemix_dfop_const$so, plot.type = "convergence")

 

-
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.

-
-f_parent_saemix_dfop_tc_moreiter <- mkin::saem(f_parent_mkin_tc["DFOP", ], quiet = TRUE,
-  control = saemixControl(nbiter.saemix = c(800, 200), print = FALSE,
-    save = FALSE, save.graphs = FALSE, displayProgress = FALSE),
-  transformations = "saemix")
-plot(f_parent_saemix_dfop_tc_moreiter$so, plot.type = "convergence")

-

-
The four combinations can be compared using the model comparison function from the saemix package:

+
The same applies in 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.

 
-compare.saemix(f_parent_saemix_sfo_const$so, f_parent_saemix_sfo_tc$so,
-  f_parent_saemix_dfop_const$so, f_parent_saemix_dfop_tc_moreiter$so)

+f_parent_saemix_dfop_tc <- mkin::saem(f_parent_mkin_tc["DFOP", ], quiet = TRUE,
+  control = saemix_control, transformations = "saemix")
+plot(f_parent_saemix_dfop_tc$so, plot.type = "convergence")

+
 The four combinations and including the variations of the DFOP/tc combination can be compared using the model comparison function from the saemix package:

+
+compare.saemix(
+  f_parent_saemix_sfo_const$so,
+  f_parent_saemix_sfo_tc$so,
+  f_parent_saemix_dfop_const$so,
+  f_parent_saemix_dfop_tc$so)

 
Likelihoods calculated by importance sampling

 
     AIC    BIC
-1 818.37 817.33
-2 820.38 819.14
-3 725.91 724.04
-4 683.64 681.55

-
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.

+1 796.37 795.33
+2 798.37 797.13
+3 713.16 711.28
+4 666.10 664.01
+

As in the case of nlme fits, the DFOP model fitted with two-component error (number 4) gives the lowest AIC. Using more iterations and/or more chains does not have a large influence on the final AIC (not shown).

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.

-
-f_parent_saemix_dfop_tc_moreiter$so <-
-  llgq.saemix(f_parent_saemix_dfop_tc_moreiter$so)
-AIC(f_parent_saemix_dfop_tc_moreiter$so)
-
[1] 683.64
-
-AIC(f_parent_saemix_dfop_tc_moreiter$so, method = "gq")
-
[1] 683.7
-
-AIC(f_parent_saemix_dfop_tc_moreiter$so, method = "lin")
-
[1] 683.17
-

The AIC values based on importance sampling and Gaussian quadrature are quite similar. Using linearisation is less accurate, but still gives a similar value.

+
+f_parent_saemix_dfop_tc$so <-
+  llgq.saemix(f_parent_saemix_dfop_tc$so)
+AIC(f_parent_saemix_dfop_tc$so)
+
[1] 666.1
+
+AIC(f_parent_saemix_dfop_tc$so, method = "gq")
+
[1] 666.03
+
+AIC(f_parent_saemix_dfop_tc$so, method = "lin")
+
[1] 665.48
+

The AIC values based on importance sampling and Gaussian quadrature are very similar. Using linearisation is known to be less accurate, but still gives a similar value.

nlmixr

-

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.

-

First, the focei algorithm is used for the four model combinations and the goodness of fit of the results is compared.

-
+
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 the First Order Conditional Estimation with Interaction (FOCEI), and the SAEM algorithm as implemented in nlmixr.

+
First, the focei algorithm is used for the four model combinations. A number of warnings are produced with unclear significance.

+
 library(nlmixr)
 f_parent_nlmixr_focei_sfo_const <- nlmixr(f_parent_mkin_const["SFO", ], est = "focei")
 f_parent_nlmixr_focei_sfo_tc <- nlmixr(f_parent_mkin_tc["SFO", ], est = "focei")
 f_parent_nlmixr_focei_dfop_const <- nlmixr(f_parent_mkin_const["DFOP", ], est = "focei")
 f_parent_nlmixr_focei_dfop_tc<- nlmixr(f_parent_mkin_tc["DFOP", ], est = "focei")

-
-AIC(f_parent_nlmixr_focei_sfo_const$nm, f_parent_nlmixr_focei_sfo_tc$nm,
-  f_parent_nlmixr_focei_dfop_const$nm, f_parent_nlmixr_focei_dfop_tc$nm)

-
                                    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

+
+aic_nlmixr_focei <- sapply(
+  list(f_parent_nlmixr_focei_sfo_const$nm, f_parent_nlmixr_focei_sfo_tc$nm,
+    f_parent_nlmixr_focei_dfop_const$nm, f_parent_nlmixr_focei_dfop_tc$nm),
+  AIC)

 
The AIC values are very close to the ones obtained with nlme which are repeated below for convenience.

 
-AIC(
-  f_parent_nlme_sfo_const, f_parent_nlme_sfo_tc, f_parent_nlme_dfop_tc
+aic_nlme <- sapply(
+  list(f_parent_nlme_sfo_const, NA, f_parent_nlme_sfo_tc, f_parent_nlme_dfop_tc),
+  function(x) if (is.na(x[1])) NA else AIC(x))
+aic_nlme_nlmixr_focei <- data.frame(
+  "Degradation model" = c("SFO", "SFO", "DFOP", "DFOP"),
+  "Error model" = rep(c("constant variance", "two-component"), 2),
+  "AIC (nlme)" = aic_nlme,
+  "AIC (nlmixr with FOCEI)" = aic_nlmixr_focei,
+  check.names = FALSE
 )

-
                        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

-
Secondly, we use the SAEM estimation routine and check the convergence plots for SFO with constant variance

+
Secondly, we use the SAEM estimation routine and check the convergence plots. The control parameters also used for the saemix fits are defined beforehand.

+
+nlmixr_saem_control <- saemControl(logLik = TRUE,
+  nBurn = 1000, nEm = 300, nmc = 15)

+
The we fit SFO with constant variance

 
 f_parent_nlmixr_saem_sfo_const <- nlmixr(f_parent_mkin_const["SFO", ], est = "saem",
-  control = nlmixr::saemControl(logLik = TRUE))
+  control = nlmixr_saem_control)
 traceplot(f_parent_nlmixr_saem_sfo_const$nm)

 

-
for SFO with two-component error

+
and SFO with two-component error.

 
 f_parent_nlmixr_saem_sfo_tc <- nlmixr(f_parent_mkin_tc["SFO", ], est = "saem",
-  control = nlmixr::saemControl(logLik = TRUE))
+  control = nlmixr_saem_control)
 traceplot(f_parent_nlmixr_saem_sfo_tc$nm)

 

-
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.

+
For DFOP with constant variance, the convergence plots show considerable instability of the fit, which indicates overparameterisation which was already observed earlier for this model combination.

 
 f_parent_nlmixr_saem_dfop_const <- nlmixr(f_parent_mkin_const["DFOP", ], est = "saem",
-  control = nlmixr::saemControl(logLik = TRUE, nBurn = 1000), nmc = 15)
+  control = nlmixr_saem_control)
 traceplot(f_parent_nlmixr_saem_dfop_const$nm)

 

-
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.

+
For DFOP with two-component error, a less erratic convergence is seen.

 
 f_parent_nlmixr_saem_dfop_tc <- nlmixr(f_parent_mkin_tc["DFOP", ], est = "saem",
-  control = nlmixr::saemControl(logLik = TRUE, nBurn = 1000, nmc = 15))
+  control = nlmixr_saem_control)
 traceplot(f_parent_nlmixr_saem_dfop_tc$nm)

 

-
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.

+
The AIC values are internally calculated using Gaussian quadrature. For an unknown reason, the AIC value obtained for the DFOP fit using constant error is given as Infinity.

 
 AIC(f_parent_nlmixr_saem_sfo_const$nm, f_parent_nlmixr_saem_sfo_tc$nm,
   f_parent_nlmixr_saem_dfop_const$nm, f_parent_nlmixr_saem_dfop_tc$nm)

 
                                   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

+f_parent_nlmixr_saem_sfo_const$nm   5 798.68
+f_parent_nlmixr_saem_sfo_tc$nm      6 808.88
+f_parent_nlmixr_saem_dfop_const$nm  9 815.95
+f_parent_nlmixr_saem_dfop_tc$nm    10 669.57

The following table gives the AIC values obtained with the three packages.

 AIC_all <- data.frame(
+  check.names = FALSE,
   "Degradation model" = c("SFO", "SFO", "DFOP", "DFOP"),
   "Error model" = c("const", "tc", "const", "tc"),
   nlme = c(AIC(f_parent_nlme_sfo_const), AIC(f_parent_nlme_sfo_tc), NA, AIC(f_parent_nlme_dfop_tc)),
   nlmixr_focei = sapply(list(f_parent_nlmixr_focei_sfo_const$nm, f_parent_nlmixr_focei_sfo_tc$nm,
   f_parent_nlmixr_focei_dfop_const$nm, f_parent_nlmixr_focei_dfop_tc$nm), AIC),
   saemix = sapply(list(f_parent_saemix_sfo_const$so, f_parent_saemix_sfo_tc$so,
-    f_parent_saemix_dfop_const$so, f_parent_saemix_dfop_tc_moreiter$so), AIC),
+    f_parent_saemix_dfop_const$so, f_parent_saemix_dfop_tc$so), AIC),
   nlmixr_saem = sapply(list(f_parent_nlmixr_saem_sfo_const$nm, f_parent_nlmixr_saem_sfo_tc$nm,
   f_parent_nlmixr_saem_dfop_const$nm, f_parent_nlmixr_saem_dfop_tc$nm), AIC)
 )
 kable(AIC_all)
- - + + @@ -355,34 +361,34 @@ f_parent_nlmixr_saem_dfop_tc$nm 10 684.51 - - - - + + + + - - - - + + + + - - - + + + - - - - + + + +
Degradation.modelError.modelDegradation modelError model nlme nlmixr_focei saemix
SFO const818.63818.63818.37820.54796.60796.62796.37798.68
SFO tc820.61820.61820.38835.26798.60798.61798.37808.88
DFOP const NA728.11725.91842.84750.91713.16815.95
DFOP tc687.84687.82683.64684.51671.91666.60666.10669.57
@@ -397,6 +403,9 @@ f_parent_nlmixr_saem_dfop_tc$nm 10 684.51

EFSA. 2018. “Peer Review of the Pesticide Risk Assessment of the Active Substance Dimethenamid-P.” EFSA Journal 16 (4): 5211.

+
+

Ranke, Johannes, Janina Wöltjen, Jana Schmidt, and Emmanuelle Comets. 2021. “Taking Kinetic Evaluations of Degradation Data to the Next Level with Nonlinear Mixed-Effects Models.” Environments 8 (8). https://doi.org/10.3390/environments8080071.

+

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.” https://open.efsa.europa.eu/study-inventory/EFSA-Q-2014-00716.

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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 @@ mkin - 1.0.5 + 1.1.0
diff --git a/docs/dev/index.html b/docs/dev/index.html index 8b0b2386..452d9bdb 100644 --- a/docs/dev/index.html +++ b/docs/dev/index.html @@ -43,7 +43,7 @@ mkin - 1.0.5 + 1.1.0
@@ -264,7 +264,7 @@ Ranke J, Wöltjen J, Meinecke S (2018) Comparison of software tools for kinetic

Dev status

    • -
  • Build Status
    • +
  • Build Status
  • codecov
diff --git a/docs/dev/news/index.html b/docs/dev/news/index.html index 5b153f37..f3cc89d9 100644 --- a/docs/dev/news/index.html +++ b/docs/dev/news/index.html @@ -71,7 +71,7 @@ mkin - 1.0.5 + 1.1.0 @@ -141,9 +141,9 @@ Source: NEWS.md -
-

-mkin 1.0.5 (unreleased)

+
+

+mkin 1.1.0 (unreleased)

Mixed-effects models

@@ -155,6 +155,13 @@

  • ‘vignettes/web_only/dimethenamid_2018.rmd’: Example evaluations of the dimethenamid data.

    • +
    +
    +

    +mkin 1.0.5 (2021-09-15)

    +
      +
    • ‘dimethenamid_2018’: Correct the data for the Borstel soil. The five observations from Staudenmaier (2013) that were previously stored as “Borstel 2” are actually just a subset of the 16 observations in “Borstel 1” which is now simply “Borstel”
      • +

    diff --git a/docs/dev/pkgdown.yml b/docs/dev/pkgdown.yml index f184b7a5..e932afd0 100644 --- a/docs/dev/pkgdown.yml +++ b/docs/dev/pkgdown.yml @@ -11,7 +11,7 @@ articles: web_only/benchmarks: benchmarks.html web_only/compiled_models: compiled_models.html web_only/dimethenamid_2018: dimethenamid_2018.html -last_built: 2021-08-04T13:49Z +last_built: 2021-09-16T15:10Z urls: reference: https://pkgdown.jrwb.de/mkin/reference article: https://pkgdown.jrwb.de/mkin/articles diff --git a/docs/dev/reference/dimethenamid_2018-1.png b/docs/dev/reference/dimethenamid_2018-1.png index 52b8a2be..b8c5355f 100644 Binary files a/docs/dev/reference/dimethenamid_2018-1.png and b/docs/dev/reference/dimethenamid_2018-1.png differ diff --git a/docs/dev/reference/dimethenamid_2018-2.png b/docs/dev/reference/dimethenamid_2018-2.png index a81b2aaf..3b8a123b 100644 Binary files a/docs/dev/reference/dimethenamid_2018-2.png and b/docs/dev/reference/dimethenamid_2018-2.png differ diff --git a/docs/dev/reference/dimethenamid_2018.html b/docs/dev/reference/dimethenamid_2018.html index a77cf0f4..919e9363 100644 --- a/docs/dev/reference/dimethenamid_2018.html +++ b/docs/dev/reference/dimethenamid_2018.html @@ -77,7 +77,7 @@ constrained by data protection regulations." /> mkin - 1.0.5 + 1.1.0

    @@ -162,7 +162,7 @@ constrained by data protection regulations.

    Format

    -

    An mkindsg object grouping eight datasets with some meta information

    +

    An mkindsg object grouping seven datasets with some meta information

    Source

    Rapporteur Member State Germany, Co-Rapporteur Member State Bulgaria (2018) @@ -177,42 +177,36 @@ specific pieces of information in the comments.

    Examples

    print(dimethenamid_2018)
-
    #> <mkindsg> holding 8 mkinds objects
+
    #> <mkindsg> holding 7 mkinds objects
 #> Title $title:  Aerobic soil degradation data on dimethenamid-P from the EU assessment in 2018 
 #> Occurrence of observed compounds $observed_n:
 #> DMTAP   M23   M27   M31  DMTA 
-#>     4     7     7     7     4 
+#>     3     7     7     7     4 
 #> Time normalisation factors $f_time_norm:
-#> [1] 1.0000000 0.9706477 0.9706477 1.2284784 1.2284784 0.6233856 0.7678922
-#> [8] 0.6733938
+#> [1] 1.0000000 0.9706477 1.2284784 1.2284784 0.6233856 0.7678922 0.6733938
 #> Meta information $meta:
-#>                       study  usda_soil_type study_moisture_ref_type
-#> Calke         Unsworth 2014      Sandy loam                     pF2
-#> Borstel 1 Staudenmaier 2013            Sand                     pF1
-#> Borstel 2 Staudenmaier 2009            Sand                     pF1
-#> Elliot 1         Wendt 1997       Clay loam                   pF2.5
-#> Elliot 2         Wendt 1997       Clay loam                   pF2.5
-#> Flaach           König 1996 Sandy clay loam                     pF1
-#> BBA 2.2          König 1995      Loamy sand                     pF1
-#> BBA 2.3          König 1995      Sandy loam                     pF1
-#>           rel_moisture study_ref_moisture temperature
-#> Calke             1.00                 NA          20
-#> Borstel 1         0.50              23.00          20
-#> Borstel 2         0.50              23.00          20
-#> Elliot 1          0.75              33.37          23
-#> Elliot 2          0.75              33.37          23
-#> Flaach            0.40                 NA          20
-#> BBA 2.2           0.40                 NA          20
-#> BBA 2.3           0.40                 NA          20
    dmta_ds <- lapply(1:8, function(i) {
+#>                      study  usda_soil_type study_moisture_ref_type rel_moisture
+#> Calke        Unsworth 2014      Sandy loam                     pF2         1.00
+#> Borstel  Staudenmaier 2009            Sand                     pF1         0.50
+#> Elliot 1        Wendt 1997       Clay loam                   pF2.5         0.75
+#> Elliot 2        Wendt 1997       Clay loam                   pF2.5         0.75
+#> Flaach          König 1996 Sandy clay loam                     pF1         0.40
+#> BBA 2.2         König 1995      Loamy sand                     pF1         0.40
+#> BBA 2.3         König 1995      Sandy loam                     pF1         0.40
+#>          study_ref_moisture temperature
+#> Calke                    NA          20
+#> Borstel               23.00          20
+#> Elliot 1              33.37          23
+#> Elliot 2              33.37          23
+#> Flaach                   NA          20
+#> BBA 2.2                  NA          20
+#> BBA 2.3                  NA          20
    dmta_ds <- lapply(1:7, function(i) {
   ds_i <- dimethenamid_2018$ds[[i]]$data
   ds_i[ds_i$name == "DMTAP", "name"] <-  "DMTA"
   ds_i$time <- ds_i$time * dimethenamid_2018$f_time_norm[i]
   ds_i
 })
 names(dmta_ds) <- sapply(dimethenamid_2018$ds, function(ds) ds$title)
-dmta_ds[["Borstel"]] <- rbind(dmta_ds[["Borstel 1"]], dmta_ds[["Borstel 2"]])
-dmta_ds[["Borstel 1"]] <- NULL
-dmta_ds[["Borstel 2"]] <- NULL
 dmta_ds[["Elliot"]] <- rbind(dmta_ds[["Elliot 1"]], dmta_ds[["Elliot 2"]])
 dmta_ds[["Elliot 1"]] <- NULL
 dmta_ds[["Elliot 2"]] <- NULL
@@ -231,33 +225,33 @@ specific pieces of information in the comments.
    
 
    #> 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)
    #> function () 
 #> {
 #>     ini({
-#>         DMTA_0 = 98.7697627680706
-#>         eta.DMTA_0 ~ 2.35171765917765
+#>         DMTA_0 = 98.7132391714013
+#>         eta.DMTA_0 ~ 2.32692496033921
 #>         log_k_M23 = -3.92162409637283
 #>         eta.log_k_M23 ~ 0.549278519419884
-#>         log_k_M27 = -4.33774620773911
-#>         eta.log_k_M27 ~ 0.864474956685295
-#>         log_k_M31 = -4.24767627688461
-#>         eta.log_k_M31 ~ 0.750297149164171
-#>         log_k1 = -2.2341008812259
-#>         eta.log_k1 ~ 0.902976221565793
-#>         log_k2 = -3.7762779983269
-#>         eta.log_k2 ~ 1.57684519529298
-#>         g_qlogis = 0.450175725479389
-#>         eta.g_qlogis ~ 3.0851335687675
-#>         f_DMTA_tffm0_1_qlogis = -2.09240906629456
+#>         log_k_M27 = -4.33057580082049
+#>         eta.log_k_M27 ~ 0.855184233768426
+#>         log_k_M31 = -4.24415516780733
+#>         eta.log_k_M31 ~ 0.745746058085877
+#>         log_k1 = -2.23515804885306
+#>         eta.log_k1 ~ 0.901033446532357
+#>         log_k2 = -3.77581484944379
+#>         eta.log_k2 ~ 1.57682329638124
+#>         g_qlogis = 0.436302910942805
+#>         eta.g_qlogis ~ 3.10190528862808
+#>         f_DMTA_tffm0_1_qlogis = -2.0914852208395
 #>         eta.f_DMTA_tffm0_1_qlogis ~ 0.3
-#>         f_DMTA_tffm0_2_qlogis = -2.18057573598794
+#>         f_DMTA_tffm0_2_qlogis = -2.17879574608926
 #>         eta.f_DMTA_tffm0_2_qlogis ~ 0.3
-#>         f_DMTA_tffm0_3_qlogis = -2.14267187609763
+#>         f_DMTA_tffm0_3_qlogis = -2.14036526460782
 #>         eta.f_DMTA_tffm0_3_qlogis ~ 0.3
-#>         sigma_low_DMTA = 0.697933852349996
+#>         sigma_low_DMTA = 0.700117227383809
 #>         rsd_high_DMTA = 0.0257724286053519
-#>         sigma_low_M23 = 0.697933852349996
+#>         sigma_low_M23 = 0.700117227383809
 #>         rsd_high_M23 = 0.0257724286053519
-#>         sigma_low_M27 = 0.697933852349996
+#>         sigma_low_M27 = 0.700117227383809
 #>         rsd_high_M27 = 0.0257724286053519
-#>         sigma_low_M31 = 0.697933852349996
+#>         sigma_low_M31 = 0.700117227383809
 #>         rsd_high_M31 = 0.0257724286053519
 #>     })
 #>     model({
@@ -295,7 +289,7 @@ specific pieces of information in the comments.
    
 #>         M31 ~ add(sigma_low_M31) + prop(rsd_high_M31)
 #>     })
 #> }
-#> <environment: 0x555559ac3820>
    # The focei fit takes about four minutes on my system
+#> <environment: 0x555559e97ac0>
    # The focei fit takes about four minutes on my system
 system.time(
   f_dmta_nlmixr_focei <- nlmixr(f_dmta_mkin_tc, est = "focei",
     control = nlmixr::foceiControl(print = 500))
@@ -308,7 +302,7 @@ specific pieces of information in the comments.
    
 #> 
    #> → optimizing duplicate expressions in inner model...
    #> [====|====|====|====|====|====|====|====|====|====] 0:00:07 
 #> 
    #> → finding duplicate expressions in EBE model...
    #> [====|====|====|====|====|====|====|====|====|====] 0:00:00 
 #> 
    #> → optimizing duplicate expressions in EBE model...
    #> [====|====|====|====|====|====|====|====|====|====] 0:00:00 
-#> 
    #> → compiling inner model...
    #>  
    #> ✔ done
    #> → finding duplicate expressions in FD model...
    #> 
    #> → optimizing duplicate expressions in FD model...
    #> 
    #> → compiling EBE model...
    #>  
    #> ✔ done
    #> → compiling events FD model...
    #>  
    #> ✔ done
    #> Needed Covariates:
    #> [1] "CMT"
    #> RxODE 1.1.0 using 8 threads (see ?getRxThreads)
+#> 
    #> → compiling inner model...
    #>  
    #> ✔ done
    #> → finding duplicate expressions in FD model...
    #> 
    #> → optimizing duplicate expressions in FD model...
    #> 
    #> → compiling EBE model...
    #>  
    #> ✔ done
    #> → compiling events FD model...
    #>  
    #> ✔ done
    #> Needed Covariates:
    #> [1] "CMT"
    #> RxODE 1.1.1 using 8 threads (see ?getRxThreads)
 #>   no cache: create with `rxCreateCache()`
    #> Key: U: Unscaled Parameters; X: Back-transformed parameters; G: Gill difference gradient approximation
 #> F: Forward difference gradient approximation
 #> C: Central difference gradient approximation
@@ -324,12 +318,12 @@ specific pieces of information in the comments.
    
 #> |.....................|        o9 |       o10 |...........|...........|
 #> calculating covariance matrix
 #> done
    #> Calculating residuals/tables
    #> done
    #> Warning: initial ETAs were nudged; (can control by foceiControl(etaNudge=., etaNudge2=))
    #> Warning: last objective function was not at minimum, possible problems in optimization
    #> Warning: S matrix non-positive definite
    #> Warning: using R matrix to calculate covariance
    #> Warning: gradient problems with initial estimate and covariance; see $scaleInfo
    #>    user  system elapsed 
-#> 232.621  14.126 246.850 
    summary(f_dmta_nlmixr_focei)
-
    #> nlmixr version used for fitting:    2.0.4 
-#> mkin version used for pre-fitting:  1.0.5 
-#> R version used for fitting:         4.1.0 
-#> Date of fit:     Wed Aug  4 15:53:54 2021 
-#> Date of summary: Wed Aug  4 15:53:54 2021 
+#> 230.015   8.962 238.957 
    summary(f_dmta_nlmixr_focei)
+
    #> nlmixr version used for fitting:    2.0.5 
+#> mkin version used for pre-fitting:  1.1.0 
+#> R version used for fitting:         4.1.1 
+#> Date of fit:     Thu Sep 16 14:06:55 2021 
+#> Date of summary: Thu Sep 16 14:06:55 2021 
 #> 
 #> Equations:
 #> d_DMTA/dt = - ((k1 * g * exp(-k1 * time) + k2 * (1 - g) * exp(-k2 *
@@ -346,23 +340,23 @@ specific pieces of information in the comments.
    
 #>            exp(-k2 * time))) * DMTA - k_M31 * M31
 #> 
 #> Data:
-#> 568 observations of 4 variable(s) grouped in 6 datasets
+#> 563 observations of 4 variable(s) grouped in 6 datasets
 #> 
 #> Degradation model predictions using RxODE
 #> 
-#> Fitted in 246.669 s
+#> Fitted in 238.792 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 
+#>      98.7132      -3.9216      -4.3306      -4.2442       0.1376       0.1388 
 #> f_DMTA_ilr_3       log_k1       log_k2     g_qlogis 
-#>      -1.7571      -2.2341      -3.7763       0.4502 
+#>      -1.7554      -2.2352      -3.7758       0.4363 
 #> 
 #> Mean of starting values for error model parameters:
 #> sigma_low  rsd_high 
-#>   0.69793   0.02577 
+#>   0.70012   0.02577 
 #> 
 #> Fixed degradation parameter values:
 #> None
@@ -371,20 +365,20 @@ specific pieces of information in the comments.
    
 #> 
 #> Likelihood calculated by focei  
 #>    AIC  BIC logLik
-#>   1936 2031 -945.9
+#>   1918 2014 -937.2
 #> 
 #> Optimised parameters:
 #>                          est.   lower   upper
-#> DMTA_0                98.7698 98.7356 98.8039
-#> log_k_M23             -3.9216 -3.9235 -3.9197
-#> log_k_M27             -4.3377 -4.3398 -4.3357
-#> log_k_M31             -4.2477 -4.2497 -4.2457
-#> log_k1                -2.2341 -2.2353 -2.2329
-#> log_k2                -3.7763 -3.7781 -3.7744
-#> g_qlogis               0.4502  0.4496  0.4507
-#> f_DMTA_tffm0_1_qlogis -2.0924 -2.0936 -2.0912
-#> f_DMTA_tffm0_2_qlogis -2.1806 -2.1818 -2.1794
-#> f_DMTA_tffm0_3_qlogis -2.1427 -2.1439 -2.1415
+#> DMTA_0                98.7132 98.6801 98.7464
+#> log_k_M23             -3.9216 -3.9235 -3.9198
+#> log_k_M27             -4.3306 -4.3326 -4.3286
+#> log_k_M31             -4.2442 -4.2461 -4.2422
+#> log_k1                -2.2352 -2.2364 -2.2340
+#> log_k2                -3.7758 -3.7776 -3.7740
+#> g_qlogis               0.4363  0.4358  0.4368
+#> f_DMTA_tffm0_1_qlogis -2.0915 -2.0926 -2.0903
+#> f_DMTA_tffm0_2_qlogis -2.1788 -2.1800 -2.1776
+#> f_DMTA_tffm0_3_qlogis -2.1404 -2.1415 -2.1392
 #> 
 #> Correlation: 
 #>                       DMTA_0 l__M23 l__M27 l__M31 log_k1 log_k2 g_qlgs
@@ -410,10 +404,10 @@ specific pieces of information in the comments.
    
 #> 
 #> Random effects (omega):
 #>                           eta.DMTA_0 eta.log_k_M23 eta.log_k_M27 eta.log_k_M31
-#> eta.DMTA_0                     2.352        0.0000        0.0000        0.0000
+#> eta.DMTA_0                     2.327        0.0000        0.0000        0.0000
 #> eta.log_k_M23                  0.000        0.5493        0.0000        0.0000
-#> eta.log_k_M27                  0.000        0.0000        0.8645        0.0000
-#> eta.log_k_M31                  0.000        0.0000        0.0000        0.7503
+#> eta.log_k_M27                  0.000        0.0000        0.8552        0.0000
+#> eta.log_k_M31                  0.000        0.0000        0.0000        0.7457
 #> eta.log_k1                     0.000        0.0000        0.0000        0.0000
 #> eta.log_k2                     0.000        0.0000        0.0000        0.0000
 #> eta.g_qlogis                   0.000        0.0000        0.0000        0.0000
@@ -425,9 +419,9 @@ specific pieces of information in the comments.
    
 #> eta.log_k_M23                  0.000      0.000        0.000
 #> eta.log_k_M27                  0.000      0.000        0.000
 #> eta.log_k_M31                  0.000      0.000        0.000
-#> eta.log_k1                     0.903      0.000        0.000
+#> eta.log_k1                     0.901      0.000        0.000
 #> eta.log_k2                     0.000      1.577        0.000
-#> eta.g_qlogis                   0.000      0.000        3.085
+#> eta.g_qlogis                   0.000      0.000        3.102
 #> eta.f_DMTA_tffm0_1_qlogis      0.000      0.000        0.000
 #> eta.f_DMTA_tffm0_2_qlogis      0.000      0.000        0.000
 #> eta.f_DMTA_tffm0_3_qlogis      0.000      0.000        0.000
@@ -456,44 +450,44 @@ specific pieces of information in the comments.
    
 #> 
 #> Variance model:
 #> sigma_low  rsd_high 
-#>   0.69793   0.02577 
+#>   0.70012   0.02577 
 #> 
 #> Backtransformed parameters:
 #>                   est.    lower    upper
-#> DMTA_0        98.76976 98.73563 98.80390
+#> DMTA_0        98.71324 98.68012 98.74636
 #> k_M23          0.01981  0.01977  0.01985
-#> k_M27          0.01307  0.01304  0.01309
-#> k_M31          0.01430  0.01427  0.01433
-#> f_DMTA_to_M23  0.10984       NA       NA
-#> f_DMTA_to_M27  0.09036       NA       NA
-#> f_DMTA_to_M31  0.08399       NA       NA
-#> k1             0.10709  0.10696  0.10722
-#> k2             0.02291  0.02287  0.02295
-#> g              0.61068  0.61055  0.61081
+#> k_M27          0.01316  0.01313  0.01319
+#> k_M31          0.01435  0.01432  0.01438
+#> f_DMTA_to_M23  0.10993       NA       NA
+#> f_DMTA_to_M27  0.09049       NA       NA
+#> f_DMTA_to_M31  0.08414       NA       NA
+#> k1             0.10698  0.10685  0.10710
+#> k2             0.02292  0.02288  0.02296
+#> g              0.60738  0.60725  0.60751
 #> 
 #> Resulting formation fractions:
 #>                ff
-#> DMTA_M23  0.10984
-#> DMTA_M27  0.09036
-#> DMTA_M31  0.08399
-#> DMTA_sink 0.71581
+#> DMTA_M23  0.10993
+#> DMTA_M27  0.09049
+#> DMTA_M31  0.08414
+#> DMTA_sink 0.71543
 #> 
 #> Estimated disappearance times:
-#>       DT50   DT90 DT50back DT50_k1 DT50_k2
-#> DMTA 10.66  59.78       18   6.473   30.26
-#> M23  34.99 116.24       NA      NA      NA
-#> M27  53.05 176.23       NA      NA      NA
-#> M31  48.48 161.05       NA      NA      NA
    plot(f_dmta_nlmixr_focei)
+#>       DT50  DT90 DT50back DT50_k1 DT50_k2
+#> DMTA 10.72  60.1    18.09    6.48   30.24
+#> M23  34.99 116.2       NA      NA      NA
+#> M27  52.67 175.0       NA      NA      NA
+#> M31  48.31 160.5       NA      NA      NA
    plot(f_dmta_nlmixr_focei)
 
    # Using saemix takes about 18 minutes
 system.time(
   f_dmta_saemix <- saem(f_dmta_mkin_tc, test_log_parms = TRUE)
 )
 
    #> Running main SAEM algorithm
-#> [1] "Wed Aug  4 15:53:55 2021"
+#> [1] "Thu Sep 16 14:06:56 2021"
 #> ....
 #>     Minimisation finished
-#> [1] "Wed Aug  4 16:12:40 2021"
    #>     user   system  elapsed 
-#> 1192.021    0.064 1192.182 
    
+#> [1] "Thu Sep 16 14:25:28 2021"
    #>     user   system  elapsed 
+#> 1176.278    0.021 1176.388 
    
 # nlmixr with est = "saem" is pretty fast with default iteration numbers, most
 # of the time (about 2.5 minutes) is spent for calculating the log likelihood at the end
 # The likelihood calculated for the nlmixr fit is much lower than that found by saemix
@@ -504,15 +498,15 @@ specific pieces of information in the comments.
    
   f_dmta_nlmixr_saem <- nlmixr(f_dmta_mkin_tc, est = "saem",
     control = nlmixr::saemControl(print = 500, logLik = TRUE, nmc = 9))
 )
-
    #> 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)
    #> ℹ parameter labels from comments are typically ignored in non-interactive mode
    #> ℹ Need to run with the source intact to parse comments
    #>  
    #> → generate SAEM model
    #> ✔ done
    #> 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
    #> Calculating covariance matrix
    #> 
    #> Calculating -2LL by Gaussian quadrature (nnodes=3,nsd=1.6)
    #> 
    #> → creating full model...
    #> → pruning branches (`if`/`else`)...
    #> ✔ done
    #> → loading into symengine environment...
    #> ✔ done
    #> → compiling EBE model...
    #>  
    #> ✔ done
    #> Needed Covariates:
    #> [1] "CMT"
    #> Calculating residuals/tables
    #> done
    #>    user  system elapsed 
-#> 813.299   3.736 151.935 
    traceplot(f_dmta_nlmixr_saem$nm)
+
    #> With est = 'saem', a different error model is required for each observed variableChanging the error model to 'obs_tc' (Two-component error for each observed variable)
    #> ℹ parameter labels from comments are typically ignored in non-interactive mode
    #> ℹ Need to run with the source intact to parse comments
    #>  
    #> → generate SAEM model
    #> ✔ done
    #> 1:    98.3400   -3.5096   -3.3392   -3.7596   -2.2055   -2.7755    1.0281   -2.7872   -2.7223   -2.8341    2.6422    0.7027    0.8124    0.7085    0.8560    1.4980    3.2777    0.3063    0.2850    0.2850    4.1120    0.3716    4.4582    0.3994    4.4820    0.4025    3.7803    0.5780
+#> 500:    97.8212   -4.4030   -4.0872   -4.1289   -2.8278   -4.3505    2.6614   -2.1252   -2.1308   -2.0749    2.9463    1.2933    0.2802    0.3467    0.4814    0.7877    3.0743    0.1508    0.1523    0.3155    0.9557    0.0333    0.4787    0.1073    0.6826    0.0707    0.7849    0.0356
    #> Calculating covariance matrix
    #> 
    #> Calculating -2LL by Gaussian quadrature (nnodes=3,nsd=1.6)
    #> 
    #> → creating full model...
    #> → pruning branches (`if`/`else`)...
    #> ✔ done
    #> → loading into symengine environment...
    #> ✔ done
    #> → compiling EBE model...
    #>  
    #> ✔ done
    #> Needed Covariates:
    #> [1] "CMT"
    #> Calculating residuals/tables
    #> done
    #>    user  system elapsed 
+#> 800.784   3.715 149.687 
    traceplot(f_dmta_nlmixr_saem$nm)
 
    #> Error in traceplot(f_dmta_nlmixr_saem$nm): could not find function "traceplot"
    summary(f_dmta_nlmixr_saem)
-
    #> nlmixr version used for fitting:    2.0.4 
-#> mkin version used for pre-fitting:  1.0.5 
-#> R version used for fitting:         4.1.0 
-#> Date of fit:     Wed Aug  4 16:16:18 2021 
-#> Date of summary: Wed Aug  4 16:16:18 2021 
+
    #> nlmixr version used for fitting:    2.0.5 
+#> mkin version used for pre-fitting:  1.1.0 
+#> R version used for fitting:         4.1.1 
+#> Date of fit:     Thu Sep 16 14:29:02 2021 
+#> Date of summary: Thu Sep 16 14:29:02 2021 
 #> 
 #> Equations:
 #> d_DMTA/dt = - ((k1 * g * exp(-k1 * time) + k2 * (1 - g) * exp(-k2 *
@@ -529,25 +523,25 @@ specific pieces of information in the comments.
    
 #>            exp(-k2 * time))) * DMTA - k_M31 * M31
 #> 
 #> Data:
-#> 568 observations of 4 variable(s) grouped in 6 datasets
+#> 563 observations of 4 variable(s) grouped in 6 datasets
 #> 
 #> Degradation model predictions using RxODE
 #> 
-#> Fitted in 151.67 s
+#> Fitted in 149.421 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 
+#>      98.7132      -3.9216      -4.3306      -4.2442       0.1376       0.1388 
 #> f_DMTA_ilr_3       log_k1       log_k2     g_qlogis 
-#>      -1.7571      -2.2341      -3.7763       0.4502 
+#>      -1.7554      -2.2352      -3.7758       0.4363 
 #> 
 #> 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 
+#>        0.70012        0.02577        0.70012        0.02577        0.70012 
 #>   rsd_high_M27  sigma_low_M31   rsd_high_M31 
-#>        0.02577        0.69793        0.02577 
+#>        0.02577        0.70012        0.02577 
 #> 
 #> Fixed degradation parameter values:
 #> None
@@ -556,32 +550,32 @@ specific pieces of information in the comments.
    
 #> 
 #> Likelihood calculated by focei  
 #>    AIC  BIC logLik
-#>   2036 2157 -989.8
+#>   1953 2074 -948.3
 #> 
 #> 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
+#> DMTA_0                97.821 95.862 99.780
+#> log_k_M23             -4.403 -5.376 -3.430
+#> log_k_M27             -4.087 -4.545 -3.629
+#> log_k_M31             -4.129 -4.639 -3.618
+#> log_k1                -2.828 -3.389 -2.266
+#> log_k2                -4.351 -5.472 -3.229
+#> g_qlogis               2.661  0.824  4.499
+#> f_DMTA_tffm0_1_qlogis -2.125 -2.449 -1.801
+#> f_DMTA_tffm0_2_qlogis -2.131 -2.468 -1.794
+#> f_DMTA_tffm0_3_qlogis -2.075 -2.540 -1.610
 #> 
 #> 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
+#> log_k_M23             -0.019                                          
+#> log_k_M27             -0.028  0.004                                   
+#> log_k_M31             -0.019  0.003  0.075                            
+#> log_k1                 0.038 -0.004 -0.006 -0.003                     
+#> log_k2                 0.046  0.011  0.008  0.009  0.068              
+#> g_qlogis              -0.067  0.004  0.006  0.001 -0.076 -0.409       
+#> f_DMTA_tffm0_1_qlogis -0.062  0.055  0.006  0.004 -0.008 -0.004  0.012
+#> f_DMTA_tffm0_2_qlogis -0.062  0.010  0.058 -0.034 -0.008 -0.007  0.014
+#> f_DMTA_tffm0_3_qlogis -0.052  0.009  0.056  0.071 -0.006 -0.001  0.008
 #>                       f_DMTA_0_1 f_DMTA_0_2
 #> log_k_M23                                  
 #> log_k_M27                                  
@@ -590,15 +584,15 @@ specific pieces of information in the comments.
    
 #> 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    
+#> f_DMTA_tffm0_2_qlogis  0.017               
+#> f_DMTA_tffm0_3_qlogis  0.014     -0.005    
 #> 
 #> 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.DMTA_0                     2.946         0.000        0.0000        0.0000
+#> eta.log_k_M23                  0.000         1.293        0.0000        0.0000
+#> eta.log_k_M27                  0.000         0.000        0.2802        0.0000
+#> eta.log_k_M31                  0.000         0.000        0.0000        0.3467
 #> 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
@@ -610,9 +604,9 @@ specific pieces of information in the comments.
    
 #> 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.log_k1                    0.4814     0.0000        0.000
+#> eta.log_k2                    0.0000     0.7877        0.000
+#> eta.g_qlogis                  0.0000     0.0000        3.074
 #> 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
@@ -624,8 +618,8 @@ specific pieces of information in the comments.
    
 #> 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_1_qlogis                    0.1508                    0.0000
+#> eta.f_DMTA_tffm0_2_qlogis                    0.0000                    0.1523
 #> eta.f_DMTA_tffm0_3_qlogis                    0.0000                    0.0000
 #>                           eta.f_DMTA_tffm0_3_qlogis
 #> eta.DMTA_0                                   0.0000
@@ -637,40 +631,40 @@ specific pieces of information in the comments.
    
 #> 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
+#> eta.f_DMTA_tffm0_3_qlogis                    0.3155
 #> 
 #> 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 
+#>        0.95572        0.03325        0.47871        0.10733        0.68264 
 #>   rsd_high_M27  sigma_low_M31   rsd_high_M31 
-#>        0.02810        0.73212        0.05942 
+#>        0.07072        0.78486        0.03557 
 #> 
 #> 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
+#> DMTA_0        97.82122 95.862233 99.78020
+#> k_M23          0.01224  0.004625  0.03239
+#> k_M27          0.01679  0.010615  0.02654
+#> k_M31          0.01610  0.009664  0.02683
+#> f_DMTA_to_M23  0.10668        NA       NA
+#> f_DMTA_to_M27  0.09481        NA       NA
+#> f_DMTA_to_M31  0.08908        NA       NA
+#> k1             0.05914  0.033731  0.10370
+#> k2             0.01290  0.004204  0.03958
+#> g              0.93471  0.695081  0.98900
 #> 
 #> Resulting formation fractions:
 #>                ff
-#> DMTA_M23  0.11033
-#> DMTA_M27  0.10218
-#> DMTA_M31  0.08784
-#> DMTA_sink 0.69965
+#> DMTA_M23  0.10668
+#> DMTA_M27  0.09481
+#> DMTA_M31  0.08908
+#> DMTA_sink 0.70943
 #> 
 #> 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
    plot(f_dmta_nlmixr_saem)
+#> DMTA 12.57  45.43    13.67   11.72   53.73
+#> M23  56.63 188.11       NA      NA      NA
+#> M27  41.29 137.18       NA      NA      NA
+#> M31  43.05 143.01       NA      NA      NA
    plot(f_dmta_nlmixr_saem)
 
    # }
    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." /> mkin - 1.0.5 + 1.1.0 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 @@ mkin - 1.0.5 + 1.1.0 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 @@ mkin - 1.0.5 + 1.1.0 diff --git a/docs/dev/reference/mkinmod.html b/docs/dev/reference/mkinmod.html index ac7c2daa..6478cda4 100644 --- a/docs/dev/reference/mkinmod.html +++ b/docs/dev/reference/mkinmod.html @@ -76,7 +76,7 @@ components." /> mkin - 1.0.5 + 1.1.0 @@ -344,7 +344,7 @@ Evaluating and Calculating Degradation Kinetics in Environmental Media

    parent = mkinsub("SFO", "m1", full_name = "Test compound"), m1 = mkinsub("SFO", full_name = "Metabolite M1"), name = "SFO_SFO", dll_dir = DLL_dir, unload = TRUE, overwrite = TRUE) -
    #> Copied DLL from /tmp/RtmpKZJMFk/file179ba717d15c81.so to /home/jranke/.local/share/mkin/SFO_SFO.so
    # Now we can save the model and restore it in a new session +
    #> Copied DLL from /tmp/RtmpTzKqT5/file7993c266a7f90.so to /home/jranke/.local/share/mkin/SFO_SFO.so
    # Now we can save the model and restore it in a new session saveRDS(SFO_SFO.2, file = "~/SFO_SFO.rds") # Terminate the R session here if you would like to check, and then do library(mkin) @@ -393,7 +393,7 @@ Evaluating and Calculating Degradation Kinetics in Environmental Media

    #> }) #> return(predicted) #> } -#> <environment: 0x555559c54f78>
    +#> <environment: 0x555559365690>
    # If we have several parallel metabolites # (compare tests/testthat/test_synthetic_data_for_UBA_2014.R) m_synth_DFOP_par <- mkinmod( diff --git a/docs/dev/reference/nlme-1.png b/docs/dev/reference/nlme-1.png index 365aaef0..e4bc2fde 100644 Binary files a/docs/dev/reference/nlme-1.png and b/docs/dev/reference/nlme-1.png differ diff --git a/docs/dev/reference/nlme-2.png b/docs/dev/reference/nlme-2.png index 40841404..31910ce4 100644 Binary files a/docs/dev/reference/nlme-2.png and b/docs/dev/reference/nlme-2.png differ diff --git a/docs/dev/reference/nlme.html b/docs/dev/reference/nlme.html index 55a94443..500ac391 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." /> mkin - 1.0.5 + 1.1.0
    @@ -216,28 +216,28 @@ datasets. They are used internally by the 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 +#> 289.8295 299.4886 -139.9148 #> #> 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: 1.839278 0.6988919 3.059894 #> #> 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_0 100.52780 1.3507449 47 74.42397 0 +#> log_k_parent_sink -3.08477 0.4124053 47 -7.47995 0 #> Correlation: #> prnt_0 -#> log_k_parent_sink 0.027 +#> log_k_parent_sink 0.019 #> #> Standardized Within-Group Residuals: -#> Min Q1 Med Q3 Max -#> -1.9942823 -0.5622565 0.1791579 0.7165038 2.0704781 +#> Min Q1 Med Q3 Max +#> -2.22350411 -0.51546184 0.04803417 0.55987705 3.49178405 #> -#> Number of Observations: 50 +#> Number of Observations: 51 #> Number of Groups: 3
    plot(augPred(m_nlme, level = 0:1), layout = c(3, 1))
    # augPred does not work on fits with more than one state # variable diff --git a/docs/dev/reference/nlme.mmkin.html b/docs/dev/reference/nlme.mmkin.html index db863392..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." /> mkin - 1.0.5 + 1.1.0
    diff --git a/docs/dev/reference/nlmixr.mmkin.html b/docs/dev/reference/nlmixr.mmkin.html index 99a7ad14..db114483 100644 --- a/docs/dev/reference/nlmixr.mmkin.html +++ b/docs/dev/reference/nlmixr.mmkin.html @@ -74,7 +74,7 @@ Expectation Maximisation algorithm (SAEM)." /> mkin - 1.0.5 + 1.1.0 @@ -4416,7 +4416,8 @@ obtained by fitting the same model to a list of datasets using 288.66432 | 94.40 | 0.8038 | 7.793 | 2.283 | #> |.....................| 5.960e-07 | 0.6941 | 1.222 | 1.493 | -#> done
    #> Calculating residuals/tables
    #> done
    #> Warning: initial ETAs were nudged; (can control by foceiControl(etaNudge=., etaNudge2=))
    #> Warning: ETAs were reset to zero during optimization; (Can control by foceiControl(resetEtaP=.))
    #> Warning: last objective function was not at minimum, possible problems in optimization
    #> Warning: parameter estimate near boundary; covariance not calculated +#> done
    #> Calculating residuals/tables
    #> done
    #> Warning: initial ETAs were nudged; (can control by foceiControl(etaNudge=., etaNudge2=))
    #> Warning: ETAs were reset to zero during optimization; (Can control by foceiControl(resetEtaP=.))
    #> Warning: last objective function was not at minimum, possible problems in optimization
    #> Warning: parameter estimate near boundary; covariance not calculated: +#> "rsd_high" #> use 'getVarCov' to calculate anyway
    #> Warning: gradient problems with initial estimate; see $scaleInfo
    AIC( f_nlmixr_sfo_saem$nm, f_nlmixr_sfo_focei$nm, @@ -4501,7 +4502,7 @@ obtained by fitting the same model to a list of datasets using k_A1=rx_expr_11; #> f_parent=1/(1+exp(-(ETA[4]+THETA[4]))); #> tad=tad(); -#> dosenum=dosenum();
    #> Needed Covariates:
    #> [1] "f_parent_to_A1" "CMT"
    #> Error in (function (data, inits, PKpars, model = NULL, pred = NULL, err = NULL, lower = -Inf, upper = Inf, fixed = NULL, skipCov = NULL, control = foceiControl(), thetaNames = NULL, etaNames = NULL, etaMat = NULL, ..., env = NULL, keep = NULL, drop = NULL) { set.seed(control$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$eta.names, control = control, env = env, keep = .keep, drop = .drop): Not all the covariates are in the dataset.
    #> Timing stopped at: 5.723 0.414 6.136
    f_nlmixr_fomc_sfo_focei_const <- nlmixr(f_mmkin_const["FOMC-SFO", ], est = "focei") +#> dosenum=dosenum();
    #> Needed Covariates:
    #> [1] "f_parent_to_A1" "CMT"
    #> Error in (function (data, inits, PKpars, model = NULL, pred = NULL, err = NULL, lower = -Inf, upper = Inf, fixed = NULL, skipCov = NULL, control = foceiControl(), thetaNames = NULL, etaNames = NULL, etaMat = NULL, ..., env = NULL, keep = NULL, drop = NULL) { set.seed(control$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$eta.names, control = control, env = env, keep = .keep, drop = .drop): Not all the covariates are in the dataset.
    #> Timing stopped at: 5.579 0.328 5.909
    f_nlmixr_fomc_sfo_focei_const <- nlmixr(f_mmkin_const["FOMC-SFO", ], est = "focei")
    #> ℹ parameter labels from comments are typically ignored in non-interactive mode
    #> ℹ Need to run with the source intact to parse comments
    #> → creating full model...
    #> → pruning branches (`if`/`else`)...
    #> ✔ done
    #> → loading into symengine environment...
    #> ✔ done
    #> → creating full model...
    #> → pruning branches (`if`/`else`)...
    #> ✔ done
    #> → loading into symengine environment...
    #> ✔ done
    #> → calculate jacobian
    #>
    #> → calculate sensitivities
    #>
    #> → calculate ∂(f)/∂(η)
    #>
    #> → calculate ∂(R²)/∂(η)
    #>
    #> → finding duplicate expressions in inner model...
    #>
    #> → optimizing duplicate expressions in inner model...
    #>
    #> → finding duplicate expressions in EBE model...
    #>
    #> → optimizing duplicate expressions in EBE model...
    #>
    #> → compiling inner model...
    #>
    #> ✔ done
    #> → finding duplicate expressions in FD model...
    #>
    #> → optimizing duplicate expressions in FD model...
    #>
    #> → compiling EBE model...
    #>
    #> ✔ done
    #> → compiling events FD model...
    #>
    #> ✔ done
    #> Model:
    #> cmt(parent); #> cmt(A1); #> rx_expr_6~ETA[1]+THETA[1]; @@ -4550,7 +4551,7 @@ obtained by fitting the same model to a list of datasets using beta=exp(rx_expr_8); #> f_parent=1/(1+exp(-(ETA[3]+THETA[3]))); #> tad=tad(); -#> dosenum=dosenum();
    #> Needed Covariates:
    #> [1] "f_parent_to_A1" "CMT"
    #> Error in (function (data, inits, PKpars, model = NULL, pred = NULL, err = NULL, lower = -Inf, upper = Inf, fixed = NULL, skipCov = NULL, control = foceiControl(), thetaNames = NULL, etaNames = NULL, etaMat = NULL, ..., env = NULL, keep = NULL, drop = NULL) { set.seed(control$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$eta.names, control = control, env = env, keep = .keep, drop = .drop): Not all the covariates are in the dataset.
    #> Timing stopped at: 6.874 0.399 7.27
    f_nlmixr_dfop_sfo_focei_const <- nlmixr(f_mmkin_const["DFOP-SFO", ], est = "focei") +#> dosenum=dosenum();
    #> Needed Covariates:
    #> [1] "f_parent_to_A1" "CMT"
    #> Error in (function (data, inits, PKpars, model = NULL, pred = NULL, err = NULL, lower = -Inf, upper = Inf, fixed = NULL, skipCov = NULL, control = foceiControl(), thetaNames = NULL, etaNames = NULL, etaMat = NULL, ..., env = NULL, keep = NULL, drop = NULL) { set.seed(control$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$eta.names, control = control, env = env, keep = .keep, drop = .drop): Not all the covariates are in the dataset.
    #> Timing stopped at: 7.125 0.34 7.462
    f_nlmixr_dfop_sfo_focei_const <- nlmixr(f_mmkin_const["DFOP-SFO", ], est = "focei")
    #> ℹ parameter labels from comments are typically ignored in non-interactive mode
    #> ℹ Need to run with the source intact to parse comments
    #> → creating full model...
    #> → pruning branches (`if`/`else`)...
    #> ✔ done
    #> → loading into symengine environment...
    #> ✔ done
    #> → creating full model...
    #> → pruning branches (`if`/`else`)...
    #> ✔ done
    #> → loading into symengine environment...
    #> ✔ done
    #> → calculate jacobian
    #>
    #> → calculate sensitivities
    #>
    #> → calculate ∂(f)/∂(η)
    #>
    #> → calculate ∂(R²)/∂(η)
    #>
    #> → finding duplicate expressions in inner model...
    #>
    #> → optimizing duplicate expressions in inner model...
    #>
    #> → finding duplicate expressions in EBE model...
    #>
    #> → optimizing duplicate expressions in EBE model...
    #>
    #> → compiling inner model...
    #>
    #> ✔ done
    #> → finding duplicate expressions in FD model...
    #>
    #> → optimizing duplicate expressions in FD model...
    #>
    #> → compiling EBE model...
    #>
    #> ✔ done
    #> → compiling events FD model...
    #>
    #> ✔ done
    #> Model:
    #> cmt(parent); #> cmt(A1); #> rx_expr_6~ETA[1]+THETA[1]; @@ -4607,10 +4608,10 @@ obtained by fitting the same model to a list of datasets using f_parent=1/(1+exp(-(ETA[3]+THETA[3]))); #> g=1/(rx_expr_20); #> tad=tad(); -#> dosenum=dosenum();
    #> Needed Covariates:
    #> [1] "f_parent_to_A1" "CMT"
    #> Error in (function (data, inits, PKpars, model = NULL, pred = NULL, err = NULL, lower = -Inf, upper = Inf, fixed = NULL, skipCov = NULL, control = foceiControl(), thetaNames = NULL, etaNames = NULL, etaMat = NULL, ..., env = NULL, keep = NULL, drop = NULL) { set.seed(control$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$eta.names, control = control, env = env, keep = .keep, drop = .drop): Not all the covariates are in the dataset.
    #> Timing stopped at: 14.83 0.382 15.21
    +#> dosenum=dosenum();
    #> Needed Covariates:
    #> [1] "f_parent_to_A1" "CMT"
    #> Error in (function (data, inits, PKpars, model = NULL, pred = NULL, err = NULL, lower = -Inf, upper = Inf, fixed = NULL, skipCov = NULL, control = foceiControl(), thetaNames = NULL, etaNames = NULL, etaMat = NULL, ..., env = NULL, keep = NULL, drop = NULL) { set.seed(control$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.
    #> Timing stopped at: 15.03 0.407 15.43
    # Variance by variable is supported by 'saem' and 'focei' f_nlmixr_fomc_sfo_saem_obs <- nlmixr(f_mmkin_obs["FOMC-SFO", ], est = "saem") -
    #> ℹ parameter labels from comments are typically ignored in non-interactive mode
    #> ℹ Need to run with the source intact to parse comments
    #>
    #> → generate SAEM model
    #> ✔ done
    #> 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
    #> Timing stopped at: 1.22 0.146 1.365
    f_nlmixr_fomc_sfo_focei_obs <- nlmixr(f_mmkin_obs["FOMC-SFO", ], est = "focei") +
    #> ℹ parameter labels from comments are typically ignored in non-interactive mode
    #> ℹ Need to run with the source intact to parse comments
    #>
    #> → generate SAEM model
    #> ✔ done
    #> 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
    #> Timing stopped at: 1.253 0.121 1.373
    f_nlmixr_fomc_sfo_focei_obs <- nlmixr(f_mmkin_obs["FOMC-SFO", ], est = "focei")
    #> ℹ parameter labels from comments are typically ignored in non-interactive mode
    #> ℹ Need to run with the source intact to parse comments
    #> → creating full model...
    #> → pruning branches (`if`/`else`)...
    #> ✔ done
    #> → loading into symengine environment...
    #> ✔ done
    #> → creating full model...
    #> → pruning branches (`if`/`else`)...
    #> ✔ done
    #> → loading into symengine environment...
    #> ✔ done
    #> → calculate jacobian
    #>
    #> → calculate sensitivities
    #>
    #> → calculate ∂(f)/∂(η)
    #>
    #> → calculate ∂(R²)/∂(η)
    #>
    #> → finding duplicate expressions in inner model...
    #>
    #> → optimizing duplicate expressions in inner model...
    #>
    #> → finding duplicate expressions in EBE model...
    #>
    #> → optimizing duplicate expressions in EBE model...
    #>
    #> → compiling inner model...
    #>
    #> ✔ done
    #> → finding duplicate expressions in FD model...
    #>
    #> → optimizing duplicate expressions in FD model...
    #>
    #> → compiling EBE model...
    #>
    #> ✔ done
    #> → compiling events FD model...
    #>
    #> ✔ done
    #> Model:
    #> cmt(parent); #> cmt(A1); #> rx_expr_6~ETA[1]+THETA[1]; @@ -4659,8 +4660,8 @@ obtained by fitting the same model to a list of datasets using beta=exp(rx_expr_8); #> f_parent=1/(1+exp(-(ETA[3]+THETA[3]))); #> tad=tad(); -#> dosenum=dosenum();
    #> Needed Covariates:
    #> [1] "f_parent_to_A1" "CMT"
    #> 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$eta.names, control = control, env = env, keep = .keep, drop = .drop): Not all the covariates are in the dataset.
    #> Timing stopped at: 6.6 0.416 7.016
    f_nlmixr_dfop_sfo_saem_obs <- nlmixr(f_mmkin_obs["DFOP-SFO", ], est = "saem") -
    #> ℹ parameter labels from comments are typically ignored in non-interactive mode
    #> ℹ Need to run with the source intact to parse comments
    #>
    #> → generate SAEM model
    #> ✔ done
    #> Error in configsaem(model = model, data = dat, inits = inits, mcmc = .mcmc, ODEopt = .ODEopt, seed = .seed, distribution = .dist, DEBUG = .DEBUG, addProp = .addProp, tol = .tol, itmax = .itmax, type = .type, powRange = .powRange, lambdaRange = .lambdaRange): covariate(s) not found: f_parent_to_A1
    #> Timing stopped at: 1.551 0.126 1.673
    f_nlmixr_dfop_sfo_focei_obs <- nlmixr(f_mmkin_obs["DFOP-SFO", ], est = "focei") +#> dosenum=dosenum();
    #> Needed Covariates:
    #> [1] "f_parent_to_A1" "CMT"
    #> Error in (function (data, inits, PKpars, model = NULL, pred = NULL, err = NULL, lower = -Inf, upper = Inf, fixed = NULL, skipCov = NULL, control = foceiControl(), thetaNames = NULL, etaNames = NULL, etaMat = NULL, ..., env = NULL, keep = NULL, drop = NULL) { set.seed(control$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.
    #> Timing stopped at: 6.487 0.387 6.872
    f_nlmixr_dfop_sfo_saem_obs <- nlmixr(f_mmkin_obs["DFOP-SFO", ], est = "saem") +
    #> ℹ parameter labels from comments are typically ignored in non-interactive mode
    #> ℹ Need to run with the source intact to parse comments
    #>
    #> → generate SAEM model
    #> ✔ done
    #> 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
    #> Timing stopped at: 1.385 0.1 1.485
    f_nlmixr_dfop_sfo_focei_obs <- nlmixr(f_mmkin_obs["DFOP-SFO", ], est = "focei")
    #> ℹ parameter labels from comments are typically ignored in non-interactive mode
    #> ℹ Need to run with the source intact to parse comments
    #> → creating full model...
    #> → pruning branches (`if`/`else`)...
    #> ✔ done
    #> → loading into symengine environment...
    #> ✔ done
    #> → creating full model...
    #> → pruning branches (`if`/`else`)...
    #> ✔ done
    #> → loading into symengine environment...
    #> ✔ done
    #> → calculate jacobian
    #>
    #> → calculate sensitivities
    #>
    #> → calculate ∂(f)/∂(η)
    #>
    #> → calculate ∂(R²)/∂(η)
    #>
    #> → finding duplicate expressions in inner model...
    #>
    #> → optimizing duplicate expressions in inner model...
    #>
    #> → finding duplicate expressions in EBE model...
    #>
    #> → optimizing duplicate expressions in EBE model...
    #>
    #> → compiling inner model...
    #>
    #> ✔ done
    #> → finding duplicate expressions in FD model...
    #>
    #> → optimizing duplicate expressions in FD model...
    #>
    #> → compiling EBE model...
    #>
    #> ✔ done
    #> → compiling events FD model...
    #>
    #> ✔ done
    #> Model:
    #> cmt(parent); #> cmt(A1); #> rx_expr_6~ETA[1]+THETA[1]; @@ -4717,7 +4718,7 @@ obtained by fitting the same model to a list of datasets using f_parent=1/(1+exp(-(ETA[3]+THETA[3]))); #> g=1/(rx_expr_19); #> tad=tad(); -#> dosenum=dosenum();
    #> Needed Covariates:
    #> [1] "f_parent_to_A1" "CMT"
    #> 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$eta.names, control = control, env = env, keep = .keep, drop = .drop): Not all the covariates are in the dataset.
    #> Timing stopped at: 15.24 0.429 15.67
    +#> dosenum=dosenum();
    #> Needed Covariates:
    #> [1] "f_parent_to_A1" "CMT"
    #> Error in (function (data, inits, PKpars, model = NULL, pred = NULL, err = NULL, lower = -Inf, upper = Inf, fixed = NULL, skipCov = NULL, control = foceiControl(), thetaNames = NULL, etaNames = NULL, etaMat = NULL, ..., env = NULL, keep = NULL, drop = NULL) { set.seed(control$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$eta.names, control = control, env = env, keep = .keep, drop = .drop): Not all the covariates are in the dataset.
    #> Timing stopped at: 15.06 0.434 15.49
    # Identical two-component error for all variables is only possible with # est = 'focei' in nlmixr f_nlmixr_fomc_sfo_focei_tc <- nlmixr(f_mmkin_tc["FOMC-SFO", ], est = "focei") @@ -4771,7 +4772,7 @@ obtained by fitting the same model to a list of datasets using beta=exp(rx_expr_8); #> f_parent=1/(1+exp(-(ETA[3]+THETA[3]))); #> tad=tad(); -#> dosenum=dosenum();
    #> Needed Covariates:
    #> [1] "f_parent_to_A1" "CMT"
    #> Error in (function (data, inits, PKpars, model = NULL, pred = NULL, err = NULL, lower = -Inf, upper = Inf, fixed = NULL, skipCov = NULL, control = foceiControl(), thetaNames = NULL, etaNames = NULL, etaMat = NULL, ..., env = NULL, keep = NULL, drop = NULL) { set.seed(control$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$eta.names, control = control, env = env, keep = .keep, drop = .drop): Not all the covariates are in the dataset.
    #> Timing stopped at: 8.644 0.416 9.058
    f_nlmixr_dfop_sfo_focei_tc <- nlmixr(f_mmkin_tc["DFOP-SFO", ], est = "focei") +#> dosenum=dosenum();
    #> Needed Covariates:
    #> [1] "f_parent_to_A1" "CMT"
    #> Error in (function (data, inits, PKpars, model = NULL, pred = NULL, err = NULL, lower = -Inf, upper = Inf, fixed = NULL, skipCov = NULL, control = foceiControl(), thetaNames = NULL, etaNames = NULL, etaMat = NULL, ..., env = NULL, keep = NULL, drop = NULL) { set.seed(control$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$eta.names, control = control, env = env, keep = .keep, drop = .drop): Not all the covariates are in the dataset.
    #> Timing stopped at: 8.599 0.38 8.975
    f_nlmixr_dfop_sfo_focei_tc <- nlmixr(f_mmkin_tc["DFOP-SFO", ], est = "focei")
    #> ℹ parameter labels from comments are typically ignored in non-interactive mode
    #> ℹ Need to run with the source intact to parse comments
    #> → creating full model...
    #> → pruning branches (`if`/`else`)...
    #> ✔ done
    #> → loading into symengine environment...
    #> ✔ done
    #> → creating full model...
    #> → pruning branches (`if`/`else`)...
    #> ✔ done
    #> → loading into symengine environment...
    #> ✔ done
    #> → calculate jacobian
    #>
    #> → calculate sensitivities
    #>
    #> → calculate ∂(f)/∂(η)
    #>
    #> → calculate ∂(R²)/∂(η)
    #>
    #> → finding duplicate expressions in inner model...
    #>
    #> → optimizing duplicate expressions in inner model...
    #>
    #> → finding duplicate expressions in EBE model...
    #>
    #> → optimizing duplicate expressions in EBE model...
    #>
    #> → compiling inner model...
    #>
    #> ✔ done
    #> → finding duplicate expressions in FD model...
    #>
    #> → optimizing duplicate expressions in FD model...
    #>
    #> → compiling EBE model...
    #>
    #> ✔ done
    #> → compiling events FD model...
    #>
    #> ✔ done
    #> Model:
    #> cmt(parent); #> cmt(A1); #> rx_expr_6~ETA[1]+THETA[1]; @@ -4830,12 +4831,12 @@ obtained by fitting the same model to a list of datasets using f_parent=1/(1+exp(-(ETA[3]+THETA[3]))); #> g=1/(rx_expr_21); #> tad=tad(); -#> dosenum=dosenum();
    #> Needed Covariates:
    #> [1] "f_parent_to_A1" "CMT"
    #> Error in (function (data, inits, PKpars, model = NULL, pred = NULL, err = NULL, lower = -Inf, upper = Inf, fixed = NULL, skipCov = NULL, control = foceiControl(), thetaNames = NULL, etaNames = NULL, etaMat = NULL, ..., env = NULL, keep = NULL, drop = NULL) { set.seed(control$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$eta.names, control = control, env = env, keep = .keep, drop = .drop): Not all the covariates are in the dataset.
    #> Timing stopped at: 18.76 0.426 19.18
    +#> dosenum=dosenum();
    #> Needed Covariates:
    #> [1] "f_parent_to_A1" "CMT"
    #> Error in (function (data, inits, PKpars, model = NULL, pred = NULL, err = NULL, lower = -Inf, upper = Inf, fixed = NULL, skipCov = NULL, control = foceiControl(), thetaNames = NULL, etaNames = NULL, etaMat = NULL, ..., env = NULL, keep = NULL, drop = NULL) { set.seed(control$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.
    #> Timing stopped at: 17.64 0.453 18.09
    # Two-component error by variable is possible with both estimation methods # Variance by variable is supported by 'saem' and 'focei' f_nlmixr_fomc_sfo_saem_obs_tc <- nlmixr(f_mmkin_tc["FOMC-SFO", ], est = "saem", error_model = "obs_tc") -
    #> ℹ parameter labels from comments are typically ignored in non-interactive mode
    #> ℹ Need to run with the source intact to parse comments
    #>
    #> 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
    #> Timing stopped at: 0.757 0.072 0.829
    f_nlmixr_fomc_sfo_focei_obs_tc <- nlmixr(f_mmkin_tc["FOMC-SFO", ], est = "focei", +
    #> ℹ parameter labels from comments are typically ignored in non-interactive mode
    #> ℹ Need to run with the source intact to parse comments
    #>
    #> 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
    #> Timing stopped at: 0.772 0.04 0.813
    f_nlmixr_fomc_sfo_focei_obs_tc <- nlmixr(f_mmkin_tc["FOMC-SFO", ], est = "focei", error_model = "obs_tc")
    #> ℹ parameter labels from comments are typically ignored in non-interactive mode
    #> ℹ Need to run with the source intact to parse comments
    #> → creating full model...
    #> → pruning branches (`if`/`else`)...
    #> ✔ done
    #> → loading into symengine environment...
    #> ✔ done
    #> → creating full model...
    #> → pruning branches (`if`/`else`)...
    #> ✔ done
    #> → loading into symengine environment...
    #> ✔ done
    #> → calculate jacobian
    #>
    #> → calculate sensitivities
    #>
    #> → calculate ∂(f)/∂(η)
    #>
    #> → calculate ∂(R²)/∂(η)
    #>
    #> → finding duplicate expressions in inner model...
    #>
    #> → optimizing duplicate expressions in inner model...
    #>
    #> → finding duplicate expressions in EBE model...
    #>
    #> → optimizing duplicate expressions in EBE model...
    #>
    #> → compiling inner model...
    #>
    #> ✔ done
    #> → finding duplicate expressions in FD model...
    #>
    #> → optimizing duplicate expressions in FD model...
    #>
    #> → compiling EBE model...
    #>
    #> ✔ done
    #> → compiling events FD model...
    #>
    #> ✔ done
    #> Model:
    #> cmt(parent); #> cmt(A1); @@ -4887,9 +4888,9 @@ obtained by fitting the same model to a list of datasets using beta=exp(rx_expr_8); #> f_parent=1/(1+exp(-(ETA[3]+THETA[3]))); #> tad=tad(); -#> dosenum=dosenum();
    #> Needed Covariates:
    #> [1] "f_parent_to_A1" "CMT"
    #> 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$eta.names, control = control, env = env, keep = .keep, drop = .drop): Not all the covariates are in the dataset.
    #> Timing stopped at: 8.417 0.388 8.803
    f_nlmixr_dfop_sfo_saem_obs_tc <- nlmixr(f_mmkin_tc["DFOP-SFO", ], est = "saem", +#> dosenum=dosenum();
    #> Needed Covariates:
    #> [1] "f_parent_to_A1" "CMT"
    #> Error in (function (data, inits, PKpars, model = NULL, pred = NULL, err = NULL, lower = -Inf, upper = Inf, fixed = NULL, skipCov = NULL, control = foceiControl(), thetaNames = NULL, etaNames = NULL, etaMat = NULL, ..., env = NULL, keep = NULL, drop = NULL) { set.seed(control$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.
    #> Timing stopped at: 8.33 0.419 8.745
    f_nlmixr_dfop_sfo_saem_obs_tc <- nlmixr(f_mmkin_tc["DFOP-SFO", ], est = "saem", error_model = "obs_tc") -
    #> ℹ parameter labels from comments are typically ignored in non-interactive mode
    #> ℹ Need to run with the source intact to parse comments
    #>
    #> 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
    #> Timing stopped at: 0.82 0.035 0.857
    f_nlmixr_dfop_sfo_focei_obs_tc <- nlmixr(f_mmkin_tc["DFOP-SFO", ], est = "focei", +
    #> ℹ parameter labels from comments are typically ignored in non-interactive mode
    #> ℹ Need to run with the source intact to parse comments
    #>
    #> 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
    #> Timing stopped at: 0.832 0.032 0.866
    f_nlmixr_dfop_sfo_focei_obs_tc <- nlmixr(f_mmkin_tc["DFOP-SFO", ], est = "focei", error_model = "obs_tc")
    #> ℹ parameter labels from comments are typically ignored in non-interactive mode
    #> ℹ Need to run with the source intact to parse comments
    #> → creating full model...
    #> → pruning branches (`if`/`else`)...
    #> ✔ done
    #> → loading into symengine environment...
    #> ✔ done
    #> → creating full model...
    #> → pruning branches (`if`/`else`)...
    #> ✔ done
    #> → loading into symengine environment...
    #> ✔ done
    #> → calculate jacobian
    #>
    #> → calculate sensitivities
    #>
    #> → calculate ∂(f)/∂(η)
    #>
    #> → calculate ∂(R²)/∂(η)
    #>
    #> → finding duplicate expressions in inner model...
    #>
    #> → optimizing duplicate expressions in inner model...
    #>
    #> → finding duplicate expressions in EBE model...
    #>
    #> → optimizing duplicate expressions in EBE model...
    #>
    #> → compiling inner model...
    #>
    #> ✔ done
    #> → finding duplicate expressions in FD model...
    #>
    #> → optimizing duplicate expressions in FD model...
    #>
    #> → compiling EBE model...
    #>
    #> ✔ done
    #> → compiling events FD model...
    #>
    #> ✔ done
    #> Model:
    #> cmt(parent); #> cmt(A1); @@ -4949,7 +4950,7 @@ obtained by fitting the same model to a list of datasets using f_parent=1/(1+exp(-(ETA[3]+THETA[3]))); #> g=1/(rx_expr_19); #> tad=tad(); -#> dosenum=dosenum();
    #> Needed Covariates:
    #> [1] "f_parent_to_A1" "CMT"
    #> 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$eta.names, control = control, env = env, keep = .keep, drop = .drop): Not all the covariates are in the dataset.
    #> Timing stopped at: 17.61 0.452 18.06
    +#> dosenum=dosenum();
    #> Needed Covariates:
    #> [1] "f_parent_to_A1" "CMT"
    #> Error in (function (data, inits, PKpars, model = NULL, pred = NULL, err = NULL, lower = -Inf, upper = Inf, fixed = NULL, skipCov = NULL, control = foceiControl(), thetaNames = NULL, etaNames = NULL, etaMat = NULL, ..., env = NULL, keep = NULL, drop = NULL) { set.seed(control$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$eta.names, control = control, env = env, keep = .keep, drop = .drop): Not all the covariates are in the dataset.
    #> Timing stopped at: 18.15 0.42 18.57
    AIC( f_nlmixr_sfo_sfo_focei_const$nm, f_nlmixr_fomc_sfo_focei_const$nm, diff --git a/docs/dev/reference/plot.mixed.mmkin.html b/docs/dev/reference/plot.mixed.mmkin.html index 746a8640..9f0eb965 100644 --- a/docs/dev/reference/plot.mixed.mmkin.html +++ b/docs/dev/reference/plot.mixed.mmkin.html @@ -72,7 +72,7 @@ mkin - 1.0.5 + 1.1.0
    @@ -296,10 +296,10 @@ corresponding model prediction lines for the different datasets.

    f_saem <- saem(f, transformations = "saemix")
    #> Running main SAEM algorithm -#> [1] "Wed Aug 4 16:21:52 2021" +#> [1] "Thu Sep 16 14:34:31 2021" #> .... #> Minimisation finished -#> [1] "Wed Aug 4 16:22:00 2021"
    plot(f_saem) +#> [1] "Thu Sep 16 14:34:38 2021"
    plot(f_saem)
    f_obs <- mmkin(list("DFOP-SFO" = dfop_sfo), ds, quiet = TRUE, error_model = "obs") f_nlmix <- nlmix(f_obs) 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. mkin - 1.0.5 + 1.1.0
    diff --git a/docs/dev/reference/saem.html b/docs/dev/reference/saem.html index 620173b2..8d986126 100644 --- a/docs/dev/reference/saem.html +++ b/docs/dev/reference/saem.html @@ -74,7 +74,7 @@ Expectation Maximisation algorithm (SAEM)." /> mkin - 1.0.5 + 1.1.0 @@ -288,27 +288,27 @@ using mmkin.

    state.ini = c(parent = 100), fixed_initials = "parent", quiet = TRUE) f_saem_p0_fixed <- saem(f_mmkin_parent_p0_fixed)
    #> Running main SAEM algorithm -#> [1] "Wed Aug 4 16:22:05 2021" +#> [1] "Thu Sep 16 14:34:42 2021" #> .... #> Minimisation finished -#> [1] "Wed Aug 4 16:22:06 2021"
    +#> [1] "Thu Sep 16 14:34:43 2021"
    f_mmkin_parent <- mmkin(c("SFO", "FOMC", "DFOP"), ds, quiet = TRUE) f_saem_sfo <- saem(f_mmkin_parent["SFO", ])
    #> Running main SAEM algorithm -#> [1] "Wed Aug 4 16:22:08 2021" +#> [1] "Thu Sep 16 14:34:45 2021" #> .... #> Minimisation finished -#> [1] "Wed Aug 4 16:22:10 2021"
    f_saem_fomc <- saem(f_mmkin_parent["FOMC", ]) +#> [1] "Thu Sep 16 14:34:47 2021"
    f_saem_fomc <- saem(f_mmkin_parent["FOMC", ])
    #> Running main SAEM algorithm -#> [1] "Wed Aug 4 16:22:10 2021" +#> [1] "Thu Sep 16 14:34:47 2021" #> .... #> Minimisation finished -#> [1] "Wed Aug 4 16:22:12 2021"
    f_saem_dfop <- saem(f_mmkin_parent["DFOP", ]) +#> [1] "Thu Sep 16 14:34:49 2021"
    f_saem_dfop <- saem(f_mmkin_parent["DFOP", ])
    #> Running main SAEM algorithm -#> [1] "Wed Aug 4 16:22:12 2021" +#> [1] "Thu Sep 16 14:34:49 2021" #> .... #> Minimisation finished -#> [1] "Wed Aug 4 16:22:16 2021"
    +#> [1] "Thu Sep 16 14:34:52 2021"
    # The returned saem.mmkin object contains an SaemixObject, therefore we can use # functions from saemix library(saemix) @@ -357,10 +357,10 @@ using mmkin.

    f_mmkin_parent_tc <- update(f_mmkin_parent, error_model = "tc") f_saem_fomc_tc <- saem(f_mmkin_parent_tc["FOMC", ])
    #> Running main SAEM algorithm -#> [1] "Wed Aug 4 16:22:19 2021" +#> [1] "Thu Sep 16 14:34:55 2021" #> .... #> Minimisation finished -#> [1] "Wed Aug 4 16:22:24 2021"
    compare.saemix(f_saem_fomc$so, f_saem_fomc_tc$so) +#> [1] "Thu Sep 16 14:35:00 2021"
    compare.saemix(f_saem_fomc$so, f_saem_fomc_tc$so)
    #> Likelihoods calculated by importance sampling
    #> AIC BIC #> 1 467.7096 464.9757 #> 2 469.6831 466.5586
    @@ -381,15 +381,15 @@ using mmkin.

    # four minutes f_saem_sfo_sfo <- saem(f_mmkin["SFO-SFO", ])
    #> Running main SAEM algorithm -#> [1] "Wed Aug 4 16:22:27 2021" +#> [1] "Thu Sep 16 14:35:03 2021" #> .... #> Minimisation finished -#> [1] "Wed Aug 4 16:22:32 2021"
    f_saem_dfop_sfo <- saem(f_mmkin["DFOP-SFO", ]) +#> [1] "Thu Sep 16 14:35:08 2021"
    f_saem_dfop_sfo <- saem(f_mmkin["DFOP-SFO", ])
    #> Running main SAEM algorithm -#> [1] "Wed Aug 4 16:22:33 2021" +#> [1] "Thu Sep 16 14:35:08 2021" #> .... #> Minimisation finished -#> [1] "Wed Aug 4 16:22:42 2021"
    # We can use print, plot and summary methods to check the results +#> [1] "Thu Sep 16 14:35:17 2021"
    # We can use print, plot and summary methods to check the results print(f_saem_dfop_sfo)
    #> Kinetic nonlinear mixed-effects model fit by SAEM #> Structural model: @@ -430,10 +430,10 @@ using mmkin.

    #> SD.g_qlogis 0.44816 -1.25437 2.1507
    plot(f_saem_dfop_sfo)
    summary(f_saem_dfop_sfo, data = TRUE)
    #> saemix version used for fitting: 3.1.9000 -#> mkin version used for pre-fitting: 1.0.5 -#> R version used for fitting: 4.1.0 -#> Date of fit: Wed Aug 4 16:22:43 2021 -#> Date of summary: Wed Aug 4 16:22:43 2021 +#> mkin version used for pre-fitting: 1.1.0 +#> R version used for fitting: 4.1.1 +#> Date of fit: Thu Sep 16 14:35:18 2021 +#> Date of summary: Thu Sep 16 14:35:18 2021 #> #> Equations: #> d_parent/dt = - ((k1 * g * exp(-k1 * time) + k2 * (1 - g) * exp(-k2 * @@ -448,7 +448,7 @@ using mmkin.

    #> #> Model predictions using solution type analytical #> -#> Fitted in 10.143 s using 300, 100 iterations +#> Fitted in 9.349 s using 300, 100 iterations #> #> Variance model: Constant variance #> diff --git a/docs/dev/reference/summary.nlmixr.mmkin.html b/docs/dev/reference/summary.nlmixr.mmkin.html index 70a71683..4831bbdf 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 mkin - 1.0.5 + 1.1.0
    @@ -258,12 +258,12 @@ nlmixr authors for the parts inherited from nlmixr.

    quiet = TRUE, error_model = "tc", cores = 5) f_saemix_dfop_sfo <- mkin::saem(f_mmkin_dfop_sfo)
    #> Running main SAEM algorithm -#> [1] "Wed Aug 4 16:22:46 2021" +#> [1] "Thu Sep 16 14:35:21 2021" #> .... #> Minimisation finished -#> [1] "Wed Aug 4 16:22:59 2021"
    f_nlme_dfop_sfo <- mkin::nlme(f_mmkin_dfop_sfo) +#> [1] "Thu Sep 16 14:35:33 2021"
    f_nlme_dfop_sfo <- mkin::nlme(f_mmkin_dfop_sfo)
    #> Warning: Iteration 4, LME step: nlminb() did not converge (code = 1). PORT message: false convergence (8)
    #> Warning: Iteration 6, LME step: nlminb() did not converge (code = 1). PORT message: false convergence (8)
    f_nlmixr_dfop_sfo_saem <- nlmixr(f_mmkin_dfop_sfo, est = "saem") -
    #> 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)
    #> ℹ parameter labels from comments are typically ignored in non-interactive mode
    #> ℹ Need to run with the source intact to parse comments
    #>
    #> → generate SAEM model
    #> ✔ done
    #> 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
    #> Timing stopped at: 1.383 0.12 1.503
    # The following takes a very long time but gives +
    #> 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)
    #> ℹ parameter labels from comments are typically ignored in non-interactive mode
    #> ℹ Need to run with the source intact to parse comments
    #>
    #> → generate SAEM model
    #> ✔ done
    #> 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
    #> Timing stopped at: 1.412 0.101 1.525
    # The following takes a very long time but gives f_nlmixr_dfop_sfo_focei <- nlmixr(f_mmkin_dfop_sfo, est = "focei")
    #> ℹ parameter labels from comments are typically ignored in non-interactive mode
    #> ℹ Need to run with the source intact to parse comments
    #> → creating full model...
    #> → pruning branches (`if`/`else`)...
    #> ✔ done
    #> → loading into symengine environment...
    #> ✔ done
    #> → creating full model...
    #> → pruning branches (`if`/`else`)...
    #> ✔ done
    #> → loading into symengine environment...
    #> ✔ done
    #> → calculate jacobian
    #>
    #> → calculate sensitivities
    #>
    #> → calculate ∂(f)/∂(η)
    #>
    #> → calculate ∂(R²)/∂(η)
    #>
    #> → finding duplicate expressions in inner model...
    #>
    #> → optimizing duplicate expressions in inner model...
    #>
    #> → finding duplicate expressions in EBE model...
    #>
    #> → optimizing duplicate expressions in EBE model...
    #>
    #> → compiling inner model...
    #>
    #> ✔ done
    #> → finding duplicate expressions in FD model...
    #>
    #> → optimizing duplicate expressions in FD model...
    #>
    #> → compiling EBE model...
    #>
    #> ✔ done
    #> → compiling events FD model...
    #>
    #> ✔ done
    #> Model:
    #> cmt(parent); #> cmt(m1); @@ -323,7 +323,7 @@ nlmixr authors for the parts inherited from nlmixr.

    #> f_parent=1/(1+exp(-(ETA[3]+THETA[3]))); #> g=1/(rx_expr_21); #> tad=tad(); -#> dosenum=dosenum();
    #> Needed Covariates:
    #> [1] "f_parent_to_m1" "CMT"
    #> 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.
    #> Timing stopped at: 18.43 0.422 18.87
    AIC(f_nlmixr_dfop_sfo_saem$nm, f_nlmixr_dfop_sfo_focei$nm) +#> dosenum=dosenum();
    #> Needed Covariates:
    #> [1] "f_parent_to_m1" "CMT"
    #> 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.
    #> Timing stopped at: 18.28 0.455 18.73
    AIC(f_nlmixr_dfop_sfo_saem$nm, f_nlmixr_dfop_sfo_focei$nm)
    #> Error in AIC(f_nlmixr_dfop_sfo_saem$nm, f_nlmixr_dfop_sfo_focei$nm): object 'f_nlmixr_dfop_sfo_saem' not found
    summary(f_nlmixr_dfop_sfo_sfo, data = TRUE)
    #> 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
    # } 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." /> mkin - 1.0.5 + 1.1.0
    diff --git a/test.log b/test.log index 90719917..f68ec45a 100644 --- a/test.log +++ b/test.log @@ -3,7 +3,7 @@ Loading required package: parallel ℹ Testing mkin ✔ | OK F W S | Context ✔ | 5 | AIC calculation -✔ | 5 | Analytical solutions for coupled models [3.3 s] +✔ | 5 | Analytical solutions for coupled models [3.4 s] ✔ | 5 | Calculation of Akaike weights ✔ | 2 | Export dataset for reading into CAKE ✔ | 12 | Confidence intervals and p-values [1.0 s] @@ -13,7 +13,7 @@ Loading required package: parallel ✔ | 14 | Results for FOCUS D established in expertise for UBA (Ranke 2014) [0.8 s] ✔ | 4 | Test fitting the decline of metabolites from their maximum [0.3 s] ✔ | 1 | Fitting the logistic model [0.2 s] -✔ | 35 1 | Nonlinear mixed-effects models [26.6 s] +✔ | 35 1 | Nonlinear mixed-effects models [26.3 s] ──────────────────────────────────────────────────────────────────────────────── Skip (test_mixed.R:161:3): saem results are reproducible for biphasic fits Reason: Fitting with saemix takes around 10 minutes when using deSolve @@ -36,7 +36,7 @@ Reason: Fitting with saemix takes around 10 minutes when using deSolve ✔ | 4 | Calculation of maximum time weighted average concentrations (TWAs) [2.3 s] ══ Results ═════════════════════════════════════════════════════════════════════ -Duration: 67.8 s +Duration: 67.6 s ── Skipped tests ────────────────────────────────────────────────────────────── • Fitting with saemix takes around 10 minutes when using deSolve (1) diff --git a/vignettes/FOCUS_D.html b/vignettes/FOCUS_D.html index 0e983b98..ba514c18 100644 --- a/vignettes/FOCUS_D.html +++ b/vignettes/FOCUS_D.html @@ -360,7 +360,7 @@ pre code {

    Example evaluation of FOCUS Example Dataset D

    Johannes Ranke

    -

    Last change 31 January 2019 (rebuilt 2021-09-15)

    +

    Last change 31 January 2019 (rebuilt 2021-09-16)

    @@ -434,10 +434,10 @@ print(FOCUS_2006_D)

    A comprehensive report of the results is obtained using the summary method for mkinfit objects.

    summary(fit)
    -
    ## mkin version used for fitting:    1.0.5 
+
    ## mkin version used for fitting:    1.1.0 
 ## R version used for fitting:       4.1.1 
-## Date of fit:     Wed Sep 15 17:39:28 2021 
-## Date of summary: Wed Sep 15 17:39:28 2021 
+## Date of fit:     Thu Sep 16 13:57:32 2021 
+## Date of summary: Thu Sep 16 13:57:33 2021 
 ## 
 ## Equations:
 ## d_parent/dt = - k_parent * parent
@@ -445,7 +445,7 @@ print(FOCUS_2006_D)
    
 ## 
 ## Model predictions using solution type analytical 
 ## 
-## Fitted using 401 model solutions performed in 0.143 s
+## Fitted using 401 model solutions performed in 0.149 s
 ## 
 ## Error model: Constant variance 
 ## 
diff --git a/vignettes/FOCUS_L.html b/vignettes/FOCUS_L.html
index 717a01be..b6ebb606 100644
--- a/vignettes/FOCUS_L.html
+++ b/vignettes/FOCUS_L.html
@@ -27,11 +27,8 @@ document.addEventListener('DOMContentLoaded', function(e) {
   }
 });
 
-