Fit nonlinear mixed models with SAEM

This function uses saemix::saemix() as a backend for fitting nonlinear mixed -effects models created from mmkin row objects using the Stochastic Approximation +

This function uses saemix::saemix() as a backend for fitting nonlinear mixed +effects models created from mmkin row objects using the Stochastic Approximation Expectation Maximisation algorithm (SAEM).

saem(object, ...)
-
-# S3 method for mmkin
-saem(
-  object,
-  transformations = c("mkin", "saemix"),
-  degparms_start = numeric(),
-  test_log_parms = TRUE,
-  conf.level = 0.6,
-  solution_type = "auto",
-  nbiter.saemix = c(300, 100),
-  control = list(displayProgress = FALSE, print = FALSE, nbiter.saemix = nbiter.saemix,
-    save = FALSE, save.graphs = FALSE),
-  fail_with_errors = TRUE,
-  verbose = FALSE,
-  quiet = FALSE,
-  ...
-)
-
-# S3 method for saem.mmkin
-print(x, digits = max(3, getOption("digits") - 3), ...)
-
-saemix_model(
-  object,
-  solution_type = "auto",
-  transformations = c("mkin", "saemix"),
-  degparms_start = numeric(),
-  test_log_parms = FALSE,
-  verbose = FALSE,
-  ...
-)
-
-saemix_data(object, verbose = FALSE, ...)

saem(object, ...)
+
+# S3 method for mmkin
+saem(
+  object,
+  transformations = c("mkin", "saemix"),
+  degparms_start = numeric(),
+  test_log_parms = TRUE,
+  conf.level = 0.6,
+  solution_type = "auto",
+  nbiter.saemix = c(300, 100),
+  control = list(displayProgress = FALSE, print = FALSE, nbiter.saemix = nbiter.saemix,
+    save = FALSE, save.graphs = FALSE),
+  fail_with_errors = TRUE,
+  verbose = FALSE,
+  quiet = FALSE,
+  ...
+)
+
+# S3 method for saem.mmkin
+print(x, digits = max(3, getOption("digits") - 3), ...)
+
+saemix_model(
+  object,
+  solution_type = "auto",
+  transformations = c("mkin", "saemix"),
+  degparms_start = numeric(),
+  test_log_parms = FALSE,
+  verbose = FALSE,
+  ...
+)
+
+saemix_data(object, verbose = FALSE, ...)

Arguments

- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

object	An mmkin row object containing several fits of the same -mkinmod model to different datasets
...	Further parameters passed to saemix::saemixModel.
transformations	Per default, all parameter transformations are done + + Arguments + object + An mmkin row object containing several fits of the same +mkinmod model to different datasets + ... + Further parameters passed to saemix::saemixModel. + transformations + Per default, all parameter transformations are done in mkin. If this argument is set to 'saemix', parameter transformations are done in 'saemix' for the supported cases. Currently this is only supported in cases where the initial concentration of the parent is not fixed, -SFO or DFOP is used for the parent and there is either no metabolite or one.
degparms_start	Parameter values given as a named numeric vector will -be used to override the starting values obtained from the 'mmkin' object.
test_log_parms	If TRUE, an attempt is made to use more robust starting +SFO or DFOP is used for the parent and there is either no metabolite or one. + degparms_start + Parameter values given as a named numeric vector will +be used to override the starting values obtained from the 'mmkin' object. + test_log_parms + If TRUE, an attempt is made to use more robust starting values for population parameters fitted as log parameters in mkin (like rate constants) by only considering rate constants that pass the t-test -when calculating mean degradation parameters using mean_degparms.
conf.level	Possibility to adjust the required confidence level -for parameter that are tested if requested by 'test_log_parms'.
solution_type	Possibility to specify the solution type in case the -automatic choice is not desired
nbiter.saemix	Convenience option to increase the number of -iterations
control	Passed to saemix::saemix.
fail_with_errors	Should a failure to compute standard errors -from the inverse of the Fisher Information Matrix be a failure?
verbose	Should we print information about created objects of -type saemix::SaemixModel and saemix::SaemixData?
quiet	Should we suppress the messages saemix prints at the beginning -and the end of the optimisation process?
x	An saem.mmkin object to print
digits	Number of digits to use for printing

- -

Value

- +when calculating mean degradation parameters using mean_degparms.

conf.level

Possibility to adjust the required confidence level +for parameter that are tested if requested by 'test_log_parms'.

solution_type

Possibility to specify the solution type in case the +automatic choice is not desired

nbiter.saemix

Convenience option to increase the number of +iterations

control

Passed to saemix::saemix.

fail_with_errors

Should a failure to compute standard errors +from the inverse of the Fisher Information Matrix be a failure?

verbose

Should we print information about created objects of +type saemix::SaemixModel and saemix::SaemixData?

quiet

Should we suppress the messages saemix prints at the beginning +and the end of the optimisation process?

An saem.mmkin object to print

digits

Number of digits to use for printing

Value

An S3 object of class 'saem.mmkin', containing the fitted -saemix::SaemixObject as a list component named 'so'. The -object also inherits from 'mixed.mmkin'.

An saemix::SaemixModel object.

An saemix::SaemixData object.

Details

- +saemix::SaemixObject as a list component named 'so'. The +object also inherits from 'mixed.mmkin'. +An saemix::SaemixModel object. +An saemix::SaemixData object.

Details

An mmkin row object is essentially a list of mkinfit objects that have been -obtained by fitting the same model to a list of datasets using mkinfit.

+obtained by fitting the same model to a list of datasets using mkinfit.

Starting values for the fixed effects (population mean parameters, argument -psi0 of saemix::saemixModel() are the mean values of the parameters found -using mmkin.

Examples

# \dontrun{
-ds <- lapply(experimental_data_for_UBA_2019[6:10],
- function(x) subset(x$data[c("name", "time", "value")]))
-names(ds) <- paste("Dataset", 6:10)
-f_mmkin_parent_p0_fixed <- mmkin("FOMC", ds,
-  state.ini = c(parent = 100), fixed_initials = "parent", quiet = TRUE)
-f_saem_p0_fixed <- saem(f_mmkin_parent_p0_fixed)
-
#> Warning: argument is not a function
#>  
#> Error in rxModelVars_(obj): Not compatible with STRSXP: [type=NULL].

-f_mmkin_parent <- mmkin(c("SFO", "FOMC", "DFOP"), ds, quiet = TRUE)
-f_saem_sfo <- saem(f_mmkin_parent["SFO", ])
-
#> Warning: argument is not a function
#>  
#> Error in rxModelVars_(obj): Not compatible with STRSXP: [type=NULL].
f_saem_fomc <- saem(f_mmkin_parent["FOMC", ])
-
#> Warning: argument is not a function
#>  
#> Error in rxModelVars_(obj): Not compatible with STRSXP: [type=NULL].
f_saem_dfop <- saem(f_mmkin_parent["DFOP", ])
-
#> Warning: argument is not a function
#>  
#> Error in rxModelVars_(obj): Not compatible with STRSXP: [type=NULL].

-# The returned saem.mmkin object contains an SaemixObject, therefore we can use
-# functions from saemix
-library(saemix)
-
#> Package saemix, version 3.1.9000
-#>   please direct bugs, questions and feedback to emmanuelle.comets@inserm.fr
#> 
-#> Attaching package: ‘saemix’
#> The following object is masked from ‘package:RxODE’:
-#> 
-#>     phi
compare.saemix(f_saem_sfo$so, f_saem_fomc$so, f_saem_dfop$so)
-
#> Error in compare.saemix(f_saem_sfo$so, f_saem_fomc$so, f_saem_dfop$so): object 'f_saem_sfo' not found
plot(f_saem_fomc$so, plot.type = "convergence")
-
#> Error in h(simpleError(msg, call)): error in evaluating the argument 'x' in selecting a method for function 'plot': object 'f_saem_fomc' not found
plot(f_saem_fomc$so, plot.type = "individual.fit")
-
#> Error in h(simpleError(msg, call)): error in evaluating the argument 'x' in selecting a method for function 'plot': object 'f_saem_fomc' not found
plot(f_saem_fomc$so, plot.type = "npde")
-
#> Error in h(simpleError(msg, call)): error in evaluating the argument 'x' in selecting a method for function 'plot': object 'f_saem_fomc' not found
plot(f_saem_fomc$so, plot.type = "vpc")
-
#> Error in h(simpleError(msg, call)): error in evaluating the argument 'x' in selecting a method for function 'plot': object 'f_saem_fomc' not found

-f_mmkin_parent_tc <- update(f_mmkin_parent, error_model = "tc")
-f_saem_fomc_tc <- saem(f_mmkin_parent_tc["FOMC", ])
-
#> Warning: argument is not a function
#>  
#> Error in rxModelVars_(obj): Not compatible with STRSXP: [type=NULL].
compare.saemix(f_saem_fomc$so, f_saem_fomc_tc$so)
-
#> Error in compare.saemix(f_saem_fomc$so, f_saem_fomc_tc$so): object 'f_saem_fomc' not found

-sfo_sfo <- mkinmod(parent = mkinsub("SFO", "A1"),
-  A1 = mkinsub("SFO"))
-
#> Temporary DLL for differentials generated and loaded
fomc_sfo <- mkinmod(parent = mkinsub("FOMC", "A1"),
-  A1 = mkinsub("SFO"))
-
#> Temporary DLL for differentials generated and loaded
dfop_sfo <- mkinmod(parent = mkinsub("DFOP", "A1"),
-  A1 = mkinsub("SFO"))
-
#> Temporary DLL for differentials generated and loaded
# The following fit uses analytical solutions for SFO-SFO and DFOP-SFO,
-# and compiled ODEs for FOMC that are much slower
-f_mmkin <- mmkin(list(
-    "SFO-SFO" = sfo_sfo, "FOMC-SFO" = fomc_sfo, "DFOP-SFO" = dfop_sfo),
-  ds, quiet = TRUE)
-# saem fits of SFO-SFO and DFOP-SFO to these data take about five seconds
-# each on this system, as we use analytical solutions written for saemix.
-# When using the analytical solutions written for mkin this took around
-# four minutes
-f_saem_sfo_sfo <- saem(f_mmkin["SFO-SFO", ])
-
#> Warning: argument is not a function
#>  
#> Error in rxModelVars_(obj): Not compatible with STRSXP: [type=NULL].
f_saem_dfop_sfo <- saem(f_mmkin["DFOP-SFO", ])
-
#> Warning: argument is not a function
#>  
#> Error in rxModelVars_(obj): Not compatible with STRSXP: [type=NULL].
# We can use print, plot and summary methods to check the results
-print(f_saem_dfop_sfo)
-
#> Error in h(simpleError(msg, call)): error in evaluating the argument 'x' in selecting a method for function 'print': object 'f_saem_dfop_sfo' not found
plot(f_saem_dfop_sfo)
-
#> Error in h(simpleError(msg, call)): error in evaluating the argument 'x' in selecting a method for function 'plot': object 'f_saem_dfop_sfo' not found
summary(f_saem_dfop_sfo, data = TRUE)
-
#> Error in h(simpleError(msg, call)): error in evaluating the argument 'object' in selecting a method for function 'summary': object 'f_saem_dfop_sfo' not found

-# The following takes about 6 minutes
-#f_saem_dfop_sfo_deSolve <- saem(f_mmkin["DFOP-SFO", ], solution_type = "deSolve",
-#  control = list(nbiter.saemix = c(200, 80), nbdisplay = 10))
-
-#saemix::compare.saemix(list(
-#  f_saem_dfop_sfo$so,
-#  f_saem_dfop_sfo_deSolve$so))
+psi0 of saemix::saemixModel() are the mean values of the parameters found
+using mmkin.
+    
+    
+    See also
+    summary.saem.mmkin plot.mixed.mmkin
+    
 
-# If the model supports it, we can also use eigenvalue based solutions, which
-# take a similar amount of time
-#f_saem_sfo_sfo_eigen <- saem(f_mmkin["SFO-SFO", ], solution_type = "eigen",
-#  control = list(nbiter.saemix = c(200, 80), nbdisplay = 10))
-# }
-

Examples

# \dontrun{
+ds <- lapply(experimental_data_for_UBA_2019[6:10],
+ function(x) subset(x$data[c("name", "time", "value")]))
+names(ds) <- paste("Dataset", 6:10)
+f_mmkin_parent_p0_fixed <- mmkin("FOMC", ds,
+  state.ini = c(parent = 100), fixed_initials = "parent", quiet = TRUE)
+f_saem_p0_fixed <- saem(f_mmkin_parent_p0_fixed)
+#>  
+#> Error in rxModelVars_(obj): Not compatible with STRSXP: [type=NULL].
+
+f_mmkin_parent <- mmkin(c("SFO", "FOMC", "DFOP"), ds, quiet = TRUE)
+f_saem_sfo <- saem(f_mmkin_parent["SFO", ])
+#>  
+#> Error in rxModelVars_(obj): Not compatible with STRSXP: [type=NULL].
+f_saem_fomc <- saem(f_mmkin_parent["FOMC", ])
+#>  
+#> Error in rxModelVars_(obj): Not compatible with STRSXP: [type=NULL].
+f_saem_dfop <- saem(f_mmkin_parent["DFOP", ])
+#>  
+#> Error in rxModelVars_(obj): Not compatible with STRSXP: [type=NULL].
+
+# The returned saem.mmkin object contains an SaemixObject, therefore we can use
+# functions from saemix
+library(saemix)
+#> Loading required package: npde
+#> 
+#> Attaching package: ‘npde’
+#> The following object is masked from ‘package:nlmixr’:
+#> 
+#>     warfarin
+#> Package saemix, version 3.0
+#>   please direct bugs, questions and feedback to emmanuelle.comets@inserm.fr
+#> 
+#> Attaching package: ‘saemix’
+#> The following objects are masked from ‘package:npde’:
+#> 
+#>     kurtosis, skewness
+#> The following object is masked from ‘package:RxODE’:
+#> 
+#>     phi
+compare.saemix(f_saem_sfo$so, f_saem_fomc$so, f_saem_dfop$so)
+#> Error in compare.saemix(f_saem_sfo$so, f_saem_fomc$so, f_saem_dfop$so): object 'f_saem_sfo' not found
+plot(f_saem_fomc$so, plot.type = "convergence")
+#> Error in h(simpleError(msg, call)): error in evaluating the argument 'x' in selecting a method for function 'plot': object 'f_saem_fomc' not found
+plot(f_saem_fomc$so, plot.type = "individual.fit")
+#> Error in h(simpleError(msg, call)): error in evaluating the argument 'x' in selecting a method for function 'plot': object 'f_saem_fomc' not found
+plot(f_saem_fomc$so, plot.type = "npde")
+#> Error in h(simpleError(msg, call)): error in evaluating the argument 'x' in selecting a method for function 'plot': object 'f_saem_fomc' not found
+plot(f_saem_fomc$so, plot.type = "vpc")
+#> Error in h(simpleError(msg, call)): error in evaluating the argument 'x' in selecting a method for function 'plot': object 'f_saem_fomc' not found
+
+f_mmkin_parent_tc <- update(f_mmkin_parent, error_model = "tc")
+f_saem_fomc_tc <- saem(f_mmkin_parent_tc["FOMC", ])
+#>  
+#> Error in rxModelVars_(obj): Not compatible with STRSXP: [type=NULL].
+compare.saemix(f_saem_fomc$so, f_saem_fomc_tc$so)
+#> Error in compare.saemix(f_saem_fomc$so, f_saem_fomc_tc$so): object 'f_saem_fomc' not found
+
+sfo_sfo <- mkinmod(parent = mkinsub("SFO", "A1"),
+  A1 = mkinsub("SFO"))
+#> Temporary DLL for differentials generated and loaded
+fomc_sfo <- mkinmod(parent = mkinsub("FOMC", "A1"),
+  A1 = mkinsub("SFO"))
+#> Temporary DLL for differentials generated and loaded
+dfop_sfo <- mkinmod(parent = mkinsub("DFOP", "A1"),
+  A1 = mkinsub("SFO"))
+#> Temporary DLL for differentials generated and loaded
+# The following fit uses analytical solutions for SFO-SFO and DFOP-SFO,
+# and compiled ODEs for FOMC that are much slower
+f_mmkin <- mmkin(list(
+    "SFO-SFO" = sfo_sfo, "FOMC-SFO" = fomc_sfo, "DFOP-SFO" = dfop_sfo),
+  ds, quiet = TRUE)
+# saem fits of SFO-SFO and DFOP-SFO to these data take about five seconds
+# each on this system, as we use analytical solutions written for saemix.
+# When using the analytical solutions written for mkin this took around
+# four minutes
+f_saem_sfo_sfo <- saem(f_mmkin["SFO-SFO", ])
+#>  
+#> Error in rxModelVars_(obj): Not compatible with STRSXP: [type=NULL].
+f_saem_dfop_sfo <- saem(f_mmkin["DFOP-SFO", ])
+#>  
+#> Error in rxModelVars_(obj): Not compatible with STRSXP: [type=NULL].
+# We can use print, plot and summary methods to check the results
+print(f_saem_dfop_sfo)
+#> Error in h(simpleError(msg, call)): error in evaluating the argument 'x' in selecting a method for function 'print': object 'f_saem_dfop_sfo' not found
+plot(f_saem_dfop_sfo)
+#> Error in h(simpleError(msg, call)): error in evaluating the argument 'x' in selecting a method for function 'plot': object 'f_saem_dfop_sfo' not found
+summary(f_saem_dfop_sfo, data = TRUE)
+#> Error in h(simpleError(msg, call)): error in evaluating the argument 'object' in selecting a method for function 'summary': object 'f_saem_dfop_sfo' not found
+
+# The following takes about 6 minutes
+#f_saem_dfop_sfo_deSolve <- saem(f_mmkin["DFOP-SFO", ], solution_type = "deSolve",
+#  control = list(nbiter.saemix = c(200, 80), nbdisplay = 10))
+
+#saemix::compare.saemix(list(
+#  f_saem_dfop_sfo$so,
+#  f_saem_dfop_sfo_deSolve$so))
+
+# If the model supports it, we can also use eigenvalue based solutions, which
+# take a similar amount of time
+#f_saem_sfo_sfo_eigen <- saem(f_mmkin["SFO-SFO", ], solution_type = "eigen",
+#  control = list(nbiter.saemix = c(200, 80), nbdisplay = 10))
+# }
+