diff --git a/docs/articles/examples.html b/docs/articles/examples.html index 6875963..f3a9237 100644 --- a/docs/articles/examples.html +++ b/docs/articles/examples.html @@ -102,7 +102,7 @@

Examples

Giulia Lestini, Martin Fink and Andrew Hooker

-

20 May, 2021

+

21 May, 2021

Source: vignettes/examples.Rmd @@ -532,7 +532,7 @@

The full code for this example is available in ex.4.PKPD.1.comp.emax.R.

Here we define a PKPD mode using analytical equations. The PK is a one compartment model with intravenous bolus administration and linear elimination. The PD is an ordinary Emax model driven by the PK concentrations. The expected output of each measurement (PK or PD) is given in the vector model_switch (see below for details).

-library(PopED)
+library(PopED)
 f_pkpdmodel <- function(model_switch,xt,parameters,poped.db){
   with(as.list(parameters),{
     y=xt
@@ -737,9 +737,9 @@ 

 
We can compare the time for design evaluation with these two methods of describing the same model.

 
 tic(); eval <- evaluate_design(poped.db); toc()
-#> Elapsed time: 3.066 seconds.
+#> Elapsed time: 3.535 seconds.
 tic(); eval <- evaluate_design(poped.db.Rcpp); toc()
-#> Elapsed time: 1.73 seconds.

+#> Elapsed time: 1.899 seconds.

The difference is noticeable and gets larger for more complex ODE models.

@@ -1039,7 +1039,7 @@ 

 ev <- evaluate_design(poped_db_2) 
 round(ev$ofv,1)
-#> [1] 41.7
+#> [1] 42

 round(ev$rse)
@@ -1058,11 +1058,11 @@

- + - + @@ -1120,8 +1120,8 @@

- - + + @@ -1130,41 +1130,41 @@

- - + + - + - - + + - - - - + + + + - - - - + + + + - - + +
WT_CL3330
WT_V2523
d_CL0% 3.25 3.3223.7918.2325.2519.38 21.02 21.95 10.0625% 3.25 3.3227.5521.1328.3321.71 21.03 21.9510.0610.07
50% 3.26 3.3328.6821.9829.8022.84 21.03 21.96 10.07
75%3.283.3533.0525.323.293.3631.9524.49 21.03 21.96 10.07
100%3.353.4336.6528.083.583.6636.2927.80 21.0321.9610.0721.9710.08
@@ -1770,7 +1770,7 @@

#> 5.030673 2.983917 14.014958 29.787587 36.758952 26.753311 31.645011 #> SIGMA[2,2] #> 25.341368 -#> Elapsed time: 0.291 seconds. +#> Elapsed time: 0.264 seconds.

We can see that the result, based on MC sampling, is somewhat variable with so few samples.

 tic();evaluate_design(poped.db,d_switch=FALSE,ED_samp_size=20); toc()
@@ -1802,7 +1802,7 @@ 

 #>   5.021700   2.980981  14.068646  29.765030  36.691675  26.754137  31.469425 
 #> SIGMA[2,2] 
 #>  25.311870
-#> Elapsed time: 0.295 seconds.
+#> Elapsed time: 0.272 seconds.

diff --git a/docs/articles/handling_LOQ.html b/docs/articles/handling_LOQ.html index 32573a5..8af6ef8 100644 --- a/docs/articles/handling_LOQ.html +++ b/docs/articles/handling_LOQ.html @@ -104,7 +104,7 @@

Optimal design with LOQ data in PopED

Optimization with a model for warfarin

Andrew Hooker

-

20 May, 2021

+

21 May, 2021

Source: vignettes/handling_LOQ.Rmd @@ -114,7 +114,7 @@

20 May, 2021

-library(PopED)
+library(PopED)
 packageVersion("PopED")
 #> [1] '0.6.0'
@@ -278,8 +278,8 @@

cat("D6 evaluation time: ",e_time_D6[1],"\n" ) cat("D2 evaluation time: ",e_time_D2[1],"\n" ) -#> D6 evaluation time: 0.501 -#> D2 evaluation time: 0.103

+#> D6 evaluation time: 0.367 +#> D2 evaluation time: 0.135

The D2 nmethod is the same as removing the last data point

 poped_db_2 <- create.poped.database(
@@ -819,13 +819,13 @@ 

 Version information

 
 sessionInfo()
-#> R version 4.0.5 (2021-03-31)
+#> R version 4.1.0 (2021-05-18)
 #> Platform: x86_64-apple-darwin17.0 (64-bit)
 #> Running under: macOS Big Sur 10.16
 #> 
 #> Matrix products: default
-#> BLAS:   /Library/Frameworks/R.framework/Versions/4.0/Resources/lib/libRblas.dylib
-#> LAPACK: /Library/Frameworks/R.framework/Versions/4.0/Resources/lib/libRlapack.dylib
+#> BLAS:   /Library/Frameworks/R.framework/Versions/4.1/Resources/lib/libRblas.dylib
+#> LAPACK: /Library/Frameworks/R.framework/Versions/4.1/Resources/lib/libRlapack.dylib
 #> 
 #> locale:
 #> [1] en_US.UTF-8/en_US.UTF-8/en_US.UTF-8/C/en_US.UTF-8/en_US.UTF-8
@@ -844,16 +844,16 @@ 

 #> [13] httr_1.4.2        pillar_1.6.1      rlang_0.4.11      rstudioapi_0.13  
 #> [17] callr_3.7.0       jquerylib_0.1.4   rmarkdown_2.8     pkgdown_1.6.1    
 #> [21] labeling_0.4.2    textshaping_0.3.4 desc_1.3.0        devtools_2.4.1   
-#> [25] webshot_0.5.2     stringr_1.4.0     munsell_0.5.0     compiler_4.0.5   
+#> [25] webshot_0.5.2     stringr_1.4.0     munsell_0.5.0     compiler_4.1.0   
 #> [29] xfun_0.23         pkgconfig_2.0.3   systemfonts_1.0.2 pkgbuild_1.2.0   
 #> [33] htmltools_0.5.1.1 tidyselect_1.1.1  tibble_3.1.2      bookdown_0.22    
 #> [37] codetools_0.2-18  viridisLite_0.4.0 fansi_0.4.2       crayon_1.4.1     
-#> [41] dplyr_1.0.6       withr_2.4.2       MASS_7.3-54       grid_4.0.5       
+#> [41] dplyr_1.0.6       withr_2.4.2       MASS_7.3-54       grid_4.1.0       
 #> [45] jsonlite_1.7.2    gtable_0.3.0      lifecycle_1.0.0   DBI_1.1.1        
 #> [49] magrittr_2.0.1    scales_1.1.1      cli_2.5.0         stringi_1.6.2    
 #> [53] cachem_1.0.5      farver_2.1.0      fs_1.5.0          remotes_2.3.0    
 #> [57] xml2_1.3.2        bslib_0.2.5.1     ellipsis_0.3.2    ragg_1.1.2       
-#> [61] vctrs_0.3.8       generics_0.1.0    boot_1.3-28       tools_4.0.5      
+#> [61] vctrs_0.3.8       generics_0.1.0    boot_1.3-28       tools_4.1.0      
 #> [65] glue_1.4.2        purrr_0.3.4       processx_3.5.2    pkgload_1.2.1    
 #> [69] fastmap_1.1.0     yaml_2.2.1        colorspace_2.0-1  sessioninfo_1.1.1
 #> [73] rvest_1.0.0       memoise_2.0.0     sass_0.4.0        usethis_2.0.1

diff --git a/docs/articles/intro-poped.html b/docs/articles/intro-poped.html
index 1cdd92c..262a24b 100644
--- a/docs/articles/intro-poped.html
+++ b/docs/articles/intro-poped.html
@@ -102,7 +102,7 @@
       
Introduction to PopED

                         
Andrew Hooker

             
-            
20 May, 2021

+            
21 May, 2021

       
       Source: vignettes/intro-poped.Rmd
       
@@ -138,7 +138,7 @@ 

 Define a model

 
Here we define a one-compartment pharmacokinetic model with linear absorption using an analytical solution. In this case the solution is applicable for both multiple and single dosing. Note that this function is also predefined in PopED as ff.PK.1.comp.oral.md.CL (see ?ff.PK.1.comp.oral.md.CL for more information).

 
-library(PopED)
+library(PopED)
 packageVersion("PopED")
 #> [1] '0.6.0'

 
@@ -411,7 +411,7 @@ 

 #>         d_CL   0.0625      28    26
 #>     sig_prop     0.04      14    15
 #> 
-#> Total running time: 22.938 seconds
+#> Total running time: 23.15 seconds
 plot_model_prediction(output$poped.db)

 

 
We see that there are four distinct sample times for this design. This means that for this model, with these exact parameter values, that the most information from the study to inform the parameter estimation is with these sample times.

@@ -456,7 +456,7 @@ 

 #>         d_CL   0.0625      28    27
 #>     sig_prop     0.04      14    15
 #> 
-#> Total running time: 12.883 seconds
+#> Total running time: 13.47 seconds
 plot_model_prediction(output_discrete$poped.db, model_num_points = 300)

Here we see that the optimization ran somewhat quicker, but gave a less efficient design.

@@ -511,10 +511,11 @@

#> d_CL 0.0625 28 28 #> sig_prop 0.04 14 14 #> -#> Total running time: 4.842 seconds +#> Total running time: 4.739 seconds

We see that the optimal doses are 31.6 and 55.2 for the two groups. This leads to population trough concentrations of 0.2 and 0.35 for the two groups of patients at 240 hours:

-plot_model_prediction(output_cost$poped.db, model_num_points = 300)+
+library(ggplot2)
+plot_model_prediction(output_cost$poped.db, model_num_points = 300)+
   coord_cartesian(xlim=c(230,250))

diff --git a/docs/articles/model_def_other_pkgs.html b/docs/articles/model_def_other_pkgs.html index 2b7d9bb..7397984 100644 --- a/docs/articles/model_def_other_pkgs.html +++ b/docs/articles/model_def_other_pkgs.html @@ -103,7 +103,7 @@

Defining models for PopED using R based PKPD simulators

Andrew Hooker, Ron Keizer and Vijay Ivaturi

-

20 May, 2021

+

21 May, 2021

Source: vignettes/model_def_other_pkgs.Rmd @@ -125,7 +125,7 @@

  • RxODE
    • -library(PopED)
+library(PopED)
 library(PKPDsim)
 library(mrgsolve)
 library(deSolve)
@@ -711,10 +711,10 @@ 
    
 Speed of FIM computation
    
 
    We can compare the speed of the computations. Analytic solutions are fast, as expected, in this case more than 20 times faster than any of the ODE methods. mrgsolve is the fastest of the ODE solvers in this example. Note that, in previous work (http://pkpdsim.ronkeizer.com/speed.html), much of the speed difference between mrgsolve, RxODE and PKPDsim has been found to be due to the overhead from pre- and post-processing of the simulation from ODE systems. Other ways of handling the pre- and post-processing may speed up these computations.
    
 
    -library(microbenchmark)
+library(microbenchmark)
 library(ggplot2)
 
-compare <- microbenchmark(
+compare <- microbenchmark(
   evaluate_design(poped_db_analytic),
   evaluate_design(poped_db_ode_desolve),
   evaluate_design(poped_db_ode_desolve_c),
@@ -734,7 +734,7 @@ 
    
 devtools::session_info()
 #> ─ Session info ───────────────────────────────────────────────────────────────
 #>  setting  value                       
-#>  version  R version 4.0.5 (2021-03-31)
+#>  version  R version 4.1.0 (2021-05-18)
 #>  os       macOS Big Sur 10.16         
 #>  system   x86_64, darwin17.0          
 #>  ui       X11                         
@@ -742,109 +742,109 @@ 
    
 #>  collate  en_US.UTF-8                 
 #>  ctype    en_US.UTF-8                 
 #>  tz       Europe/Stockholm            
-#>  date     2021-05-20                  
+#>  date     2021-05-21                  
 #> 
 #> ─ Packages ───────────────────────────────────────────────────────────────────
 #>  ! package       * version  date       lib source                            
-#>    assertthat      0.2.1    2019-03-21 [2] CRAN (R 4.0.2)                    
-#>    backports       1.2.1    2020-12-09 [2] CRAN (R 4.0.2)                    
-#>    BH              1.75.0-0 2021-01-11 [2] CRAN (R 4.0.2)                    
-#>    bookdown        0.22     2021-04-22 [2] CRAN (R 4.0.5)                    
-#>    boot            1.3-28   2021-05-03 [2] CRAN (R 4.0.5)                    
-#>    bslib           0.2.5.1  2021-05-18 [2] CRAN (R 4.0.2)                    
-#>    cachem          1.0.5    2021-05-15 [2] CRAN (R 4.0.5)                    
-#>    callr           3.7.0    2021-04-20 [2] CRAN (R 4.0.5)                    
-#>    checkmate       2.0.0    2020-02-06 [2] CRAN (R 4.0.2)                    
-#>    cli             2.5.0    2021-04-26 [2] CRAN (R 4.0.2)                    
-#>    codetools       0.2-18   2020-11-04 [2] CRAN (R 4.0.5)                    
-#>    colorspace      2.0-1    2021-05-04 [2] CRAN (R 4.0.5)                    
-#>    crayon          1.4.1    2021-02-08 [2] CRAN (R 4.0.2)                    
-#>    data.table      1.14.0   2021-02-21 [2] CRAN (R 4.0.2)                    
-#>    DBI             1.1.1    2021-01-15 [2] CRAN (R 4.0.2)                    
-#>    desc            1.3.0    2021-03-05 [2] CRAN (R 4.0.2)                    
-#>    deSolve       * 1.28     2020-03-08 [2] CRAN (R 4.0.2)                    
-#>    devtools        2.4.1    2021-05-05 [2] CRAN (R 4.0.2)                    
-#>    digest          0.6.27   2020-10-24 [2] CRAN (R 4.0.2)                    
-#>    dparser         1.3.1-4  2021-04-07 [2] CRAN (R 4.0.4)                    
-#>    dplyr           1.0.6    2021-05-05 [2] CRAN (R 4.0.2)                    
-#>    ellipsis        0.3.2    2021-04-29 [2] CRAN (R 4.0.2)                    
-#>    evaluate        0.14     2019-05-28 [2] CRAN (R 4.0.1)                    
-#>    fansi           0.4.2    2021-01-15 [2] CRAN (R 4.0.2)                    
-#>    farver          2.1.0    2021-02-28 [2] CRAN (R 4.0.4)                    
-#>    fastmap         1.1.0    2021-01-25 [2] CRAN (R 4.0.2)                    
-#>    fs              1.5.0    2020-07-31 [2] CRAN (R 4.0.2)                    
-#>    generics        0.1.0    2020-10-31 [2] CRAN (R 4.0.2)                    
-#>    ggplot2         3.3.3    2020-12-30 [2] CRAN (R 4.0.2)                    
-#>    glue            1.4.2    2020-08-27 [2] CRAN (R 4.0.2)                    
-#>    gtable          0.3.0    2019-03-25 [2] CRAN (R 4.0.2)                    
-#>    gtools          3.8.2    2020-03-31 [2] CRAN (R 4.0.2)                    
-#>    highr           0.9      2021-04-16 [2] CRAN (R 4.0.4)                    
-#>    htmltools       0.5.1.1  2021-01-22 [2] CRAN (R 4.0.2)                    
-#>    httr            1.4.2    2020-07-20 [2] CRAN (R 4.0.2)                    
-#>    jquerylib       0.1.4    2021-04-26 [2] CRAN (R 4.0.2)                    
-#>    jsonlite        1.7.2    2020-12-09 [2] CRAN (R 4.0.2)                    
-#>    kableExtra    * 1.3.4    2021-02-20 [2] CRAN (R 4.0.2)                    
-#>    knitr         * 1.33     2021-04-24 [2] CRAN (R 4.0.5)                    
-#>    labeling        0.4.2    2020-10-20 [2] CRAN (R 4.0.2)                    
-#>    lifecycle       1.0.0    2021-02-15 [2] CRAN (R 4.0.2)                    
-#>    lotri           0.3.1    2021-01-05 [2] CRAN (R 4.0.2)                    
-#>    lubridate       1.7.10   2021-02-26 [2] CRAN (R 4.0.2)                    
-#>    magrittr        2.0.1    2020-11-17 [2] CRAN (R 4.0.2)                    
-#>    MASS            7.3-54   2021-05-03 [2] CRAN (R 4.0.5)                    
-#>    memoise         2.0.0    2021-01-26 [2] CRAN (R 4.0.2)                    
-#>    mrgsolve      * 0.11.1   2021-05-10 [2] CRAN (R 4.0.2)                    
-#>    munsell         0.5.0    2018-06-12 [2] CRAN (R 4.0.2)                    
-#>    mvtnorm         1.1-1    2020-06-09 [2] CRAN (R 4.0.2)                    
-#>    pillar          1.6.1    2021-05-16 [2] CRAN (R 4.0.5)                    
-#>    pkgbuild        1.2.0    2020-12-15 [2] CRAN (R 4.0.2)                    
-#>    pkgconfig       2.0.3    2019-09-22 [2] CRAN (R 4.0.2)                    
-#>    pkgdown         1.6.1    2020-09-12 [2] CRAN (R 4.0.2)                    
-#>    pkgload         1.2.1    2021-04-06 [2] CRAN (R 4.0.2)                    
-#>    PKPDsim       * 1.0.7    2021-05-20 [2] Github (InsightRX/PKPDsim@bd9b9e4)
-#>  P PopED         * 0.6.0    2021-05-20 [?] local                             
-#>    PreciseSums     0.4      2020-07-10 [2] CRAN (R 4.0.2)                    
-#>    prettyunits     1.1.1    2020-01-24 [2] CRAN (R 4.0.2)                    
-#>    processx        3.5.2    2021-04-30 [2] CRAN (R 4.0.2)                    
-#>    ps              1.6.0    2021-02-28 [2] CRAN (R 4.0.4)                    
-#>    purrr           0.3.4    2020-04-17 [2] CRAN (R 4.0.2)                    
-#>    qs              0.24.1   2021-03-07 [2] CRAN (R 4.0.2)                    
-#>    R6              2.5.0    2020-10-28 [2] CRAN (R 4.0.2)                    
-#>    ragg            1.1.2    2021-03-17 [2] CRAN (R 4.0.2)                    
-#>    RApiSerialize   0.1.0    2014-04-19 [2] CRAN (R 4.0.2)                    
-#>    Rcpp          * 1.0.6    2021-01-15 [2] CRAN (R 4.0.2)                    
-#>    RcppParallel    5.1.4    2021-05-04 [2] CRAN (R 4.0.5)                    
-#>    remotes         2.3.0    2021-04-01 [2] CRAN (R 4.0.2)                    
-#>    rlang           0.4.11   2021-04-30 [2] CRAN (R 4.0.2)                    
-#>    rmarkdown       2.8      2021-05-07 [2] CRAN (R 4.0.2)                    
-#>    rprojroot       2.0.2    2020-11-15 [2] CRAN (R 4.0.2)                    
-#>    rstudioapi      0.13     2020-11-12 [2] CRAN (R 4.0.2)                    
-#>    rvest           1.0.0    2021-03-09 [2] CRAN (R 4.0.2)                    
-#>    RxODE         * 1.0.9    2021-05-11 [2] CRAN (R 4.0.2)                    
-#>    sass            0.4.0    2021-05-12 [2] CRAN (R 4.0.2)                    
-#>    scales          1.1.1    2020-05-11 [2] CRAN (R 4.0.2)                    
-#>    sessioninfo     1.1.1    2018-11-05 [2] CRAN (R 4.0.2)                    
-#>    stringfish      0.15.1   2021-03-16 [2] CRAN (R 4.0.2)                    
-#>    stringi         1.6.2    2021-05-17 [2] CRAN (R 4.0.5)                    
-#>    stringr         1.4.0    2019-02-10 [2] CRAN (R 4.0.2)                    
-#>    svglite         2.0.0    2021-02-20 [2] CRAN (R 4.0.2)                    
-#>    sys             3.4      2020-07-23 [2] CRAN (R 4.0.2)                    
-#>    systemfonts     1.0.2    2021-05-11 [2] CRAN (R 4.0.2)                    
-#>    testthat      * 3.0.2    2021-02-14 [2] CRAN (R 4.0.2)                    
-#>    textshaping     0.3.4    2021-05-11 [2] CRAN (R 4.0.2)                    
-#>    tibble          3.1.2    2021-05-16 [2] CRAN (R 4.0.5)                    
-#>    tidyselect      1.1.1    2021-04-30 [2] CRAN (R 4.0.2)                    
-#>    usethis         2.0.1    2021-02-10 [2] CRAN (R 4.0.2)                    
-#>    utf8            1.2.1    2021-03-12 [2] CRAN (R 4.0.2)                    
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-#>    viridisLite     0.4.0    2021-04-13 [2] CRAN (R 4.0.2)                    
-#>    webshot         0.5.2    2019-11-22 [2] CRAN (R 4.0.2)                    
-#>    withr           2.4.2    2021-04-18 [2] CRAN (R 4.0.4)                    
-#>    xfun            0.23     2021-05-15 [2] CRAN (R 4.0.5)                    
-#>    xml2            1.3.2    2020-04-23 [2] CRAN (R 4.0.2)                    
-#>    yaml            2.2.1    2020-02-01 [2] CRAN (R 4.0.2)                    
+#>    assertthat      0.2.1    2019-03-21 [2] CRAN (R 4.1.0)                    
+#>    backports       1.2.1    2020-12-09 [2] CRAN (R 4.1.0)                    
+#>    BH              1.75.0-0 2021-01-11 [2] CRAN (R 4.1.0)                    
+#>    bookdown        0.22     2021-04-22 [2] CRAN (R 4.1.0)                    
+#>    boot            1.3-28   2021-05-03 [2] CRAN (R 4.1.0)                    
+#>    bslib           0.2.5.1  2021-05-18 [2] CRAN (R 4.1.0)                    
+#>    cachem          1.0.5    2021-05-15 [2] CRAN (R 4.1.0)                    
+#>    callr           3.7.0    2021-04-20 [2] CRAN (R 4.1.0)                    
+#>    checkmate       2.0.0    2020-02-06 [2] CRAN (R 4.1.0)                    
+#>    cli             2.5.0    2021-04-26 [2] CRAN (R 4.1.0)                    
+#>    codetools       0.2-18   2020-11-04 [2] CRAN (R 4.1.0)                    
+#>    colorspace      2.0-1    2021-05-04 [2] CRAN (R 4.1.0)                    
+#>    crayon          1.4.1    2021-02-08 [2] CRAN (R 4.1.0)                    
+#>    data.table      1.14.0   2021-02-21 [2] CRAN (R 4.1.0)                    
+#>    DBI             1.1.1    2021-01-15 [2] CRAN (R 4.1.0)                    
+#>    desc            1.3.0    2021-03-05 [2] CRAN (R 4.1.0)                    
+#>    deSolve       * 1.28     2020-03-08 [2] CRAN (R 4.1.0)                    
+#>    devtools        2.4.1    2021-05-05 [2] CRAN (R 4.1.0)                    
+#>    digest          0.6.27   2020-10-24 [2] CRAN (R 4.1.0)                    
+#>    dparser         1.3.1-4  2021-04-07 [2] CRAN (R 4.1.0)                    
+#>    dplyr           1.0.6    2021-05-05 [2] CRAN (R 4.1.0)                    
+#>    ellipsis        0.3.2    2021-04-29 [2] CRAN (R 4.1.0)                    
+#>    evaluate        0.14     2019-05-28 [2] CRAN (R 4.1.0)                    
+#>    fansi           0.4.2    2021-01-15 [2] CRAN (R 4.1.0)                    
+#>    farver          2.1.0    2021-02-28 [2] CRAN (R 4.1.0)                    
+#>    fastmap         1.1.0    2021-01-25 [2] CRAN (R 4.1.0)                    
+#>    fs              1.5.0    2020-07-31 [2] CRAN (R 4.1.0)                    
+#>    generics        0.1.0    2020-10-31 [2] CRAN (R 4.1.0)                    
+#>    ggplot2         3.3.3    2020-12-30 [2] CRAN (R 4.1.0)                    
+#>    glue            1.4.2    2020-08-27 [2] CRAN (R 4.1.0)                    
+#>    gtable          0.3.0    2019-03-25 [2] CRAN (R 4.1.0)                    
+#>    gtools          3.8.2    2020-03-31 [2] CRAN (R 4.1.0)                    
+#>    highr           0.9      2021-04-16 [2] CRAN (R 4.1.0)                    
+#>    htmltools       0.5.1.1  2021-01-22 [2] CRAN (R 4.1.0)                    
+#>    httr            1.4.2    2020-07-20 [2] CRAN (R 4.1.0)                    
+#>    jquerylib       0.1.4    2021-04-26 [2] CRAN (R 4.1.0)                    
+#>    jsonlite        1.7.2    2020-12-09 [2] CRAN (R 4.1.0)                    
+#>    kableExtra    * 1.3.4    2021-02-20 [2] CRAN (R 4.1.0)                    
+#>    knitr         * 1.33     2021-04-24 [2] CRAN (R 4.1.0)                    
+#>    labeling        0.4.2    2020-10-20 [2] CRAN (R 4.1.0)                    
+#>    lifecycle       1.0.0    2021-02-15 [2] CRAN (R 4.1.0)                    
+#>    lotri           0.3.1    2021-01-05 [2] CRAN (R 4.1.0)                    
+#>    lubridate       1.7.10   2021-02-26 [2] CRAN (R 4.1.0)                    
+#>    magrittr        2.0.1    2020-11-17 [2] CRAN (R 4.1.0)                    
+#>    MASS            7.3-54   2021-05-03 [2] CRAN (R 4.1.0)                    
+#>    memoise         2.0.0    2021-01-26 [2] CRAN (R 4.1.0)                    
+#>    mrgsolve      * 0.11.1   2021-05-10 [2] CRAN (R 4.1.0)                    
+#>    munsell         0.5.0    2018-06-12 [2] CRAN (R 4.1.0)                    
+#>    mvtnorm         1.1-1    2020-06-09 [2] CRAN (R 4.1.0)                    
+#>    pillar          1.6.1    2021-05-16 [2] CRAN (R 4.1.0)                    
+#>    pkgbuild        1.2.0    2020-12-15 [2] CRAN (R 4.1.0)                    
+#>    pkgconfig       2.0.3    2019-09-22 [2] CRAN (R 4.1.0)                    
+#>    pkgdown         1.6.1    2020-09-12 [2] CRAN (R 4.1.0)                    
+#>    pkgload         1.2.1    2021-04-06 [2] CRAN (R 4.1.0)                    
+#>    PKPDsim       * 1.0.7    2021-05-21 [2] Github (InsightRX/PKPDsim@bd9b9e4)
+#>  P PopED         * 0.6.0    2021-05-21 [?] local                             
+#>    PreciseSums     0.4      2020-07-10 [2] CRAN (R 4.1.0)                    
+#>    prettyunits     1.1.1    2020-01-24 [2] CRAN (R 4.1.0)                    
+#>    processx        3.5.2    2021-04-30 [2] CRAN (R 4.1.0)                    
+#>    ps              1.6.0    2021-02-28 [2] CRAN (R 4.1.0)                    
+#>    purrr           0.3.4    2020-04-17 [2] CRAN (R 4.1.0)                    
+#>    qs              0.24.1   2021-03-07 [2] CRAN (R 4.1.0)                    
+#>    R6              2.5.0    2020-10-28 [2] CRAN (R 4.1.0)                    
+#>    ragg            1.1.2    2021-03-17 [2] CRAN (R 4.1.0)                    
+#>    RApiSerialize   0.1.0    2014-04-19 [2] CRAN (R 4.1.0)                    
+#>    Rcpp          * 1.0.6    2021-01-15 [2] CRAN (R 4.1.0)                    
+#>    RcppParallel    5.1.4    2021-05-04 [2] CRAN (R 4.1.0)                    
+#>    remotes         2.3.0    2021-04-01 [2] CRAN (R 4.1.0)                    
+#>    rlang           0.4.11   2021-04-30 [2] CRAN (R 4.1.0)                    
+#>    rmarkdown       2.8      2021-05-07 [2] CRAN (R 4.1.0)                    
+#>    rprojroot       2.0.2    2020-11-15 [2] CRAN (R 4.1.0)                    
+#>    rstudioapi      0.13     2020-11-12 [2] CRAN (R 4.1.0)                    
+#>    rvest           1.0.0    2021-03-09 [2] CRAN (R 4.1.0)                    
+#>    RxODE         * 1.0.9    2021-05-11 [2] CRAN (R 4.1.0)                    
+#>    sass            0.4.0    2021-05-12 [2] CRAN (R 4.1.0)                    
+#>    scales          1.1.1    2020-05-11 [2] CRAN (R 4.1.0)                    
+#>    sessioninfo     1.1.1    2018-11-05 [2] CRAN (R 4.1.0)                    
+#>    stringfish      0.15.1   2021-03-16 [2] CRAN (R 4.1.0)                    
+#>    stringi         1.6.2    2021-05-17 [2] CRAN (R 4.1.0)                    
+#>    stringr         1.4.0    2019-02-10 [2] CRAN (R 4.1.0)                    
+#>    svglite         2.0.0    2021-02-20 [2] CRAN (R 4.1.0)                    
+#>    sys             3.4      2020-07-23 [2] CRAN (R 4.1.0)                    
+#>    systemfonts     1.0.2    2021-05-11 [2] CRAN (R 4.1.0)                    
+#>    testthat      * 3.0.2    2021-02-14 [2] CRAN (R 4.1.0)                    
+#>    textshaping     0.3.4    2021-05-11 [2] CRAN (R 4.1.0)                    
+#>    tibble          3.1.2    2021-05-16 [2] CRAN (R 4.1.0)                    
+#>    tidyselect      1.1.1    2021-04-30 [2] CRAN (R 4.1.0)                    
+#>    usethis         2.0.1    2021-02-10 [2] CRAN (R 4.1.0)                    
+#>    utf8            1.2.1    2021-03-12 [2] CRAN (R 4.1.0)                    
+#>    vctrs           0.3.8    2021-04-29 [2] CRAN (R 4.1.0)                    
+#>    viridisLite     0.4.0    2021-04-13 [2] CRAN (R 4.1.0)                    
+#>    webshot         0.5.2    2019-11-22 [2] CRAN (R 4.1.0)                    
+#>    withr           2.4.2    2021-04-18 [2] CRAN (R 4.1.0)                    
+#>    xfun            0.23     2021-05-15 [2] CRAN (R 4.1.0)                    
+#>    xml2            1.3.2    2020-04-23 [2] CRAN (R 4.1.0)                    
+#>    yaml            2.2.1    2020-02-01 [2] CRAN (R 4.1.0)                    
 #> 
-#> [1] /private/var/folders/g6/mk9zc6552f7g93c457xzgvfc0000gp/T/RtmpsIQNbH/temp_libpath2cc01a0b083c
-#> [2] /Library/Frameworks/R.framework/Versions/4.0/Resources/library
+#> [1] /private/var/folders/g6/mk9zc6552f7g93c457xzgvfc0000gp/T/Rtmp2dRrIZ/temp_libpath7ebb50981b8f
+#> [2] /Library/Frameworks/R.framework/Versions/4.1/Resources/library
 #> 
 #>  P ── Loaded and on-disk path mismatch.
 #sessionInfo()
    
diff --git a/docs/pkgdown.yml b/docs/pkgdown.yml
index 012742f..69c2001 100644
--- a/docs/pkgdown.yml
+++ b/docs/pkgdown.yml
@@ -6,5 +6,5 @@ articles:
   handling_LOQ: handling_LOQ.html
   intro-poped: intro-poped.html
   model_def_other_pkgs: model_def_other_pkgs.html
-last_built: 2021-05-20T14:47Z
+last_built: 2021-05-21T11:30Z
 
diff --git a/docs/reference/Doptim.html b/docs/reference/Doptim.html
index 13742c2..dad2c2e 100644
--- a/docs/reference/Doptim.html
+++ b/docs/reference/Doptim.html
@@ -393,7 +393,7 @@ 
    See a
 poped_optim()

    Examples

    - 
    library(PopED)
+    
    library(PopED)
 
 ############# START #################
 ## Create PopED database
@@ -419,7 +419,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f855b96f698>
+#> <bytecode: 0x7fe20a979808>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
diff --git a/docs/reference/Dtrace.html b/docs/reference/Dtrace.html
index ddce2ec..dcbdb94 100644
--- a/docs/reference/Dtrace.html
+++ b/docs/reference/Dtrace.html
@@ -271,7 +271,7 @@ 
    Arg
 
 
     
    Examples
    
-    
    library(PopED)
+    
    library(PopED)
 
 ############# START #################
 ## Create PopED database
@@ -297,7 +297,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f855b96f698>
+#> <bytecode: 0x7fe20a979808>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
diff --git a/docs/reference/LEDoptim.html b/docs/reference/LEDoptim.html
index d503d94..dddaa2e 100644
--- a/docs/reference/LEDoptim.html
+++ b/docs/reference/LEDoptim.html
@@ -339,7 +339,7 @@ 
    See a
 poped_optim()
    
 
     
    Examples
    
-    
    library(PopED)
+    
    library(PopED)
 
 ############# START #################
 ## Create PopED database
@@ -366,7 +366,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f855b96f698>
+#> <bytecode: 0x7fe20a979808>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
diff --git a/docs/reference/LinMatrixL.html b/docs/reference/LinMatrixL.html
index da9a470..02c6ca6 100644
--- a/docs/reference/LinMatrixL.html
+++ b/docs/reference/LinMatrixL.html
@@ -199,7 +199,7 @@ 
    Value
    
 
 
     
    Examples
    
-    
    library(PopED)
+    
    library(PopED)
 
 ############# START #################
 ## Create PopED database
@@ -225,7 +225,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f855b96f698>
+#> <bytecode: 0x7fe20a979808>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
diff --git a/docs/reference/LinMatrixLH.html b/docs/reference/LinMatrixLH.html
index 2e73402..f262d82 100644
--- a/docs/reference/LinMatrixLH.html
+++ b/docs/reference/LinMatrixLH.html
@@ -229,7 +229,7 @@ 
    See a
 ofv_fim()
    
 
     
    Examples
    
-    
    library(PopED)
+    
    library(PopED)
 
 ############# START #################
 ## Create PopED database
@@ -255,7 +255,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f855b96f698>
+#> <bytecode: 0x7fe20a979808>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
diff --git a/docs/reference/LinMatrixL_occ.html b/docs/reference/LinMatrixL_occ.html
index 428f219..b6dfe44 100644
--- a/docs/reference/LinMatrixL_occ.html
+++ b/docs/reference/LinMatrixL_occ.html
@@ -227,7 +227,7 @@ 
    See a
 ofv_fim()
    
 
     
    Examples
    
-    
    library(PopED)
+    
    library(PopED)
 
 ############# START #################
 ## Create PopED database
@@ -253,7 +253,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f855b96f698>
+#> <bytecode: 0x7fe20a979808>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
diff --git a/docs/reference/PopED.html b/docs/reference/PopED.html
index dd5edd7..ed0201c 100644
--- a/docs/reference/PopED.html
+++ b/docs/reference/PopED.html
@@ -205,14 +205,13 @@ 
    R
 Computer Methods and Programs in Biomedicine, 108, 2012.
    
 
  • M. Foracchia, A.C. Hooker, P. Vicini and A. Ruggeri, "PopED, a software for optimal 
 experimental design in population kinetics", Computer Methods and Programs in Biomedicine, 74, 2004.
    • 
-
  • poped.sf.net
    • 
-
  • https://github.com/andrewhooker/PopED.git
    • 
+
  • https://andrewhooker.github.io/PopED/
    • 
 
 
 
     
    Examples
    
     
    
-library(PopED)
+library(PopED)
 
 ##-- Model: One comp first order absorption
 ## -- Analytic solution for both mutiple and single dosing
diff --git a/docs/reference/RS_opt.html b/docs/reference/RS_opt.html
index 459c180..bae47b9 100644
--- a/docs/reference/RS_opt.html
+++ b/docs/reference/RS_opt.html
@@ -398,7 +398,7 @@ 
    See a
 poped_optim()
    
 
     
    Examples
    
-    
    library(PopED)
+    
    library(PopED)
 
 ############# START #################
 ## Create PopED database
@@ -425,7 +425,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f855b96f698>
+#> <bytecode: 0x7fe20a979808>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
@@ -543,7 +543,7 @@ 
    Examp
 #>    SIGMA[1,1]     0.01      33    33
 #>    SIGMA[2,2]     0.25      26    26
 #> 
-#> Total running time: 0.048 seconds
    
+#> Total running time: 0.043 seconds
    
 if (FALSE) {
   
   RS_opt(poped.db)
diff --git a/docs/reference/a_line_search.html b/docs/reference/a_line_search.html
index 0f3537e..2e8ea6c 100644
--- a/docs/reference/a_line_search.html
+++ b/docs/reference/a_line_search.html
@@ -253,7 +253,7 @@ 
    See a
 poped_optim()
    
 
     
    Examples
    
-    
    library(PopED)
+    
    library(PopED)
 
 ############# START #################
 ## Create PopED database
@@ -279,7 +279,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f855b96f698>
+#> <bytecode: 0x7fe20a979808>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
@@ -359,10 +359,10 @@ 
    Examp
 #> Best value for OFV(MF) = 56.7067
 #> 
 #> Best value for a: 
-#> Group 1: 100
+#> Group 1: 100 [0.01,100]
 #> 
 #> 
-#> Line search run time: 0.354 seconds
+#> Line search run time: 0.424 seconds
 #> ***************************
 #> 
    
 if (FALSE) {  
diff --git a/docs/reference/bfgsb_min.html b/docs/reference/bfgsb_min.html
index 6bd6a14..47424e9 100644
--- a/docs/reference/bfgsb_min.html
+++ b/docs/reference/bfgsb_min.html
@@ -210,7 +210,7 @@ 
    See a
 poped_optim()
    
 
     
    Examples
    
-    
    library(PopED)
+    
    library(PopED)
 
 ############# START #################
 ## Create PopED database
@@ -236,7 +236,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f855b96f698>
+#> <bytecode: 0x7fe20a979808>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
diff --git a/docs/reference/blockexp.html b/docs/reference/blockexp.html
index 0446782..b8fcdba 100644
--- a/docs/reference/blockexp.html
+++ b/docs/reference/blockexp.html
@@ -208,7 +208,7 @@ 
    See a
 blockopt()
    
 
     
    Examples
    
-    
    library(PopED)
+    
    library(PopED)
 
 ############# START #################
 ## Create PopED database
@@ -234,7 +234,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f855b96f698>
+#> <bytecode: 0x7fe20a979808>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
@@ -278,37 +278,38 @@ 
    Examp
 #> Number of population model fixed parameters            bpop[j] : Nbpop = 4
 #> Number of population model random effects parameters   b[j]    : Nb    = 3
 #> 
-#> Typical Population Parameters:
-#> bpop[1]:  0.15 
-#> bpop[2]:     8 
-#> bpop[3]:     1 
-#> bpop[4]:     1 
+#> Typical Population Parameters:
    #> Warning: 5 arguments not used by format '%s[%g%s]: %5.4g %s
+#> '
    #> bpop[1]:  0.15 
    #> Warning: 5 arguments not used by format '%s[%g%s]: %5.4g %s
+#> '
    #> bpop[2]:     8 
    #> Warning: 5 arguments not used by format '%s[%g%s]: %5.4g %s
+#> '
    #> bpop[3]:     1 
    #> Warning: 5 arguments not used by format '%s[%g%s]: %5.4g %s
+#> '
    #> bpop[4]:     1 
 #> 
 #> Between Subject Variability matrix D (variance units) 
 #> 0.07 0.00 0.00
 #> 0.00 0.02 0.00
 #> 0.00 0.00 0.60
 #> 
-#> Diagonal Elements of D [sqrt(param)]:
-#> D[1,1]:  0.07 [0.2646] 
-#> D[2,2]:  0.02 [0.1414] 
-#> D[3,3]:   0.6 [0.7746] 
+#> Diagonal Elements of D [sqrt(param)]:
    #> Warning: 5 arguments not used by format '%s[%g%s]: %5.4g %s
+#> '
    #> D[1,1]:  0.07 [0.2646] 
    #> Warning: 5 arguments not used by format '%s[%g%s]: %5.4g %s
+#> '
    #> D[2,2]:  0.02 [0.1414] 
    #> Warning: 5 arguments not used by format '%s[%g%s]: %5.4g %s
+#> '
    #> D[3,3]:   0.6 [0.7746] 
 #> 
 #> Residual Unexplained Variability matrix SIGMA (variance units) : 
 #> 0.01 0.00
 #> 0.00 0.25
 #> 
-#> Diagonal Elements of SIGMA [sqrt(param)]:
-#> SIGMA[1,1]:  0.01 [  0.1] 
-#> SIGMA[2,2]:  0.25 [  0.5] 
+#> Diagonal Elements of SIGMA [sqrt(param)]:
    #> Warning: 5 arguments not used by format '%s[%g%s]: %5.4g %s
+#> '
    #> SIGMA[1,1]:  0.01 [  0.1] 
    #> Warning: 5 arguments not used by format '%s[%g%s]: %5.4g %s
+#> '
    #> SIGMA[2,2]:  0.25 [  0.5] 
 #> 
 #> ==============================================================================
 #> Experiment description (design and design space)
-#> 
-#> Number of individuals: 32
+#> 
    #> Warning: 2 arguments not used by format 'Number of individuals: %g
+#> '
    #> Number of individuals: 32
 #> Number of groups (individuals with same design): 1
 #> Number of individuals per group:
-#>      Group 1: 32
+#>  
    #> Warning: 2 arguments not used by format '    Group %g: %g
+#> '
    #>     Group 1: 32
 #> Number of samples per group:
 #>  Number of discrete experimental variables: 0
 #> Number of model covariates: 1
@@ -323,7 +324,7 @@ 
    Examp
 #> Group 1:    120    120    120    120    120    120    120    120
 #> 
 #> Covariates:
-#> Group 1: 70
+#> Group 1: 
    #> Warning: 2 arguments not used by format '%g'
    #> 70
 #> 
    #> NULL
    
 
    
   
    
diff --git a/docs/reference/blockfinal.html b/docs/reference/blockfinal.html
index b82d002..f542dc3 100644
--- a/docs/reference/blockfinal.html
+++ b/docs/reference/blockfinal.html
@@ -310,7 +310,7 @@ 
    See a
 blockopt()
    
 
     
    Examples
    
-    
    library(PopED)
+    
    library(PopED)
 
 ############# START #################
 ## Create PopED database
@@ -336,7 +336,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f855b96f698>
+#> <bytecode: 0x7fe20a979808>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
@@ -413,7 +413,7 @@ 
    Examp
 #>     sig_prop     0.01      32    32
 #>      sig_add     0.25      26    26
 #> 
-#> Total running time: 1.594 seconds
    
+#> Total running time: 1.799 seconds
    
 
 
    
   
    
diff --git a/docs/reference/blockheader.html b/docs/reference/blockheader.html
index d3636de..27214cf 100644
--- a/docs/reference/blockheader.html
+++ b/docs/reference/blockheader.html
@@ -293,7 +293,7 @@ 
    See a
 blockopt()
    
 
     
    Examples
    
-    
    library(PopED)
+    
    library(PopED)
 
 ############# START #################
 ## Create PopED database
@@ -319,7 +319,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f855b96f698>
+#> <bytecode: 0x7fe20a979808>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
diff --git a/docs/reference/blockopt.html b/docs/reference/blockopt.html
index f8cf21e..361f8d4 100644
--- a/docs/reference/blockopt.html
+++ b/docs/reference/blockopt.html
@@ -179,7 +179,7 @@ 
    See a
 blockheader()
    
 
     
    Examples
    
-    
    library(PopED)
+    
    library(PopED)
 
 ############# START #################
 ## Create PopED database
@@ -205,7 +205,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f855b96f698>
+#> <bytecode: 0x7fe20a979808>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
diff --git a/docs/reference/build_sfg.html b/docs/reference/build_sfg.html
index fabdfc4..92b1d9f 100644
--- a/docs/reference/build_sfg.html
+++ b/docs/reference/build_sfg.html
@@ -200,14 +200,14 @@ 
    Examp
 
    #> function (x, a, bpop, b, bocc) 
 #> parameters = c(CL = bpop[1] * exp(b[1]), Favail = bpop[2], KA = bpop[3] * 
 #>     exp(b[2]), V = bpop[4] * exp(b[3]), DOSE = a[1], TAU = a[2])
-#> <environment: 0x7f84fb71ea70>
    
+#> <environment: 0x7fe20d5952a8>
    
 etas <- c(Favail="exp",KA="exp",V="add",CL="exp")
 build_sfg(model="ff.PK.1.comp.oral.md.CL",etas = etas)
 
    #> function (x, a, bpop, b, bocc) 
 #> parameters = c(CL = bpop[1] * exp(b[1]), Favail = bpop[2] * exp(b[2]), 
 #>     KA = bpop[3] * exp(b[3]), V = bpop[4] + b[4], DOSE = a[1], 
 #>     TAU = a[2])
-#> <environment: 0x7f84fb71ea70>
    
+#> <environment: 0x7fe20d5952a8>
    
   
    
   
 
     
    Examples
    
-    
    library(PopED)
+    
    library(PopED)
 
 ############# START #################
 ## Create PopED database
@@ -325,7 +325,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f855b96f698>
+#> <bytecode: 0x7fe20a979808>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
diff --git a/docs/reference/calc_ofv_and_fim.html b/docs/reference/calc_ofv_and_fim.html
index e4d489f..106feb4 100644
--- a/docs/reference/calc_ofv_and_fim.html
+++ b/docs/reference/calc_ofv_and_fim.html
@@ -332,7 +332,7 @@ 
    See a
 ofv_fim()
    
 
     
    Examples
    
-    
    library(PopED)
+    
    library(PopED)
 
 ############# START #################
 ## Create PopED database
@@ -359,7 +359,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f855b96f698>
+#> <bytecode: 0x7fe20a979808>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
diff --git a/docs/reference/calc_ofv_and_grad.html b/docs/reference/calc_ofv_and_grad.html
index cb12ba9..c4b8c76 100644
--- a/docs/reference/calc_ofv_and_grad.html
+++ b/docs/reference/calc_ofv_and_grad.html
@@ -283,7 +283,7 @@ 
    See a
 poped_optim()
    
 
     
    Examples
    
-    
    library(PopED)
+    
    library(PopED)
 
 ############# START #################
 ## Create PopED database
@@ -309,7 +309,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f855b96f698>
+#> <bytecode: 0x7fe20a979808>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
diff --git a/docs/reference/cell.html b/docs/reference/cell.html
index cfbe658..753d745 100644
--- a/docs/reference/cell.html
+++ b/docs/reference/cell.html
@@ -186,19 +186,19 @@ 
    Examp
     
    
 cell(3)
 
    #>      [,1]      [,2]      [,3]     
-#> [1,] Numeric,0 Numeric,0 Numeric,0
-#> [2,] Numeric,0 Numeric,0 Numeric,0
-#> [3,] Numeric,0 Numeric,0 Numeric,0
    cell(2,3)
+#> [1,] numeric,0 numeric,0 numeric,0
+#> [2,] numeric,0 numeric,0 numeric,0
+#> [3,] numeric,0 numeric,0 numeric,0
    cell(2,3)
 
    #>      [,1]      [,2]      [,3]     
-#> [1,] Numeric,0 Numeric,0 Numeric,0
-#> [2,] Numeric,0 Numeric,0 Numeric,0
    
+#> [1,] numeric,0 numeric,0 numeric,0
+#> [2,] numeric,0 numeric,0 numeric,0
    
 ## define possible values of 2 categorical design variable
 x.space <- cell(1,2)
 x.space[1,1] <- list(seq(10,100,10))
 x.space[1,2] <- list(seq(10,300,10))
 x.space
 
    #>      [,1]       [,2]      
-#> [1,] Numeric,10 Numeric,30
    x.space[1,1]
+#> [1,] numeric,10 numeric,30
    x.space[1,1]
 
    #> [[1]]
 #>  [1]  10  20  30  40  50  60  70  80  90 100
 #> 
    x.space[1,2]
diff --git a/docs/reference/create.poped.database.html b/docs/reference/create.poped.database.html
index 1165463..27a48a8 100644
--- a/docs/reference/create.poped.database.html
+++ b/docs/reference/create.poped.database.html
@@ -1029,7 +1029,7 @@ 
    Examp
 ##   for population pharmacokinetics-pharmacodynamics studies", 
 ##   Br. J. Clin. Pharm., 2014. 
 
-library(PopED)
+library(PopED)
 
 ## find the parameters that are needed to define from the structural model
 ff.PK.1.comp.oral.md.CL
@@ -1045,7 +1045,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f84fb7561b0>
+#> <bytecode: 0x7fe25cadfcb0>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
diff --git a/docs/reference/create_design.html b/docs/reference/create_design.html
index 4d1bca1..f861d33 100644
--- a/docs/reference/create_design.html
+++ b/docs/reference/create_design.html
@@ -218,7 +218,7 @@ 
    See a
 poped.choose()
    
 
     
    Examples
    
-    
    library(PopED)
+    
    library(PopED)
 
 xt1 <- list(c(1,2,3),c(1,2,3,4))
 xt4 <- list(c(1,2,3,4,5),c(1,2,3,4))
diff --git a/docs/reference/create_design_space.html b/docs/reference/create_design_space.html
index de6c8ad..dde5fc2 100644
--- a/docs/reference/create_design_space.html
+++ b/docs/reference/create_design_space.html
@@ -312,7 +312,7 @@ 
    See a
 poped.choose()
    
 
     
    Examples
    
-    
    library(PopED)
+    
    library(PopED)
 
 design_1 <- create_design(xt=list(c(1,2,3,4,5),
                                   c(1,2,3,4)),
diff --git a/docs/reference/ed_laplace_ofv.html b/docs/reference/ed_laplace_ofv.html
index 1bb0bdc..ef36c0d 100644
--- a/docs/reference/ed_laplace_ofv.html
+++ b/docs/reference/ed_laplace_ofv.html
@@ -309,7 +309,7 @@ 
    Examp
 
 ## Optimization using an additive + proportional reidual error to 
 ##   avoid sample times at very low concentrations (time 0 or very late samoples).
-library(PopED)
+library(PopED)
 
 ## find the parameters that are needed to define from the structural model
 ff.PK.1.comp.oral.sd.CL
@@ -322,7 +322,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f855b96f698>
+#> <bytecode: 0x7fe20a979808>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
@@ -368,7 +368,7 @@ 
    Examp
 
 ## ED evaluate using LaPlace approximation 
 tic(); output <- evaluate.e.ofv.fim(poped.db.n,use_laplace=TRUE); toc()
-
    #> Error in poped.db$settings$iEDCalculationType <- use_laplace: object 'poped.db.n' not found
    #> Elapsed time: 0.001 seconds.
    output$E_ofv
+
    #> Error in poped.db$settings$iEDCalculationType <- use_laplace: object 'poped.db.n' not found
    #> Elapsed time: 0.002 seconds.
    output$E_ofv
 
    #> Error in eval(expr, envir, enclos): object 'output' not found
    
 if (FALSE) {
   
diff --git a/docs/reference/ed_mftot.html b/docs/reference/ed_mftot.html
index 02fee54..b35a412 100644
--- a/docs/reference/ed_mftot.html
+++ b/docs/reference/ed_mftot.html
@@ -267,7 +267,7 @@ 
    See a
 evaluate.e.ofv.fim()
    
 
     
    Examples
    
-    
    library(PopED)
+    
    library(PopED)
 
 ############# START #################
 ## Create PopED database
@@ -294,7 +294,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f855b96f698>
+#> <bytecode: 0x7fe20a979808>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
diff --git a/docs/reference/evaluate.e.ofv.fim.html b/docs/reference/evaluate.e.ofv.fim.html
index a16c261..6c01fd7 100644
--- a/docs/reference/evaluate.e.ofv.fim.html
+++ b/docs/reference/evaluate.e.ofv.fim.html
@@ -333,7 +333,7 @@ 
    See a
 ofv_fim()
    
 
     
    Examples
    
-    
    library(PopED)
+    
    library(PopED)
 
 ############# START #################
 ## Create PopED database
@@ -360,7 +360,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f855b96f698>
+#> <bytecode: 0x7fe20a979808>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
@@ -420,7 +420,7 @@ 
    Examp
 tic()
 output <- evaluate.e.ofv.fim(poped.db,use_laplace=TRUE)
 toc()
-
    #> Elapsed time: 0.946 seconds.
    output$E_ofv
+
    #> Elapsed time: 1.3 seconds.
    output$E_ofv
 
    #> [1] 1.302806e+24
    
 if (FALSE) {
 
diff --git a/docs/reference/evaluate.fim.html b/docs/reference/evaluate.fim.html
index fbad041..fadfd79 100644
--- a/docs/reference/evaluate.fim.html
+++ b/docs/reference/evaluate.fim.html
@@ -299,7 +299,7 @@ 
    Examp
 ##   for population pharmacokinetics-pharmacodynamics studies", 
 ##   Br. J. Clin. Pharm., 2014. 
 
-library(PopED)
+library(PopED)
 
 ## find the parameters that are needed to define from the structural model
 ff.PK.1.comp.oral.md.CL
@@ -315,7 +315,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f84fb7561b0>
+#> <bytecode: 0x7fe25cadfcb0>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
diff --git a/docs/reference/evaluate_design.html b/docs/reference/evaluate_design.html
index 7ab218a..2613079 100644
--- a/docs/reference/evaluate_design.html
+++ b/docs/reference/evaluate_design.html
@@ -179,7 +179,7 @@ 
    See a
 plot_model_prediction()
    
 
     
    Examples
    
-    
    library(PopED)
+    
    library(PopED)
 
 ############# START #################
 ## Create PopED database
@@ -202,7 +202,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f855b96f698>
+#> <bytecode: 0x7fe20a979808>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
diff --git a/docs/reference/evaluate_fim_map.html b/docs/reference/evaluate_fim_map.html
index 6b0745c..a20c86a 100644
--- a/docs/reference/evaluate_fim_map.html
+++ b/docs/reference/evaluate_fim_map.html
@@ -203,17 +203,19 @@ 
    R
   Frey, N., & Mentre, F. (2013). Prediction of shrinkage of individual
   parameters using the Bayesian information matrix in non-linear mixed effect
   models with evaluation in pharmacokinetics. Pharmaceutical Research, 30(9),
-  2355-67. https://doi.org/10.1007/s11095-013-1079-3.
    
+  2355-67. doi: 10.1007/s11095-013-1079-3
+.
    
 
  • Hennig, S., Nyberg, J., Fanta, S., Backman, J.
   T., Hoppu, K., Hooker, A. C., & Karlsson, M. O. (2012). Application of the
   optimal design approach to improve a pretransplant drug dose finding design
   for ciclosporin. Journal of Clinical Pharmacology, 52(3), 347-360.
-  https://doi.org/10.1177/0091270010397731.
    • 
+  doi: 10.1177/0091270010397731
+.
    
 
 
 
     
    Examples
    
-    
    library(PopED)
+    
    library(PopED)
 
 ############# START #################
 ## Create PopED database
@@ -236,7 +238,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f855b96f698>
+#> <bytecode: 0x7fe20a979808>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
diff --git a/docs/reference/evaluate_power.html b/docs/reference/evaluate_power.html
index 494aad1..bddbae7 100644
--- a/docs/reference/evaluate_power.html
+++ b/docs/reference/evaluate_power.html
@@ -228,12 +228,14 @@ 
    R
   F. (2007). Design in nonlinear mixed effects models: Optimization using the
   Fedorov-Wynn algorithm and power of the Wald test for binary covariates.
   Statistics in Medicine, 26(28), 5162-5179.
-  https://doi.org/10.1002/sim.2910.
    
+  doi: 10.1002/sim.2910
+.
    
 
  • Ueckert, S., Hennig, S.,
   Nyberg, J., Karlsson, M. O., and Hooker, A. C. (2013). Optimizing disease
   progression study designs for drug effect discrimination. Journal of
   Pharmacokinetics and Pharmacodynamics, 40(5), 587-596.
-  https://doi.org/10.1007/s10928-013-9331-3.
    • 
+  doi: 10.1007/s10928-013-9331-3
+.
    
 
 
     
    See also
    
diff --git a/docs/reference/feps.add.html b/docs/reference/feps.add.html
index 0c99918..46583ec 100644
--- a/docs/reference/feps.add.html
+++ b/docs/reference/feps.add.html
@@ -211,7 +211,7 @@ 
    See a
 
     
    Examples
    
     
    
-library(PopED)
+library(PopED)
 
 ## find the parameters that are needed to define from the structural model
 ff.PK.1.comp.oral.sd.KE
@@ -224,7 +224,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f853bae30b0>
+#> <bytecode: 0x7fe24aba5148>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
diff --git a/docs/reference/feps.add.prop.html b/docs/reference/feps.add.prop.html
index 7489857..a69083a 100644
--- a/docs/reference/feps.add.prop.html
+++ b/docs/reference/feps.add.prop.html
@@ -210,7 +210,7 @@ 
    See a
 feps.prop()
    
 
     
    Examples
    
-    
    library(PopED)
+    
    library(PopED)
 
 ## find the parameters that are needed to define in the structural model
 ff.PK.1.comp.oral.md.CL
@@ -226,7 +226,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f84fb7561b0>
+#> <bytecode: 0x7fe25cadfcb0>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
diff --git a/docs/reference/feps.prop.html b/docs/reference/feps.prop.html
index 3ca13f8..19ad7e9 100644
--- a/docs/reference/feps.prop.html
+++ b/docs/reference/feps.prop.html
@@ -210,7 +210,7 @@ 
    See a
 feps.add()
    
 
     
    Examples
    
-    
    library(PopED)
+    
    library(PopED)
 
 ############# START #################
 ## Create PopED database
@@ -233,7 +233,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f855b96f698>
+#> <bytecode: 0x7fe20a979808>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
diff --git a/docs/reference/ff.PK.1.comp.oral.md.CL.html b/docs/reference/ff.PK.1.comp.oral.md.CL.html
index 8053d21..70b1bfd 100644
--- a/docs/reference/ff.PK.1.comp.oral.md.CL.html
+++ b/docs/reference/ff.PK.1.comp.oral.md.CL.html
@@ -207,7 +207,7 @@ 
    See a
 ff.PKPD.1.comp.sd.CL.emax()
    
 
     
    Examples
    
-    
    library(PopED)
+    
    library(PopED)
 
 ## find the parameters that are needed to define in the structural model
 ff.PK.1.comp.oral.md.CL
@@ -223,7 +223,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f84fb7561b0>
+#> <bytecode: 0x7fe25cadfcb0>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
diff --git a/docs/reference/ff.PK.1.comp.oral.md.KE.html b/docs/reference/ff.PK.1.comp.oral.md.KE.html
index f1e0438..fbaaf83 100644
--- a/docs/reference/ff.PK.1.comp.oral.md.KE.html
+++ b/docs/reference/ff.PK.1.comp.oral.md.KE.html
@@ -207,7 +207,7 @@ 
    See a
 ff.PKPD.1.comp.sd.CL.emax()
    
 
     
    Examples
    
-    
    library(PopED)
+    
    library(PopED)
 
 ## find the parameters that are needed to define in the structural model
 ff.PK.1.comp.oral.md.KE
@@ -223,7 +223,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f84facff158>
+#> <bytecode: 0x7fe20d7bf9d0>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
diff --git a/docs/reference/ff.PK.1.comp.oral.sd.CL.html b/docs/reference/ff.PK.1.comp.oral.sd.CL.html
index fbc69f4..2936c69 100644
--- a/docs/reference/ff.PK.1.comp.oral.sd.CL.html
+++ b/docs/reference/ff.PK.1.comp.oral.sd.CL.html
@@ -207,7 +207,7 @@ 
    See a
 ff.PKPD.1.comp.sd.CL.emax()
    
 
     
    Examples
    
-    
    library(PopED)
+    
    library(PopED)
 
 ############# START #################
 ## Create PopED database
@@ -230,7 +230,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f855b96f698>
+#> <bytecode: 0x7fe20a979808>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
diff --git a/docs/reference/ff.PK.1.comp.oral.sd.KE.html b/docs/reference/ff.PK.1.comp.oral.sd.KE.html
index 850dab7..3b5c6ae 100644
--- a/docs/reference/ff.PK.1.comp.oral.sd.KE.html
+++ b/docs/reference/ff.PK.1.comp.oral.sd.KE.html
@@ -208,7 +208,7 @@ 
    See a
 
     
    Examples
    
     
    
-library(PopED)
+library(PopED)
 
 ## find the parameters that are needed to define from the structural model
 ff.PK.1.comp.oral.sd.KE
@@ -221,7 +221,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f853bae30b0>
+#> <bytecode: 0x7fe24aba5148>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
diff --git a/docs/reference/ff.PKPD.1.comp.oral.md.CL.imax.html b/docs/reference/ff.PKPD.1.comp.oral.md.CL.imax.html
index 827e3e5..9e70b80 100644
--- a/docs/reference/ff.PKPD.1.comp.oral.md.CL.imax.html
+++ b/docs/reference/ff.PKPD.1.comp.oral.md.CL.imax.html
@@ -209,7 +209,7 @@ 
    See a
 
     
    Examples
    
     
    
-library(PopED)
+library(PopED)
 
 ## find the parameters that are needed to define from the structural model
 ff.PKPD.1.comp.oral.md.CL.imax
@@ -227,7 +227,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f853b263678>
+#> <bytecode: 0x7fe1fae1c9e0>
 #> <environment: namespace:PopED>
    ff.PK.1.comp.oral.md.CL
 
    #> function (model_switch, xt, parameters, poped.db) 
 #> {
@@ -241,7 +241,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f84fb7561b0>
+#> <bytecode: 0x7fe25cadfcb0>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
diff --git a/docs/reference/ff.PKPD.1.comp.sd.CL.emax.html b/docs/reference/ff.PKPD.1.comp.sd.CL.emax.html
index 0c48058..b656fa3 100644
--- a/docs/reference/ff.PKPD.1.comp.sd.CL.emax.html
+++ b/docs/reference/ff.PKPD.1.comp.sd.CL.emax.html
@@ -206,7 +206,7 @@ 
    See a
 
     
    Examples
    
     
    
-library(PopED)
+library(PopED)
 
 ## find the parameters that are needed to define from the structural model
 ff.PKPD.1.comp.sd.CL.emax
@@ -222,7 +222,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f853baa4ed8>
+#> <bytecode: 0x7fe1fd8e6ea8>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
diff --git a/docs/reference/get_all_params.html b/docs/reference/get_all_params.html
index 4bc2093..5c2464c 100644
--- a/docs/reference/get_all_params.html
+++ b/docs/reference/get_all_params.html
@@ -175,7 +175,7 @@ 
    Value
    
 
 
     
    Examples
    
-    
    library(PopED)
+    
    library(PopED)
 
 ############# START #################
 ## Create PopED database
@@ -198,7 +198,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f855b96f698>
+#> <bytecode: 0x7fe20a979808>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
diff --git a/docs/reference/get_rse.html b/docs/reference/get_rse.html
index 004b12c..b0eb765 100644
--- a/docs/reference/get_rse.html
+++ b/docs/reference/get_rse.html
@@ -243,7 +243,7 @@ 
    Examp
 ##   for population pharmacokinetics-pharmacodynamics studies", 
 ##   Br. J. Clin. Pharm., 2014. 
 
-library(PopED)
+library(PopED)
 
 ## find the parameters that are needed to define from the structural model
 ff.PK.1.comp.oral.md.CL
@@ -259,7 +259,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f84fb7561b0>
+#> <bytecode: 0x7fe25cadfcb0>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
diff --git a/docs/reference/gradf_eps.html b/docs/reference/gradf_eps.html
index fa9e495..15bdf73 100644
--- a/docs/reference/gradf_eps.html
+++ b/docs/reference/gradf_eps.html
@@ -217,7 +217,7 @@ 
    See a
 ofv_fim()
    
 
     
    Examples
    
-    
    library(PopED)
+    
    library(PopED)
 
 ############# START #################
 ## Create PopED database
@@ -243,7 +243,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f855b96f698>
+#> <bytecode: 0x7fe20a979808>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
diff --git a/docs/reference/mfea.html b/docs/reference/mfea.html
index ea7abe6..9ddbe85 100644
--- a/docs/reference/mfea.html
+++ b/docs/reference/mfea.html
@@ -314,7 +314,7 @@ 
    See a
 poped_optim()
    
 
     
    Examples
    
-    
    library(PopED)
+    
    library(PopED)
 
 ############# START #################
 ## Create PopED database
@@ -340,7 +340,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f855b96f698>
+#> <bytecode: 0x7fe20a979808>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
@@ -439,7 +439,7 @@ 
    Examp
 #>     sig_prop     0.01      32    23
 #>      sig_add     0.25      26    30
 #> 
-#> Total running time: 0.039 seconds
    
+#> Total running time: 0.046 seconds
    
 
 if (FALSE) {
   
diff --git a/docs/reference/mftot.html b/docs/reference/mftot.html
index 4764713..aa17844 100644
--- a/docs/reference/mftot.html
+++ b/docs/reference/mftot.html
@@ -240,7 +240,7 @@ 
    See a
 ofv_fim()
    
 
     
    Examples
    
-    
    library(PopED)
+    
    library(PopED)
 
 ############# START #################
 ## Create PopED database
@@ -266,7 +266,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f855b96f698>
+#> <bytecode: 0x7fe20a979808>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
diff --git a/docs/reference/model_prediction.html b/docs/reference/model_prediction.html
index 922c2a9..cc6a000 100644
--- a/docs/reference/model_prediction.html
+++ b/docs/reference/model_prediction.html
@@ -303,7 +303,7 @@ 
    Examp
 ##   for population pharmacokinetics-pharmacodynamics studies", 
 ##   Br. J. Clin. Pharm., 2014. 
 
-library(PopED)
+library(PopED)
 
 ## find the parameters that are needed to define from the structural model
 ff.PK.1.comp.oral.md.CL
@@ -319,7 +319,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f84fb7561b0>
+#> <bytecode: 0x7fe25cadfcb0>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
diff --git a/docs/reference/ofv_criterion.html b/docs/reference/ofv_criterion.html
index a331517..698c312 100644
--- a/docs/reference/ofv_criterion.html
+++ b/docs/reference/ofv_criterion.html
@@ -210,7 +210,7 @@ 
    See a
 ofv_fim()
    
 
     
    Examples
    
-    
    library(PopED)
+    
    library(PopED)
 
 ############# START #################
 ## Create PopED database
@@ -236,7 +236,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f855b96f698>
+#> <bytecode: 0x7fe20a979808>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
diff --git a/docs/reference/ofv_fim.html b/docs/reference/ofv_fim.html
index 0b2dda6..82525c9 100644
--- a/docs/reference/ofv_fim.html
+++ b/docs/reference/ofv_fim.html
@@ -227,7 +227,7 @@ 
    See a
 evaluate.fim()
    
 
     
    Examples
    
-    
    library(PopED)
+    
    library(PopED)
 
 ############# START #################
 ## Create PopED database
@@ -253,7 +253,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f855b96f698>
+#> <bytecode: 0x7fe20a979808>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
diff --git a/docs/reference/optim_ARS.html b/docs/reference/optim_ARS.html
index 111bddb..932c26a 100644
--- a/docs/reference/optim_ARS.html
+++ b/docs/reference/optim_ARS.html
@@ -422,7 +422,7 @@ 
    Examp
 #> It. 400 | OFV = 67.5762
 #> 
 #> Total iterations: 400 
-#> Elapsed time: 0.19 seconds.
+#> Elapsed time: 0.189 seconds.
 #> 
 #> Final OFV =  67.57618 
 #> Parameters: -15.35198 
@@ -511,7 +511,7 @@ 
    Examp
 #> Maximum number of identical optimal values reached (max_run=200), optimization stopped.
 #> 
 #> Total iterations: 392 
-#> Elapsed time: 0.168 seconds.
+#> Elapsed time: 0.174 seconds.
 #> 
 #> Final OFV =  67.6696 
 #> Parameters: -15.97183 
@@ -645,7 +645,7 @@ 
    Examp
 #> It. 400 | OFV = 503.399
 #> 
 #> Total iterations: 400 
-#> Elapsed time: 0.197 seconds.
+#> Elapsed time: 0.271 seconds.
 #> 
 #> Final OFV =  503.399 
 #> Parameters: 2.130566 2 2 2.059427 2 2 2.167358 2 2 2.142739 2 2 2.030765 2.254329 2 2 2.56842 2.045564 2.276299 2 2 2 2 2 3.690364 
@@ -753,7 +753,7 @@ 
    Examp
 #> It. 400 | OFV = 15264
 #> 
 #> Total iterations: 400 
-#> Elapsed time: 0.242 seconds.
+#> Elapsed time: 0.278 seconds.
 #> 
 #> Final OFV =  15264 
 #> Parameters: 1 19 8 5 4 3 18 2 14 9 12 15 13 16 17 6 11 7 20 10 21 1 
@@ -892,7 +892,7 @@ 
    Examp
 #> It. 400 | OFV = 47.7055
 #> 
 #> Total iterations: 400 
-#> Elapsed time: 0.193 seconds.
+#> Elapsed time: 0.191 seconds.
 #> 
 #> Final OFV =  47.7055 
 #> Parameters: 6.562641 
diff --git a/docs/reference/optim_LS.html b/docs/reference/optim_LS.html
index 0014ecc..d255468 100644
--- a/docs/reference/optim_LS.html
+++ b/docs/reference/optim_LS.html
@@ -325,7 +325,7 @@ 
    Examp
 #>    Searching parameter 1 
 #>      Changed from 50 to -15.8166 ; OFV = 67.485 
 #> 
-#>    Elapsed time: 0.035 seconds.
+#>    Elapsed time: 0.045 seconds.
 #> 
 #>    Final OFV =  67.48502 
 #>    Parameters: -15.81658 
@@ -350,7 +350,7 @@ 
    Examp
 #>    Searching parameter 1 
 #>      Changed from 50 to -5.0055 ; OFV = 69.8766 
 #> 
-#>    Elapsed time: 0.04 seconds.
+#>    Elapsed time: 0.048 seconds.
 #> 
 #>    Final OFV =  69.87659 
 #>    Parameters: -5.005501 
@@ -364,7 +364,7 @@ 
    Examp
 #>    Searching parameter 1 
 #>      Changed from 50 to -17 ; OFV = 68.5368 
 #> 
-#>    Elapsed time: 0.001 seconds.
+#>    Elapsed time: 0 seconds.
 #> 
 #>    Final OFV =  68.53679 
 #>    Parameters: -17 
@@ -462,7 +462,7 @@ 
    Examp
 #>    Searching parameter 14 
 #>      Changed from 3 to 2 ; OFV = 446.962 
 #> 
-#>    Elapsed time: 0.183 seconds.
+#>    Elapsed time: 0.191 seconds.
 #> 
 #>    Final OFV =  446.9622 
 #>    Parameters: 2 2.144144 2 2.144144 2 2 2.144144 2 2.144144 2 2.144144 2 2.144144 2 2 2.144144 2 2.144144 2 2.144144 2 2 2 2.108108 4 
diff --git a/docs/reference/pargen.html b/docs/reference/pargen.html
index e15754d..6948fc7 100644
--- a/docs/reference/pargen.html
+++ b/docs/reference/pargen.html
@@ -196,7 +196,7 @@ 
    Value
    
   number_of_parameters)
    
 
     
    Examples
    
-    
    library(PopED)
+    
    library(PopED)
 
 ############# START #################
 ## Create PopED database
@@ -219,7 +219,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f855b96f698>
+#> <bytecode: 0x7fe20a979808>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
diff --git a/docs/reference/plot_efficiency_of_windows.html b/docs/reference/plot_efficiency_of_windows.html
index 162c479..36a2675 100644
--- a/docs/reference/plot_efficiency_of_windows.html
+++ b/docs/reference/plot_efficiency_of_windows.html
@@ -281,7 +281,7 @@ 
    See a
 plot_model_prediction()
    
 
     
    Examples
    
-    
    library(PopED)
+    
    library(PopED)
 
 ############# START #################
 ## Create PopED database
@@ -307,7 +307,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f855b96f698>
+#> <bytecode: 0x7fe20a979808>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
diff --git a/docs/reference/plot_model_prediction.html b/docs/reference/plot_model_prediction.html
index 3c8ae89..3729069 100644
--- a/docs/reference/plot_model_prediction.html
+++ b/docs/reference/plot_model_prediction.html
@@ -354,7 +354,7 @@ 
    Examp
 ##   for population pharmacokinetics-pharmacodynamics studies", 
 ##   Br. J. Clin. Pharm., 2014. 
 
-library(PopED)
+library(PopED)
 
 ## find the parameters that are needed to define from the structural model
 ff.PK.1.comp.oral.md.CL
@@ -370,7 +370,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f84fb7561b0>
+#> <bytecode: 0x7fe25cadfcb0>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
diff --git a/docs/reference/poped_optim.html b/docs/reference/poped_optim.html
index 6f5280b..4da4569 100644
--- a/docs/reference/poped_optim.html
+++ b/docs/reference/poped_optim.html
@@ -425,7 +425,7 @@ 
    See a
 poped_optimize()
    
 
     
    Examples
    
-    
    library(PopED)
+    
    library(PopED)
 
 ############# START #################
 ## Create PopED database
@@ -451,7 +451,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f855b96f698>
+#> <bytecode: 0x7fe20a979808>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
@@ -531,7 +531,7 @@ 
    Examp
 #> Initial OFV = 55.3964
 #> 
 #> Total iterations: 2 
-#> Elapsed time: 0.016 seconds.
+#> Elapsed time: 0.03 seconds.
 #> 
 #> Final OFV =  55.39645 
 #> Parameters: 70 
@@ -553,7 +553,7 @@ 
    Examp
 #>    Searching parameter 1 
 #>      Changed from 83.2011 to 100 ; OFV = 56.032 
 #> 
-#>    Elapsed time: 0.022 seconds.
+#>    Elapsed time: 0.024 seconds.
 #> 
 #>    Final OFV =  56.03204 
 #>    Parameters: 100 
@@ -596,7 +596,7 @@ 
    Examp
 #>     sig_prop     0.01      32    23
 #>      sig_add     0.25      26    30
 #> 
-#> Total running time: 0.412 seconds
    
+#> Total running time: 0.524 seconds
    
 
 # cost function
 # PRED at 120 hours
@@ -643,7 +643,7 @@ 
    Examp
 #> Initial OFV = 0.939866
 #> 
 #> Total iterations: 2 
-#> Elapsed time: 0.007 seconds.
+#> Elapsed time: 0.012 seconds.
 #> 
 #> Final OFV =  1.244413 
 #> Parameters: 92.68227 
@@ -665,7 +665,7 @@ 
    Examp
 #>    Searching parameter 1 
 #>      Changed from 93.2764 to 100 ; OFV = 1.34267 
 #> 
-#>    Elapsed time: 0.013 seconds.
+#>    Elapsed time: 0.017 seconds.
 #> 
 #>    Final OFV =  1.342665 
 #>    Parameters: 100 
@@ -693,7 +693,7 @@ 
    Examp
 #> Initial OFV = 1.34267
 #> 
 #> Total iterations: 2 
-#> Elapsed time: 0.006 seconds.
+#> Elapsed time: 0.008 seconds.
 #> 
 #> Final OFV =  1.342665 
 #> Parameters: 100 
@@ -715,7 +715,7 @@ 
    Examp
 #>    Searching parameter 1 
 #>      Changed from 100 to 100 ; OFV = 1.34267 
 #> 
-#>    Elapsed time: 0.012 seconds.
+#>    Elapsed time: 0.018 seconds.
 #> 
 #>    Final OFV =  1.342665 
 #>    Parameters: 100 
@@ -758,7 +758,7 @@ 
    Examp
 #>     sig_prop     0.01      32    23
 #>      sig_add     0.25      26    30
 #> 
-#> Total running time: 0.476 seconds
    
+#> Total running time: 0.582 seconds
    
 # minimize the cost function
 out_3 <- poped_optim(poped.db,opt_a =TRUE,
                      ofv_fun=crit_fcn,
@@ -785,7 +785,7 @@ 
    Examp
 #> Initial OFV = 0.939866
 #> 
 #> Total iterations: 2 
-#> Elapsed time: 0.006 seconds.
+#> Elapsed time: 0.007 seconds.
 #> 
 #> Final OFV =  0.833124 
 #> Parameters: 62.05002 
@@ -807,7 +807,7 @@ 
    Examp
 #>    Searching parameter 1 
 #>      Changed from 54.3773 to 0.01 ; OFV = 0.000134267 
 #> 
-#>    Elapsed time: 0.009 seconds.
+#>    Elapsed time: 0.023 seconds.
 #> 
 #>    Final OFV =  0.0001342665 
 #>    Parameters: 0.01 
@@ -835,7 +835,7 @@ 
    Examp
 #> Initial OFV = 0.000134267
 #> 
 #> Total iterations: 2 
-#> Elapsed time: 0.007 seconds.
+#> Elapsed time: 0.009 seconds.
 #> 
 #> Final OFV =  0.0001342665 
 #> Parameters: 0.01 
@@ -857,7 +857,7 @@ 
    Examp
 #>    Searching parameter 1 
 #>      Changed from 0.01 to 0.01 ; OFV = 0.000134267 
 #> 
-#>    Elapsed time: 0.013 seconds.
+#>    Elapsed time: 0.014 seconds.
 #> 
 #>    Final OFV =  0.0001342665 
 #>    Parameters: 0.01 
@@ -888,7 +888,7 @@ 
    Examp
 #> Efficiency: 
 #>   (ofv_final / ofv_init) = 0.00014286
 #> 
-#> Total running time: 0.452 seconds
    
+#> Total running time: 0.669 seconds
    
 
 if (FALSE) {
   
diff --git a/docs/reference/poped_optimize.html b/docs/reference/poped_optimize.html
index 0f85812..1da3f72 100644
--- a/docs/reference/poped_optimize.html
+++ b/docs/reference/poped_optimize.html
@@ -404,7 +404,7 @@ 
    See a
 poped_optim()
    
 
     
    Examples
    
-    
    library(PopED)
+    
    library(PopED)
 
 ############# START #################
 ## Create PopED database
@@ -430,7 +430,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f855b96f698>
+#> <bytecode: 0x7fe20a979808>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
@@ -520,7 +520,7 @@ 
    Examp
 #> 
 #> *********************************
 #> 
-#> Run time for random search: 0.017 seconds
+#> Run time for random search: 0.02 seconds
 #> 
 #> SG - It. : 1  OFV : 55.45   Diff. :     1
 #> SG - It. : 2  OFV : 55.61   Diff. : 0.002799
@@ -551,7 +551,7 @@ 
    Examp
 #> OFV(mf)    : 55.6095
 #> diff       : 0.00279928
 #> *************************************************************
-#> Stochastic gradient run time: 0.37 seconds
+#> Stochastic gradient run time: 0.463 seconds
 #> 
 #> *****************************
 #>             Line Search
@@ -588,10 +588,10 @@ 
    Examp
 #> Best value for OFV(MF) = 56.5866
 #> 
 #> Best value for a: 
-#> Group 1: 100
+#> Group 1: 100 [0.01,100]
 #> 
 #> 
-#> Line search run time: 0.26 seconds
+#> Line search run time: 0.367 seconds
 #> ***************************
 #> 
 #> ===============================================================================
@@ -619,7 +619,7 @@ 
    Examp
 #>     sig_prop     0.01      32    25
 #>      sig_add     0.25      26    16
 #> 
-#> Total running time: 0.651 seconds
    
+#> Total running time: 0.853 seconds
    
 if (FALSE) {
   
   # RS+SG+LS optimization of sample times 
diff --git a/docs/reference/shrinkage.html b/docs/reference/shrinkage.html
index d8182fa..4c6f34d 100644
--- a/docs/reference/shrinkage.html
+++ b/docs/reference/shrinkage.html
@@ -188,17 +188,19 @@ 
    R
   Frey, N., & Mentre, F. (2013). Prediction of shrinkage of individual
   parameters using the Bayesian information matrix in non-linear mixed effect
   models with evaluation in pharmacokinetics. Pharmaceutical Research, 30(9),
-  2355-67. https://doi.org/10.1007/s11095-013-1079-3.
    
+  2355-67. doi: 10.1007/s11095-013-1079-3
+.
    
 
  • Hennig, S., Nyberg, J., Fanta, S., Backman, J.
   T., Hoppu, K., Hooker, A. C., & Karlsson, M. O. (2012). Application of the
   optimal design approach to improve a pretransplant drug dose finding design
   for ciclosporin. Journal of Clinical Pharmacology, 52(3), 347-360.
-  https://doi.org/10.1177/0091270010397731.
    • 
+  doi: 10.1177/0091270010397731
+.
    
 
 
 
     
    Examples
    
-    
    library(PopED)
+    
    library(PopED)
 
 ############# START #################
 ## Create PopED database
@@ -221,7 +223,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f855b96f698>
+#> <bytecode: 0x7fe20a979808>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
diff --git a/docs/reference/summary.poped_optim.html b/docs/reference/summary.poped_optim.html
index 1639694..0d77e84 100644
--- a/docs/reference/summary.poped_optim.html
+++ b/docs/reference/summary.poped_optim.html
@@ -168,7 +168,7 @@ 
    Arg
 
 
     
    Examples
    
-    
    library(PopED)
+    
    library(PopED)
 
 ############# START #################
 ## Create PopED database
@@ -194,7 +194,7 @@ 
    Examp
 #>         return(list(y = y, poped.db = poped.db))
 #>     })
 #> }
-#> <bytecode: 0x7f855b96f698>
+#> <bytecode: 0x7fe20a979808>
 #> <environment: namespace:PopED>
    
 ## -- parameter definition function 
 ## -- names match parameters in function ff
@@ -272,7 +272,7 @@ 
    Examp
 #> Initial OFV = 55.3964
 #> 
 #> Total iterations: 2 
-#> Elapsed time: 0.013 seconds.
+#> Elapsed time: 0.018 seconds.
 #> 
 #> Final OFV =  55.39645 
 #> Parameters: 70 
@@ -294,7 +294,7 @@ 
    Examp
 #>    Searching parameter 1 
 #>      Changed from 83.2011 to 100 ; OFV = 56.032 
 #> 
-#>    Elapsed time: 0.021 seconds.
+#>    Elapsed time: 0.031 seconds.
 #> 
 #>    Final OFV =  56.03204 
 #>    Parameters: 100 
@@ -337,7 +337,7 @@ 
    Examp
 #>     sig_prop     0.01      32    23
 #>      sig_add     0.25      26    30
 #> 
-#> Total running time: 0.288 seconds
    
+#> Total running time: 0.399 seconds
    
 
 summary(out_1)
 
    #> ===============================================================================
@@ -363,7 +363,7 @@ 
    Examp
 #>     sig_prop     0.01      32    23
 #>      sig_add     0.25      26    30
 #> 
-#> Total running time: 0.288 seconds
    
+#> Total running time: 0.399 seconds
    
   
    
   
    #> Elapsed time: 0.003 seconds.
    
   
    
   
    #> Elapsed time: 0.003 seconds.
    tic()
 toc()
-
    #> Elapsed time: 0 seconds.
    toc()
-
    #> Elapsed time: 0.001 seconds.
    tic()
+
    #> Elapsed time: 0.001 seconds.
    toc()
+
    #> Elapsed time: 0.002 seconds.
    tic()
 toc(name="foo")
-
    #> Elapsed time: 0.004 seconds.
    
+
    #> Elapsed time: 0.006 seconds.