multiple dose full TMDD model in POPED

[nitkaila]

I am having an issue in implementing a multiple dose TMDD model estimated in nonmem to optimize over 4 analytes in PopED. The error message, verbatim pasted below indicates, a needed missing value of an attribute.

Run the attached code. Appreciate any help to identify and fix the needed attribute.

Nitin

Problems inverting the matrix. Results could be misleading. Error in if (any(ret == 0)) { : missing value where TRUE/FALSE needed In addition: Warning message: In sqrt(param_vars[i]) : NaNs produced

tmdd_18.txt

[andrewhooker]

Hi Nitin,

I do not see the same error when I run your code. Which version are you using? I am using the latest development version of PopED and the latest R:

> devtools::session_info()

─ Session info ───────────────────────────────────────────────────────────────────────────────
 setting  value
 version  R version 4.3.2 (2023-10-31)
 os       macOS Ventura 13.6.1
 system   aarch64, darwin20
 ui       RStudio
 rstudio  2023.09.1+494 Desert Sunflower (desktop)

─ Packages ───────────────────────────────────────────────────────────────────────────────────
 package     * version    date (UTC) lib source
 deSolve     * 1.38       2023-09-05 [1] CRAN (R 4.3.0)
 devtools    * 2.4.5      2022-10-11 [1] CRAN (R 4.3.0)
 ggplot2     * 3.4.4      2023-10-12 [1] CRAN (R 4.3.1)
 PopED       * 0.6.0.9002 2023-06-08 [1] local
 usethis     * 2.2.2      2023-07-06 [1] CRAN (R 4.3.0)

 [1] /Library/Frameworks/R.framework/Versions/4.3-arm64/Resources/library

What I do see is that the last SIGMA parameter is very poorly estimated with the planned design. Below are the RSE(in %) for the parameters in your model with the initial design:

> round(bs0$rse,0)
   bpop[1]    bpop[2]    bpop[3]    bpop[4]    bpop[5]    bpop[6]    bpop[7]    bpop[8] 
         1          7          7          0         15          0          2          4 
   bpop[9]     D[1,1]     D[2,2]     D[3,3]     D[4,4]     D[5,5]     D[6,6]     D[7,7] 
         1         34         33         33         33         34         25         34 
    D[8,8]     D[9,9] SIGMA[1,1] SIGMA[2,2] SIGMA[5,5] SIGMA[6,6] SIGMA[7,7] SIGMA[8,8] 
        35         33          9         18          8         33          8       1175 

Best regards, Andy

[nitkaila]

Thanks Andy. It is very helpful to know that the error message is not due to model implementation.

It has been a few years, since I implemented the multiple dose TMDD model in PopED and recall having no such error message, until recently on attempting to re-run same code, found the error message.

I could never have been sure if the error message could have originated from a difference in R version.

The error message was originating in the following installation of R:

sessionInfo() R version 4.1.1 (2021-08-10) Platform: x86_64-pc-linux-gnu (64-bit) Running under: Ubuntu 18.04.5 LTS

Matrix products: default BLAS: /usr/lib/x86_64-linux-gnu/openblas/libblas.so.3 LAPACK: /usr/lib/x86_64-linux-gnu/libopenblasp-r0.2.20.so

locale: [1] LC_CTYPE=en_US.UTF-8 LC_NUMERIC=C LC_TIME=en_US.UTF-8 LC_COLLATE=en_US.UTF-8
[5] LC_MONETARY=en_US.UTF-8 LC_MESSAGES=en_US.UTF-8 LC_PAPER=en_US.UTF-8 LC_NAME=C
[9] LC_ADDRESS=C LC_TELEPHONE=C LC_MEASUREMENT=en_US.UTF-8 LC_IDENTIFICATION=C

attached base packages: [1] grid stats graphics grDevices utils datasets methods base

other attached packages: [1] lotri_0.3.1 RxODE_1.0.9 forcats_0.5.1 stringr_1.4.0 dplyr_1.0.7 readr_2.0.0 tidyr_1.1.3
[8] tibble_3.1.3 tidyverse_1.3.1 ggforce_0.3.3 gridExtra_2.3 purrr_0.3.4 reshape2_1.4.4 reshape_0.8.8
[15] GGally_2.1.2 ggplot2_3.3.5 nlme_3.1-152 MASS_7.3-54 lattice_0.20-44 deSolve_1.28 PopED_0.6.0

But has been fixed in the following R version:

sessionInfo() R version 4.2.2 (2022-10-31 ucrt) Platform: x86_64-w64-mingw32/x64 (64-bit) Running under: Windows 10 x64 (build 19045)

Matrix products: default

locale: [1] LC_COLLATE=English_United States.utf8 LC_CTYPE=English_United States.utf8 LC_MONETARY=English_United States.utf8 LC_NUMERIC=C
[5] LC_TIME=English_United States.utf8

attached base packages: [1] stats graphics grDevices utils datasets methods base

other attached packages: [1] ggplot2_3.4.0 deSolve_1.38 PopED_0.6.0

[nitkaila]

Also confirmed that on artificially assigning the (%rse) of the SIGMA to a low value.

The issue is entirely fixed in the previous installation of R.