Re: [NMusers] Simulate with ETAs from .phi and residual variability
Thank you Leonid and Andreas! Can we have Nonmem support the combination of $ETAS and $SIMULATION ONLYSIM? That would enable NMsim to completely automate simulations of known subjects with residual variability, just like it already automates simulation of new subjects with residual variability. Currently, I am using the "mixed option" mentioned by Leonid. This is only needed with NMsim if simulating "known" subjects (ETAs) or if the Nonmem model for some reason does not produce a variable with residual variability. See the "patch" below for examples. *NMsim automates simulation with new or known subjects* The reason why I am searching for a Nonmem-native method is that NMsim automates simulation of Nonmem models based on the estimation control stream and a simulation dataset. The idea is to avoid any reimplementation but let Nonmem run the simulation. It works nicely and can automatically grab ETAs from a phi file to simulate estimated/"known" subjects. The syntax for this feature is ``` results.sim <- NMsim(file.mod="path/to/input/control.mod", data=data.sim, method.sim=NMsim_known) ``` Currently, it searches for a .phi file next to the control.mod (which can be called control.ctl or anything) but this will be generalized in next version so you can pull in other subjects. If you omit `method.sim` it will use the default method which is generation of new subjects (ETAs) using $SIMULATION ONLYSIM. In that case the residual variability is simulated too. *NMsim's patch called addResVar* NMsim's addResVar() grabs the parameter estimates from .ext and adds residual variability. The following example reproduces the residual variability implemented in Nonmem with SIGMA parameters where SIGMA(1,1) is the variance of the proportional error component, SIGMA(2,2) the one of the additive component (and SIGMA(1,2) the covariance). `simres` is a data.frame containing results from a simulation without residual variability (but with IPRED): ``` simres.var <- addResVar(data=simres, path.ext = "path/to/model.ext" ,prop = 1 ,add = 2 ,par.type = "SIGMA" ,log = FALSE) ``` If using par.type="THETA", prop and add (obviously not both if the error model is not combined) have to provide the THETA element numbers in use. If par.type="THETA", addResVar is by default interpreting the parameters as standard devs, with SIGMAs, they are variances. This can be modified using another argument, see help. log=TRUE means the variability is on log scale, i.e. the "exponential error model". `addResVar` is a last-resort patch. Since it reimplements the residual error model, it is up to your QC to check that the right parameters are selected etc. It would be way better if we can have Nonmem do the sim, and we would know it is the exact same model that was used for simulation and for estimation. *Further interested?* NMsim is on CRAN. If you are interested in discussions on these issues, you are very welcome at https://github.com/philipdelff/NMsim/issues. Thank you, Philip On 10/8/23 22:22, Leonid Gibiansky wrote: The only way I know to simulate with residual variability is to use $SIM SIMONLY If ETAs need to be fixed, they have to be in the data file $INPUT ,PKETA1, CL=THETA(1)*EXP(PKETA1+0*ETA(1)) -- another option is to use mrgsolve or similar R packages (after reading in estimated ETA values). -- Mixed option is to simulate IPRED and then add noise in the R code after reading IPRED. Thank you Leonid On 10/8/2023 3:30 PM, Philip Harder Delff wrote: Dear all, I want to simulate subjects with ETAs estimated. I use the .phi file using a $ETAS statement like: $ETAS FILE=file.phi FORMAT=s1pE15.8 TBLN=1 As far as I understand that has to be accompanied by a $ESTIMATION step that specifies FNLETA=2 like this: $ESTIMATION MAXEVAL=0 NOABORT METHOD=1 INTERACTION FNLETA=2 $SIM ONLYSIM does not work with $ESTIMATION so instead I just do: $SIMULATION (220412) This however means that in the following from $ERROR we don't get the ERR(1) and ERR(2) simulated and so Y=IPRED. Y=F+F*ERR(1)+ERR(2) I need to be able to edit the phi file to only simulate a subset of the patients so I can't use msf based solutions. Can I somehow use $ETAS without $ESTIMATION? Or how else can I get it to simulate the residual variability? Thank you, Philip
RE: [NMusers] Simulate with ETAs from .phi and residual variability
Dear Philp,
You may also want to have a look at the open-source R package campsis
(https://calvagone.github.io/).
Below is some R-code that illustrates how you can easily simulate individual
profiles taking the ETAs from a NONMEM output table.
Best regards, Andreas.
---
library(tidyverse)
library(campsis)
# Load a standard model from the library
# you can also set-up a custom model using the free online simulator
e-campsis.com)
model <- model_library$advan2_trans2
# set the parameter values
model <- model %>% replace(Theta("V", value=20))
model <- model %>% replace(Theta("CL", value=5))
model <- model %>% replace(Omega("V", value=0.1,type = 'var'))
model <- model %>% replace(Omega("CL", value=0.1,type = 'var'))
model <- model %>% replace(Sigma("PROP", value=0.02,type = 'var'))
# Have a look at the model
model
# load NONMEM output table containing the ETAS (and covariates if you have)
ETA.tab <- read_table("patab001",skip = 1) %>%
group_by(ID) %>% slice(1) %>% # take only the first record of each subject
rename(ETA_CL=ETA1,ETA_V=ETA2) # you may need to rename variables to match
with the model code
# set-up the simulation schedule; the number of subject must equal that of
ETA.tab
dataset <- Dataset(subjects = n_distinct(ETA.tab$ID)) %>%
add(Bolus(time=0, amount=1000, ii=12, addl=2)) %>%
add(Observations(times=seq(0, 36, by=0.5)))
# add the ETAs by using the bootstrap functionality
dataset <- dataset %>%
add(Bootstrap(data= ETA.tab, id="ID", replacement=FALSE, random=FALSE,
export_id=TRUE))
# we need to discard the random IIV as the ETAs are taken from the dataset
model@parameters@list <- model@parameters@list %>% purrr::discard(.p=~is(.x,
"omega"))
# run the simulation
results <- model %>% simulate(dataset=dataset,outvars = c('BS_ID')) # BS_ID is
the original ID in the ETA.tab
# plot the results
spaghettiPlot(results,'OBS_CP')
-Original Message-
From: owner-nmus...@globomaxnm.com On Behalf Of
Philip Harder Delff
Sent: Sunday, October 8, 2023 9:30 PM
To: nmusers@globomaxnm.com
Subject: [NMusers] Simulate with ETAs from .phi and residual variability
Dear all,
I want to simulate subjects with ETAs estimated. I use the .phi file using a
$ETAS statement like:
$ETAS FILE=file.phi FORMAT=s1pE15.8 TBLN=1
As far as I understand that has to be accompanied by a $ESTIMATION step that
specifies FNLETA=2 like this:
$ESTIMATION MAXEVAL=0 NOABORT METHOD=1 INTERACTION FNLETA=2
$SIM ONLYSIM does not work with $ESTIMATION so instead I just do:
$SIMULATION (220412)
This however means that in the following from $ERROR we don't get the
ERR(1) and ERR(2) simulated and so Y=IPRED.
Y=F+F*ERR(1)+ERR(2)
I need to be able to edit the phi file to only simulate a subset of the
patients so I can't use msf based solutions. Can I somehow use $ETAS without
$ESTIMATION? Or how else can I get it to simulate the residual variability?
Thank you,
Philip
Re: [NMusers] Simulate with ETAs from .phi and residual variability
The only way I know to simulate with residual variability is to use $SIM SIMONLY If ETAs need to be fixed, they have to be in the data file $INPUT ,PKETA1, CL=THETA(1)*EXP(PKETA1+0*ETA(1)) -- another option is to use mrgsolve or similar R packages (after reading in estimated ETA values). -- Mixed option is to simulate IPRED and then add noise in the R code after reading IPRED. Thank you Leonid On 10/8/2023 3:30 PM, Philip Harder Delff wrote: Dear all, I want to simulate subjects with ETAs estimated. I use the .phi file using a $ETAS statement like: $ETAS FILE=file.phi FORMAT=s1pE15.8 TBLN=1 As far as I understand that has to be accompanied by a $ESTIMATION step that specifies FNLETA=2 like this: $ESTIMATION MAXEVAL=0 NOABORT METHOD=1 INTERACTION FNLETA=2 $SIM ONLYSIM does not work with $ESTIMATION so instead I just do: $SIMULATION (220412) This however means that in the following from $ERROR we don't get the ERR(1) and ERR(2) simulated and so Y=IPRED. Y=F+F*ERR(1)+ERR(2) I need to be able to edit the phi file to only simulate a subset of the patients so I can't use msf based solutions. Can I somehow use $ETAS without $ESTIMATION? Or how else can I get it to simulate the residual variability? Thank you, Philip
[NMusers] Simulate with ETAs from .phi and residual variability
Dear all, I want to simulate subjects with ETAs estimated. I use the .phi file using a $ETAS statement like: $ETAS FILE=file.phi FORMAT=s1pE15.8 TBLN=1 As far as I understand that has to be accompanied by a $ESTIMATION step that specifies FNLETA=2 like this: $ESTIMATION MAXEVAL=0 NOABORT METHOD=1 INTERACTION FNLETA=2 $SIM ONLYSIM does not work with $ESTIMATION so instead I just do: $SIMULATION (220412) This however means that in the following from $ERROR we don't get the ERR(1) and ERR(2) simulated and so Y=IPRED. Y=F+F*ERR(1)+ERR(2) I need to be able to edit the phi file to only simulate a subset of the patients so I can't use msf based solutions. Can I somehow use $ETAS without $ESTIMATION? Or how else can I get it to simulate the residual variability? Thank you, Philip
