Dear Luann, "How did you determine that ALT, HGB, and TB should be in the model for TVCL?" I have determined these covariates as significant covariates by stepwise forward selection and backward elimination. Sincerely, I really concerned that I answered you in the right way?
kind regards, Pete On Wed, Jul 10, 2019 at 1:23 AM Luann Phillips <lu...@cognigencorp.com> wrote: > Hi Vichapat, > > I was just asking which method that you had used. Some people do use the > baseline value for the whole dataset even for long studies . I disagree > with this method. I think time-varying covariate values should always be > used for long study periods. It sounds like the way you built your data is > fine. > The ctl stream looks the same whether you use stationary or time-varying > covariates. When NM is fitting the model, it uses which ever covariate > value is available. > > As the differential equation solver in NONMEM steps from TIME=N to > TIME=N+1, the covariate value from TIME=N+1 is used (see example below) > > Example: > > TIME=0 AMT=40 DV=. COVAR=55 > TIME=11.833 AMT=. DV=25 COVAR=55 > TIME=12 AMT=40 DV=. COVAR=55 > TIME=23.833 AMT=. DV=30 COVAR=55 > TIME=24 AMT=40 DV=. COVAR=60 > TIME=35.833 AMT=. DV=25 COVAR=60 > TIME=36 AMT=40 DV=. COVAR=60 > TIME=47.833 AMT=. DV=27 COVAR=60 > etc. > > As NONMEM steps from TIME=0 to TIME=11.833 the value of COVAR=55 from the > TIME=11.833 record is used > As NONMEM steps from TIME=11.833 to TIME=12 the value of COVAR=55 from the > TIME=12 record is used > As NONMEM steps from TIME=12 to TIME=23.833 the value of COVAR=55 from the > TIME=23.833 record is used > As NONMEM steps from TIME=23.833 to TIME=24 the value of COVAR=60 from the > TIME=24 record is used > As NONMEM steps from TIME=24 to TIME=35.833 the value of COVAR=60 from the > TIME=35.833 record is used > As NONMEM steps from TIME=35.833 to TIME=36 the value of COVAR=60 from the > TIME=36 record is used > As NONMEM steps from TIME=36 to TIME=47.833 the value of COVAR=60 from the > TIME=47.833 record is used > etc. > > If the value of COVAR=55 for all records NONMEM still works the same way, > it's just that the value of COVAR will never change. > > So in your case, > TVCL=THETA(1)*EXP(THETA(4)*(ALT/388))*((HGB/10.50)**THETA(5))*((TB/4.7)**THETA(6)) > changes value every time that ALT, HGB, or TB changes value. > The ETA(1) value remains the same for all observations within an > individual but CL will still change with time because ALT, HGB, and TB > change with time. > > How did you determine that ALT, HGB, and TB should be in the model for > TVCL? > > Luann > > > ------------------------------ > *From: *"Vichapat Tharanon" <vichapa...@gmail.com> > *To: *"Luann Phillips" <luann.phill...@cognigencorp.com> > *Cc: *"nmusers" <nmusers@globomaxnm.com> > *Sent: *Tuesday, July 9, 2019 1:53:18 PM > *Subject: *Re: [NMusers] Is it possible that IIV (%CV) of final model was > higher than IIV of base model? > > Dear Luann, > > (1) My data file was recorded with covariates values changed > each times in according to the lab monitored. Hence, I think I have > time-vary covariates in datafile. Now, I use normal control stream to model > these data. So, you suggested me to put a new value on a record with > matching date and then retain forward to the next covariate sample. From > this suggestion, let me confirm that I should have one column for baseline > covariate (1st Lab monitoring) and another column for exact covariates > recorded on that day? > > (2) Then, how could I code the control stream for the covariate > model with time-varying covarites? (sorry that I have never get into it) > > (3) Btw, I have one doubtful question about stationary > covariates on the data file. Is it possible to model the PPKs of the drugs > with stationary covariates. I mean that is it rationale to use > only one value of each covariates in the model wheres the > concentration+dose were dynamic especially if the study period take quite > long time. > > Thank you so much for your reply, valued comments and > suggestions. > > Kind regards, > Vichapat > > > On Tue, Jul 9, 2019 at 8:58 PM Luann Phillips <lu...@cognigencorp.com> > wrote: > >> Vichapat, >> >> Your ctl stream appears to be correct. To model with time-varying >> covariates involves a change in the database. >> (A) Did you use the covariate values at the time of each patient's first >> dose (ie, baseline values) in the data? >> or >> (B) Did you use the covariate values each time that they were collected? >> >> (A) is stationary covariates and (B) is time-vary covariates. >> >> To include time-varying covariates in the data, put the new value on a >> record with a matching date and then retain forward to the next covariate >> sample. >> >> Please be aware that the dosing and sample time assumptions (which >> sometimes are required) will also add to unexplained variability. I would >> look at plot of the data prior to running any models and exclude any >> concentrations that look very wrong (ie, collected at a peak instead of a >> trough). Perform the modeling and then try re-including the 'wrong' >> concentrations to show the impact to the model but I would still make the >> final model the one excluding those concentrations. >> >> Luann >> >> ------------------------------ >> *From: *"Vichapat Tharanon" <vichapa...@gmail.com> >> *To: *"Luann Phillips" <luann.phill...@cognigencorp.com> >> *Sent: *Monday, July 8, 2019 10:06:06 PM >> *Subject: *Re: [NMusers] Is it possible that IIV (%CV) of final model >> was higher than IIV of base model? >> >> Dear Luann, >> >> Thank you so much for your valued suggestions. I greatly >> appreciated it. By the way, The suggestion given me that mean I should use >> "Time varying covariates" on the model? I am really new with NONMEM, If >> you do not mind helping me. Could you suggest me how to code the control >> file for that model in right way. I really know that my request may disturb >> you, but I do not know how to start it. Thank you in advance. >> >> Best regards, >> >> PS, This is my original control file for final model. There are 1170 >> Tacrolimus concentration from 50 patients (retrospective data) then I >> assumed all patient took a drug at same time (every 12 hours: AM, PM on >> time) and Trough concentrations were monitored at 11.50 hours (Before the >> next morning dose 30 minutes). >> Briefly, tacrolimus was reported high inter- & intra-variability and >> primarily metabolized by liver via Cytochrome enzyme and eliminated via >> bile. >> >> ;Model Desc: Final model >> ;Project Name: step3cov >> ;Project ID: NO PROJECT DESCRIPTION >> ;Project ID: NO PROJECT DESCRIPTION >> >> $PROB RUN# ALTHGBTB >> $INPUT C ID TIME AMT ADDL II TAD DV MDV EVID BW POD AST ALT ALP GGT TB DB >> ALB HGB HCT BUN SCR >> $DATA MASTER.CSV IGNORE=C >> $SUBROUTINES ADVAN2 TRANS2 >> $PK >> >> >> TVCL=THETA(1)*EXP(THETA(4)*(ALT/388))*((HGB/10.50)**THETA(5))*((TB/4.7)**THETA(6)) >> CL=TVCL*EXP(ETA(1)) >> TVV=THETA(2) >> V=TVV*EXP(ETA(2)) >> TVKA=THETA(3) >> KA=TVKA*EXP(ETA(3)) >> S2=V/1000 >> >> $ERROR >> IPRE=F >> W= 1 >> IRES= DV-IPRE >> IWRE=(DV-IPRE)/W >> Y = F + ERR(1) >> >> $EST METHOD=1 INTERACTION PRINT=5 MAX=9999 SIG=3 MSFO=ALTHGBTB.msf >> $THETA >> (0,20) ;[CL/F] >> (0,500) ;[V/F] >> (fixed,4.48) ;[KA] >> (0.001);[ALT] >> (0.001);[HGB] >> (0.001);[TB] >> >> $OMEGA >> 0.04 ;[P] omega(1,1) >> 0.04 ;[P] omega(2,2) >> (fixed,0) ;[A] omega(3,3) >> $SIGMA >> 0.04 ;[A] sigma(1,1) >> >> $COV >> $TABLE ID CL V KA ETA1 ETA2 ETA3 PRED RES WRES IPRE IWRE CPRED CWRES TIME >> AMT ADDL II TAD DV BW POD AST ALT ALP GGT TB DB ALB HGB HCT BUN SCR TIME >> ONEHEADER NOPRINT FILE=ALTHGBTB.tab >> $TABLE ID TIME CL V KA ETA1 ETA2 ETA3 ONEHEADER NOPRINT FILE=PATABALTHGBTB >> $TABLE ID BW POD AST ALT ALP GGT TB DB ALB HGB HCT BUN SCR ONEHEADER >> NOPRINT FILE=COTABALTHGBTB >> $TABLE ID ONEHEADER NOPRINT FILE=CATABALTHGBTB >> $TABLE ID TIME PRED RES WRES IPRE IWRE CPRED CWRES ONEHEADER NOPRINT >> FILE=SDTABALTHGBTB >> $TABLE ID CL V KA NOAPPEND NOPRINT FILE=ALTHGBTB.par >> $TABLE ID ETA1 ETA2 ETA3 NOAPPEND NOPRINT FILE=ALTHGBTB.eta >> >> >> >> On Tue, Jul 9, 2019 at 1:27 AM Luann Phillips <lu...@cognigencorp.com> >> wrote: >> >>> Vichapat, >>> >>> I just had another thought. You may want to check CL/F as a function of >>> time post transplant. As an initial, look you could try >>> CL=BLCL + BLCL*MAX*TIME/(TIME50+TIME) >>> where BLCL would be CL/F when TIME=0 or baseline CL >>> MAX = maximum proportional increase in CL relative to Baseline >>> TIME50=the time since transplot required to achieve 50% of the maximum >>> value of CL/F post transplant. >>> >>> If this shows significant improvement in model fit, then you should try >>> a model with continuous time in the $DES block. >>> >>> Best regards, >>> Luann >>> >>> ------------------------------ >>> *From: *"Vichapat Tharanon" <vichapa...@gmail.com> >>> *To: *"nmusers" <nmusers@globomaxnm.com> >>> *Sent: *Monday, July 8, 2019 10:21:12 AM >>> *Subject: *[NMusers] Is it possible that IIV (%CV) of final model was >>> higher than IIV of base model? >>> >>> Dear All, >>> >>> >>> I am a hospital pharmacist and I am working on NONMEM as a >>> new user. I have modeled the oral immediate-released tacrolimus (Prograf) >>> in adult liver transplant patients. >>> >>> Most of the data were trough concentration (about 1170 levels) from routine >>> monitoring tacrolimus data in the period of first day post-transplantation >>> to 6 months. The model was constructed by NONMEM 7.2 using FOCE >>> INTERACTION methods with the subroutines ADVAN2 TRANS2 (one compartment >>> model with linear absorption and elimination). The ka could not be >>> estimated and then was fixed at 4.48 h-1. The IIIV and RUV were >>> described by exponential and additive error model, respectively. Forward >>> addition of a liver enzyme (ALT), Hemoglobin and total bilirubin (TB) on >>> CL/F reduced OFV significantly (delta OFV ~98, 42, 28, respectively) but >>> IIV of CL/F was increased from 37.2% to 38.1%. It was found that no >>> significant covariates influenced to V/F but IIV of V/F was also >>> increased from 55% to 63%. Residual variability was reduced from a SD >>> of 2.80 to 2.65, when compared final model and base model. >>> >>> I feel uncomfortable with these findings. Is it possible >>> that IIV of CL/F and V/F were rising after adding the significant >>> covariates whereas %RSE of the CL/F and V/F estimate as well as IIV of CL/F >>> and IIV of V/F in final model were slightly decreasing. May I have your >>> comment or suggestion; I would really appreciate it. Thank you in >>> advance. >>> >>> Best regards, >>> >>> Pete >>> >> >