RE: RES and WRES output with Beal's M3 method

-----Original Message----- From: [email protected] [mailto:[email protected]] On Behalf Of Sebastien Bihorel Sent: Wednesday, April 07, 2010 1:57 PM To: Martin Bergstrand Cc: 'Sebastien Bihorel'; [email protected] Subject: Re: [NMusers] RES and WRES output with Beal's M3 method Hi Martin, Thanks for your reply. I tend to agree with you this should be considered as a bug. I tried different options to access to the actual RES and WRES inside the $ERROR block. The best I could do so far was to access to PRED values using (COMACT.EQ.1). With this call, I can assign PRED values to a PPRED variable that I used to compute some residuals PRES (DV-PPRED) and some weighted residuals PWRES (RES/W) using your defining of W. This provides some non-zero values for non-BLOQ samples. By checking PRES and PWRES against RES and WRES for patients without BLOQ samples, it appears that PWRES is correct as long as I don't include inter-individual variability in my model (PRES seems to be always correct). Any idea how the formula for PWRES should be altered? Sebastien New code: $ERROR (ONLY OBSERVATIONS) ;Information needed for BLQF and > BLQF samples LOQ=5 SIG = THETA(3) DFLG=0 ;create a dose record flag IF(AMT.NE.0) DFLG=1 IPRED=F+DFLG W=IPRED*SIG IF (COMACT.EQ.1) PPRED=F+DFLG PRES=DV-PPRED PWRES=PRES/W ;Computations for samples with DV > LOQ (BLQF=0) IF (BLQF.LT.0.25) THEN F_FLAG=0 FFLG=0 IRES=DV-IPRED IWRES=IRES/W Y=IPRED+W*SIG*EPS(1) ;NOTE: Prediction is a concentration ENDIF ;Computations for samples with DV <= LOQ (BLQF=1) IF (BLQF.GE.0.25) THEN F_FLAG=1 FFLG=1 DUM=(LOQ-IPRED)/(W*SIG) IPRED=PHI(DUM) Y=IPRED ;NOTE: prediction is a *probability* ENDIF Martin Bergstrand wrote: > Dear Sebastien and NONMEM users, > > It is correct that NONMEM doesn't return any RES or WRES for individuals who > have at least one observation with F_FLAG=1. It is understandable that > NONMEM can't return residuals for the BQL observations (F_FLAG=1) since PRED > is a likelihood in this case and not a prediction (furthermore the > observation is an interval and can neither be used to calculate a residual). > However, I don't understand why it doesn't do so for the observations for > which F_FLAG=0? Can this be considered a bug? > > You can of course always get out individual residuals (IRES) and individual > weighted residuals (IWRES) (below this paragraph you can see my definition > of IWRES). What you can do if you really want to get RES and WRES is to run > a MAXEVAL=0 run with your final estimates. The BQL data should in this case > be omitted (or set to a fix value) and all M3 code taken out. Remember in > this case that the IRES and IWRES and other EBE dependent variables will not > be correct following the MAXEVAL=0 run (i.e. use only the PRED, RES and WRES > out of this run and the rest from your original fit with the M3 code). In > case you are using the FOCE estimation method you would preferably want to > look at conditional weighted residuals (CWRES) rather than WRES. However I > have yet not seen any example of a workaround to get these when using the M3 > method (Obs! CWRES will not be correctly calculated with the MAXEVAL=0 > trick). > > $ERROR > IPRED = F > W = THETA(11) ; SD for additive > residual error > ; W = THETA(11) * IPRED ; SD for proportional > residual error > ; W = SQRT(THEATA(11)**2+THETA(12)**2*IPRED**2) ; SD for combined > residual error > Y = IPRED + W*EPS(1) > IRES = DV - IPRED > IWRES = IRES/W > > $SIGMA 1 FIX > > If you use Xpose to do your diagnostic plots it can be good to know that > Xpose by default omits all rows with WRES=0 (this is done to omit > information on dosing row from being plotted). You can change this setting > in Xpose by using the command inclZeroWRES=TRUE (you should then enter some > other subset to omit the dose rows e.g. subset="EVID==0"). > > My favorite type of diagnostics are VPCs (I think I share this with Prof. > Nick Holford). VPCs can easily be adopted to handle the presence of BQL > data. How to do this with PsN and Xpose is explained in a PAGE poster from > 2009 > ( http://www.page-meeting.org/pdf_assets/7002-Poster_PAGE_VPC_090618_fina l.pd > f). > > Best regards, > > Martin Bergstrand, MSc, PhD student > ----------------------------------------------- > Pharmacometrics Research Group, > Department of Pharmaceutical Biosciences, > Uppsala University > ----------------------------------------------- > [email protected] > ----------------------------------------------- > Work: +46 18 471 4639 > Mobile: +46 709 994 396 > Fax: +46 18 471 4003 > > > -----Original Message----- > From: [email protected] [mailto:[email protected]] On > Behalf Of Sebastien Bihorel > Sent: den 7 april 2010 17:31 > To: [email protected] > Subject: [NMusers] RES and WRES output with Beal's M3 method > > Dear NONMEM users, > > We have noticed some problems with the table outputs of RES and WRES, > when we implemented Beal's M3 method as proposed by Ahn and colleagues > (J Pharmacokinet Pharmacodyn (2008) 35:401-421). While RES and WRES are > correctly calculated and reported for patients without BLOQ records, > these metrics are reported as being 0 for patients with at least one > BLOQ sample, even for the records that were not flagged as BLOQ. This > behavior seems to be common to NONMEM 6 and 7. > > Does anybody know about an NONMEM option or a workaround that would > allow the user to access to the actual RES and WRES for the non-BLQ records? > > Any feedback would be greatly appreciated. > > Sebastien Bihorel > > PS: this is the $ERROR block code we used for a simple proportional RV model > > $ERROR (ONLY OBSERVATIONS) > > ;Information needed for BLQF and > BLQF samples > LOQ=5 > SIG = THETA(3) > > DFLG=0 ;create a dose record flag > IF(AMT.NE.0) DFLG=1 > > IPRED=F+DFLG > W=IPRED > > ;Computations for samples with DV > LOQ (BLQF=0) > IF (BLQF.LT.0.25) THEN > F_FLAG=0 > FFLG=0 > IRES=DV-IPRED > IWRES=IRES/W > Y=IPRED+W*SIG*EPS(1) ;NOTE: Prediction is a concentration > ENDIF > > ;Computations for samples with DV <= LOQ (BLQF=1) > IF (BLQF.GE.0.25) THEN > F_FLAG=1 > FFLG=1 > DUM=(LOQ-IPRED)/(W*SIG) > IPRED=PHI(DUM) > Y=IPRED ;NOTE: prediction is a *probability* > ENDIF > >