Hi Martin,
If you write P(3) =1-P(1)-P(2) you reduce the risk of writing something incorrect J Mats Karlsson Mats Karlsson, PhD Professor of Pharmacometrics FIRST WORLD CONFERENCE ON PHARMACOMETRICS, 5-7 September 2012, Seoul ( <http://www.go-wcop.org/> www.go-wcop.org) Dept of Pharmaceutical Biosciences Faculty of Pharmacy Uppsala University Box 591 75124 Uppsala Phone: +46 18 4714105 Fax + 46 18 4714003 From: owner-nmus...@globomaxnm.com [mailto:owner-nmus...@globomaxnm.com] On Behalf Of Martin Bergstrand Sent: 26 May 2012 09:06 To: 'Andy Stein'; yapingz2...@gmail.com Cc: nmusers@globomaxnm.com; lgibian...@quantpharm.com Subject: RE: [NMusers] Question about handling BLOQ data with mixture model Dear Andy and Yaping, I am sorry for my embarrassingly bad advice. I can now see that it is my clumsy code that does not sum up to 1. That I should have written and how normally code it is this: $MIX NSPOP=3 P(1) = THETA(8)/100 P(2) = (1-THETA(8)/100)*THETA(9)/100 P(3) = 1-THETA(8)/100 -((1-THETA(8)/100)*THETA(9)/100) $THETA (0, 3.78, 100) ; PMIX1 $THETA (80, 91, 100) ; PMIX2/(1-PMIX1) This is as the sober me can see mathematically identical to what you did. I should get an alcohol lock for outlook so that I can't do NMusers postings after more than 1 beer. For what it is worth coming from me you could try to add a very small number to the CUMD (e.g. 10^-6). If you have a BQL observation that NONMEM predicts a very low probability NONMEM will in my experience crash. When you get a run working with this arbitrary imputation you can investigate what observations that has this extremely low probability and investigate if there seem to be something fishy about them. In general it can be said that the Laplacian estimation method in NONMEM is notoriously instable and slightly prone to local minima. It can for that reason be useful to by default try running with perturbed initial estimates. Good luck, Martin From: owner-nmus...@globomaxnm.com [mailto:owner-nmus...@globomaxnm.com] On Behalf Of Andy Stein Sent: den 26 maj 2012 01:45 To: lgibian...@quantpharm.com Cc: nmusers@globomaxnm.com; yapingz2...@gmail.com Subject: Re: [NMusers] Question about handling BLOQ data with mixture model I wanted to follow up on the comments to Yaping's email. First, the three probabilities below from the original code do in fact sum to 1. P(1)=THETA(8)/100 P(2)=(1-THETA(8)/100)*THETA(9)/1000 P(3)=(1-THETA(8)/100)*(1-THETA(9)/1000) Note that: P(2) + P(3) = 1-THETA(8)/100 And thus P(1) + P(2) + P(3) = 1 Also, the model worked completely fine when the BLOQ part of the code was left out and only the mixture was modeled. That is what led us to think that the combination of BLOQ with a Mixture was causing the problem. Andy On Fri, May 25, 2012 at 1:07 PM, lgibian...@quantpharm.com <lgibian...@quantpharm.com> wrote: Sum of probabilities should sum to 1. More standard way would be to use P(1) = 1/(1+THETA(8)+THETA(9)) P(2) = THETA(8)/(1+THETA(8)+THETA(9)) P(3) = THETA(9)/(1+THETA(8)+THETA(9)) where THETA(8) and THETA(9) are any positive numbers Regards Leonid Original Message: ----------------- From: Martin Bergstrand martin.bergstr...@farmbio.uu.se Date: Fri, 25 May 2012 22:59:45 +0700 To: yapingz2...@gmail.com, nmusers@globomaxnm.com Subject: RE: [NMusers] Question about handling BLOQ data with mixture model Dear Yaping, I can see that you need to make any particular consideration because you are applying a mixture model. CUMD is dependent on IPRED that in its turn is dependent on the assigned mixture. That should be enough. However, I spot what must be an error in your way of defining your mixture probabilities. As it is now you total probability does not sum up to 1. Why don't you parameterize it his way: $MIX NSPOP=3 P(1) = THETA(8)/100 P(2) = (1-THETA(8)/100)*THETA(9)/100 P(3) = 1-THETA(8)/100 -THETA(9)/100 $THETA (0, 3.78, 100) ; PMIX1 $THETA (80, 91, 100) ; PMIX2/(1-PMIX1) I have kept the division of THETAs by 100 since I assume that you want estimates in %. However the division with 1000 did not make any sense to me despite the correctly assigned THETA boundaries? Finally a word of caution, be careful with the use of NONMEM reserved variables such as T (integrated time in $DES) and F (default model prediction with some ADVANS). In my experience things can go wrong when you use them outside the way it was intended, conflicts can occur. Kind regards, Martin Bergstrand, PhD Pharmacometrics Research Group Dept of Pharmaceutical Biosciences Uppsala University Sweden martin.bergstr...@farmbio.uu.se Visiting scientist: Mahidol-Oxford Tropical Medicine Research Unit, Bangkok, Thailand From: owner-nmus...@globomaxnm.com [mailto:owner-nmus...@globomaxnm.com] On Behalf Of Yaping Zhang Sent: den 25 maj 2012 02:04 To: nmusers@globomaxnm.com Subject: [NMusers] Question about handling BLOQ data with mixture model Hello NMUsers, I am trying to analyze BLOQ data using the M3 method (Stuart Beal, Ways to Fit a PK Model with Some Data Below the Quantification Limit, 2001). The model I have is a mixture model to describe PD response of three subpopulations. The complete control stream is pasted below. I have implemented just the mixture model (no BLOQ) and just the BLOQ error model (no mixture) and it works fine with nonmem 6. But the run crashed immediately using nonmem 6 if including both BLOQ and the mixture model. I am wondering if I need to account for the mixture in the section of the code below when putting a mixture model together with the BLOQ error model IF (BLOQ.EQ.1) THEN F_FLAG=1 Y =CUMD + something based on MIXNUM? ENDIF Any ideas are gratefully received! Many thanks, Yaping $PROB AMN107A2303 $INPUT NUM=DROP STUD=DROP SUBJ=DROP ID AGE0=DROP SEX=DROP RACE=DROP DART=DROP ARM ACTT=DROP POP PPK=DROP COUN=DROP SOK OTIM=DROP TIME TVIS=DROP AMT=DROP DOSE=DROP SCHD=DROP AUC=DROP CMIN=DROP ODV=DROP MDV DV BLOQ STY=DROP EVDT=DROP $DATA ../data/AMN2303_ENEST.csv ; currently modified with matlab and saved with oocalc IGNORE=@ IGNORE=(MDV.EQ.1) IGNORE=(ID.EQ.66, ID.EQ.92, ID.EQ.335, ID.EQ.346, ID.EQ.348, ID.EQ.416, ID.EQ.496, ID.EQ.527, ID.EQ.762, ID.EQ.790) $PRED mu =THETA(1)*EXP(ETA(1)) AA =THETA(2)*EXP(ETA(2)) alpha =THETA(3)*EXP(ETA(3)) BB =THETA(4)*EXP(ETA(4)) beta =THETA(5)*EXP(ETA(5)) InCC =THETA(6)+ETA(6) gamma =THETA(7)*EXP(ETA(7)) T = TIME IF (TIME.LE.0) T = 0 EST=MIXEST IF (MIXNUM.EQ.1) F =AA*EXP(mu*T/8766) IF (MIXNUM.EQ.2) F =AA*EXP(alpha*T/8766)+BB*EXP(beta*T/8766) IF (MIXNUM.EQ.3) F =AA*EXP(alpha*T/8766)+BB*EXP(beta*T/8766)+EXP(InCC)*EXP(gamma*T/8766) PROP=THETA(10) W=SQRT(PROP*PROP) IPRED=-2.8 IF(F.GT.0)IPRED =LOG10(F) LLOQ=-2.5 DUM=(LLOQ-IPRED)/W CUMD=PHI(DUM) IF (BLOQ.EQ.0) THEN F_FLAG=0 Y =IPRED+W*ERR(1) ENDIF IF (BLOQ.EQ.1) THEN F_FLAG=1 Y =CUMD ENDIF $MIX NSPOP=3 P(1)=THETA(8)/100 P(2)=(1-THETA(8)/100)*THETA(9)/1000 P(3)=(1-THETA(8)/100)*(1-THETA(9)/1000) $THETA (-10,-0.57,0) ; mu THETA(1) $THETA (0.0001,50.7,100) ; AA THETA(2) $THETA (-100,-14.2,0) ; alpha THETA(3) $THETA (0.0001,0.196,10) ; BB THETA(4) $THETA (-10,-0.678,0) ; beta THETA(5) $THETA (-100,-6.92,0) ; InCC THETA(6) $THETA (0, 2.15) ; gamma THETA(7) $THETA (0, 3.78, 100) ; THETA(8) $THETA (800, 910, 1000) ; THETA(9) $THETA (0.001,0.104, 5) ; ERR THETA(10) $OMEGA 0.001 FIX ; mu $OMEGA 0.767 ; AA $OMEGA 0.236 ; alpha $OMEGA 3.58 ; BB $OMEGA 0.148 ; beta $OMEGA 5 ; CC $OMEGA 0.858 ; gamma $SIGMA 1 FIX $EST METHOD=1 LAPLACIAN NOABORT MAXEVAL=9990 PRINT=1 MSFO=run012.nmmsf SIG=2 $COV $TABLE ID TIME DV MDV IPRED EST FILE=run012.nmfit NOPRINT ONEHEADER $TABLE ID ETA1 ETA2 ETA3 ETA4 ETA5 ETA6 ETA7 mu AA alpha BB beta InCC gamma NOAPPEND FIRSTONLY FILE=run012.nmpar NOPRINT ONEHEADER -------------------------------------------------------------------- mail2web LIVE - Free email based on MicrosoftR Exchange technology - http://link.mail2web.com/LIVE
