RE: AW: Simulations with/without residual error

-----Original Message----- From: [email protected] [mailto:[email protected]] On Behalf Of Nick Holford Sent: Sunday, July 26, 2009 10:42 PM To: nmusers Subject: Re: AW: [NMusers] Simulations with/without residual error Mats, Thanks for extending the code fragment I proposed earlier to add some extra useful features. I don't know what was incorrect about the code I suggested but resampling the uncertainty ETA values is a pragmatic way to avoid PREDPP errors caused by randomly generated non-positive CL or V values. The code below produces the same results as your code but it shows how to check on reasonable values for CL and V that do not depend on the value of CL or V defined by THETA or other things such as the effect of covariates on the group parameter value. I note that your example using simulation and estimation does not use the same residual error model for simulation and estimation. The simulation residual error is exp(EPS(1)) but METHOD=CONDITIONAL INTERACTION would approximate this by (1+EPS(1)). You may remember the commentary on this point that Stuart Beal wrote in 2002 :-) Best wishes, Nick Beal SL. Commentary on Significance Levels for Covariate Effects in NONMEM. Journal of Pharmacokinetics & Pharmacodynamics. 2002;29(4):403-10. $SIM (20090726 NEW) ONLYSIM SUBPROBLEMS=100 ; estimates of THETA and OMEGA from previous run $THETA 1 ; POP_CL theta1 10 ; POP_V theta2 $OMEGA 0.5 ; PPV_CL eta1 0.5 ; PPV_V eta2 ;variance-covariance matrix of the THETA estimates from previous run $OMEGA BLOCK(2) 0.2 ; UNC_POP_CL eta3 0.1 3 ; UNC_POP_V eta 4 $SIGMA .01 $SUB ADVAN1 $PK ; get CL and V uncertainties IF (ICALL.EQ.4.AND.NEWIND.EQ.0) THEN ; do this just once per subproblem UNCCL=THETA(1)+ETA(3) UNCV=THETA(2)+ETA(4) DO WHILE (UNCCL.LE.0.OR.UNCV.LE.0) ;resample if values unreasonable CALL SIMETA(ETA) UNCCL=THETA(1)+ETA(3) UNCV=THETA(2)+ETA(4) END DO ENDIF CL=UNCCL*EXP(ETA(1)) ; with uncertainty for CL V =UNCV*EXP(ETA(2)) ; with uncertainty for V K=CL/V $ERROR Y =F*EXP(EPS(1)) Mats Karlsson wrote: > > Dear Nick, Marc and all, > > An even later addition to this thread. Nick pointed out the > possibility to do simulations in NONMEM that incorporated error in > simulation parameters. The code provided gave a good hint at how to do > that but would work incorrectly unless some additional NONMEM switches > were flicked. Also, as pointed out by Marc and others, one might like > to truncate the parameter distribution for simulation (avoid negative > CL etc). Also it may be convenient to do simulation followed by > re-estimation in a single run. For appropriate post-processing this > requires that simulation parameters are output somewhere. A model > file, extending Nick's example, that does these things are provided > below. > > $PROB > > $DATA data1 > > $INPUT ID DV TIME TVCL TVV AMT > > ;data1= > > ; 1 0 0 0 0 100 > > ; 1 0 1 0 0 0 > > ; 1 0 21 0 0 0 > > ; 2 0 0 0 0 100 > > ; etc > > $SIM (20090726 NEW) SUBPROBLEMS=100 > > $THETA ; estimates of THETA and OMEGA from previous run > > (0,1) ; POP_CL theta1 > > (0,10) ; POP_V theta2 > > $OMEGA > > 0.5 ; PPV_CL eta1 > > 0.5 ; PPV_V eta2 > > ;variance-covariance matrix of the THETA estimates from previous run > > $OMEGA BLOCK(2) > > 0.2 ; UNC_POP_CL eta3 > > 0.1 3 FIX; UNC_POP_V eta 4 > > $SIGMA .01 > > $SUB ADVAN1 > > $PK > > CL=THETA(1)*EXP(ETA(1)) ; with uncertainty for CL > > V =THETA(2)*EXP(ETA(2)) ; with uncertainty for V > > K=CL/V > > IF (ICALL.EQ.4.AND.NEWIND.EQ.0) THEN ; do this just once per subproblem > > DO WHILE (ETA(3).LT.-.99.OR.ETA(4).LT.-9.9) CALL SIMETA(ETA) ;resample > if "bad" values > > END DO > > TVCL=THETA(1)+ETA(3) > > TVV =THETA(2)+ETA(4) > > ENDIF > > IF (ICALL.EQ.4) THEN ; do this for all simulated values > > CL=TVCL*EXP(ETA(1)) ; with uncertainty for CL > > V =TVV*EXP(ETA(2)) ; with uncertainty for V > > ENDIF > > $ERROR > > Y =F*EXP(EPS(1)) > > $INFN > > IF (NEWIND.EQ.0) THEN > > WRITE (52,*) THETA ; Output estimated THETAs to file 52 > > WRITE (53,*) TVCL, TVV ; Output simulated THETAs to file 53 > > ENDIF > > $EST MAX=9999 METH=1 INTER > > Mats Karlsson, PhD > > Professor of Pharmacometrics > > Dept of Pharmaceutical Biosciences > > Uppsala University > > Box 591 > > 751 24 Uppsala Sweden > > phone: +46 18 4714105 > > fax: +46 18 471 4003 > Nick Holford wrote: > $SIM (20090709) ONLYSIM SUBPROBLEMS=100 > ; estimates of THETA and OMEGA from previous run > $THETA > 1 ; POP_CL theta1 > 10 ; POP_V theta2 > $OMEGA > 0.5 ; PPV_CL eta1 > 0.5 ; PPV_V eta2 > ;variance-covariance matrix of the THETA estimates from previous run > $OMEGA BLOCK(2) > 0.2 ; UNC_POP_CL eta3 > 0.1 3 ; UNC_POP_V eta 4 > > $PK > ; get CL and V uncertainties > IF (NEWIND.EQ.0) THEN ; do this just once per subproblem > UNCCL=THETA(1)+ETA(3) > UNCV=THETA(2)+ETA(4) > ENDIF > CL=UNCCL*EXP(ETA(1)) ; with uncertainty for CL > V =UNCV*EXP(ETA(2)) ; with uncertainty for V > ... > -- Nick Holford, Professor Clinical Pharmacology Dept Pharmacology & Clinical Pharmacology University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand [email protected] tel:+64(9)923-6730 fax:+64(9)373-7090 mobile: +64 21 46 23 53 http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford