Problems with recursive PRED models...

From: "Eleveld, DJ" d.j.eleveld@anest.umcg.nl Subject: [NMusers] Problems with recursive PRED models... Date: Thu, 22 Sep 2005 15:18:38 +0200 Hello Everyone, I have a question about 'recursive PRED' models... I have a model in which the bioavailability of a compartment depends on the state of other compartments as well as a model parameter. Since bioavailability must be set in $PK but the compartmental amounts are not available there, I used COMRES to provide $PK with information from $ERROR using COM(1) following advice from the very helpful readers of this list. The doses are directed to the correct compartment (CENTRAL or POTENT) with a CMT field in the $DATA. In my searching of the mailing list archives regarding recursive PRED routines I found the following quote from Alison Fri Sep 27 10:30:50 1996: ...any left hand quantity in abbreviated code that depends on random variables (ETA and/or EPS) must be computed EXACTLY ONCE AND UNCONDITIONALLY. If an either/or choice is involved, indicator variables (e.g., Q and 1-Q in many examples) can be used, because this rule is obeyed. But if the computation involves random variables computed with a prior data or event record, it cannot be done correctly. As I understand it F5 (bioavailability) is a left hand quantity that is calculated exactly once and unconditionally, so that is not a problem. However, the calculation of F5 involves a random variable (POTR) as well as prior data because it depends on the state of other compartments (A(4) via COM(1)). If this interpretation is correct as well as the comment from Alison (I assume it is) then I must conclude that this model cannot be done correctly in NONMEM. I am of course reluctant to make such a sweeping conclusion without expert advice. This model seems to simulate just fine and estimations on individual data seem fine also. Straightforward FO estimation leads to high condition numbers with the data I have. Setting some $OMEGA values to FIXED values gets the condition number to less than 1000. FOCE methods often abort with a floating point overflow error or rounding errors, even those with a corresponding FO estimation having a low condition number. I have had only one FOCE estimation run to completion. The results and the prediction are reasonable and parameters are in the expected range. However, even small changes to the initial estimates cause floating point overflow errors and it is difficult to have confidence in the results when the estimation breaks so easily. Before diving deeper into the specifics of this problem I think it is prudent to make sure that NONMEM can correctly implement the model. Can anyone tell me if this model is indeed a recursive PRED type and whether or not the model can be correctly implemented in NONMEM? Thanks very much, Doug Eleveld The following control file aborts (crashes) after 2 iterations with a floating point overflow error (Open Watcom compiler): $PROB Potentiation fitting $DATA potpd.prn IGNORE=C $INPUT ID TIME DV MDV CFLG AMT RATE CMT V1 V2 V3 CL Q2 Q3 $SUBROUTINES ADVAN6 TOL=4 $ABBREVIATED COMRES=1 $MODEL COMP(CENTRAL DEFDOSE) COMP(PERIF1 NOOFF NODOSE) COMP(PERIF2 NOOFF NODOSE) COMP(EFFECT NOOFF NODOSE) COMP(POTENT NOOFF) $PK S1=V1 KEO=THETA(1)*EXP(ETA(1)) EC50=THETA(2)*EXP(ETA(2)) GAMM=THETA(3)*EXP(ETA(3)) POTR=ABS(THETA(4)+ETA(4)) POTK=THETA(5)*EXP(ETA(5)) SCAL=THETA(6)+ETA(6) PD1=COM(1)**GAMM PD2=EC50**GAMM MNMB=1-PD1/(PD1+PD2) F5=POTR*MNMB/1000 $DES C1=A(1)/V1 ; Conc in V1 C2=A(2)/V2 ; Conc in V2 C3=A(3)/V3 ; Conc in V3 DADT(1)=-CL*C1+Q2*(C2-C1)+Q3*(C3-C1) ; Change in V1 DADT(2)=Q2*(C1-C2) ; Change in V2 DADT(3)=Q3*(C1-C3) ; Change in V3 DADT(4)=(C1-A(4))*KEO ; Effect compartment conc DADT(5)=-POTK*A(5) ; Decay potentiation $ERROR CPRE=A(1)/V1 CEFF=A(4) IF (CEFF.LT.0) CEFF=0 DPOT=1+A(5) ; The degree of potentiation EPD1=CEFF**GAMM EPD2=EC50**GAMM ENMB=1-EPD1/(EPD1+EPD2) RPRE=(SCAL+100)*DPOT*ENMB ; Twitch prediction Y=RPRE+ERR(1) COM(1)=CEFF $THETA (0,0.2,0.4)(1000,1800,3000)(3,5,8) (0,5,20)(0,0.05,1)(-1 FIXED) $OMEGA (0.05 FIXED)(0.05)(0.05 FIXED) (4 FIXED)(0.1 FIXED)(4 FIXED) $SIGMA (12) $ESTIMATION MAX=9999 SIG=3 METHOD=1 NOABORT POSTHOC PRINT=1 $COVARIANCE PRINT=E $TABLE ID TIME CPRE CEFF RPRE MNMB DPOT Y DV NOPRINT NOHEADER NOAPPEND FILE=potent.txt $TABLE ID V1 V2 V3 CL Q2 Q3 KEO EC50 GAMM POTR POTK SCAL NOPRINT NOHEADER NOAPPEND FILE=potent1.txt MONITORING OF SEARCH: 0ITERATION NO.: 0 OBJECTIVE VALUE: 0.1077E+05 NO. OF FUNC. EVALS.: 8 CUMULATIVE NO. OF FUNC. EVALS.: 8 PARAMETER: 0.1000E+00 0.1000E+00 0.1000E+00 0.1000E+00 0.1000E+00 0.1000E+00 0.1000E+00 GRADIENT: 0.2022E+04 0.1228E+04 0.6046E+03 0.1841E+04 -0.7099E+03 0.1724E+02 0.4353E+02 0ITERATION NO.: 1 OBJECTIVE VALUE: 0.1072E+05 NO. OF FUNC. EVALS.:10 CUMULATIVE NO. OF FUNC. EVALS.: 18 PARAMETER: 0.8500E-01 0.9089E-01 0.9551E-01 0.8634E-01 0.1053E+00 0.9987E-01 0.9968E-01 GRADIENT: 0.7187E+03 -0.1404E+03 0.3946E+03 0.8371E+03 -0.9275E+03 0.7030E+02 -0.1695E+04 _______________________________________________________