NONMEM Users Network Archive

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Re: computational issues preventing COV

From: Leonid Gibiansky <LGibiansky>
Date: Sun, 14 Feb 2010 08:51:48 -0500

Hi Markus
Sometimes you just cannot force $COV to converge using defaults. If you
use NONMEM 7, try
$COV UNCONDITIONAL
option
Also, nommem should explain somehow what is wrong (R matrix is singular,
parameter is on the boundary, or something similar). If this is the
case, then you can try MATRIX=S

Could you provide more details of the output ?
Thanks
Leonid



--------------------------------------
Leonid Gibiansky, Ph.D.
President, QuantPharm LLC
web: www.quantpharm.com
e-mail: LGibiansky at quantpharm.com
tel: (301) 767 5566




markus joerger wrote:
> dear NONMEM community,
>
> The following MESSAGE:
>
> MINIMIZATION SUCCESSFUL
> HOWEVER, PROBLEMS OCCURRED WITH THE MINIMIZATION.
> REGARD THE RESULTS OF THE ESTIMATION STEP CAREFULLY, AND ACCEPT THEM ONLY
> AFTER CHECKING THAT THE COVARIANCE STEP PRODUCES REASONABLE OUTPUT.
>
> ...has already been discussed in 2008, and seems to be a computational
> issue preventing successful COV (Prof. Nick Holford). I encounter the
> same problem with an i.v. Gemcitabine model. COV is successful with GEM
> and its metabolite dFdU. However, if I add intracellular triphosphates
> (dFdCTP), minimisation is just fine, but no COV. This has persisted
> after attempts to simplify model or computation (e.g. fixing ETAs, using
> just one EPS, introducing simulated PK-curves (based on PK-estimates)
> back into the model). Mass-transport to triphosphate-CMPT is
> intentionally fixed very low (low concentrations), and
> volume-of-distribution of intracellular triphosphates scaled to V1.
>
> Thanks for support,
>
> kind regards, Markus
>
>
> --
> Markus Joerger MD PhD
> Department of Medical Oncology
> Rorschacherstr. 95
> 9007 St. Gallen
> markus.joerger
> markus.joerger
> phone: +41-765591070
> fax: +41-714946368
>
>
> CONTROL STREAM:
> ------------------------------
> ---------------------------------------------------------------------------------------------
>
> $DATA MO5_gem33.CSV IGNORE=C
> $SUBROUTINES ADVAN5
> $MODEL COMP=(GEM) COMP=(P1) COMP=(dFdU) COMP(dFdCTP)
>
> $PK
>
> TVCL1=THETA(1)
> CL1=TVCL1*EXP(ETA(1))
>
> TVV1=THETA(2)
> V1=TVV1*EXP(ETA(2))
>
> TVQ1=THETA(3)
> Q1=TVQ1*EXP(ETA(3))
>
> TVV2=THETA(4)
> V2=TVV2*EXP(ETA(4))
>
> TVCL2=THETA(5)
> CL2=TVCL2*EXP(ETA(5))
>
> TVV3=THETA(6)
> V3=TVV3*EXP(ETA(6))
>
> TVK40=THETA(7)
> K40=TVK40*EXP(ETA(7))
>
> K12=Q1/V1
> K21=Q1/V2
> K13=CL1/V1
> K30=CL2/V3
>
> RF=THETA(8)
>
> K14=0.000001*K13
> V4=K14*RF*V1/K13
>
> S1=V1/1000
> S3=V3/1000
> S4=V4/1000
>
> $ERROR CALLFL=0
> IPRE=-3
> FLG1=0
> FLG3=0
> FLG4=0
> IF(CMT.EQ.1)FLG1=1
> IF(CMT.EQ.3)FLG3=1
> IF(CMT.EQ.4)FLG4=1
> IF(F.GT.0) IPRE=LOG(F)
> Y=LOG(F)+EPS(1)*FLG1+EPS(2)*FLG3+EPS(3)*FLG4
> W=LOG(F)
> IRES=DV-IPRE
> IWRES=IRES/W
>
> $THETA
> (0,163) ;CL-gemcitabine.1
> (0,11.9) ;V1.2
> (0,95.1) ;Q1.3
> (0,20) ;V2.4
> (0,14.1) ;CL-dFdU.5
> (0,28) ;V3.6
> (0,0.21) ;K40.7
> (0,646) ;RF.8
>
> $OMEGA
> 0.37 ;CL1.1
> 0.23 ;V1.2
> 0.0094 ;Q1.3
> 0.036 ;V2.4
> 0.14 ;CL2.5
> 0.14 ;V3.6
> 0.27 ;K40.9.7
>
> $SIGMA
> 0.07 ;IIV-1
> 0.0355 ;IIV-3
> 0.757 ;IIV-4
>
> $ESTIMATION PRINT=5 MAXEVAL=3000 METHOD=1
> NOABORT POSTHOC SIGDIG=3 MSFO=MSF004BBAB
Received on Sun Feb 14 2010 - 08:51:48 EST

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