NONMEM Users Network Archive

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Re: computational issues preventing COV

From: Leonid Gibiansky <LGibiansky>
Date: Sun, 14 Feb 2010 09:26:19 -0500

Hi Markus,

On a separate note, this does not look like a traditional definition of
IWRES (=IRES/sqrt(variance)):
>> W=LOG(F)
>> IRES=DV-IPRE
>> IWRES=IRES/W

Leonid

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




Leonid Gibiansky wrote:
> 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 - 09:26:19 EST

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