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Re: Estimation of standard error

From: Huali Wu <hualiw>
Date: Thu, 3 Jul 2008 16:18:29 -0400

Dear Dr. Gibiansky:

Thank you very much for your suggestions.

MATRIX=S did work. But S2 = V2 did not. Also, S2 = V1 is not an error, I
validated that by comparing the simulation results from WinNonlin and NONMEM
without adding any error. I don't understand why but if S2 = V2 will only
give discrepant result.

For the error model, I have tried separate errors for each CMT. But it did
not give good fit of released drug.

Thanks again,

Best regards,

Huali

----- Original Message -----
From: Leonid Gibiansky <LGibiansky
To: "Huali Wu" <hualiw
Cc: <nmusers
Sent: Thursday, July 03, 2008 3:00 PM
Subject: Re: [NMusers] Estimation of standard error


> Huali and Nick,
> Failure of $COV step sometimes tells about errors in the code. In this
> case, I think the problem is in
> S2 = V1
>
> should it be
> S2 = V2 ?
>
> Also,
> > Y1=F+F*EPS(1)
> > Y2=F+F*EPS(1)
> > Y=R1*Y1+R2*Y2
>
> results in
> Y =F+F*EPS(1)
> for both MCT=1 and CMT=2
> so R1 / R2 /Y1 /Y2 part can be omitted. Or you can use separate errors for
> each CMT:
>
> > Y1=F+F*EPS(1)
> > Y2=F+F*EPS(2)
> > Y=R1*Y1+R2*Y2
> --
>
> S2 = V2 should help to get SE. If not, try MATRIX=S on $COV line.
> Leonid
>
> --------------------------------------
> Leonid Gibiansky, Ph.D.
> President, QuantPharm LLC
> web: www.quantpharm.com
> e-mail: LGibiansky at quantpharm.com
> tel: (301) 767 5566
>
>
>
>
> Huali Wu wrote:
>> Dear NMusers:
>> I am trying to fit a data set with concentrations of encapsulated drug
>> and released drug. These concentrations were measured after an hour
>> infusion of encapsulated drug. The problem is that I cannot get standard
>> error estimated from simultaneous fitting of all the data. And I got an
>> error message as below:
>> 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.
>> NO. OF FUNCTION EVALUATIONS USED: 968
>> NO. OF SIG. DIGITS IN FINAL EST.: 3.2
>> R MATRIX ALGORITHMICALLY NON-POSITIVE-SEMIDEFINITE
>> BUT NONSINGULAR
>> R MATRIX IS OUTPUT
>> COVARIANCE STEP ABORTED
>> But if I fit the encapsulated drug first and then fit data of both
>> encapsulated drug and released drug by fixing the typical values of
>> parameters associated with encapsulated drug compartment, I can get an
>> estimation of standard errors. And GOF plots look good.
>> So my question is can I use this stepwise strategy to build up my base
>> model? If not, what can I do to get standard error estimated in
>> simultaneous fitting?
>> Any comment or suggestion will be highly appreciated.
>> Below is my code:
>> $SUBROUTINES ADVAN9 TRANS1 TOL=3
>> $MODEL NPAR=8, NCOMP=3, COMP=(CENTRAL,DEFOBS),
>> COMP=(PERIPH1), COMP=(PERIPH2)
>> $PK
>> V1 = THETA(1)*EXP(ETA(1))
>> V2 = THETA(2)*EXP(ETA(2))
>> V3 = THETA(3)
>> VM = THETA(4)
>> KM = THETA(5)
>> Q2 = THETA(6)*EXP(ETA(3))
>> Q3 = THETA(7)
>> Q4 = THETA(8) S1 = V1
>> S2 = V1
>> $ERROR
>> R1=0
>> IF (CMT.EQ.1) R1=1
>> R2=0
>> IF (CMT.EQ.2) R2=1
>> Y1=F+F*EPS(1)
>> Y2=F+F*EPS(1)
>> Y=R1*Y1+R2*Y2
>> IPRED=F
>> IRES=DV-IPRED
>> $DES
>> C1 = A(1)/V1
>> DADT(1) = - C1*VM/(KM+C1)-Q2*A(1)/V1
>> DADT(2) = C1*VM/(KM+C1)+Q2*A(1)/V1 + Q4*A(3)/V3-
>> Q3*A(2)/V2-Q4*A(2)/V2
>> DADT(3) = Q4*A(2)/V2-Q4*A(3)/V3 $THETA (5.27 FIX) (0,
>> 0.5) (0, 3.38) (0.329 FIX) (4.38 FIX) (0.136 FIX) (0, 0.0626) (0, 0.0461)
>> $OMEGA (0.01) (0.01) (0.01)
>> $SIGMA (.1)
>>
>> $EST MAXEVAL=9999 PRINT=5
>> $COV
>> $TABLE ID TIME DV AMT RATE CMT NOPRINT FILE=ENCAP4 ONEHEADER
>> $SCAT (RES WRES) VS TIME BY ID
>> Best regards,
>> Huali
>>
>
Received on Thu Jul 03 2008 - 16:18:29 EDT

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