Re: Standard error for estimates
Dear Navin,
I suggest following codes, but you need carefuilly check it - I.m just on holidays and writing from my head only.
$PROBLEM BIOAVAILABILITY MODEL
$INPUT ID TIME AMT MDV DV EVID CMT
$DATA file1.csv IGNORE=C
$SUBROUTINE ADVAN8 TRANS1 TOL=7
$MODEL
COMP=(DEPOT,DEFDOSE) ; ABSORPTION COMPARTMENT
COMP=(CENTRAL, DEFOBS) ; PLASMA COMPARTMENT
$PK
F1=THETA(1)*ETA(1)+ETA(2) ; HETEROSCEDASTIC LINEAR MODEL OF INTERSUBJECTS VARIANCE - IF NOT GOOD PLEASE CORRECT KA=4.0 ; IDENTICAL KA PARAMETER FOR ALL PATIENTS IN [1/H] K=0.20 ; IDENTICAL K - ELIMINATION RATE CONSTANT IN [1/H] = BETA
TVCL=THETA(2) ; TYPICAL VALUE CL = 75 ML/MIN/KG (FROM INTRAVENOUS STUDY ?) CL=TVCL*EXP(ETA(3)) ; INDYVIDUAL CL ACCORDING TO ETA (3) MODEL TVVC=TVCL/K ; TYPICAL VALUE VOLUME OF DISTRIBUTION IN [ML/KG] = 75 [ML/KG/H]/0.2 [1/H] = 375 [ML/KG] VC=TVVC*EXP(ETA(4)) ; INDYVIDUAL VC ACCORDING TO ETA (4) MODEL S2=VC/1000 ; S2 IS SCALED ACCORDING TO DOSE [MICROGRAMS/KG] AND OUTPUT IN [NG/ML]
$ERROR
IPRED=F
IRES=DV-IPRED
DEL=0
IF (IPRED.EQ.0) DEL=1
IWRES=(1-DEL)*IRES/(IPRED+DEL)
Y=F+F*ERR(1)
$DES
DADT(1)=-KA*A(1)
DADT(2)=KA*A(1)-CL/K*A(2)
$THETA
(0.01,0.5,0.8) ; TVF1 - THETA(1)
(75 FIXED) ; TVCL -THETA(1)
$OMEGA 0.02 0.1 0.1 0.05 ; ETA(1,2,3,4) - INTERSUBJECTS VARIANCES
$SIGMA 0.07 ; ERR(1) - INTRASUBJECT VARIANCE
$ESTIMATION METHOD=1 INTERACTION LAPLACE SIGDIGITS=6 MAXEVAL=9999 PRINT=5 MSF=SDMSFSAB.335
$COVARIANCE UNCONDITIONAL MATRIX=S
$TABLE ID TIME AMT MDV DV EVID CMT IPRED IWRES IRES NOPRINT ONEHEADER FILE=SDTABSAB.335
sincerely
Kazimierz H. Kozlowski
navin goyal wrote:
> Dear Kazimierz,
>
> I guess I did not quite follow your suggestion Sir. Could you please elaborate briefly on it. I think what I intended o do was havea fixed theta value and apply some variability ETA(3) and ETA(4) to those parameter estimates. I apologise for not following you correctly. I failed to understand the last line modification that you suggested.
>
> S2=VC; OUTPUT IN ng/ml =====> scale S2 vs DOSE
>
> Thanks a lot for your help
>
Quoted reply history
> On 6/15/07, Kazimierz H. Kozlowski <[EMAIL PROTECTED] < mailto:[EMAIL PROTECTED]>> wrote:
>
> Dear Navin,
>
> You probably have double definition code for VC and also problem
> that CL and VC are not constants between patients because of
> ETA(3) and ETA(4)
>
> $PK
>
> F1=THETA(1)*EXP(ETA(1)+ETA(2))
> K12=4;Abso constant
> TVCL=THETA(2);Clearance
> CL=TVCL*EXP(ETA(3))
> TVVC=THETA(3);vol of dist of drug =====> delete
> VC=TVVC*EXP(ETA(4)) =====> delete
> K20=0.20;elim rate const of drug
> VC=CL/K20 ====> OR rename VC1=CL/K20
> S2=VC; OUTPUT IN ng/ml =====> scale S2 vs DOSE
>
> sincerely
> Kazimierz H. Kozlowski
>
> navin goyal wrote:
>
> > Hello everybody
> > I am using Nonmem VI to model some Population Pk (10 subjects)
> > data that I have.
> >
> > When I run this file.. I get the parameter estimates.
> > However I fail to get any STANDARD ERROR of the estimates.
> > I do sometimes get the R,S, T matrices when I change my initial
> > estimates.
> > Also the output file has following messages
> >
> > MINIMIZATION SUCCESSFUL
> > MATRIX ALGORITHMICALLY SINGULAR
> > AND ALGORITHMICALLY NON-POSITIVE-SEMIDEFINITE
> > 0R MATRIX IS OUTPUT
> > 0COVARIANCE STEP ABORTED
> >
> > My understanding (maybe I got it wrong) is that these R,S, T
> > matrices are printed out when there are more than one solutions
> > to the parameter estimates.
> > is this right or does my control stream have some error within it.
> >
> > I checked the individual plots with the output data file. The
> > individual and population predicted fits are quite decent..
> >
> > It also gives me the following error message in the dos window
> >
> > (WARNING 50) OPTION "UNCONDITIONAL" OF $COVARIANCE RECORD IS
> > IGNORED WITH
> > THIS RELEASE OF NONMEM.
> >
> > Could someone kindly help me with what is the error in my control
> > stream or how would I be able to get the Std error for the estimates
> >
> > $PROBLEM PK
> > $INPUT ID TIME AMT MDV DV EVID CMT
> > $DATA file1.csv IGNORE=C
> > $SUBROUTINE ADVAN6 TRANS1 TOL=5
> > $MODEL
> > COMP=(DEPOT,DEFDOSE);
> > COMP=(CENTRAL);PLASMA
> >
> > $PK
> >
> > F1=THETA(1)*EXP(ETA(1)+ETA(2))
> > K12=4;Abso constant
> > TVCL=THETA(2);Clearance
> > CL=TVCL*EXP(ETA(3))
> > TVVC=THETA(3);vol of dist of drug
> > VC=TVVC*EXP(ETA(4))
> > K20=0.20;elim rate const of drug
> > VC=CL/K20
> > S2=VC; OUTPUT IN ng/ml
> >
> > $ERROR
> > IPRED=F
> > IRES=DV-IPRED
> > DEL=0
> > IF (IPRED.EQ.0) DEL=1
> > IWRES=(1-DEL)*IRES/(IPRED+DEL)
> > Y=F+F*ERR(1)
> >
> > $DES
> > DADT(1)=-K12*A(1)
> > DADT(2)=K12*A(1)-K20*A(2)
> >
> > $THETA
> > (0.01,0.5,0.8); bioavailability
> > (75 FIXED);CL
> > (375 FIXED);VC
> >
> > $OMEGA
> >
> > $SIGMA
> >
> > $ESTIMATION METHOD=1 SIGDIGITS=2 MAXEVAL=9999 PRINT=5 POSTHOC
> > $COVARIANCE UNCONDITIONAL
> >
> > $TABLE ID TIME AMT MDV DV EVID CMT IPRED IWRES IRES
> > NOPRINT ONEHEADER FILE=sdtabsab335
> >
> > thanks a lot