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
Standard error for estimates
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
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