Re: Sequential PD model parameter stays at initial estimation problem
Lei,
Have you checked in a $TABLE file that CP has the expected value and that A(4) is indeed initialized at a non zero value of 'base'? You don't explicitly define 'base' in your code. If it zero then of A(4) will remain at zero and Vmax will have a gradient of zero.
You don't give any clue what kind of PD marker you are trying to model but it is rather strange that you don't allow any input of the marker in DADT(4). Even if CP remained zero the marker would disappear because there is no input.
You seem to be using the very old fashioned NONMEM V method of initializing a differential equation by putting a AMT of 1 in CMT 4 at TIME=0.
Since NONMEM VI this has become much simpler.
Just use this:
A_0(4)=base
Don't set F4 to anything and don't put and AMT into CMT=4.
Nick
Quoted reply history
On 11/11/2011 8:18 a.m., Lei Diao wrote:
> Hi Dear NMusers,
>
> I have a sequential PD model and I listed the code here. base is the baseline level of the PD parameter for each individual and was included in the dataset. The problem with this code is that my only parameter to be estimated Vmax stays at the initial estimation whatever I provide and the gradient for THETA1 stays at 0 from the beginning. And the run time is extremely long. If I change F4 to another THETA to be estimated, the same problem still exists.
>
> Will anyone please shed some light on this problem?
>
> Thanks a lot!
>
> Lei
>
> $PROBLEM PD model
> $INPUT ID ETACL ETAV2 ETAKA Weight AMT DV TIME STUDYbase CMT
>
> $DATAPD.csv IGNORE=@ WIDE
> $SUBROUTINES ADVAN6 TOL=3
>
> $MODEL NCOMP=4
> COMP=GUT COMP=CENTRAL COMP=PERI COMP=EFFECT
>
> ;---------------
> $PKSCALE= Weight
> SCALE2 = Weight ** 0.75; allometric
>
> THETACL=1 ; L/day
> THETAV1= 1; L/kg
> THETACLRA= 1 ; L/day
> THETAV2=1 ; L/kg
> THETAKA= 1 ; 1/day
> THETAALAG1= 1 ;days
> THETAF1= 1
> THETACLHILL= 1
> THETACLTITER= 1
> THETACLRAHILL= 1
>
> CL= SCALE2 * THETACL * EXP(ETACL)
> V1= SCALE * THETAV1
> CLRA= SCALE2 * THETACLRA
> V2= SCALE * THETAV2 * EXP(ETAV2)
> KA= THETAKA * EXP(ETAKA)
> ALAG1= THETAALAG1
> F1 = THETAF1
> S2=V1
> Vmax= THETA(1)* EXP(ETA(1))
> Km = 100
> F4=base ; R0 is the baseline for each individual
>
> K= CL / V1
> K23= CLRA / V1
> K32= CLRA / V2
>
> $DES DADT(1)= -KA * A(1)
> DADT(2)= (KA * A(1)) - ((K + K23) * A(2)) + (K32 * A(3))
> DADT(3)= K23 * A(2) - K32 * A(3)
> CP= A(2)/S2
> DADT(4)= -Vmax*CP*A(4)/(Km+A(4))
>
> $ERROR
> IPRED=F
> Y= A(4)*(1+ERR(1))+ERR(2)
> ;---------------
> $THETA(0,10)
> $OMEGA (0 FIXED)
> $SIGMA 0.1 10
> ;---------------
> $EST METHOD=0 MAXEVAL=9999 NOABORT PRINT=5
> $COVARIANCE
--
Nick Holford, Professor Clinical Pharmacology
Dept Pharmacology& Clinical Pharmacology, Bldg 505 Room 202D
University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand
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http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford