POSTHOC and ETA values disagree
From: "Eleveld, DJ" d.j.eleveld@anest.umcg.nl
Subject: [NMusers] POSTHOC and ETA values disagree
Date: Wed, June 29, 2005 1:45 pm
Hi everyone,
Thanks to the advice from this list, especially from Leonid and Katya, I have been
able to make NONMEM do estimations of my PD-potentiation model. Many thanks.
Although I have no problem with individual fittings, I am having problems getting
population estimations to produce reasonable POSTHOC and ETA values for one of the
model parameters. In some previous model-building advice, Leonid had suggested to
simplify the model so I split the PK and PD estimations.
What might cause all individual POSTHOC values to be exactly the same, while the
corresponding ETA value might be some large value? What might cause a gradient
for an ETA to be zero?
I am estimating PD parameters from 6 individuals and about 2500 total data points.
Individual fits work just fine, with an expected degree of variation in the
parameters. The model parameters I find from individual fits are:
THETA(1) THETA(2) THETA(3) THETA(4) THETA(5) THETA(5)
1.17E-01 1.22E+03 4.90E+00 1.26E-02 9.33E-02 9.62E+01
1.47E-01 1.44E+03 4.64E+00 2.82E-03 3.56E-02 1.00E+02
1.36E-01 1.74E+03 4.76E+00 4.38E-03 7.05E-02 9.71E+01
1.02E-01 1.28E+03 3.41E+00 6.81E-03 7.99E-02 9.97E+01
2.09E-01 1.60E+03 3.96E+00 1.22E-02 6.20E-01 9.82E+01
1.69E-01 1.86E+03 5.80E+00 6.39E-03 1.07E-01 1.03E+02
When I do a population fit (log-normal parameter distributions) I get reasonable THETA values:
THETA(1) THETA(2) THETA(3) THETA(4) THETA(5) THETA(5)
1.47E-01 1.26E+03 4.45E+00 5.47E-03 6.26E-03 9.97E+01
ETA and POSTHOC values for most of the parameters seem ok, however ETA(4) and the
POSTHOC values for THETA(4) are not reasonable:
ETA1 ETA2 ETA3 ETA4 ETA5 ETA6
5.26E-02
0.00E+00 4.62E-02
0.00E+00 0.00E+00 9.62E-02
0.00E+00 0.00E+00 0.00E+00 4.89E-01<-- This value is always similar to the initial value
0.00E+00 0.00E+00 0.00E+00 0.00E+00 1.94E+01(*)
0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 1.12E-03
The POSTHOC values for the individuals:
THETA(1) THETA(2) THETA(3) THETA(4) THETA(5) THETA(5)
1.13E-01 1.22E+03 5.23E+00 5.47E-03 3.92E-02 1.05E+02
1.49E-01 1.40E+03 4.77E+00 5.47E-03 3.30E+02(*) 1.15E+02
1.38E-01 1.74E+03 4.69E+00 5.47E-03 8.84E-02 9.59E+01
1.01E-01 1.28E+03 3.45E+00 5.47E-03 6.65E-02 1.02E+02
1.93E-01 1.29E+03 2.57E+00 5.47E-03 1.57E-04 9.56E+01
1.68E-01 1.85E+03 5.82E+00 5.47E-03 9.17E-02 1.04E+02
Values marked with (*) seem to be too high.
The POSTHOC values for THETA(4) are the exactly the same for all individuals (equal to the
typical value) while ETA(4) non-zero. This seems illogical to me. Can anyone suggest
why this may be occurring?
During the estimation the gradient for ETA(4) remains zero or extremely small, and the
value doesn’t seem to change much at all during estimation. This seems to be true
regardless of what initial value I use for ETA(4) for a wide range of values. This
could be the source of the ETA(4) and POSTHOC problems but I cannot imagine why this
might be the case given that individual fits seemed to be just fine.
Thanks very much for all your help so far,
Doug Eleveld
-----------------------------------------------------------------------------------------
$PROB Potentiation fitting
$DATA potpd__.prn
$INPUT ID TIME CPLA DV MDV AMT RATE
$SUBROUTINES ADVAN9 TOL=4
$ABBREVIATED COMRES=1
$MODEL NCOMPARTMENTS=2
NPARAMETERS=6
COMP(POTENT NOOFF)
COMP(EFFECT NOOFF NODOSE)
$PK
CALLFL=0
KEO=THETA(1)*EXP(ETA(1))
EC50=THETA(2)*EXP(ETA(2))
GAMM=THETA(3)*EXP(ETA(3))
POTR=THETA(4)*EXP(ETA(4))
POTK=THETA(5)*EXP(ETA(5))
SCAL=THETA(6)*EXP(ETA(6))
F1=COM(1) ; Also possible as AMT=COM(1)
$DES
DADT(1)=-POTK*A(1) ; Decay potentiation
DADT(2)=(CPLA-A(2))*KEO ; Effect compartment conc
$ERROR
FPOT=1+A(1) ; Potentiation factor
CEFF=A(2)
DPD1=CEFF**GAMM ; Degree of NMB
DPD2=EC50**GAMM
MNMB=1-DPD1/(DPD1+DPD2)
Y=SCAL*FPOT*MNMB+ERR(1) ; Twitch prediction
COM(1)=POTR*MNMB
$THETA (0,0.137)(1000,1270,1500)(3,4.51,6)
(0,0.005)(0,0.129)(95,100,105)
$OMEGA 0.5 0.5 0.5 0.5 0.5 0.1
$SIGMA 1
$ESTIMATION MAX=9999 SIG=3
METHOD=0 POSTHOC REPEAT
PRINT=1
;$COVARIANCE
$TABLE TIME KEO EC50 GAMM POTR POTK SCAL
NOAPPEND NOHEADER FILE=potent2.txt
$TABLE TIME CEFF FPOT MNMB DV Y
NOAPPEND NOHEADER FILE=potent3.txt