From: musor000@optonline.net
Subject: [NMusers] ADVAN2 and ADVAN6: biased results
Date: 2/13/2004 11:21 PM
Hi, NONMEM users,
I tried to fit a simple one compartment model with first order absorbtion.
First, I used ADVAN2 and TRANS1. The model converged well. Second, I used
ADVAN6 to fit the seme model. Results of ADVAN2 and ADVAN6 were almost identical
(K=0.0776, V=0.481, Ka=2.79). Then I looked at plots and residuals and realized
that the results are very biased:
1. Means of residuals are very far from zero;
2. Plots of residuals and dependent variable vs time look quite different.
I canot fix the problem.
Can you identify the problem? Here are codes and data:
$PROBLEM FIRST ADVAN2 -- POPULATION DATA
$INPUT ID TIME CP=DV DOSE=AMT MDV
$DATA A2IN2
$SUBROUTINES ADVAN2
$PK
;THETA(1)=MEAN ELIMINATION RATE CONSTANT K (1/HR)
;THETA(2)=VOLUME OF DISTRIBUTION
;THETA(3)=MEAN ABSORPTION RATE CONSTANT KA (1/HR)
CALLFL=1
K=THETA(1)+ETA(1)
KA=THETA(2)+ETA(2) ;ETA(1) - INTERINDIVIDUAL VARIABILITY OF KA (NU)
S2= THETA(3)+ETA(3)
;CL=K*V;
$THETA (.001,.7,5) (.001,1,10) (.001,0.3,20)
$OMEGA BLOCK(3) .1 .0001 .01 .0001 .0001 .1 ;VARIANCE OF ETA
$ERROR
Y=F+EPS(1)
$SIGMA .3 ;VARIANCE OF EPS
$EST MAXEVAL=450 PRINT=5
$COV ;COVARIANCE STEP IS IMPLEMENTED
$TABLE ID TIME DOSE PRED DV
$SCAT (DV PRED) VS TIME BY ID
********************************************
$PROB REPLICATE OF ADVAN2 USING DIFF EQUATIONS-- POPULATION DATA
$INPUT ID TIME CP=DV DOSE=AMT
$DATA A2IN2
$SUBROUTINES ADVAN6 TOL=7 ;TOL - THE NUMBER OF ACCURATE DIGITS
$MODEL COMP=(DEPOT,DEFDOSE) COMP=(CENTRAL,DEFOBS,NOOFF)
$PK
;THETA(1)=MEAN ELIMINATION RATE CONSTANT K (1/HR) = 0.076
;THETA(2)=VOLUME OF DISTRIBUTION = 0.481
;THETA(3)=MEAN ABSORPTION RATE CONSTANT KA (1/HR) = 2.790
CALLFL=1
K= THETA(1)+ETA(1)
V= THETA(2)+ETA(2)
KA=THETA(3)+ETA(3) ;ETA(1) - INTERINDIVIDUAL VARIABILITY OF KA (NU)
;CL=K*V
$THETA (.001,.1,5) (.001,.5,20) (.001,3,10)
$OMEGA BLOCK(3) .1 .0001 .01 .0001 .0001 .1 ;VARIANCE OF ETA
$DES
DADT(1)=-KA*A(1)
DADT(2)= KA/V*A(1)-K*A(2) ;A(2) = CP
$ERROR
Y=F+EPS(1)
$SIGMA .3 ;VARIANCE OF EPS
$EST MAXEVAL=450 PRINT=5
$COV ;COVARIANCE STEP IS IMPLEMENTED
$TABLE ID TIME DOSE PRED ETA1 ETA2 ETA3
$SCAT (DV PRED) VS TIME BY ID
*********************************************
1 0.00 . 4.02 1
1 0.00 0.74 . 0
1 0.25 2.84 . 0
1 0.57 6.57 . 0
1 1.12 10.50 . 0
1 2.02 9.66 . 0
1 3.82 8.58 . 0
1 5.10 8.36 . 0
1 7.03 7.47 . 0
1 9.05 6.89 . 0
1 12.12 5.94 . 0
1 24.37 3.28 . 0
2 0.00 . 4.40 1
2 0.00 0.00 . 0
2 0.27 1.72 . 0
2 0.52 7.91 . 0
2 1.00 8.31 . 0
2 1.92 8.33 . 0
2 3.50 6.85 . 0
2 5.02 6.08 . 0
2 7.03 5.40 . 0
2 9.00 4.55 . 0
2 12.00 3.01 . 0
2 24.30 0.90 . 0
3 0.00 . 4.53 1
3 0.00 0.00 . 0
3 0.27 4.40 . 0
3 0.58 6.90 . 0
3 1.02 8.20 . 0
3 2.02 7.80 . 0
3 3.62 7.50 . 0
3 5.08 6.20 . 0
3 7.07 5.30 . 0
3 9.00 4.90 . 0
3 12.15 3.70 . 0
3 24.17 1.05 . 0
4 0.00 . 4.40 1
4 0.00 0.00 . 0
4 0.35 1.89 . 0
4 0.60 4.60 . 0
4 1.07 8.60 . 0
4 2.13 8.38 . 0
4 3.50 7.54 . 0
4 5.02 6.88 . 0
4 7.02 5.78 . 0
4 9.02 5.33 . 0
4 11.98 4.19 . 0
4 24.65 1.15 . 0
5 0.00 . 5.86 1
5 0.00 0.00 . 0
5 0.30 2.02 . 0
5 0.52 5.63 . 0
5 1.00 11.40 . 0
5 2.02 9.33 . 0
5 3.50 8.74 . 0
5 5.02 7.56 . 0
5 7.02 7.09 . 0
5 9.10 5.90 . 0
5 12.00 4.37 . 0
5 24.35 1.57 . 0
6 0.00 . 4.00 1
6 0.00 0.00 . 0
6 0.27 1.29 . 0
6 0.58 3.08 . 0
6 1.15 6.44 . 0
6 2.03 6.32 . 0
6 3.57 5.53 . 0
6 5.00 4.94 . 0
6 7.00 4.02 . 0
6 9.22 3.46 . 0
6 12.10 2.78 . 0
6 23.85 0.92 . 0
7 0.00 . 4.95 1
7 0.00 0.15 . 0
7 0.25 0.85 . 0
7 0.50 2.35 . 0
7 1.02 5.02 . 0
7 2.02 6.58 . 0
7 3.48 7.09 . 0
7 5.00 6.66 . 0
7 6.98 5.25 . 0
7 9.00 4.39 . 0
7 12.05 3.53 . 0
7 24.22 1.15 . 0
8 0.00 . 4.53 1
8 0.00 0.00 . 0
8 0.25 3.05 . 0
8 0.52 3.05 . 0
8 0.98 7.31 . 0
8 2.02 7.56 . 0
8 3.53 6.59 . 0
8 5.05 5.88 . 0
8 7.15 4.73 . 0
8 9.07 4.57 . 0
8 12.10 3.00 . 0
8 24.12 1.25 . 0
9 0.00 . 3.10 1
9 0.00 0.00 . 0
9 0.30 7.37 . 0
9 0.63 9.03 . 0
9 1.05 7.14 . 0
9 2.02 6.33 . 0
9 3.53 5.66 . 0
9 5.02 5.67 . 0
9 7.17 4.24 . 0
9 8.80 4.11 . 0
9 11.60 3.16 . 0
9 24.43 1.12 . 0
10 0.00 . 5.50 1
10 0.00 0.24 . 0
10 0.37 2.89 . 0
10 0.77 5.22 . 0
10 1.02 6.41 . 0
10 2.05 7.83 . 0
10 3.55 10.21 . 0
10 5.05 9.18 . 0
10 7.08 8.02 . 0
10 9.38 7.14 . 0
10 12.10 5.68 . 0
10 23.70 2.42 . 0
11 0.00 . 4.92 1
11 0.00 0.00 . 0
11 0.25 4.86 . 0
11 0.50 7.24 . 0
11 0.98 8.00 . 0
11 1.98 6.81 . 0
11 3.60 5.87 . 0
11 5.02 5.22 . 0
11 7.03 4.45 . 0
11 9.03 3.62 . 0
11 12.12 2.69 . 0
11 24.08 0.86 . 0
12 0.00 . 5.30 1
12 0.00 0.00 . 0
12 0.25 1.25 . 0
12 0.50 3.96 . 0
12 1.00 7.82 . 0
12 2.00 9.72 . 0
12 3.52 9.75 . 0
12 5.07 8.57 . 0
12 7.07 6.59 . 0
12 9.03 6.11 . 0
12 12.05 4.57 . 0
12 24.15 1.17 . 0
ADVAN2 and ADVAN6: biased results
From: Nick Holford - n.holford@auckland.ac.nz
Subject: Re: [NMusers] ADVAN2 and ADVAN6: biased results
Date: 2/14/2004 2:15 AM
Hi,
When I tried your ADVAN2 code it terminated by running
out of function evaluations.
You can get it to converge and run the $COV step if you
allow more function evalutions and tweak your initial estimates a bit.
I can't see any problem when I look at graphs of your fit.
THETA: K KA V
ETA: PPVK PPVKA PPVV
ERR: SD
advan2.lst 101.072 eval=122 sig=+3.4 sub=12 obs=132 CCIL=NNNN NV1.1 PIV1.1
THETA = 0.0809 2.82 0.481
ETASD = 0.0181384 2.49199 0.070214
ETAR12 = 0.241
ETAR23 = 0.159 -0.213
ERRSD = 0.618061
THETA:se% = 11.4 25.0 4.8
OMEGA:se% = 81.8 85.3 37.9
SIGMA:se% = 26.0
$PROBLEM FIRST ADVAN2 -- POPULATION DATA
$INPUT ID TIME CP=DV DOSE=AMT MDV
$DATA A2IN2.dat IGNORE #
$EST MAXEVAL=9990 SIG=3 PRINT=0
POSTHOC
$COV
$THETA
(.001,0.0806,5) ;K
(.001,2.81,10) ;KA
(.001,0.481,20) ;V
$OMEGA BLOCK(3)
0.00032 ;PPVK
0.0104 6.2 ;PPVKA
0.00021 -0.0369 0.00492 ;PPVV
$SIGMA 0.382 ;SD
$SUBROUTINES ADVAN2
$PK
CALLFL=1
K=THETA(1)+ETA(1)
KA=THETA(2)+ETA(2)
V=THETA(3)+ETA(3)
S2=V
$ERROR
CONC=F
Y=CONC+ERR(1)
$TABLE ID TIME DOSE Y
ONEHEADER NOPRINT FILE=advan2.fit
$SCAT (DV PRED) VS TIME BY ID
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand
email:n.holford@auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
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