# Re: NONMEM code for Mixture Model

From: Huali Wu <hualiw>
Date: Fri, 13 Mar 2009 10:56:13 -0400

Dear Dr. Grevel:

Thank you very much for your detailed suggestions and comments. I have =
tried the codes and it works. But as you suggested, I think I should try =
to divide patients into subgroups according to their disease state. Can =
I incorporate this into covariate model as below?

VM = THETA(1)*TYPE*EXP(ETA(1))+THETA(2)*(1-TYPE)*EXP(ETA(2))

Where, TYPE =0 for patients without this disease and TYPE=1 for =
patients with this disease.

Will this covariate model be acceptable?

Thanks again,

Best regards,

Huali

----- Original Message -----
From: Joachim.Grevel
To: nmusers
Sent: Friday, March 13, 2009 3:23 AM
Subject: Re: [NMusers] NONMEM code for Mixture Model

Dear Huali,

you also need some code which specifies what is different between the =
populations. The differences could be ETAs (but do not have to be!) or =
certain factors which allow a PK parameter to have a different typical =
value in one population.

EST=MIXEST
IF(MIXNUM.EQ.2)THEN
V1=TVV1*EXP(ETA(3))
VM=THETA(x)*TVVM*EXP(ETA(4))
ELSE
V1=TVV1*EXP(ETA(1))
VM=TVVM*EXP(ETA(2))
ENDIF

The for the \$OMEGA block you have two options:

either:
\$OMEGA BLOCK(2) 0.1 ;ETA1 for V1 for =
population 1
0.01 0.1 ;ETA2 for VM for =
population 1
\$OMEGA BLOCK(2) SAME ;ETA3 ETA4 for population =
2

or:
\$OMEGA BLOCK(2) 0.1 ;ETA1 for V1 for =
population 1
0.01 0.1 ;ETA2 for VM for =
population 1
\$OMEGA BLOCK(2) 0.1 ;ETA3 for V1 for =
population 2
0.01 0.1 ;ETA4 for VM for =
population 2

But you still face a more fundamental question: Why do you want to =
define two populations when you already know that "patients in different =
disease states seems have different distribution of clearance". I use =
the Mixture models solely when the source of variability is still =
unknown and when it is clear that a normal distribution will not be =
adequate (ETABAR message with p<0.05). In you case I would build the =
knowledge about the influence of the disease states directly into the =
code which specifies only one population.

Good luck,

Joachim

__________________________________________
Joachim GREVEL, Ph.D.
Merck Serono S.A. - Genève
Human Pharmacology
1202 Geneva
Tel: +41.22.414.4751
Fax: +41.22.414.3059
Email: joachim.grevel

nidal.alhuniti
Sent by: owner-nmusers
03/12/2009 08:44 PM
To Huali Wu <hualiw
cc nmusers
Subject Re: [NMusers] NONMEM code for Mixture Model

Hi Huali,
You could use \$MIX. Please see the NM help files for \$MIX. You have to =
specify the number of populations (in your case 2) so

\$MIX
NSPOP=2
P(1)=THETA(4)
P(2)=1.-THETA(4)

Then use
EST= MIXEST

Hopefully this helps.
Best,
Nidal

Nidal AL-Huniti, PhD
Associate Director, Modeling and Simulations
ICON Development Solutions SM

On 3/12/09, Huali Wu <hualiw
Dear NMusers:

I am working on dataset with high variability on clearance and =
patients in different disease states seems have different distribution =
of clearance. So I want to try the mixture model but I don't know how to =
do the coding. I listed the code of my base model as below:

\$PROB 1hr IV INFUSION SINGLE DOSE WITHOUT COVARIATES
\$DATA data01.CSV IGNORE=C
\$INPUT ID TIME DV AMT RATE MDV

\$MODEL NPAR=3, NCOMP=1, COMP=(CENTRAL,DEFOBS)

\$PK
V1 = THETA(1)*EXP(ETA(1))
VM = THETA(2)*EXP(ETA(2))
KM = THETA(3)

S1 = V1

\$ERROR

Y=F+F*EPS(1)+EPS(2)

IPRED=F
IRES=DV-IPRED
IF(AMT.NE.0)W=1
IF(AMT.EQ.0)W=F
IWRES=IRES/W

\$DES
C1 = A(1)/V1

\$THETA (0, 4.47) (0, 155) (0, 1380)
\$OMEGA BLOCK (2)
0.5
0.3 0.9

\$SIGMA (0.01) (0.1)

\$EST POSTHOC METHOD=1 MAXEVAL=9990 PRINT=5
\$COV
\$TABLE ID TIME DV AMT RATE V1 VM KM IWRES IPRED NOPRINT =
\$SCAT (RES WRES) VS TIME BY ID

Any suggestion will be highly appreciated!

Best regards,

Huali

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Received on Fri Mar 13 2009 - 10:56:13 EDT

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