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RE: OMEGA BLOCK with mixture model?

From: Bob Leary <bleary>
Date: Wed, 15 Apr 2009 09:16:09 -0400

If you want both CL1 and CL2 to be correlated with F (i.e. allow =
Omega(CL1,F) and Omega(CL2,F) to be free in
the objective function optimization),
then I don't think there is any simple reordering of the random effects =
that will allow the correlation
between CL1 and CL2 to be fixed to zero - i.e. the element =
Omega(CL1,CL2) must also be free.
The reason for the Nonmem manual entry
 part VIII, p 94 ($OMEGA), "If FIXED appears anywhere among the list of =
values, the entire block is fixed."
that Andreas pointed out is that internally Nonmem parameterizes the =
Omega matrix by its
Cholesky factor elements, not the elements of the Omega matrix itself. =
The Cholesky factor has the
same block diagonal structure as the Omega matrix, but due to the =
'fill-in' phenomenon during
a factorization, an internal zero element inside an Omega block will not =
necessarily be preserved
as a zero in the Cholesky factor. So there is no way to force an =
internal element in an Omega block to be zero.

Robert H. Leary, PhD

Pharsight - A Certara(tm) Company

5625 Dillard Dr., Suite 205
Cary, NC 27511

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Email: bleary

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-----Original Message-----
From: owner-nmusers
Sent: Wednesday, April 15, 2009 6:6 AM
To: nele.plock
Cc: nmusers
Subject: Re: [NMusers] OMEGA BLOCK with mixture model?


going by the nonmem user manual, part VIII, p 94 ($OMEGA), "If FIXED =
appears anywhere among the list of values, the entire block is fixed."
I did not see anyone pointing that out yet.

This does in fact imply that you need to reorder the sequence of random =
effects (which can be quite a nuisance if you have a sequence of models =
and the parameters do not correspond any more across models).



Andreas Krause, PhD
Lead Scientist Modeling and Simulation

Actelion Pharmaceuticals Ltd / Gewerbestrasse 16 / CH-4123 Allschwil / =
phone +41 61 565 6891 / fax +41 61 565 66 96

Sent by: owner-nmusers

04/14/2009 05:08 PM



[NMusers] OMEGA BLOCK with mixture model?


Dear all,

I am trying to fit a PK model to oral data. In the data, we observed two =
things: First, CL seems to be negatively correlated with F1. Secondly, =
there seem to be two subpopulations in the exposure, let's say a large =
group with 'normal' and a second group with high exposure. I would like =
to identify the subpopulations using a mixture model, but keep the =
correlation between CL and F1. Now I ran into problems when coding the =

I figured the block to be something like:
0.1 ;CL1
0 FIX 0.1 ;CL2
0.01 0.01 0.1 ;F1

The error message that appears is:
a covariance is zero, but the block is not a band matrix

I assume that this means that I am not allowed to fix the correlation =
between the two clearance-omegas to zero. However, it would be =
unreasonable to allow a correlation, because the omegas belong to =
different subpopulations, so there can't be a correlation. On the other =
hand, I did not include subpopulations for F1, so how can I keep this =
correlation to both CL-subgroups?

Any thoughts on this would be highly appreciated!
Best wishes

Dr. Nele Plock
Pharmacometrics -- Modeling and Simulation

Nycomed GmbH
Byk-Gulden-Str. 2
D-78467 Konstanz, Germany

Fon: (+49) 7531 / 84 - 4759
Fax: (+49) 7531 / 84 - 94759

mailto: nele.plock

County Court: Freiburg, Commercial Register HRB 701257
Chairman Supervisory Board: Charles Depasse
Management Board: Dr. Barthold Piening, Gilbert Rademacher, Dr. Anders =

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Received on Wed Apr 15 2009 - 09:16:09 EDT

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