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 ($OMEGA), "If FIXED appears anywhere among the list of values, the entire block is fixed." that Andreas pointed out is that internally Nonmem parameterizes the Omega matrix by its Cholesky factor elements, not the elements of the Omega matrix itself. The Cholesky factor has the same block diagonal structure as the Omega matrix, but due to the 'fill-in' phenomenon during a factorization, an internal zero element inside an Omega block will not necessarily be preserved as a zero in the Cholesky factor. So there is no way to force an internal element in an Omega block to be zero.
Robert H. Leary, PhD Fellow Pharsight - A Certara(tm) Company 5625 Dillard Dr., Suite 205 Cary, NC 27511 Phone/Voice Mail: (919) 852-4625, Fax: (919) 859-6871 Email: ble...@pharsight.com This email message (including any attachments) is for the sole use of the intended recipient and may contain confidential and proprietary information. Any disclosure or distribution to third parties that is not specifically authorized by the sender is prohibited. If you are not the intended recipient, please contact the sender by reply email and destroy all copies of the original message. -----Original Message----- From: owner-nmus...@globomaxnm.com [mailto:owner-nmus...@globomaxnm.com]on Behalf Of andreas.kra...@actelion.com Sent: Wednesday, April 15, 2009 6:6 AM To: nele.pl...@nycomed.com Cc: nmusers@globomaxnm.com Subject: Re: [NMusers] OMEGA BLOCK with mixture model? Nele, going by the nonmem user manual, part VIII, p 94 ($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 ----- Andreas Krause, PhD Lead Scientist Modeling and Simulation Actelion Pharmaceuticals Ltd / Gewerbestrasse 16 / CH-4123 Allschwil / Switzerland phone +41 61 565 6891 / fax +41 61 565 66 96 andreas.kra...@actelion.com / www.actelion.com nele.pl...@nycomed.com Sent by: owner-nmus...@globomaxnm.com 04/14/2009 05:08 PM To nmusers@globomaxnm.com cc Subject [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 $OMEGA BLOCK. I figured the block to be something like: $OMEGA BLOCK(3) 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 Nele ______________________________________________________________ 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.pl...@nycomed.com http://www.nycomed.com County Court: Freiburg, Commercial Register HRB 701257 Chairman Supervisory Board: Charles Depasse Management Board: Dr. Barthold Piening, Gilbert Rademacher, Dr. Anders Ullman ---------------------------------------------------------------------- Proprietary or confidential information belonging to Nycomed Group may be contained in this message. If you are not the addressee indicated in this message, please do not copy or deliver this message to anyone. In such case, please destroy this message and notify the sender by reply e-mail. Please advise the sender immediately if you or your employer do not consent to Internet e-mail for messages of this kind. Opinions, conclusions and other information in this message that pertain to the sender's employer and its products and services represent the opinion of the sender and do not necessarily represent or reflect the views and opinions of the employer. ---------------------------------------------------------------------- The information of this email and in any file transmitted with it is strictly confidential and may be legally privileged. It is intended solely for the addressee. If you are not the intended recipient, any copying, distribution or any other use of this email is prohibited and may be unlawful. In such case, you should please notify the sender immediately and destroy this email. The content of this email is not legally binding unless confirmed by letter. Any views expressed in this message are those of the individual sender, except where the message states otherwise and the sender is authorised to state them to be the views of the sender's company. For further information about Actelion please see our website at http://www.actelion.com
