From: Yaning WangSubject:[NMusers] fundamental questions about NONMEM Date: Mon, 10 Mar 2003 20:07:20 -0500 Dear NONMEM users: In order to compare PKBUGs/WinBUGs with NONMEM, I read NONMEM Users guide part VII to have a better understanding about NONMEM. Here are some questions I don?t understand after I read the manual. 1. On page 4, it seems to me that the approximation equation for -2*log(Li) was obtained via first-order Laplacian approximation without taking etahat as the posterior mode of eta, otherwise there should be only the first four terms. Could someone recommend me a reference where I can learn how to derive this version of Laplacian approximation at any estimate of eta? 2. The last term in the approximation equation mentioned above should be zero for the conditional estimation methods, such as Laplacian method and FOCE method, but not zero for non-conditional estimation method (FO method) and constrained conditional estimation method (Hybrid method), right? 3. In FOCE method (A.2.), the replacement of the hessian matrix with a function of the gradient matrix (1/2*Gamma?*Gamma) was stated to be ?a type of first-order approximation?, which is where and how ?first-order approximation? happened, a second level of approximation on top of Laplacian approximation (the first level of approximation) during parameter estimation. Could someone recommend me a reference on this type of first-order approximation? What is the relationship between this type of first-order approximation and the first-order model approximation (first-order Taylor expansion) introduced in A.6. and NONMEM Users guide I? 4. In FO method (A.3.), the third level of approximation, all eta?s being zero, was applied during parameter estimation in addition to the two levels of approximation mentioned above. This is a new definition of FO method, compared with that described in NONMEM Users guide I. And under A.6.(the centering FOCE method with the first-order model), it was stated that the new FO method is equivalent to applying non-centering FOCE to the first-order model. Based on this statement and the rationale behind the hierarchical methods, Laplacian>FOCE>Hybrid>FO, can I say that the centering FOCE method with the first-order model is somewhere between FOCE and FO? Has anyone applied this method? 5. I thought all the error terms in NONMEM were modeled by normal distribution until I read this manual. It is emphasized on page 1 that normal assumption is only made to keep the discussion simple. If I want to model the oral biavailability (F) with a beta(a, b) distribution, how do I give the initial estimates for a and b and specify this distribution in NONMEM? Thanks a lot for any input. -- Yaning Wang, Graduate student Department of Pharmaceutics College of Pharmacy University of Florida _______________________________________________________ From:Yaning Wang Subject:[NMusers] fundamental questions (ignore 1 and 2) about NONMEM Date:Wed, 12 Mar 2003 10:04:33 -0500 Ignore question 1 and 2. I figured them out. Any suggestion on 3, 4 and 5? _______________________________________________________