Re: NONMEM

From: "Stephen Duffull" stephen.duffull@stonebow.otago.ac.nz Subject: Re: [NMusers] NONMEM Date: Fri, 15 Sep 2006 11:58:49 +1200 Marc Thought that I might escape comment on this :-) >> I'm curious to learn of examples where FIM-based optimization >> methods have been useful for achieving designs that minimize >> bias (#2 in your post below) of parameter estimates. I know of no examples for NL MEM. That doesn't mean it can't be done of course... >> It was >> my understanding that in order to assess bias of parameter >> estimates, it is necessary to run batches of MC >> simulation-estimation cycles and compare estimated values >> back to a reference "true" value (e.g. simulation model >> parameter values). As a gross simplification, I might suggest that bias in parameter estimates can arise from 2 main sources (I am sure someone will correct me here). 1) due to not finding the true maximum of the likelihood 2) due to model misspecification The latter case is a special construct since bias doesn't truly exist it just appears to exist because you're thinking about one model and fitting another and then the parameter estimate you obtain you apply to the wrong model and hence it appears to be biased. I don't think there's much you can do about case 1 (other than use a better search algorithm). Case 2 is a real problem and can be implicit (e.g. due to linearisation) or explicit (e.g. your data does not support estimation of a slow distribution phase hence your estimate of half-life while perhaps accurate for your model is inaccurate to describe the actual time course of disposition). Case 2, you can optimize designs (to minimize the effects of this bias) by using information theoretic techniques without the need for MC. I hasten to add here that this may not necessarily be based solely on FIM - but may have other analytic computation. So I should correct my last statement: >>> > In addition to maximizing precision, FIM based designs can > >> be used to: To: "In addition to maximizing precision, information theoretic designs (not necessarily based solely on FIM but under the overall umbrella of "Optimum Design of Experiments") can be used to:" Regards Steve -- Professor Stephen Duffull Chair of Clinical Pharmacy School of Pharmacy University of Otago PO Box 913 Dunedin New Zealand E: stephen.duffull@otago.ac.nz P: +64 3 479 5044 F: +64 3 479 7034 Design software: www.winpopt.com