Re: Implementation of interindividual variability in residual variance

From: Mats Karlsson - mats.karlsson@farmbio.uu.se Subject: Re: [NMusers] Implementation of interindividual variability in residual variance Date: 2/18/2004 9:39 AM Hi Atul, The traditional assumption in NONMEM analyses has been that all subjects have the same residual error magnitude. This probably stems from early times when it was believed that residual variability was similar to assay variability (which usually is the same for all subjects!). However, assay variability usually has very little to do with the residual error we see (this conclusion can be based merely on the fact that residual variability is so much larger than assay variability). With other sources being responsible for the residual variability it makes sense not to make the rather strong assumption that it is the same for all subjects. However, if you have sparse data, it is usually not possible to distinguish different variabilities between subjects (another reason it wasn't considered in the early days of pop PK). However, whenever you have relatively rich data it is a good idea to try it. It does require that you use METH=1 INTER as the interaction allows the magnitude to vary between individuals (it is no use at all to use it with FO or FOCE without the interaction term). We introduced it in a paper back in 1998 (Assumption testing in population pharmacokinetic models: illustrated with an analysis of moxonidine data from congestive heart failure patients.J Pharmacokinet Biopharm. 1998 Apr;26(2):207-46), but there hasn't been many other publications using it. Despite this, I've often found it useful. It often makes screening for outlying data points or odd individuals easier or unnecessary as it does allow you to use all data without subjectively omit one data point or another. Precision of parameters and less (odd) influential individuals are other advantages. Hope this was helpful, Mats -- Mats Karlsson, PhD Professor of Pharmacometrics Div. of Pharmacokinetics and Drug Therapy Dept. of Pharmaceutical Biosciences Faculty of Pharmacy Uppsala University Box 591 SE-751 24 Uppsala Sweden phone +46 18 471 4105 fax +46 18 471 4003 mats.karlsson@farmbio.uu.se