Re: truncation & simulation

Ron, When you truncate the simulated parameter distribution it can lead to a major violation of the assumptions of maximum likelihood i.e. that all random effects are normally distributed. This means that the likelihood ratio test will have a larger Type 1 error than expected from using the chi-2 distribution assumption. You should use a randomization test in order to determine what change in OFV is needed in order to reject the null under your desired hypothesis. Nick Ron Mathôt wrote: > Dear NONMEM users, > > Currently I am working on the simulation of a bio-equavalence trial. For the reference compound a population PK model has been derived on basis of data from 100 patients. Values for between-and within-patient variability are available for all PK parameters. The simulation comprises a randomized cross-over study with 12 patients taking the test and reference compound. Two-hunderd trials are simulated and summarized. During the simulations I noticed that truncation of the simulated of PK parameters significantly influences the power of the study to confirm bio-equivalence. For instance truncation of simulated oral clearances of both compounds from a range of 1-300 L/hr to 5 - 30 L/hr doubled the number of positive trials (due to decreased within- patient variability). Post-hoc estimates form the popPK study indicated that clearance values of the reference compound are all within the latter range of 5 to 30 L/hr. I expect that oral clearance of the test compound will not differ more than 5% from the reference compound. In my opinion simulation of trials with the smallest range will produce more reliable estimates of the power to detect bio-equivalence. > > I would greatly appreciate your comments on this subject. > Best regards, > > Ron Mathôt > > Department of Hospital Pharmacy and Clincal Pharmacology > Erasmus University Medical Center > Rotterdam > The Netherlands -- Nick Holford, Dept Pharmacology & Clinical Pharmacology University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand [EMAIL PROTECTED] tel:+64(9)373-7599x86730 fax:+64(9)373-7090 www.health.auckland.ac.nz/pharmacology/staff/nholford