some issues about NONMEM

From: Nick Holford - n.holford@auckland.ac.nz Subject Re: [NMusers] some issues about NONMEM Date: 2/11/2004 2:30 PM Xiaofeng, NONMEM patches -- the silence from Maryland is deafening. You can find some information about methods for determining the null distribution of objective function differences here http://wfn.sourceforge.net/wfnrt.htm. Note that these methods can only guide you in making model building decisions based on P value criteria. They cannot diagnose nor fix problems with bias or imprecision in parameter estimates that might arise from any NOMMEM estimation method such as FO or FOCE. You can use simulation (parametric bootstrap) to explore the possible bias in estimation. Confidence intervals in parameter estimates can be obtained using the non-parametric bootstrap ( http://wfn.sourceforge.net/wfnbs.htm). All these methods are time consuming (and often impractical) because they typically involve hundreds if not thousands of runs for each model you want to test. Before assuming (based only on advice from your colleagues) that FDA will not accept results I suggest you try talking to FDA. If you can talk to a pharmacometrician at FDA you should get practical and helpful advice tailored to your particular problem. Nick -- Nick Holford, Dept Pharmacology & Clinical Pharmacology University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand email:n.holford@auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556 http://www.health.auckland.ac.nz/pharmacology/staff/nholford/