RE: Difference between typical values and geometricmea n of posthoc values

From: "Wang, Yaning" WangYA@cder.fda.gov Subject: RE: [NMusers] Difference between typical values and geometricmea n of posthoc values Date: Fri, April 1, 2005 1:08 pm Eleveld: Try a simple linear mixed effect model in NONMEM, like Yij=Intercepti+slopei*tij, to see whether you still have this kind of observation. Here are some of my opinions about nonlinear mixed effect modeling regarding your questions. 1. Nonlinear mixed effect modeling (parametric) is not a pure maximum likelihood estimation method. The likelihood is approximated in NONMEM (also in other softwares). Furthermore, there are different methods for approximation. The impact of these approximation on the consistency of the parameter estimates is not clear yet (as far as I know). 2. Log-normal distribution is also approximated as a result of likelihood approximation or in order to approximate the likelihood depending on whether you start with linearization of the random effect or Laplacian approximation of the likelihood. Therefore, even though you simulated log-normal samples, they are not fitted as log-normal, but constant CV normal. 3. The quality of posthoc estimates depends on both the typical values (THETA) and the individual data (how many data points per subject and where they are collected). Therefore, the observation that "the geometric mean of posthoc values is closer to the 'real' values than the typical (THETA) values" may not always hold. 4. With "INTERACTION" or without "INTERACTION" in NONMEM is another source of approximation. If your residual error model is Y=F*(1+ERR(1)) or Y=F*(1+ERR(1))+ERR(2) or Y=F*EXP(ERR(1)). You should have INTERACTION for FOCE. Otherwise, you introduced more approximation during the estimation process. I hope this helps Yaning ----------------------------------------------------------------------------- Yaning Wang, Ph.D. Pharmacometrician Office of Clinical Pharmacology and Biopharmaceutics Center of Drug Research and Evaluation Food and Drug Administration Office: 301-827-9763