RE: Very small P-Value for ETABAR

Hi Jian, As Bill says, including a covariate may fix your problem. However, two other underlying problems may also be causing this: 1. Asymmetric shrinkage of the eta. Two examples of this that I have seen is if you have an eta on epsilon (different residual-error magnitude in different subjects) or if the doses yield a clear effect in some subjects but not in others (eta on EC50/EC50 may become more shrunk on the right tail, since any drug effect in the less sensitive subjects is difficult to separate from the background noise or circadian variation). An important covariate may reduce the degree of shrinkage and the asymmetry in the shrinkage. Other than that, shrinkage is not an issue unless you use the empirical Bayes estimates for diagnostics, i.e. use the individual parameters in graphs, calculations, PK predictions as input to the PD model (IPK approach), etc. 2. Incorrect distributional assumptions: The parametric model assumes e.g. a log-normal distribution of the parameter, around its typical value. If this is not correct eta bar may become biased. You may try other transformations in nonmem, e.g. proportional or other, so-called semi-parametric distributions. For references on Semi-parameteric distributions, search abstracts from Petterson, Hanze, Savic and Karlsson. For reference on shrinkage, see the publication below. Cheers Jakob Clin Pharmacol Ther. 2007 Jul;82(1):17-20. Links Diagnosing model diagnostics.Karlsson MO, Savic RM. Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden. Conclusions from clinical trial results that are derived from model-based analyses rely on the model adequately describing the underlying system. The traditionally used diagnostics intended to provide information about model adequacy have seldom discussed shortcomings. Without an understanding of the properties of these diagnostics, development and use of new diagnostics, and additional information pertaining to the diagnostics, there is risk that adequate models will be rejected and inadequate models accepted. Thus, a diagnosis of available diagnostics is desirable.