RE: Bootstrap resampling! -> Randomization test

From: "KOWALSKI, KENNETH G. [PHR/1825]" <kenneth.g.kowalski@pharmacia.com> Subject: RE: Bootstrap resampling! -> Randomization test Date: Thu, 29 Mar 2001 14:50:22 -0600 Dear Joga, I agree that we need to be concerned about which estimation method we use (eg., FO, FOCE or FOCE-INT) but we also have to consider other forms of model misspecification when assessing the validity of the chi-square distribution for the likelihood ratio tests (LRT). For example, I have done simulations showing that when we design a patient study with sparse sampling say over a narrow range of sampling times within a dosing interval, which may only support fitting a one-compartment model when we know say from dense sampling in healthy volunteers that the kinetics obey two compartments, we can get inflated alphas regardless of the estimation method used. Because we still have model misspecification of the structural model. We have shown (Kowalski and Hutmacher, Stats in Med, 2001;20:75-91) that although such an approximation (one-compartment model approximation in a narrow range of data simulated with two-compartment kinetics) can provide fairly accurate estimates of CL/F and accurate estimates of the covariate effect on CL/F, but the LRT for the covariate effect can have an inflated alpha level. Thus, any form of model misspecifation (not just related to the estimation method) can result in the failure of the chi-square distribution to adequately describe the LRT under the null. Ken