Re: Problems with an apparent compiler-senstive model

From: Leonid Gibiansky leonidg@metrumrg.com Subject: Re: [NMusers] Problems with an apparent compiler-senstive model Date: Wed, 02 Aug 2006 10:24:01 -0400 Nick, The root of the non-convergence is the instability of the model-data combination. For example, there was PAGE poster by Lindbom et al. http://www.page-meeting.org/default.asp?abstract=997 that concluded: "The condition number of the covariance matrix of the original model is a strong predictor of NONMEM stability in the bootstrap and case-deletion diagnostics." You may choose to ignore this instability, and get away with a reasonably good model, but this is not the reason to dismiss a perfectly useful and very important diagnostic like the convergence status. Note also that in your examples the authors started with the models that were studied to death to insure that these are the best possible models (for the data in hands). It was not clear whether the final models in those examples converged, and discussion was centered only on the bootstrap samples. Bootstrap samples by a nature of the problem (too many of them) cannot receive as much attention as the final model. In any case, it is premature to conclude from these examples that convergence is not important. If you like confirmation of the statement "non-convergence indicates problems with the model or with the data", try to estimate bioavailability, CL and V at the same time in the absence of the reference formulation. You may end up with the model that can even pass the most stringent scrutiny using the predictive check procedure, but still is deficient, and this deficiency is easily revealed by either non-convergence or by the failure of the covariance step. Leonid