Application of resampling techniques to estimate exact significance levels for covariate selection during nonlinear mixed effects model building: Some inferences

Purpose. One of the main objectives of the nonlinear mixed effects modeling is to provide rational individualized dosing strategies by explaining the interindividual variability using intrinsic and/or extrinsic factors (covariates). The aim of the current study was to evaluate, using computer simulations and real data, methods for estimating the exact significance level for including or excluding a covariate during model building. Methods. Original data were simulated using a simple one-compartment pharmacokinetic model with (full model) or without (null model) covariates (one or two). The covariate values in the original data were resampled (using either permutations or parametric bootstrap methods) to generate data under the null hypothesis that there is no covariate effect. The original and permuted data were fitted to null and full models, using first-order and first-order condition estimation (with or without interaction) methods in NONMEM, to compare the asymptotic and conditional p-value. Target log-likelihood ratio cutoffs for assessing covariate effects were derived. Results. The simulations showed that for sparse as well as dense data, the first-order condition estimation methods yielded the bust results while the first-order method performs somewhat better for sparse data. Depending on the modeling objective, the appropriate asymptotic p-value can be substituted for the conditional significance level. Target log-likelihood ratio cutoffs should be determined separately for each covariate when exact p-values are important. Conclusions. Resampling methods can be employed to estimate the exact significance level for including a covariate during nonlinear mixed effects model building. Some reasonable inferences can be drawn for potential application to design future population analyses.