Approximate testing in two-stage nonlinear mixed models

Abstract

We investigate here small sample properties of approximate F-tests about fixed effects parameters in nonlinear mixed models. For estimation of population fixed effects parameters as well as variance components, we apply the two-stage approach. This method is useful and popular when the number of observations per sampling unit is large enough. The approximate F-test is constructed based on large-sample approximation to the distribution of nonlinear least-squares estimates of subject-specific parameters. We recommend a modified test statistic that takes into consideration approximation to the large-sample Fisher information matrix (See [Volaufova J, Burton JH. Note on hypothesis testing in mixed models. Oral presentation at: LINSTAT 2012/21st IWMS; 2012; Bedlewo, Poland]). Our main focus is on comparing finite sample properties of broadly used approximate tests (Wald test and likelihood ratio test) and the modified F-test under the null hypothesis, especially accuracy of p-values (See [Volaufova J, LaMotte L. Comparison of approximate tests of fixed effects in linear repeated measures design models with covariates. Tatra Mountains. 2008;39:17–25]). For that purpose two extensive simulation studies are conducted based on pharmacokinetic models (See [Hartford A, Davidian M. Consequences of misspecifying assumptions in nonlinear mixed effects models. Comput Stat and Data Anal. 2000;34:139–164; Pinheiro J, Bates D. Approximations to the log-likelihood function in the non-linear mixed-effects model. J Comput Graph Stat. 1995;4(1):12–35]).

Keywords:

• two-stage nonlinear mixed model
• approximate test
• accuracy of p-value

AMS Subject Classification:

• 62H15
• 62H05
• 62F05

Acknowledgements

This work was supported by the National Institute of General Medical Sciences of the National Institutes of Health which funds the Louisiana Clinical and Translational Science Center under Grant 1 U54 GM104940.