title: Performance of nonlinear mixed effects models in the presence of informative dropout.
abstract: Informative dropout can lead to bias in statistical analyses if not handled appropriately. The objective of this simulation study was to investigate the performance of nonlinear mixed effects models with regard to bias and precision, with and without handling informative dropout. An efficacy variable and dropout depending on that efficacy variable were simulated and model parameters were reestimated, with or without including a dropout model. The Laplace and FOCE-I estimation methods in NONMEM 7, and the stochastic simulations and estimations (SSE) functionality in PsN, were used in the analysis. For the base scenario, bias was low, less than 5% for all fixed effects parameters, when a dropout model was used in the estimations. When a dropout model was not included, bias increased up to 8% for the Laplace method and up to 21% if the FOCE-I estimation method was applied. The bias increased with decreasing number of observations per subject, increasing placebo effect and increasing dropout rate, but was relatively unaffected by the number of subjects in the study. This study illustrates that ignoring informative dropout can lead to biased parameters in nonlinear mixed effects modeling, but even in cases with few observations or high dropout rate, the bias is relatively low and only translates into small effects on predictions of the underlying effect variable. A dropout model is, however, crucial in the presence of informative dropout in order to make realistic simulations of trial outcomes.
authors.affiliation: AstraZeneca R&D, 15185, Södertälje, Sweden, marcus.bjornsson@glocalnet.net.
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Björnsson
authors.forename: Lena E
authors.initials: LE
authors.lastname: Friberg
authors.forename: Ulrika S H
authors.initials: US
authors.lastname: Simonsson
mesh_terms: D015982:Bias; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data; D003198:Computer Simulation; D003627:Data Interpretation, Statistical; D006801:Humans; D015233:Models, Statistical; D017711:Nonlinear Dynamics; D010352:Patient Dropouts