Mixed Models and Longitudinal Analysis

MMRM, linear mixed-effects models, and their application in clinical trials and observational studies

2026-06-07 18:16 PDT

Overview

The mixed-effects model for repeated measures (MMRM) has become the primary analysis tool for longitudinal endpoints in confirmatory clinical trials, and for good reason: it accommodates arbitrary covariance patterns, handles missing data under the missing-at-random assumption without imputation, and is robust to certain forms of model misspecification. Despite wide adoption, important questions remain about MMRM’s behavior at boundary conditions – when the true covariance structure departs from the fitted model, when dropout is informative, or when the underlying trajectory is nonlinear.

This program examines mixed models both as analytic targets and as simulation-generating processes, with application to Alzheimer’s disease trials (ADCS, ADNI), PTSD randomized controlled trials, and post-traumatic headache studies.

Papers in development

  • Power and Type I error consequences of misspecifying the functional form of the longitudinal trajectory in MMRM.

  • Operating characteristics of MMRM versus time-to-event analysis for continuous endpoints in Alzheimer’s disease trials.

  • R²-analogues for linear mixed models: development and evaluation for effect-size reporting and meta-analysis.

  • Longitudinal mixed-model analysis of a prazosin randomized controlled trial for post-traumatic headache in veterans.

  • Reanalysis of the VA Cooperative Studies Program prazosin PTSD trial using contemporary mixed-model methods.

Methods

MMRM (unstructured, compound symmetric, AR(1), Toeplitz covariance structures); linear mixed-effects models via lme4, lmerTest, and nlme; emmeans-based marginal contrasts; zzlongplot for longitudinal visualization; permutation tests via coin as nonparametric sensitivity analyses.

Software

  • zzlongplot – Longitudinal plotting for clinical trials, supporting MMRM-style trajectory displays with confidence ribbons and individual-profile overlays.

Publications

Selected publications are accessible through the full publications list by filtering on the keywords mixed-models or longitudinal. The publication record spans methodological papers on MMRM behavior and applied analyses of Alzheimer’s and PTSD trial data.