The relative efficiency of time-to-progression and continuous measures of cognition in presymptomatic Alzheimer's disease

INTRODUCTION: Clinical trials on preclinical Alzheimer’s disease are challenging because of the slow rate of disease progression. We use a simulation study to demonstrate that models of repeated cognitive assessments detect treatment effects more efficiently than models of time to progression. METHODS: Multivariate continuous data are simulated from a Bayesian joint mixed-effects model fit to data from the Alzheimer’s Disease Neuroimaging Initiative. Simulated progression events are algorithmically derived from the continuous assessments using a random forest model fit to the same data. RESULTS: We find that power is approximately doubled with models of repeated continuous outcomes compared with the time-to-progression analysis. The simulations also demonstrate that a plausible informative missing data pattern can induce a bias that inflates treatment effects, yet 5% type I error is maintained. DISCUSSION: Given the relative inefficiency of time to progression, it should be avoided as a primary analysis approach in clinical trials of preclinical Alzheimer’s disease.