title: Statistical analysis of longitudinal neuroimage data with Linear Mixed Effects models.
abstract: Longitudinal neuroimaging (LNI) studies are rapidly becoming more prevalent and growing in size. Today, no standardized computational tools exist for the analysis of LNI data and widely used methods are sub-optimal for the types of data encountered in real-life studies. Linear Mixed Effects (LME) modeling, a mature approach well known in the statistics community, offers a powerful and versatile framework for analyzing real-life LNI data. This article presents the theory behind LME models, contrasts it with other popular approaches in the context of LNI, and is accompanied with an array of computational tools that will be made freely available through FreeSurfer - a popular Magnetic Resonance Image (MRI) analysis software package. Our core contribution is to provide a quantitative empirical evaluation of the performance of LME and competing alternatives popularly used in prior longitudinal structural MRI studies, namely repeated measures ANOVA and the analysis of annualized longitudinal change measures (e.g. atrophy rate). In our experiments, we analyzed MRI-derived longitudinal hippocampal volume and entorhinal cortex thickness measurements from a public dataset consisting of Alzheimer's patients, subjects with mild cognitive impairment and healthy controls. Our results suggest that the LME approach offers superior statistical power in detecting longitudinal group differences.
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Harvard Medical School/Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Bernal-Rusiel
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Harvard Medical School/Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Douglas N
authors.initials: DN
authors.lastname: Greve
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Harvard Medical School/Massachusetts General Hospital, Charlestown, MA, USA; Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Reuter
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Harvard Medical School/Massachusetts General Hospital, Charlestown, MA, USA; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Fischl
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Harvard Medical School/Massachusetts General Hospital, Charlestown, MA, USA; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA. Electronic address: msabuncu@nmr.mgh.harvard.edu.
authors.forename: Mert R
authors.initials: MR
authors.lastname: Sabuncu
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D000544:Alzheimer Disease / Q000473:pathology*; D001921:Brain / Q000473:pathology*; D060825:Cognitive Dysfunction / Q000473:pathology*; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000379:methods*; D016014:Linear Models; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged
keywords: Linear Mixed Effects models; Longitudinal studies; Statistical analysis