Study design features that improve effect sizes in cross-sectional and longitudinal brain-wide association studies

Abstract

AbstractBrain-wide association studies (BWAS) are a fundamental tool in discovering brain-behavior associations. Several recent studies showed that thousands of study participants are required to improve the replicability of BWAS because actual effect sizes are much smaller than those reported in smaller studies. Here, we perform analyses and meta-analyses of a robust effect size index (RESI) using 63 longitudinal and cross-sectional magnetic resonance imaging studies (77,695 total scans) to demonstrate that optimizing study design is an important way to improve standardized effect sizes and replicability in BWAS. A meta-analysis of brain volume associations with age indicates that BWAS with larger covariate variance have larger effect size estimates and that the longitudinal studies we examined have systematically larger standardized effect sizes than cross-sectional studies. We propose a cross-sectional RESI to adjust for the systematic difference in effect sizes between cross-sectional and longitudinal studies that allows investigators to quantify the benefit of conducting their study longitudinally. Analyzing age effects on global and regional brain measures in the Lifespan Brain Chart Consortium, we show that modifying longitudinal study design to increase between-subject variability and adding a single additional longitudinal measurement per subject improves effect sizes. However, evaluating these longitudinal sampling schemes on cognitive, psychopathology, and demographic associations with structural and functional brain outcome measures in the Adolescent Brain and Cognitive Development dataset shows that longitudinal studies can, counterintuitively, be detrimental to effect sizes. We demonstrate that the benefit of conducting longitudinal studies depends on the strengths of the between- and within-subject associations of the brain and non-brain measures. Explicitly modeling between- and within-subject effects avoids conflating the effects and allows optimizing effect sizes for them separately. These findings underscore the importance of considering design features in BWAS and emphasize that increasing sample size is not the only approach to improve the replicability of BWAS.