Study design features increase replicability in brain-wide association studies

Kaidi Kang (), Jakob Seidlitz, Richard A. I. Bethlehem, Jiangmei Xiong, Megan T. Jones, Kahini Mehta, Arielle S. Keller, Ran Tao, Anita Randolph, Bart Larsen, Brenden Tervo-Clemmens, Eric Feczko, Oscar Miranda Dominguez, Steven M. Nelson, Jonathan Schildcrout, Damien A. Fair, Theodore D. Satterthwaite, Aaron Alexander-Bloch and Simon Vandekar ()
Additional contact information
Kaidi Kang: Vanderbilt University Medical Center
Jakob Seidlitz: The Children’s Hospital of Philadelphia
Richard A. I. Bethlehem: University of Cambridge
Jiangmei Xiong: Vanderbilt University Medical Center
Megan T. Jones: Vanderbilt University Medical Center
Kahini Mehta: University of Pennsylvania
Arielle S. Keller: University of Connecticut
Ran Tao: Vanderbilt University Medical Center
Anita Randolph: University of Minnesota Medical School
Bart Larsen: University of Minnesota Medical School
Brenden Tervo-Clemmens: University of Minnesota
Eric Feczko: University of Minnesota Medical School
Oscar Miranda Dominguez: University of Minnesota Medical School
Steven M. Nelson: University of Minnesota Medical School
Jonathan Schildcrout: Vanderbilt University Medical Center
Damien A. Fair: University of Minnesota Medical School
Theodore D. Satterthwaite: University of Pennsylvania
Aaron Alexander-Bloch: The Children’s Hospital of Philadelphia
Simon Vandekar: Vanderbilt University Medical Center

Nature, 2024, vol. 636, issue 8043, 719-727

Abstract: Abstract Brain-wide association studies (BWAS) are a fundamental tool in discovering brain–behaviour associations1,2. Several recent studies have shown that thousands of study participants are required for good replicability of BWAS1–3. Here we performed analyses and meta-analyses of a robust effect size index using 63 longitudinal and cross-sectional MRI studies from the Lifespan Brain Chart Consortium4 (77,695 total scans) to demonstrate that optimizing study design is critical for increasing standardized effect sizes and replicability in BWAS. A meta-analysis of brain volume associations with age indicates that BWAS with larger variability of the covariate and longitudinal studies have larger reported standardized effect size. Analysing age effects on global and regional brain measures from the UK Biobank and the Alzheimer’s Disease Neuroimaging Initiative, we showed that modifying study design through sampling schemes improves standardized effect sizes and replicability. To ensure that our results are generalizable, we further evaluated the longitudinal sampling schemes on cognitive, psychopathology and demographic associations with structural and functional brain outcome measures in the Adolescent Brain and Cognitive Development dataset. We demonstrated that commonly used longitudinal models, which assume equal between-subject and within-subject changes can, counterintuitively, reduce standardized effect sizes and replicability. Explicitly modelling the between-subject and within-subject effects avoids conflating them and enables optimizing the standardized effect sizes for each separately. Together, these results provide guidance for study designs that improve the replicability of BWAS.

Date: 2024
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DOI: 10.1038/s41586-024-08260-9

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