Reproducible brain-wide association studies require thousands of individuals

TLDR

MRI has enabled detailed brain mapping, yet mental‑health studies still struggle to replicate brain–behaviour associations because most BWAS use sample sizes (~25) that are too small to capture reproducible effects. The study aimed to quantify how BWAS effect sizes and reproducibility change with sample size using three large datasets totaling ~50,000 participants. The authors pooled three of the largest neuroimaging cohorts to analyze BWAS effect sizes and replication rates across varying sample sizes. They found that BWAS effect sizes are smaller than previously thought, leading to underpowered studies and inflated estimates, but replication rates improve and effect‑size inflation decreases as sample sizes reach thousands, with stronger signals for fMRI, cognitive tests, and multivariate methods.

Abstract

Abstract Magnetic resonance imaging (MRI) has transformed our understanding of the human brain through well-replicated mapping of abilities to specific structures (for example, lesion studies) and functions 1–3 (for example, task functional MRI (fMRI)). Mental health research and care have yet to realize similar advances from MRI. A primary challenge has been replicating associations between inter-individual differences in brain structure or function and complex cognitive or mental health phenotypes (brain-wide association studies (BWAS)). Such BWAS have typically relied on sample sizes appropriate for classical brain mapping 4 (the median neuroimaging study sample size is about 25), but potentially too small for capturing reproducible brain–behavioural phenotype associations 5,6 . Here we used three of the largest neuroimaging datasets currently available—with a total sample size of around 50,000 individuals—to quantify BWAS effect sizes and reproducibility as a function of sample size. BWAS associations were smaller than previously thought, resulting in statistically underpowered studies, inflated effect sizes and replication failures at typical sample sizes. As sample sizes grew into the thousands, replication rates began to improve and effect size inflation decreased. More robust BWAS effects were detected for functional MRI (versus structural), cognitive tests (versus mental health questionnaires) and multivariate methods (versus univariate). Smaller than expected brain–phenotype associations and variability across population subsamples can explain widespread BWAS replication failures. In contrast to non-BWAS approaches with larger effects (for example, lesions, interventions and within-person), BWAS reproducibility requires samples with thousands of individuals.