Mapping Lifetime Brain Volumetry with Covariate-Adjusted Restricted Cubic Spline Regression from Cross-sectional Multi-site MRI.

Understanding brain volumetry is essential to understand neurodevelopment and disease. Historically, age-related changes have been studied in detail for specific age ranges (e.g., early childhood, teen, young adults, elderly, etc.) or more sparsely sampled for wider considerations of lifetime aging. Recent advancements in data sharing and robust processing have made available considerable quantities of brain images from normal, healthy volunteers. However, existing analysis approaches have had difficulty addressing (1) complex volumetric developments on the large cohort across the life time (e.g., beyond cubic age trends), (2) accounting for confound effects, and (3) maintaining an analysis framework consistent with the general linear model (GLM) approach pervasive in neuroscience. To address these challenges, we propose to use covariate-adjusted restricted cubic spline (C-RCS) regression within a multi-site cross-sectional framework. This model allows for flexible consideration of non-linear age-associated patterns while accounting for traditional covariates and interaction effects. As a demonstration of this approach on lifetime brain aging, we derive normative volumetric trajectories and 95% confidence intervals from 5111 healthy patients from 64 sites while accounting for confounding sex, intracranial volume and field strength effects. The volumetric results are shown to be consistent with traditional studies that have explored more limited age ranges using single-site analyses. This work represents the first integration of C-RCS with neuroimaging and the derivation of structural covariance networks (SCNs) from a large study of multi-site, cross-sectional data.