Multivariate brain-based dimensions of child psychiatric problems: degrees of generalizability

Multivariate machine learning techniques are a promising set of tools for identifying complex brain-behavior associations. However, failure to replicate results from these methods across samples has hampered their clinical relevance. This study aimed to delineate dimensions of brain functional connectivity that are associated with child psychiatric symptoms in two large and independent cohorts: the Adolescent Brain Cognitive Development (ABCD) Study and the Generation R Study (total n =8,605). Using sparse canonical correlations analysis, we identified three brain-behavior dimensions in ABCD: attention problems, aggression and rule-breaking behaviors, and withdrawn behaviors. Importantly, out-of-sample generalizability of these dimensions was consistently observed in ABCD, suggesting robust multivariate brain-behavior associations. Despite this, out-of-study generalizability in Generation R was limited. These results highlight that the degree of generalizability can vary depending on the external validation methods employed as well as the datasets used, emphasizing that biomarkers will remain elusive until models generalize better in true external settings.