Brain–phenotype models fail for individuals who defy sample stereotypes

Individual differences in brain functional organization track a range of traits, symptoms and behaviours(1–12). So far, work modelling linear brain–phenotype relationships has assumed that a single such relationship generalizes across all individuals, but models do not work equally well in all participants(13,14). A better understanding of in whom models fail and why is crucial to revealing robust, useful and unbiased brain–phenotype relationships. To this end, here we related brain activity to phenotype using predictive models—trained and tested on independent data to ensure generalizability(15)—and examined model failure. We applied this data-driven approach to a range of neurocognitive measures in a new, clinically and demographically heterogeneous dataset, with the results replicated in two independent, publicly available datasets(16,17). Across all three datasets, we find that models reflect not unitary cognitive constructs, but rather neurocognitive scores intertwined with sociodemographic and clinical covariates; that is, models reflect stereotypical profiles, and fail when applied to individuals who defy them. Model failure is reliable, phenotype specific and generalizable across datasets. Together, these results highlight the pitfalls of a one-size-fits-all modelling approach and the effect of biased phenotypic measures(18–20) on the interpretation and utility of resulting brain–phenotype models. We present a framework to address these issues so that such models may reveal the neural circuits that underlie specific phenotypes and ultimately identify individualized neural targets for clinical intervention.