Neuroimaging-based variability in subtyping biomarkers for psychiatric heterogeneity

Neuroimaging-based subtyping is increasingly used to explain heterogeneity in psychiatric disorders. However, the clinical utility of these subtyping efforts remains unclear, and replication has been challenging. Here we examined how the choice of neuroimaging measures influences the derivation of neuro-subtypes and the consequences for clinical delineation. On a clinically heterogeneous dataset (total n = 566) that included controls (n = 268) and cases (n = 298) of psychiatric conditions, including individuals diagnosed with post-traumatic stress disorder (PTSD), traumatic brain injury (TBI), and comorbidity of both (PTSD&TBI), we identified neuro-subtypes among the cases using either structural, resting-state, or task-based measures. The neuro-subtypes for each modality had high internal validity but did not significantly differ in their clinical and cognitive profiles. We further show that the choice of neuroimaging measures for subtyping substantially impacts the identification of neuro-subtypes, leading to low concordance across subtyping solutions. Similar variability in neuro-subtyping was found in an independent dataset (n = 1642) comprised of major depression disorder (MDD, n = 848) and controls (n = 794). Our results suggest that the highly anticipated relationships between neuro-subtypes and clinical features may be difficult to discover.