Abstract
Neuroimaging-based brain age is a biomarker that is generated by machine learning (ML) predictions. The brain age gap (BAG) is typically defined as the difference between the predicted brain age and chronological age. Studies have consistently reported a positive BAG in individuals with schizophrenia (SCZ). However, there is little understanding of which specific factors drive the ML-based brain age predictions, leading to limited biological interpretations of the BAG. We gathered data from three publicly available databases - COBRE, MCIC, and UCLA - and an additional dataset (TOPSY) of early-stage schizophrenia (82.5% untreated first-episode sample) and calculated brain age with pre-trained gradient-boosted trees. Then, we applied SHapley Additive Explanations (SHAP) to identify which brain features influence brain age predictions. We investigated the interaction between the SHAP score for each feature and group as a function of the BAG. These analyses identified total gray matter volume (group × SHAP interaction term β = 1.71 [0.53; 3.23]; p(corr) < 0.03) as the feature that influences the BAG observed in SCZ among the brain features that are most predictive of brain age. Other brain features also presented differences in SHAP values between SCZ and HC, but they were not significantly associated with the BAG. We compared the findings with a non-psychotic depression dataset (CAN-BIND), where the interaction was not significant. This study has important implications for the understanding of brain age prediction models and the BAG in SCZ and, potentially, in other psychiatric disorders.