Characterizing multivariate regional hubs for schizophrenia classification, sex differences, and brain age estimation using explainable AI.

Purpose: To investigate multivariate regional patterns for schizophrenia (SZ) classification, sex differences, and brain age by utilizing structural MRI, demographics, and explainable artificial intelligence (AI). Methods: Various AI models were employed, and the outperforming model was identified for SZ classification, sex differences, and brain age predictions. For the SZ and sex classification tasks, support vector classifier (SVC), k-nearest neighbor (KNN), and deep learning neural network (DL) models were compared. In the case of regression-based brain age prediction, Lasso regression (LR), Ridge regression (RR), support vector regression (SVR), and DL models were compared. For each regression or classification task, the optimal model was further integrated with the Shapley additive explanations (SHAP) and the significant multivariate brain regional patterns were identified. Results: Our results demonstrated that the DL model outperformed other models in SZ classification, sex differences, and brain age predictions. We then integrated outperforming DL model with SHAP, and this integrated DL-SHAP was used to identify the individualized multivariate regional patterns associated with each prediction. Using DL-SHAP approach, we found that individuals with SZ had anatomical changes particularly in left pallidum, left posterior insula, left hippocampus, and left putamen regions, and such changes associated with SZ were different between female and male patients. Finally, we further applied DL-SHAP method to brain age prediction and suggested important brain regions related to aging in health controls (HC) and SZ processes. Conclusion: This study systematically utilized predictive modeling and novel explainable AI approaches and identified the complex multivariate brain regions involved with SZ classification, sex differences, and brain aging and built a deeper understanding of neurobiological mechanisms involved in the disease, offering new insights to future SZ diagnosis and treatments and laying the foundation of the development of precision medicine.