Diagnosing schizophrenia using deep learning: Novel interpretation approaches and multi-site validation

Schizophrenia is a profound and enduring mental disorder that imposes significant negative impacts on individuals, their families, and society at large. The development of more accurate and objective diagnostic tools for schizophrenia can be expedited through the employment of deep learning (DL), that excels at deciphering complex hierarchical non-linear patterns. However, the limited interpretability of deep learning has eroded confidence in the model and restricted its clinical utility. At the same time, if the data source is only derived from a single center, the model's generalizability is difficult to test. To enhance the model's reliability and applicability, leave-one-center-out validation with a large and diverse sample from multiple centers is crucial. In this study, we utilized Nine different global centers to train and test the 3D Resnet model's generalizability, resulting in an 82% classification performance (area under the curve) on all datasets sourced from different countries, employing a leave-one-center-out-validation approach. Per our approximation of the feature significance of each region on the atlas, we identified marked differences in the thalamus, pallidum, and inferior frontal gyrus between individuals with schizophrenia and healthy controls, lending credence to prior research findings. At the same time, in order to translate the model's output into clinically applicable insights, the SHapley Additive exPlanations (SHAP) permutation explainer method with an anatomical atlas have been refined, thereby offering precise neuroanatomical and functional interpretations of different brain regions.