On the Search for Data-Driven and Reproducible Schizophrenia Subtypes Using Resting State fMRI Data From Multiple Sites

For decades, fMRI data have been used to search for biomarkers for patients with schizophrenia. Still, firm conclusions are yet to be made, which is often attributed to the high internal heterogeneity of the disorder. A promising way to disentangle the heterogeneity is to search for subgroups of patients with more homogeneous biological profiles. We applied an unsupervised multiple co-clustering (MCC) method to identify subtypes using functional connectivity data from a multisite resting-state data set. We merged data from two publicly available databases and split the data into a discovery data set (143 patients and 143 healthy controls (HC)) and an external test data set (63 patients and 63 HC) from independent sites. On the discovery data, we investigated the stability of the clustering toward data splits and initializations. Subsequently we searched for cluster solutions, also called "views," with a significant diagnosis association and evaluated these based on their subject and feature cluster separability, and correlation to clinical manifestations as measured with the positive and negative syndrome scale (PANSS). Finally, we validated our findings by testing the diagnosis association on the external test data. A major finding of our study was that the stability of the clustering was highly dependent on variations in the data set, and even across initializations, we found only a moderate subject clustering stability. Nevertheless, we still discovered one view with a significant diagnosis association. This view reproducibly showed an overrepresentation of schizophrenia patients in three subject clusters, and one feature cluster showed a continuous trend, ranging from positive to negative connectivity values, when sorted according to the proportions of patients with schizophrenia. When investigating all patients, none of the feature clusters in the view were associated with severity of positive, negative, and generalized symptoms, indicating that the cluster solutions reflect other disease related mechanisms.