LAUSR

Abstract Background Previous machine learning studies using structural MRI (sMRI) have been able to separate schizophrenia from controls with relatively high (about 80%) sensitivity and specificity (Kambeitz et al. Neuropsychopharmacology 2015). Interestingly, prediction accuracy in first-episode psychosis is lower compared to older and probably more chronic patients. One possibility is that the appearance of the neurodiagnostic fingerprints (NF) originated from the schizophrenia vs. controls classifier become more visible over time in schizophrenia due to the progressive nature of the disorder. Methods Using the Cobre sample (70 schizophrenia and 74 controls), we trained support vector machine (SVM) to differentiate schizophrenia from controls using sMRI. Next, we utilized the Northern Finland Birth Cohort 1966 (NFBC 1966) sample of 29 schizophrenia and 61 non-psychotic controls who participated in the nine-year follow-up. We applied the Cobre-trained SVM models at the baseline (participants 34 years old) and the follow-up (participants 43 years old) using out of sample cross-validation without any in-between retraining. Two independent schizophrenia datasets (the Neuromorphometry by Computer Algorithm Chicago [NMorphCH] and the Consortium for Neuropsychiatric Phenomics [CNP]) were utilized for replication analyses of the SVM generalizability. To address the possibility that the NF mainly capture some general psychopathology, we tested whether the NF generalize to depression using two independent MDD samples from Munich and Münster, Germany. Results Using the Cobre-trained SVM models for schizophrenia vs. controls differentiation in the NFBC 1966, we found balanced accuracy (i.e. mean of sensitivity and specificity, [BAC]) of 72.8% (sensitivity=58.6%, specificity=86.9%) at the baseline and BAC of 79.7% (sensitivity=75.9%, specificity=83.6%) at the follow-up. In the NFBC 1966 schizophrenia patients, we found that SVM decision scores varied as a function of timepoint into the direction of more schizophrenia-likeness at the follow-up (paired T-test, Cohen’s d=0.58, P=0.004). The same was not true in controls (Cohen’s d=0.09, P=0.49). The SVM decision score difference*timepoint interaction related to the decrease of hippocampus and medial prefrontal cortex. The SVM models’ performance was also validated at the two replication samples (BAC of 77.5% in the CNP and BAC of 69.1% in the NMorphCH). In the NFBC 1966 the strongest clinical variable correlating with the trajectory of SVM decision scores over the follow-up was poor performance in the California Verbal Learning Test. This finding was also replicated in the CNP dataset. Further, in the NFBC 1966, those schizophrenia patients with a low degree of SVM decision scores had a higher probability of being in remission, being able to work, and being without antipsychotic medication at the follow-up. The generalization of the SVM models to MDD was worse compared to schizophrenia classification (DeLong’s tests for the two ROC curves: P<0.001). Discussion The degree of schizophrenia-related neurodiagnostic fingerprints appear to magnify over time in schizophrenia. By contrast, the discernibility of these fingerprints in controls does not change over time. This indicates that the NF captures some schizophrenia-related progressive neural changes, and not, e.g., normal aging-related brain volume loss. The fingerprints were also generalizable to other schizophrenia samples. Further, the fingerprints seem to have some disorder specificity as the SVM models do not generalize to depression. Lastly, it appears that a low degree of schizophrenia-related NF in schizophrenia might possess some value in predicting patients’ future remission and recovery-related factors.