Making the Most of Errors: Utilizing Erroneous Classifications Generated by Machine-Learning Models of Neuroimaging Data to Capture Disorder Heterogeneity

Within-disorder heterogeneity complicates mapping the neurobiological features of psychopathology to Diagnostic and Statistical Manual of Mental Disorders conceptualizations. The present study explored the patterns of diagnostic classification errors among disorders with commonly co-occurring features to examine this heterogeneity. Classification analyses were conducted with the University of California, Los Angeles Phenomics Study database using a support-vector classifier to differentiate disorders via whole brain taskbased functional connectivity, predicting that model misclassifications would provide insight about brain connectivity characteristics shared across disorders. Whether symptoms and specific brain networks could account for misclassification rates was also explored. The classification model performed better than chance (44% accuracy, p=.01) and revealed that misclassification of schizophrenia (SCZ) as bipolar disorder (BD; 38%) and BD as SCZ (36%)was symmetrical. Attention-deficit/hyperactivity disorder (ADHD) was misclassified as BD at the highest rate (46%) and higher than the converse (17%). SCZ and ADHD were misclassified least (15% SCZ as ADHD and 22% ADHD as SCZ). Considerable variance in misclassification of SCZ as BD (R²=.83) and BD as SCZ (R²=.71) could be accounted for by symptoms of both SCZ and BD. Permutation testing revealed disorder- and network-specific effects, with certain networks improving classification accuracy and others hindering it for specific disorders. An approach focused on classification errors replicated known disorder overlap, producing errors in the expected configuration. Further, it identified clinical and neural features within and across diagnostic categories that contribute to disorder misclassification and within-disorder heterogeneity. This approach may facilitate neurobiologically informed phenotypic differentiation within diagnostic groups.