Hierarchical Phenotyping of Psychopathology: Implications and Opportunities for Precision Psychiatry when Biology Could be Associated with both Symptoms and Syndromes

As psychiatry increasingly embraces precision medicine principles, there has been increasing efforts to characterize the specificity of biology–psychopathology associations (e.g., is biology associated with syndromes or symptoms?). Unfortunately, the vast majority of research selects to test syndromes (e.g., case-control, symptom total/average scores) or individual symptoms a priori based on untested assumptions. Alternatively, most studies that attempt to empirically compare these options test biology as a predictor of a) syndromes and b) symptoms in separate models that are unable to directly falsify the specificity of observed associations because these options are not directly competing for the same variance. In this review, we will (i) discuss the historical tension between symptom- and syndrome-focused psychiatry; (ii) introduce hierarchical phenotyping as an approach to determining the specificity of biology–psychopathology associations; (iii) highlight how hierarchical phenotyping approaches are complementary to leading nosological movements in psychopathology research; (iv) illustrate how a hierarchical phenotyping lens can generate promising future directions for precision psychiatry using immunopsychiatric, genetic, and neurophysiological examples (1); (v) highlight clinical implications of hierarchical phenotyping approaches to psychiatry; (vi) discuss methodological implications of hierarchical phenotyping for best practices in measuring and modeling psychopathology; and (vii) introduce methodological resources for readers interested in investigating hierarchical phenotyping in their own work. In doing so, this review seeks to build the case for hierarchical phenotyping approaches while simultaneously preparing motivated readers to use these methods in their own work to advance precision psychopathology research.