Understanding Heterogeneity in Clinical Cohorts Using Normative Models: Beyond Case-Control Studies

Despite many successes, the case-control approach is problematic in biomedical science. It introduces an artificial symmetry whereby all clinical groups (e.g., patients and control subjects) are assumed to be well defined, when biologically they are often highly heterogeneous. By definition, it also precludes inference over the validity of the diagnostic labels. In response, the National Institute of Mental Health Research Domain Criteria proposes to map relationships between symptom dimensions and broad behavioral and biological domains, cutting across diagnostic categories. However, to date, Research Domain Criteria have prompted few methods to meaningfully stratify clinical cohorts.

We introduce normative modeling for parsing heterogeneity in clinical cohorts, while allowing predictions at an individual subject level. This approach aims to map variation within the cohort and is distinct from, and complementary to, existing approaches that address heterogeneity by employing clustering techniques to fractionate cohorts. To demonstrate this approach, we mapped the relationship between trait impulsivity and reward-related brain activity in a large healthy cohort (N = 491).