Rationale: Pediatric pulmonary hypertension (PH) is a heterogeneous condition with varying natural history and therapeutic response. Precise classification of PH subtypes is therefore crucial for individualizing care. However, gaps remain in our understanding of the spectrum of PH in children. Objective: We seek to study the manifestations of PH in children, and to assess the feasibility of applying a network-based approach to discern disease subtypes from comorbidity data recorded in longitudinal datasets. Methods and Results: A retrospective cohort study comprising 6,943,263 children (<18 years of age) enrolled in a commercial health insurance plan in the US, between January 2010 and May 2013. A total of 1,583 (0.02%) children met the criteria for PH. We identified comorbidities significantly associated with PH compared with the general population of children without PH. A Bayesian comorbidity network was constructed to model the interdependencies of these comorbidities, and network clustering analysis was applied to derive disease subtypes comprising subgraphs of highly connected comorbid conditions. A total of 186 comorbidities were found to be significantly associated with PH. Network analysis of comorbidity patterns captured most of the major PH subtypes with known etiological basis defined by the World Health Organization and Panama classifications. The analysis further identified a number of subtypes documented in only a few case studies, including rare subtypes associated with several well-described genetic syndromes. Conclusions: Application of network science to model comorbidity patterns recorded in longitudinal datasets can facilitate the discovery of disease subtypes. Our analysis relearned established subtypes, thus validating the approach, and identified rare subtypes that are difficult to discern through clinical observations, providing impetus for deeper investigation of the disease subtypes that will enrich current disease classifications.
Learning a Comorbidity-Driven Taxonomy of Pediatric Pulmonary Hypertension.