Dataset Information

Learning a Comorbidity-Driven Taxonomy of Pediatric Pulmonary Hypertension.

ABSTRACT: 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 data sets. 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 United States, between January 2010 and May 2013. A total of 1583 (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 pathological basis defined by the World Health Organization and Panama classifications. The analysis further identified many 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 data sets 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.

SUBMITTER: Ong MS

PROVIDER: S-EPMC5559726 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Learning a Comorbidity-Driven Taxonomy of Pediatric Pulmonary Hypertension.

Ong Mei-Sing MS Mullen Mary P MP Austin Eric D ED Szolovits Peter P Natter Marc D MD Geva Alon A Cai Tianxi T Kong Sek Won SW Mandl Kenneth D KD

Circulation research 20170613 4

<h4>Rationale</h4>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.<h4>Objective</h4>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 ...[more]

PMID: 28611076

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Project description:Rationale: Pulmonary hypertension (PH) is a life-threatening cardiopulmonary disorder in which inflammation and immunity have emerged as critical early pathogenic elements. Although proinflammatory processes in PH and pulmonary arterial hypertension (PAH) are the focus of extensive investigation, the initiating mechanisms remain elusive.Objectives: We tested whether activation of the complement cascade is critical in regulating proinflammatory and pro-proliferative processes in the initiation of experimental hypoxic PH and can serve as a prognostic biomarker of outcome in human PAH.Methods: We used immunostaining of lung tissues from experimental PH models and patients with PAH, analyses of genetic murine models lacking specific complement components or circulating immunoglobulins, cultured human pulmonary adventitial fibroblasts, and network medicine analysis of a biomarker risk panel from plasma of patients with PAH.Measurements and Main Results: Pulmonary perivascular-specific activation of the complement cascade was identified as a consistent critical determinant of PH and PAH in experimental animal models and humans. In experimental hypoxic PH, proinflammatory and pro-proliferative responses were dependent on complement (alternative pathway and component 5), and immunoglobulins, particularly IgG, were critical for activation of the complement cascade. We identified Csf2/GM-CSF as a primary complement-dependent inflammatory mediator. Furthermore, using network medicine analysis of a biomarker risk panel from plasma of patients with PAH, we demonstrated that complement signaling can serve as a prognostic factor for clinical outcome in PAH.Conclusions: This study establishes immunoglobulin-driven dysregulated complement activation as a critical pathobiological mechanism regulating proinflammatory and pro-proliferative processes in the initiation of experimental hypoxic PH and demonstrates complement signaling as a critical determinant of clinical outcome in PAH.

Dataset Information

Learning a Comorbidity-Driven Taxonomy of Pediatric Pulmonary Hypertension.

Publications

Learning a Comorbidity-Driven Taxonomy of Pediatric Pulmonary Hypertension.

Similar Datasets

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