학술논문
Novel Liver Injury Phenotypes and Outcomes in Clinical Trial Participants with Pulmonary Hypertension.
Document Type
Academic Journal
Author
Scott JV; Penn Medicine, Philadelphia, Pennsylvania, United States; jackies2009@gmail.com.; Moutchia J; University of Pennsylvania Perelman School of Medicine, Medicine , Philadelphia, Pennsylvania, United States.; McClelland RL; University of Washington School of Public Health, Biostatistics, Seattle, Washington, United States.; Al-Naamani N; University of Pennsylvania, Philadelphia, Pennsylvania, United States.; Weinberg E; Penn Medicine, Philadelphia, Pennsylvania, United States.; Palevsky HI; University of Pennsylvania, Pulmonary, Allergy, Critical Care, Philadelphia, Pennsylvania, United States.; Minhas J; University of Pennsylvania, Pulmonary, Allergy and Critical Care, Philadelphia, Pennsylvania, United States.; Appleby DK; University of Pennsylvania, Department of Biostatistics, Epidemiology, & Informatics, Philadelphia, Pennsylvania, United States.; Smith A; University of Pennsylvania, Philadelphia, Pennsylvania, United States.; Pugliese SC; University of Pennsylvania, Pulmonary, Allergy, Critical Care, Philadelphia, Pennsylvania, United States.; Ventetuolo CE; Brown University, Medicine , Providence, Rhode Island, United States.; Kawut SM; University of Pennsylvania Perelman School of Medicine, Medicine , Philadelphia, Pennsylvania, United States.
Source
Publisher: American Thoracic Society Country of Publication: United States NLM ID: 9421642 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1535-4970 (Electronic) Linking ISSN: 1073449X NLM ISO Abbreviation: Am J Respir Crit Care Med Subsets: MEDLINE
Subject
Language
English
Abstract
Rationale: Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) cause right ventricular dysfunction which can impact other solid organs. However, the profiles and consequences of hepatic injury due to PAH and CTEPH have not been well-studied.
Objectives: We aimed to identify underlying patterns of liver injury in a cohort of PAH and CTEPH patients enrolled in 15 randomized clinical trials conducted between 1998 and 2014.
Methods: We used unsupervised machine learning to identify liver injury clusters in 13 trials and validated the findings in two additional trials. We then determined whether these liver injury clusters were associated with clinical outcomes or treatment effect heterogeneity.
Measurements and Main Results: Our training dataset included 4,219 patients and our validation dataset included 1,756 patients with serum total bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and albumin data. Using k-means clustering, we identified phenotypes with no liver injury, hepatocellular injury, cholestatic injury, and combined injury patterns. Patients in the cholestatic injury liver cluster had the shortest time to clinical worsening and the highest risk of mortality. The cholestatic injury group also experienced the greatest placebo-corrected treatment effect on six-minute walk distance. Randomization to the experimental arm transitioned patients to a healthier liver status.
Conclusions: Liver injury was associated with adverse outcomes in patients with PAH and CTEPH. Randomization to active treatment had beneficial effects on liver health compared to placebo. The role of liver disease (often subclinical) in determining outcomes warrants prospective studies.
Objectives: We aimed to identify underlying patterns of liver injury in a cohort of PAH and CTEPH patients enrolled in 15 randomized clinical trials conducted between 1998 and 2014.
Methods: We used unsupervised machine learning to identify liver injury clusters in 13 trials and validated the findings in two additional trials. We then determined whether these liver injury clusters were associated with clinical outcomes or treatment effect heterogeneity.
Measurements and Main Results: Our training dataset included 4,219 patients and our validation dataset included 1,756 patients with serum total bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and albumin data. Using k-means clustering, we identified phenotypes with no liver injury, hepatocellular injury, cholestatic injury, and combined injury patterns. Patients in the cholestatic injury liver cluster had the shortest time to clinical worsening and the highest risk of mortality. The cholestatic injury group also experienced the greatest placebo-corrected treatment effect on six-minute walk distance. Randomization to the experimental arm transitioned patients to a healthier liver status.
Conclusions: Liver injury was associated with adverse outcomes in patients with PAH and CTEPH. Randomization to active treatment had beneficial effects on liver health compared to placebo. The role of liver disease (often subclinical) in determining outcomes warrants prospective studies.