The NIH/NHLBI launched an initiative, “Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics (PVDOMICS)” that aims to augment the current PH classification based on shared biological features. PVDOMICS will enroll 1,500 participants with PH and disease and healthy comparators. Enrollees will undergo deep clinical phenotyping and blood will be acquired for comprehensive “omic” analyses that will focus on discovery of molecular-based subtypes of PVD through application of high dimensional model-based clustering methods. In addition to an updated, molecular classification of PVD, the phenomic data generated will be a rich resource to the broad community of heart and lung disease investigators.

The Division of Lung Diseases of the NHLBI and the Cardiovascular Medical Education and Research Fund held a workshop to discuss how to leverage the anticipated scientific output from the recently launched “Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics” (PVDOMICS) program to develop newer approaches to pulmonary vascular disease. PVDOMICS is a collaborative, protocol-driven network to analyze all patient populations with pulmonary hypertension to define novel pulmonary vascular disease (PVD) phenotypes. Stakeholders, including basic, translational, and clinical investigators; clinicians; patient advocacy organizations; regulatory agencies; and pharmaceutical industry experts, joined to discuss the application of precision medicine to PVD clinical trials. Recommendations were generated for discussion of research priorities in line with NHLBI Strategic Vision Goals that include: (1) A national effort, involving all the stakeholders, should seek to coordinate biosamples and biodata from all funded programs to a web-based repository so that information can be shared and correlated with other research projects. Example programs sponsored by NHLBI include PVDOMICS, Pulmonary Hypertension Breakthrough Initiative, the National Biological Sample and Data Repository for PAH, and the National Precision Medicine Initiative. (2) A task force to develop a master clinical trials protocol for PVD to apply precision medicine principles to future clinical trials. Specific features include: (a) adoption of smaller clinical trials that incorporate biomarker-guided enrichment strategies, using adaptive and innovative statistical designs; and (b) development of newer endpoints that reflect well-defined and clinically meaningful changes. (3) Development of updated and systematic variables in imaging, hemodynamic, cellular, genomic, and metabolic tests that will help precisely identify individual and shared features of PVD and serve as the basis of novel phenotypes for therapeutic interventions.

Background: Health disparities have a major impact in the quality of life and clinical care received by minorities in the United States. Pulmonary arterial hypertension (PAH) is a rare cardiopulmonary disorder that affects children and adults and that, if untreated, results in premature death. The impact of health disparities in the diagnosis, treatment, and clinical outcome of patients with PAH has not been systematically investigated. Objectives: The specific goals of this research statement were to conduct a critical review of the literature concerning health disparities in PAH, identify major research gaps and prioritize direction for future research. Methods: Literature searches from multiple reference databases were performed using medical subject headings and text words for pulmonary hypertension and health disparities. Members of the committee discussed the evidence and provided recommendations for future research. Results: Few studies were found discussing the impact of health disparities in PAH. Using recent research statements focused on health disparities, the group identified six major study topics that would help address the contribution of health disparities to PAH. Representative studies in each topic were discussed and specific recommendations were made by the group concerning the most urgent questions to address in future research studies. Conclusions: At present, there are few studies that address health disparities in PAH. Given the potential adverse impact of health disparities, we recommend that research efforts be undertaken to address the topics discussed in the document. Awareness of health disparities will likely improve advocacy efforts, public health policy and the quality of care of vulnerable populations with PAH.

Introduction: While the performance of the emPHasis-10 (e10) score has been evaluated against limited patient characteristics within the United Kingdom, there is an unmet need for exploring the performance of the e10 score among pulmonary arterial hypertension (PAH) patients in the United States.Methods: Using the Pulmonary Hypertension Association Registry, we evaluated relationships between the e10 score and demographic, functional, haemodynamic and additional clinical characteristics at baseline and over time. Furthermore, we derived a minimally important difference (MID) estimate for the e10 score.Results: We analysed data from 565 PAH (75% female) adults aged mean±sd55.6±16.0 years. At baseline, the e10 score had notable correlation with factors expected to impact quality of life in the general population, including age, education level, income, smoking status and body mass index. Clinically important parameters including 6-min walk distance and B-type natriuretic peptide (BNP)/N-terminal proBNP were also significantly associated with e10 score at baseline and over time. We generated a MID estimate for the e10 score of −6.0 points (range −5.0–−7.6 points).Conclusions: The e10 score was associated with demographic and clinical patient characteristics, suggesting that health-related quality of life in PAH is influenced by both social factors and indicators of disease severity. Future studies are needed to demonstrate the impact of the e10 score on clinical decision-making and its potential utility for assessing clinically important interventions.

Understanding the genetic basis of gene expression can shed light on the regulatory mechanisms underlying complex traits and diseases. Single cell-resolved measures of RNA levels and single-cell expression quantitative trait loci (sc-eQTLs) have revealed genetic regulation that drives sub-tissue cell states and types across diverse human tissues. Here, we describe the first phase of TenK10K, the largest-to-date dataset of matched whole-genome sequencing (WGS) and single-cell RNA-sequencing (scRNA-seq). We leverage scRNA-seq data from over 5 million cells across 28 immune cell types, and matched WGS, from 1,925 individuals, which provides power to detect associations between rare and low-frequency genetic variants that have largely been uncharacterised in their impact on cell-specific gene expression. We map the effects of both common and rare variants in a cell type-specific manner using a recently introduced method that increases power by modelling single cells directly rather than relying on aggregated ‘pseudobulk’ counts. We identify putative common regulatory variants for 83% of all 21,404 genes tested and cumulative rare variant signals for 47% of genes. We explore how genetic effects vary across cell type and state spectra, develop a framework to determine the degree to which sc-eQTLs are cell type-specific, and show that about half of the effects are observed only in one or a few cell types. By integrating our results with functional annotations and disease information, we also further characterise the likely molecular modes of action for many disease-variant associations. Finally, we explore the effects that genetic variants have on gene expression across continuous cell states and functions, and effects that vary cell state abundance directly.