Unbiased Phenome-Wide Association Studies of Red Cell Distribution Width Identifies Key Associations with Pulmonary Hypertension

Abstract

Rationale: Red cell distribution width (RDW) is a prognostic factor in many diseases; however, its clinical utility remains limited because the relative value of RDW as a biomarker across disease states has not been established.Objectives: To establish an unbiased RDW disease hierarchy to guide the clinical use of RDW and to assess its relationship to cardiovascular hemodynamic and structural parameters.Methods: We performed phenome-wide association studies for RDW in discovery and replication cohorts derived from a deidentified electronic health record in nonanemic individuals. RDW values obtained within 30 days of echocardiogram or right heart catheterization were tested for association with structural and hemodynamic variables.Results: RDW was associated with 263 phenotypes in both men and women in the discovery cohort (n = 121,530), 48 of which replicated in an independent cohort (n = 2,039). The strongest associations were observed with pulmonary arterial hypertension (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.9-2.3), chronic pulmonary heart disease (OR, 2.0; 95% CI, 1.9-2.2), and congestive heart failure (OR, 1.9; 95% CI, 1.8-2.0); P , 1 3 10 274 for all. By echocardiography, RDW was higher in the setting of right ventricular dysfunction than left ventricular dysfunction (P , 0.001). Measured invasively, mean pulmonary arterial pressure was associated with RDW (21 vs. 33 mm Hg at 25th vs. 75th percentile RDW; P , 1 3 10 27 ) and remained strongly significant even when controlling for mean pulmonary capillary wedge pressure (21 vs. 29 mm Hg at 25th vs. 75th percentile RDW; P , 1 3 10 27 ).Conclusions: Among 1,364 coded medical conditions, increased RDW was strongly associated with pulmonary hypertension and heart failure. Hemodynamic and echocardiographic phenotyping confirmed these associations and underscored that the most clinically relevant phenotype associated with RDW was pulmonary hypertension. These hypothesis-generating findings highlight the potential shared pathophysiology of pulmonary hypertension and elevated RDW. Elevated RDW in the absence of anemia should alert clinicians to the potential for underlying cardiopulmonary disease.

Mendelian randomisation analysis of red cell distribution width in pulmonary arterial hypertension

“…https://doi.org/10.1183/13993003.01486-2019 associated with RDW with a similar effect size (OR 2.0, 95% CI 1.75-2.4 per % increase in RDW) [7]. Our MR analysis was adequately powered to detect a causal role for RDW with an effect of this magnitude.…”

“…We and others have demonstrated that one factor strongly correlated with survival in PAH is red cell distribution width (RDW) [5,6]. A recent hypothesis-free phenome-wide analysis indicated PAH, among several disease descriptors, as the most strongly associated with RDW (OR 2.0, 95% CI 1.75-2.4 per % increase in RDW) in a hospital population [7]. RDW (a measure of red blood cell (RBC) size variability in an individual) is part of the full blood count in standard hospital practice and readily available as a biomarker.…”

Biventricular diastolic dysfunction, thrombocytopenia, and red blood cell macrocytosis in experimental pulmonary arterial hypertension

“…Thayer et al recently found that RDW portends poor outcomes for non-anemic PAH patients. 9 The value of RDW as a biomarker for multiple cardiovascular diseases has long been suggested, 44,45 but the pathophysiology involved has not been fully elucidated. Interestingly, our PAH rat model developed a non-anemic macrocytic red blood cell phenotype, with increased immature red blood cell production resulting in an increase in RDW.…”

A Clinical Phenotyping Algorithm to Identify Cases of Chronic Obstructive Pulmonary Disease in Electronic Health Records

“…Phecodes are aggregated ICD-9 codes that condense similar disease entities into one code, reducing the number of phenotypes from over 14,000 separate ICD-9 codes to 1,645 phecode groups, and have been utilized in multiple EHR and genetic studies. (38)(39)(40)(41)(42)(43)(44) We also conducted genetic analyses using COPD-associated…”

“…We also compared the frequency of phecodes across the two groups. (38)(39)(40)(41)(42)(43)(44) In COPD cases, the most frequent phecodes were chronic airway obstruction (100%), hypertension (77.1%), other symptoms of respiratory system (75.4%), essential hypertension (75.4%), and tobacco use disorder (63.0%).…”