Equivalency of Multiple Biomarkers to Clinical Pulmonary Arterial Hypertension Survival Risk Models

Risk assessment in pulmonary arterial hypertension (PAH) is fundamental to guiding treatment and improved outcomes. Clinical models are excellent at identifying high-risk patients, but leave uncertainty amongst moderate-risk patients.

Can a multiple blood biomarker model of PAH, using previously described biomarkers, improve risk discrimination over current models?

Using a multiplex enzyme-linked immunosorbent assay, we measured N-terminal pro-B-type natriuretic peptide (NT-proBNP), soluble suppressor of tumorigenicity, IL-6, endostatin, galectin 3, hepatoma derived growth factor, and insulin-like growth factor binding proteins (IGFBP1-7) in training (n = 1,623), test (n = 696), and validation (n = 237) cohorts. Clinical variables and biomarkers were evaluated by principal component analysis. NT-proBNP was not included to develop a model independent of NT-proBNP. Unsupervised k-means clustering classified participants into clusters. Transplant-free survival by cluster was examined using Kaplan-Meier and Cox proportional hazard regressions. Hazard by cluster was compared with NT-proBNP, Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL), and European Society of Cardiology and European Respiratory Society risk models alone and combined clinical and biomarker models.

The algorithm generated five clusters with good risk discrimination using six biomarkers, weight, height, and age at PAH diagnosis. In the test and validation cohorts, the biomarker model alone performed equivalent to REVEAL (area under the receiver operating characteristic curve, 0.74). Adding the biomarker model to the European Society of Cardiology and European Respiratory Society score and REVEAL score improved the European Society of Cardiology and European Respiratory Society score and REVEAL score. The best overall model was the biomarker model adjusted for NT-proBNP with the best C statistic, Akaike information criterion, and calibration for the adjusted model compared with either the biomarker or NT-proBNP model alone.

In this study, a multibiomarker model alone was equivalent to current PAH clinical mortality risk prediction models and improved performance when combined and added to NT-proBNP. Clinical risk scores offer excellent predictive models, but require multiple tests; adding blood biomarkers to models can improve prediction or can enable more frequent, noninvasive monitoring of risk in PAH to support therapeutic decision-making.