A protein risk score for all-cause and respiratory-specific mortality in non-Hispanic white and African American individuals who smoke

TL;DR

A blood-based protein risk score improves prediction of all-cause and respiratory mortality in smokers, especially in some groups.

Contribution

A novel protein risk score is developed to predict mortality in smokers, showing improved prediction over clinical factors.

Findings

A protein risk score was strongly associated with respiratory mortality (OR 9.2) and included 15 proteins.

Adding the protein risk score improved all-cause mortality prediction in COPDGene and SPIROMICS cohorts.

Network analyses linked the score to cytokine signaling, immune responses, and extracellular matrix processes.

Abstract

Protein biomarkers are associated with mortality in cardiovascular disease, but their effect on predicting respiratory and all-cause mortality is not clear. We tested whether a protein risk score (protRS) can improve prediction of all-cause mortality over clinical risk factors in smokers. We utilized smoking-enriched (COPDGene, LSC, SPIROMICS) and general population-based (MESA) cohorts with SomaScan proteomic and mortality data. We split COPDGene into training and testing sets (50:50) and developed a protRS based on respiratory mortality effect size and parsimony. We tested multivariable associations of the protRS with all-cause, respiratory, and cardiovascular mortality, and performed meta-analysis, area-under-the-curve (AUC), and network analyses. We included 2232 participants. In COPDGene, a penalized regression-based protRS was most highly associated with respiratory mortality (OR 9.2) and parsimonious (15 proteins). This protRS was associated with all-cause mortality (random effects HR 1.79 [95% CI 1.31–2.43]). Adding the protRS to clinical covariates improved all-cause mortality prediction in COPDGene (AUC 0.87 vs 0.82) and SPIROMICS (0.74 vs 0.6), but not in LSC and MESA. Protein–protein interaction network analyses implicate cytokine signaling, innate immune responses, and extracellular matrix turnover. A blood-based protein risk score predicts all-cause and respiratory mortality, identifies potential drivers of mortality, and demonstrates heterogeneity in effects amongst cohorts.

Figures