Proteomic biomarkers of progressive fibrosing interstitial lung disease: a multicentre cohort analysis

Fund

Progressive fibrosing interstitial lung disease (PPI) is characterized by the formation of parenchymal scars, resulting in high morbidity and mortality. The ability to predict this phenotype remains elusive. We performed proteomic analysis to identify novel plasma biomarkers of progressive fibrosing ILD and developed a proteomic signature to predict this phenotype.

Methods

Relative plasma concentrations of 368 biomarkers were determined using a semi-quantitative targeted proteomic platform in patients with PID associated with connective tissue disease, chronic hypersensitivity pneumonitis, or unclassifiable PID that provided research blood samples to the University of California (discovery cohort) and the University of Texas (validation cohort). Univariate logistic regression was used to identify individual biomarkers associated with 1-year progression of IRS, defined as death, lung transplantation, or a 10% or greater decrease in relative forced vital capacity (FVC). A proteomic signature of progressive fibrotic ILD was then derived using machine learning in the University of California cohort and validated in the University of Texas cohort.

Results

The discovery cohort included 385 patients (mean age 63.6 years, 59% female) and the validation cohort included 204 patients (mean age 60.7 years, 61% female). 31 biomarkers were associated with progressive fibrotic PID in the discovery cohort, 17 retaining an association in the validation cohort. Validated biomarkers showed a consistent association with progressive fibrosing PID, regardless of the clinical diagnosis of PID. A proteomic signature comprising 12 biomarkers was derived by machine learning and validated in the University of Texas cohort, in which it had a sensitivity of 0.90 and a corresponding negative predictive value of 0.91, suggesting that approximately 10 % of patients with low-risk proteomic signature would experience IRS progression within one year of blood draw. Those with a low-risk proteomic signature experienced a change in FVC of +85 7 mL (95% CI 6 9 to 164 4) and those with a high-risk signature experienced a change in FVC of −227 1 mL (−286 7 to −167 5). A theoretical clinical trial limited to patients with a high-risk proteomic signature would require 80% fewer patients than a trial designed without considering the proteomic signature.

Interpretation

17 plasma biomarkers of progressive fibrosing ILD have been identified and have shown consistent associations between ILD subtypes. A proteomic signature of progressive fibrotic PID could enrich clinical trial cohorts and obviate the need for antecedent progression when defining progressive fibrotic PID for clinical trial enrollment.

Funding

National Heart, Lung and Blood Institute.


Source link

Comments are closed.