Performance of age-adjusted whole genome sequencing telomere length in idiopathic pulmonary fibrosis

Abstract Rationale Whole genome sequencing–estimated telomere length (WGS-TL) correlates with directly measured peripheral blood telomere length. However, raw WGS-TL does not account for normal age-related telomere attrition to identify patients with idiopathic pulmonary fibrosis (IPF) with pathologically short telomeres. Objectives To determine utility of age-adjusted WGS-TL to identify adults with telomere-related qualifying variants (TRQVs) and whether it associates with survival. Methods WGS-TL from two samples of community-dwelling adults (MESA) and people who smoke cigarettes (COPDGene) were used to construct an age-adjusted WGS-TL nomogram (n = 9940) using linear regression models that regressed on raw WGS-TL and adjusted for chronologic age. Using this nomogram, age-adjusted WGS-TL was generated in IPF cases from the Pulmonary Fibrosis Foundation Patient Registry (PFF-PR) (n = 825) to determine diagnostic performance characteristics for identifying TRQV and survival discrimination. Measurements and Main Results There was a higher proportion of IPF patients from the PFF-PR with abnormally short age-adjusted WGS-TL Conclusions Age-adjusted WGS-TL enables identification of IPF patients with pathologically short telomeres, modestly improves detection of TRQV, and associates with survival.