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

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 <10th percentile (28%) compared with MESA (5%) or COPDGene (10%). Among IPF patients, age-adjusted WGS-TL <10th percentile outperformed raw WGS-TL <10th percentile at discriminating TRQV (area under the receiver operating curve = 0.66 [95% CI, 0.60-0.73] vs 0.62 [95% CI, 0.56-0.69]). At both the shorter age-adjusted and raw WGS-TL thresholds, specificity (0.74-0.99) was higher than sensitivity (0.10-0.58). Age-adjusted WGS-TL below the 10th percentile was associated with shorter 3-year transplant-free survival (HR, 1.35 [95% CI, 1.05-1.74]) but did not improve survival discrimination over clinical variables alone. CONCLUSIONS: Age-adjusted WGS-TL enables identification of IPF patients with pathologically short telomeres, modestly improves detection of TRQV, and associates with survival.