Aging Signals on Chest Radiographs: Association of Chest Radiograph-Derived Age Acceleration With Future Lung Cancer Incidence

Abstract Purpose To evaluate whether chest radiograph–derived age acceleration is associated with incident lung cancer and whether it improves discrimination beyond established lung cancer risk factors. Materials and Methods This retrospective analysis used prospectively collected data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Baseline digitized chest radiographs from the initial screening year were analyzed using a previously validated deep learning model that estimates chest radiograph–derived age (Xp-age). Age acceleration (AgeAccel) was defined as the residual of Xp-age after calibration to chronological age using a regression model from the development dataset. A 1-year landmark design excluded participants diagnosed with lung cancer or censored within 1 year of baseline. Associations with incident lung cancer were assessed using multivariable Cox proportional-hazards models adjusted for prespecified demographic and clinical predictors, including smoking variables used in the PLCOm2012 risk prediction model. Discrimination was evaluated using the concordance index and 6-year time-dependent area under the receiver-operating-characteristic curve. Results The analytic cohort included 23,213 participants (mean age, 62.5 years); 790 developed incident lung cancer after the landmark (mean follow-up, 16.7 years). Higher AgeAccel was associated with increased lung cancer incidence (hazard ratio, 1.10 per 1-SD increase; 95% confidence interval: 1.03–1.17); however, addition of AgeAccel to an established risk factor model resulted in minimal change in discrimination (C-index, 0.840 vs. 0.839; time-dependent AUC at 6 years, 0.852 vs. 0.852). Attribution maps emphasized the aortic arch/mediastinal region with similar spatial patterns across smoking and lung cancer strata. Conclusion Chest radiograph–derived age acceleration was independently associated with future lung cancer incidence. Summary Chest radiograph–derived age acceleration was associated with future lung cancer incidence in the PLCO cohort after adjustment for established demographic and smoking-related risk factors. Key points In 23,213 participants with baseline chest radiographs and a 1-year landmark design, higher chest radiograph–derived age acceleration was independently associated with incident lung cancer over a mean follow-up of 16.7 years (790 events); the adjusted hazard ratio was 1.10 per 1 standard deviation increase (95% confidence interval, 1.03–1.17; p = 0.003). The association between chest radiograph–derived age acceleration and incident lung cancer persisted after full adjustment for smoking status, cigarette consumption, duration, and years since cessation, suggesting that this imaging-based aging phenotype captures a dimension of lung cancer susceptibility beyond smoking exposure and may reflect interindividual variation in thoracic aging that conventional risk factors do not fully represent.