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

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.