Abstract
Background: Non-smokers and individuals with minimal smoking history represent a significant proportion of lung cancer cases but are often overlooked in current risk assessment models. Pulmonary nodules are commonly detected incidentally-appearing in approximately 24-31% of all chest CT scans regardless of smoking status. However, most established risk models, such as the Brock model, were developed using cohorts heavily enriched with individuals who have substantial smoking histories. This limits their generalizability to non-smoking and light-smoking populations, highlighting the need for more inclusive and tailored risk prediction strategies. Purpose: We aimed to develop a longitudinal radiomics-based approach for lung cancer risk prediction, integrating time-varying radiomic modeling to enhance early detection in USPSTF-ineligible patients. Methods: Unlike conventional models that rely on a single scan, we conducted a longitudinal analysis of 122 patients who were later diagnosed with lung cancer, with a total of 622 CT scans analyzed. Of these patients, 69% were former smokers, while 30% had never smoked. Quantitative radiomic features were extracted from serial chest CT scans to capture temporal changes in nodule evolution. A time-varying survival model was implemented to dynamically assess lung cancer risk. Additionally, we evaluated the integration of handcrafted radiomic features and the deep learning-based Sybil model to determine the added value of combining local nodule characteristics with global lung assessments. Results: Our radiomic analysis identified specific CT patterns associated with malignant transformation, including increased nodule size, voxel intensity, textural entropy, as indicators of tumor heterogeneity and progression. Integrating radiomics, delta-radiomics, and longitudinal imaging features resulted in the optimal predictive performance during cross-validation (concordance index [C-index]: 0.69), surpassing that of models using demographics alone (C-index: 0.50) and Sybil alone (C-index: 0.54). Compared to the Brock model (67% accuracy, 100% sensitivity, 33% specificity), our composite risk model achieved 78% accuracy, 89% sensitivity, and 67% specificity, demonstrating improved early cancer risk stratification. Kaplan-Meier curves and individualized cancer development probability functions further validated the model's ability to track dynamic risk progression for individual patients. Visual analysis of longitudinal CT scans confirmed alignment between predicted risk and evolving nodule characteristics. Conclusions: Our study demonstrates that integrating radiomics, sybil, and clinical factors enhances future lung cancer risk prediction in USPSTF-ineligible patients, outperforming existing models and supporting personalized screening and early intervention strategies.