Reproducible Benchmarking for Lung Nodule Detection and Malignancy Classification Across Multiple Low-Dose CT Datasets

Evaluation of artificial intelligence (AI) models for low-dose CT lung cancer screening is limited by heterogeneous datasets, annotation standards, and evaluation protocols, making performance difficult to compare and translate across clinical settings. We establish a public, reproducible multi-dataset benchmark for lung nodule detection and nodule-level cancer classification and quantify cross-dataset generalizability. Using the Duke Lung Cancer Screening (DLCS) dataset as a clinically curated development set, we evaluate performance across LUNA16/LIDC-IDRI, NLST-3D, and LUNA25. Detection models trained on DLCS and LUNA16 were evaluated externally on NLST-3D using free-response ROC analysis. For malignancy classification, we compared five strategies: randomly initialized ResNet50, Models Genesis, Med3D, a Foundation Model for Cancer Biomarkers, and a Strategic Warm-Start (ResNet50-SWS) approach pretrained using detection-derived candidate patches stratified by confidence. Performance was summarized using AUC with 95% confidence intervals and DeLong tests. Detection performance varied substantially by training dataset, with DLCS-trained models outperforming LUNA16-trained models on external NLST-3D evaluation (sensitivity at 2 false positives per scan: 0.72 vs. 0.64; p < 0.001). For malignancy classification, ResNet50-SWS achieved AUCs of 0.71 (DLCS), 0.90 (LUNA16), 0.81 (NLST-3D), and 0.80 (LUNA25), consistently matching or exceeding alternative pretraining strategies. These results demonstrate that dataset characteristics strongly influence lung cancer AI performance and highlight the need for transparent, multi-dataset benchmarking.