Simulation-Driven Annotation-Free Deep Learning for Automated Detection and Segmentation of Airway Mucus Plugs on Non-Contrast CT Images

Mucus plugs are airway-obstructing accumulations of inspissated secretions frequently observed in obstructive lung diseases (OLDs), including chronic obstructive pulmonary disease (COPD), severe asthma, and cystic fibrosis. Their presence on chest CT is strongly associated with airflow limitation, reduced lung function, and increased mortality, making them emerging imaging biomarkers of disease burden and treatment response. However, manual delineation of mucus plugs is labor-intensive, subjective, and impractical for large cohorts, leading most prior studies to rely on coarse segment-level scoring systems that overlook lesion-level characteristics such as size, extent, and location. Automated plug-level quantification remains challenging due to substantial heterogeneity in plug morphology, overlap in attenuation with adjacent vessels and airway walls on non-contrast CT, and pronounced size imbalance in clinical datasets, which are typically dominated by small distal plugs. To address these challenges, we developed and validated a simulation-driven, annotation-free deep learning framework for automated detection and segmentation of airway mucus plugs on non-contrast chest CT. A total of 200 COPD CT scans were analyzed (98 plug-positive, 83 plug-negative, and 19 uncertain). Synthetic mucus plugs were generated within segmented airways by transferring voxel-intensity statistics from adjacent intrapulmonary vessels, preserving realistic morphology and texture while enabling controlled sampling of plug phenotypes. An nnU-Net trained exclusively on synthetic data (S-Model) was evaluated on an independent, expert-annotated test set and compared with an nnU-Net trained on manual annotations using 10-fold cross-validation (M-Model). The S-Model achieved significantly higher detection performance than the M-Model (sensitivity 0.837 [95% CI: 0.818-0.854] vs. 0.757 [95% CI: 0.737-0.776]; 1.91 false positives per scan vs. 3.68; <i>p</i> < 0.001), with performance gains most pronounced for medium-to-large plugs (≥6 mm). This simulation-driven approach enables accurate, scalable quantification of mucus plugs without voxel-wise manual annotation in thin-slice (<1.5 mm) non-contrast chest CT scans. While the framework could, in principle, be extended to other annotation-limited medical imaging tasks, its generalizability beyond this COPD cohort and imaging protocol has not yet been established, and future work is required to validate performance across diverse populations and scanning conditions.