M3Net: A Macro-to-Meso-to-Micro Clinical-inspired Hierarchical 3D Network for Pulmonary Nodule Classification

Lung cancer causes more deaths than any other malignancy, and low-dose CT screening is the main pathway to early diagnosis. That pathway hinges on the smallest lesions, yet nodules below six millimeters remain hard to detect, because most methods treat a nodule as a generic object and ignore the imaging physics behind its appearance. We show that this appearance is highly regular. Intensity peaks at the geometric center of a nodule and decays radially in a Gaussian pattern, and a fit to 18,218 annotated lesions from three public benchmarks yields a mean radial coefficient of determination above 0.86 in every dataset and size stratum. A square convolution samples both axes uniformly and is mismatched to this radial signal, most severely for small nodules. Guided by this evidence, we propose GRIPNet (Gaussian Radial Intensity Prior Network), a detector in which every module maps to a measurable property of the intensity distribution. Pinwheel convolutions decompose radial gradients, a dual-frequency module separates boundary detail from structural context, dilated masked attention matches the decay extent, and an adaptive loss reweights samples by conspicuity. GRIPNet raises mAP@0.5 to 95.3, 91.6 and 97.9 percent on KanserSet, LUNA16 and Lung-PET-CT-Dx while sharpening high-IoU localization at real-time speed.

Foundation models provide transferable CT representations, but predictions based directly on these embeddings are difficult to interpret. We developed concept bottleneck models that map two frozen CT foundation-model representations to eight radiologist-defined pulmonary-nodule attributes and predict malignancy from the estimated concepts and nodule size. The models included CT-FM, a whole-CT self-supervised encoder using a 96^3-voxel nodule-centered patch, and FMCIB, a nodule-focused contrastive encoder using a 50-mm crop. Eight ridge-regression concept heads were trained on 2,610 LIDC-IDRI nodules. Malignancy models were trained on LUNA25 and evaluated on a held-out internal test set and the external DLCS cohort. Concept fidelity was assessed using five-fold cross-validated R^2, and malignancy discrimination was assessed using AUROC with 95% confidence intervals estimated by patient-grouped bootstrap resampling. Concept fidelity was modest but higher for FMCIB than CT-FM for subtlety (R2, 0.24 vs. 0.11), spiculation (0.17 vs. 0.08), texture (0.17 vs. 0.07), and lobulation (0.15 vs. 0.05). Internally, the CT-FM and FMCIB concept+size models achieved AUROCs of 0.86 (95% CI, 0.80-0.92) and 0.86 (0.79-0.92), respectively. Externally, AUROCs were 0.72 (0.68-0.75) and 0.73 (0.70-0.76), compared with 0.73 for nodule size alone and 0.60 and 0.67 for the corresponding embedding only probes. Additive predictions could be decomposed into feature-level contributions and modified through controlled concept interventions. Concept bottlenecks provided transparent malignancy predictions with discrimination similar to nodule size alone, while differences in concept fidelity suggest that concept recovery depends on the underlying foundation-model representation.

Medical expert annotators are scarce, and blind reliance on artificial intelligence (AI) can be misleading, motivating approaches in which humans, particularly junior medical trainees or even non-medical personnel, collaborate with AI to achieve robust medical segmentation. Although the Segment Anything Model (SAM) shows promise for general-purpose image segmentation, its performance in human-AI collaboration for specialized medical tasks has not been thoroughly evaluated. Here we present Hi-Seg, a human-in-the-loop segmentation framework for pulmonary nodules built on SAM. Humans iteratively refine prompts through trial-and-error learning and semantic reasoning, progressively guiding SAM toward higher-quality masks. Using chest CT scans from 1,179 patients across 12 centers, we conducted the first large-scale external validation of collaborative human-SAM segmentation. Across all annotator groups, Hi-Seg achieved a mean Dice score of almost 85%, outperforming five state-of-the-art deep learning models by 10-22% and 13 SAM variants by 1-29%. Hi-Seg improved segmentation accuracy while reducing annotation time for medical annotators, and briefly trained non-medical annotators achieved performance comparable to that of the junior medical student. These findings suggest that human-in-the-loop segmentation can reduce clinician workload, enable scalable crowdsourced annotation, and transform clinical workflows by facilitating the safe and efficient integration of foundation models into routine clinical practice.