Negative controls reveal volume-driven confounding in radiomics and imaging foundation model features

Radiomics is the established approach for CT-based lung cancer phenotyping, yet comparisons with foundation models rarely isolate contributions of feature extractor, classification head, and segmentation choice, or test cross-cohort robustness. We benchmark five feature extractors (Curia, Curia-2, DINOv3, Radiomics2D, Radiomics3D), seven classification heads (TabPFN, TabICL, XGBoost, CatBoost, Random Forest, logistic regression, Ridge), and three segmentation regimes on five tasks: tumor volume and stage classification, 2-year survival prediction, histology classification, and age prediction. Models are trained on LUNG1 (n=338) and evaluated on an internal test set (n=84) and the external LUNG2 cohort (n=211), with worst-case cross-cohort performance as the primary metric. The dominant design factor is task-dependent: segmentation drives volume and stage classification, while classifier choice drives survival, histology, and age prediction. Radiomics is competitive for tumor volume, tumor stage and survival (partly due to label-derivation effects for the former); Curia variants reach comparable peak scores for survival; DINOv3 falls slightly short across tasks. Patch and slice aggregation have negligible impact. We recommend Curia with tumor segmentation and a CatBoost head as a safe default, achieving the best mean rank across the three primary clinical tasks, though task-specific selection consistently outperforms any cross-task default. When tumor delineations are unavailable, Curia-2 with lung segmentation and logistic regression offers a competitive alternative. All pipelines use a two-stage design suited to small cohort sizes where end-to-end fine-tuning would risk overfitting.

Objective: Radiomic texture features are usually computed in voxel-index neighborhoods, implicitly assuming isotropic spatial relationships. In anisotropic images, this can confound voxel geometry with interpolation-induced signal changes. We developed a voxel-spacing-aware radiomic framework that incorporates physical geometry into texture computation without resampling. Approach: We modified PyRadiomics to account for voxel spacing while preserving the native image signal. Four configurations were compared: native non-resampled extraction (NR), isotropic resampling (RS), voxel-spacing-aware extraction (VS), and fake-isotropic preprocessing (FK), in which spacing metadata were overwritten without altering the image array. Experiments included 685 LIDC-IDRI pulmonary nodules and 209 I-SPY2 breast MRI cases, with 196 radiomic descriptors. Robustness was assessed using ICC, within-subject variability, Friedman testing, feature selection, machine learning, a multilayer perceptron, and external validation. Main results: VS showed near-native agreement with NR: median ICC(A,1) was 0.9976 in CT and 0.9984 in MRI. RS produced lower agreement and larger deviations, while FK showed intermediate behavior, confirming that spacing metadata alone can affect radiomic features. Gradient-derived and neighborhood-sensitive descriptors were most affected by preprocessing. VS preserved predictive performance comparable to NR in external CT validation, whereas MRI showed greater variability across preprocessing strategies and classifiers. Significance: Voxel-spacing-aware extraction separates geometric modeling from interpolation-induced signal modification while preserving the native image signal, offering a coherent alternative to isotropic resampling for radiomic analysis of anisotropic CT and MRI.

Radiomic features derived from medical images and segmentation masks are used to support decision making in clinical imaging pipelines. In practice, these features are often computed from predicted masks, but segmentation models can be overconfident or poorly calibrated, making derived measurements appear more reliable than they are. Conformal prediction (CP) provides distribution-free prediction intervals with finite-sample marginal coverage guarantees, but black-box intervals for segmentation-derived radiomics can be inefficient because they ignore test-time information about image appearance, mask geometry, and segmentation uncertainty. We propose ConRad, a conformal framework for scalar radiomic targets that uses covariates derived from the predicted mask, input image, predicted radiomics, and boundary uncertainty to construct adaptive intervals while maintaining coverage. Across five 2D medical imaging datasets and 171 retained radiomic targets, we show that ConRad improves feature-level efficiency compared to baselines while maintaining near-nominal empirical coverage. Ablation results further indicate that segmentation boundary uncertainty features are the largest contributors to interval efficiency.