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.

Accurate preoperative subtype classification of renal cell carcinoma (RCC) from contrast-enhanced computed tomography remains clinically challenging. Radiomics provides structured tumour descriptors, whereas foundation representations offer transferable image features. However, it remains unclear whether radiomics still adds value beyond pretrained representations, and how 2D and 3D MedVAE encoders compare in this setting. We compared handcrafted radiomics, 2D MedVAE, 3D MedVAE, and their fusion for binary clear-cell RCC versus non-clear-cell RCC classification on KiTS23 under a unified preprocessing pipeline. Concatenation, cross-attention, and gated fusion were evaluated as representative integration strategies, and radiomics feature importance was analysed to support decision-centric interpretability. Fusion consistently improved discrimination over image-only MedVAE branches. The best overall performance was achieved by 3D gated fusion, with an AUC of 82.7%, outperforming the best 2D fusion model (79.6%), the radiomics baseline (74.4%), and the single-modality MedVAE branches. Ablation analysis further showed clear gains of the full fusion model over both image-only and radiomics-only variants, indicating complementary contributions from radiomics and image representations. These findings suggest that radiomics remains relevant for RCC CT classification in the presence of foundation representations, and that its integration with MedVAE is more effective in the 3D setting. More broadly, the study supports a complementary role for radiomics and foundation representations in clinically meaningful imaging decision support.

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.