Physically Aware Radiomics Without Interpolation: Disentangling Voxel Geometry and Signal Modification in CT and MRI

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.