Validating an explainable radiomics approach in non-small cell lung cancer combining high energy physics with clinical and biological analyses

Purpose: This study aims at establishing a validation framework for an explainable radiomics-based model, specifically targeting classification of histopathological subtypes in non-small cell lung cancer (NSCLC) patients. Methods: We developed an explainable radiomics pipeline using open-access CT images from the cancer imaging archive (TCIA). Our approach incorporates three key prongs: SHAP-based feature selection for explainability within the radiomics pipeline, a technical validation of the explainable technique using high energy physics (HEP) data, and a biological validation using RNA-sequencing data and clinical observations. Results: Our radiomic model achieved an accuracy of 0.84 in the classification of the histological subtype. The technical validation performed on the HEP domain over 150 numerically equivalent datasets, maintaining consistent sample size and class imbalance, confirmed the reliability of SHAP-based input features. Biological analysis found significant correlations between gene expression and CT-based radiomic features. In particular, gene MUC21 achieved the highest correlation with the radiomic feature describing the10th percentile of voxel intensities (r = 0.46, p < 0.05). Conclusion: This study presents a validation framework for explainable CT-based radiomics in lung cancer, combining HEP-driven technical validation with biological validation to enhance interpretability, reliability, and clinical relevance of XAI models.