Uncontrolled Confounders May Lead to False or Overvalued Radiomics Signature: A Proof of Concept Using Survival Analysis in a Multicenter Cohort of Kidney Cancer

PURPOSE: We aimed to explore potential confounders of prognostic radiomics signature predicting survival outcomes in clear cell renal cell carcinoma (ccRCC) patients and demonstrate how to control for them. MATERIALS AND METHODS: Preoperative contrast enhanced abdominal CT scan of ccRCC patients along with pathological grade/stage, gene mutation status, and survival outcomes were retrieved from The Cancer Imaging Archive (TCIA)/The Cancer Genome Atlas—Kidney Renal Clear Cell Carcinoma (TCGA-KIRC) database, a publicly available dataset. A semi-automatic segmentation method was applied to segment ccRCC tumors, and 1,160 radiomics features were extracted from each segmented tumor on the CT images. Non-parametric principal component decomposition (PCD) and unsupervised hierarchical clustering were applied to build the radiomics signature models. The factors confounding the radiomics signature were investigated and controlled sequentially. Kaplan–Meier curves and Cox regression analyses were performed to test the association between radiomics signatures and survival outcomes. RESULTS: 183 patients of TCGA-KIRC cohort with available imaging, pathological, and clinical outcomes were included in this study. All 1,160 radiomics features were included in the first radiomics signature. Three additional radiomics signatures were then modelled in successive steps removing redundant radiomics features first, removing radiomics features biased by CT slice thickness second, and removing radiomics features dependent on tumor size third. The final radiomics signature model was the most parsimonious, unbiased by CT slice thickness, and independent of tumor size. This final radiomics signature stratified the cohort into radiomics phenotypes that are different by cancer-specific and recurrence-free survival; HR (95% CI) = 3.0 (1.5–5.7), p <0.05 and HR (95% CI) = 6.6 (3.1–14.1), p <0.05, respectively. CONCLUSION: Radiomics signature can be confounded by multiple factors, including feature redundancy, image acquisition parameters like slice thickness, and tumor size. Attention to and proper control for these potential confounders are necessary for a reliable and clinically valuable radiomics signature.