18F-FDG PET/CT-based habitat radiomics combining stacking ensemble learning for predicting prognosis in hepatocellular carcinoma: a multi-center study

This study aims to develop habitat radiomic models to predict overall survival (OS) for hepatocellular carcinoma (HCC), based on the characterization of the intratumoral heterogeneity reflected in 18F-FDG PET/CT images. A total of 137 HCC patients from two institutions were retrospectively included. First, intratumoral habitats were achieved by a two-step unsupervised clustering process based on k-means clustering. Second, a total of 4032 radiomic features were extracted based on each habitat, including 2016 PET-based and 2016 CT-based radiomic features. Then, after feature selection, the stacking ensemble learning approach which combined six machine learning classifiers as the first-level learners with Cox proportional hazards regression as the second-level learner, was employed to build multiple radiomic models. Finally, the optimal model was selected based on the calculation of the C-index, and a combined model integrating with a clinical model was also constructed to identify the potentially complementary effect. Three spatially distinct habitats were identified in the two cohorts. Among a total of 30 stacking ensemble learning models established based on different combinations of 5 types of segmented volumes of interest (VOIs) with 6 types of classifiers, the MLP-Cox-habitat-2 model was selected as the optimal radiomic model with a C-index of 0.702 in the external validation cohort. Furthermore, the combined model integrating the optimal radiomic model with the clinical model achieved an improved C-index of 0.747. Consistently, the combined model outperformed the other models for OS prediction, with a time-dependent AUC of 0.835, 0.828, and 0.800 in the 1-year, 2-year, and 3-year OS, respectively. 18F-FDG PET/CT-based habitat radiomics outperformed traditional radiomics in OS prediction for HCC, with a further improved predictive power by integrating with the clinical model. The optimal combined habitat model was potentially promising in guiding individualized treatment for HCC. This study was a retrospective study, so it was free from registration.