Development and validation of an ensemble machine-learning model for predicting early mortality among patients with bone metastases of hepatocellular carcinoma
Authors: Long Ze , Yi Min , Qin Yong , Ye Qianwen , Che Xiaotong , Wang Shengjie , Lei Mingxing 
Published: February 2023

PurposeUsing an ensemble machine learning technique that incorporates the results of multiple machine learning algorithms, the study’s objective is to build a reliable model to predict the early mortality among hepatocellular carcinoma (HCC) patients with bone metastases.MethodsWe extracted a cohort of 124,770 patients with a diagnosis of hepatocellular carcinoma from the Surveillance, Epidemiology, and End Results (SEER) program and enrolled a cohort of 1897 patients who were diagnosed as having bone metastases. Patients with a survival time of 3 months or less were considered to have had early death. To compare patients with and without early mortality, subgroup analysis was used. Patients were randomly divided into two groups: a training cohort (n = 1509, 80%) and an internal testing cohort (n = 388, 20%). In the training cohort, five machine learning techniques were employed to train and optimize models for predicting early mortality, and an ensemble machine learning technique was used to generate risk probability in a way of soft voting, and it was able to combine the results from the multiply machine learning algorithms. The study employed both internal and external validations, and the key performance indicators included the area under the receiver operating characteristic curve (AUROC), Brier score, and calibration curve. Patients from two tertiary hospitals were chosen as the external testing cohorts (n = 98). Feature importance and reclassification were both operated in the study.ResultsThe early mortality was 55.5% (1052/1897). Eleven clinical characteristics were included as input features of machine learning models: sex (p = 0.019), marital status (p = 0.004), tumor stage (p = 0.025), node stage (p = 0.001), fibrosis score (p = 0.040), AFP level (p = 0.032), tumor size (p = 0.001), lung metastases (p &lt; 0.001), cancer-directed surgery (p &lt; 0.001), radiation (p &lt; 0.001), and chemotherapy (p &lt; 0.001). Application of the ensemble model in the internal testing population yielded an AUROC of 0.779 (95% confidence interval [CI]: 0.727–0.820), which was the largest AUROC among all models. Additionally, the ensemble model (0.191) outperformed the other five machine learning models in terms of Brier score. In terms of decision curves, the ensemble model also showed favorable clinical usefulness. External validation showed similar results; with an AUROC of 0.764 and Brier score of 0.195, the prediction performance was further improved after revision of the model. Feature importance demonstrated that the top three most crucial features were chemotherapy, radiation, and lung metastases based on the ensemble model. Reclassification of patients revealed a substantial difference in the two risk groups’ actual probabilities of early mortality (74.38% vs. 31.35%, p &lt; 0.001). Patients in the high-risk group had significantly shorter survival time than patients in the low-risk group (p &lt; 0.001), according to the Kaplan–Meier survival curve.ConclusionsThe ensemble machine learning model exhibits promising prediction performance for early mortality among HCC patients with bone metastases. With the aid of routinely accessible clinical characteristics, this model can be a trustworthy prognostic tool to predict the early death of those patients and facilitate clinical decision-making.