Benchmarking clinical risk prediction algorithms with ensemble machine learning for the noninvasive diagnosis of liver fibrosis in NAFLD

Background and Aims: Ensemble machine-learning methods, like the superlearner, combine multiple models into a single one to enhance predictive accuracy. Here we explore the potential of the superlearner as a benchmarking tool for clinical risk prediction, illustrating the approach to identifying significant liver fibrosis among patients with NAFLD. Approach and Results: We used 23 demographic/clinical variables to train superlearner(s) on data from the NASH-clinical research network observational study (n = 648) and validated models with data from the FLINT trial (n = 270) and National Health and Nutrition Examination Survey (NHANES) participants with NAFLD (n = 1244). Comparing the superlearner’s performance to existing models (Fibrosis-4 [FIB-4], NAFLD fibrosis score, Forns, AST to Platelet Ratio Index [APRI], BARD, and Steatosis-Associated Fibrosis Estimator [SAFE]), it exhibited strong discriminative ability in the FLINT and NHANES validation sets, with AUCs of 0.79 (95% CI: 0.73–0.84) and 0.74 (95% CI: 0.68–0.79) respectively. Conclusions: Notably, the SAFE score performed similarly to the superlearner, both of which outperformed FIB-4, APRI, Forns, and BARD scores in the validation data sets. Surprisingly, the superlearner derived from 12 base models matched the performance of one with 90 base models. Overall, the superlearner, being the “best-in-class” machine-learning predictor, excelled in detecting fibrotic NASH, and this approach can be used to benchmark the performance of conventional clinical risk prediction models.