Random Survival Forest Versus Elastic-Net Regularized Cox Regression for Survival Prediction in Acute Myeloid Leukemia at Distinct Treatment Time Points: Model Performance Comparison Study

Background: Risk group stratification based on the prediction of survival of patients with acute myeloid leukemia (AML) is complex. Despite common risk group categorization guidelines, the overall prognosis remains poor. Machine learning techniques have been shown to provide more accurate risk group stratification than conventional approaches using trial data. However, many time-to-event (TTE) models do not use training sets constrained to specific time windows, instead using aggregations of trial data. Objective: This study aimed to evaluate the performance of (1) random survival forest (RSF) and (2) Cox proportional hazard regression with elastic net regularization (CoxNet) for survival prediction of patients with AML within a censoring window trained with available data recorded at discrete time points during the United Kingdom National Cancer Research Institute Acute Myeloid Leukaemia 17 randomized controlled trial (AML17). Methods: For each stage in the AML17 trial, separate models were trained for each exhaustive k-choice combination of available AML17 data subsets. Data combinations for each model were further constrained according to the respective trial stage to avoid data leakage. Preliminary Pearson correlation methods were used to remove directly correlating features with the TTE prediction (time-to-death/5-y censoring point). Repeated k-fold stratified cross-validation was used on each dataset ablation to find candidate models. Permutation importance and elastic net regularization were used to monitor stability across validation folds and reduce the feature set of the highest performing stage RSF and Cox proportional hazard regression models, respectively. Finally, selected ablated models were re-evaluated using the nested, k-fold, stratified sampling cross-validation method with bootstrapping. Results: Concordance index ranked the best models for data constricted up to the end of induction (RSF=0.68, CoxNet=0.67), stages 1 (RSF=0.69, CoxNet=0.68), 2 (RSF=0.68, CoxNet=0.66), and 3 (RSF=0.69, CoxNet=0.63) of the trial. Conclusions: This study details the high prediction accuracy for time-to-survival-event predictions when training sets of CoxNet and RSF models, which are sequentially constricted to data measured up to the end of respective AML17 trial stages. The performance of these sequential TTE models is intended to justify their use as part of a wider digital twin system simulating multiple TTE outcomes for patients with AML.

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