Individualized treatment effect was predicted best by modeling baseline risk in interaction with treatment assignment

Abstract: Objective: To compare different risk-based methods for optimal prediction of treatment effects. Methods: We simulated RCT data using diverse assumptions for the average treatment effect, a baseline prognostic index of risk (PI), the shape of its interaction with treatment (none, linear, quadratic or non-monotonic), and the magnitude of treatment-related harms (none or constant independent of the PI). We predicted absolute benefit using: models with a constant relative treatment effect; stratification in quarters of the PI; models including a linear interaction of treatment with the PI; models including an interaction of treatment with a restricted cubic spline (RCS) transformation of the PI; an adaptive approach using Akaike's Information Criterion. We evaluated predictive performance using root mean squared error and measures of discrimination and calibration for benefit. Results: The linear-interaction model displayed optimal or close-to-optimal performance across many simulation scenarios with moderate sample size (N=4,250 patients; ~ 785 events). The RCS-model was optimal for strong non-linear deviations from a constant treatment effect, particularly when sample size was larger (N=17,000). The adaptive approach also required larger sample sizes. These findings were illustrated in the GUSTO-I trial. Conclusion: An interaction between baseline risk and treatment assignment should be considered to improve treatment effect predictions.