Meta-Analysis of High-Dimensional Surrogate Markers

Abstract: When direct measurement of a clinically relevant primary endpoint in a clinical trial is infeasible, a surrogate endpoint may be used instead to infer treatment effects. Trial-level surrogates predict the average treatment effect on the primary endpoint and may be evaluated within the meta-analytic framework. However, traditional methods are ill-suited to the complex high-dimensional data now increasingly collected in modern trials, such as omics data. Although methods for high-dimensional surrogate evaluation exist, they have largely been developed for single-trial settings and therefore cannot assess surrogate generalisability. Here, we propose RISE-Meta, an approach for evaluating trial-level surrogate markers in the multi-trial, high-dimensional setting. In the first stage, an existing nonparametric method is applied to individual participant data to derive study-level surrogacy metrics for each candidate marker. Next, random-effects meta-analysis combines these metrics across studies, and equivalence testing provides operational criteria for surrogate validity. Finally, a subset of candidates is combined into a composite signature through a weighting scheme to improve surrogacy relative to any individual candidate. We evaluate RISE-Meta in both simulation studies and real data applications. In an application to high-dimensional data, we analyse gene expression as trial-level surrogate markers for the antibody response to seasonal influenza vaccination, while in a low-dimensional application we compare RISE-Meta to a reference meta-analytic approach and observe strong agreement between the two.