Meta-Analysis of High-Dimensional Surrogate Markers
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arXiv
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| Autori principali: | , , , |
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| Natura: | Preprint |
| Pubblicazione: |
2026
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| _version_ | 1866914531332063232 |
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| author | Hughes, Arthur Thiébaut, Rodolphe Parast, Layla Hejblum, Boris P. |
| author_facet | Hughes, Arthur Thiébaut, Rodolphe Parast, Layla Hejblum, Boris P. |
| contents | 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. |
| format | Preprint |
| id |
arxiv_https___arxiv_org_abs_2605_03819 |
| institution | arXiv |
| publishDate | 2026 |
| record_format | arxiv |
| spellingShingle | Meta-Analysis of High-Dimensional Surrogate Markers Hughes, Arthur Thiébaut, Rodolphe Parast, Layla Hejblum, Boris P. Methodology 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. |
| title | Meta-Analysis of High-Dimensional Surrogate Markers |
| topic | Methodology |
| url | https://arxiv.org/abs/2605.03819 |