When Does a Pathway Score Preserve a Mediated Effect? Aggregation Geometry, Minimax Adequacy, and Gap Inference for High-Dimensional Mediation
Abstract
High-dimensional mediators are routinely collapsed into low-dimensional scores before mediation analysis, but aggregation can change the mediated estimand rather than merely reduce noise. We characterize when a linear score preserves the full mediated effect. Exact preservation for every outcome model occurs precisely when the score contains the covariance-adjusted exposure-predictive mediator direction, the classical sufficient reduction for exposure under a Gaussian inverse-regression model. We introduce a distribution-free minimax adequacy loss equal to the fraction of exposure-relevant mediator information discarded by the score and exactly linked to overlap recovered by aggregation. A split-sample inverse-Wishart correction yields unbiased estimators of retained and full exposure information in moderate dimensions. Under spherically symmetric outcome-effect benchmarks, relative aggregation error has a Cauchy location-scale profile, and paired influence-function inference targets the realized gap for an observed outcome. In simulations, paired interval coverage ranged from 93.3% to 97.5%. In an outcome-free TCGA lung adenocarcinoma audit of 1,314 smoking-responsive genes, the pooled gene-mean loss was 0.811 (descriptive 95% gene-bootstrap interval 0.797 to 0.823), versus a dimension-only random-subspace benchmark of 0.913; retaining promoter and non-promoter means separately reduced pooled loss to 0.625. Independent half-sample screening was unstable, but top-100 and top-250 cross-screen pooled gene-mean losses ranged from 0.827 to 0.932. The framework separates structural adequacy, benchmark fragility, and outcome-specific discrepancy.
02 /Specification & Classification
Click any tag to browse matching papers- Citations
- 0
- Organism
- Assay
- Research Focus
- Approach
Reproducibility ledger
Nobody has reported trying to reproduce this paper yet. Did you replicate an experiment or run the code? Your report saves the next lab a week.
Sign in to file a reproducibility report.
Related papers
- Estimation of total mediation effect for a binary trait in a case-control study for high-dimensional omics mediators
Zhiyu Kang, Li Chen, … Tianzhong Yang·bioRxiv·Jan 28, 2025
- Estimation of Mediation Effect for High-dimensional Omics Mediators with Application to the Framingham Heart Study
Tianzhong Yang, Jingbo Niu, … Peng Wei·bioRxiv·Sep 19, 2019
- Measuring weak effects in high dimensional mediation analysis
Chunlin Li, Li Chen, … Tianzhong Yang·medRxiv·Jan 30, 2025
- MASH: Mediation Analysis of Survival Outcome and High-dimensional Omics Mediators with Application to Complex Diseases
Sunyi Chi, Christopher R. Flowers, … Peng Wei·The Annals of Applied StatisticsPeer-reviewed·Apr 5, 2024
- Speeding up interval estimation for R2-based mediation effect of high-dimensional mediators via cross-fitting
Zhichao Xu, Chunlin Li, … Peng Wei·bioRxiv·Feb 6, 2023
- Efficient Estimation of Indirect Effects in Case-Control Studies Using a Unified Likelihood Framework
Glen A. Satten, Sarah W. Curtis, … Michael P. Epstein·Statistics in MedicinePeer-reviewed·Mar 30, 2022