When Does a Pathway Score Preserve a Mediated Effect? Aggregation Geometry, Minimax Adequacy, and Gap Inference for High-Dimensional Mediation
Hait, S.
Show 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.
Matching journals
The top 5 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Testing and controlling for horizontal pleiotropy with the probabilistic Mendelian randomization in transcriptome-wide association studies 94%
- Discovering genetic interactions bridging pathways in genome-wide association studies 93%
- Simultaneous estimation of bi-directional causal effects and heritable confounding from GWAS summary statistics 93%
Similar papers in this journal
- TarDis: Achieving Robust and Structured Disentanglement of Multiple Covariates 94%
- Inferring high-dimensional pathways of trait acquisition in evolution and disease 93%
- Learning multi-cellular representations of single-cell transcriptomics data enables characterization of patient-level disease states 93%
Similar papers in this journal
- Generative prediction of causal gene sets responsible for complex traits 94%
- Mendelian Randomization for causal inference accounting for pleiotropy and sample structure using genome-wide summary statistics 94%
- Universal contact statistics of looped polymers resolve cohesin density and stoichiometry in vivo 93%
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.