A Statistical Framework for Co-Mediators of Zero-Inflated Single-Cell RNA-Seq Data

2025/07/08 by Ahn, Seungjun, Chen, Li, van Gerwen, Maaike +2
#Applications (stat.AP) #FOS: Biological sciences #FOS: Computer and information sciences #Genomics (q-bio.GN) #Methodology (stat.ME) #Quantitative Methods (q-bio.QM)

paper · doi:10.48550/arxiv.2507.06113

Abstract

Single-cell RNA sequencing (scRNA-seq) has revolutionized the study of cellular heterogeneity, enabling detailed molecular profiling at the individual cell level. However, integrating high-dimensional single-cell data into causal mediation analysis remains challenging due to zero inflation and complex mediator structures. We propose a novel mediation framework leveraging zero-inflated negative binomial models to characterize cell-level mediator distributions and beta regression for zero-inflation proportions. The model can identify expression level as well as expressed proportion that could mediate disease-leading causal pathway. Extensive simulation studies demonstrate improved power and controlled false discovery rates. We further illustrate the utility of this approach through application to ROSMAP single-cell transcriptomic data, uncovering biologically meaningful mediation effects that enhance understanding of disease mechanisms.

Citations

• Structure learning for zero-inflated counts, with an application to single-cell RNA sequencing data
• Separating measurement and expression models clarifies confusion in single-cell RNA sequencing analysis
• MarZIC: A Marginal mediation model for Zero-Inflated Compositional mediators with applications to microbiome data
• Beyond bulk: a review of single cell transcriptomics methodologies and applications
• Mediation Analysis: A Practitioner's Guide
• High-dimensional Multivariate Mediation: with Application to\n Neuroimaging Data
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• The moderator–mediator variable distinction in social psychological research: Conceptual, strategic, and statistical considerations.

Related

• Root Causal Inference from Single Cell RNA Sequencing with the Negative Binomial
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• MarZIC: A Marginal mediation model for Zero-Inflated Compositional mediators with applications to microbiome data
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