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This study introduces MACtest, an R package for multimediator analysis in genomics, improving the identification of sparse mediation effects in large datasets. It enhances statistical power for discovering causal mechanisms in complex biological studies.

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Area of Science:

  • Genomics
  • Statistical genetics
  • Bioinformatics

Background:

  • Mediation analysis assesses causal pathways from exposure to outcome via mediators.
  • High-throughput technologies generate large-scale genomic and proteomic data, necessitating robust statistical methods.
  • Conventional mediation analysis methods lack statistical power for sparse effects under composite null hypotheses, leading to missed discoveries.

Purpose of the Study:

  • To extend composite null hypothesis testing for mediation analysis to multimediator scenarios.
  • To develop an R package (MACtest) for efficient and powerful multimediator analysis in genomic studies.
  • To identify novel genes and networks regulated by smoking-induced epigenetic aberrations.

Main Methods:

  • Utilized generalized Berk-Jones statistics combined with a composite test framework.
  • Developed three approaches: multivariate (dense/diverse effects), decorrelation (sparse/consistent effects), and hybrid.
  • Implemented the methods in the R package MACtest.

Main Results:

  • The MACtest package provides adjusted P-values for multimediator analyses, enhancing power for sparse effects.
  • Analysis of lung adenocarcinoma datasets identified potential genes and networks regulated by smoking-induced epigenetic aberrations.
  • Demonstrated the utility of MACtest in real-world genomic and proteomic studies.

Conclusions:

  • MACtest offers a powerful and flexible tool for multimediator analysis in the era of high-throughput genomics.
  • The developed methods improve the detection of true causal mechanisms, especially under sparse effect scenarios.
  • The package facilitates the investigation of complex biological questions, such as epigenetic regulation by environmental factors.