Pathway testing for longitudinal metabolomics

Statistics in Medicine, vol. 40, pp. 3053–3065

Abstract

We propose a top-down approach for pathway analysis of longitudinal metabolite data. We apply a score test based on a shared latent process mixed model which can identify pathways with differentially progressing metabolites. The strength of our approach is that it can handle unbalanced designs, deals with potential missing values in the longitudinal markers, and gives valid results even with small sample sizes. Contrary to bottom-up approaches, correlations between metabolites are explicitly modeled leveraging power gains. For large pathway sizes, a computationally efficient solution is proposed based on pseudo-likelihood methodology. We demonstrate the advantages of the proposed method in identification of differentially expressed pathways through simulation studies. Finally, longitudinal metabolite data from a mice experiment is analyzed to demonstrate our methodology.

Authors 4

1. Mitra Ebrahimpoor corresponding Aachen Medical Statistics Department of Biomedical Data Sciences Leiden University Medical Center Leiden The Netherlands Medical Statistics Department of Biomedical Data Sciences

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Medical Statistics, Department of Biomedical Data Sciences Leiden University Medical Center Leiden The Netherlands

   Medical Statistics, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands

2. Pietro Spitali Aachen Department of Human Genetics Leiden University Medical Center Leiden The Netherlands Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics Leiden University Medical Center Leiden The Netherlands

   Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

3. Jelle J. Goeman Aachen Medical Statistics Department of Biomedical Data Sciences Leiden University Medical Center Leiden The Netherlands Medical Statistics Department of Biomedical Data Sciences

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Medical Statistics, Department of Biomedical Data Sciences Leiden University Medical Center Leiden The Netherlands

   Medical Statistics, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands

4. Roula Tsonaka Aachen Medical Statistics Department of Biomedical Data Sciences Leiden University Medical Center Leiden The Netherlands Medical Statistics Department of Biomedical Data Sciences

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Medical Statistics, Department of Biomedical Data Sciences Leiden University Medical Center Leiden The Netherlands

   Medical Statistics, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands