Improving Visualization and Interpretation of Metabolome-Wide Association Studies: An Application in a Population-Based Cohort Using Untargeted (1)H NMR Metabolic Profiling

TitleImproving Visualization and Interpretation of Metabolome-Wide Association Studies: An Application in a Population-Based Cohort Using Untargeted (1)H NMR Metabolic Profiling
Publication TypeJournal Article
Year of Publication2017
AuthorsCastagné R., Boulangé C.L, Karaman I., Campanella G., Ferreira D.LSantos, Kaluarachchi M.R, Lehne B., Moayyeri A., Lewis M.R, Spagou K., Dona A.C, Evangelos V., Tracy R., Greenland P., Lindon J.C, Herrington D., Ebbels T.MD, Elliott P., Tzoulaki I., Chadeau-Hyam M.
JournalJ Proteome ResJournal of Proteome ResearchJournal of Proteome Research
Volume16
Pagination3623-3633
Date PublishedOct 6
ISBN Number1535-3893
Accession Number28823158
KeywordsCohort Studies, full resolution 1H NMR, high-throughput analysis, Mesa, metabolic profiling, metabolome wide association study, Molecular Epidemiology, multiple testing correction, results visualization and prioritization, significance level
Abstract

(1)H NMR spectroscopy of biofluids generates reproducible data allowing detection and quantification of small molecules in large population cohorts. Statistical models to analyze such data are now well-established, and the use of univariate metabolome wide association studies (MWAS) investigating the spectral features separately has emerged as a computationally efficient and interpretable alternative to multivariate models. The MWAS rely on the accurate estimation of a metabolome wide significance level (MWSL) to be applied to control the family wise error rate. Subsequent interpretation requires efficient visualization and formal feature annotation, which, in-turn, call for efficient prioritization of spectral variables of interest. Using human serum (1)H NMR spectroscopic profiles from 3948 participants from the Multi-Ethnic Study of Atherosclerosis (MESA), we have performed a series of MWAS for serum levels of glucose. We first propose an extension of the conventional MWSL that yields stable estimates of the MWSL across the different model parameterizations and distributional features of the outcome. We propose both efficient visualization methods and a strategy based on subsampling and internal validation to prioritize the associations. Our work proposes and illustrates practical and scalable solutions to facilitate the implementation of the MWAS approach and improve interpretation in large cohort studies.

Short TitleJ. Proteome Res.J. Proteome Res.
Alternate JournalJournal of proteome research