Improving visualisation and interpretation of metabolome-wide association studies (MWAS): an application in a population-based cohort using untargeted 1H NMR metabolic profiling.

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Title: Improving visualisation and interpretation of metabolome-wide association studies (MWAS): an application in a population-based cohort using untargeted 1H NMR metabolic profiling.
Authors: Castagne, R
Boulange, CL
Karaman, I
Santos Ferreira, DL
Kaluarachchi, MR
Moayyeri, A
Lewis, MR
Spagou, K
DOna, AC
Evangelos, V
Tracy, R
Greenland, P
Lindon, JC
Ebbels, TMD
Chadeau, M
Item Type: Journal Article
Abstract: 1H 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 1H 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.
Issue Date: 20-Aug-2017
Date of Acceptance: 19-Aug-2017
ISSN: 1535-3893
Publisher: American Chemical Society
Start Page: 3623
End Page: 3633
Journal / Book Title: Journal of Proteome Research
Volume: 16
Issue: 10
Copyright Statement: This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Sponsor/Funder: Commission of the European Communities
Funder's Grant Number: 305422
Keywords: MESA
cohort studies
full resolution 1H NMR
high-throughput analysis
metabolic profiling
metabolome wide association study
molecular epidemiology
multiple testing correction
results visualization and prioritization
significance level
06 Biological Sciences
03 Chemical Sciences
Biochemistry & Molecular Biology
Publication Status: Published
Appears in Collections:Division of Surgery
Faculty of Medicine
Epidemiology, Public Health and Primary Care

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