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

1H nuclear magnetic resonance (NMR) spectroscopy of biofluids generates reproducible data allowing detection and quantification of small molecules in large population cohorts.Statistical models to analyse 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 relies 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, calls for efficient prioritisation of spectral variables of interest.Using human serum 1H NMR spectroscopic profiles from 3,948 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 parametrisations and distributional features of the outcome. We propose both efficient visualisation 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.