Improving Visualizationand Interpretation of Metabolome-WideAssociation Studies: An Application in a Population-Based Cohort UsingUntargeted 1H NMR Metabolic Profiling

摘要

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 distributionalfeatures of the outcome. We propose both efficient visualization methodsand a strategy based on subsampling and internal validation to prioritizethe associations. Our work proposes and illustrates practical andscalable solutions to facilitate the implementation of the MWAS approachand improve interpretation in large cohort studies.