Using MetaboAnalyst 6.0 for exposomics data analysis-from LC-MS2 spectra processing to dose-response modeling and causal inference.

Exposomics is an emerging field of research that aims to comprehensively investigate individuals' environmental exposures and how these exposures relate to health outcomes. Liquid chromatography-tandem mass spectrometry is widely used in exposomics studies. MetaboAnalyst ( https://www.metaboanalyst.ca/ ) is a widely used platform for statistical and functional analysis of metabolomics data. The current MetaboAnalyst 6.0 release incorporates updates to meet the needs of exposomics studies, including improved support for tandem mass spectrometry compound identification, exposome annotation, dose-response analysis and linking to genetics and functions. Here we extend our 2022 Nature Protocol by providing step-by-step instructions on how to use MetaboAnalyst 6.0 for exposomics data analysis, including: liquid chromatography-tandem mass spectrometry spectra processing and compound identification (Stage 1), exposomics data processing and exploratory analysis (Stage 2), dose-response modeling to study metabolic responses to exposure levels (Stage 3) and leveraging known genetic associations for causal inference (Stage 4). We demonstrate Stages 1-3 using data from a recent blood exposomics study concerning electronic waste exposure. Stage 4 is illustrated through an investigation of the potential causal link between ʟ-isoleucine and type 2 diabetes. Stage 1 may take ~2 h to complete depending on server load, and the remaining stages may be executed in a total of ~90 min.