Design and methodology challenges of environment-wide association studies: A systematic review.

Environment-wide association studies (EWAS) are an untargeted, agnostic, and hypothesis-generating approach to exploring environmental factors associated with health outcomes, akin to genome-wide association studies (GWAS). While design, methodology, and replicability standards for GWAS are established, EWAS pose many challenges. We systematically reviewed published literature on EWAS to categorize scope, impact, types of analytical approaches, and open challenges in designs and methodologies. The Web of Science and PubMed databases were searched through multiple queries to identify EWAS articles between January 2010 and December 2018, and a systematic review was conducted following the Preferred Reporting Item for Systematic Reviews and Meta-Analyses (PRISMA) reporting standard. Twenty-three articles met our inclusion criteria and were included. For each study, we categorized the data sources, the definitions of study outcomes, the sets of environmental variables, and the data engineering/analytical approaches, e.g. neighborhood definition, variable standardization, handling of multiple hypothesis testing, model selection, and validation. We identified limited exploitation of data sources, high heterogeneity in analytical approaches, and lack of replication. Despite of the promising utility of EWAS, further development of EWAS will require improved data sources, standardization of study designs, and rigorous testing of methodologies.