Exposome-wide association study of semen quality: Systematic discovery of endocrine disrupting chemical biomarkers in fertility require large sample sizes

Objectives: Exposome-wide association studies (EWAS) are a systematic and unbiased way to investigate multiple environmental factors associated with phenotype. We applied EWAS to study semen quality and queried the sample size requirements to detect modest associations in a reproductive cohort. Study design and setting: We conducted 1) a multivariate EWAS of 128 endocrine disrupting chemicals (EDCs) from 15 chemical classes measured in urine/serum relative to 7 semen quality endpoints in a prospective cohort study comprising 473 men and 2) estimated the sample size requirements for EWAS etiologic investigations. Results: None of the EDCs were associated with semen quality endpoints after adjusting for multiple tests. However, several EDCs (e.g., polychlorinated biphenyl congeners 99, 105, 114, and 167) were associated with raw p < 0.05. In a post hoc statistical power analysis with the observed effect sizes, we determined that EWAS research in male fertility will require a mean sample size of 2696 men (1795-3625) to attain a power of 0.8. The average size of four published studies is 201 men. Conclusion: Existing cohort studies with hundreds of participants are underpowered (< 0.8) for EWAS-related investigations. Merging cohorts to ensure a sufficient sample size can facilitate the use of EWAS methods for assessing EDC mixtures that impact semen quality.