Exploring beyond diagnoses in electronic health records to improve discovery: a review of the phenome-wide association study.

Abstract

Objective: The phenome-wide association study (PheWAS) systematically examines the phenotypic spectrum extracted from electronic health records (EHRs) to uncover correlations between phenotypes and exposures. This review explores methodologies, highlights challenges, and outlines future directions for EHR-driven PheWAS.

Materials and methods: We searched the PubMed database for articles spanning from 2010 to 2023, and we collected data regarding exposures, phenotypes, cohorts, terminologies, replication, and ancestry.

Results: Our search yielded 690 articles. Following exclusion criteria, we identified 291 articles published between January 1, 2010, and December 31, 2023. A total number of 162 (55.6%) articles defined phenomes using phecodes, indicating that research is reliant on the organization of billing codes. Moreover, 72.8% of articles utilized exposures consisting of genetic data, and the majority (69.4%) of PheWAS lacked replication analyses.

Discussion: Existing literature underscores the need for deeper phenotyping, variability in PheWAS exposure variables, and absence of replication in PheWAS. Current applications of PheWAS mainly focus on cardiovascular, metabolic, and endocrine phenotypes; thus, applications of PheWAS in uncommon diseases, which may lack structured data, remain largely understudied.

Conclusions: With modern EHRs, future PheWAS should extend beyond diagnosis codes and consider additional data like clinical notes or medications to create comprehensive phenotype profiles that consider severity, temporality, risk, and ancestry. Furthermore, data interoperability initiatives may help mitigate the paucity of PheWAS replication analyses. With the growing availability of data in EHR, PheWAS will remain a powerful tool in precision medicine.