A system for phenotype harmonization in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program

Genotype-phenotype association studies often combine phenotype data from multiple studies to increase power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data sharing mechanisms. This system was developed for the National Heart, Lung and Blood Institute’s Trans-Omics for Precision Medicine (TOPMed) program, which is generating genomic and other omics data for >80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants from up to 17 TOPMed studies per phenotype. We discuss the challenges faced in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled-access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include ([1][1]) the code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify or extend these harmonizations to additional studies; and ([2][2]) results of labeling thousands of phenotype variables with controlled vocabulary terms. ### Competing Interest Statement Adrienne Stilp receives funding from Seven Bridges Genomics to develop tools for the NHLBI BioData Catalyst consortium. Bruce Psaty serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Pradeep Natarajan received grant support from Amgen, Apple, and Boston Scientific, and consulting fees from Apple, all unrelated to the present work. Stella Aslibekyan is currently employed by and holds equity in 23andMe, Inc. May Montasser receives funding from Regeneron Pharmaceutical Inc. unrelated to this work. * DCC : Data Coordinating Center dbGaP : database for Genotypes and Phenotypes JSON : JavaScript Object Notation LDL-C : Low-density lipoprotein cholesterol NHLBI : National Heart, Lung, and Blood Institute NIH : National Institutes of Health QC : quality control TOPMed : Trans-Omics for Precision Medicine UMLS : Unified Medical Language System WG : Working Group [1]: #ref-1 [2]: #ref-2