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Leveraging Human Genetics to Identify Safety Signals Prior to Drug Marketing Approval and Clinical Use

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Abstract

Introduction

When a new drug or biologic product enters the market, its full spectrum of side effects is not yet fully understood, as use in the real world often uncovers nuances not suggested within the relatively narrow confines of preapproval preclinical and trial work.

Objective

We describe a new, phenome-wide association study (PheWAS)- and evidence-based approach for detection of potential adverse drug effects.

Methods

We leveraged our established platform, which integrates human genetic data with associated phenotypes in electronic health records from 29,722 patients of European ancestry, to identify gene-phenotype associations that may represent known safety issues. We examined PheWAS data and the published literature for 16 genes, each of which encodes a protein targeted by at least one drug or biologic product.

Results

Initial data demonstrated that our novel approach (safety ascertainment using PheWAS [SA-PheWAS]) can replicate published safety information across multiple drug classes, with validated findings for 13 of 16 gene–drug class pairs.

Conclusions

By connecting and integrating in vivo and in silico data, SA-PheWAS offers an opportunity to supplement current methods for predicting or confirming safety signals associated with therapeutic agents.

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Funding

The project described was supported by CTSA award No. UL1 TR002243 from the National Center for Advancing Translational Sciences. Its contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health.

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Authors and Affiliations

  1. Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, TN, USA

    Rebecca N. Jerome, Meghan Morrison Joly, Nan Kennedy, Jana K. Shirey-Rice, Gordon R. Bernard, Kenneth J. Holroyd & Jill M. Pulley

  2. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Dan M. Roden

  3. Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA

    Dan M. Roden

  4. Department of Biomedical Informatics, Vanderbilt University, Nashville, TN, USA

    Dan M. Roden & Joshua C. Denny

  5. Center for Technology Transfer and Commercialization, Vanderbilt University, Nashville, TN, USA

    Kenneth J. Holroyd

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  1. Rebecca N. Jerome
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  2. Meghan Morrison Joly
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  3. Nan Kennedy
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  4. Jana K. Shirey-Rice
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  5. Dan M. Roden
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  7. Kenneth J. Holroyd
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  8. Joshua C. Denny
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  9. Jill M. Pulley
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Corresponding author

Correspondence to Rebecca N. Jerome.

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Ethics approval

This project was reviewed and received a nonhuman subjects research determination from the Vanderbilt University Institutional Review Board (IRB number 151121).

Conflict of interest

VUMC has licensed PheWAS technology to Nashville Biosciences, a VUMC-owned entity. Dr. Denny receives a portion of those royalty payments. Rebecca Jerome, Meghan Joly, Nan Kennedy, Jana Shirey-Rice, Dan Roden, Gordon Bernard, Kenneth Holroyd, and Jill Pulley have no conflicts of interest that are directly relevant to the content of this study.

Data sharing

The data used and analyzed during the current study are available from the corresponding author on reasonable request.

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Jerome, R.N., Joly, M.M., Kennedy, N. et al. Leveraging Human Genetics to Identify Safety Signals Prior to Drug Marketing Approval and Clinical Use. Drug Saf 43, 567–582 (2020). https://doi.org/10.1007/s40264-020-00915-6

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