Objective In spite of evidence and recommendations reflecting the importance of pharmacogenomic testing, most prescriptions are still given without testing. We demonstrate the real world implications of the use of testing and evaluate adverse events and outcomes in individuals who did not receive pharmacogenomic testing for clopidogrel.

Methods We analyzed ~100K individuals with paired EHR and exome sequencing data from population health studies administered at multiple medical centers using the Helix Exome+® assay. We inferred clopidogrel dosage by processing the prescription with an LLM. We identified all instances of individuals with at least one prescription that is not in concordance with their CYP2C19 genotype. Lastly, we identify instances of thrombosis using a comprehensive codeset based on ICD9, ICD10, and SNOMED terms.

Results We identified 16,140 prescriptions of clopidogrel given to 3,853 participants. We found that 29% of these individuals have a mismatch between the recommended clopidogrel dosage guideline based on their CYP2C19 genotype and their actual prescribed daily dosage. 25% of poor metabolizers experienced thrombosis, with 40% occurring within 2 months of treatment. Poor and intermediate metabolizers receiving clopidogrel are much more likely to experience thrombosis and myocardial infarction (binomial p-value = 0.001).

Conclusions We estimate a 38% excess of adverse events occur in poor and intermediate metabolizers relative to normal and rapid metabolizers. The lack of testing may be responsible for 1 thrombosis event per every ~30 people prescribed clopidogrel.

Authors affiliated with Helix are employees of Helix Opco LLC.

Funding was provided to the Healthy Nevada Project by the Renown Institute for Health Innovation and the Renown Health Foundation. The Healthy Nevada Project receives funding from Gilead Sciences, outside the scope of this research. Funding was provided to the myGenetics program by HealthPartners.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Helix cohorts were reviewed by Salus IRB (Reliance on Salus for all sites) and approved (approval number 21143), the WIRB CG IRB (Western Institutional Review Board, WIRB-Copernicus Group) and approved (approval number 20224919), the MUSC Institutional Review Board for Human Research and approved (approval number Pro00129083), and the University of Nevada, Reno Institutional Review Board and approved (approval number 7701703417). All participants gave their informed, written consent before participation. All data used for research were de-identified.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

The Helix cohorts data and code associated with these analyses are available to qualified researchers upon request and with permission of the participating health systems. The Helix cohorts encourage and collaborate with scientific researchers on an individual basis. Examples of restrictions that will be considered in requests to data access include but are not limited to (1) whether the request comes from an academic institution in good standing and will collaborate with our team to protect the privacy of the participants and the security of the data requested, (2) type and amount of data requested, (3) feasibility of the research suggested, and (4) amount of resource allocation required to support the collaboration. Any correspondence and data availability requests related to this data should be addressed to N.T. (natalie.telishelix.com).