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Owusu Obeng et al. J Transl Genet Genom 2021;5:64-79 I http://dx.doi.org/10.20517/jtgg.2020.52 Page 69

SELECTING THE PATIENTS TO TEST
Target patient populations
The question of “who to test” still remains an important and often uncertain one. Some may argue that
choosing patients who have experienced adverse events, failed therapy, or simply focusing on “high risk
[24]
patients” may be a reasonable approach . Others suggest selecting patients who have an indication for
[24]
a procedure for which a prescription for pharmacogenetic medication(s) can be anticipated . Elective
percutaneous coronary intervention (PCI) is an example of such procedures as patients are likely to be
started on antiplatelet therapy for which CYP2C19 genotyping is important. Current data suggest that
in many instances, patients who are genotyped for a certain indication such as PCI or with initiation of
new medications are often prescribed other medications for which the pharmacogenetic test may also be
relevant . Early implementors have focused on patients who are expected to be prescribed medication
[25]
with pharmacogenetic evidence such as the RIGHT patients in the Mayo Clinic and the PREDICT
population as summarized by Dunnenberger et al. .
[26]

Early adopters of genomic medicine and pharmacogenetics envisioned a time where genetic information
will be generated on every patient, to be used along other data to individualize therapy. While this will
be ideal to realize the widespread promise of precision medicine, barriers such as lack of institutional
resources, cost of testing, lack of insurance coverage, and lack of infrastructure to support the use of
genomic information pose a challenge to the “Genotype Everyone” approach . Thus, selecting a candidate
[27]
patient population to either justify payer’s coverage of a pharmacogenetic test or build evidence for the
utility of the data is still an approach most commonly taken by many institutions. Research investigators
and implementers continue to collect data on patient outcomes, cost effectiveness, and the clinical utility of
pharmacogenetic testing.

Some institutions initiated with a single drug-gene pair indicated by a clinical procedure or indication
before expanding into other drug-gene pairs in the ambulatory setting [28,29] . Others start with medications
with robust evidence for serious adverse events (such as thiopurine methyltransferase and thiopurines)
[30]
before evolving into a preemptive testing approach . Some institutions have also utilized algorithms
to predict and prioritize those who would benefit the most from testing. For example, enterprise-level
pharmacogenetic testing was performed by the Mayo Clinic and Vanderbilt University, both of which use
a preemptive testing approach [31,32] . Through the RIGHT protocol at Mayo Clinic, a multivariate prediction
algorithm identifies patients with high cardiovascular risk profile who are likely to be prescribed multiple
medications with pharmacogenetic evidence, and therefore benefit from preemptive testing, was used to
recruit 1000 patients [31,33] . INGENIOUS Trial at Indiana University uses a multi-gene panel to test patients
who receive a first prescription for at least one of 27 medications with pharmacogenetic guidelines .
[34]

Where resources are limited, clinicians may adopt the model that prioritizes patients likely to be prescribed
multiple pharmacogenetic medications (e.g., mediations with CPIC guidance) as their initial roll out. A
recent study investigating the utilization of pharmacogenetic medications using commercial claims of
more than 100,000 patients with PCI, documented that 50% and 68% of patients were prescribed one or
more drugs with pharmacogenetic evidence (CPIC level 1A or 1B) in addition to the antiplatelet therapy,
over one and five years, respectively. This data suggest that a multi-gene panel testing may have a high
utility in patients with PCI as these patients are frequently prescribed multiple medications with high
[25]
pharmacogenetic evidence . And therefore, PCI patients who are genotyped for CYP2C19 for antiplatelet
selection may be good targets for additional gene testing to guide other commonly prescribed medications
in this high-risk cardiac patient population. Furthermore, a United States Department of Veterans Affairs
(VA) study recently demonstrated that among over seven million veterans, 55% were prescribed one or
more CPIC level medications, with 15% and 11% being prescribed two and three of such medications,
[35]
respectively . The study projected that 92%, 26%, and 4% of veterans could have been prescribed warfarin,