Clinically actionable genotypes among 10,000 patients with preemptive pharmacogenomic testing

Abstract

Since September 2010, more than 10,000 patients have undergone preemptive, panel-based pharmacogenomic testing through the Vanderbilt Pharmacogenomic Resource for Enhanced Decisions in Care and Treatment program. Analysis of the genetic data from the first 9,589 individuals reveals that the frequency of genetic variants is concordant with published allele frequencies. Based on five currently implemented drug-gene interactions, the multiplexed test identified one or more actionable variants in 91% of the genotyped patients and in 96% of African American patients. Using medication exposure data from electronic medical records, we compared a theoretical "reactive," prescription-triggered, serial single-gene testing strategy with our preemptive, multiplexed genotyping approach. Reactive genotyping would have generated 14,656 genetic tests. These data highlight three advantages of preemptive genotyping: (i) the vast majority of patients carry at least one pharmacogenetic variant; (ii) data are available at the point of care; and (iii) there is a substantial reduction in testing burden compared with a reactive strategy.

Figure 1. Actionable genotypes in individual and cumulative Drug-Genome Interactions (DGIs)

The frequencies of non-actionable, actionable and high risk genotypes for each DGI. The final bar shows frequency of individuals having at least one actionable or high risk genotype among all five DGIs.

Figure 2. Predicted and observed actionable genotypes and associated medication exposures

In panels A-C, for each Drug-Genome Interaction (DGI), the frequencies of expected actionable genotypes based on reported minor allele frequencies (open triangles), observed actionable genotypes (open circles), expected frequency of medication exposures among patients with actionable genotypes (filled triangles) and observed actionable genotype with exposure to the associated medication (filled circles) are shown for all 9,589 genotyped patients (A), 6,986 patients of European-American descent (B), and 953 patients of African-American decent (C). Clopidogrel exposure includes clopidogrel and/or prasugrel, the alternative agent. Statin exposure includes simvastatin and/or alternative HMG-CoA reductase inhibitors (atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin). In panels D-F, cumulative frequency of individuals having observed actionable genotypes based on the five currently implemented DGIs (open circles), cumulative frequency of individuals with actionable genotypes exposed to associated medications (filled circles), and predicted cumulative frequency of actionable genotypes based on a total of 12 pharmacogenes (x’s) are shown for all genotyped patients (D), patients of European-American descent (E), and patients of African-American decent (F).

Figure 3. Medication exposures among genotyped individuals

A. Medication exposure among all (open circles) and PREDICT preemptive model target population (filled circles) individuals for each medication currently implemented in the PREDICT program. B. Cumulative number of drug exposures to medications implemented in the PREDICT program, in order of implementation. Drug 1 - clopidogrel and/or prasugrel; 2 - statins; 3 - warfarin; 4 - thiopurines; 5 - tacrolimus. The solid horizontal line indicates the total number of panel tests completed in the entire cohort, and the dotted line indicates the number of panel tests completed in the target population.