Patients' Perspectives on Psychiatric Pharmacogenetic Testing.

INTRODUCTION: There is growing interest to adopt pharmacogenetic (PGx) testing in psychiatric medicine, despite mixed views regarding its clinical utility. Nevertheless, providers are utilizing PGx testing among patients with mental health disorders. This study sought to assess genotyped patients' perspectives and experiences with psychiatric PGx testing. METHODS: Individual semi-structured interviews were conducted among patients with depression who had undergone psychiatric PGx testing. The audio-recorded interviews were transcribed and analyzed inductively and deductively for salient themes. RESULTS: Twenty patients (100% Caucasian, 60% female, mean age 39±18 years) were interviewed. The majority of the PGx tests were provider-initiated for patients who failed multiple pharmacotherapies (50%) and/or had medication intolerances (45%). Patients' pre-testing expectations ranged from hopefulness to indifference to skepticism. Their post-testing experiences varied from optimism to disappointment, with the perceived value of the test influenced by the results and cost of the test. DISCUSSION: Genotyped patients had mixed perspectives, expectations, and experiences with psychiatric PGx testing. Their perceived value of the test was influenced by the test outcomes and its cost.

Association of Genetic Variants With Warfarin-Associated Bleeding Among Patients of African Descent.

Importance: Major warfarin-related bleeding occurs more frequently in African Americans than in other populations. Identification of potential genetic factors related to this adverse event may help identify at-risk patients. Objective: To identify genetic factors associated with warfarin-related bleeding in patients of African descent at an international normalized ratio (INR) of less than 4. Design, Setting, and Participants: A case-control genome-wide association study involving patients of African descent taking warfarin was conducted in a discovery cohort (University of Chicago [2009-2011] and the University of Illinois at Chicago [2002-2011]), and associations were confirmed in a replication cohort (University of Chicago [2015-2016]). Potential population stratification was examined in the discovery cohort by principal component analysis. Odds ratios (ORs) and 95% CIs were computed for bleeding risk by logistic regression analysis. Summary statistics from the discovery and the replication cohorts were analyzed with a fixed effects meta-analysis. The potential influence of single-nucleotide polymorphisms (SNPs) on gene expression was studied by luciferase expression assays. Exposures: Single-nucleotide polymorphisms associated with warfarin-related bleeding. Main Outcomes and Measures: Major bleeding-defined as bleeding requiring hospitalization, causing a decrease in hemoglobin level of more than 2 g/dL, requiring blood transfusion, or any combination of the 3-while taking warfarin at an INR of less than 4. Results: The discovery cohort consisted of 31 cases (mean age, 60.1 years [SD, 14.9 years], 26 women [83.9%]) and 184 warfarin-treated controls (mean age, 57.1 years [SD, 15.7 years]) with no documented bleeding. The replication cohort consisted of 40 cases (mean age, 55.6 years [SD, 17.3 years], 27 women [67.5%]), and 148 warfarin-treated controls (mean age, 55.4 years [SD, 17.1 years]; 98 women [66.2%]) with no documented bleeding. In the discovery cohort, 4 SNPs in linkage disequilibrium on chromosome 6 (rs115112393, rs16871327, rs78132896, and rs114504854) were associated with warfarin-related bleeding but did not reach genome-wide significance. The SNP rs78132896 occurred in 11 cases (35.5%) and 9 controls (4.9%) in the discovery cohort (OR, 8.31; 95% CI, 3.2-21.5; P < 6.21 × 10-8), and the association was confirmed in the replication cohort (the SNP was present in 14 cases [35.0%] and 7 controls [4.8%]; OR, 8.24; 95% CI, 3.1-25.3, P = 5.64 × 10-5). Genome-wide significance of this SNP was achieved when the cohorts were combined via meta-analysis (OR, 8.27; 95% CI, 4.18-16.38; P = 2.05 × 10-11). These SNPs are found only in people of African descent. In vitro luciferase expression assays demonstrated that rs16871327 (enhancer SNP) and rs78132896 (promoter SNP) risk alleles together increased EPHA7 gene (Entrez Gene 2045) transcription by a mean of 14.95 (SD, 1.7) compared with wild-type alleles (mean, 9.56 [SD, 0.84]; difference, 5.39; 95% CI, 4.1-6.6; P < .001). Conclusions and Relevance: In this preliminary study involving patients of African descent taking warfarin, 4 single-nucleotide polymorphisms in linkage disequilibrium on chromosome 6 were associated with an increased risk of major bleeding at INR of less than 4. Validation of these findings in an independent prospective cohort is required.

Implementation of a pharmacist-provided pharmacogenomics service in an executive health program.

PURPOSE: We describe the implementation of a pharmacist-provided pharmacogenomics (PGx) service in an executive health program (EHP) at an academic medical center. SUMMARY: As interest in genomic testing grows, pharmacists have the opportunity to advance the use of PGx in EHPs, in collaboration with other healthcare professionals. In November 2018, a pharmacist-provided PGx service was established in the EHP at the University of Colorado Hospital. The team members included 3 physicians, a pharmacist trained in PGx, a registered dietitian/exercise physiologist, a nurse, and 2 medical assistants. We conducted 4 preimplementation steps: (1) assessment of the patient population, (2) selection of a PGx test, (3) establishment of a visit structure, and (4) selection of a billing model. The PGx consultations involved two 1-hour visits. The first visit encompassed pretest PGx education, review of the patient's current medications and previous medication intolerances, and DNA sample collection for genotyping. After this visit, the pharmacist developed a therapeutic plan based on the PGx test results, discussed the results and plan with the physician, and created a personalized PGx report. At the second visit, the pharmacist reviewed the PGx test results, personalized the PGx report, and discussed the PGx-guided therapeutic plan with the patient. Overall, the strategy worked well; minor challenges included evaluation of gene-drug pairs with limited PGx evidence, communication of information to non-EHP providers, scheduling issues, and reimbursement. CONCLUSION: The addition of a PGx service within an EHP was feasible and provided pharmacists the opportunity to lead PGx efforts and collaborate with physicians to expand the precision medicine footprint at an academic medical center.

Providers' perspectives on the clinical utility of pharmacogenomic testing in pediatric patients.

Aim: To assess providers' knowledge, attitudes, perceptions, and experiences related to pharmacogenomic (PGx) testing in pediatric patients. Materials & methods: An electronic survey was sent to multidisciplinary healthcare providers at a pediatric hospital. Results: Of 261 respondents, 71.3% were slightly or not at all familiar with PGx, despite 50.2% reporting prior PGx education or training. Most providers, apart from psychiatry, perceived PGx to be at least moderately useful to inform clinical decisions. However, only 26.4% of providers had recent PGx testing experience. Unfamiliarity with PGx and uncertainty about the clinical value of testing were common perceived challenges. Conclusion: Low PGx familiarity among pediatric providers suggests additional education and electronic resources are needed for PGx examples in which data support testing in children.

Clinical implementation of pharmacogenomics via a health system-wide research biobank: the University of Colorado experience.

In recent years, the genomics community has witnessed the growth of large research biobanks, which collect DNA samples for research purposes. Depending on how and where the samples are genotyped, biobanks also offer the potential opportunity to return actionable genomic results to the clinical setting. We developed a preemptive clinical pharmacogenomic implementation initiative via a health system-wide research biobank at the University of Colorado. Here, we describe how preemptive return of clinical pharmacogenomic results via a research biobank is feasible, particularly when coupled with strong institutional support to maximize the impact and efficiency of biobank resources, a multidisciplinary implementation team, automated clinical decision support tools, and proactive strategies to engage stakeholders early in the clinical decision support tool development process.

Clinical effect of CYP2C9*5/*6 genotype on a patient's warfarin dose requirement.

We describe a 38-year-old African-American female treated with warfarin for acute bilateral pulmonary emboli who is a carrier of two rare CYP2C9 variant alleles, *5 and *6, along with VKORC1 -1639GG and CYP4F2 433Val/Val genotypes. Warfarin was dosed according to the hospital's Personalized Medicine Program recommendations of 5-6 mg/day for the first 6 days, and reduced to 2.5 mg/day starting on day 8 and continued for the following 3 weeks. This case sheds further light on the cumulative clinical impact of the CYP2C9 variant alleles, *5 and *6, on warfarin dose requirements and practical considerations for warfarin genotyping in a racially and ethnically diverse population.