Individuals with CYP2C8 and CYP2C9 reduced metabolism haplotypes self-adjusted ibuprofen dose in the Coriell Personalized Medicine Collaborative.

OBJECTIVES: The objectives of this study were to determine whether differences in CYP2C8 and CYP2C9 haplotype influence the dose of ibuprofen self-administered by individuals, and to examine the potential relationship between CYP2C8 and CYP2C9 reduced metabolism haplotypes and adverse events. PARTICIPANTS AND METHODS: We investigated relationships between genetic variations in CYP2C8 and CYP2C9 and ibuprofen use, dose, and side effects (reported by questionnaire) in 445 participants from the Coriell Personalized Medicine Collaborative. RESULTS: Carriers of reduced metabolism haplotypes for CYP2C8 (*2, *3, *4) and CYP2C9 (*2, *3) were significantly (P=0.0171) more likely than those lacking these variants to take less than the recommended dose of ibuprofen, after controlling for sex, age, race, and cohort. In contrast to ibuprofen dose, there were no differences in ibuprofen use frequency or reported side effects based on haplotype. However, there are often no early signs of acute kidney injury, the most serious side effect of elevated ibuprofen exposure. CONCLUSION: These results suggest a subset of individuals with genetic variation in CYP2C8 and CYP2C9 recognize that they obtain adequate drug efficacy with lower ibuprofen doses, or take lower doses due to prior side effects. However, most (82.6%) individuals with reduced metabolism haplotypes nonetheless took recommended or higher doses, potentially putting them at increased risk for side effects.

Operationalizing the Reciprocal Engagement Model of Genetic Counseling Practice: a Framework for the Scalable Delivery of Genomic Counseling and Testing.

With the advent of widespread genomic testing for diagnostic indications and disease risk assessment, there is increased need to optimize genetic counseling services to support the scalable delivery of precision medicine. Here, we describe how we operationalized the reciprocal engagement model of genetic counseling practice to develop a framework of counseling components and strategies for the delivery of genomic results. This framework was constructed based upon qualitative research with patients receiving genomic counseling following online receipt of potentially actionable complex disease and pharmacogenomics reports. Consultation with a transdisciplinary group of investigators, including practicing genetic counselors, was sought to ensure broad scope and applicability of these strategies for use with any large-scale genomic testing effort. We preserve the provision of pre-test education and informed consent as established in Mendelian/single-gene disease genetic counseling practice. Following receipt of genomic results, patients are afforded the opportunity to tailor the counseling agenda by selecting the specific test results they wish to discuss, specifying questions for discussion, and indicating their preference for counseling modality. The genetic counselor uses these patient preferences to set the genomic counseling session and to personalize result communication and risk reduction recommendations. Tailored visual aids and result summary reports divide areas of risk (genetic variant, family history, lifestyle) for each disease to facilitate discussion of multiple disease risks. Post-counseling, session summary reports are actively routed to both the patient and their physician team to encourage review and follow-up. Given the breadth of genomic information potentially resulting from genomic testing, this framework is put forth as a starting point to meet the need for scalable genetic counseling services in the delivery of precision medicine.

Precision Military Medicine: Conducting a multi-site clinical utility study of genomic and lifestyle risk factors in the United States Air Force.

Following several years enrolling disease-specific and otherwise healthy cohorts into the Coriell Personalized Medicine Collaborative, a prospective study aimed at evaluating the clinical utility of personal genomic information for common complex disease and pharmacogenomics, the Coriell Personalized Medicine Collaborative expanded to create a military cohort, specifically, the United States Air Force. Initial recruitment focused on Air Force Medical Service personnel and later expanded to include all Active Duty Air Force members and beneficiaries. Now in its 6th year, the study has produced a wide variety of insights, including optimal study design for military-sponsored genomic research, and discussion on genetic information sharing between and amongst Air Force study participants, civilian and military researchers, and the United States Department of Defense. Over the longer term, analyses will further contribute to the development of policies and processes relevant to clinical decision support and data sharing within the US military, and on-going work with the Air Force Medical Service sub-cohort will generate critical insights into how best to deploy useful genomic information in clinical care. Here we discuss challenges faced and critical success factors for military-civilian collaborations around genomic research.

Clinical pharmacogenomics: patient perspectives of pharmacogenomic testing and the incidence of actionable test results in a chronic disease cohort.

AIM: This study aimed to examine pharmacogenomic test results and patient perspectives at an academic cardiovascular medicine clinic. PATIENTS & METHODS: Test results for three common cardiovascular drug-gene tests (warfarin-CYP2C9-VKORC1, clopidogrel-CYP2C19 and simvastatin-SLCO1B1) of 208 patients in the Ohio State University-Coriell Personalized Medicine Collaborative were examined to determine the incidence of potentially actionable test results. A post-hoc, anonymous, patient survey was also conducted. RESULTS: Potentially actionable test results for at least one of the three drug-gene tests were determined in 170 (82%) patients. Survey responses (n = 134) suggested that patients generally considered their test results to be important (median of 7.5 on a 10-point scale of importance) and were interested (median of 7.3 on a 10-point scale of interest) in a Clinical Pharmacogenomic Service. CONCLUSION: Attitudes toward pharmacogenomic testing were generally favorable, and potentially actionable test results were not uncommon in this cardiovascular medicine cohort.

Outcomes of a Randomized Controlled Trial of Genomic Counseling for Patients Receiving Personalized and Actionable Complex Disease Reports.

There has been very limited study of patients with chronic disease receiving potentially actionable genomic based results or the utilization of genetic counselors in the online result delivery process. We conducted a randomized controlled trial on 199 patients with chronic disease each receiving eight personalized and actionable complex disease reports online. Primary study aims were to assess the impact of in-person genomic counseling on 1) causal attribution of disease risk, 2) personal awareness of disease risk, and 3) perceived risk of developing a particular disease. Of 98 intervention arm participants (mean age = 57.8; 39% female) randomized for in-person genomic counseling, 76 (78%) were seen. In contrast, control arm participants (n = 101; mean age = 58.5; 54% female) were initially not offered genomic counseling as part of the study protocol but were able to access in-person genomic counseling, if they requested it, 3-months post viewing of at least one test report and post-completion of the study-specific follow-up survey. A total of 64 intervention arm and 59 control arm participants completed follow-up survey measures. We found that participants receiving in-person genomic counseling had enhanced objective understanding of the genetic variant risk contribution for multiple complex diseases. Genomic counseling was associated with lowered participant causal beliefs in genetic influence across all eight diseases, compared to control participants. Our findings also illustrate that for the majority of diseases under study, intervention arm participants believed they knew their genetic risk status better than control arm subjects. Disease risk was modified for the majority during genomic counseling, due to the assessment of more comprehensive family history. In conclusion, for patients receiving personalized and actionable genomic results through a web portal, genomic counseling enhanced their objective understanding of the genetic variant risk contribution to multiple common diseases. These results support the development of additional genomic counseling interventions to ensure a high level of patient comprehension and improve patient-centered health outcomes.

CYP2D6 Genetic Variation and Beta-Blocker Maintenance Dose in Patients with Heart Failure.

PURPOSE: This study examined whether a CYP2D6 polymorphism (CYP2D6*4) was related to beta-blocker maintenance dose in patients with heart failure. METHODS: Logistic regression modeling was utilized in a retrospective chart-review analysis of heart-failure patients (60% Male, 90% of European descent) to assess whether CYP2D6*4 (non-functional CYP2D6 allele present in 1 of 5 individuals of European descent) is associated with maintenance dose of carvedilol (n = 65) or metoprolol (n = 33). RESULTS: CYP2D6*4 was associated with lower maintenance dose of metoprolol (OR 0.13 [95% CI 0.02-0.75] p = 0.023), and a trend was observed between CYP2D6*4 and higher maintenance dose of carvedilol (OR 2.94 [95% CI 0.84-10.30] p = 0.093). None of the patients that carried CYP2D6*4 achieved the recommended target dose of metoprolol (200 mg/day). CONCLUSION: Consistent with the role of CYP2D6 in the metabolism of metoprolol, the tolerated maintenance dose of metoprolol was lower in CYP2D6*4 carriers compared to non-carriers. Consistent with the role of CYP2D6 in activation of carvedilol, tolerated maintenance dose of carvedilol was higher in CYP2D6*4 carriers compared to non-carriers. Further investigation is warranted to ascertain the potential of CYP2D6 as a potential predictive biomarker of beta-blocker maintenance dose in heart failure patients.

Counselees' Perspectives of Genomic Counseling Following Online Receipt of Multiple Actionable Complex Disease and Pharmacogenomic Results: a Qualitative Research Study.

Genomic applications raise multiple challenges including the optimization of genomic counseling (GC) services as part of the results delivery process. More information on patients' motivations, preferences, and informational needs are essential to guide the development of new, more efficient practice delivery models that capitalize on the existing strengths of a limited genetic counseling workforce. Semi-structured telephone interviews were conducted with a subset of counselees from the Coriell Personalized Medicine Collaborative following online receipt of multiple personalized genomic test reports. Participants previously had either in-person GC (chronic disease cohort, n = 20; mean age 60 years) or telephone GC (community cohort, n = 31; mean age 46.8 years). Transcripts were analyzed using a Grounded Theory framework. Major themes that emerged from the interviews include 1) primary reasons for seeking GC were to clarify results, put results into perspective relative to other health-related concerns, and to receive personalized recommendations; 2) there is need for a more participant driven approach in terms of mode of GC communication (in-person, phone, video), and refining the counseling agenda pre-session; and 3) there was strong interest in the option of follow up GC. By clarifying counselees' expectations, views and desired outcomes, we have uncovered a need for a more participant-driven GC model when potentially actionable genomic results are received online.

A randomized trial Examining The Impact Of Communicating Genetic And Lifestyle Risks For Obesity.

OBJECTIVE: Genetic testing for obesity is available directly to consumers, yet little is understood about its behavioral impact and its added value to nongenetic risk communication efforts based on lifestyle factors. METHODS: A randomized trial examined the short-term impact of providing personalized obesity risk information, using a 2 × 2 factorial design. Participants were recruited from the Coriell Personalized Medicine Collaborative (CPMC) and randomized to receive (1) no risk information (control), (2) genetic risk, (3) lifestyle risk, or (4) combined genetic/lifestyle risks. Baseline and 3-month follow-up survey data were collected. Analyses examined the impact of risk feedback on intentions to lose weight and self-reported weight. RESULTS: A total of 696 participants completed the study. A significant interaction effect was observed for genetic and lifestyle information on intent to lose weight (P = 0.0150). Those who received genetic risk alone had greater intentions at follow-up, compared with controls (P = 0.0034). The impact of receiving elevated risk information on intentions varied by source and combination of risks presented. Non-elevated genetic risk did not lower intentions. No group differences were observed for self-reported weight. CONCLUSIONS: Genetic risk information for obesity may add value to lifestyle risk information depending on the context in which it is presented.

Challenges in Translating GWAS Results to Clinical Care.

Clinical genetic testing for Mendelian disorders is standard of care in many cases; however, it is less clear to what extent and in which situations clinical genetic testing may improve preventive efforts, diagnosis and/or prognosis of complex disease. One challenge is that much of the reported research relies on tag single nucleotide polymorphisms (SNPs) to act as proxies for assumed underlying functional variants that are not yet known. Here we use coronary artery disease and melanoma as case studies to evaluate how well reported genetic risk variants tag surrounding variants across population samples in the 1000 Genomes Project Phase 3 data. We performed a simulation study where we randomly assigned a "functional" variant and evaluated how often this simulated functional variant was correctly tagged in diverse population samples. Our results indicate a relatively large error rate when generalizing increased genetic risk of complex disease across diverse population samples, even when generalizing within geographic regions. Our results further highlight the importance of including diverse populations in genome-wide association studies. Future work focused on identifying functional variants will eliminate the need for tag SNPs; however, until functional variants are known, caution should be used in the interpretation of genetic risk for complex disease using tag SNPs.

An expanded pharmacogenomics warfarin dosing table with utility in generalised dosing guidance.

Pharmacogenomics (PGx) guided warfarin dosing, using a comprehensive dosing algorithm, is expected to improve dose optimisation and lower the risk of adverse drug reactions. As a complementary tool, a simple genotype-dosing table, such as in the US Food and Drug Administration (FDA) Coumadin drug label, may be utilised for general risk assessment of likely over- or under-anticoagulation on a standard dose of warfarin. This tool may be used as part of the clinical decision support for the interpretation of genetic data, serving as a first step in the anticoagulation therapy decision making process. Here we used a publicly available warfarin dosing calculator (www.warfarindosing.org) to create an expanded gene-based warfarin dosing table, the CPMC-WD table that includes nine genetic variants in CYP2C9, VKORC1, and CYP4F2. Using two datasets, a European American cohort (EUA, n=73) and the Quebec Warfarin Cohort (QWC, n=769), we show that the CPMC-WD table more accurately predicts therapeutic dose than the FDA table (51 % vs 33 %, respectively, in the EUA, McNemar's two-sided p=0.02; 52 % vs 37 % in the QWC, p<1×10(-6)). It also outperforms both the standard of care 5 mg/day dosing (51 % vs 34 % in the EUA, p=0.04; 52 % vs 31 % in the QWC, p<1×10(-6)) as well as a clinical-only algorithm (51 % vs 38 % in the EUA, trend p=0.11; 52 % vs 45 % in the QWC, p=0.003). This table offers a valuable update to the PGx dosing guideline in the drug label.

Toward clinical genomics in everyday medicine: perspectives and recommendations.

Precision or personalized medicine through clinical genome and exome sequencing has been described by some as a revolution that could transform healthcare delivery, yet it is currently used in only a small fraction of patients, principally for the diagnosis of suspected Mendelian conditions and for targeting cancer treatments. Given the burden of illness in our society, it is of interest to ask how clinical genome and exome sequencing can be constructively integrated more broadly into the routine practice of medicine for the betterment of public health. In November 2014, 46 experts from academia, industry, policy and patient advocacy gathered in a conference sponsored by Illumina, Inc. to discuss this question, share viewpoints and propose recommendations. This perspective summarizes that work and identifies some of the obstacles and opportunities that must be considered in translating advances in genomics more widely into the practice of medicine.

Genetic Knowledge Among Participants in the Coriell Personalized Medicine Collaborative.

Genetic literacy is essential for the effective integration of genomic information into healthcare; yet few recent studies have been conducted to assess the current state of this knowledge base. Participants in the Coriell Personalized Medicine Collaborative (CPMC), a prospective study assessing the impact of personalized genetic risk reports for complex diseases and drug response on behavior and health outcomes, completed genetic knowledge questionnaires and other surveys through an online portal. To assess the association between genetic knowledge and genetic education background, multivariate linear regression was performed. 4 062 participants completed a genetic knowledge and genetic education background questionnaire. Most were older (mean age: 50), Caucasian (90 %), female (59 %), highly educated (69 % bachelor's or higher), with annual household income over $100 000 (49 %). Mean percent correct was 76 %. Controlling for demographics revealed that health care providers, participants previously exposed to genetics, and participants with 'better than most' self-rated knowledge were significantly more likely to have a higher knowledge score (p < 0.001). Overall, genetic knowledge was high with previous genetic education experience predictive of higher genetic knowledge score. Education is likely to improve genetic literacy, an important component to expanded use of genomics in personalized medicine.

Using the Coriell Personalized Medicine Collaborative Data to conduct a genome-wide association study of sleep duration.

Sleep is critical to health and functionality, and several studies have investigated the inherited component of insomnia and other sleep disorders using genome-wide association studies (GWAS). However, genome-wide studies focused on sleep duration are less common. Here, we used data from participants in the Coriell Personalized Medicine Collaborative (CPMC) (n = 4,401) to examine putative associations between self-reported sleep duration, demographic and lifestyle variables, and genome-wide single nucleotide polymorphism (SNP) data to better understand genetic contributions to variation in sleep duration. We employed stepwise ordered logistic regression to select our model and retained the following predictive variables: age, gender, weight, physical activity, physical activity at work, smoking status, alcohol consumption, ethnicity, and ancestry (as measured by principal components analysis) in our association testing. Several of our strongest candidate genes were previously identified in GWAS related to sleep duration (TSHZ2, ABCC9, FBXO15) and narcolepsy (NFATC2, SALL4). In addition, we have identified novel candidate genes for involvement in sleep duration including SORCS1 and ELOVL2. Our results demonstrate that the self-reported data collected through the CPMC are robust, and our genome-wide association analysis has identified novel candidate genes involved in sleep duration. More generally, this study contributes to a better understanding of the complexity of human sleep.

Common genetic risk for melanoma encourages preventive behavior change.

There is currently great interest in using genetic risk estimates for common disease in personalized healthcare. Here we assess melanoma risk-related preventive behavioral change in the context of the Coriell Personalized Medicine Collaborative (CPMC). As part of on-going reporting activities within the project, participants received a personalized risk assessment including information related to their own self-reported family history of melanoma and a genetic risk variant showing a moderate effect size (1.7, 3.0 respectively for heterozygous and homozygous individuals). Participants who opted to view their report were sent an optional outcome survey assessing risk perception and behavioral change in the months that followed. Participants that report family history risk, genetic risk, or both risk factors for melanoma were significantly more likely to increase skin cancer preventive behaviors when compared to participants with neither risk factor (ORs = 2.04, 2.79, 4.06 and p-values = 0.02, 2.86 × 10-5, 4.67 × 10-5, respectively), and we found the relationship between risk information and behavior to be partially mediated by anxiety. Genomic risk assessments appear to encourage positive behavioral change in a manner that is complementary to family history risk information and therefore may represent a useful addition to standard of care for melanoma prevention.

Design and implementation of a randomized controlled trial of genomic counseling for patients with chronic disease.

We describe the development and implementation of a randomized controlled trial to investigate the impact of genomic counseling on a cohort of patients with heart failure (HF) or hypertension (HTN), managed at a large academic medical center, the Ohio State University Wexner Medical Center (OSUWMC). Our study is built upon the existing Coriell Personalized Medicine Collaborative (CPMC®). OSUWMC patient participants with chronic disease (CD) receive eight actionable complex disease and one pharmacogenomic test report through the CPMC® web portal. Participants are randomized to either the in-person post-test genomic counseling-active arm, versus web-based only return of results-control arm. Study-specific surveys measure: (1) change in risk perception; (2) knowledge retention; (3) perceived personal control; (4) health behavior change; and, for the active arm (5), overall satisfaction with genomic counseling. This ongoing partnership has spurred creation of both infrastructure and procedures necessary for the implementation of genomics and genomic counseling in clinical care and clinical research. This included creation of a comprehensive informed consent document and processes for prospective return of actionable results for multiple complex diseases and pharmacogenomics (PGx) through a web portal, and integration of genomic data files and clinical decision support into an EPIC-based electronic medical record. We present this partnership, the infrastructure, genomic counseling approach, and the challenges that arose in the design and conduct of this ongoing trial to inform subsequent collaborative efforts and best genomic counseling practices.

Genetic testing of children for predisposition to mood disorders: anticipating the clinical issues.

Large-scale sequencing information may provide a basis for genetic tests for predisposition to common disorders. In this study, participants in the Coriell Personalized Medicine Collaborative (N = 53) with a personal and/or family history of Major Depressive Disorder or Bipolar Disorder were interviewed based on the Health Belief Model around hypothetical intention to test one's children for probability of developing a mood disorder. Most participants (87 %) were interested in a hypothetical test for children that had high ("90 %") positive predictive value, while 51 % of participants remained interested in a modestly predictive test ("20 %"). Interest was driven by beliefs about effects of test results on parenting behaviors and on discrimination. Most participants favored testing before adolescence (64 %), and were reluctant to share results with asymptomatic children before adulthood. Participants anticipated both positive and negative effects of testing on parental treatment and on children's self-esteem. Further investigation will determine whether these findings will generalize to other complex disorders for which early intervention is possible but not clearly demonstrated to improve outcomes. More information is also needed about the effects of childhood genetic testing and sharing of results on parent-child relationships, and about the role of the child in the decision-making process.

Personalized genomic results: analysis of informational needs.

Use of genomic information in healthcare is increasing; however data on the needs of consumers of genomic information is limited. The Coriell Personalized Medicine Collaborative (CPMC) is a longitudinal study investigating the utility of personalized medicine. Participants receive results reflecting risk of common complex conditions and drug-gene pairs deemed actionable by an external review board. To explore the needs of individuals receiving genomic information we reviewed all genetic counseling sessions with CPMC participants. A retrospective qualitative review of notes from 157 genetic counseling inquiries was conducted. Notes were coded for salient themes. Five primary themes; "understanding risk", "basic genetics", "complex disease genetics", "what do I do now?" and "other" were identified. Further review revealed that participants had difficulty with basic genetic concepts, confused relative and absolute risks, and attributed too high a risk burden to individual single nucleotide polymorphisms (SNPs). Despite these hurdles, counseled participants recognized that behavior changes could potentially mitigate risk and there were few comments alluding to an overly deterministic or fatalistic interpretation of results. Participants appeared to recognize the multifactorial nature of the diseases for which results were provided; however education to understand the complexities of genomic risk information was often needed.

A randomized trial of the clinical utility of genetic testing for obesity: design and implementation considerations.

BACKGROUND: Obesity rates in the United States have escalated in recent decades and present a major challenge in public health prevention efforts. Currently, testing to identify genetic risk for obesity is readily available through several direct-to-consumer companies. Despite the availability of this type of testing, there is a paucity of evidence as to whether providing people with personal genetic information on obesity risk will facilitate or impede desired behavioral responses. PURPOSE: We describe the key issues in the design and implementation of a randomized controlled trial examining the clinical utility of providing genetic risk information for obesity. METHODS: Participants are being recruited from the Coriell Personalized Medicine Collaborative, an ongoing, longitudinal research cohort study designed to determine the utility of personal genome information in health management and clinical decision making. The primary focus of the ancillary Obesity Risk Communication Study is to determine whether genetic risk information added value to traditional communication efforts for obesity, which are based on lifestyle risk factors. The trial employs a 2 × 2 factorial design in order to examine the effects of providing genetic risk information for obesity, alone or in combination with lifestyle risk information, on participants' psychological responses, behavioral intentions, health behaviors, and weight. RESULTS: The factorial design generated four experimental arms based on communication of estimated risk to participants: (1) no risk feedback (control), (2) genetic risk only, (3) lifestyle risk only, and (4) both genetic and lifestyle risk (combined). Key issues in study design pertained to the selection of algorithms to estimate lifestyle risk and determination of information to be provided to participants assigned to each experimental arm to achieve a balance between clinical standards and methodological rigor. Following the launch of the trial in September 2011, implementation challenges pertaining to low enrollment and differential attrition became apparent and required immediate attention and modifications to the study protocol. Although monitoring of these efforts is ongoing, initial observations show a doubling of enrollment and reduced attrition. LIMITATIONS: The trial is evaluating the short-term impact of providing obesity risk information as participants are followed for only 3 months. This study is built upon the structure of an existing personalized medicine study wherein participants have been provided with genetic information for other diseases. This nesting in a larger study may attenuate the effects of obesity risk information and has implications for the generalizability of study findings. CONCLUSIONS: This randomized trial examines value of obesity genetic information, both when provided independently and when combined with lifestyle risk assessment, to motivate individuals to engage in healthy lifestyle behaviors. Study findings will guide future intervention efforts to effectively communicate genetic risk information.

The Coriell personalized medicine collaborative pharmacogenomics appraisal, evidence scoring and interpretation system.

Implementation of pharmacogenomics (PGx) in clinical care can lead to improved drug efficacy and reduced adverse drug reactions. However, there has been a lag in adoption of PGx tests in clinical practice. This is due in part to a paucity of rigorous systems for translating published clinical and scientific data into standardized diagnostic tests with clear therapeutic recommendations. Here we describe the Pharmacogenomics Appraisal, Evidence Scoring and Interpretation System (PhAESIS), developed as part of the Coriell Personalized Medicine Collaborative research study, and its application to seven commonly prescribed drugs.