Strategic vision for improving human health at The Forefront of Genomics.

Starting with the launch of the Human Genome Project three decades ago, and continuing after its completion in 2003, genomics has progressively come to have a central and catalytic role in basic and translational research. In addition, studies increasingly demonstrate how genomic information can be effectively used in clinical care. In the future, the anticipated advances in technology development, biological insights, and clinical applications (among others) will lead to more widespread integration of genomics into almost all areas of biomedical research, the adoption of genomics into mainstream medical and public-health practices, and an increasing relevance of genomics for everyday life. On behalf of the research community, the National Human Genome Research Institute recently completed a multi-year process of strategic engagement to identify future research priorities and opportunities in human genomics, with an emphasis on health applications. Here we describe the highest-priority elements envisioned for the cutting-edge of human genomics going forward-that is, at 'The Forefront of Genomics'.

Prophylactic Fixation Can Be Cost-effective in Preventing a Contralateral Bisphosphonate-associated Femur Fracture.

BACKGROUND: Bisphosphonates reduce the risk of fractures associated with osteoporosis but increase the risk of atypical subtrochanteric femur fractures. After unilateral atypical femur fracture, there is risk of contralateral fracture, but the indications for prophylactic fixation are controversial. QUESTIONS/PURPOSES: The purpose of this study is to use Markov modeling to determine whether contralateral prophylactic femur fracture fixation is cost-effective after a bisphosphonate-associated atypical femur fracture and, if so, what patient-related factors may influence that determination. METHODS: Markov modeling was used to determine the cost-effectiveness of contralateral prophylactic fixation after an initial atypical femur fracture. Simulated patients aged 60 to 90 years were included and separated into standard and high fracture risk cohorts. Patients with standard fracture risk were defined as those presenting with one atypical femur fracture but without symptoms or findings in the contralateral femur, whereas patients with high fracture risk were typified as those with more than one risk factor, including Asian ethnicity, prodromal pain, femoral geometry changes, or radiographic findings in the contralateral femur. Outcome probabilities and utilities were derived from studies matching to patient characteristics, and fragility fracture literature was used when atypical femur fracture data were not available. Associated costs were largely derived from Medicare 2015 reimbursement rates. Sensitivity analysis was performed on all model parameters within defined ranges. RESULTS: Prophylactic fixation for a 70-year-old patient with standard risk for fracture costs USD 131,300/quality-adjusted life-year (QALY) and for high-risk patients costs USD 22,400/QALY. Sensitivity analysis revealed that prophylaxis for high-risk patients is cost-effective at USD 100,000/QALY when the cost of prophylaxis was less than USD 29,400, the probability of prophylaxis complications was less than 21%, or if the patient was younger than 89 years old. The parameters to which the model was most sensitive were the cost of prophylaxis, patient age, and probability of prophylaxis-related complications. CONCLUSIONS: Prophylactic fixation of the contralateral side after unilateral atypical femur fracture is not cost-effective for standard-risk patients but is cost-effective among high-risk patients between 60 and 89 years of age with a high risk for an atypical femur fracture defined by patients with more than one risk factor such as Asian ethnicity, prodromal pain, varus proximal femur geometry, femoral bowing, or radiographic changes such as periosteal beaking and a transverse radiolucent line. However, our findings are based on several key assumptions for modeling such as the probability of fractures and complications, the costs associated for each health state, and the risks of surgical treatment. Future research should prospectively evaluate the degree of risk contributed by known radiographic and demographic parameters to guide management of the contralateral femur after a patient presents with an atypical femur fracture. LEVEL OF EVIDENCE: Level III, economic and decision analyses.

High Rate of Failure After Revision of a Constrained Liner.

BACKGROUND: The purpose of this study was to examine the outcomes of repeat revision after failure of a constrained liner. METHODS: We reviewed 1212 consecutive revisions and identified 74 (6%) revisions of a failed constrained liner in 46 patients with a mean age of 65 years. The most common reasons for revision of a constrained liner were recurrent instability (64.9%) and infection (25.7%). RESULTS: At a mean of 35 months, 42 of the 74 hips (57%) required repeat revision. Kaplan-Meier revision-free survival was 24% at 10 years. Thirty-two of the 74 revisions (43%) had a dislocation event after the index revision. Kaplan-Meier dislocation-free survival was 43% at 10 years. There was a higher failure rate among the 34 patients with abductor deficiency (hazard ratio 1.90, 95% confidence interval, 1.06-3.43; P = .032). CONCLUSION: Patients undergoing revision of a failed constrained liner have a high likelihood of recurrent dislocation and repeat revision surgery. LEVEL OF EVIDENCE: Level IV.

A Survey of U.S Adults' Opinions about Conduct of a Nationwide Precision Medicine Initiative® Cohort Study of Genes and Environment.

OBJECTIVES: A survey of a population-based sample of U.S adults was conducted to measure their attitudes about, and inform the design of the Precision Medicine Initiative's planned national cohort study. METHODS: An online survey was conducted by GfK between May and June of 2015. The influence of different consent models on willingness to share data was examined by randomizing participants to one of eight consent scenarios. RESULTS: Of 4,777 people invited to take the survey, 2,706 responded and 2,601 (54% response rate) provided valid responses. Most respondents (79%) supported the proposed study, and 54% said they would definitely or probably participate if asked. Support for and willingness to participate in the study varied little among demographic groups; younger respondents, LGBT respondents, and those with more years of education were significantly more likely to take part if asked. The most important study incentive that the survey asked about was learning about one's own health information. Willingness to share data and samples under broad, study-by-study, menu and dynamic consent models was similar when a statement about transparency was included in the consent scenarios. Respondents were generally interested in taking part in several governance functions of the cohort study. CONCLUSIONS: A large majority of the U.S. adults who responded to the survey supported a large national cohort study. Levels of support for the study and willingness to participate were both consistent across most demographic groups. The opportunity to learn health information about one's self from the study appears to be a strong motivation to participate.

Navigating a research partnership between academia and industry to assess the impact of personalized genetic testing.

PURPOSE: To describe the process of structuring a partnership between academic researchers and two personalized genetic testing companies that would manage conflicts of interest while allowing researchers to study the impact of this nascent industry. METHODS: We developed a transparent process of ongoing communication about the interests of all research partners to address challenges in establishing study goals, survey development, data collection, analysis, and manuscript preparation. Using the existing literature on conflicts of interest and our experience, we created a checklist for academic and industry researchers seeking to structure research partnerships. RESULTS: Our checklist includes questions about the risk to research participants, sponsorship of the study, control of data analysis, freedom to publish results, the impact of the research on industry customers, openness to input from all partners, sharing results before publication, and publication of industry-specific data. Transparency is critical to building trust between partners. Involving all partners in the research development enhanced the quality of our research and provided an opportunity to manage conflicts early in the research process. CONCLUSION: Navigating relationships between academia and industry is complex and requires strategies that are transparent and responsive to the concerns of all. Employing a checklist of questions prior to beginning a research partnership may help to manage conflicts of interest.

Risky business: risk perception and the use of medical services among customers of DTC personal genetic testing.

Direct-to-consumer genetic testing has generated speculation about how customers will interpret results and how these interpretations will influence healthcare use and behavior; however, few empirical data on these topics exist. We conducted an online survey of DTC customers of 23andMe, deCODEme, and Navigenics to begin to address these questions. Random samples of U.S. DTC customers were invited to participate. Survey topics included demographics, perceptions of two sample DTC results, and health behaviors following DTC testing. Of 3,167 DTC customers invited, 33% (n = 1,048) completed the survey. Forty-three percent of respondents had sought additional information about a health condition tested; 28% had discussed their results with a healthcare professional; and 9% had followed up with additional lab tests. Sixteen percent of respondents had changed a medication or supplement regimen, and one-third said they were being more careful about their diet. Many of these health-related behaviors were significantly associated with responses to a question that asked how participants would perceive their colon cancer risk (as low, moderate, or high) if they received a test result showing an 11% lifetime risk, as compared to 5% risk in the general population. Respondents who would consider themselves to be at high risk for colon cancer were significantly more likely to have sought information about a disease (p = 0.03), discussed results with a physician (p = 0.05), changed their diet (p = 0.02), and started exercising more (p = 0.01). Participants' personal health contexts--including personal and family history of disease and quality of self-perceived health--were also associated with health-related behaviors after testing. Subjective interpretations of genetic risk data and personal context appear to be related to health behaviors among DTC customers. Sharing DTC test results with healthcare professionals may add perceived utility to the tests.

Public opinion about the importance of privacy in biobank research.

Concerns about privacy may deter people from participating in genetic research. Recruitment and retention of biobank participants requires understanding the nature and magnitude of these concerns. Potential participants in a proposed biobank were asked about their willingness to participate, their privacy concerns, informed consent, and data sharing. A representative survey of 4659 U.S. adults was conducted. Ninety percent of respondents would be concerned about privacy, 56% would be concerned about researchers having their information, and 37% would worry that study data could be used against them. However, 60% would participate in the biobank if asked. Nearly half (48%) would prefer to provide consent once for all research approved by an oversight panel, whereas 42% would prefer to provide consent for each project separately. Although 92% would allow academic researchers to use study data, 80% and 75%, respectively, would grant access to government and industry researchers. Concern about privacy was related to lower willingness to participate only when respondents were told that they would receive $50 for participation and would not receive individual research results back. Among respondents who were told that they would receive $200 or individual research results, privacy concerns were not related to willingness. Survey respondents valued both privacy and participation in biomedical research. Despite pervasive privacy concerns, 60% would participate in a biobank. Assuring research participants that their privacy will be protected to the best of researchers' abilities may increase participants' acceptance of consent for broad research uses of biobank data by a wide range of researchers.

Preimplantation genetic screening: a survey of in vitro fertilization clinics.

PURPOSE: The purpose of this study was to determine which US in vitro fertilization clinics provide preimplantation genetic screening for aneuploidy in treating infertility, and to explore clinic directors' attitudes toward this technique. METHODS: Online survey included 415 US assisted reproductive technology clinics. The survey had a valid response rate of 45% or 186 clinics. RESULTS: Nearly 68% of US in vitro fertilization clinics responding to the survey provided preimplantation genetic screening in an effort to increase success rates of fertility treatment. More than half of these in vitro fertilization clinics (56%) provided preimplantation genetic screening for advanced maternal age and the same percentage provided preimplantation genetic screening to treat repeated in vitro fertilization failure, whereas 66% provided preimplantation genetic screening to treat women with repeated miscarriage. Opinions of the effectiveness of preimplantation genetic screening for these indications varied widely, even among those providing it. Most directors (85%) of clinics providing preimplantation genetic screening believed that more data are needed to determine whether and to whom it should be offered. CONCLUSIONS: Despite the lack of data supporting the use of preimplantation genetic screening for recurrent pregnancy loss, in vitro fertilization failure, and advanced maternal age, a majority of in vitro fertilization clinics in the United States offer preimplantation genetic screening for these purposes. There is significant support among clinic directors for more research into the effectiveness of preimplantation genetic screening and for professional guidelines in this area.

Prevalence of smoking and its relationship with carotid atherosclerosis in Alaskan Eskimos of the Norton Sound region: the GOCADAN study.

Since 2000, the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) study has been collecting information on cardiovascular disease (CVD) and its risk factors from 1,214 Alaska Natives of the Norton Sound region, a population with increasing rates of heart disease and stroke. Because smoking was reported in a large proportion of the participants, this analysis was undertaken to evaluate smoking patterns and their relation to other risk factors and to CVD. The relationships among smoking habits and demographic factors, body mass index, plasma fibrinogen, prevalent hypertension, and carotid plaque were evaluated. Eighty percent of participants had smoked 100+ cigarettes in their lifetime. Fifty-seven percent of women and 63% of men (p = .12) were current smokers: one in four smokers had quit. Current smokers (OR = 2.1; 95% CI = 1.1-3.8) and those who had quit <5 years ago (OR = 1.6; 95% CI = 1.1-2.2) were more likely than non-smokers to have carotid plaque. Pack-years smoked also were correlated with carotid plaque. The high prevalence of smoking and low rates of cessation in this population demonstrate an urgent need for smoking prevention and cessation programs among Alaskan Eskimos of the Norton Sound region and other Alaska Native groups.

A genetic and epidemiologic study of cardiovascular disease in Alaska natives (GOCADAN): design and methods.

This article is a report of the design and methods of the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) Study. This longitudinal, population-based study was initiated to investigate the genetic determinants of cardiovascular disease and its risk factors. Between October 2000 and April 2004, this family study enrolled 1,214 Eskimos from several coastal villages in the Norton Sound region of Western Alaska. Examinations included a physical, laboratory determinations, and measures of subclinical disease. This study will generate a genome-wide scan for loci influencing cardiovascular disease-related traits. Relations between subclinical atherosclerosis and markers of inflammation will be examined using historic and newly drawn samples. The study will provide data on CVD prevalence, risk factors and the relative contribution of genetic and environmental determinants in Alaska Native peoples. Data from this study will contribute to the delivery of health-care and prevention of CVD in Alaska Eskimos and other populations.

The PRICE clinic for low-income elderly: a managed care model for implementing pharmacist-directed services.

OBJECTIVES: The Medicare Modernization Act of 2003 calls for medication therapy management programs (MTMPs) to control anticipated growth in drug use and expenditures. In 2006, prescription drug plan sponsors, including health plans, pharmacy benefit managers, and other entities, will be required to offer MTMP services performed by pharmacists or other health professionals. The Pharmacist Review to Increase Cost Effectiveness (PRICE) Clinic in Sacramento, California, is a pharmacist-directed, multidisciplinary model that is adaptable to providing MTMP services in a managed care setting. The PRICE Clinic serves a 3-fold mission: (1) to help low-income elderly patients decrease out-of-pocket (OOP) drug expenses; (2) to ensure that patients receive clinically appropriate, cost-effective drug regimens; and (3) to improve access to needed medications. The objectives of this study were to characterize and document the number and type of PRICE clinic interventions; measure changes in generic drug use; document savings in OOP drug costs; and measure patient access to drugs that had been, or would have been, discontinued because of cost. METHODS: A noncontrolled retrospective PRICE Clinic database review was conducted for the 520 patients seen in the PRICE Clinic in calendar year 2002. Study participants were low-income elderly with multiple chronic diseases, multiple medications, and high drug costs. For each patient, researchers documented the number and type of interventions performed by pharmacists and the drug class involved in each intervention. Changes in generic drug use and OOP costs were assessed by a preanalysis and postanalysis of selected outcome variables and a comparison of results with comparable patient populations in large state and national databases. Self-report was used to examine whether patients had discontinued medications because of cost, and the PRICE Clinic database analysis examined whether interventions enabled patients to resume previously discontinued medications. RESULTS: PRICE clinic conducted 1,297 interventions among the 520 study patients in 2002, an average of 2.5 interventions per patient. The most common drug classes involved in interventions were lipid-lowering drugs, angiotensin-converting enzyme inhibitors, and asthma and allergy drugs. Generic drug use increased from 51% before PRICE clinic interventions to 56% afterward, a relative increase of 9.8% and more than 30% higher relative to the benchmark value. OOP medication expenditures decreased 68%, from dollar 185 to dollar 60 per patient per month, or dollar 1,500 per patient per year. A total of 215 patients (41%) reported that they had or would soon discontinue drugs because of cost; 186 (87%) of these patients were able to continue or resume the drug as the result of PRICE Clinic interventions. The most common interventions were pharmaceutical industry-sponsored patient assistance programs, generic substitution, and therapeutic interchange. CONCLUSION: Results from this pilot study indicate the benefits of providing pharmacist-directed services to the population targeted by MTMP services, which encompasses Medicare beneficiaries with multiple chronic diseases, multiple drugs, and high drug costs. By providing pharmacist consultation at the point of care to ensure appropriate drug use, decrease OOP expenditures, and improve access to needed drugs, the PRICE Clinic is a possible model for further development in the implementation of MTMP services.

Segregation analysis of 231 Ashkenazi Jewish families for evidence of additional breast cancer susceptibility genes.

Between 5 and 10% of breast cancer is attributable to inherited cancer susceptibility genes. Mutations in the genes BRCA1 and BRCA2 account for two-thirds of hereditary breast cancer cases. Using segregation analysis, families of cases without BRCA1/2 mutations were studied for statistical evidence of another major breast cancer gene in a community-based sample of Jewish probands tested previously for the presence of three BRCA founder mutations. A total of 231 probands with breast cancer, who do not carry a founder mutation, reported complete data on 602 female first-degree relatives of probands over age 20; 78 of these relatives had breast cancer. Segregation analysis was used to evaluate the likelihood of various genetic and nongenetic models. Sporadic, environmental, and general Mendelian genetic models fit the family data poorly and were rejected. A Mendelian recessive model fit better than dominant and codominant models, although none of these could be rejected. Cumulative incidence curves predicted by the recessive and codominant models fit observed incidence among first-degree relatives well. The assumption of Mendelian transmission of a major recessive gene(s) is compatible with the data. The recessive model predicts that 4% of women would carry the high-risk genotype, with 85% of them developing breast cancer by age 70. There was significant heterogeneity between these families and the 114 BRCA1/2 mutation-positive families from the same study population, implying that this apparent recessive effect is not because of undetected BRCA1/2 mutations. The study adds support for a major autosomal recessive component to breast cancer susceptibility.