Clinical impact and cost-effectiveness of a 176-condition expanded carrier screen.

PURPOSE: Carrier screening identifies couples at high risk for conceiving offspring affected with serious heritable conditions. Minimal guidelines recommend offering testing for cystic fibrosis and spinal muscular atrophy, but expanded carrier screening (ECS) assesses hundreds of conditions simultaneously. Although medical societies consider ECS an acceptable practice, the health economics of ECS remain incompletely characterized. METHODS: Preconception screening was modeled using a decision tree comparing minimal screening and a 176-condition ECS panel. Carrier rates from >60,000 patients, primarily with private insurance, informed disease incidence estimates, while cost and life-years-lost data were aggregated from the literature and a cost-of-care database. Model robustness was evaluated using one-way and probabilistic sensitivity analyses. RESULTS: For every 100,000 pregnancies, 290 are predicted to be affected by ECS-panel conditions, which, on average, increase mortality by 26 undiscounted life-years and individually incur $1,100,000 in lifetime costs. Relative to minimal screening, preconception ECS reduces the affected birth rate and is estimated to be cost-effective (i.e.,<$50,000 incremental cost per life-year), findings robust to perturbation. CONCLUSION: Based on screened patients predominantly with private coverage, preconception ECS is predicted to reduce the burden of Mendelian disease in a cost-effective manner compared with minimal screening. The data and framework herein may facilitate similar assessments in other cohorts.

Clinical utility of expanded carrier screening: results-guided actionability and outcomes.

PURPOSE: Expanded carrier screening (ECS) informs couples of their risk of having offspring affected by certain genetic conditions. Limited data exists assessing the actions and reproductive outcomes of at-risk couples (ARCs). We describe the impact of ECS on planned and actual pregnancy management in the largest sample of ARCs studied to date. METHODS: Couples who elected ECS and were found to be at high risk of having a pregnancy affected by at least one of 176 genetic conditions were invited to complete a survey about their actions and pregnancy management. RESULTS: Three hundred ninety-one ARCs completed the survey. Among those screened before becoming pregnant, 77% planned or pursued actions to avoid having affected offspring. Among those screened during pregnancy, 37% elected prenatal diagnostic testing (PNDx) for that pregnancy. In subsequent pregnancies that occurred in both the preconception and prenatal screening groups, PNDx was pursued in 29%. The decision to decline PNDx was most frequently based on the fear of procedure-related miscarriage, as well as the belief that termination would not be pursued in the event of a positive diagnosis. CONCLUSION: ECS results impacted couples' reproductive decision-making and led to altered pregnancy management that effectively eliminates the risk of having affected offspring.

Sequencing as a first-line methodology for cystic fibrosis carrier screening.

PURPOSE: Medical society guidelines recommend offering genotyping-based cystic fibrosis (CF) carrier screening to pregnant women or women considering pregnancy. We assessed the performance of sequencing-based CF screening relative to genotyping, in terms of analytical validity, clinical validity, clinical impact, and clinical utility. METHODS: Analytical validity was assessed using orthogonal confirmation and reference samples. Clinical validity was evaluated using the CFTR2 database. Clinical impact was assessed using ~100,000 screened patients. Three screening strategies were compared: genotyping 23 guideline-recommended variants ("CF23"), sequencing all coding bases in CFTR ("NGS"), and sequencing with large copy-number variant (CNV) identification ("NGS + CNV"). Clinical utility was determined via self-reported actions of at-risk couples (ARCs). RESULTS: Analytical accuracy of NGS + CNV was 100% for SNVs, indels, and CNVs; interpretive clinical specificity relative to CFTR2 was 99.5%. NGS + CNV detected 58 ARCs, 18 of whom would have gone undetected with CF23 alone. Most ARCs (89% screened preconceptionally, 56% prenatally) altered pregnancy management, and no significant differences were observed between ARCs with or without at least one non-CF23 variant. CONCLUSION: Modern NGS and variant interpretation enable accurate sequencing-based CF screening. Limiting screening to 23 variants does not improve analytical validity, clinical validity, or clinical utility, but does fail to detect approximately 30% (18/58) of ARCs.

What works in genomics education: outcomes of an evidenced-based instructional model for community-based physicians.

PURPOSE: Education of practicing health professionals is likely to be one factor that will speed appropriate integration of genomics into routine clinical practice. Yet many health professionals, including physicians, find it difficult to keep up with the rapid pace of clinical genomic advances and are often uncomfortable using genomic information in practice. METHODS: Having identified the genomics educational needs of physicians in a Silicon Valley-area community hospital, we developed, implemented, and evaluated an educational course entitled Medicine's Future: Genomics for Practicing Doctors. The course structure and approach were based on best practices in adult learning, including interactivity, case-based learning, skill-focused objectives, and sequential monthly modules. RESULTS: Approximately 20-30 physicians attended each module. They demonstrated significant gains in genomics knowledge and confidence in practice skills that were sustained throughout and following the course. Six months following the course, the majority of participants reported that they had changed their practice to incorporate skills learned during the course. CONCLUSION: We believe the adult-learning principles underlying the development and delivery of Medicine's Future were responsible for participants' outcomes. These principles form a model for the development and delivery of other genomics educational programs for health professionals.Genet Med 18 7, 737-745.

Challenges and Opportunities for Genomics Education: Insights from an Institute of Medicine Roundtable Activity.

Despite the growing availability of genomic tools for clinical care, many health care providers experience gaps in genomics knowledge and skills that serve as impediments to widespread and appropriate integration of genomics into routine care. A workshop recently held by the Institute of Medicine (IOM) Roundtable on Translating Genomics-Based Research for Health explored 1) the barriers that result in a perception among health care providers that the need for genomics education is not urgent and 2) the drivers that may spur a change in that attitude. This commentary promotes continuing and graduate education-informed by an awareness of barriers, drivers, and best practices-as the most effective approaches for preparing the workforce for genomic medicine and ultimately improving patient care, and argues that the time for education is now.

Genomic-based tools for the risk assessment, management, and prevention of type 2 diabetes.

Type 2 diabetes (T2D) is a common and serious disorder and is a significant risk factor for the development of cardiovascular disease, neuropathy, nephropathy, retinopathy, periodontal disease, and foot ulcers and amputations. The burden of disease associated with T2D has led to an emphasis on early identification of the millions of individuals at high risk so that management and intervention strategies can be effectively implemented before disease progression begins. With increasing knowledge about the genetic basis of T2D, several genomic-based strategies have been tested for their ability to improve risk assessment, management and prevention. Genetic risk scores have been developed with the intent to more accurately identify those at risk for T2D and to potentially improve motivation and adherence to lifestyle modification programs. In addition, evidence is building that oral antihyperglycemic medications are subject to pharmacogenomic variation in a substantial number of patients, suggesting genomics may soon play a role in determining the most effective therapies. T2D is a complex disease that affects individuals differently, and risk prediction and treatment may be challenging for health care providers. Genomic approaches hold promise for their potential to improve risk prediction and tailor management for individual patients and to contribute to better health outcomes for those with T2D.

Pharmacogenomic knowledge gaps and educational resource needs among physicians in selected specialties.

BACKGROUND: The use of pharmacogenomic testing in the clinical setting has the potential to improve the safety and effectiveness of drug therapy, yet studies have revealed that physicians lack knowledge about the topic of pharmacogenomics, and are not prepared to implement it in the clinical setting. This study further explores the pharmacogenomic knowledge deficit and educational resource needs among physicians. MATERIALS AND METHODS: Surveys of primary care physicians, cardiologists, and psychiatrists were conducted. RESULTS: Few physicians reported familiarity with the topic of pharmacogenomics, but more reported confidence in their knowledge about the influence of genetics on drug therapy. Only a small minority had undergone formal training in pharmacogenomics, and a majority reported being unsure what type of pharmacogenomic tests were appropriate to order for the clinical situation. Respondents indicated that an ideal pharmacogenomic educational resource should be electronic and include such components as how to interpret pharmacogenomic test results, recommendations for prescribing, population subgroups most likely to be affected, and contact information for laboratories offering pharmacogenomic testing. CONCLUSION: Physicians continue to demonstrate pharmacogenomic knowledge gaps, and are unsure about how to use pharmacogenomic testing in clinical practice. Educational resources that are clinically oriented and easily accessible are preferred by physicians, and may best support appropriate clinical implementation of pharmacogenomics.

The promise and challenges of next-generation genome sequencing for clinical care.

With increased speed and decreased costs, next-generation gene sequencing has the potential to improve medical care by making possible widespread evaluation of patients' genomes in clinical settings. The entire genome of an individual can now be sequenced in less than 1 week at a cost of $5000 to $10,000; the cost will continue to decline. Analyses based on next-generation sequencing include whole-genome sequencing and whole-exome sequencing; DNA sequences that encode proteins are collectively known as the exome. In some instances, whole genome and whole-exome sequencing have already helped to accurately diagnose diseases with atypical manifestations, that are difficult to diagnose using clinical or laboratory criteria alone, or that otherwise require extensive or costly evaluation. For some patients with malignant neoplasms, next-generating sequencing can improve tumor classification, diagnosis, and management. Many challenges remain, however, such as the storage and interpretation of vast amounts of sequence data, training physicians and other health care professionals whose knowledge of genetics may be insufficient, effective genetic counseling and communication of results to patients, and establishing standards for the appropriate use of the technology. Rigorous studies are needed to assess the utility of whole-genome and whole-exome sequencing in large groups of patients, including comparative studies with other approaches to screening and diagnosis, and the evaluation of clinical end points and health care costs. The successes to date have been in single cases or in very small groups of patients. At present, although whole-genome or whole-exome sequencing show great promise, they should be incorporated into patient care only in limited clinical situations.

Male breast cancer: risk factors, diagnosis, and management (Review).

Male breast cancer (MBC) is extremely rare, with an incidence in the general US population of <1%. It tends to be diagnosed at later stages than breast cancer in females, likely because of low awareness on the part of the patient and low suspicion by the physician. Risk factors include genetic predisposition, alterations to the estrogen-testosterone ratio, radiation exposure, and occupational hazards. Because of the rarity of MBC, mammography in men is more often utilized as a diagnostic tool to evaluate breast symptoms rather than as a tool for widespread screening. While clinical breast examinations are effective at evaluating breast symptoms, mammography also may be beneficial in separating malignant from benign breast disease. This study reviews MBC and its risk factors, recommendations for screening and diagnosis, the roles of mammography and genetic testing in surveillance, and management of patients with MBC. Heightened awareness of the increased risk in certain men by both physicians and patients, and adherence to guidelines recommended for the surveillance of men at increased risk, may result in earlier detection.