Adam H. Buchanan

Evaluating the Clinical Validity of Gene-Disease Associations: An Evidence-Based Framework Developed by the Clinical Genome Resource

With advances in genomic sequencing technology, the number of reported gene-disease relationships has rapidly expanded. However, the evidence supporting these claims varies widely, confounding accurate evaluation of genomic variation in a clinical setting. Despite the critical need to differentiate clinically valid relationships from less well-substantiated relationships, standard guidelines for such evaluation do not currently exist. The NIH-funded Clinical Genome Resource (ClinGen) has developed a framework to define and evaluate the clinical validity of gene-disease pairs across a variety of Mendelian disorders. In this manuscript we describe a proposed framework to evaluate relevant genetic and experimental evidence supporting or contradicting a gene-disease relationship and the subsequent validation of this framework using a set of representative gene-disease pairs. The framework provides a semiquantitative measurement for the strength of evidence of a gene-disease relationship that correlates to a qualitative classification: Definitive, Strong, Moderate, Limited, No Reported Evidence, or Conflicting Evidence. Within the ClinGen structure, classifications derived with this framework are reviewed and confirmed or adjusted based on clinical expertise of appropriate disease experts. Detailed guidance for utilizingxa0this framework and access to the curation interface is available on our website. This evidence-based, systematic method to assess the strength of gene-disease relationships will facilitate more knowledgeable utilization of genomic variants in clinical and research settings.

Randomized Trial of Telegenetics vs. In-Person Cancer Genetic Counseling: Cost, Patient Satisfaction and Attendance

Telegenetics—genetic counseling via live videoconferencing—can improve access to cancer genetic counseling (CGC) in underserved areas, but studies on cancer telegenetics have not applied randomized methodology or assessed cost. We report cost, patient satisfaction and CGC attendance from a randomized trial comparing telegenetics with in-person CGC among individuals referred to CGC in four rural oncology clinics. Participants (nu2009=u2009162) were randomized to receive CGC at their local oncology clinic in-person or via telegenetics. Cost analyses included telegenetics system; mileage; and personnel costs for genetic counselor, IT specialist, and clinic personnel. CGC attendance was tracked via study database. Patient satisfaction was assessed 1xa0week post-CGC via telephone survey using validated scales. Total costs were

Implementing Family Health History Risk Stratification in Primary Care: Impact of Guideline Criteria on Populations and Resource Demand

106 per telegenetics patient and

Multi-disciplinary summit on genetics services for women with gynecologic cancers: A Society of Gynecologic Oncology White Paper

244 per in-person patient. Patient satisfaction did not differ by group on either satisfaction scale. In-person patients were significantly more likely to attend CGC than telegenetics patients (89 vs. 79xa0%, pu2009=u20090.03), with bivariate analyses showing an association between lesser computer comfort and lower attendance rate (Chi-squareu2009=u20095.49, pu2009=u20090.02). Our randomized trial of telegenetics vs. in-person counseling found that telegenetics cost less than in-person counseling, with high satisfaction among those who attended. This study provides support for future randomized trials comparing multiple service delivery models on longer-term psychosocial and behavioral outcomes.

Clinical utility of a Web-enabled risk-assessment and clinical decision support program.

The Genomic Medicine Model aims to facilitate patient engagement, patient/provider education of genomics/personalized medicine, and uptake of risk‐stratified evidence‐based prevention guidelines using MeTree, a patient‐facing family health history (FHH) collection and clinical decision support (CDS) program. Here we report the number of increased risk (above population‐level risk) patients identified for breast/ovarian cancer, colon cancer, hereditary syndrome risk, and thrombosis; the prevalence of FHH elements triggering increased‐risk status; and the resources needed to manage their risk. Study design: hybrid implementation‐effectiveness study of adults with upcoming well‐visits in 2 primary care practices in Greensboro, NC. Participants: 1,184, mean ageu2009=u200958.8, femaleu2009=u200958% (Nu2009=u2009694), non‐whiteu2009=u200920% (Nu2009=u2009215). Increased Risk: 44% (Nu2009=u2009523). Recommendations: genetic counselingu2009=u200926% (Nu2009=u2009308), breast MRIu2009=u20090.8% (Nu2009=u200910), breast chemoprophylaxisu2009=u20095% (Nu2009=u200958), early/frequent colonoscopiesu2009=u200919% (Nu2009=u2009221), ovarian cancer screening referralu2009=u20091% (Nu2009=u200914), thrombosis testing/counselingu2009=u20092.4% (Nu2009=u200971). FHH elements: 8 FHH elements lead to 37.3% of the increased risk categorizations (by frequency): first‐degree‐relative (FDR) with polyps age ≥60 (7.1%, Nu2009=u200985), three relatives with Lynch‐related cancers (5.4%, Nu2009=u200965), FDR with polyps age <60 (5.1%, Nu2009=u200961), three relatives on same side of family with same cancer (4.9%, Nu2009=u200959), Gail score ≥1.66% (4.9%, Nu2009=u200958), two relatives with breast cancer (one ≤age 50) (4.1%, Nu2009=u200949), one relative with breast cancer ≤age 40 (4.1%, Nu2009=u200948), FDR with colon cancer age ≥60 (1.7%, Nu2009=u200920). MeTree identifies a high percentage of individuals in the general primary care population needing non‐routine risk management/prevention for the selected conditions. Implementing risk‐stratification in primary care will likely increase demand for related‐resources, particularly colon screening and GC. Understanding the prevalence of FHH elements helps predict resource needs and may aid in guideline development.

Adherence to Recommended Risk Management among Unaffected Women with a BRCA Mutation

OBJECTIVEnTo assess current practice, advise minimum standards, and identify educational gaps relevant to genetic screening, counseling, and testing of women affected by gynecologic cancers.nnnMETHODSnThe Society of Gynecologic Oncology (SGO) organized a multidisciplinary summit that included representatives from the American College of Obstetricians and Gynecologists (ACOG), the American Society Clinical Oncology (ASCO), the National Society of Genetic Counselors (NSGC), and patient advocacy groups, BrightPink and Facing our Risk of Cancer Empowered (FORCE). Three subject areas were discussed: care delivery models for genetic testing, barriers to genetic testing, and educational opportunities for providers of genetic testing.nnnRESULTSnThe group endorsed current SGO, National Comprehensive Cancer Network (NCCN), and NSGC genetic testing guidelines for women affected with ovarian, tubal, peritoneal cancers, or DNA mismatch repair deficient endometrial cancer. Three main areas of unmet need were identified: timely and universal genetic testing for women with ovarian, fallopian tube, and peritoneal cancers; education regarding minimum standards for genetic counseling and testing; and barriers to implementation of testing of both affected individuals as well as cascade testing of family members. Consensus building among all stakeholders resulted in an action plan to address gaps in education of gynecologic oncology providers and delivery of cancer genetics care.

Patient-Centered Precision Health In A Learning Health Care System: Geisinger’s Genomic Medicine Experience

Purpose:Risk-stratified guidelines can improve quality of care and cost-effectiveness, but their uptake in primary care has been limited. MeTree, a Web-based, patient-facing risk-assessment and clinical decision support tool, is designed to facilitate uptake of risk-stratified guidelines.Methods:A hybrid implementation-effectiveness trial of three clinics (two intervention, one control). Participants: consentable nonadopted adults with upcoming appointments. Primary outcome: agreement between patient risk level and risk management for those meeting evidence-based criteria for increased-risk risk-management strategies (increased risk) and those who do not (average risk) before MeTree and after. Measures: chart abstraction was used to identify risk management related to colon, breast, and ovarian cancer, hereditary cancer, and thrombosis.Results:Participants = 488, female = 284 (58.2%), white = 411 (85.7%), mean age = 58.7 (SD = 12.3). Agreement between risk management and risk level for all conditions for each participant, except for colon cancer, which was limited to those <50 years of age, was (i) 1.1% (N = 2/174) for the increased-risk group before MeTree and 16.1% (N = 28/174) after and (ii) 99.2% (N = 2,125/2,142) for the average-risk group before MeTree and 99.5% (N = 2,131/2,142) after. Of those receiving increased-risk risk-management strategies at baseline, 10.5% (N = 2/19) met criteria for increased risk. After MeTree, 80.7% (N = 46/57) met criteria.Conclusion:MeTree integration into primary care can improve uptake of risk-stratified guidelines and potentially reduce “overuse” and “underuse” of increased-risk services.Genet Med 18 10, 1020–1028.

Cancer Genetic Counseling and Testing in an Era of Rapid Change

Identifying unaffected women with a BRCA mutation can have a significant individual and population health impact on morbidity and mortality if these women adhere to guidelines for managing cancer risk. But, little is known about whether such women are adherent to current guidelines. We conducted telephone surveys of 97 unaffected BRCA mutation carriers who had genetic counseling at least one year prior to the survey to assess adherence to current guidelines, factors associated with adherence, and common reasons for performing and not performing recommended risk management. More than half of participants reported being adherent with current risk management recommendations for breast cancer (69xa0%, nxa0=xa067), ovarian cancer (82xa0%, nxa0=xa074) and both cancers (66xa0%, nxa0=xa064). Older age (ORxa0=xa010.53, pxa0=xa00.001), white race (ORxa0=xa08.93, pxa0=xa00.019), higher breast cancer genetics knowledge (ORxa0=xa01.67, pxa0=xa00.030), higher cancer-specific distress (ORxa0=xa01.07, pxa0=xa00.002) and higher physical functioning (ORxa0=xa01.09, pxa0=xa00.009) were significantly associated with adherence to recommended risk management for both cancers. Responses to open-ended questions about reasons for performing and not performing risk management behaviors indicated that participants recognized the clinical utility of these behaviors. Younger individuals and those with lower physical functioning may require targeted interventions to improve adherence, perhaps in the setting of long-term follow-up at a multi-disciplinary hereditary cancer clinic.

Early cancer diagnoses through BRCA1/2 screening of unselected adult biobank participants

Health care delivery is increasingly influenced by the emerging concepts of precision health and the learning health care system. Although not synonymous with precision health, genomics is a key enabler of individualized care. Delivering patient-centered, genomics-informed care based on individual-level data in the current national landscape of health care delivery is a daunting challenge. Problems to overcome include data generation, analysis, storage, and transfer; knowledge management and representation for patients and providers at the point of care; process management; and outcomes definition, collection, and analysis. Development, testing, and implementation of a genomics-informed program requires multidisciplinary collaboration and building the concepts of precision health into a multilevel implementation framework. Using the principles of a learning health care system provides a promising solution. This article describes the implementation of population-based genomic medicine in an integrated learning health care system-a working example of a precision health program.

Evidence-based assessments of clinical actionability in the context of secondary findings: Updates from ClinGen's Actionability Working Group

The impacts of the Association for Molecular Pathology vs. Myriad Supreme Court decision regarding patenting DNA segments and multi-gene testing on cancer genetic counseling practice have not been well described. We aimed to assess genetic counselors’ perceptions of how their genetic testing-related practices for hereditary breast and/or ovarian cancer (HBOC) changed after these events. One-hundred fifty-two genetic counselors from the National Society of Genetic Counselors Cancer Special Interest Group completed an anonymous, online, mixed-methods survey in November 2013. The survey presented four hypothetical patients and asked about changes in testing practice. Across the vignettes, a majority of participants reported specific changes in testing decisions following Association for Molecular Pathology vs. Myriad and availability of multi-gene testing. Ninety-three percent of participants reported changing the types of first- and second-line tests they order for HBOC; the degree of change varied geographically. Qualitative analysis indicated that some counselors have altered the counseling session content, trading depth of information for breadth and spending more time counseling about uncertainty. This study shows that cancer genetic counselors are adapting quickly to genetic testing changes, but with wide variability. Findings suggest future research to elucidate clinicians’ and patients’ preferences for guidance on the clinical implementation of next-generation sequencing.