Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine.

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine.

Cost savings through molecular diagnosis for hereditary hemorrhagic telangiectasia.

PURPOSE: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder of vascular development resulting in direct connections between the arterial and venous systems, bypassing capillaries. Symptoms and signs can appear throughout life and marked intrafamilial variability confounds diagnosis based purely on clinical criteria. We set out to determine the impact of genetic testing on the cost of screening for HHT in at-risk relatives. METHODS: We performed economic modeling of idealized pedigrees following two scenarios: repeated clinical screening until an HHT diagnosis could be either affirmed or excluded, and mutation testing in the proband, followed by genetic testing of at-risk relatives and clinical monitoring of only those relatives who test positive for the familial mutation. RESULTS: Based on actual reimbursement data from our region's largest health insurer, the molecular diagnostic model saved over $22,000 for a family with four relatives at risk for the initial diagnostic work-up. For a cohort of 100 probands, the total savings for the molecular diagnostic model over a reasonable period of follow-up was greater than $9 million. CONCLUSION: In this idealized setting in which all probands and at-risk relatives accepted molecular testing, the economic advantages of genetic screening over repeated clinical screening are substantial.

When genetic screening is useful, but not used.

In families with genetic disorders due to a known genetic mutation, presymptomatic genetic testing can lead to early detection and treatment of inherited disorders that may manifest later in life. The health benefits for family members at increased risk, however, is limited by the predictive value of the genetic test, the availability of effective treatments, and individuals' and families' willingness to undergo genetic testing in the first place. This Issue Brief describes the case of a genetic condition for which genetic screening of family members is clearly useful, and just as clearly underused. It explores the barriers to the use of genetic screening and has implications for the future as genetic technologies become more complex and produce more uncertainty.

Self-surveillance by adolescents and young adults transitioning to self-management of a chronic genetic disorder.

Adolescents and young adults with Marfan syndrome (MFS) use information from self-surveillance to manage their disorder. Thirty-seven male and female adolescents with MFS aged 14 to 21 years were interviewed. They identified 58 distinct self-surveillance behaviors that fell into four categories and multiple subcategories (SCs): tracking phenotype (SCs: physical appearance, physical fitness, medical problems, and other observations); tracking medical care (SCs: medical evaluations and treatments, and pharmacotherapy); tracking behavior (SCs: personal choices and social relations); and tracking emotions (SCs: positive emotional impact and negative emotional impact). The frequency and range of self-monitoring increased with the age of the child. On average, a child of 14 self-monitored from 1 to 3 times per day, whereas a person aged 21 might self-monitor many more times per day. The patient-parent-physician relationship is the context for teaching adolescents and young adults self-surveillance skills. Self-surveillance by patients is first-line symptom assessment and an adjunct to medical monitoring.

Utilization of BRCA1/2 genetic testing in the clinical setting: report from a single institution.

BACKGROUND: Clinical testing for BRCA1/2 has been available since 1996. Interest in testing in the research and hypothetical situations has been consistently high, but there have been limited reports on its clinical utilization. METHODS: This is a retrospective study of BRCA1/2 test utilization by high-risk patients who were seen at the Johns Hopkins Breast and Ovarian Surveillance Service. RESULTS: Between February 1996 and December 1999, 258 families who had at least a 10% chance of carrying a BRCA1/2 mutation were offered genetic testing. Of these, 26 families seen between February 1996 and October 1996 had access to free testing. Overall, 68 of 258 (26%) underwent genetic testing. Educational level, number of children or daughters, breast carcinoma screening behavior, smoking and drinking behavior, perceived risk of breast carcinoma, and family history was not associated with test utilization. Eligibility for free testing, prior history of breast or ovarian carcinoma, Ashkenazi Jewish versus non-Ashkenazi Jewish heritage, genetic risk category, and age category were associated with test utilization, and in multivariate analysis, the first three remained statistically significant factors associated with genetic testing. Only 26% of the 50 patients who did not have access to free testing sought insurance reimbursement, of which greater than 50% (7 of 13) had a prior diagnosis of breast or ovarian carcinoma. CONCLUSIONS: The actual utilization of BRCA1/2 genetic testing in a clinical setting is lower than in the research and hypothetical settings. Potential obstacles include cost, fear of insurance discrimination, and need to involve an affected family member in the testing process.

Mapping the human genome: an assessment of media coverage and public reaction.

PURPOSE: To assess public reactions to the June 26, 2000, announcement that scientists had nearly finished mapping the human genome. METHODS: We conducted a random-digit telephone survey of 407 Maryland residents as well as a content analysis of 55 relevant media reports. RESULTS: African Americans were more likely than Caucasians to report a negative reaction (P < 0.001) to the genome announcement. Overall, privacy/discrimination (16%) and human cloning (14%) were the most commonly mentioned concerns regarding the impact of the genome mapping. CONCLUSIONS: These findings highlight the need for continued public discourse, including through the media, to address concerns regarding the Human Genome Project.