Integrating Genomics into Healthcare: A Global Responsibility.

Genomic sequencing is rapidly transitioning into clinical practice, and implementation into healthcare systems has been supported by substantial government investment, totaling over US$4 billion, in at least 14 countries. These national genomic-medicine initiatives are driving transformative change under real-life conditions while simultaneously addressing barriers to implementation and gathering evidence for wider adoption. We review the diversity of approaches and current progress made by national genomic-medicine initiatives in the UK, France, Australia, and US and provide a roadmap for sharing strategies, standards, and data internationally to accelerate implementation.

BRCA Challenge: BRCA Exchange as a global resource for variants in BRCA1 and BRCA2.

The BRCA Challenge is a long-term data-sharing project initiated within the Global Alliance for Genomics and Health (GA4GH) to aggregate BRCA1 and BRCA2 data to support highly collaborative research activities. Its goal is to generate an informed and current understanding of the impact of genetic variation on cancer risk across the iconic cancer predisposition genes, BRCA1 and BRCA2. Initially, reported variants in BRCA1 and BRCA2 available from public databases were integrated into a single, newly created site, www.brcaexchange.org. The purpose of the BRCA Exchange is to provide the community with a reliable and easily accessible record of variants interpreted for a high-penetrance phenotype. More than 20,000 variants have been aggregated, three times the number found in the next-largest public database at the project's outset, of which approximately 7,250 have expert classifications. The data set is based on shared information from existing clinical databases-Breast Cancer Information Core (BIC), ClinVar, and the Leiden Open Variation Database (LOVD)-as well as population databases, all linked to a single point of access. The BRCA Challenge has brought together the existing international Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium expert panel, along with expert clinicians, diagnosticians, researchers, and database providers, all with a common goal of advancing our understanding of BRCA1 and BRCA2 variation. Ongoing work includes direct contact with national centers with access to BRCA1 and BRCA2 diagnostic data to encourage data sharing, development of methods suitable for extraction of genetic variation at the level of individual laboratory reports, and engagement with participant communities to enable a more comprehensive understanding of the clinical significance of genetic variation in BRCA1 and BRCA2.

ClinGen advancing genomic data-sharing standards as a GA4GH driver project.

The Clinical Genome Resource (ClinGen)'s work to develop a knowledge base to support the understanding of genes and variants for use in precision medicine and research depends on robust, broadly applicable, and adaptable technical standards for sharing data and information. To forward this goal, ClinGen has joined with the Global Alliance for Genomics and Health (GA4GH) to support the development of open, freely-available technical standards and regulatory frameworks for secure and responsible sharing of genomic and health-related data. In its capacity as one of the 15 inaugural GA4GH "Driver Projects," ClinGen is providing input on the key standards needs of the global genomics community, and has committed to participate on GA4GH Work Streams to support the development of: (1) a standard model for computer-readable variant representation; (2) a data model for linking variant data to annotations; (3) a specification to enable sharing of genomic variant knowledge and associated clinical interpretations; and (4) a set of best practices for use of phenotype and disease ontologies. ClinGen's participation as a GA4GH Driver Project will provide a robust environment to test drive emerging genomic knowledge sharing standards and prove their utility among the community, while accelerating the construction of the ClinGen evidence base.

The contribution of genomic research to explaining racial disparities in cardiovascular disease: a systematic review.

After nearly a decade of genome-wide association studies, no assessment has yet been made of their contribution toward an explanation of the most prominent racial health disparities observed at the population level. We examined populations of African and European ancestry and focused on cardiovascular diseases, which are collectively the largest contributor to the racial mortality gap. We conducted a systematic search for review articles and meta-analyses published in 2007-2013 in which genetic data from both populations were available. We identified 68 articles relevant to this question; however, few reported significant associations in both racial groups, with just 3 variants meeting study-specific significance criteria. For most outcomes, there were too few estimates for quantitative summarization, but when summarization was possible, racial group did not contribute to heterogeneity. Most associations reported from genome-wide searches were small, difficult to replicate, and in no consistent direction that favored one racial group or another. Although the substantial investment in this technology might have produced clinical advances, it has thus far made little or no contribution to our understanding of population-level racial health disparities in cardiovascular disease.

Multimodal therapy for rigid, persistent avoidant/restrictive food intake disorder (ARFID) since infancy: A case report.

Avoidant/restrictive food intake disorder (ARFID) is a feeding and eating disorder that results in nutritional inadequacies, weight loss, and/or dependence on enteral feeds, and for which three clinical subtypes have been described. We present a unique case of an 11-year-old boy with rigid ARFID since infancy and features of all three ARFID subtypes. The patient presented with a life-long history of sensory aversion, limited intake and phobia of vomiting resulting in restriction to a single food item (yogurt) for more than 5 years. He presented with severe iron-deficiency anaemia, and deficiencies of vitamins A, C, D, E and zinc. We employed a multimodal therapeutic approach that incorporated elements of cognitive-behavioural therapy (CBT), family-based therapy (FBT) and pharmacological management with an antidepressant medication (sertraline) and an atypical antipsychotic agent (olanzapine). Over the course of a 7-week admission, our approach assisted the patient in successful weight restoration and incorporation of at least three new food items into his daily diet. While there are currently no first-line recommendations for ARFID management, our study lends support to the efficacy of CBT, FBT and pharmacological management for ARFID patients, including complex cases with multiple subtype features. Further research is needed to strengthen ARFID clinical guidelines.

GA4GH: International policies and standards for data sharing across genomic research and healthcare.

The Global Alliance for Genomics and Health (GA4GH) aims to accelerate biomedical advances by enabling the responsible sharing of clinical and genomic data through both harmonized data aggregation and federated approaches. The decreasing cost of genomic sequencing (along with other genome-wide molecular assays) and increasing evidence of its clinical utility will soon drive the generation of sequence data from tens of millions of humans, with increasing levels of diversity. In this perspective, we present the GA4GH strategies for addressing the major challenges of this data revolution. We describe the GA4GH organization, which is fueled by the development efforts of eight Work Streams and informed by the needs of 24 Driver Projects and other key stakeholders. We present the GA4GH suite of secure, interoperable technical standards and policy frameworks and review the current status of standards, their relevance to key domains of research and clinical care, and future plans of GA4GH. Broad international participation in building, adopting, and deploying GA4GH standards and frameworks will catalyze an unprecedented effort in data sharing that will be critical to advancing genomic medicine and ensuring that all populations can access its benefits.

BRCA1/2 Variant Data-Sharing Practices.

Accessing BRCA1/2 data facilitates the detection of disease-associated variants, which is critical to informing clinical management of risks. BRCA1/2 data sharing is complex and many practices exist. We describe current BRCA1/2 data-sharing practices, in the United States and globally, and discuss obstacles and incentives to sharing, based on 28 interviews with personnel at U.S. and non-U.S. clinical laboratories and databases. Our examination of the BRCA1/2 data-sharing landscape demonstrates strong support for and robust sharing of BRCA1/2 data around the world, increasing global accesses to diverse data sets.

Publisher Correction: Federated discovery and sharing of genomic data using Beacons.

In the version of this article initially published, Lena Dolman's second affiliation was given as Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK. The correct second affiliation is Ontario Institute for Cancer Research, Toronto, Ontario, Canada. The error has been corrected in the HTML and PDF versions of the article.

A targeted analysis identifies a high frequency of BRCA1 and BRCA2 mutation carriers in women with ovarian cancer from a founder population.

BACKGROUND: The frequency of BRCA1 and BRCA2 mutations in ovarian cancer patients varies depending on histological subtype and population investigated. The six most commonly recurring BRCA1 and BRCA2 mutations previously identified in a founder French Canadian population were investigated in 439 histologically defined ovarian, fallopian tube and primary peritoneal cancer cases that were ascertained at one hospital servicing French Canadians. To further assess the frequency of BRCA1/BRCA2 mutations, a defined subgroup of 116 cases were investigated for all mutations previously reported in this population. METHODS: A PCR-based assay was used to screen 439 ovarian, fallopian tube or extra-ovarian cancers comprised of serous, high grade endometrioid and mixed cell adenocarcinomas with serous components for specific BRCA1: C4446T and 2953delGTAinsC and BRCA2: 8765delAG, G6085T, 3398del5 and E3002K mutations. A multiplex bead-array-based Luminex assay was used to evaluate 19 specific mutations that have ever been reported in French Canadians, which included the six mutations assayed by PCR, in 116 cases representing all women ascertained within a defined 3-year window. RESULTS: A targeted analysis of six mutations identified 34/439 (7.7%) mutation carriers and at least two mutation carriers for each mutation screened were found. The BRCA1:C4446T mutation was the most frequently identified variant (15/34, 44.1%) among mutation-positive cases. The expanded mutation screen that also included 13 additional variants identified 19/116 (16.4%) mutation carriers, where C4446T was the most common variant (8/19, 42.1%) identified among mutation-positive carriers in this subgroup. Mutations were identified in women with serous, endometrioid, mixed cell, and undifferentiated adenocarcinomas. Within this subgroup there were 73 high-grade (G3) serous ovarian carcinomas, the most common subtype, with mutations identified in 19.2% (n = 14) serous cases. CONCLUSIONS: Our results reaffirm that specific BRCA1 and BRCA2 mutations found previously to recur in French Canadian breast cancer and breast-ovarian cancer families, also recur in women with ovarian cancer not selected for family history of cancer. The high frequency of mutation carriers rationalizes genetic testing of ovarian cancer patients in this demographically defined population.