The Matchmaker Exchange: a platform for rare disease gene discovery.

There are few better examples of the need for data sharing than in the rare disease community, where patients, physicians, and researchers must search for "the needle in a haystack" to uncover rare, novel causes of disease within the genome. Impeding the pace of discovery has been the existence of many small siloed datasets within individual research or clinical laboratory databases and/or disease-specific organizations, hoping for serendipitous occasions when two distant investigators happen to learn they have a rare phenotype in common and can "match" these cases to build evidence for causality. However, serendipity has never proven to be a reliable or scalable approach in science. As such, the Matchmaker Exchange (MME) was launched to provide a robust and systematic approach to rare disease gene discovery through the creation of a federated network connecting databases of genotypes and rare phenotypes using a common application programming interface (API). The core building blocks of the MME have been defined and assembled. Three MME services have now been connected through the API and are available for community use. Additional databases that support internal matching are anticipated to join the MME network as it continues to grow.

Association of Genetics and B Vitamin Status With the Magnitude of Optic Disc Edema During 30-Day Strict Head-Down Tilt Bed Rest.

IMPORTANCE: Optic disc edema among astronauts after long-duration spaceflight is associated with 1-carbon pathway single-nucleotide polymorphisms and B vitamin status. A recent strict 6° head-down tilt bed rest (HDTBR) study documented development of optic disc edema and increased total retinal thickness in participants exposed to carbon dioxide, 0.5%, for 30 days, but genetic risk factors have not been explored in the cohort. OBJECTIVE: To examine whether peripapillary retinal thickness measures obtained from optical coherence tomography images during HDTBR and carbon dioxide, 0.5%, exposure are associated with B vitamin status and single-nucleotide polymorphisms involved in folate-dependent and vitamin B12-dependent 1-carbon metabolism pathways. DESIGN, SETTING, AND PARTICIPANTS: This study was conducted with a cohort of healthy volunteers at the Institute of Aerospace Medicine at the German Aerospace Center in Cologne, Germany. Data collection occurred from October 2017 to November 2017. After a 14-day ambulatory phase without carbon dioxide, participants maintained strict HDTBR with carbon dioxide, 0.5%, for 30 days, followed by a 13-day ambulatory phase without carbon dioxide. MAIN OUTCOMES AND MEASURES: Blood samples were collected before HDTBR to assess vitamin levels and single-nucleotide polymorphism status. Optical coherence tomographic images were collected before HDTBR; at days 1, 15, and 30 of the resting period; and 6 and 13 days after the period ended. Total retinal thickness was measured from a radial-24 B-scan centered over the optic disc, and global retinal nerve fiber layer thickness was measured from a circle scan. The changes in total retinal thickness and retinal nerve fiber layer thickness were evaluated against the number of risk alleles (defined as 5-methyltetrahydrofolate-homocysteine methyltransferase reductase [MTRR] 66 G and serine hydroxymethyltransferase 1 [SHMT1] 1420C alleles), along with folate, vitamin B6 (pyridoxine), and vitamin B12 (cobalamin) status. RESULTS: Eleven heathy volunteers (6 men and 5 women) had a mean (SD) age of 33.4 (8.0) years and a mean (SD) body mass index of 23.4 (2.2). After statistical adjustment for B vitamin status, total retinal thickness at the end of HDTBR in participants with 3 or 4 risk alleles was 40 um (SE, 19 µm) greater than in participants with 0 to 2 risk alleles. In addition, the baseline retinal nerve fiber layer thickness was 14 um (SE, 2 µm) greater in those with 3 or 4 risk alleles compared with those with 0 to 2 risk alleles. CONCLUSIONS AND RELEVANCE: The magnitude of optic disc edema in individuals experiencing HDTBR and exposed to a chronic headward fluid shift in a mild hypercapnic environment was higher in participants with more MTRR 66 G and SHMT1 1420C alleles, even when this finding was statistically adjusted for B vitamin status. These findings may help explain the variability in magnitude of optic disc edema observed during bed rest and spaceflight and thereby improve efforts to counteract this phenomenon.

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.

Simplifying research access to genomics and health data with Library Cards.

The volume of genomics and health data is growing rapidly, driven by sequencing for both research and clinical use. However, under current practices, the data is fragmented into many distinct datasets, and researchers must go through a separate application process for each dataset. This is time-consuming both for the researchers and the data stewards, and it reduces the velocity of research and new discoveries that could improve human health. We propose to simplify this process, by introducing a standard Library Card that identifies and authenticates researchers across all participating datasets. Each researcher would only need to apply once to establish their bona fides as a qualified researcher, and could then use the Library Card to access a wide range of datasets that use a compatible data access policy and authentication protocol.

Registered access: authorizing data access.

The Global Alliance for Genomics and Health (GA4GH) proposes a data access policy model-"registered access"-to increase and improve access to data requiring an agreement to basic terms and conditions, such as the use of DNA sequence and health data in research. A registered access policy would enable a range of categories of users to gain access, starting with researchers and clinical care professionals. It would also facilitate general use and reuse of data but within the bounds of consent restrictions and other ethical obligations. In piloting registered access with the Scientific Demonstration data sharing projects of GA4GH, we provide additional ethics, policy and technical guidance to facilitate the implementation of this access model in an international setting.

A community effort to protect genomic data sharing, collaboration and outsourcing.

The human genome can reveal sensitive information and is potentially re-identifiable, which raises privacy and security concerns about sharing such data on wide scales. In 2016, we organized the third Critical Assessment of Data Privacy and Protection competition as a community effort to bring together biomedical informaticists, computer privacy and security researchers, and scholars in ethical, legal, and social implications (ELSI) to assess the latest advances on privacy-preserving techniques for protecting human genomic data. Teams were asked to develop novel protection methods for emerging genome privacy challenges in three scenarios: Track (1) data sharing through the Beacon service of the Global Alliance for Genomics and Health. Track (2) collaborative discovery of similar genomes between two institutions; and Track (3) data outsourcing to public cloud services. The latter two tracks represent continuing themes from our 2015 competition, while the former was new and a response to a recently established vulnerability. The winning strategy for Track 1 mitigated the privacy risk by hiding approximately 11% of the variation in the database while permitting around 160,000 queries, a significant improvement over the baseline. The winning strategies in Tracks 2 and 3 showed significant progress over the previous competition by achieving multiple orders of magnitude performance improvement in terms of computational runtime and memory requirements. The outcomes suggest that applying highly optimized privacy-preserving and secure computation techniques to safeguard genomic data sharing and analysis is useful. However, the results also indicate that further efforts are needed to refine these techniques into practical solutions.

Addressing Beacon re-identification attacks: quantification and mitigation of privacy risks.

The Global Alliance for Genomics and Health (GA4GH) created the Beacon Project as a means of testing the willingness of data holders to share genetic data in the simplest technical context-a query for the presence of a specified nucleotide at a given position within a chromosome. Each participating site (or "beacon") is responsible for assuring that genomic data are exposed through the Beacon service only with the permission of the individual to whom the data pertains and in accordance with the GA4GH policy and standards.While recognizing the inference risks associated with large-scale data aggregation, and the fact that some beacons contain sensitive phenotypic associations that increase privacy risk, the GA4GH adjudged the risk of re-identification based on the binary yes/no allele-presence query responses as acceptable. However, recent work demonstrated that, given a beacon with specific characteristics (including relatively small sample size and an adversary who possesses an individual's whole genome sequence), the individual's membership in a beacon can be inferred through repeated queries for variants present in the individual's genome.In this paper, we propose three practical strategies for reducing re-identification risks in beacons. The first two strategies manipulate the beacon such that the presence of rare alleles is obscured; the third strategy budgets the number of accesses per user for each individual genome. Using a beacon containing data from the 1000 Genomes Project, we demonstrate that the proposed strategies can effectively reduce re-identification risk in beacon-like datasets.