Stephanie O.M. Dyke

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.

International Cooperation to Enable the Diagnosis of All Rare Genetic Diseases

Provision of a molecularly confirmed diagnosis in a timely manner for children and adults with rare genetic diseases shortens their “diagnostic odyssey,” improves disease management, and fosters genetic counseling with respect to recurrence risks while assuring reproductive choices. In a general clinical genetics setting, the current diagnostic rate is approximately 50%, but for those who do not receive a molecular diagnosis after the initial genetics evaluation, that rate is much lower. Diagnostic success for these more challenging affected individuals depends to a large extent on progress in the discovery of genes associated with, and mechanisms underlying, rare diseases. Thus, continued research is required for moving toward a more complete catalog of disease-related genes and variants. The International Rare Diseases Research Consortium (IRDiRC) was established in 2011 to bring together researchers and organizations invested in rare disease research to develop a means of achieving molecular diagnosis for all rare diseases. Here, we review the current and future bottlenecks to gene discovery and suggest strategies for enabling progress in this regard. Each successful discovery will define potential diagnostic, preventive, and therapeutic opportunities for the corresponding rare disease, enabling precision medicine for this patient population.

Consent Codes: Upholding Standard Data Use Conditions

Author Summary A systematic way of recording data use conditions that are based on consent permissions as found in the datasets of the main public genome archives (NCBI dbGaP and EMBL-EBI/CRG EGA).

Managing clinically significant findings in research: the UK10K example

Recent advances in sequencing technology allow data on the human genome to be generated more quickly and in greater detail than ever before. Such detail includes findings that may be of significance to the health of the research participant involved. Although research studies generally do not feed back information on clinically significant findings (CSFs) to participants, this stance is increasingly being questioned. There may be difficulties and risks in feeding clinically significant information back to research participants, however, the UK10K consortium sought to address these by creating a detailed management pathway. This was not intended to create any obligation upon the researchers to feed back any CSFs they discovered. Instead, it provides a mechanism to ensure that any such findings can be passed on to the participant where appropriate. This paper describes this mechanism and the specific criteria, which must be fulfilled in order for a finding and participant to qualify for feedback. This mechanism could be used by future research consortia, and may also assist in the development of sound principles for dealing with CSFs.

Developing and implementing an institute-wide data sharing policy

The Wellcome Trust Sanger Institute has a strong reputation for prepublication data sharing as a result of its policy of rapid release of genome sequence data and particularly through its contribution to the Human Genome Project. The practicalities of broad data sharing remain largely uncharted, especially to cover the wide range of data types currently produced by genomic studies and to adequately address ethical issues. This paper describes the processes and challenges involved in implementing a data sharing policy on an institute-wide scale. This includes questions of governance, practical aspects of applying principles to diverse experimental contexts, building enabling systems and infrastructure, incentives and collaborative issues.

Controlled Access under Review: Improving the Governance of Genomic Data Access

In parallel with massive genomic data production, data sharing practices have rapidly expanded over the last decade. To ensure authorized access to data, access review by data access committees (DACs) has been utilized as one potential solution. Here we discuss core elements to be integrated into the fabric of access review by both established and emerging DACs in order to foster fair, efficient, and responsible access to datasets. We particularly highlight the fact that the access review process could be adversely influenced by the potential conflicts of interest of data producers, particularly when they are directly involved in DACs management. Therefore, in structuring DACs and access procedures, possible data withholding by data producers should receive thorough attention.

Epigenome data release: a participant-centered approach to privacy protection.

Large-scale epigenome mapping by the NIH Roadmap Epigenomics Project, the ENCODE Consortium and the International Human Epigenome Consortium (IHEC) produces genome-wide DNA methylation data at one base-pair resolution. We examine how such data can be made open-access while balancing appropriate interpretation and genomic privacy. We propose guidelines for data release that both reduce ambiguity in the interpretation of open-access data and limit immediate access to genetic variation data that are made available through controlled access.

Registered access: a ‘Triple-A’ approach

We propose a standard model for a novel data access tier – registered access – to facilitate access to data that cannot be published in open access archives owing to ethical and legal risk. Based on an analysis of applicable research ethics and other legal and administrative frameworks, we discuss the general characteristics of this Registered Access Model, which would comprise a three-stage approval process: Authentication, Attestation and Authorization. We are piloting registered access with the Demonstration Projects of the Global Alliance for Genomics and Health for which it may provide a suitable mechanism for access to certain data types and to different types of data users.

Sharing health-related data: a privacy test?

Greater sharing of potentially sensitive data raises important ethical, legal and social issues (ELSI), which risk hindering and even preventing useful data sharing if not properly addressed. One such important issue is respecting the privacy-related interests of individuals whose data are used in genomic research and clinical care. As part of the Global Alliance for Genomics and Health (GA4GH), we examined the ELSI status of health-related data that are typically considered ‘sensitive’ in international policy and data protection laws. We propose that ‘tiered protection’ of such data could be implemented in contexts such as that of the GA4GH Beacon Project to facilitate responsible data sharing. To this end, we discuss a Data Sharing Privacy Test developed to distinguish degrees of sensitivity within categories of data recognised as ‘sensitive’. Based on this, we propose guidance for determining the level of protection when sharing genomic and health-related data for the Beacon Project and in other international data sharing initiatives.

Are Data Sharing and Privacy Protection Mutually Exclusive

We review emerging strategies to protect the privacy of research participants in international epigenome research: open consent, genome donation, registered access, automated procedures, and privacy-enhancing technologies.