1. 2016

   Encyclopedia of DNA Elements (ENCODE). After completing the full sequence of the human genome, scientists faced the challenge of understanding what that sequence means and how it contributes to health and disease. One approach NHGRI has taken to address this question is to support the Encyclopedia of DNA Elements (ENCODE) Project, which aims to identify the parts of the human genome sequence that are functional, that is, sequences that are thought to play a critical role in biological processes as measured by having some biochemical activity. Research laboratories participating in the ENCODE Project use a variety of methods to catalog the functional elements of the human genome. The resulting list of functional elements, which includes genes and regions that control the expression of genes, is presented as a resource that is freely available on the internet. This resource gives scientists a new set of tools to use while investigating biological phenomena and human disease.

   $30,000,000

2. 2017

   ClinGen aims to build an authoritative central resource that defines the clinical relevance of genes and variants for use in precision medicine and research. To do so, ClinGen investigators are developing standard approaches for sharing genomic and phenotypic data provided by clinicians, researchers, and patients through centralized databases, such as ClinVar, and are working to standardize the clinical annotation and interpretation of genomic variants. Working groups are implementing evidence-based expert consensus methods to curate the clinical validity and medical actionability of genes and variants. Experts in the areas of cardiovascular disease, pharmacogenomics, hereditary (germline) cancer, somatic cancer, and inborn errors of metabolism have been brought together to assist in these curation efforts. ClinGen also aims to develop machine-learning algorithms to improve the throughput of variant interpretation and to improve understanding of variation in diverse populations as it relates to interpreting genetic test results. Lastly, ClinGen will disseminate the collective knowledge and resources for unrestricted use in the community and for use in EHR ecosystems.

3. 2018

   The ELSI Research Program funds research studies, training opportunities and workshops, and develops and supports research consortia and conferences in the following broad areas.

   Genomic Research - Projects in this area examine and address the issues that arise in the design and conduct of genomic research, particularly as it involves the production, analysis and broad sharing of individual genomic data that is frequently coupled with detailed health information.
   Genomic Health Care - Projects in this area explore how rapid advances in genomic technologies and the availability of increasing amounts of genomic information influence how health care is provided and how it affects the health of individuals, families and communities. Broader Societal Issues - Projects in this area examine the normative underpinnings of beliefs, practices and policies regarding genomic information and technologies, as well as the implications of genomics for how we conceptualize and understand such concepts as health, disease, and individual responsibility. Legal, Regulatory and Public Policy Issues - Projects in this area explore the effects of existing genomic research, health and public policies and regulations and provide data to inform the development of new policies and regulatory approaches.

   A more detailed description of these areas and a list of examples of possible research questions related to each are available on the ELSI Research Priorities website: http://www.genome.gov/27543732.

4. 2019

   The mission of the ENCODE Project is to enable scientific and medical communities to interpret the human genome sequence to better understand human biology and to improve health. ENCODE seeks to achieve that goal through several means, one of which is through data production. ENCODE data are rapidly released to the research community after undergoing rigorous quality control analysis. Data are compiled into an “encyclopedia” (see: www.encodeproject.org/data/annotations/) to provide genome annotations that can be accessed by a wide range of users. The ENCODE Consortium is an open project that includes investigators with diverse scientific backgrounds and expertise in the production and analysis of data. In addition to the production of nearly 900 ENCODE Consortium publications, there are now more than 2200 scientific publications from groups without ENCODE funding who have used ENCODE data for their published work (community publications). The widespread use of ENCODE data is fostered by outreach and collaboration efforts. Efforts to annotate both protein-coding and non-coding regions of the human genome have been implemented by the ENCODE Project. Genome-wide association studies (GWAS) studies have shown that most disease-related variants reside in non-coding regions and that most of the heritability of common diseases has been linked to non-coding regions. The potential influence of non-coding regions in disease highlights the importance of the ENCODE Project’s genome annotations. Throughout the project, standards to ensure high-quality data have been implemented and novel algorithms have been developed to facilitate analysis. Data and derived results are made available as a community resource through a freely accessible database (see: www.encodeproject.org/), enabling broad use of the ENCODE catalog of functional elements by experimental and computational biologists. The ENCODE Project seeks to identify all functional

5. 2021

   Clinical Sequencing Evidence-Generating Research (CSER) Program A key feature of CSER was integrated and coordinated efforts to address challenges and opportunities in targeted areas, implemented largely through Working Groups: Actionability-Return of Results, Electronic Health Records, Genetic Counseling, Informed Consent and Governance, Outcomes and Measures, Pediatrics, Practitioner Education, Sequencing Standards, and Tumor. At individual sites and across CSER, investigators have produced over 340 papers describing challenges and opportunities across the spectrum of clinical sequencing and its implementation. Findings are also disseminated through talks and plenary sessions at major national meetings, such as the ASHG, ACMG, NSGC, ASCO, AACR, and ASBH annual meetings. These efforts have culminated in numerous scientific advances, including models for genomics-oriented informed consent tailored to the care setting, recommendations to improve the consistency of genomic variant interpretation, and approaches to the disclosure of primary pediatric and tumor findings and of secondary findings more broadly. Collaborating with the Electronic Medical Records and Genomics (eMERGE) network, CSER identified barriers and recommended approaches to incorporating genomic information in electronic health records. Valuable CSER products also included contributions to and leadership on three sets of ACMG recommendations (relating to secondary findings, variant interpretation, and clinical laboratory standards), case studies and single site publications, methodological and tool development, and collaborations with other consortia. CSER research products are available at: https://cser-consortium.org/cser-research-materials. The second phase of CSER is building on work produced in the first phase to rigorously assess the clinical utility of genome sequencing and to support the integration of genomic, clinical, and healthcare utilization data in real-world healthcare systems to inform clinical decision making. In February 2017, NHGRI Council reviewed a funding plan for 6 CSER sites to be funded under RFA-HG-16-011, and a Coordinating Center to be funded under RFA-HG-16-012, and awards were made in August 2017. Across the CSER sites, approximately 8,000 participants, at least 60% of whom will be from racial or ethnic minority or medically underserved populations, will be recruited. Crucial and complementary to these efforts is a continuing focus on ELSI research across the aims of each funded project and a dedicated focus on engaging stakeholders such as patients and parents of pediatric patients, clinicians, community members, patient advocates, health system leadership, and payers. The CSER sites and their goals are described further in the September 2018 marker paper (Amendola, et al. AJHG, PMID 30193136). Goals of the consortium include assessing the clinical utility of genomic sequencing, exploring medical follow up and cascade testing of relatives, and evaluating patient-provider-laboratory level interactions that influence the use of this technology. Five of the 6 extramural sites are focused on pediatric populations. Recruitment is underway at all clinical sites, and 8 Working Groups are developing ideas for manuscripts to leverage cross-CSER data. Having just begun its fourth project year, CSER has developed a set of harmonized baseline and follow-up measures for study participants and providers, a decliner survey, and a survey of health system experts (https://cser-consortium.org/cser-research-materials). These measures were chosen to align with a comprehensive framework for genomic medicine integrative research (Horowitz, et al. AJHG, PMID 31104772). Bruce Korf (UAB/SouthSeq study) created a CSER schema that outlines the workflow and major research questions surrounding the clinical application of genome sequencing. This schema is being used to categorize CSER publications according to which part of the workflow they address. Participant recruitment and follow-up, establishment of a consortium-wide data sharing platform, and data collection for CSER-wide manuscripts are in process. Ultimately, the findings from the CSER consortium will offer patients, healthcare systems, and policymakers a clearer understanding of the opportunities and challenges of providing genomic medicine in diverse populations and settings, and contribute evidence toward developing best practices for the delivery of clinically useful and cost-effective genomic sequencing in diverse healthcare settings. The NHGRi Genomic Data Science Analysis, Visualization, and Informatics Lab-Space (AnVIL) Since its soft launch in June 2019, AnVIL has publicly released high-value datasets, such as GTEx version 8 and the high-coverage 1000 Genomes data, and currently holds data from the NHGRI Genome Sequencing Program (GSP) and the Electronic Medical Records and Genomics (eMERGE) for access by GSP consortium members. Key analysis tools and packages such as Jupyter Notebooks, RStudio, and Bioconductor have also been made available in the users’ workspaces. To get objective advice on technical achievements and future milestones, the AnVIL team has convened two meetings with the project’s External Consultant Committee (ECC).

   As a training event for researchers of the Centers for Common Disease Genomics (CCDGs) and Centers for Mendelian Genomics (CMGs) programs, the AnVIL Outreach working group held the Massive Genome Informatics in the Cloud (MaGIC) Jamboree on June 10 – 11, 2020—an event to introduce consortium researchers to the available data, tools, workflows, training materials, and support channels on AnVIL.

   AnVIL is also a component of the emerging NIH federated data resource ecosystem and is expected to collaborate and integrate with other genomic data resources through the adoption of the FAIR (Findable, Accessible, Interoperable, Reusable) principles, as their specifications emerge from the genomics community. AnVIL program staff have a major role in current trans-NIH activities to facilitate interoperability and maintain communication among NIH cloud-based genomic resources, such as the NCI Cancer Research Data Commons, the NHLBI BioData Catalyst, and the Gabriella Miller Kids First Pediatric Research Program. The AnVIL program team leads and coordinates the cross-platform interoperability projects and workshops with key personnel of these resources, under the project name NIH Cloud Platforms Interoperability (NCPI). Within one year since the project began, the AnVIL team has hosted a virtual, project-wide conference for the NCPI working groups to share their progress and collaborate. Additionally, the AnVIL project team led a “Train Your Colleague” workshop, a cross-training event where users and developers of the NCPI project learned about each of the four platforms.

6. 2024

   The NHGRI Genomic Data Science Analysis, Visualization, and Informatics Lab-Space (AnVIL) facilitates integration and computing across large datasets integrated by NHGRI-funded projects, as well as other initiatives funded by NIH and other agencies that support human genomics research. AnVIL contains over 600,000 samples (over 4.56Pb of data), encompassing several platforms with one easy-to-use interface. The AnVIL platform will continue to expand by adding analysis tools and workflows, improving interoperability with other cloud-based resources, and providing more educational offerings. Other collaborative projects supported by NHGRI include efforts to calculate the total number of disease-associated genomic variants in an individual’s genome, which can be used to assess the individual’s risk for developing certain diseases. NHGRI supports the Clinical Genome Resource (ClinGen), which provides information about the clinical relevance of genes and genomic variants for use in medicine and research. ClinGen has become a global variant curation collaboration involving over 2800 investigators in nearly 70 countries. ClinGen has developed an online patient registry that securely shares genetic and health information, tools that associate genetic variants with pathogenicity, a data exchange, an evidence repository, and a genomic knowledge base. NHGRI also supports research on the ethical, legal, and social implications (ELSI) of the of genomics research for different communities. NHGRI’s ELSIhub helps researchers interested in ELSI topics find grant funding. NHGRI’s ELSI research has resulted in several findings that showcase parental views of genetic diagnoses for their offspring, patient-supported approaches to genetic medical services, informed consent for biomarkers and biobanking, and guidance on how to potentially navigate genetic data. NHGRI has also supported efforts to promote educational partnerships to help people at all educational levels learn about genomics research.

Single Audit Applies (2 CFR Part 200 Subpart F):

For additional information on single audit requirements for this program, review the current Compliance Supplement.

42 CFR 52; 42 CFR 66; 45 CFR 74; 45 CFR 92; NIH Extramural Programs brochure and other miscellaneous program literature are available from Headquarters Office. Grants will be available under the authority of and administered in accordance with the PHS Grants Policy Statement and Federal regulations at 42 CFR 52 and 42 U.S.C. 241; Omnibus Solicitation of the Public Health Service for Small Business Innovation Research (SBIR) Grant and Cooperative Agreement Applications. Omnibus Solicitation of the National Institutes of Health for Small Business Technology Transfer (STTR) Grant applications.

1. Public Health Service Act, Sections 301, 461 and 487, as amended; Public Laws 78-410 and 99-158, 42 U.S.C. 241, as amended; 42 U.S.C. 285k; 42 U.S.C. 288; Small Business Research and Development Enhancement Act of 1992, Public Law 102-564.