Human Genome Research

 

NHGRI supports the development of resources and technologies that will accelerate genome research and its application to human health and genomic medicine. A critical part of the NHGRI mission continues to be the study of the ethical, legal and social implications (ELSI) of genome research. NHGRI also supports the training and career development of investigators and the dissemination of genome information to the public and to health professionals. The Small Business Innovation Research (SBIR) program is used to increase private sector commercialization of innovations derived from Federal research and development; to increase small business participation in Federal research and development; and to foster and encourage participation of socially and economically disadvantaged small business concerns and women-owned small business concerns in technological innovation. The Small Business Technology Transfer (STTR) program is used to foster scientific and technological innovation through cooperative research and development carried out between small business concerns and research institutions; to foster technology transfer between small business concerns and research institutions; to increase private sector commercialization of innovations derived from Federal research and development; and to foster and encourage participation of socially and economically disadvantaged small business concerns and women-owned small business concerns in technological innovation.

Active 93.172 National Institutes of Health, Department of Health and Human Services B - Project Grants; M - Training Fiscal Year 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
Fiscal Year 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.
Fiscal Year 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.
Fiscal Year 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
Fiscal Year 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.
Fiscal Year 2023 The AnVIL Program serves as an interoperable resource for the research community by co-locating data, storage, and computing infrastructure with commonly used services and tools for analyzing and sharing data. Since its launch in June 2019, the AnVIL Program has onboarded and publicly released several high-value datasets (see the AnVIL Dataset Catalog), and deployed key genomic analysis tools and packages such as Jupyter Notebooks, RStudio, Galaxy, Dockstore, Bioconductor, and PharmCAT. The AnVIL platform was also integral to the analysis of the first complete human genome of the Telomere-to-Telomere Consortium effort. A summary of the AnVIL Program's accomplishments includes: the ingestion of over 600,000 samples (4.56 Pb of data) into AnVIL the deployment of Terra, for workspaces, interactive and batch computing the deployment of Gen3 within AnVIL release of Galaxy within AnVIL/Terra enhanced capabilities for Dockstore enhanced capabilities for Jupyter notebooks deployment of RStudio available within Terra the development and deployment of the Bioconductor AnVIL packages establishing the AnVIL Portal as a meta-portal to each of the AnVIL components several successful outreach events launched two cohorts of the AnVIL Cloud Credits Program launched a new Genomic Data Science Community Network developing an initial catalog of clinical genomics tools launch of major efforts through the NIH Cloud Platform Interoperability (NCPI) program to increase usability across NIH funded cloud platforms the piloting of the Data Use Oversight System (DUOS) egress-free Release of the GTEx V8 Protected Data The AnVIL team continues to engage the genomics research communities by presenting posters and holding workshops. For example, the AnVIL team has presented at the Bioinformatics Community Conference, the American Society of Human Genetics meeting, and has hosted a webinar at the 2021 Bioconductor Virtual Conference. In 2021 the AnVIL team launched the AnVIL Cloud Credits Program (AC2) which invited genomic researchers to submit proposals that use the AnVIL platform for large-scale data analysis with cloud computing credits supported by the NIH STRIDES program. Six investigators received awards from the AC2 program to use AnVIL as their analysis platform. After the success of AC2, the program was expanded in 2022 with 13 additional cloud credit awardees. The AnVIL Program is also committed to addressing disparities in equitable access to resources for performing large scale genomic based analysis. In March 2021, the AnVIL team helped organize the first meeting of the Genomic Data Science Community Data Network (GDSCN). This meeting brought together over 40 researchers from a diverse spectrum of institutions. The focus of the GDSCN is to build partnerships and develop genomic data science curricula for undergraduate students. The AnVIL team also partnered with the NIH Office of Data Science Strategy and Howard University’s Virtual Applied Data Science Training Institute (VADSTI) to develop a free eight-week virtual training series. VADSTI aims to attract and engage underrepresented students and researchers interested in applying data science applications to biomedical, clinical, and genomic research, with a focus on diseases common to minority populations. The training sessions covered foundational analytic skills needed for research using big data and included an AnVIL team led session on how to use the cloud to make biomedical data science discoveries. The AnVIL Program is a key component of the emerging ecosystem of data resources at NIH 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. The AnVIL team has collaborated with the Researcher Auth Service (RAS) Initiative to facilitate access to NIH’s controlled data assets and repositories in a consistent manner. The AnVIL Program is committed to contributing to and ensuring interoperability with Fast Healthcare Interoperability Resources (FHIR) to help address the needs of the clinical genomic research community. The FHIR standard describes data formats and elements (known as "resources") and an API for exchanging electronic health records (EHR). In support of this need, Bioconductor and Galaxy have leveraged FHIR for research purposes. Furthermore, the open-source AnVIL-FHIR python package (pyAnVIL) was initiated on github, and over the course of the past year, has been substantially expanded and enhanced. 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. Research Projects: Awards can be made to any public or private, for-profit or nonprofit university, college, hospital, laboratory, or other institution, and to individuals. Non-federal public and private domestic organizations may apply for an Institutional National Research Service Award. Individual National Research Service awardees must be nominated and sponsored by a public or nonprofit private institution having staff and facilities appropriate to the proposed research training program. All awardees must be citizens or have been admitted to the United States for permanent residence. Predoctoral awardees must have completed the baccalaureate degree, and postdoctoral awardees must have a professional or scientific degree (M.D., Ph.D., D.O., D.V.M., Sc.D., E.Eng., or equivalent domestic or foreign degree). Any nonprofit or for-profit organization, company, or institution engaged in biomedical research can apply for research support. Each applicant for a research project must present a research plan and furnish evidence that scientific competence, facilities, equipment, and supplies are appropriate to carry out the plan. The applicant must have the expertise to carry out the project. Applications must submit an electronic grant application form SF424 which can be accessed from the funding opportunity announcement. For applicants for National Research Service Awards, the academic record, research experience, citizenship, institutional sponsorship, and the proposed area and plan of training must be included in the application. The applicant institution must show the objectives, methodology, and resources for the research training program, the qualifications and experience of directing staff, the criteria to be used in selecting individuals for the award, and a detailed budget and justification for the grant funds requested. For-profit organizations, costs are determined in accordance with 48 CFR. For other grantees, costs will be determined in accordance with HHS Regulation 45 CFR 75. For SBIR and STTR grants, applicant organization (small business concern) must present in a research plan an idea that has potential for commercialization and furnish evidence that scientific competence, experimental methods, facilities, equipment, and funds requested are appropriate to carry out the plan. SF424 applications are used for SBIR and STTR programs. SBIR and STTR applicant organizations must comply with the SBA's definition of a small business. In order to be eligible for a NRSA award, the individual must be a US citizen or permanent resident of the US. Preapplication coordination is not applicable. 2 CFR 200, Uniform Administrative Requirements, Cost Principles, and Audit Requirements for Federal Awards applies to this program. Only application submitted in response to a funding opportunity announcement will be accepted.The standard application forms, as furnished in the Funding Opportunity Announcements at www.grants.gov, must be used for this program. This program is subject to the provisions of 45 CFR 75. The SBIR and STTR Solicitations may be obtained electronically through the NIH "Small business Funding Opportunities" homepage at: https://sbir.nih.gov/ All applications must respond to a funding opportunity announcement, must be reviewed for scientific merit by an appropriate initial review group, and must be considered by the National Advisory Council for Human Genome Research (NACHGR) for program relevance. Individual NRSA applications are not reviewed by council. All scored applications compete for available funds on the basis of scientific merit and program emphasis, and availability of funds. Applications in response to a Request for Applications have council approved set aside funds, but awards are based primarily on the quality of the applications. Awards are issued throughout the year. All applications receiving a impact score ranging from the best (10) to worst (90) compete for the available funds on the basis of scientific and technical merit (SBIR/STTR applications must also demonstrate the potential for commercial application for SBIR/STTR applications), program relevance, and program balance among the areas of research. However, in reality, applications with impact scores of 30 or greater are rarely considered for funding. January 5, 2022 to October 5, 2022 Receipt dates for applications can be found at this URL: https://grants.nih.gov/grants/how-to-apply-application-guide/due-dates-and-submission-policies/due-dates.htm. Requests for Applications and Program Announcements for Special Review or Set Aside are not submitted on standard due dates. The submission dates of these funding opportunity announcements can be found at: https://grants.nih.gov/funding/searchguide/index.html#/. More than 180 days. From submission to award of funds: Individual, project and institutional grants about 9 months; SBIR/STTR and AIDS projects about 6 months. Not applicable. Not applicable. The major elements in evaluating proposals include assessments of: (1) The scientific merit and general significance of the proposed study and its objectives; (2) the technical adequacy of the experimental design and approach; (3) the competency of the proposed investigator or group to successfully pursue the project; (4) the adequacy of the available and proposed project; and (5) the relevance and importance to announced program objectives. The following criteria will be used in considering the scientific and technical merit of SBIR/STTR Phase I grant applications: (1) The soundness and technical merit of the proposed approach; (2) the qualifications of the proposed principal investigator, supporting staff, and consultants; (3) the technological innovation of the proposed research; (4) the potential of the proposed research for commercial application; (5) the appropriateness of the budget requested; (6) the adequacy and suitability of the facilities and research environment; and (7) where applicable, the adequacy of assurances detailing the proposed means for (a) safeguarding human or animal subjects, and/or (b) protecting against or minimizing any adverse effect on the environment. Phase II grant applications will be reviewed based upon the following criteria: (1) The degree to which the Phase I objectives were met and feasibility demonstrated; (2) the scientific and technical merit of the proposed approach for achieving the Phase II objectives; (3) the qualifications of the proposed principal investigator, supporting staff, and consultants; (4) the technological innovation, originality, or societal importance of the proposed research; (5) the potential of the proposed research for commercial application; (6) the reasonableness of the budget request for the work proposed; (7) the adequacy and suitability of the facilities and research environment; and (8) where applicable, the adequacy of assurances detailing the proposed means for (a) safeguarding human or animal subjects, and/or (b) protecting against or minimizing any adverse effect on the environment. The research project grant is awarded to an eligible institution in the name of a principal investigator for a discrete project or group of related projects representing the investigator's interest and competence. Funds may be used for salaries and wages, equipment, supplies, travel and other costs required to carry out the research project. National Research Service Awards are made directly to individuals for research training in disciplines supporting the research areas. In addition, grants may be made to institutions to enable them to select individuals for National Research Service Awards. Each individual who receives a National Research Service Award is responsible for certain service and payback provisions. Small Business Innovation Research (SBIR) Program: SBIR Phase I grants (of approximately 6 months' duration) are to establish the technical merit and feasibility of a proposed research effort that may lead to a commercial product or process. Phase II grants are for the continuation of research initiated in Phase I and which are likely to result in commercial products or processes. Only Phase I awardees are eligible to apply for Phase II support. STTR Phase I grants (normally of 1-year duration) are to determine the scientific, technical, and commercial merit and feasibility of the proposed cooperative effort that has potential for commercial application. Phase II funding is based on results of research initiated in Phase I and scientific and technical merit and commercial potential of Phase II application. Responsibilities of grantees and restrictions on use of funds are set forth in the Public Health Service policy statement on grants for research projects, which is available on request from the Division of Extramural Outreach and Information Resources, Office of Extramural Research, National Institutes of Health (NIH), 6701 Rockledge Drive, Room 6207, MSC 7910, Bethesda, MD 20892-7910. Telephone: (301) 435-0714. Fax (301) 480- 0525. E-mail: asknih.od.nih.gov. Performance Reports: Program Directors review the reports and may contact the PIs for a verbal discussion that expands upon the written report. If problems are noted, the program director will note this in the report and talk with the PI about what can be done to ensure progress is satisfactory. For more complex grants, the Program Director may request the PI to provide more frequent accounting of progress and/or teleconferences. The Grants Management Specialist/Officer reviews applications for the appropriateness of the budget requested. Not applicable. Expenditures and other financial records must be retained for 3 years from the day on which the grantee submits the last expenditure report for the report period. Statutory formula is not applicable to this assistance listing.

Matching requirements are not applicable to this assistance listing.

MOE requirements are not applicable to this assistance listing. Research and program projects are awarded for 2-5 years. Institutional training grants are awarded for 5 years. Individual fellowships and career development awards are from 2-5 years. For SBIR and STTR applications, normally Phase I awards are for 6 months and Phase II awards are or 2 years. Method of awarding/releasing assistance: Letter. None/Not specified. Bettie J. Graham, Ph.D
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Phone: 301-496-7531 http://www.genome.gov/ 75-0891-0-1-552 (Project Grants) FY 22$412,677,362.00; FY 23 est $429,004,335.00; FY 24 est $426,487,055.00; FY 21$403,900,844.00; FY 20$302,856,860.00; FY 19$379,784,779.00; - (Project Grants (with Formula Distribution)) FY 22$16,681,890.00; FY 23 est $17,453,286.00; FY 24 est $17,349,122.00; FY 21$16,449,038.00; FY 20$134,320,703.00; FY 19$15,319,054.00; - (Training) FY 22$11,812,210.00; FY 23 est $12,698,340.00; FY 24 est $12,871,040.00; FY 21$11,254,209.00; FY 20$11,949,497.00; FY 19$9,053,644.00; - For Research project grants the range is from $26,000 - $19,996,553. 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. Fiscal Year 2016 Centers for Common Disease Genomics. The National Human Genome Research Institute (NHGRI) seeks to fund a collaborative large-scale genome sequencing effort to comprehensively identify rare risk and protective variants contributing to multiple common disease phenotypes. This initiative will explore a range of diseases with the ultimate goal of undertaking variant discovery for enough different examples of disease architectures and study designs to better understand the general principles of genomic architecture underlying common, complex inherited diseases; understand how best to design rare variant studies for common disease; and develop resources, informatics tools, and innovative approaches and technologies for multiple disease research communities and the wider biomedical research community. NHGRI plans to make 2-5 awards in FY16.
Fiscal Year 2017 The Genomics of Gene Regulation (GGR) projects will use genomic data and technologies to understand how genetic regulatory systems are assembled and how genetic regulatory systems function to determine biological processes at a mechanistic level. GGR projects are designed to advance genomic science towards the long-term goal of NHGRI research in this area, which is to be able to predict, from reading DNA sequence, when and at what level a gene is expressed, in the context of a particular cell fate/state. Understanding gene regulatory networks could facilitate interpreting the phenotypic consequences (e.g. disease) of genetic variation, particularly in non-coding regions of the genome. This is a highly significant problem, as the vast majority of disease-associated variants found using GWAS lie outside of protein-coding sequences. Many of these disease associations map to ENCODE-annotated regions, thus highlighting the importance of these ENCODE annotations. While genomic annotations are important, they are not sufficient to understand dynamic biological processes. GGR is one path to bring together modeling methods with catalogs of genomic data to understand what elements are controlling what genes, in what cell types. The ability to make accurate predictions from gene regulatory networks could support genomic medicine and precision medicine, by providing us one more tool to understand the consequences of genetic variation. As set out in the RFA, individual projects collect genomic data on gene expression, as well as surrogate markers of regulatory elements, in different cell fates or cell states. They use the gene expression and functional element data to construct gene regulatory network models, taking advantage of the dynamics of the system as the cells transition from one physiologic fate or state to another. These models will describe the biological role of the identified functional elements and how they interact to form a genetic regulatory circuit. The predictions of the initial model would then be tested experimentally by appropriate assays, for instance by perturbing (by genetic or environmental means) identified key regulators and comparing the measured biological response to the predicted response. Analysis of the outcomes of these experiments would be used to refine and further develop the model in an iterative process of modeling, prediction, and experimentation. It is hoped that this approach will lead to a detailed understanding of the individual genetic regulatory circuits under study. It is further hoped that by investigating several genetic regulatory circuits this way and organizing the projects in a collaborative research network, the GGR investigators will form an interactive group, accelerating discovery through the sharing of technical and biological insights gained during the course of the project. These interactions will be important in learning the features that are generalizable and the features that are unique, because the individual projects will be using different approaches and biological systems.
Fiscal Year 2018 ClinGen is building an authoritative central resource that defines the clinical relevance of genes and variants for use in 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, hereditary (germline) cancer, somatic cancer, pediatric neurology, hearing loss, inborn errors of metabolism among others have been brought together to assist in these curation efforts. ClinGen is also developing tools 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 through the website (www.clinicalgenomeresource.org). Important Collaborations: • NICHD developed a three-year U24 funding opportunity (FY17-FY20) to support three curation committees to implement ClinGen frameworks into priority diseases and conditions for their institute (RFA-HD-17-001) • The American Society of Hematology (ASH) plans to support two curation committees in malignant hematology and platelet disorders. • The FDA is collaborating with ClinGen to identify novel opportunities for using high-quality public databases of clinically relevant variants to streamline review and approval of NGS-based in vitro diagnostics. The criteria for such databases are outlined in the draft guidance, “Use of Public Human Genetic Variant Databases to Support Clinical Validity for Next Generation Sequencing (NGS)-Based In Vitro Diagnostics.”
Fiscal Year 2019 The NHGRI Genomic Data Science Analysis, Visualization, and Informatics Lab-space (AnVIL) Advances in genomic technologies, as well as decreasing costs for sequencing, have enabled genomic data to become a routine component in elucidating ways to improve health. However, the rate of genomic data generation has overtaxed existing resources available for data storage, curation, and analysis, resulting in a critical need for high-performance computing infrastructure, and specialized bioinformatics expertise. Without the proper data management and technical support, such problems will remain a bottleneck in the use of genomic data for advancing biomedical research and its implementation into clinical care. The NHGRI Genomic Data Science Analysis, Visualization, and Informatics Lab-space (AnVIL) is a scalable and interoperable resource for basic and clinical genomic research communities, that leverages a cloud-based infrastructure to democratize genomic data access, sharing and computing across large genomic, and genomic-related, datasets. The AnVIL will facilitate integration and computing on and across large datasets generated by NHGRI programs, as well as initiatives funded by National Institutes of Health (NIH), or by other agencies that support human genomics research. The AnVIL will provide a collaborative environment, where datasets and analysis workflows can be shared within a consortium and be prepared for public release to the broad genomics community through user interfaces. The AnVIL will be tailored for users that have limited computational expertise as well as sophisticated data scientist users. Scientific Description The AnVIL aims to create an interoperable resource for the research community by co-locating data, storage and computing infrastructure with commonly used services and tools for analyzing and sharing data. In particular, the AnVIL resource will provide genomic researchers with the following: • Cloud-based infrastructure and software platform • Shared analysis and computing environment • Participation in a federated genomic data resource ecosystem • Cloud services cost control • Genomic datasets, phenotypes and metadata • Data access and data security • User training and outreach • Incorporation of scientific and technology advances As an NIH Designated Data Repository, the AnVIL is authorized to share controlled-access datasets with the research community. This is done in compliance with the NIH Genomic Data Sharing (GDS) Policy for controlled-access genomic datasets, including associated metadata and phenotypic data. In addition, the AnVIL is implementing security configurations and controls for its data management system that are equivalent to those of certified FISMA Moderate systems. These procedures include standard user authorization and authentication procedures, as well as methods for allowing third party applications to be built on top of the AnVIL. Since the grant awards in September 2018 the AnVIL has made significant strides in organizing its program management structure, including the establishment of six working groups and the setup of communication platforms to effectively streamline information sharing and tracking among investigators across multiple research institutions. Within one year, the AnVIL team convened three in-person meetings of key personnel and NHGRI program staff and established an External Consultant Committee (ECC) to advise NHGRI on AnVIL operations and make recommendations about future activities. The AnVIL had a beta release of the platform at the end of Q2 2019 with high-value datasets such as GTEx version 8 and the high-coverage sequenced samples from the 1000 Genomes Project. Key analysis tools and packages such as Jupyter Notebooks and RStudio were also made available to users in their AnVIL workspaces. Future Directions The public launch of the AnVIL is scheduled for late Q4 2019 or early Q1 2020. The AnVIL will be 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. The 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 Data Commons Framework and the NHLBI Data Stage. In collaboration with other ICs, AnVIL program staff are organizing a meeting in early October of the key personnel of these resources and are engaged with the identity and access management discussions of the NIH Technical Implementation Working Group headed by the NIH Office of Data Science Strategy. In addition to its existing and planned features and datasets, the AnVIL plans to develop and deploy the Data Use Oversight System (DUOS) and Library Card pilots, which will leverage a semi-automated process for requesting controlled access datasets hosted by the AnVIL. The AnVIL team is also engaging with the NIH STRIDES Initiative to leverage the NIH negotiated discount rates for the Google cloud resources that the AnVIL’s infrastructure is built on.
Fiscal Year 2021 The Genome Technology (GTP) program at NHGRI supports research to innovate and develop new methods, technologies and systems that enable rapid, low-cost determination of nucleic acid sequence and genotyping along with epigenetic, functional, and synthetic genomics experiments. The development of completely novel approaches and achieving orders-of-magnitude improvements in genomic technologies are foundational efforts of the program. The refinement of current technologies to increase efficiency and decrease cost while maintaining or improving data quality and the integration of process steps is key to achieving these goals. The program also supports and coordinates technology transfer from developers to users, and promotes collaborative, multidisciplinary programs that closely integrate research projects in academic and industrial laboratories.
Fiscal Year 2023 Lay Description: From its inception in the late 20th century with the Human Genome Project, a three-decade effort in technology development has and continues to enable a broad swath of research and medical advances. The initial project lasted over a decade and was a tremendous, focused effort to sequence just one human genome for the first time. This initial effort and the many others that followed demonstrated the great impact of technologies including nucleic acid sequencing. Today research illuminating genomic contributions to disease is rooted in a rapidly growing body of human genome sequences currently numbering in the tens of millions. Concomitant efforts to understand function in relation to health and disease use both newly developed and established methods for probing genomic regulation, structure, and interactions. Through both focused efforts and those embedded in other activities, the broad area of genomic technology development has blossomed and enabled research and knowledge on an ever-widening scale and scope across biomedical research, human health, and disease. Scientific Description: The Genome Technology Program fuels study of the human genome, genetic variation, mutation, and perturbation. New technologies enable the expanding use of genomics in both basic and clinical research and application. Over the decades the Genome Technology Program has expanded from a strong focus on nucleic acid sequencing to broadly encompass a wide set of efforts including single-molecule protein sequencing technologies. Today the program emphasizes the importance of novelty, funding work that will move the field of genomics beyond the likely next steps in technological advancement by seeking improvements greater than one order of magnitude. Efforts also include a coordinating center to enhance integration between the components of the Genome Technology Program. Awards in FY22 will continue to support and coordinate efforts in novel nucleic acid sequencing, single-molecule protein sequencing, and from across the breadth of genomic technology development. Future Directions: The program aims to encourage the development of novel investigator-initiated technology for genomics, nucleic acid sequencing, and single-molecule protein sequencing. Expected outcomes of the Genome Technology Development program are the publication and commercialization of the innovative work that this program funds.