National Institutes of Health (NIH)
National Human Genome Research Institute (NHGRI)
Expanding the Encyclopedia of DNA Elements (ENCODE) in the Human and Mouse (UM1)
UM1 Research Project with Complex Structure Cooperative Agreement
The Encyclopedia of DNA Elements (ENCODE) Project has cataloged a significant number of candidate functional elements in the human and mouse (Mus musculus) genomes. These catalogs are being used by the research community to expand on basic biological knowledge, to develop research tools and to interpret the results of disease-mapping studies (see https://www.encodeproject.org/search/?type=publication&published_by=community for publications from the research community that use ENCODE resources). Although much progress has been made over the past decade, these catalogs are incomplete. The purpose of this FOA is to solicit applications for research projects to apply state-of-the-art, high-throughput and cost-effective data generation pipelines to develop an expanded catalog of candidate functional elements in the human and mouse genomes. As part of this effort, applicants may map candidate elements in biological samples relevant to specific diseases to help expand the catalog while at the same time informing on how to direct disease studies in the long run. The funded projects will participate in the ENCODE Consortium.
January 14, 2016
February 21, 2016
February 21, 2016
March 21, 2016, by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on this date.
Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
March 22, 2016
Required Application Instructions
It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.
I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information
The Encyclopedia of DNA Elements (ENCODE) Project has cataloged a significant number of candidate functional elements in the human and mouse (Mus musculus) genomes. These catalogs are being used by the research community to expand on basic biological knowledge, to develop research tools and to interpret the results of disease-mapping studies (see https://www.encodeproject.org/search/?type=publication&published_by=community for publications from the research community that use ENCODE resources). Although much progress has been made over the past decade, these catalogs are incomplete. The purpose of this FOA is to solicit applications for research projects to apply state-of-the-art, high-throughput and cost-effective data generation pipelines to develop an expanded catalog of candidate functional elements in the human and mouse genomes. As part of this effort, applicants may map candidate elements in biological samples relevant to specific diseases to help expand the catalog while at the same time informing on how to direct disease studies in the future. The funded projects will participate in the ENCODE Consortium.
A critical step in moving from genome sequence to understanding the impact of genetic variation on biology, health and disease is the identification of the parts of the genome that contribute to function. To facilitate this understanding, the National Human Genome Research Institute (NHGRI) has been supporting the Encyclopedia of DNA Elements (ENCODE) Project (www.genome.gov/ENCODE). The long-term goals of ENCODE are to identify all of the sequence-based functional elements in the human genome and to share catalogs of these elements freely with the research community in readily accessible and interpretable formats. ENCODE aims to annotate both protein-coding and non-coding regions of the genome. To date, fewer resources have been devoted to the study of non-coding variation, but evidence for its important role in establishing healthy and disease phenotypes continues to grow. Genome-wide association studies (GWAS) have revealed that most disease-associated variants map to non-coding regions, and most of the heritability of common diseases has been imputed to stem from non-coding regions. Non-coding variation accounts for most of the heritability in the Mendelian disorder Fragile X Syndrome, and is a major source of heritability in polygenic disorders such as Amyotrophic Lateral Sclerosis. As whole genome sequencing is increasingly being undertaken to understand the genetic basis of disease, the importance of being able to interpret these data in their entirety (including non-coding regions) will increase. NHGRI and ENCODE are thus especially interested in creating resources to help researchers interpret non-coding genome variation.
The main strategy employed by ENCODE has been the identification of candidate functional elements using genome-wide biochemical assays associated with specific classes of DNA elements. This approach has been augmented by comparison of sequences and candidate elements across species. “Functional elements” are genes (protein-coding and non-coding) and regulatory regions. Decades of gene regulation studies have identified mechanistic events (such as changes in chromatin structure and protein occupancy) that are being used to make predictions of regulatory elements; given that the accuracy of any untested prediction is unknown, the term “candidate functional elements” is used here. As many functional elements are manifest only in specific cellular contexts, multiple cell types have been interrogated to maximize discovery of candidate elements. A portion of ENCODE’s effort has been devoted to analysis of the mouse genome, as annotation of the mouse genome has facilitated understanding of the human genome.
Candidate functional elements that have been identified by ENCODE include genes, RNA transcripts, regulatory elements encoded in DNA (including enhancers, promoters, and insulators) and regulatory elements acting at the RNA level (including those that regulate splicing, translation, and RNA stability). ENCODE has used genomic methods (e.g., RNA-seq, ChIP-seq, DNase-seq) based on biochemical assays that have been developed and widely used by the research community to study gene regulation. These assays, which map features that have been mechanistically linked to gene regulation, have been used by epigenomics projects (such as ENCODE, the Roadmap Epigenomics Mapping Centers [REMC], and the International Human Epigenome Consortium [IHEC]), as well as many individual investigators in the research community to identify functional regions of the genome.
Any researcher may freely download, analyze and publish results based on any ENCODE data (without embargo or restrictions) as soon as the data are released. The catalogs of candidate elements are intended to complement ongoing efforts to understand the functions resident in the genome and to serve as the basis for hypothesis generation for more focused studies. As of October 2015, ENCODE has released approximately 3500 experiments, each containing at least two replicates, examining approximately 300 human cell types (cell lines, primary cells, cells differentiated in culture, and explants), and approximately 1000 experiments in more than 150 mouse cell types. To date, ENCODE human and mouse data have appeared in approximately 1200 papers published by researchers outside of ENCODE, including investigations of the role of the genome in human disease (https://www.encodeproject.org/search/?type=publication&published_by=community).
ENCODE is also integrating these data to produce an “Encyclopedia,” a compendium of candidate functional elements designed to enable exploration of the role of functional elements in disease mechanisms and basic biological processes. A developmental version of the Encyclopedia is available at https://www.encodeproject.org/data/annotations/.
NHGRI convened a planning workshop “From Genome Function to Biomedical Insight: ENCODE and Beyond” on March 10-11, 2015, to consider what projects in functional genomics should be supported that build on the work of ENCODE. Details about this workshop, including the workshop report can be found at: http://www.genome.gov/27560819. The overall conclusion from the workshop was that much work still remains to complete the Encyclopedia and to maximize its utility: While many elements are functionally active in restricted cell contexts, only a small fraction of these (cell types, fates, states) have been studied to date. Further, only a very small fraction of the candidate functional elements have been experimentally characterized with respect to specific biological function(s) and new technologies have emerged over the past few years that have made the cost-effective and high-throughput study of these biological functions feasible. Functional studies on samples related to disease serve as an untapped opportunity to simultaneously expand the Encyclopedia, provide insights about disease and help uncover general strategies for applying these assays to disease. Finally, to meet the long-term goals of functional genomics, continued technology development is needed.
Based on the workshop recommendations, NHGRI proposes to extend the ENCODE effort through the support of five Funding Opportunity Announcements (FOAs) to address the following specific goals: expand the catalog of functional elements; move beyond cataloging towards a general understanding of the functional role of genomic elements, which occurs in specific biological contexts; develop strategies to apply these studies to disease; increase the number of scientists from the research community contributing to the creation of the encyclopedia of functional elements; develop analytical tools to enhance the utility of the data; and make the data, tools, analyses and assembled encyclopedia freely available to the research community.
These related initiatives are:
ENCODE will be organized as a research consortium that brings participants together in a highly collaborative and synergistic effort. Data produced in the Mapping Centers funded through this initiative (HG-16-002) as well as by the Characterization Centers (funded through HG-16-003) will serve as the raw material for generating annotations of functional DNA sequence elements. These data will be submitted to the ENCODE Data Coordination Center (DCC). The DCC will uniformly process the mapping data as well as develop, house, and maintain databases to track, store, and provide access to all ENCODE data and related resources. The DCC will also import from the research community, related mapping data that meet ENCODE quality standards. The ENCODE Data Analysis Center (DAC) will coordinate high-level analytical activities of the consortium, including development of the Encyclopedia, and provide computational support for these analyses. Computational Analysis groups will develop novel methods and tools for processing, analyzing, and enhancing the utility of ENCODE data, and contribute broadly to consortium analytical efforts.
This initiative solicits applications to support functional element Mapping Centers to continue ENCODE’s efforts to create comprehensive catalogs of candidate functional elements in the human and mouse genomes. These centers should employ high-throughput, genome-wide and cost-effective experimental pipelines for a range of genomic assays capable of generating high quality data to map biochemical activities, exhibited by the human and mouse genomes, that are associated with functional elements. The primary activity of the Mapping Centers will be data generation in an expanded number of cell contexts (cell types, fates, states) relative to those studied to date in ENCODE. For information on existing ENCODE data and biological samples assayed, see: https://www.encodeproject.org/search/?type=experiment.
This FOA seeks to support high-throughput, genome-wide and cost-effective assays that generate high quality data that have been mechanistically associated with gene regulatory activities and genes (e.g., certain histone marks are associated with gene enhancer and/or promoter activity) to be used to identify candidate functional elements. Determination of specific functions of elements in particular biological contexts is beyond the scope of this initiative (but may be supported under related RFA-HG-16-003; "Characterizing the Functional Elements in the Encyclopedia of DNA Elements (ENCODE) Catalog (UM1)"). It is anticipated that through the funding of multiple Mapping Centers, this initiative will support the generation of multiple datatypes from multiple assays associated with a variety of classes of functional elements. However, to encourage highly focused research projects and streamline data management, projects are sought that propose the use of only one biochemical assay (e.g., ChIP-seq, RNA-seq, and variations thereof). An additional 1-2 assay(s) per application may be considered if they are strongly justified in terms of how centralizing data production within one group, compared with data generation by other groups within the consortium, will result in production efficiencies or other synergistic benefits.
Experimental assays that have already been used in ENCODE may be proposed on cell samples not previously interrogated (see below for more information on biological samples), if these assays remain state-of-the-art. New and improved methods beyond those currently being used in ENCODE that can be applied in a high-throughput manner to either identify new classes of functional elements or overcome previous technical limitations (e.g., using smaller number of cells or single cells, providing higher resolution, lower cost, or otherwise more informative data) are encouraged. Depending on the demonstrated capabilities of the different assays, these new or improved assays may be applied across a relatively small set of common samples previously used within ENCODE (for which significant amounts of ENCODE data already exist) or, if technically feasible as demonstrated by preliminary data, across a wide range of cell types.
NHGRI seeks projects to produce the following to expand on data generated by ENCODE and related projects:
In addition to generating these maps in new cell contexts and/or with new assays, as described above, projects are also sought to map the binding sites of RNA binding proteins and sequence-specific transcription factors not previously studied in ENCODE, in a small number of biological contexts in order to identify binding motifs. These projects should maximize the number of unique factors studied to the extent technically feasible.
The above description represents NHGRI’s highest priorities. Other sequence-based functional components of the genome may be studied if the applicant can demonstrate high value of the data to the research community, as well as the existing capacity to generate high quality data for these functional elements using efficient, high-throughput methods.
This FOA seeks applications with primarily experimental approaches to generating data. Computational approaches may be included as part of the research plan, but applications for which the majority of the proposed work is computational are not responsive to this FOA. Such applications may be responsive to the companion FOA RFA-HG-16-004 “Computational Analysis of the Encyclopedia of DNA Elements (ENCODE) Data (U01)”).
Since many functional elements are manifest only in restricted cell contexts, many additional cell contexts will be needed to create a more comprehensive catalog of candidate functional elements. This FOA seeks projects that will generate data on new samples that will significantly expand the catalog, i.e., those samples with the greatest potential for new discovery. These could be samples that fill a particular gap in the cell space that has been previously interrogated by ENCODE, samples that have a particular biological focus (e.g., developmental or differentiation pathway, environmental exposure), or samples from disease-relevant tissues not previously studied by ENCODE. (For a list of biological samples studied in ENCODE to date, see: https://www.encodeproject.org/search/?type=biosample&award.project=ENCODE.) Biological samples could be primary cells, experimentally derived cells, e.g., differentiated iPS/ES cells, explants, single cells or other cell samples that help address the challenges posed by biological sample purity/heterogeneity, physiological relevance, and accessibility.
Disease-relevant samples: Disease relevant samples may be specialized cells of high relevance to a disease from unaffected individuals if not previously studied in ENCODE, and from affected individuals. Up to 25% of data production effort proposed by any one center may be devoted to disease-relevant samples from affected individuals; however, plans to work on disease-relevant samples is not required in the application. Data from these sources should simultaneously help build the catalog of functional elements, inform about differences between normal and affected samples, and support the long term goal of developing a general strategy to apply these approaches to disease.
Biological samples from the research community: In order to broaden the participation of researchers involved in this effort and to draw from unique biological and disease expertise, the Mapping Centers should engage with the research community to seek contributions of unique biological samples for mapping. (See Outreach section below and guidance to applicants in Section IV.2 for more information.)
Informed consent: In order to maximize the utility of ENCODE data, all samples to be studied under this initiative are expected to have been obtained using consents that (a) explicitly allow for open (non-restricted) data sharing and (b) allow for sharing samples with other ENCODE-funded groups. (See http://www.genome.gov/ENCODE for sample language for open access consent forms examples of open access consent forms previously used in ENCODE.) Exceptions may be granted by NHGRI for studies employing new methods being applied across a relatively small set of common samples previously used within ENCODE (for which significant amounts of ENCODE data already exist).
Coordination of biological samples: To the extent possible, all groups funded through this initiative will conduct experiments on biological samples that will be used in common by all the Mapping Centers. Therefore, all Mapping Centers are expected to acquire samples in sufficient quantities to be assayed by all of the other groups funded through this initiative so that the range of assays can be applied to all samples, and are expected to be willing and able to share with other groups. For more information, see additional instructions in Section IV.2 Research Strategy.
Once awards are made, the mapping center groups will work together and with NHGRI, in consultation with the rest of the ENCODE Consortium, to prioritize shared samples to be studied across all assays and groups, and to develop a process for obtaining additional samples from collaborations with the broader research community. In addition, early in the funding period, the ENCODE Data Analysis Center (RFA HG-16-006) will analyze existing ENCODE data, and the biological samples that were studied to derive those data, to identify gaps in areas of anatomy, physiology, health and disease that the Mapping Centers, in this new phase of ENCODE, can target to maximize discovery of new elements. (See below – Bounding the cell space for completing the catalog.) As a result of these processes, it is likely that only a subset of the samples proposed by each group will be studied.
Mouse samples: It is anticipated that mouse studies will constitute approximately 10% of the overall data production effort. These data will be used primarily to further understand the human genome. Applications may, but are not required, to propose studies to identify candidate functional elements in the mouse genome in addition to the human genome, or indicate the willingness to work on mouse samples agreed upon by the mapping groups collectively. For more information, see additional instructions in Section IV.2 Research Strategy.
Bounding the cell space for completing the catalog: Since many functional elements are manifest in only restricted cell contexts, many additional cell contexts are needed to create a comprehensive catalog of candidate functional elements in the human genome. However, there is an almost infinite number of conceivable cell contexts that could be assayed in the search for functional elements in the human genome, i.e., all specialized cell types, developmental time points, environmental conditions and disease states. Therefore, a significant challenge for ENCODE is determining when the catalog of functional elements is reasonably complete, both on a scientific and a practical (i.e., resource and technology-limited) level. This will be addressed at two levels by the Consortium once awards are made:
Flexibility of mapping pipeline: NHGRI will need to maintain flexibility in the collective production pipelines to adjust to a rapidly changing landscape. Centers funded under this initiative will be expected to collaborate effectively with each other and with NHGRI Program Staff with respect to assays and experimental samples in order to maximize the chance of success of the collective effort. For example:
To maintain flexibility, NHGRI will reserve 15-25% of funds in each of the out years of the award and may shift funding from one group to another as dictated by the opportunities outlined above.
Groups funded under this initiative will be expected to collaborate effectively with each other to maximize the chances of overall success of the program and to participate in the ENCODE Research Consortium. The Awardees funded through the concurrent FOAs, RFA-HG-16-003, “Characterizing the Functional Elements in the Encyclopedia of DNA Elements (ENCODE) Catalog", to support characterization of candidate functional elements, RFA-HG-16-004 “Computational Analysis of the Encyclopedia of DNA Elements (ENCODE) Data” to support additional analysis activities, RFA-HG-16-005 “ENCODE Data Coordination Center, to support ENCODE’s data management and Consortium coordination and outreach activities, and RFA-HG-16-006, “ENCODE Data Analysis Center” to support the analysis activities of ENCODE, will also participate in the ENCODE Research Consortium.
This FOA is open to all investigators, specifically including those who are not currently participating in the ENCODE Project. Applicants are free to apply to the companion FOAs. However, to encourage participation from a broad representation of the research community, when making funding decisions, NHGRI intends to consider whether an applicant will be funded as a PD/PI through other ENCODE FOAs and may choose to limit awards from multiple FOAs. As in the ENCODE Project to date, the ENCODE Research Consortium will continue to be open, beyond the funded investigators, to all academic, government and private sector scientists who are interested in participating in an open process to facilitate the generation of comprehensive catalogs of the ENCODE-targeted genomes.
All applicants are strongly encouraged to contact NHGRI Staff to discuss the alignment of their proposed work with the goals of this FOA, and with the ENCODE Project. A Technical Assistance teleconference will be held for potential applicants to this FOA and the companion FOAs. NHGRI staff will be available to answer questions related to these FOAs. Time, date, and dial in information for the call will be announced in an NIH Guide Notice and will be posted on the ENCODE website: http://www.genome.gov/ENCODE. During the Information Session, NHGRI staff will present an overview of these FOAs and answer questions from prospective applicants. The Information Session is open to all prospective applicants, but participation is not a prerequisite to applying.
Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities. See Section VI.2 for additional information about the substantial involvement for this FOA.
The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
NHGRI intends to commit $15.5-20M in FY 2017 to fund 6-8 awards.
Application budgets are not limited but need to reflect the actual needs of the proposed project.
The total project period for an application submitted in response to this FOA may not exceed 4 years.
NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.
Higher Education Institutions
The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:
Nonprofits Other Than Institutions of Higher Education
Non-domestic (non-U.S.) Entities (Foreign Institutions) are
not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.
Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.
Program Directors/Principal Investigators (PD(s)/PI(s))
All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.
Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.
For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.
This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.
Applicant organizations may submit more than one application, provided that each application is scientifically distinct.
The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:
Applicants must obtain the SF424 (R&R) application package associated with this funding opportunity using the “Apply for Grant Electronically” button in this FOA or following the directions provided at Grants.gov.
It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.
For information on Application Submission and Receipt, visit Frequently Asked Questions – Application Guide, Electronic Submission of Grant Applications.
Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.
By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:
The letter of intent should be sent to:
Elise Feingold, Ph.D.
All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed, with the following exceptions or additional requirements:
The Research Strategy must consist of the following sub-sections with the indicated page limits:
The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed.
The effective management of a production project requires a significant commitment by the Program Director(s)/Principal Investigator(s). For an application proposing a single PD/PI, that PD/PI is expected to devote at least 3 calendar months annually to the project. If multi-PDs/PIs are proposed, then one PD/PI is expected to commit at least 3 calendar months annually and the other(s) should devote sufficient time to serve his/her proposed role.
Budgets should include support for a dedicated Project Manager who will devote a minimum of 4 calendar months to oversee the day-to-day activities of the project, coordinate across project sites, if applicable, and be responsible for promptly providing requested reporting information to NHGRI Program Staff. A PD/PI may serve as the Project Manager.
Applicants should budget for obtaining biological samples in sufficient quantities to be assayed by all of the Mapping Centers funded through this initiative so that the range of assays can be applied to all samples. Since applicants will not know in advance what assays will be funded, the quantity of available samples and applicability to widely used assays should be addressed in general terms. Once awards are issued and decisions are made about which common samples will be used and an assessment can be made about what the experimental requirements are, awardees will likely be asked to re-budget in order to have sufficient funds to provide the necessary samples to all Mapping Centers.
Budgets should include any funds required to obtain samples with explicit informed consent for: (a) genomic data generation, (b) unrestricted access data sharing (e.g., GEO (http://www.ncbi.nlm.nih.gov/geo/), ENCODE Portal (https://www.encodeproject.org) and (c) sharing samples with other consortium members.
Applicants should provide research plans for four years at a constant funding level; however they should understand that in order to maintain this flexibility, NHGRI will reserve 15-25% of funds in each of the out years of the award and may shift funding from one group to another as dictated by new opportunities, as described in the research scope.
The ENCODE Project has regular conference calls and meetings. Awardees and additional key personnel from each center will be required to attend one Consortium meeting per year. Applicants should request funds for 2-6 group members to attend annual meetings and to attend Consortium-led tutorials, as appropriate.
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:
Research Strategy: The Research Strategy should consist of the following subsections, uploaded as a single pdf attachment:
1) Overall Goals Section
2) Experimental Assay Section
3) Selection of Biological Samples Section
4) Data Management Plan
5) Project Management Plan
1) Overall Goals Section
Applicants should state concisely the goals of the proposed project and summarize the expected outcomes with respect to meeting the goal of expanding the catalog of candidate functional elements in the human and mouse genomes.
A description of the experimental assay(s) being proposed should be provided along with a justification for the proposed number of samples and how the data to be generated will lead to the discovery of a significant number of new candidate functional elements. Applicants are strongly encouraged to propose the use of only one biochemical assay (e.g., ChIP-seq, RNA-seq, and variations thereof). An additional 1-2 assay(s) will be allowed; however if more than one assay is being proposed, applicants should provide a justification for how centralizing data production within one group, compared with data generation by other groups within the consortium, will result in production efficiencies or other synergistic benefits.
Applicants should also provide a brief description of the selection of biological samples to be used, describing plans to use samples that will be obtained with consents allowing for unrestricted data access and explaining how these samples will address gaps in the current ENCODE catalog, and indicate a willingness to analyze samples chosen by the consortium.
A description of the informatics infrastructure for managing data, metadata, quality control and tracking to support the proposed activities should also be provided.
Finally, applicants should describe the organization of the proposed center and its management structure, including integration of components to maintain efficient operation, key personnel, and reporting relationships. Proposed collaborations and plans for outreach to the research community should also be described.
2) Experimental Assay Section
To encourage highly focused research projects and streamline data management, projects are sought that propose the use of only one biochemical assay (e.g., ChIP-seq, RNA-seq, and variations thereof). An additional 1-2 assay(s) per application may be considered; however applicants must provide a strong justification for more than one assay with respect to how centralizing data production within one group, compared with data generation by other groups within the consortium, will result in production efficiencies or other synergistic benefits. Applicants should propose plans to generate high-quality data using methods that have been mechanistically associated with gene regulatory activities (e.g., certain histone marks are associated with gene enhancer and/or promoter activity), and that have been demonstrated to be high-throughput and cost-effective, to identify candidate functional elements in the human and mouse genomes. Preliminary data to support the proposed approach(es) should be provided. The planned assay(s) should have the capability to be comprehensive, i.e., to accurately and efficiently identify essentially “all” instances of a particular class of candidate functional elements within the genome that are active in any given biological sample. Applicants should attempt to provide a reasonable estimate of the sensitivity of the proposed assay(s) and discuss the basis for the estimate. This may involve preliminary data identifying candidate functional elements using an independent method for comparison and/or information from the literature.
Applicants proposing to map the binding sites of RNA binding proteins or sequence-specific transcription factors not previously studied in ENCODE should provide plans to map binding sites only in a small (two-five) number of cell types/tissues. Both the specific biological samples proposed as well as the study of more than two samples should be well justified in terms of identifying binding motifs. Applicants should propose to maximize the number of unique RNA binding proteins and/or sequence-specific transcription factors studied to the extent technically feasible based on preliminary data. Mapping factor-binding sites in a large number of biological samples remains costly and is considered to be out of scope for this initiative. In order to avoid the need for costly and limiting factor-specific affinity reagents for ChIP-seq or related assays, the only affinity-based projects being encouraged are those using epitope-tagged factors using standard affinity reagents against those tags. Alternative, non-affinity-based assays may also be considered if their ability to map factor binding sites genome wide at high specificity and sensitivity can be demonstrated. To avoid unnecessary duplication of data generation, at the time of the award awardees will work with NHGRI to determine the specific list of factors to be studied based on the current ENCODE data.
Applicants proposing to discover elements that were not listed among NHGRI’s highest priorities in the Research Objectives should justify their importance to the community. At least two specific questions must be addressed: acknowledging that biochemical activities are often a proxy for function, what is the evidence that the proposed biological activity is associated with actual biological function, for example in gene regulation? Second, how will the proposed work scale to be able to assay the function, with high specificity and sensitivity, and cost-effectively, over the entire genome in multiple cell types?
Applicants should propose approaches to generating data that are primarily experimental in nature. Computational approaches may be included as part of the research strategy, but not projects for which the majority of the proposed work is computational.
Applicants must propose to work on the entire genome, and should define “entire genome”, i.e., should clearly describe any regions in the genome that are likely to be refractory to the proposed methods (e.g., any repetitive sequences that are masked in the analysis of sequencing data). In such cases, applicants should justify why the proposed approach will be sufficient to meet the goals of the FOA and/or provide alternative strategies for interrogating the remainder of the genome.
Candidate functional elements should be identified precisely, ideally to the resolution of the specific nucleotide sequences that confer the function. NHGRI recognizes that this will not be possible in all cases, for a variety of reasons. For example, some assays may not provide nucleotide resolution of the precise protein binding site (e.g., ChIP-seq) and beyond that, some functional elements are composed of multiple sites that comprise a larger module (such as cis-regulatory elements). Applicants should explicitly discuss the issue of resolution and should clearly describe the resolution to which their proposed method(s) will identify the targeted functional element(s). If the resolution is not to the nucleotide level, the applicant should discuss the utility of the information that will be obtained (i.e., the value of defining an element at the proposed resolution) and the cost/benefit of attempting higher resolution studies.
Generation of new reagents or physical resources, such as specific clone libraries, to carry out the proposed analyses should only be proposed to the extent that they are needed to identify targeted functional element(s). The creation of a set of physical resources for the primary purpose of generating a community resource independent of discovery or validation studies will not be supported.
In addition to the above, applicants should also discuss the following:
Data Quality: The quality of the data used to develop the catalogs of candidate functional elements is critical to the utility of the ENCODE resources. The approach to data quality will be based on what has been employed successfully in the ENCODE Project to date, by demonstrating experimental reproducibility and high signal to noise ratio of the primary data and employing experimental platform(s) that have been well-characterized (quantitatively measured, benchmarked) using Consortium- agreed upon quality metrics. The data standards that have been developed by ENCODE can be found at https://www.encodeproject.org/about/experiment-guidelines/ but it should be noted that these standards are continually updated based on additional data analysis and technical improvements. Applicants should indicate plans to follow these or other more stringent standards, to agree to meet any new standards developed by the Consortium and, as needed, to develop similar standards for novel technologies.
For those proposing to use affinity-tagging approaches to generate ChIP-seq or similar data, a thorough discussion of the quality of these data compared with data obtained by using factor-specific antibodies, as well as the ability of the approach to reach “completeness” with respect to the number of factors studied, must be provided in the application.
Data Utility: Applicants should discuss the evidence that the experimental assays proposed generate data that will be of high utility for identifying candidate functional elements. This should include information demonstrating that the data to be generated are biologically relevant and have been mechanistically associated with gene regulatory activities (e.g., certain histone marks are associated with gene enhancer and/or promoter activity). Applicants proposing new assays that have not been previously used in ENCODE must explain how the new data type to be generated significantly adds value to or is superior to what has already been generated, e.g., study of biological samples previously difficult to study, novel discovery, higher resolution, increased information content, higher-throughput, lower cost, etc.
Production Pipeline: If the ENCODE Project is to meet its ultimate goal of the comprehensive identification of functional elements in the human genome, the individual projects involved in the effort must attain a high level of production at an affordable cost. As with other large-scale genomic efforts, it is anticipated that increasing throughput and lowering costs will have concomitant effects on improved data quality through an overall improvement in the technological state of the art. Applicants should address a number of issues related to data production for each experimental assay:
3. Selection of Biological Samples Section
Applicants should propose to apply their experimental assay(s) to biological samples that will significantly expand the catalog and should justify their selections based on potential for discovery of new candidate functional elements. These could be samples that fill a particular gap in the cell space that has been previously interrogated by ENCODE, samples that have a particular biological focus (e.g., developmental or differentiation pathway, environmental perturbation) or samples from disease-relevant tissues not previously studied by ENCODE. Biological samples could be primary cells, experimentally derived cells, e.g., differentiated iPS/ES cells, explants, single cells, or other cell samples that help address the challenges posed by tissue purity/heterogeneity, physiological relevance and accessibility.
All applicants should provide plans to work on human samples. In addition, applicants may propose to work on mouse samples (see below).
Disease-relevant samples: Applicants may, but are not required to, include plans to study samples that are disease relevant and should provide a strong justification for their use in terms of discovery of new candidate functional elements. Disease-relevant samples may be specialized cells of high relevance to a disease from unaffected individuals, if not previously studied in ENCODE, and from affected individuals. Applicants may propose to devote up to 25% of their data production effort to disease-relevant samples from affected individuals. Data from these sources should simultaneously help build the catalog of functional elements, inform about differences between normal and affected samples, and support the long term goal of developing a general strategy to apply these approaches to disease.
Biological samples from the research community: In order to broaden the participation of researchers involved in this effort and to tap into unique biological and disease expertise, the Mapping Centers should engage with the research community to seek contribution of unique biological samples for mapping. Applicants should indicate the types of samples they propose to obtain from collaborators, as well as the collaborator’s expertise in the specific area of biology or disease. In addition to the samples proposed in the application, applicants should indicate their willingness to work with the research community during the course of the project to identify unique samples that will help to meet the needs of the Mapping Centers to maximize discovery of new elements. (See Outreach section under Project Management Plan below for more information.)
Coordination of biological samples: To the extent possible, all groups funded through this initiative will conduct experiments on samples that will be used in common by all of the Mapping Centers. Applicants should propose specific samples they plan to use in at least the first 18 months of the project. Applicants should describe plans to acquire samples in sufficient quantities to be shared with and assayed by all of the groups funded through this initiative so that the range of assays can be applied to all samples, and also indicate their willingness and ability to share with other groups. Since applicants will not know in advance what assays will be funded, the quantity of available samples and applicability to widely used assays should be addressed in general terms.
Once awards are made, the Mapping Centers will work together with NHGRI, in consultation with the rest of the ENCODE Consortium, to prioritize shared samples to be studied across all assays and groups, and to develop a process for obtaining additional samples from collaborations with the broader research community. In addition, early in the funding period, the ENCODE Data Analysis Center (RFA-HG-16-006) will analyze existing ENCODE data, and the biological samples that were studied to derive those data, to identify gaps in areas of anatomy, physiology, health and disease that the Mapping Centers target to maximize discovery of new elements. (See below – Bounding the cell space for completing the catalog.) Once decisions are made about which common samples will be used and an assessment can be made about what the experimental requirements are, awardees will likely be asked to re-budget in order to have sufficient funds to provide the necessary samples to all Mapping Centers. As a result of these processes, it is likely that only some of the samples proposed by each group will be studied. Applicants should express their willingness to participate in the development of a consensus set of experimental conditions and common reagents for the Project and agree to include those in their research projects.
Informed consent: In order to maximize the utility of ENCODE data, all samples to be studied under this initiative are expected to have been obtained using consents that (a) explicitly allow for open (non-restricted) data sharing and (b) allow for sharing samples with other ENCODE-funded groups. (See http://www.genome.gov/ENCODE for sample language for open access consent forms and examples of open access consent forms previously used in ENCODE.) Exceptions may be granted by NHGRI for studies employing new methods being applied across a relatively small set of common samples previously used within ENCODE (for which significant amounts of ENCODE data already exist). Applicants should describe previous experience with obtaining samples using consents allowing for unrestricted data sharing (if any) and indicate their agreement to obtain and use such samples in the mapping studies.
Mouse samples: It is anticipated that mouse studies will constitute approximately 10% of the overall data production effort. These data will be used primarily to further understand the human genome. Applicants may, but are not required, to propose studies to identify candidate functional elements in the mouse genome in addition to the human genome, or indicate their willingness to work on mouse samples agreed upon by the mapping groups collectively. Since much effort has already been devoted to map candidate functional elements in mouse embryonic development, proposed work should be limited to adult tissues unless additional mapping in embryonic samples can be very strongly justified, for example through the use of new or significantly improved assays not previously employed that add considerable value to the existing mouse data. For a list of mouse data released by ENCODE see: https://www.encodeproject.org/search/?type=experiment&replicates.library.biosample.donor.organism.scientific_name=Mus%20musculus
Bounding the cell space for completing the catalog: As described in the Research Objectives section above, a significant challenge for ENCODE is determining when the catalog of functional elements is reasonably complete, both on a scientific and a practical (i.e., resource and technology-limited) level. Applicants should indicate their willingness to conduct experiments directed at addressing this challenge, as needed based on Consortium discussions and in consultation with NHGRI. However, applicants do not need to propose experiments to address this challenge in their application.
Finally, NHGRI will need to maintain flexibility in the collective production pipelines to adjust to a rapidly changing landscape. Once awards are made, and then on a continuing basis, the ENCODE Consortium, working together with NHGRI staff and the Project’s External Consultants Panel (see Section VI.2 below), will continue to refine the overall Project milestones and targets. Applicants should not propose alternative research plans in anticipation of these new developments.
4. Data Management Plan
Data management: A key aspect of a successful mapping center is strong data management. Each mapping center is expected to have sufficient informatics infrastructure to handle all pertinent issues associated with the generation of high quality data and deposition of data and associated metadata (including tracking the provenance of data and biological samples) to consortium-designated databases. Informatics activities will include basic IT infrastructure/system administration, a laboratory information management system (LIMS) and a system for data handling, data and metadata submission and primary data analysis to ensure data quality. In all cases, any needed software development should be described in detail.
Data and metadata submission: Applicants should describe plans for working with the DCC to establish an informatics pipeline for the submission of both data and metadata. Plans should include the submission of the primary data in standardized formats to the DCC and to other appropriate public repositories as specified by the ENCODE Consortium. Applicants should include plans to generate only data that can be deposited into unrestricted access databases (see information on unrestricted access consent in Selection of Biological Samples Section, (above)). In addition, applicants should describe plans to submit any metadata such as information about biological samples, experimental procedures and primary analysis methods used to generate the data to the DCC through this pipeline. Finally, this submission pipeline should capture and submit a workflow with links to all software, data and metadata that will enable other investigators to reproduce any published analyses. Applicants should indicate a willingness to work with the DCC to establish the exact types and formats of data and metadata that will be transferred to the DCC.
Primary data analysis: Processing pipelines for primary data will be established for each data type produced by the Mapping Centers to generate signal tracks and a list of genomic regions associated with the mapped feature, to generate a list of candidate functional elements found under the experimental conditions studied. Applicants must describe an efficient, accurate informatics pipeline for processing the primary data to generate a list of the sequence-based functional elements found under the experimental conditions. Once funded, each mapping center will work with the DAC and the DCC to develop, test and implement uniform data processing pipelines (for examples from the current phase of ENCODE please see https://www.encodeproject.org/pipelines/). For some data types, a mapping center may need to develop, test, and implement its own processing pipeline. All processing pipelines must be well documented and have procedures in place to capture metadata associated with any data transformation that is applied during analysis.
Integrative data analysis: The primary responsibility for integrative analysis of the data being generated by using the different technologies being employed within the ENCODE Consortium will be directed by the ENCODE Analysis Working Group (AWG) that will be comprised of members of the ENCODE Consortium and facilitated by the ENCODE Data Analysis Center (DAC). The main focus of those activities will be on generating and updating the Encyclopedia (https://www.encodeproject.org/data/annotations/). This FOA will not support the integrated analysis of data produced across the Mapping Centers. A mapping center may use funds awarded in response to this FOA only for limited analysis as necessary to integrate and cross-validate the data produced within their own center. More in-depth analyses of the data are outside of the scope of this FOA and should be supported by other funding mechanisms.
5. Project Management Plan
The Project Management Plan should describe how the PD(s)/PI(s) will manage the proposed project, who will serve as the project’s Program Manager to oversee the day-to-day activities and how the management structure will support achievement of the proposed goals and milestones. Elements of this description may include the organization of the proposed production effort; its management structure, including the integration of the separate components to form an efficient pipeline; key personnel; section leaders and reporting relationships; and any advisory board, if relevant. The role of the advisory board (if any) should be described, including how often it will meet, what types of scientific expertise will be needed on the board, and what specific activities will be performed by the board members. However, applicants should not contact potential advisors prior to the review of the application, nor should potential advisors be named in the application to avoid conflict of interest in the review process. Recruitment and training of personnel may also be discussed. The plan should also describe how the various components of the proposed production effort will be integrated, and how collaborations or subcontracts, if proposed, will be managed.
Milestones and goals: The success of ENCODE and many other genomics projects has been facilitated by the adoption of clear, quantitative milestones by each of the participating research groups. Applicants to this FOA are expected to define a clear set of goals (e.g., number of replicated experiments for each assay, number of biological samples to be mapped with each assay) for the overall project and propose quantitative milestones and appropriate metrics to measure the progress for their proposed experiments for each assay. It is expected that applicants will have already developed significant production capabilities prior to any award and that there will not be any need to scale the existing capabilities significantly in order to meet the proposed milestones. For new and improved methods beyond those that are currently being used in ENCODE, the proposed experimental scale should be based on a demonstrated capability of the proposed assay(s). These new or improved assays may be applied across a relatively small set of common samples previously used in ENCODE (for which significant amounts of ENCODE data already exist) or, if technically feasible as demonstrated by preliminary data, across a wide range of cell types. As mentioned above, to maintain flexibility, NHGRI will reserve 15-25% of funds in each of the out years of the award and may shift funding from one group to another as dictated by the opportunities outlined above. It is possible, based on progress, scientific opportunity and budgetary flexibility, that one or more assays performed on a relatively small set of common samples will be scaled up, to a wider range of samples. However, plans to do so should not be included in the application.
Milestones should reflect the ability to produce data from the beginning of the project and should be supported by preliminary data. (See Experimental Assay Section above.) At the time of the award, NHGRI will negotiate milestones for each award, which will then be incorporated into the Terms and Conditions in the Notice of Award. Milestones will be reviewed on at least an annual basis and updated as appropriate, with the approval of the NHGRI Project Officials.
Outreach: Successful applicants will be expected to study samples from other funded groups as well as from biology and disease experts from the community to enable the study of specific cell lineages, biologically relevant conditions and diseases that are of high value for discovery of new candidate functional elements but that might not be readily available. Applicants should describe plans to engage the research community to obtain such samples for the mapping center pipelines.
Applicants should also describe plans for outreach to the research community to educate researchers about the ENCODE resource through, for example, talks, papers, and tutorials. Once funded, groups are expected to participate in consortium-wide outreach activities such as tutorials led by the DCC.
Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:
All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
Data Sharing: The NHGRI is committed to the principle of rapid data release to the scientific community from projects of broad community interest. This principle was initially implemented during the Human Genome Project and has been widely recognized by the community as leading to one of the most effective ways of promoting the use of the genome sequence data to advance scientific knowledge. In keeping with this principle, the ENCODE Project has a history of rapid data dissemination to maximize access by the entire scientific community. ENCODE established and currently operates under a common Data Release Policy (see: https://www.encodeproject.org/about/data-use-policy/) of rapid pre-publication data release. External data users may freely download, analyze and publish results based on any ENCODE data without restrictions as soon as they are released. Users of these data are asked to cite the ENCODE Consortium, as specified in the data release policy. Agreement to abide by this policy is a current requirement for membership in the Consortium. NHGRI expects that the rapid data release principles of this policy will continue to be implemented during the next phase of the ENCODE Project.
Unrestricted access to human data: As the current ENCODE Project has increased its study of primary cells and tissues, it has begun working on human biological samples that have been explicitly consented for unrestricted data access in order to maximize the accessibility and broad utility of ENCODE data. This means that data can be deposited and displayed in freely accessible databases, e.g., GEO (http://www.ncbi.nlm.gov/geo) without registration or request. Moving forward, all samples to be studied under this initiative are expected to have been obtained using consents that (a) explicitly allow for unrestricted (open) data sharing and (b) allow for sharing samples with other ENCODE-funded groups. (See http://www.genome.gov/ENCODE for sample language for open access consent forms and examples of open access consent forms previously used in ENCODE.) Exceptions may be granted by NHGRI for studies employing new methods being applied across a relatively small set of common samples previously used within ENCODE (for which significant amounts of ENCODE data already exist).
Applicants should propose a data release policy in their applications that addresses rapid data sharing with the community, consistent with achieving the goals of the project and with the current data release policy. In addition, applicants should discuss the use of human biological samples obtained with consents allowing for unrestricted data access. Specifically, applicants should describe previous experience with obtaining samples using consents allowing for unrestricted data sharing, if relevant, as well as the feasibility of obtaining such consent for biological samples proposed in the research plan, and indicate their agreement to obtain and use these appropriately-consented samples in the proposed studies.
After the initial review, NHGRI program staff will conduct an additional administrative review of the plan for sharing data and may negotiate modifications of the data sharing plan with the prospective awardee. The final negotiated version of the data sharing plan will become a term and condition of the award of the cooperative agreement.
At the start of the next phase of ENCODE, the Consortium will review the current policy and the ENCODE Steering Committee will approve any updates, as appropriate; however, NHGRI expects that there will not be any significant change to this policy that will affect the timing in which data is released to the public. Applicants should indicate their willingness to participate in the development of such a final plan and to accept it.
Software and Data Analysis Sharing: NHGRI is also committed to the timely release of open source software and well-documented data analyses. The current ENCODE Project is working under a Software and Analysis Release Policy for Consortium members that encourages the timely release of stable software and data analyses to maximize the value of ENCODE resources to the research community and to enhance the reproducibility of its work. Software and analyses are expected to be well-documented and made available on version-controlled public repositories (software) or accessioned and released through the ENCODE DCC. Applicants should provide a plan for release of software and analyses, if applicable, in the application that is consistent with the current policy.
After the initial review, NHGRI program staff will conduct an additional administrative review of the plan for sharing software and analyses, and may negotiate modifications of this plan with the prospective awardee. The final negotiated version of the resource sharing plan will become a term and condition of the award of the cooperative agreement.
At the start of the next phase of ENCODE, the Consortium will review the current policy and the ENCODE Steering Committee will approve any updates, as appropriate; however, NHGRI expects that there will not be any significant change to this policy that will affect the rapidity with which software and analyses are released to the public. Applicants should indicate their willingness to participate in the development of such a final plan and to accept it.
Resource Sharing: As the ENCODE Project is creating a community resource, NHGRI intends that, in addition to data, software and analyses, any physical resources, such as DNA clones and cell lines, generated by the ENCODE awards should be made rapidly available to the research community and that resource sharing plans should follow the same principles and spirit as data, software and analysis release plans. As demonstrated by previous genomics community resource projects, these resources are of high value to the broader biomedical research community in enabling scientific studies. Since the cost and effort involved in generating the resources can be high, rapid dissemination of these resources would accelerate scientific exploration since individual researchers would not need to replicate such efforts. The applicant should provide specific plans for resource sharing and distribution in the application, if applicable. After the initial review, NHGRI program staff will conduct an additional administrative review of the plan for sharing resources and may negotiate modifications of the resource sharing plan with the prospective awardee. The final negotiated version of the resource sharing plan will become a term and condition of the award of the cooperative agreement.
Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.
When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.
When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.
See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov
Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.
Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.
Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.
Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.
This initiative is not subject to intergovernmental review.
All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
Pre-award costs are allowable only as described in the NIH Grants Policy Statement.
To maintain flexibility in the collective data production pipelines to adjust to a rapidly changing landscape, NHGRI will restrict 15-25% of funds in each of the out years of the award and may shift funds from one group to another as dictated by opportunities that arise in the previous funding period.
Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.
Applicants must complete all required registrations before the application due date.Section III. Eligibility Information contains information about registration.
For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.
All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.
The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.
See more tips for avoiding common errors.
Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.
Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.
Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.
Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).
Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.
Does the project address an important problem or a critical barrier to progress in the field? Is there a strong scientific premise for the project? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? Will the proposed assay(s) generate data that will be of high utility to the research community? Has the assay(s) been well justified in terms of biologic relevance and mechanistic association with gene regulatory activities? Are the proposed samples and assay(s) likely to achieve significant new discovery of candidate functional elements?
Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project? Are the track records of the PD(s)/PI(s) and other key personnel in producing and disseminating high-throughput data adequate to conduct the proposed research successfully? Has adequate leadership for the day-to-day project management activities, e.g., a project manager or sufficient PD(s)/PI(s) effort, been described? Does the applicant indicate a willingness to work with other Mapping Centers and participate in other Consortium activities?
Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?
Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?
If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?
Has the applicant proposed credible plans for obtaining samples with consent allowing for unrestricted (open) data access?
Is the proposed assay(s) high-throughput, cost effective and state-of-the-art, and capable of producing high quality data? Is it likely that the proposed project will produce high quality data at a reasonable cost based on the applicant's past experience and proposed future plans? If relevant, are the plans to continue increasing throughput and decreasing cost reasonable and appropriate?
Are the plans for bioinformatics, including infrastructure, laboratory information management systems and data submission reasonable and appropriate?
Are the plans for quality assessment and quality control reasonable and adequate?
Are the plans for submitting data to the relevant database(s) appropriate and reasonable and is there evidence that systems are in place to support the data submission process?
Are the milestones, timelines and goals proposed for the research project reasonable and appropriate?
Is the management plan well-described and commensurate with the level of complexity required for this FOA?
Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?
As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.
For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.
For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.
When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.
The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.
Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.
As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.
Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).
Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).
For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.
Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.
Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NHGRI, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.
As part of the scientific peer review, all applications:
Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.
Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Council for Human Genome Research. The following will be considered in making funding decisions:
After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.
Information regarding the disposition of applications is available in the NIH Grants Policy Statement.
If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.
A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.
Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.
Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.
All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.
Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.
For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.
The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75, and other HHS, PHS, and NIH grant administration policies.
The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.
The PD(s)/PI(s) will have the primary responsibility for:
NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:
An NIH Project Scientist is a scientist of the NHGRI extramural staff who will have substantial scientific and programmatic involvement that is above and beyond the normal stewardship role in awards, including providing technical assistance, advice, and coordination for the ENCODE Project and its component parts. It is anticipated that decisions in all activities will be reached by consensus of the ENCODE Research Consortium Steering Committee and that NIH staff will be given the opportunity to offer input to the process. One NHGRI Project Scientist will participate as a member of the Steering Committee and will have one vote.
The Project Scientist will:
Areas of Joint Responsibility include:
The ENCODE Research Consortium Steering Committee will serve as the main coordinating board of the ENCODE Research Consortium established under this FOA and the accompanying RFAs HG-16-003; HG-16-004, HG-16-005 and HG-16-006. The Steering Committee will be comprised of one P.D./P.I. from the DCC, DAC, each Mapping Center, and each Characterization Center, plus one NHGRI Program Staff member. Once formed, the Steering Committee will decide upon an organization and leadership structure and establish steering committee sub-committees. The Steering Committee may add additional members on an ad hoc basis, e.g., the P.D.s/P.I.s funded in response to RFA HG-16-004, “Computational Analysis of the Encyclopedia of DNA Elements (ENCODE) Data. Other government staff may attend the Steering Committee meetings if their expertise is required for specific discussions. It is anticipated that additional coordination mechanisms will be set up with other U.S. and international groups that may join this effort.
The Steering Committee will be responsible for coordinating the activities being conducted by the ENCODE Research Consortium. To address particular issues, the Steering Committee may establish working groups as needed, which will include representatives from the Research Consortium and the NHGRI and possibly other experts. Such groups might include ones to: 1) develop a list of common biological samples and other reagents needed for the Project; 2) address data management issues; 3) analyze Project data; 4) develop quality standards and methods to assess data quality; and 5) handle communication issues and develop principles for reporting findings. Minutes of the Steering Committee meetings will be available to the Steering Committee members within 30 days after each meeting.
Each full member will have one vote. Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee.
An External Consultants Panel will be established by the NHGRI to evaluate the progress of the ENCODE Research Consortium. The External Consultants Panel will provide recommendations to the Director, Division of Genome Sciences and Director, NHGRI about the progress and scientific direction of all components of the program. The External Consultants Panel will be composed of five to eight senior scientists with relevant expertise, although the membership may be enlarged permanently or on an ad hoc basis as needed.
The External Consultants Panel will meet at least twice a year; some meetings may be conducted by telephone conference. At least once a year, there will be a joint meeting with the Steering Committee to allow the members of the both the External Consultants Panel and the Steering Committees to interact directly with each other. Twice a year the External Consultants Panel will make recommendations regarding progress of the ENCODE Research Consortium and present advice to the Director, Division of Genome Sciences and/or the Director, NHGRI about changes, if any, that may be necessary in the ENCODE Research Consortium program.
Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.
A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.
The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.
We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.
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Elise Feingold, Ph.D.
National Human Genome Research Institute (NHGRI)
Ken Nakamura, Ph.D.
National Human Genome Research Institute (NHGRI)
National Human Genome Research Institute (NHGRI)
Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.