National Institutes of Health (NIH)
National Human Genome Research Institute (NHGRI)
Characterizing the Functional Elements in the Encyclopedia of DNA Elements (ENCODE) Catalog (UM1)
UM1 Research Project with Complex Structure Cooperative Agreement
This FOA seeks applications to develop and apply generalizable approaches to characterize the role of candidate functional elements identified by the ENCyclopedia Of DNA Elements (ENCODE) in specific biological contexts. ENCODE has identified different classes of candidate functional regions based on their correlation with biochemical signatures, but has not tested the majority of those to determine what, if any, biological roles they actually play. This FOA solicits activities that include employing one or more assays to characterize the biological function of candidate elements, testing the impact of natural or engineered genetic variants on element function, or using human diseases or biological systems as test cases to evaluate the approaches. Awardees will also work together to characterize the strengths and weaknesses of the collection of assays funded by comparing their performance, and to identify a set of well-characterized functional elements in healthy and/or disease states. These products are expected to provide an understanding of the utility and generalizability of functional characterization approaches, and to facilitate investigation of the role of genetic variation in human disease. 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
This FOA seeks applications to develop and apply generalizable approaches to characterize the role of candidate functional elements identified by the ENCyclopedia Of DNA Elements (ENCODE) in specific biological contexts. “Functional elements” are genes (protein-coding and non-coding) and regulatory regions. ENCODE has identified different classes of candidate functional regions based on their correlation with biochemical signatures, but has not tested the majority of those to determine what, if any, biological roles they actually play. 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. In the absence of universally agreed-upon definitions and tests for function, any practical test is subject to potential false positive and false negative results, and different tests may not arrive at consistent determinations; consequently, the term “functional characterization” is used here. This FOA solicits activities that include employing one or more assays to characterize the biological function of candidate elements, testing the impact of natural or engineered genetic variants on element function, or using human diseases or biological systems as test cases to evaluate the approaches. Awardees will also work together to characterize the strengths and weaknesses of the collection of assays funded by comparing their performance, and to identify a set of well-characterized functional elements in healthy and/or disease states. These products are expected to provide an understanding of the utility and generalizability of functional characterization approaches, and to facilitate investigation of the role of genetic variation in human disease.
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 RFA-HG-16-002) as well as by the Characterization Centers (funded through RFA-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, funded through RFA-HG-16-005). 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, funded through RFA-HG-16-006) will coordinate high-level analytical activities of the consortium, including development of the Encyclopedia, and provide computational support for these analyses. Computational Analysis groups (funded through RFA-HG-16-004) will develop novel methods and tools for processing, analyzing, and enhancing the utility of ENCODE data, and contribute broadly to consortium analytical efforts.
NHGRI seeks research projects that that apply innovative, robust, and generalizable methods to characterize candidate functional elements identified using ENCODE data. These projects may characterize function along the continuum from molecular phenotypes (e.g., transcription, splicing) to organismal phenotypes (e.g., height, brain anatomy). These projects may use defined cell systems (e.g. primary cells, ES/iPSC derivatives, organoids, or model organisms) in particular biological contexts for in-depth studies. Studies of specific diseases or biological questions using relevant cell sources are especially encouraged. Because of the need for highly specialized expertise in biological systems and functional genomics, this FOA lends itself well to participation by multiple investigators with different expertise on a single application. The focus will be to develop and test strategies that could be broadly applied by the community, and to begin to ask how to make better predictions of function, rather than to attempt to characterize the entire catalog of candidate functional elements in all cell contexts.
As part of this project, the individual functional characterization centers will work together to determine whether it is feasible to identify a generalizable approach. Functional characterization of candidate functional elements is an inherently broad endeavor given multiple scales of function (molecular to organismal), the dependence of function on context (e.g., cell fate/state, organismal environment, disease) and the variety of functional elements (e.g., enhancer, promoter, splice site). It is likely that individual centers will use approaches that vary with respect to throughput, scale of function and types of function. To assess the generalizability of the approaches supported by this FOA, applicants should reserve part of their experimental capacity to test a common set of elements across the multiple funded characterization centers.
The goals of this FOA are to develop innovative approaches to characterizing candidate functional elements, and to evaluate these approaches by applying them to test systems. Extensive mapping efforts (i.e., identifying new candidate functional elements) will not be considered to be within this scope. Applications that do not use existing ENCODE mapping data as part of the process to identify candidate functional elements are not within this scope. Projects that primarily test the function of changes in protein coding sequences are not within the scope of this FOA, as such approaches are relatively well developed relative to characterization of non-coding elements. Applications that are dependent on production of new data by the functional element mapping centers (see: RFA-HG-16-002) are beyond the scope of this FOA.
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-16-002; “Expanding the Encyclopedia of DNA Elements (ENCODE) in the Human and Mouse”, to support mapping of 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. In addition, as in the ENCODE Project to date, the ENCODE Research Consortium will continue to be open, beyond investigators funded through the above FOAs, 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 call information 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 $5.9-6.5 M in FY 2017 to fund 7-10 awards.
Application budgets are not limited but need to reflect the actual needs of the proposed project.
The maximum project period is 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:
Mike Pazin, 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 subsections 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.
For single PI applications, the PD/PI funded under this FOA is expected to devote at least 2.4 person months, based on a 12-month calendar to the project. If multi-PDs/PIs are proposed, then each PD/PI is expected to commit sufficient time to serve his/her proposed role, with a minimum aggregate PD/PI effort of 2.4 calendar months. The appropriateness of the effort of key personnel must be justified in the budget justification.
Project budgets should include funds to allow 25% of the samples to be used for analysis of a common set of candidate functional elements, to be chosen by the consortium.
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, ENCODE Portal) and (c) sharing samples with other consortium members.
The ENCODE Project has regular conference calls and meetings. Applicants should request funds to attend an annual meeting for 2-6 group members, 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:
A. Overall Research section:
Applicants should follow the general format of the form SF424 Application Guide (i.e., Significance, Innovation, Approach, Preliminary studies) while addressing the objectives described in the Funding Opportunity Description section above, including the overall rationale for the approach, the potential of the approach to be generalizable to other diseases and biological processes, the rationale for the proposed assay(s), the rationale for the biological systems/diseases used as test cases, the rationale for identifying candidate functional elements using ENCODE data, the rationale for choosing candidate functional elements for testing, a timeline for the proposed work, an informatics system to analyze the data (if appropriate), and how the proposed work will enhance the utility of the ENCODE data. Applicants should indicate the number of candidate elements that are expected to be characterized using each assay and biological system. This section should include all details about the data generation and analysis pipeline(s). Applicants should document their prior use, throughput, estimate the accuracy of the assay(s), and also the success rates for the proposed assays and systems. Applicants should indicate their commitment to reserve at least 25% of their capacity for common samples, and to work as a group to assess the generalizability of the approaches used across the consortium.
Projects proposed by applicants may include, but are not limited to, the following features:
B. Management Plan section:
This section should include a description of the decision-making process and the leadership (if the project is a collaboration of more than one research group). Personnel responsible for key tasks, such as data collection by data type, data analysis by data type, data submission, and overall project leadership should be identified. The reporting relationship for these personnel should be described. Management of external collaborations, if any, should be described. Mechanisms for reporting progress to NHGRI should be described (see Terms and Conditions, below). Applicants should propose and describe a LIMS system to track and submit data production, as well as submission of metadata and data (raw and processed) to the Data Coordinating Center (RFA-HG-16-005). Applicants should explain how they will share their approach(es) with the community, including the overall approach, any methods development, and software. The management plan should discuss past experiences (if any) in working in large collaborative projects.
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:
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.nih.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.
All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
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.
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. The goals of this FOA are to develop innovative approaches to characterizing candidate functional elements, and to evaluate these approaches by applying them to test systems. Applications proposing projects that contain extensive mapping efforts (i.e., identifying new candidate functional elements) will be considered nonresponsive. Applications that do not use existing ENCODE mapping data as part of the process to identify candidate functional elements will be considered nonresponsive. Applications proposing projects that primarily test the function of changes in protein coding sequences will be considered nonresponsive, as such approaches are relatively well developed relative to characterization of non-coding elements. Applications that are dependent on production of new data by the functional element mapping centers (see: RFA-HG-16-002) will be considered nonresponsive.
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 project enhance the utility of the ENCODE data?
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?
Do the PD(s)/PI(s) commit sufficient time to serve their proposed role(s)?
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?
Are the overall approach, assays and model systems well-justified, and appropriate to the problem being studied? Is the approach generalizable to diseases and biological processes other than those proposed. Are the characterization assays likely to provide accurate information? Are the rationales for identifying candidate functional elements using ENCODE data, and choosing candidate elements to characterize, well-reasoned? Is the proposed approach likely to add new information about the utility of ENCODE data, beyond the specific examples tested? Is the informatics infrastructure described adequate to support proposed analyses, and data deposition requirements? Is the timeline logical and realistic? Does the applicant provide a credible plan for how the newly-developed approach will be made readily accessible to other investigators? Does the management plan clearly describe how the effort will be managed? Are there clearly described roles and reporting relationships for key personnel?
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?
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 the National Human Genome Research Institute, 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.
Cooperative Agreement Terms and Conditions of Award
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 this process. One NHGRI Project Scientist will participate as a member of the Steering Committee and will have one vote. They will participate with the other Steering Committee members in the group process of setting research priorities, deciding optimal research approaches and protocol designs, and contributing to the adjustment of research protocols or approaches as warranted.
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-16-002, 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.
eRA Service Desk (Questions regarding ASSIST, eRA Commons
registration, submitting and tracking an application, documenting system
problems that threaten submission by the due date, post submission issues)
Finding Help Online: https://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
(Questions regarding application instructions and process, finding NIH grant
Email: GrantsInfo@nih.gov (preferred method of contact)
Mike Pazin, 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.
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