Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Human Genome Research Institute (NHGRI)
Funding Opportunity Title	Expanding the Encyclopedia of DNA Elements (ENCODE) in the Human and Model Organisms (U54)
Activity Code	U54 Specialized Center- Cooperative Agreements
Announcement Type	New
Related Notices	November 16, 2011 - See Notice NOT-HG-12-002. The purpose of this Notice is to inform interested applicants from eligible institutions that NHGRI is changing the receipt date. October 19, 2011 - See Notice NOT-HG-12-001. The purpose of this Notice is to modify the language in the FOA research scope.
Funding Opportunity Announcement (FOA) Number	RFA-HG-11-024
Companion FOA	RFA-HG-11-025, U01 Research Project Cooperative Agreements RFA-HG-11-026, U41 Biotechnology Resource Cooperative Agreements
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.172
FOA Purpose	The Encyclopedia of DNA Elements (ENCODE) and modENCODE Projects have, since their inception, cataloged a significant fraction of the functional elements in the human and well-studied model organism genomes, respectively, and these catalogs are increasingly being used by the research community to expand on basic biological knowledge and to interpret the results of disease-mapping studies. The purpose of this FOA is to solicit applications for research projects to apply high-throughput, cost-efficient approaches to greatly extend these resources toward as complete catalogs as is feasible employing state-of-the-art technologies. The funded projects will participate in a single Research Network that will be a consolidation of the existing ENCODE and modENCODE Research Consortia.

Posted Date	October 4, 2011
Letter of Intent Due Date	November 6, 2011
Application Due Date(s)	(New Date December 21, 2011 per NOT-HG-12-002), Original Date December 6, 2011
AIDS Application Due Date(s)	Not Applicable
Scientific Merit Review	March, 2012
Advisory Council Review	May 2012
Earliest Start Date(s)	July, 2012
Expiration Date	(New Expiration Date December 22, 2011 per NOT-HG-12-002), Original Date December 7, 2011
Due Dates for E.O. 12372	Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the PHS398 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. While some links are provided, 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.

Part 1. Overview Information
Part 2. Full Text of Announcement
Section 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

Purpose:

The Encyclopedia of DNA Elements (ENCODE) and modENCODE Projects have, since their inception, cataloged a significant fraction of the functional elements in the human and well-studied model organism genomes, respectively, and these catalogs are increasingly being used by the research community to expand on basic biological knowledge and to interpret the results of disease-mapping studies. The purpose of this FOA is to solicit applications for research projects to apply high-throughput, cost-efficient approaches to greatly extend these resources toward as complete catalogs as is feasible employing state-of-the-art technologies. The funded projects will participate in a single Research Network that will be a consolidation of the existing ENCODE and modENCODE Research Consortia.

This FOA will use the U54 Center Cooperative Agreement mechanism. It is being issued in conjunction with two other FOAs: RFA-HG-11-026, Data Analysis and Coordination Centers for the Encyclopedia of DNA Elements (ENCODE) Project and RFA-HG-11-025, Computational Analysis of the Encyclopedia of DNA Elements (ENCODE) Data .

Background:

The long-term goal of the Encyclopedia of DNA Elements (ENCODE) Project has been to identify comprehensively all of the sequence-based functional elements in the human genome. The modENCODE Project is a parallel effort to annotate the genomes of worm (C. elegans) and fly (D. melanogaster) comprehensively. In addition, with funds from the American Recovery and Reinvestment Act (ARRA) of 2009, a small, two-year effort was supported to generate comparable data from the mouse (M. musculus) to facilitate the annotation of the human genome. For the purpose of this solicitation, these efforts will collectively be referred to as the ENCODE projects. These projects have been designated as community resource projects by NHGRI to accelerate access to and use of the data by the entire scientific community. Accordingly, pre-publication data is released rapidly to public databases. For more information about the ENCODE projects, see: http://www.genome.gov/ENCODE.

Functional elements that have been elucidated in the ENCODE projects include transcribed sequences, transcriptional control elements (including enhancers, promoters, and insulators), chromatin features, and regulatory elements acting at the RNA level post-transcriptionally (including those that may regulate splicing, translation, and stability). Using a variety of high-throughput methods, such as RNA-seq, ChIP-seq, RIP-seq, and DNase-seq, these functional elements have been identified by mapping different types of marks, including transcription factor binding sites, histone modifications, various measures of chromatin structure, sites where RNA-binding proteins bind, and different classes of transcribed sequences. These growing catalogs of functional elements are directly adding to our general understanding of genome structure and function, and also are enabling targeted research projects to examine the role of these elements in the regulation of genes of interest and in specific biological processes. As genetic and epigenetic variation at these elements is undoubtedly responsible for some observed phenotypes, comprehensive identification of functional elements is also expected to enhance our understanding of human health and disease.

Currently, several different levels of data analysis are being conducted within the ENCODE Projects. Each data production center has an analysis pipeline to process the primary data, to use particular data types to identify one or more specific classes of functional elements, and to identify any biological insights from these data. The data producers also process the data to prepare them for submission to a Data Coordination Center (DCC). There are two DCCs, one for ENCODE (http://www.encodeproject.org) and one for modENCODE (http://www.modencode.org), that are responsible for developing, housing, and maintaining databases to track, store, and provide access to the ENCODE and modENCODE data, respectively. Finally, each consortium has an Analysis Working Group (AWG) that is responsible for integrative analyses of the entire data sets of the respective projects. Supporting each AWG is a Data Analysis Center (DAC) that coordinates the high-level analytical activities and provides computational support for these analyses.

Each of the ENCODE Projects has functioned as a research consortium that brings the participants together in a highly collaborative and synergistic effort. For the last four years, the ENCODE Projects have focused on the comprehensive analysis of a limited set of common cell types, mainly cell lines, along with a survey of functional elements in other cell types. Analyses that have integrated the datasets within and across a variety of cell types for a given organism have amplified the amount of useful information that has been derived from the data (See: Nature 447:799-816, 2007; Science 330:1775-1787, 2010; Science 330:1787-1797, 2010; PLoS Biol 9:e1001046, 2011). The use of multiple cell types and multiple assays is, in fact, key to obtaining a comprehensive description of the functional elements in these genomes, as there is no one cell type or type of assay that can be used to identify all functional elements.

Despite these advances, current limitations in technology and available resources are barriers to the application of all assays to all cell types of interest. By the conclusion of the current ENCODE production period, these projects will have interrogated only a fraction of the cells and tissues needed for a comprehensive catalog of functional elements. Generation of truly comprehensive catalogs will require revolutionary new technologies to dramatically reduce the cost and increase the sensitivity of finding functional elements, and applications to develop such technologies were recently solicited through three FOAs: RFA-HG-11-013; RFA-HG-11-014 and RFA-HG-11-015.

The NHGRI now proposes to extend the ENCODE Projects activities, while at the same time, consolidating them into a single Consortium, with a new set of FOAs. Through this solicitation, RFA-HG-11-024, NHGRI will continue to support focused production-scale activities directed at expanding the catalog of functional elements using state-of-the-art methods because there is considerable value in supporting simultaneous and collaborative production and technology development efforts to drive the development and implementation of robust methods. The continuation of the ENCODE Project will be comprised of high-throughput data-generation projects that will significantly extend, towards completion, the current catalogs of sequence-based functional elements in the human and mouse genomes, as well as possibly the fly and worm genomes (see Research Scope). A companion FOA, RFA-HG-11-026, solicits applications to establish an ENCODE Data Coordination and Analysis Center (EDCAC) for these projects. A second companion FOA, RFA-HG-11-025, solicits applications for individual-investigator research projects to conduct additional analyses that will improve the quality of the ENCODE data or use the data in the ENCODE catalogs to develop and test predictions in genome biology or disease studies.

Research Scope:

This FOA solicits applications for projects that continue the ENCODE Projects efforts to develop comprehensive catalogs of functional elements. The current phase of the human ENCODE Project has focused on two major classes of functional elements: genes (both protein-coding and non-coding) and their RNA transcripts, and transcriptional regulatory regions. All data types are being generated on a core set of cell lines, known as the Tier 1 and Tier 2 lines (and the recently added Tier 2.5 lines for the current year of study; see http://www.genome.gov/26524238 for more information) and a more limited subset of the data has also been generated on a wider set of cell lines and tissues. See PLoS Biology 9:e1001046, 2011 for data available as of January 2011 and the preview browser at UCSC (http://genome-preview.ucsc.edu/cgi-bin/hgTracks?db=hg19) for the most current data available. The annotation of the genes and their transcripts involved manual annotation of the genome from existing transcript data as well as newly generated RNA maps developed from RNA-seq analyses. For the transcriptional regulatory regions, a variety of elements were assayed, including DNase hypersensitive regions, open chromatin, selected histone modifications, and the binding sites of transcription factors. A smaller mouse ENCODE Project has examined similar functional elements in a limited number of cell lines and mouse tissues (see: http://encodeproject.org/ENCODE/dataPlansMouse.html. Finally, the modENCODE project has generated similar data for the fly and worm genomes (see: http://www.modencode.org).

In summary, the ENCODE Projects have cataloged many types of functional elements deeply across a limited number of cell types, and the DNA binding sites for a fraction of transcription factors (each factor in a smaller number of cell types), and is in the process of developing similar catalogs in a larger number of cell types. NHGRI now seeks to continue this progress, which has been made through the establishment of high-throughput, efficient production pipelines. Accordingly, this FOA solicits applications for ENCODE data production centers that can attain even greater economies of scale than currently exist by focusing on the use of one or a few high-throughput methods to generate one or more data types. It is envisioned that compared with the current ENCODE Consortia, a smaller number of more centralized production centers will be funded and that these will feature more focused management and coordination (e.g., standardized cell sources and data formats). In this way, the FOA solicits applications to expand the current catalogs of functional elements, with primary emphasis on the human genome, secondary emphasis on the mouse genome and a significantly reduced and scientifically more restricted effort for the fly and worm genomes, as specified below.

Projects are solicited to develop:

• Maps of all classes of functional RNA molecules in a larger number of cell types and tissues;
• Fine structural genome annotation (of the human and mouse genomes only) by improving gene models using newly available data, e.g., RNA-seq data
• Maps of sites of open chromatin in a larger number of cell types and tissues
• Maps of selected histone marks and other relevant chromatin proteins in a larger number of cell types and tissues
• Maps of sites of DNA methylation in a larger number of cell types and tissues, and at higher resolution, where applicable
• Maps of all classes of functional RNA molecules in a well justified set of cell types and tissues
• Maps of the binding sites for more transcription factors, using a minimum of two Tier 1 (or Tier 2 if a factor is not expressed in Tier 1) cell types for each previously unstudied factor, and additional, well justified cell types as resources permit
• For transcription factors for which binding site maps already exist, development of maps in additional cell types will be considered, but will be of lower priority and expansion of this data set must be strongly justified

This list represents NHGRI’s highest priorities. Maps of functional elements which represent smaller efforts in the previous ENCODE Projects, such as origins of replication and higher order chromatin structure, and functional elements not previously studied in ENCODE, will be considered but applicants must demonstrate the existing capability to catalog high quality data for these functional elements using efficient, high-throughput methods as well as the value of the data to the research community.

Applicants should propose primarily experimental approaches to generating data. Computational approaches may be included, but applications that propose purely computational approaches will not be considered to be responsive to this FOA.

As described above, this solicitation will allow the submission of applications for continued studies in C. elegans and D. melanogaster, but such efforts will comprise a significantly smaller fraction of the ENCODE production capacity going forward. Any application to work on these organisms must provide a very strong rationale for the continued need for 1) a highly centralized production effort for the specific data type(s) proposed, and 2) this work to be carried out as part of a highly interactive research consortium. Much progress was made in the modENCODE Project’s effort to catalog functional elements in these two organisms and, although the catalogs are not complete, the technology has progressed to a stage where a large, centralized effort is no longer needed for most of the elements. Increased accessibility to high-throughput sequencing technologies, which are at the core of many of the approaches used in the modENCODE Project, has enabled individual investigators to generate genome-wide data rapidly and efficiently to study specific biological questions. Thus, on the basis of the firm foundation of the modENCODE Project, most of the relevant studies can be conducted largely through investigator-initiated projects.

In summary, in funding applications received in response to this FOA, priority will be given to work to further populate the catalog of functional elements in the human genome, secondarily to support efforts in the mouse, and thirdly, to those analyses of functional elements in the fly and worm genomes. Applicants proposing projects in fly and/or worm need to justify that the work to be undertaken still requires a consortium-based approach.

In addition to describing research plans for data production, there are a number of additional issues that should be addressed in the applications for the data production component of the continuing ENCODE Projects, described below and in the additional instructions to applicants in section IV.2.

Applicants should propose to identify all of the functional elements (of one or more types) that exist in the genome(s) of study and propose to use methods that have been demonstrated to be high-throughput, to generate high-quality data, to be cost-effective and to be comprehensive (to have the capability to accurately and efficiently identify the entire set of one or more types of functional elements contained within the genome, see below for a further discussion of comprehensiveness). Applicants must propose to work on the entire genome, and should define entire genome , i.e., should clearly describe the way(s), if any, in which the technology proposed will not be able to analyze all bases of the genome (e.g., any repetitive sequences that are excluded from microarrays or masked in the analysis of next-generation sequencing data). In such cases, applicants should discuss 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. Similarly, as analysis of a single cell line or tissue will not reveal many tissue- or stage-specific functional elements, applicants should address the use of multiple cell lines or tissues to find all instances of a functional element in the genome.

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, like ChIP-seq do not provide nucleotide resolution of the precise protein binding site and beyond that, some functional elements, such as cis-acting regulatory elements, are composed of multiple binding sites that comprise a larger module. Applicants should explicitly discuss the issue of resolution and should clearly describe the resolution to which their proposed method(s) will identify each targeted functional element. 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.

Milestones and goals: The success of ENCODE, modENCODE and many other genome 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 for the overall project and propose quantitative milestones and appropriate metrics to measure the progress for their targeted class(es) of functional elements. It is expected that applicants will have already developed significant production capabilities prior to any award and that there will be no need to ramp up production activities at the start of the project. Milestones should reflect the ability to produce data from the beginning of the project and should be supported by preliminary data. (See below and additional guidance to the applicant in section IV.2.) 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.

Data Quality and Utility: The catalogs of functional elements being generated by the ENCODE Project will be important, and probably unique, reference data sets and will be used in a wide range of studies. Therefore, the quality, biological relevance and comprehensiveness of the ENCODE data are critical to the success of the Project.

Data Quality. The approaches to data quality will continue to be based on those that have been employed successfully in the ENCODE Projects to date. One approach to verifying the quality of the primary data has been to demonstrate experimental reproducibility. Second, the experimental platform(s) must be well-characterized (quantitatively measured, benchmarked), and the authenticity of the biochemical events detected by the primary experimental approach has to be confirmed by the use of one or more independent method(s). This approach should also identify any inherent biases in the primary method. Each affinity reagent must be well-characterized to demonstrate its specificity in capturing the target protein. The data standards that have been developed by the ENCODE Projects can be found at http://www.encodeproject.org/ENCODE/dataStandards.html, but it should be noted that they are continually updated based on additional data analysis and technical improvements. Applicants should describe plans to follow these or develop more stringent standards, and to develop similar standards for novel technologies.

Biological relevance. To help ensure that the quality and utility of the catalog of biochemically validated elements are high it will be necessary to demonstrate the biological relevance of the elements within the collection, i.e., to show that the sequences identified as being members of a particular functional class actually do have the inferred function. In the current ENCODE Projects, for example, some putative functional elements are being subjected to cell-based assays to test their biological activity. Applicants must describe in detail how the biological authenticity of the identified elements will be assessed. These studies of biological relevance should be limited to a fraction of the elements that is sufficient to confirm the functional role of the class of elements. These validation experiments should employ a biological system for which significant knowledge already exists, with the purpose of demonstrating the biological role of identified functional elements in a particular cellular process or the biological role of the class of functional elements. This aspect of the program is not intended to support a detailed determination of the biological function of individual elements. The studies to confirm biological utility should be limited to no more than $300,000 direct costs per year unless a compelling case can be made for why additional funds need to be devoted to this activity. These studies should be initiated as soon as there are sufficient data to analyze so that the biological role of the functional elements can be confirmed early on in the data production cycle and not lag until the end of the project.

NHGRI recognizes that, eventually, the research community will want to know the precise biological role that each of the individual elements plays in the biology of the organism under study. However, at that level of detail, the studies that will be necessary to uncover these roles will best be done in individual laboratories rather than by a large-scale effort. Furthermore, such studies will require a significant investment, one which is beyond the funds currently available for this ENCODE initiative. Therefore, they are outside of the scope of this FOA. Instead, what this ENCODE initiative will require is a statistically valid demonstration that the majority of the members of the type of element being identified do have the function attributed to that type.

Comprehensiveness. The catalog generated by the ENCODE Project must be as comprehensive as possible. In practice, achieving a complete catalog of most classes of functional elements is likely not to be feasible, at least with existing technologies. Usually, only a subset of each class of functional elements will express that function (and be detectable) in one or a restricted set of tissues, in a developmentally-specific manner, or in response to specific environmental challenges. As it will not be practical to study every tissue, developmental stage or environmental condition, some fraction of such elements will escape detection. Applicants should propose a set of experimental conditions (e.g., cell lines, tissues, environmental stimuli) that will maximize the discovery of functional elements to the point of diminishing returns, i.e., at which the cost/benefit ratio is no longer favorable. Applicants should also define comprehensiveness for the proposed project, describing how close to that target the proposed project will get in a four-year timeframe for each data type being investigated. NHGRI recognizes that this is potentially difficult, as the actual number of such elements in each genome is generally not known, and there is no gold standard for comparison of data across the entire genome. However, the applicant should attempt to provide a reasonable estimate of the sensitivity of each of the proposed approaches and discuss the basis for the estimate. This may involve identification of the functional elements using an independent method for comparison and/or information from the literature.

Common cell types. The human ENCODE project has designated common reagents to be worked on by all participating groups to the extent feasible (see: http://www.genome.gov/2652438). The mouse ENCODE participants are conducting experiments in two common cell lines (MEL and CH12) as well as a range of tissue types in C57Bl/6 mice. Similarly, the modENCODE Consortium participants have used common fly and worm strains and fly cell lines (see Nature (2009) 459:927-930). Applicants proposing analysis of new data types not previously studied in the ENCODE Projects should include work on these cell sources and may propose additional cell lines or tissues as appropriate. However, for data types for which ENCODE data already exists in public databases (see above), applicants should avoid unnecessary overlap with existing data sets in their proposed efforts to move the catalog towards completion.

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. Awardees will be expected 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. The coordination of cell sources and other reagents will allow for controlled overlap to maximize the diversity of biological space that is interrogated while also allowing for a limited amount of comparative analysis between groups, as an internal approach to quality control.

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 or validate the 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. For example, the generation of a large set of antibodies to DNA binding proteins for ChIP-seq studies, although valuable, will be considered outside of the scope of this project. Through the Common Fund program, NIH has recently initiated a Protein Capture Reagents initiative (see: http://commonfund.nih.gov/proteincapture/) to develop a renewable resource of protein capture reagents with an initial focus on affinity reagents for transcription factors. While it is anticipated that these reagents will be widely available to the research community (including awardees of this FOA), the antigen and antibody production projects are just beginning and the list of specific antigens and validated antibodies available for use during the next phase of ENCODE cannot be predicted at this time. Therefore, applicants should describe how they will obtain the necessary reagents to conduct the proposed research and take advantage of the resources generated by the Protein Capture Reagents initiative to avoid overlap with that effort. For those proposing to use affinity-tagging approaches rather than factor-specific antibodies to generate ChIP-seq data, a thorough discussion of the quality of these data compared with factor-specific antibodies, as well as the ability of the approach to reach completeness both with respect to the number of factors studied and obtaining information on all instances of factor binding (i.e., depth of cell space) must be provided in the application.

Since the experiments demonstrating biological relevance will only address a fraction of the elements in the entire genome, the generation of reagents or resources needed for validation studies should be limited to the extent that is necessary to conduct such studies, unless it can be demonstrated that it would be at least two orders of magnitude more efficient, in terms of unit costs, to generate a complete set of reagents than to generate a subset.

Informatics.

Primary data analysis: 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. The pipeline should include the informatics and statistical tools necessary to integrate both the primary data and any validation data obtained using different technologies. This informatics pipeline must be well documented and have procedures in place to capture metadata associated with any data transformation that is applied during analysis.

Data submission: A separate informatics pipeline should be described for the submission of the primary data and validation data in standardized formats to the ENCODE Data Coordination and Analysis Centers (EDCAC), which will be funded in response to RFA-HG-11-026, or to other appropriate public repositories as specified by the ENCODE Consortium Data Release Policy (see: http://www.genome.gov/27528022 and as updated in the next funding period). In addition, any metadata such as information about experimental procedures and analysis methods used to generate the data should be submitted to the EDCAC. Finally, upon publication of data and analyses, 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. All groups participating in the ENCODE Consortium will work with the EDCAC to establish the exact types and formats of data and metadata that will be transferred to the EDCAC.

Integrated Data Analysis. The primary responsibility for integrative analysis of the data being generated by 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 EDCAC. Applicants to this FOA may include an additional informatics component for integrative analyses, but a willingness to coordinate analysis with the AWG and EDCAC should be indicated in the application. These integrative analyses should be limited to those necessary to cross-validate the conclusions from each technology. More in-depth analyses of the data are outside of the scope of this FOA and should be supported by other funding mechanisms. A component of the AWG efforts in the next phase of ENCODE will be a critical, comparative analysis of the relative value and cost-benefit of the different data types being generated to determine if it is possible to identify a minimum core set of data that can serve as a surrogate for a comprehensive catalog of functional elements. Such a core set could be useful in directing data generation for more focused analyses, especially disease-specific analyses.

Production pipeline issues that must be addressed in the application. The sections below outline issues associated with production activities that need to be addressed by all applicants. For additional instructions, see section IV.2: additional guidance to the applicant.

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. Thus, to be competitive, applicants should address a number of issues related to production in their applications:

Costs. Applicants need to demonstrate an understanding of costs and how to track them. Without a clear understanding, it will be difficult to approach effectively the goal of lowering costs and achieving economies of scale. Applicants should propose a cost model that accommodates the proposed process. For more details, see additional information for applicants; section IV.2.

Information Technology (IT). Applicants should discuss all pertinent informatics issues associated with defining sequence-based elements for each platform proposed in the application. These include, but are not limited to, the informatics infrastructure of the production system, such as the basic IT infrastructure/system administration, the laboratory information management system, and the system for data handling, data submission and data analysis. In all cases, any needed software development should be described in detail.

Technology Development. Incremental technology improvements will play an important role in increasing the efficiency and decreasing the cost of identifying functional elements. NHGRI encourages applicants to include plans for such technology development activities in their applications. The plans for technology improvement should be well described and the cost of the proposed technology development should be justified in terms of reducing production costs. The cost of such technology development should be included in the overall production cost.

Management Plan and PD(s)/PI(s) Effort. The effective management of a production project requires a significant commitment by the Program Director(s)/Principal Investigator(s). The PD/PIof a project funded under this FOA must devote at least 25% effort (3 person months) to the project. The applicant should describe how s/he will manage the proposed project, who will oversee the day-to-day activities (e.g., a project manager if not the PD(s)/PI(s)) and how the management structure will support achievement of the proposed goals and milestones. Useful elements of this description 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 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.

Awardees must agree to the "Cooperative Agreement Terms and Conditions of Award" in Section VI "Award Administration Information".

Awardees and additional key personnel from each center will be required to attend one research network meeting per year; applicants should request travel funds for this meeting.

In summary, all applicants for awards under this FOA:

• should discuss the application of high-throughput, cost efficient approaches or strategies to identify comprehensively a set of functional elements in the genome of study;
• should define comprehensiveness for the proposed project;
• should clearly describe the resolution to which the proposed method(s) will identify the targeted functional element(s);
• should propose a plan for assessing the quality of the data produced;
• should propose a plan for assessing the biological authenticity of the class of identified elements;
• should provide a detailed analysis of the total costs needed to carry out the proposed experiments;
• should describe how the process of identifying functional elements will be improved during the course of the project, with the goal of reducing costs and increasing throughput;
• should present explicit project milestones and timelines when describing production goals;
• should explicitly discuss the different informatics components and infrastructure needed for the project;
• should explicitly discuss project management and how various components of the center will be integrated;
• should propose a comprehensive plan for the rapid release of data and state willingness to abide by the ENCODE Consortium Data Release Policy; and
• non-U.S. applicants should provide information regarding the uniqueness of the resource or approach being proposed and a well-documented data release plan.

This solicitation is open to all investigators, specifically including those who are not currently participating in the ENCODE or modENCODE projects. As in the ENCODE Projects to date, the ENCODE Research Network 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, and who meet the Projects criteria for participation (see http://www.genome.gov/12513439). Similarly, the Awardees funded through the concurrent FOAs, RFA-HG-11-026, Data Analysis and Coordination Centers for the Encyclopedia of DNA Elements (ENCODE) Project , which will support the database and data analysis needs for the ENCODE Project, and RFA-HG-11-025, Computational Analysis of the Encyclopedia of DNA Elements (ENCODE) Data , which will support additional analysis activities, will also participate in the ENCODE Research Network.

Funding Instrument	Cooperative Agreement
Application Types Allowed	New The OER Glossary and the PHS398 Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	NHGRI intends to commit $23 million in total costs in FY 2012 and to fund 6-8 awards, depending on the availability of funds and the receipt of meritorious applications.
Award Budget	Application budgets are not limited, but need to reflect actual needs of the proposed project.
Award Project Period	The total project period for an application submitted in response to this RFA may not exceed four 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

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant organizations must complete the following registrations as described in the PHS398 Application Guide to be eligible to apply for or receive an award. Applicants must have a valid Dun and Bradstreet Universal Numbering System (DUNS) number in order to begin each of the following registrations.

• Central Contractor Registration (CCR) must maintain an active registration, to be renewed at least annually
• eRA Commons

All Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) must also work with their institutional officials to register with the eRA Commons or ensure their existing eRA Commons account is affiliated with the eRA Commons account of the applicant organization.

All registrations must be completed by the application due date. Applicant organizations are strongly encouraged to start the registration process at least four (4) weeks prior to the application due date.

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.

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.

NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial peer review unless the applicant withdraws the pending application.

Applicants are required to prepare applications according to the current PHS 398 application forms in accordance with the PHS 398 Application Guide.

It is critical that applicants follow the instructions in the PHS398 Application Guide, 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.

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:

• Descriptive title of proposed research
• Name, address, and telephone number of the PD(s)/PI(s)
• Names of other key personnel
• Participating institutions
• Number and title of this funding opportunity

The letter of intent should be sent to:

Elise A. Feingold, Ph.D.
Program Director, Genome Analysis
Division of Extramural Research
National Human Genome Research Institute (NHGRI)
5635 Fishers Lane, Ste. 4076, MSC 9305
Bethesda, MD 20892-9305 (U.S Postal Service Express or regular mail)
Rockville, MD 20852 (for express/courier service; non-USPS service)
Telephone: 301-496-7531
FAX: 301-480-2770
E-mail: [email protected]

Please transmit Letter of Intent to: [email protected] by email.

Applications must be prepared using the PHS 398 research grant application forms and instructions for preparing a research grant application. Submit a signed, typewritten original of the application, including the checklist, and three signed photocopies in one package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)

At the time of submission, two additional paper copies of the application and all copies of the appendix files must be sent to:

Ken Nakamura, Ph.D.
Scientific Review Officer
Scientific Review Branch
National Human Genome Research Institute (NHGRI)
5635 Fishers Lane, Ste. 4076, MSC 9305
Bethesda, MD 20892-9305 (U.S Postal Service Express or regular mail)
Rockville, MD 20852 (for express/courier service; non-USPS service)
Telephone: 301-402-0838
FAX: 301-435-1580
E-mail: [email protected]

All page limitations described in the PHS398 Application Guide must be followed, with the following requirements:

• Research Strategy section is limited to 30 pages.

All instructions in the PHS398 Application Guide must be followed, with the following additional instructions:

Resource Sharing Plan

Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the PHS398 Application Guide, with the following modifications:

• 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. The implementation of the concept of rapid, prepublication data release has evolved over time in response to the changing technological and scientific landscapes, as described in the report from a meeting held in Toronto in 2009 (http://www.nature.com/nature/journal/v461/n7261/full/461168a.html). Although the Toronto meeting report specifically did not use the earlier term community resource project, it did recommend that funding agencies should require rapid pre-publication data release for projects that generate data sets that have broad utility, are large in scale, are 'reference' in character and typically have community 'buy-in'.
• The ENCODE Project is one such project, and NHGRI will continue to consider it as a community resource project. The ENCODE and modENCODE Consortia established and currently operate under a common Data Release Policy (see http://www.genome.gov/27528022), which expects rapid pre-publication data release. The current policy allows a nine-month moratorium period on presentations and publications, during which time data users may freely use the ENCODE and modENCODE data to design and carry out their own research programs, but are asked not to submit publications or make public presentations that use the unpublished ENCODE/modENCODE data without prior consent. The purpose of this moratorium period has been to allow the data producers to have an opportunity to publish on their initial findings. At present, after the nine-month moratorium, all data are freely available to anyone to use in any manner in presentations and publications. Agreement to abide by that policy is a requirement for anyone to join one of the Consortia.
• NHGRI expects that the rapid data release principles of this policy will continue to be implemented during the next phase of the ENCODE Project. Applicants will be expected to propose a data release policy in their applications (see below) that addresses rapid data sharing with the community, consistent with achieving the goals of the project. However, NHGRI is concerned that the nine-month moratorium has not been achieving the goal of getting data to be used rapidly by the research community, and plans, at the start of the next phase of ENCODE, to raise for discussion amongst consortium members that there be no such moratorium. NHGRI’s rationale for such an approach is that while the utility of the ENCODE data is increasing, the data types themselves are no longer novel because of the maturation of both the ENCODE Project and the associated technologies. As a result, biological interpretation of the data, which is outside the scope of this initiative and which may take longer than nine months to complete, is increasingly being required for publication. A longer moratorium period to accommodate this would be inconsistent with the primary purpose of ENCODE to generate a high quality, comprehensive and broadly useful catalog of functional elements, and to make it available expeditiously to the research community. It is also NHGRI’s intent, going forward through this FOA, to fund fewer, more centralized, and higher throughput production centers that will not focus on specific biological studies beyond the minimum amount needed to validate the quality of the forthcoming data.
• Another issue that has arisen since the current ENCODE data release policy was developed is that of the pre-publication release of integrative data analyses from a community resource project. In situations where the analysis methods are stable and the Consortium thinks that the resultant analyses may be of value to the community, NHGRI believes that these analyses should also be rapidly released to the community prior to publication to further the advancement of research.
• Once the next phase of ENCODE begins, the ENCODE Consortium members will be asked to revisit the data release policy, consider the issues NHGRI has raised above and any other issues raised by the research community, and establish an updated data release policy as appropriate.
• Applicants should provide a specific proposal for release of production data in the application, and are encouraged to address the issue of the release of data analyses. The reasonableness of the proposed data sharing plan will be assessed by the reviewers who will provide their assessment of the proposed data sharing plan as an administrative note and will not factor it into the determination of scientific merit or the impact score. After the initial review, NHGRI program staff will be responsible for any additional administrative review of the plan for sharing data and may negotiate modifications of the data sharing plan with the prospective awardee before recommending funding of an application. The adequacy of the negotiated data sharing plan will be considered by program staff when making funding recommendations. The final negotiated version of the data sharing plan will become a term and condition of the award of the cooperative agreement with the expectation that the Consortium will develop a common plan for data release once the awards are funded, and that this common plan will be adopted by all awardees.
• In summary, in considering data sharing, applicants should understand that NHGRI’s interest is for the ENCODE Consortium going forward to again have a common data release policy to which all participants in the Consortium will adhere. NHGRI will negotiate an interim data release plan as appropriate with each prospective awardee before an award is issued. After all of the awards have been made, the ENCODE Steering Committee, of which all awardees will be members, will develop a final, common data release plan as appropriate for the Project that will address the interests of the data producers and analysts, as well as the users of the ENCODE catalogs. Applicants should indicate their willingness to participate in the development of such a final plan and to accept it.
• The effectiveness of data sharing will be evaluated as part of the administrative review of the annual non-competing Grant Progress Report (PHS 2590).
• See Section VI.3. Reporting.
• Resource Sharing: As the ENCODE Project is generating a community resource, NHGRI intends that, in addition to data, resources 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 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 of generating the resources can be high, rapid dissemination of these resources would accelerate scientific exploration since individual researchers would not have to replicate such efforts. The applicant should provide specific plans for resource sharing and distribution in the application. The reasonableness of the proposed resource sharing plan will be assessed by the reviewers who will provide their assessment of the proposed plan as an administrative note and will not factor it into the determination of scientific merit or the impact score. After the initial review, NHGRI program staff will be responsible for any additional administrative review of the plan for sharing resources and may negotiate modifications of the resource sharing plan with the prospective awardee before recommending funding of an application. The adequacy of the negotiated resource sharing plan will be considered by program staff when making funding recommendations. The final negotiated version of the resource sharing plan will become a term and condition of the award of the cooperative agreement. The effectiveness of the resource sharing plan will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590). See Section VI.3. Reporting.

Appendix

Do not use the appendix to circumvent page limits. Follow all instructions for the Appendix (please note all format requirements) as described in the PHS398 Application Guide. All paper PHS 398 applications submitted must provide appendix material on CDs only. See http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-031.html.

Foreign (non-US) Institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the PHS398 Application Guide.

Part I. Overview Information contains information about Key Dates.

Information on the process of receipt and determining if your application is considered on-time is described in detail in the PHS398 Application Guide.

Applicants may track the status of the application in the eRA Commons, NIH’s electronic system for grants administration.

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 received on or before the due dates in Part I. Overview Information. If an application is received after that date, it will not be reviewed.

Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review and responsiveness by NHGRI, NIH. Applications that are incomplete and/or nonresponsive will not be reviewed.

Applicants should include discussion of the following issues in their applications:

Operating at scale. Applicants should demonstrate the ability to operate at scale at the inception of the project. Evidence of current capacity, how production goals are set and then met, and any plans for further development of the pipeline should be provided. Applicants should also demonstrate the ability to identify rate-limiting steps and to address them. Plans for improving the pipeline through standardization of procedures, automation, reagent reduction, division of labor and management should be included.

Pipeline Description. Applicants should demonstrate an understanding that an effective production pipeline is comprised of a succession of well-integrated individual process steps. Applicants should describe all of the individual steps and components of the proposed process clearly, and discuss how the proposed plans relate to current activities. Illustrative materials, such as pipeline descriptions, flow charts, Gantt charts and/or standard operating procedures (SOPs) should be used as appropriate. Applicants should describe the resources that will be required at each step, including personnel, equipment, reagents and informatics support.

Quality Control. Adequate process control requires the establishment of quantitative quality metrics at key points in the production pipeline. The pipeline description above should identify the procedures that will be used to monitor and assess quality at appropriate intermediate points in the process. Applicants should further describe those quality control steps included in the above pipeline description and should include a background description of how those procedures have been or will be developed. Monitoring the process may be done by sample and reagent tracking, real-time reporting systems, problem detection systems, bar coding, inventory control, or other means. Quantitative metrics, minimum quality standards, and/or the thresholds for moving onto the next step should be clearly defined for individual steps in the process. Applicants should describe the process(es) by which failure rates will be determined and what are acceptable failure rates for individual steps that will still allow the production of a high-quality product.

Quality control measures for the overall process should also be addressed and, if possible, evidence of the effectiveness of the proposed quality control programs should be provided, including verification of the reproducibility of the experimental approach and quantitatively measured, benchmarked performance of the experimental platform(s) being used. This approach should also identify any inherent biases in the primary method. Where appropriate, each affinity reagent must be well characterized to demonstrate the specificity of the reagent in capturing the target protein. The ENCODE and modENCODE Consortia have established data standards that are currently in use and are periodically updated (see: http://www.encodeproject.org/ENCODE/dataStandards.html). Applicants should describe plans to follow these or more stringent standards and to develop similar standards for novel technologies.

Applicants should provide current estimates of data quality and precise plans for how data quality will be evaluated during the course of the project, i.e., how the specificity and sensitivity of an experimental method will be measured, and how data quality will be maintained or improved during the proposed production phase.

Costs: Applicants should propose a cost model that accommodates the proposed data production process. The model should incorporate a standardized cost structure, including a useful unit (e.g., per experiment or per element identified) on which to base costs for the technology or approach proposed, and a description of all of the components used in this cost model, including failure rates. Applicants should consider all aspects (bioinformatics, reagents, personnel, equipment) of the production process and identify large-cost items that dominate the cost model, if appropriate, e.g., sequencing reagents or instrument costs. Cost analysis should be structured in such a way that reductions in the cost of applying the technology over the course of the project can be accurately monitored and projected (e.g., reduction in reagent costs or equipment amortization). Using the proposed model, applicants should present a description of costs at the start of the project and then describe anticipated cost reductions. All cost analyses should include an explicit item for Indirect Costs, and then present the final costs in terms of Total Costs.

Milestones and goals. Applications should define a clear set of goals for the overall project, and annual production milestones with metrics that will document progress towards the achievement of the ultimate goals. Applications should include plans for critically evaluating and revising these milestones on a regular basis. For each functional element being determined, applicants should also describe an appropriate level of comprehensiveness for the genome. For each approach, clear, quantitative endpoints must be set and described. Specific items that applicants should include in the milestones are listed below. Applicants are not limited to only these items but, at a minimum, all of them should be included in the application. The number and duration of milestones will depend on the project being proposed, so applicants should include these items for every year, as appropriate. Milestones may be revised at the time of the award as described in the terms and conditions of a Cooperative Agreement in section VI.2.

For a) the past 6 months of your current operation, b) yearly milestones, and c) ultimate goals of the project period, indicate:

• Number of attempted experiments. (Define experiment as it relates to the proposed method(s). For example, an experiment for the ChIP-seq technology could be defined as an immunoprecipitation followed by library construction and sequencing in two replicates.)
• Number of verified experiments. ( Data verification is defined by the ENCODE Data Release Policy (see: http://www.genome.gov/Pages/Research/ENCODE/Mod-ENCODE_Consortia_Data_Release_Policy_revised_11-22-09.pdf) as an assessment of the reproducibility of an experiment, such as by performing multiple biological replicates of a given experiment. Describe the verification standard that will be used and the definition of experiment if it differs from the definition given in response to the first item.)
• Data quality, as measured by platform characterization experiments and use of ENCODE and modENCODE data standards, as relevant.
• Number of cell lines, tissues, and/or environmental conditions tested.
• Number of antibodies tested (if applicable).
• Cost per experiment, including informatics (total cost per both production and biological relevance experiments; as defined above).

Additional information:

An Information Session for this FOA and related FOAs RFA-HG-11-025 and RFA-HG-11-026 will be held on October 31, 2011, from 12 noon-3 PM Eastern Daylight Savings Time. The Information Session will be conducted as a teleconference. No provisions will be made for in-person attendance. 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.

Prospective applicants who plan to participate in the Information Session should send an e-mail expressing their interest as soon as possible to NHGRI at [email protected] in order to receive logistical information about the Information Session, including dial-in numbers, which will be provided no later than October 27, 2011. In the Subject line of the e-mail request, please write: Information Session . The email message should contain:

Name,
Institution,
E-mail address,
Number of telephone lines that your group plans to use for the teleconference

Prospective applicants are encouraged to submit their questions about the FOAs to [email protected] before October 27, 2011. Prospective applicants may ask additional questions during the Information Session, and NHGRI staff will respond to those questions. Following the Information Session, by November 4, 2011, NHGRI will post a summary of questions and answers at http://www.genome.gov/ENCODE. Prospective applicants with inquiries concerning these FOAs who are unable to participate in the Information Session are encouraged to view the summary of questions and answers after they are posted. For any additional questions that are not addressed in the summary, please contact the program contacts listed in the FOAs for which you plan to apply.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-10-115.

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/priority 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.

Significance

Does the project address an important problem or a critical barrier to progress in the field? 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?

Investigator(s)

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(s)/PI(s), 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 day-to-day project management activities, e.g., a project manager or sufficient PD(s)/PI(s) effort, been described?

Innovation

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?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? 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?

If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed? What is the likelihood that the proposed project can produce a high-quality set of data at a reasonable cost? Is the applicant’s definition of comprehensiveness reasonable and is it likely that it will be reached? Are the milestones, timelines and goals proposed for the research project reasonable and appropriate? 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 appropriate? Are the plans for submitting data to the appropriate database(s) appropriate and reasonable, and is there evidence that the systems are in place to support the data submission processes?

Environment

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/priority score, but will not give separate scores for these items.

Protections for Human Subjects

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 Human Subjects Protection and Inclusion Guidelines.

Inclusion of Women, Minorities, and Children

When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the Human Subjects Protection and Inclusion Guidelines.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

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.

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

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/priority score.

Applications from Foreign Organizations

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Select Agent Research

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).

Resource Sharing Plans

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) Genome Wide Association Studies (GWAS).

Budget and Period of Support

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 NHGRI , in accordance with NIH peer review policy and procedures, using the stated review criteria. Review assignments will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review), will be discussed and assigned an overall impact/priority score.
• Will receive a written critique.

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 and 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:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.
• Programmatic priorities with respect to organism(s) of study
• Programmatic balance

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.

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 the DUNS, CCR Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants 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.

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 Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), 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:

• Defining the details for the project within the guidelines of RFA HG-11-024 and for performing the scientific activities.
• Providing milestones for throughput, quality, and cost to the NHGRI as requested (usually at the outset of the award and annually thereafter, but also at other times as requested by NHGRI program staff).
• Analyzing the entire genome, or explain why that is not possible.
• Producing data on any common cell source or with any common reagents identified for the project before undertaking experiments under other conditions, or explain why doing so is not possible.
• Sharing results according to the data release policy developed for and by this project.
• Participating in group activities, including attending periodic workshops to discuss the ENCODE Project's progress and coordinating publication of research results.
• Serving as a member of the ENCODE Research Consortium Steering Committee.
• Fully disclosing algorithms, software source code, and experimental methods to the other members of the Consortium for the purpose of scientific evaluation.
• Not disclosing confidential information obtained from other members of the Consortium.
• Adhering to NHGRI policies regarding intellectual property and other policies that might be established during the course of this activity.
• Submitting quarterly progress reports in a standard format, as agreed upon by the Steering Committee and the External Consultants Panel.
• Accepting and implementing the common guidelines and procedures approved by the Steering Committee, External Consultants Panel and NHGRI.
• Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

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. However, the role of NIH staff will be to facilitate and not to direct the activities. 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.

The Project Scientist 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.
• Negotiate milestones, e.g., throughput, quality, cost goals, and targets (sample sources or affinity reagents) with the awardees as necessary.
• Serve as a liaison, helping to coordinate activities among and for the awardees, including acting as a liaison to the NHGRI, and as an information resource about extramural genome research activities.
• Coordinate the efforts of the entire Research Consortium, including other participating groups not funded through this FOA.
• Attend all Steering Committee meetings as a voting member and assist in developing operating guidelines, quality control procedures, and consistent policies for dealing with recurrent situations that require coordinated action. The Project Scientist must be informed of all major interactions of members of the Steering Committee.
• Report periodically on the progress of the ENCODE Project to the Director, NHGRI.
• Provide relevant expertise and overall knowledge of NIH-sponsored research to facilitate the selection of scientists not affiliated with the awardee institutions to serve on the External Consultants Panel.
• Serve as a liaison between the Steering Committee and the External Consultants Panel, attending External Consultants Panel meetings in a non-voting liaison member role
• Serve on subcommittees of the Steering Committee and the External Consultants Panel, as appropriate.
• Assist awardees in the development, if needed, of policies for dealing with situations that require coordinated action.
• Provide advice in the management and technical performance of the investigation.
• Assist in promoting the availability of the ENCODE and related resources developed in the course of this project to the scientific community at large.
• Participate in data analyses, interpretations, and, where warranted, co-authorship of the publication of results of studies conducted through the ENCODE Research Consortium.

Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

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, NHGRI about the progress and scientific direction of all components of the program. The External Consultants Panel will be composed of six 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 of NHGRI about changes, if any, that may be necessary in the ENCODE Research Consortium program.

Areas of Joint Responsibility include:

The Steering Committee will serve as the main coordinating board of the ENCODE Research Consortium established under this FOA. 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 membership will include one NIH Project Scientist and the PD(s)/PI(s) from each awarded cooperative agreement. The Steering Committee may add additional members. Other government staff may attend the Steering Committee meetings if their expertise is required for specific discussions.

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 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

Dispute Resolution:

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.

When multiple years are involved, awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.

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.

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone 301-710-0267
TTY 301-451-5936
Email: [email protected]

eRA Commons Help Desk(Questions regarding eRA Commons registration, tracking application status, post submission issues)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)
TTY: 301-451-5939
Email: [email protected]

Elise A. Feingold, Ph.D.
Program Director, Genome Analysis
Division of Extramural Research
National Human Genome Research Institute (NHGRI)
5635 Fishers Lane, Ste. 4076, MSC 9305
Bethesda, MD 20892-9305 (U.S Postal Service Express or regular mail)
Rockville, MD 20852 (for express/courier service; non-USPS service)
Telephone: 301-496-7531
FAX: 301-480-2770
E-mail: [email protected]

Ken Nakamura, Ph.D.
Scientific Review Officer
Scientific Review Branch
National Human Genome Research Institute (NHGRI)
5635 Fishers Lane, Ste. 4076, MSC 9305
Bethesda, MD 20892-9305 (U.S Postal Service Express or regular mail)
Rockville, MD 20852 (for express/courier service; non-USPS service)
Telephone: 301-402-0838
FAX: 301-435-1580
E-mail: [email protected]

Cheryl Chick
Grants Administration Branch
National Human Genome Research Institute (NHGRI)
5635 Fishers Lane, Suite 3058
Bethesda, MD 20892-9307
Phone: 301-435-7858
Fax: 301-451-5434
E-mail: [email protected]

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 Parts 74 and 92.