Department of Health and Human Services

Participating Organizations
National Institutes of Health (NIH) (http://www.nih.gov)

Components of Participating Organizations
National Human Genome Research Institute (NHGRI) (http://www.genome.gov)

Title: Creating the Encyclopedia of DNA Elements (ENCODE) in the Human Genome (U01 and U54)

Announcement Type
New

Update: The following update relating to this announcement has been issued:

• January 18, 2007 - See Notice (NOT-HG-07-007) Clarification and Additional Information on this RFA.

Due Dates for E.O. 12372

Not Applicable

Additional Overview Content

Executive Summary

• This RFA solicits applications for research projects that will contribute to attaining the goals of the ENCODE Project by applying high-throughput, cost-efficient approaches to generate a catalog of sequence-based functional elements in the human genome. Proposals to interrogate the whole genome are being sought, as are proposals to further develop effective large-scale approaches by using the ENCODE target regions of the genome (30 Mb) as a test bed, as was the case during the pilot phase of ENCODE.
• This RFA will use the U01 and U54 Cooperative Agreement grant mechanisms.
• $23 million in FY 2007 funds have been committed to fund applications received in response to this RFA.
• It is anticipated that between 6 and 10 awards will be made under this RFA. Awards are contingent on the availability of funds and the submission of a sufficient number of meritorious applications.
• The total project period for an application submitted in response to this RFA may not exceed three years for U01 projects or four years for U54 projects.
• Eligible Organizations: For-profit organizations; non-profit organizations; public or private institutions, such as universities, colleges, hospitals, and laboratories; units of State and local governments; eligible agencies of the Federal government; and domestic or foreign institutions.
• Eligible Principal Investigators (P.I.s): Individuals with the skills, knowledge, and resources necessary to carry out the proposed research are invited to work with their institution 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.
• Initial merit review will be convened by the NHGRI Scientific Review Branch.
• Applicants may submit more than one application, provided they are scientifically distinct.
• See Section IV.1 for application materials.
• Telecommunications for the hearing impaired is available at: TTY 301-451-5936

Table of Contents

Part I Overview Information

Part II Full Text of Announcement

Section I. Funding Opportunity Description
1. Research Objectives

Section II. Award Information
1. Mechanism(s) of Support
2. Funds Available

Section III. Eligibility Information
1. Eligible Applicants
A. Eligible Institutions
B. Eligible Individuals
2.Cost Sharing or Matching
3. Other - Special Eligibility Criteria

Section IV. Application and Submission Information
1. Address to Request Application Information
2. Content and Form of Application Submission
3. Submission Dates and Times
A. Receipt and Review and Anticipated Start Dates
1. Letter of Intent
B. Sending an Application to the NIH
C. Application Processing
4. Intergovernmental Review
5. Funding Restrictions
6. Other Submission Requirements

Section V. Application Review Information
1. Criteria
2. Review and Selection Process
A. Additional Review Criteria
B. Additional Review Considerations
C. Sharing Research Data
D. Sharing Research Resources
3. Anticipated Announcement and Award Dates

Section VI. Award Administration Information
1. Award Notices
2. Administrative and National Policy Requirements
A. Cooperative Agreement Terms and Conditions of Award
1. Principal Investigator Rights and Responsibilities
2. NIH Responsibilities
3. Collaborative Responsibilities
4. Arbitration Process
3. Reporting

Section VII. Agency Contact(s)
1. Scientific/Research Contact(s)
2. Peer Review Contact(s)
3. Financial/ Grants Management Contact(s)

Section VIII. Other Information - Required Federal Citations

Part II - Full Text of Announcement

Section I. Funding Opportunity Description

1. Research Objectives

Purpose

The purpose of this RFA is to solicit applications for research projects to achieve the aims of the ENCODE (Encyclopedia of DNA Elements) Project by applying high-throughput, cost-efficient approaches to generate a catalog of functional elements in the human genome. Both computational and experimental approaches will be critical components of the overall effort. The ENCODE Project is currently in a pilot phase focused on the development of efficient large-scale approaches to identify all of the sequence-based functional elements in genomic DNA by focusing on a selected 30 Mb (1%) of the human genome (see www.genome.gov/ENCODE). This RFA solicits applications for production-level efforts to find functional elements across the whole human genome, or for pilot-scale efforts to pursue new large-scale, in-depth analyses by focusing on the ENCODE target regions.

This RFA is being issued in conjunction with a second RFA-HG-07-031, A Data Coordination Center for the Encyclopedia of DNA Elements (ENCODE) Project .

The funded projects will participate in a Research Consortium that will be a continuation of the existing ENCODE Research Consortium. The ENCODE Research Consortium will be separate from, but affiliated with, the Research Consortium that will be organized for the modENCODE Project following the funding of applications submitted in response to RFA HG-06-006, Identification of All Functional Elements in Selected Model Organism Genomes in spring 2007. The modENCODE Project will analyze either the Caenorhabditis elegans genome or the Drosophila melanogaster genome, or both.

Background

In April 2003, the sequence of the human genome was essentially completed. For the scientific community to make the best use of that fundamental information resource, the identity and precise location of all sequence-based functional elements in the genome must be determined. While many of the protein-coding sequences are already known, others still remain to be identified. Beyond open reading frames, most other sequence-based functional elements, such as non-protein-coding genes, transcriptional regulatory elements and determinants of chromosome structure and function, remain largely unknown. A comprehensive encyclopedia of all of these features is needed to fully utilize the sequence of the human genome to better understand human biology, to understand the biology of disease, to predict potential disease risk, and to stimulate the development of new therapies and other interventions for preventing and treating disease.

To address this need, the NHGRI initiated the Encyclopedia of DNA Elements (ENCODE) Project in 2003. The goal of the ENCODE Project is to identify sequence-based functional elements in the human genome sequence in a comprehensive manner. The ENCODE Project started with two components. The first was a pilot in which available methods for the identification of functional sequence elements were to be tested and compared in a defined one percent (30 Mb) of human genomic DNA. (For information about the selected target sequences, see http://www.genome.gov/10506161). The projects that composed this pilot addressed the comprehensive identification of coding sequences, transcriptional units, transcriptional control elements, chromatin modifications and certain chromosomal features such as origins of replication and DNase hypersensitive sites. The goals of the pilot phase were to test the ability of existing technologies to be applied at high-throughput in an efficient and cost-effective manner, to identify gaps in our ability to fully annotate the human genome and to set a clear path forward for scaling up these efforts to efficiently and effectively characterize the entire human genome in detail. The participants in the pilot project were organized as a Research Consortium and many were supported through the funding of applications received in response to RFA HG-03-003. The ENCODE pilot project was, however, an open effort and additional groups, who were not initially participants but who agreed to abide by the Consortium’s criteria for participation, subsequently joined the Consortium.

The second original component of the ENCODE Project addressed the need for new or better technologies to identify these and other sequence-based functional elements on a genome-wide scale. Technology development has been supported through the funding of applications received in response to two RFAs in 2003 and 2004 (HG-03-004 and HG-04-001) and RFAs to solicit a third round of applications were released in August 2006 (HG-07-028 and HG-07-029). For a full list of the participants in the ENCODE pilot and technology development components, see http://www.genome.gov/12513391.

The pilot project has been successful in bringing together a set of individual groups to work together in a highly collaborative and synergistic effort. The ENCODE Consortium participants developed and agreed to abide by a common data release policy (http://www.genome.gov/encode/#3) that requires rapid data release, and they are developing common quantitative data standards for each of the technologies being used in the pilot. Consortium members have generated data using common cell lines and, where relevant, using a common set of DNA binding factors. All ENCODE data are made available in appropriate public databases (http://www.genome.gov/encode/#4). Analysis groups within the Consortium have focused on different aspects of the project to assemble and analyze the data that have been generated. These analyses, which will be published within the next year, have revealed interesting scientific discoveries, and have enabled NHGRI to identify strengths and gaps in the current knowledge about how to scale up these efforts to analyze the complete human genome.

The technology development component of ENCODE has also progressed well. New and improved methods are emerging that will allow a more precise definition of gene structures, including their boundaries, better mapping of DNA-binding sites, localization of sites of DNA methylation, identification of areas of chromatin accessible to chemical cleavage, and mapping of chromosomal regions that interact in vivo. Some of these new approaches have been developed to the point where they are now being applied to the full set of ENCODE regions.

These accomplishments have led NHGRI to continue the pursuit of the goal of the ENCODE Project to identify sequence-based functional elements in the human genome comprehensively. As the initial phase of the ENCODE Project will be completed in September 2007, this RFA is being issued to solicit applications for research projects to continue the ENCODE-based analysis of the human genome sequence. The continuation of the ENCODE Project will be comprised of three kinds of efforts: 1) production efforts that scale to the entire human genome, using methods that have been clearly demonstrated to identify sequence-based functional elements efficiently, comprehensively, cost-effectively, and in a reasonable time frame; 2) continued pilot efforts that analyze the ENCODE target regions in new and interesting ways; and 3) new pilot projects using novel technologies, such as those developed by the first set of technology development projects, to study the ENCODE target regions.

This RFA will use the U54 cooperative agreement mechanism for production effort applications to analyze the whole genome, and the U01 cooperative agreement mechanism for pilot project applications to analyze the ENCODE target regions. This solicitation is open to all investigators, both those who participated in the initial ENCODE pilot project and those who did not.

Research Scope

This RFA solicits applications that will conduct research efforts to identify all of the functional elements in the human genome.

The sequence-based functional elements that will be targeted include, but are not limited to:

• Transcribed sequences, including both protein coding and non-protein coding sequences. A description of gene structure with transcription start sites and polyadenylation sites, along with all biologically relevant alternative transcripts, is an example.
• Conserved non-coding sequences that specify functional elements.
• Cis-acting DNA elements that regulate transcription and/or chromatin structure. These include promoters, enhancers, repressors and insulators.
• Cis-acting RNA elements that regulate steps in RNA metabolism, e.g., modification, stability, and transport.
• DNA sequence features that affect and/or control chromosome biology. Examples include origins of replication and hot spots for recombination.
• Epigenetic marks, such as DNA methylation and chromatin modifications.

Functional elements should be identified precisely, ideally as 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 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 the proposed method will identify the 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.

This solicitation is open to all investigators, both those who are currently participating in the ENCODE pilot project and those who are not. The ENCODE Research Consortium will continue to be open to all academic, government and private sector scientists willing to participate in an open process to facilitate the comprehensive annotation of the human genome. Groups with funding from other sources will be able to participate in the ENCODE Project provided they meet the criteria for participation and, therefore, funding through this initiative is not a prerequisite for participation in the ENCODE Consortium. The criteria for participation in the pilot phase of ENCODE can be found at http://www.genome.gov/12513439, but applicants should understand that these criteria may be modified for the next, expanded phase of the ENCODE Project, e.g., for projects proposing to work on the entire human genome sequence. The Awardee funded through the concurrent RFA, HG-07-031, A Data Coordination Center for the Encyclopedia of DNA Elements (ENCODE) Project, which will support the database needs of the ENCODE Project, will also participate in the Research Consortium.

Three types of projects will be supported through this solicitation: 1) projects that propose to analyze the complete human genome sequence, 2) continuations of existing pilot projects, and 3) new pilot projects using novel technologies, such as those developed in the initial phases of ENCODE. In all cases, both computational and experimental approaches are encouraged; however, applications proposing computational approaches as the primary means of discovery do require an experimental validation component to be responsive to this RFA.

Genome-scale Projects (U54s): Applicants are invited to propose projects that will identify all of the functional elements (of one or more types) that exist in the human genome and that will involve a limited biological validation of these elements. Applicants may request up to four years of support. Applicants will be expected to propose methods that have been demonstrated to be high-throughput, to generate high-quality data, to be cost-effective and to be comprehensive (have the capability to accurately and efficiently identify the entire set of one or more types of functional elements contained within the human genome). Applicants must propose to work on the entire human 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 three billion bases of the human genome. For example, microarrays generally do not include the repetitive sequences in the human genome. In such cases, applicants should discuss why the proposed approach will be sufficient to meet the goals of the RFA and/or provide alternative strategies for interrogating the remainder of the genome. Similarly, analysis of a single cell line will not reveal many tissue- or stage-specific functional elements and therefore applicants should address the use of multiple cell lines or tissues to find all instances of a functional element in the human genome. For further discussion, see Approaching a Complete Catalog below.

Pilot Project Continuations (U01s): Applicants currently participating in the ENCODE pilot project may propose to continue to work on the selected ENCODE target regions for up to three more years, if necessary, to generate more data and conduct more in-depth analyses of the ENCODE target regions, leading to greater insights into the most effective approaches to uncover functionally important regions in the human genome.

New Pilot Projects (U01s): Applicants are invited to propose projects that will apply novel technologies, i.e., those that are not currently being employed in the ENCODE pilot project, to the ENCODE target regions. The purpose of such new projects would be to test new, potentially high-throughput, comprehensive and cost-effective methods for their ability to facilitate whole genome studies. New pilot projects will also be supported for up to three years.

For pilot-scale projects, applicants must propose to work on the entire set of ENCODE target regions. Pilot projects requesting less than three years of support are allowable; however NHGRI does not anticipate issuing and funding another solicitation for genome-wide studies any time sooner than three years from the date of funding this RFA; therefore, projects funded for less than three years create the potential for a gap in funding. Applicants proposing pilot projects should discuss plans for continuing the project beyond the pilot phase, including ideas for scaling to whole genome analysis.

During the first phase of the pilot project, the Consortium initially designated two cell lines (HeLa S3, a cervical adenocarcinoma cell line, and GM06990, a lymphoblastoid cell line) as common reagents to be worked on by all participating groups (see http://www.genome.gov/12513455#3). Three additional common cell lines were identified for use by Consortium members during the ENCODE pilot project. These are BJ-TERT, an immortalized foreskin fibroblast cell line; K562, an erythroblastoid cell line which expresses the globin genes; and HepG2, a hepatocarcinoma cell line which expresses lipoproteins. K562 and HepG2 were selected because they express genes of interest that lie within the ENCODE regions. Applicants proposing pilot projects should include work on these five cell lines and may propose additional cell lines or tissues as appropriate.

Approaching a Complete Catalog: In practice, achieving a complete catalog of most classes of functional elements is likely not to be feasible. 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. Once awards are made, the ENCODE Consortium will agree on a set of experimental conditions for the Project and the generation and/or use of common reagents, as needed. As the Project progresses, the Consortium, working together with NHGRI staff and the Project’s External Consultant Panel (see section 2.A.2 below), will continue to refine the overall Project milestones and targets.

For other large-scale data generation projects such as genomic sequencing, the success of the project has been facilitated by the adoption of clear, quantitative milestones by each of the participating research groups. Applicants to the ENCODE program should, similarly, propose milestones and appropriate metrics to measure the progress for their targeted class of functional elements. For each technology being used, applicants should also describe an appropriate level of completeness for the genome, i.e., what is the stopping point? Clear quantitative endpoints must be set and described. At the time of the award, NHGRI will negotiate quantitative milestones for each award. These may include setting goals for percent coverage and data quality.

The generation of a large set of antibodies to DNA binding proteins for e.g., ChIP-chip studies, although valuable, will be considered outside of the scope of this project. NHGRI is considering other means to support such an effort.

Data Quality and Utility: Through the ENCODE Project, NHGRI intends to support the generation of a comprehensive catalog of sequence-based functional elements in the human genome using high-throughput methods that measure biochemical events in a robust and reproducible manner. As this catalog of functional elements will become an important, and probably unique, reference data set and will be used in a wide range of studies, the quality, comprehensiveness, and biological relevance of ENCODE data will be critical to the success of the Project.

• Quality. The authenticity of the biochemical events detected by the primary experimental approach must be confirmed using one or more, preferably completely independent, validation method(s). To the extent that they are available, the validation method(s) employed should also be cost-effective, efficient and high-throughput. Even if such methods are available, validation will add significant time and cost to the project. To control such costs, it will be sufficient for the applicant to propose validating only that fraction of identified elements that is needed to provide a 95% confidence level that the detected biochemical events occur in vivo. If the applicant believes that the 95% confidence level is inappropriate for demonstrating data quality, s/he should propose and justify a different level of confidence.
• Comprehensiveness. In addition to being comprised of very high quality data, the catalog generated by the ENCODE Project must be as comprehensive as possible. Thus, the applicant should define comprehensiveness for the proposed project and note whether it can be achieved during the proposed project period, or whether a longer-term effort would be necessary. The applicant should then address the ability of each of the proposed approaches to identify a significant fraction of the instances of the functional element under investigation. NHGRI recognizes that this is potentially difficult, as the actual number of such elements in the human 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.
• Biological relevance. Once a catalog of biochemically validated elements is created, 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. The applicant must describe in detail how the biological authenticity of the identified elements will be established. As above, these studies of biological relevance should be limited to that fraction of elements needed to confirm the functional role of the class of elements. While this aspect of the program is intended to extend the scope of this project beyond that of the original ENCODE pilot project by including analysis of the function of detected elements as a class, it 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.

NHGRI recognizes that, eventually, the research community will want to know the precise biological role that each of the individual elements plays in human biology. 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 RFA. Instead, what this ENCODE initiative will require is a statistically valid demonstration that the majority of the members of the type of element being determined do have the function attributed to that type.

Discovery methods and validation methods that take advantage of existing resources and biological knowledge (e.g., data in databases and the literature) are strongly encouraged. However, NHGRI recognizes that it may be necessary to generate a new set of reagents or physical resources, such as specific clone libraries, to carry out the proposed analyses. Generation of such resources should be proposed only 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, a set of antibodies to all DNA-binding proteins or a set of BAC clones tiling across the human genome, would not be supported. Since the validation experiments should not address the entire genome, the generation of reagents or resources needed for validation studies should be limited to the extent necessary to conduct such studies, unless it can be demonstrated that it would be significantly more efficient, in terms of unit costs, to generate a complete set of reagents than to generate a subset.

Data Analysis: Applicants must describe an 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. An additional informatics component may consider integrative analysis of the data being generated by the different technologies being employed within the ENCODE Consortium. 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 RFA and should be supported by other funding mechanisms.

Data submission: A component of the informatics pipeline should include submission of the primary data and validation data in standardized formats to the ENCODE Data Coordination Center (DCC), which will be funded in response to RFA HG-07-031, or to other appropriate public repositories as specified by the ENCODE Consortium Data Release Policy (http://www.genome.gov/12513440). In addition, any metadata such as information about experimental procedures and analysis methods used to generate the data should be submitted to the DCC. All groups participating in the ENCODE Consortium will work with the DCC to establish the exact types and formats of data and metadata that will be transferred to the DCC.

Production pipeline issues that must be addressed in applications for production-scale projects.

The sections below outline issues associated with production activities that need to be addressed by applicants proposing production-scale projects. Many of these issues are also relevant to the applicants proposing pilot-scale projects. Applicants proposing pilot projects should, therefore, also address these issues to the extent possible, and should describe how the pilot project will prepare the applicant to be able to address these issues more fully by the end of the pilot phase of the project. Pilot project applicants should also discuss plans for continuing the project beyond the pilot phase, including how a whole-genome project could follow from the pilot effort.

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 proposals:

Operating at scale. Applicants should demonstrate the ability to operate at scale at the inception of the project or should describe detailed plans to scale up from a pilot level. A ramp-up of activities over the course of first one to two years of the project will be considered for production scale efforts only. For operations currently at scale, the applicant should provide evidence of current capacity, how production goals are set and then met, and any plans for further development of the pipeline. For pilot-level efforts proposing to scale up, applicants should demonstrate the ability to improve the pipeline to increase throughput and quality, and to lower costs. Detailed plans for achieving full scale should be presented.

In either case, applicants should 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. Plans for data verification and validation should be included in this description. Data verification is defined by the ENCODE Data Release Policy (http://www.genome.gov/12513440) as assessing the reproducibility of an experiment, while data validation is defined as confirming the biochemical authenticity of the results of an experiment by another, preferably independent, method.

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 of how data quality will be maintained or improved during the proposed production phase.

Costs. Another important factor that needs to be addressed in scaling up the ENCODE Project is demonstrating 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. 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. 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., microarray, primer 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, reuse of arrays, 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. Proposals 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. Proposals 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 proposal. 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 2.A.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-chip technology could be defined as an immunoprecipitation followed by hybridization onto a microarray.)
  
• Number of verified experiments. ( Data verification is defined by the ENCODE Data Release Policy (http://www.genome.gov/12513440) 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.)
  
• Number of elements found. (Define element as it relates to the proposed method(s) and specify the cut-off value used to call a positive result. For example, for the ChIP-chip technology, an element could be defined as the number of positive hits not within X bp of one another using the proposed cutoff value.)
  
• Number of validation experiments. ( Data validation is defined by the ENCODE Data Release Policy (http://www.genome.gov/12513440) as a confirmation of data using a secondary - ideally independent - method of detection. Describe the validation process that will be used, including the definition of experiment for the validation process and the number of data points that will be validated.)
  
• Data Quality, as measured by validation experiments.
  
• Number of cell lines, tissues, and/or environmental conditions tested.
  
• Number of antibodies tested (if applicable).
  
• Cost per experiment (total cost per both production and validation experiments; as defined above).
  
• Cost per element identified (total cost per element identified; as defined above).

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 and 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 proposals. 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 will be included in the overall production cost.

Management Plan and P.I. Effort. The effective management of a production project requires a significant commitment by the Principal Investigator (P.I.). The P.I. of a production-scale project funded under this RFA is expected to devote at least 25% effort to the project. (There is no minimum percent effort for pilot project P.I.s, but applicants should demonstrate a sufficient level of effort for the work proposed.) The applicant should describe how s/he will manage the proposed project, and how that management 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 advisory groups. 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.

In summary, all applicants for awards under this RFA:

• should discuss the application of high-throughput, cost efficient approaches or strategies to identify comprehensively a set of functional elements in the human genome;
• 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, including methods for data verification and validation, specifically addressing issues of sensitivity and specificity;
• 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 informatics 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;
• non-U.S. applicants should provide information regarding the uniqueness of the resource or approach being proposed and a well-documented data release plan.

See Section VIII, Other Information - Required Federal Citations, for policies related to this announcement.

Section II. Award Information

1. Mechanism(s) of Support

This funding opportunity will use the U01 and U54 Cooperative Agreement award mechanisms.

The NIH U01 and U54 are cooperative agreement award mechanisms. In the cooperative agreement mechanism, the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the Section VI. 2. Administrative Requirements, "Cooperative Agreement Terms and Conditions of Award". This is a one-time solicitation. At the current time, plans for continuing the ENCODE project beyond the next four years are not definitive and will depend, to some extent, on the progress made during the next grant period.

2. Funds Available

The NHGRI intends to commit approximately $23 million dollars in FY 2007 to fund 6-10 new and/or competing continuation grants in response to this RFA. An applicant may request a project period of up to 3 years for U01 applications and up to 4 years for U54 applications. The earliest anticipated start date for awards is September 30, 2007. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. It is expected that the size of the awards will range from approximately $250,000 to $4 million direct costs per year, however these are estimates and not budgetary limits. A moderate ramp-up (up to 50% during the first one to two years) will be considered for production efforts only (U54s).

Although the financial plans of the IC(s) provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications.

Facilities and administrative costs requested by consortium participants are not included in the direct cost limitation, see NOT-OD-05-004.

Section III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

You may submit (an) application(s) if your organization has any of the following characteristics:

• For-profit organizations
• Non-profit organizations
• Public or private institutions, such as universities, colleges, hospitals, and laboratories
• Units of State government
• Units of local government
• Eligible agencies of the Federal government
• Foreign Institutions
• Domestic Institutions

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution 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.

2. Cost Sharing or Matching

No cost sharing or matching is required for applications submitted in response to this RFA.

The most current Grants Policy Statement can be found at: http://grants.nih.gov/grants/policy/nihgps_2003/nihgps_Part2.htm#matching_or_cost_sharing

3. Other-Special Eligibility Criteria

Applicants may submit more than one application, provided they are scientifically distinct.

Section IV. Application and Submission Information

1. Address to Request Application Information

The PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. Applicants must use the currently approved version of the PHS 398. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: [email protected].

Telecommunications for the hearing impaired: TTY 301-451-5936.

2. Content and Form of Application Submission

Applications must be prepared using the most current PHS 398 research grant application instructions and forms. Applications must have a D&B Data Universal Numbering System (DUNS) number as the universal identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

The title and number of this funding opportunity must be typed on line 2 of the face page of the application form and the YES box must be checked.

Foreign Organizations

Several special provisions apply to applications submitted by foreign organizations:

• Charge back of customs and import fees is not allowed.
• Format: every effort should be made to comply with the format specifications, which are based upon a standard US paper size of 8.5" x 11."
• Funds for up to 8% administrative costs (excluding equipment) can now be requested (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-028.html)
• Organizations must comply with federal/NIH policies on human subjects, animals, and biohazards.
• Organizations must comply with Federal/NIH biosafety and biosecurity regulations. See Section VI.2., Administrative and National Policy Requirements.
• Additional information regarding foreign grants is available in the NIH Grants Policy Statement (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part12.htm#_Toc54600260).

Proposed research should provide special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions in other countries that are not readily available in the United States or that augment existing U.S. resources.

3. Submission Dates and Times

Applications must be received on or before the receipt date described below (Section IV.3.A). Submission times N/A.

3.A. Receipt, Review and Anticipated Start Dates
Letters of Intent Receipt Date(s): February 27, 2007
Application Receipt Date(s): March 29, 2007
Peer Review Date(s): June-July 2007
Council Review Date(s): September 2007
Earliest Anticipated Start Date(s): September 30, 2007

Applicant Information Meeting. There will be a meeting at the Conference Center at 5635 Fishers Lane, Rockville, Maryland 20852 from 1:00 p.m. to 3:00 p.m. EST on Monday, December 18, 2006 to answer questions about this RFA from prospective applicants. Attendance at this meeting is not a prerequisite for responding to this RFA. For information about calling into this meeting, email: [email protected]

3.A.1. Letter of Intent

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 Principal Investigator
• Names of other key personnel
• Participating institutions
• Number and title of this funding opportunity

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.

The letter of intent is to be sent by the date listed at the beginning of this document.

The letter of intent should be sent to:

Elise Feingold, PhD
Program Director, Genome Analysis
Division of Extramural Research
National Human Genome Research Institute
5635 Fishers Lane, Suite 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
Email: [email protected]

3.B. Sending an Application to the NIH

Applications must be prepared using the research grant applications found in the PHS 398 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)

Personal deliveries of applications are no longer permitted (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-040.html).

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

Rudy Pozzatti, PhD
Scientific Review Administrator
Scientific Review Branch
National Human Genome Research Institute
5635 Fishers Lane, Ste. 4076, MSC 9306
Bethesda, MD 20892-9306 (U.S Postal Service Express or regular mail)
Rockville, MD 20852 (for express/courier service; non-USPS service)
Telephone: (301) 402-0838
Email: [email protected]

Using the RFA Label: The RFA label available in the PHS 398 application instructions must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/labels.pdf.

3.C. Application Processing

Applications must be received on or before the application receipt date(s) described above (Section IV.3.A.). If an application is received after that date, it will be returned to the applicant without review. Upon receipt, applications will be evaluated for completeness by the CSR and responsiveness by the NHGRI. Incomplete and non-responsive applications will not be reviewed.

The NIH will not accept any application in response to this funding opportunity that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to a funding opportunity, it is to be prepared as a NEW application. That is, the application for the funding opportunity must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application.

Information on the status of an application should be checked by the Principal Investigator in the eRA Commons at: https://commons.era.nih.gov/commons/.

4. Intergovernmental Review

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

Pre-Award Costs are allowable. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new or competing continuation award if such costs: are necessary to conduct the project, and would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new or competing continuation award.

The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project. See NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part6.htm.

6. Other Submission Requirements

The Research Plan (sections A-D) for all U01 applications (for both new and continuing pilot projects) should be limited to the standard 25 pages; whereas the Research Plan (sections A-D) for U54 applications should not exceed 40 pages.

Plan for Sharing Research Data

The NHGRI is committed to the principle of rapid data release to the scientific community. This principle was initially implemented during the Human Genome Project and has been recognized as leading to one of the most effective ways of promoting the use of the genome sequence data to advance scientific knowledge. At a meeting in Ft. Lauderdale, FL that was co-sponsored by the Wellcome Trust and NHGRI in January 2003, the concept of rapid data release by genomic sequence data producers was reaffirmed, and the attendees strongly recommended applying the practice to other types of data produced by community resource projects . The attendees recognized, however, that different issues, particularly with respect to data validation, would be involved in the development of appropriate release practices for different types of data. Since they also recognized that sustaining the practice of rapid, prepublication data release by community resources requires that the interests of all involved - including the data producers, data users, and funding agencies - be addressed, they emphasized the need to develop a tripartite system of responsibility. The meeting report from the Ft. Lauderdale meeting can be found on the Wellcome Trust website at: http://www.wellcome.ac.uk/doc_wtd003208.html

The NHGRI has identified the ENCODE Project as a community resource project. As such, the ENCODE Project aims to function openly by making all data available to the scientific community in a timely manner prior to publication. During the pilot phase, the ENCODE Consortium established a common Data Release Policy (see http://www.genome.gov/12513440) and all participants agreed to abide by that policy. It is expected that the general principles of this policy will continue during the next phase of the ENCODE Project. Additional specifications may be added, e.g., relating to timing of release of validated data. All applicants should provide specific plans for data release in the application and indicate their willingness to abide by the ENCODE Consortium Data Release Policy and any changes that may be made during the next funding period by the Consortium. The reasonableness of the data sharing plan will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score.

After completion of the initial review, NHGRI program staff will be responsible for any additional administrative review of the plan for sharing data. The adequacy of the data sharing plan will be considered by program staff of the funding organization when making recommendations about funding applications. Program staff may negotiate modifications of the data sharing plan with the prospective awardee before recommending funding of an application. The final negotiated version of the data sharing plan will become a condition of the award of the cooperative agreement. The effectiveness of the data sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590). See Section VI.3. Reporting.

Sharing Research Resources

NIH policy expects that grant recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm and http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.htm#_Toc54600131). Investigators responding to this funding opportunity should include a plan for sharing research resources addressing how unique research resources will be shared or explain why sharing is not possible.

The adequacy of the resources sharing plan and any related data sharing plans will be considered by Program staff of the funding organization when making recommendations about funding applications. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590, http://grants.nih.gov/grants/funding/2590/2590.htm). See Section VI.3. Reporting.

As the ENCODE Project is a community resource project, NHGRI expects that not only data, but also resources generated during the course of the program should be made rapidly available to the research community and that sharing plans should follow the same principles and spirit as the rapid data release policy. The applicant should provide specific plans for resource sharing and distribution in the application. The reasonableness of the data sharing plan will be assessed by the reviewers. However, reviewers will not factor the proposed resources sharing plan into the determination of scientific merit or the priority score. The adequacy of the resources sharing plan will be considered by the funding organization when making recommendations about funding applications. The presence of a resources sharing plan will be part of the terms and conditions of the award. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590, http://grants.nih.gov/grants/funding/2590/2590.htm. See Section VI.3. Reporting.

Section V. Application Review Information

1. Criteria

The following will be considered in making funding decisions:

• Scientific merit of the proposed project as determined by peer review
• Availability of funds
• Relevance of program priorities
• Balance among the projects to ensure funding the discovery of a range of functional elements

2. Review and Selection Process

Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by NHGRI in accordance with the review criteria stated below.

As part of the initial merit review, all applications will:

• Undergo a selection process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed and assigned a priority score.
• Receive a written critique.
• Receive a second level of review by the National Advisory Council for Human Genome Research

The goals of NIH supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that an application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward.

Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge or clinical practice be advanced? What will be the effect of these studies on the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Approach: Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics?

• 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 and laboratory information management systems reasonable and appropriate?
• Are the plans for quality assessment and quality control, including biochemical validation and determination of biological relevance reasonable and appropriate?
• Are the plans for release of data and materials, including evidence that the systems are in place to support data release, reasonable and appropriate?

Innovation: Is the project original and innovative? For example: Does the project challenge existing paradigms or clinical practice; address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area?

Investigators: Are the investigators appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers? Does the investigative team bring complementary and integrated expertise to the project (if applicable)?

• Are the track records of the Principal Investigator and other key personnel in producing and disseminating high-throughput data adequate to successfully conduct the proposed research?

Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support?

2.A. Additional Review Criteria:

In addition to the above criteria, the following items will continue to be considered in the determination of scientific merit and the priority score:

Protection of Human Subjects from Research Risk: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed (see the Research Plan, Section E on Human Subjects in the PHS Form 398).

Inclusion of Women, Minorities and Children in Research: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated (see the Research Plan, Section E on Human Subjects in the PHS Form 398).

Care and Use of Vertebrate Animals in Research: If vertebrate animals are to be used in the project, the five items described under Section F of the PHS Form 398 research grant application instructions will be assessed.

Biohazards: If materials or procedures are proposed that are potentially hazardous to research personnel and/or the environment, determine if the proposed protection is adequate.

2.B. Additional Review Considerations

Budget: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. The priority score should not be affected by the evaluation of the budget.

2.C. Sharing Research Data

Data Sharing Plan: The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score. The presence of a data sharing plan will be part of the terms and conditions of the award. The funding organization will be responsible for monitoring the data sharing policy. Reviewers will be asked to consider the data sharing plan in the context of the ENCODE Consortium Data Release Policy, as described in Section IV.6.

2.D. Sharing Research Resources

NIH policy expects that grant recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (See the NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps/part_ii_5.htm#availofrr and http://www.ott.nih.gov/policy/rt_guide_final.html). Investigators responding to this funding opportunity should include a sharing research resources plan addressing how unique research resources will be shared or explain why sharing is not possible.

The reasonableness of the resources sharing plan will be assessed by the reviewers. However, reviewers will not factor the proposed resource sharing plan into the determination of scientific merit or the priority score.

Program staff will be responsible for the administrative review of the plan for sharing research resources. The adequacy of the resources sharing plan will be considered by Program staff of the funding organization when making recommendations about funding applications. Program staff may negotiate modifications of the data and resource sharing plans with the awardee before recommending funding of an application. The final version of the data and resource sharing plans negotiated by both will become a condition of the award of the grant. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590). See Section VI.3. Reporting.

3. Anticipated Announcement and Award Dates

Not Applicable

Section VI. Award Administration Information

1. Award Notices

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.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part4.htm).

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official (designated in item 12 on the Application Face Page). If a grantee is not email enabled, a hard copy of the NoA will be mailed to the business official.

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. See Also Section IV.5. Funding Restrictions.

2. Administrative and National Policy Requirements

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 (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part4.htm) and Part II Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part9.htm).

The following Terms and Conditions will be incorporated into the award statement and will be provided to the Principal Investigator as well as to the appropriate institutional official, at the time of award.

2.A. Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS 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 (U01 and U54), "assistance" mechanisms (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 following terms apply to the Encyclopedia of DNA Elements (ENCODE) Project and the ENCODE Research Consortium as described in RFAs HG-07-030 and HG-07-031.

2.A.1. Principal Investigator Rights and Responsibilities

The Principal Investigator (P.I.) will have the primary responsibility for defining the details for the project within the guidelines of RFA HG-07-030 and for performing the scientific activities. The P.I. will agree to accept close coordination, cooperation, and participation of NIH staff in those aspects of the scientific and technical management of the project as described under "NIH Responsibilities".

The P.I. of an ENCODE Project component will:

• Determine experimental approaches, design protocols, implement data validation and deposition pipelines, set project milestones, and conduct experiments.
• Provide 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).
• Analyze the entire set of the ENCODE target regions (for the U01 mechanism) or the entire human genome (for the U54 mechanism) and not just a subset of these sequences.
• Produce data on the common cell lines and with any common reagents identified for the project before undertaking experiments under other conditions, or explain why doing so is not possible.
• Share results according to the data release policy developed for and by this project.
• Participate in group activities, including attending periodic workshops to discuss the Project's progress and coordinating the publication of research results.
• Serve as a member of the ENCODE Research Consortium Steering Committee.
• Fully disclose all algorithms, software source code, and experimental methods to the other members of the Consortium for purposes of scientific evaluation.
• Not disclose confidential information obtained from other members of the Consortium.
• Adhere to NHGRI policies regarding intellectual property and other policies that might be established during the course of this activity.
• Submit periodic progress reports in a standard format, as agreed upon by the Steering Committee and External Consultant Panel.
• Accept and implement the common guidelines and procedures approved by the Steering Committee, External Consultant 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 HHS, PHS, and NIH policies.

2.A.2. NIH Responsibilities

An NIH Project Scientist will 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. The Project Scientist will assist and facilitate the group process and not direct it.
• Negotiate milestones, e.g., throughput, quality, cost goals, and targets (cell lines, tissues 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 RFA.
• 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 Consultant Panel.
• Serve as a liaison between the Steering Committee and the External Consultant Panel, attending External Consultant Panel meetings in a non-voting liaison member role.
• Serve on subcommittees of the Steering Committee and the External Consultant 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.

An External Consultant Panel will be established by the NHGRI to evaluate the progress of the ENCODE Research Consortium. The External Consultant Panel will provide recommendations to the Director, NHGRI about the progress and scientific direction of all components of the program. The External Consultant 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 Consultant 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 Consultant Panel and the Steering Committees to interact directly with each other. Twice a year the External Consultant 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.

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. The assigned program director may also serve as an NIH Project Scientist.

2.A.3. Collaborative Responsibilities

The Steering Committee will serve as the main coordinating board of the ENCODE Research Consortium established under this RFA. 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 P.I. 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 with 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.

2.A.4. Arbitration Process

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 arbitration. An Arbitration 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 arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

3. Reporting

Awardees will be required to submit periodic (at least every six months) progress reports in a standard format, as agreed upon by the Steering Committee and External Consultant Panel.

Awardees will be required to submit the PHS Non-Competing Grant Progress Report, Form 2590 annually (http://grants.nih.gov/grants/funding/2590/2590.htm) and financial statements as required in the NIH Grants Policy Statement.

Section VII. Agency Contacts

We encourage your inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues:

1. Scientific/Research Contacts:

Elise Feingold, PhD or Peter Good, PhD
Program Directors
Division of Extramural Research
National Human Genome Research Institute
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
Email: [email protected] or [email protected]

2. Peer Review Contacts:

Rudy Pozzatti, PhD
Scientific Review Administrator
Scientific Review Branch
National Human Genome Research Institute
5635 Fishers Lane, Ste. 4076, MSC 9306
Bethesda, MD 20892-9306 (U.S Postal Service Express or regular mail)
Rockville, MD 20852 (for express/courier service; non-USPS service)
Telephone: (301) 402-0838
Email: [email protected]

3. Financial or Grants Management Contacts:

Cheryl Chick
Grants Management Officer
Division of Extramural Research
National Human Genome Research Institute
5635 Fishers Lane, Ste. 4076, MSC 9306
Bethesda, MD 20892-9306 (U.S Postal Service Express or regular mail)
Rockville, MD 20852 (for express/courier service; non-USPS service)
Telephone: (301) 435-7858
Email: [email protected]

Section VIII. Other Information

Required Federal Citations

Use of Animals in Research:
Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf) as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm) as applicable.

Human Subjects Protection:
Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Sharing Research Data:
Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing).

Investigators should seek guidance from their institutions, on issues related to institutional policies and local IRB rules, as well as local, State and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score.

Access to Research Data through the Freedom of Information Act:
The Office of Management and Budget (OMB) Circular A-110 has been revised to provide access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this funding opportunity in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award.

Sharing of Model Organisms:
NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm). At the same time the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with Federal funding pursuant to the Bayh Dole Act (see the NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm). All investigators submitting an NIH application or contract proposal, beginning with the October 1, 2004 receipt date, are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.

Required Education on the Protection of Human Subject Participants:
NIH policy requires education on the protection of human subject participants for all investigators submitting NIH applications for research involving human subjects and individuals designated as key personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

Human Embryonic Stem Cells (hESC):
Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov). It is the responsibility of the applicant to provide in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review.

NIH Public Access Policy:
NIH-funded investigators are requested to submit to the NIH manuscript submission (NIHMS) system (http://www.nihms.nih.gov) at PubMed Central (PMC) an electronic version of the author's final manuscript upon acceptance for publication, resulting from research supported in whole or in part with direct costs from NIH. The author's final manuscript is defined as the final version accepted for journal publication, and includes all modifications from the publishing peer review process.

NIH is requesting that authors submit manuscripts resulting from 1) currently funded NIH research projects or 2) previously supported NIH research projects if they are accepted for publication on or after May 2, 2005. The NIH Public Access Policy applies to all research grant and career development award mechanisms, cooperative agreements, contracts, Institutional and Individual Ruth L. Kirschstein National Research Service Awards, as well as NIH intramural research studies. The Policy applies to peer-reviewed, original research publications that have been supported in whole or in part with direct costs from NIH, but it does not apply to book chapters, editorials, reviews, or conference proceedings. Publications resulting from non-NIH-supported research projects should not be submitted.

For more information about the Policy or the submission process please visit the NIH Public Access Policy Web site at http://publicaccess.nih.gov/ and view the Policy or other Resources and Tools including the Authors' Manual (http://publicaccess.nih.gov/publicaccess_Manual.htm).

Standards for Privacy of Individually Identifiable Health Information:
The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule", on August 14, 2002 . The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. For publications listed in the appendix and/or Progress report, internet addresses (URLs) must be used for publicly accessible on-line journal articles. Unless otherwise specified in this solicitation, Internet addresses (URLs) should not be used to provide any other information necessary for the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site.

Healthy People 2010:
The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This PA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

Authority and Regulations:
This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. 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 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

Loan Repayment Programs:
NIH encourages applications for educational loan repayment from qualified health professionals who have made a commitment to pursue a research career involving clinical, pediatric, contraception, infertility, and health disparities related areas. The LRP is an important component of NIH's efforts to recruit and retain the next generation of researchers by providing the means for developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is not required for eligibility and concurrent career award and LRP applications are encouraged. The periods of career award and LRP award may overlap providing the LRP recipient with the required commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20 hours per week based on a 40 hour week) for two years to the research. For further information, please see: http://www.lrp.nih.gov.

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