Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Human Genome Research Institute (NHGRI)
Funding Opportunity Title	Genomics of Gene Regulation (U01)
Activity Code	U01 Research Project Cooperative Agreements
Announcement Type	New
Related Notices	August 21, 2013: Removed reference to ASSIST in section IV.3, since ASSIST is currently only available for multi-project applications.
Funding Opportunity Announcement (FOA) Number	RFA-HG-13-012
Companion Funding Opportunity	None
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.172
Funding Opportunity Purpose	This Funding Opportunity Announcement (FOA) solicits applications to start a new initiative, the Genomics of Gene Regulation (GGR), which is intended to explore genomic approaches to understanding the role of genomic sequence in the regulation of gene networks. A long-term goal of functional genomics is to decipher the rules by which gene networks are regulated and to understand how such regulation affects cellular function, development and disease. The GGR initiative will address the genome-proximal component of the regulation of gene networks by supporting a set of demonstration projects to develop and validate models that describe how a comprehensive set of sequence-based functional elements work in concert to regulate the finite set of genes that determine a biological phenomenon, using RNA amounts, and perhaps transcript structure, as the readout. This FOA seeks to support substantial improvement in the methods for developing gene regulatory network models, rather than an incremental improvement on existing methods. This work will move the field closer to the long-term goal of reading DNA sequence and accurately predicting when and at what levels a gene is expressed, in the context of a particular cell state. These demonstration projects will be organized as a research consortium to accelerate progress through the coordination of analytical methods and functional genomic data.

Posted Date	August 6, 2013
Open Date (Earliest Submission Date)	October 15, 2013
Letter of Intent Due Date(s)	October 15, 2013
Application Due Date(s)	November 15, 2013, by 5:00 PM local time of applicant organization. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
AIDS Application Due Date(s)	Not Applicable
Scientific Merit Review	March 2014
Advisory Council Review	May 2014
Earliest Start Date	July 2014
Expiration Date	November 16, 2013
Due Dates for E.O. 12372	Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 1. Overview Information
Part 2. Full Text of the Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

This Funding Opportunity Announcement (FOA) solicits applications to start a new initiative, the Genomics of Gene Regulation (GGR), which is intended to explore genomic approaches to understanding the role of genomic sequence in the regulation of gene networks. A long-term goal of functional genomics is to decipher the rules by which gene networks are regulated, and to understand how such regulation affects cellular function, development and disease. The GGR initiative will address the genome-proximal component of the regulation of gene networks by supporting a set of demonstration projects to develop and validate models that describe how a comprehensive set of sequence-based functional elements work in concert to regulate the finite set of genes that determine a biological phenomenon, using RNA amounts, and perhaps transcript structure, as the readout. This FOA seeks to support substantial improvement in the methods for developing gene regulatory network models, rather than an incremental improvement on existing methods. This work will move the field closer to the long-term goal of reading DNA sequence and accurately predicting when and at what levels a gene is expressed, in the context of a particular cell state. These demonstration projects will be organized as a research consortium to accelerate progress through the coordination of analytical methods and functional genomic data.

One of the great challenges in the past fifty years of biomedical research has been to understand how the information in the genome sequence is used by the cell to regulate gene expression, and how regulated gene expression systems determine cellular function, development, response to environmental factors, and disease. Over this time, literally thousands of studies of gene regulation, mostly focused on one or a few genes, have been conducted, and a great deal has been learned about the mechanisms of transcriptional regulation. This literature includes the description of a very limited number of systems, such as the regulation of -globin gene expression, that have been studied in great depth, resulting in the discovery of new biological principles. More recently, the development of technologies that allow high-throughput analysis at a genomic level has led to previously unimaginable experimental opportunities and new information resources, such as complete genome sequences and deep catalogs of sequence-based functional elements, which can now be applied to obtaining a fuller understanding of gene regulation.

An organized genomic approach to the challenge of understanding global gene regulation began after the completion of the sequencing of the human genome and the genomes of important model organisms when the NHGRI initiated two projects to identify all of the sequence-based functional elements in the human genome (the Encyclopedia of DNA Elements (ENCODE) Project), and in the genomes of Caenorhabditis elegans and Drosophila melanogaster (the modENCODE Project), respectively. More recently, the ENCODE Project was expanded to include analysis of the mouse genome. Since their inception, these projects have generated very large datasets from which a great deal of functional information has been extracted. Integrating the disparate data types within each cell type, as well as integrating data across cell types, has greatly amplified the amount of useful information that has been obtained from these datasets (See: Science 330:1775-1787, 2010; Science 330:1787-1797, 2010; PLoS Biol 9:e1001046, 2011; Nature 489-57,2012). However, investigation of how these functional elements interact with one another and are interpreted by cells to program gene expression is beyond the scope of the ENCODE projects.

To consider the value of genomic approaches in understanding gene regulation networks and, ultimately, the issue of inferring gene activity from primary sequence, the NHGRI convened a workshop entitled Genomics of Gene Regulation in October 2009. To be able to examine genomic sequence and predict which genes are expressed, and at what level they are expressed, in a given cellular state, we must be able to decipher the language of gene regulation or the grammatical rules that govern regulation. The discussions at the workshop focused on whether the goal of obtaining a complete understanding of the rules could be achieved; specifically, what more would we need to learn in order to achieve that goal, and what can genomic approaches contribute. The workshop participants discussed these issues from three viewpoints: the function of primary regulatory DNA sequences, natural and experimental variation of gene regulation, and gene regulatory networks. The workshop recommendations highlighted: 1) the need for comprehensive mechanistic analysis of a representative set of cis-regulatory elements; 2) the need for more detailed information about the structure and dynamics of chromatin in relation to the regulation of gene expression; 3) the need for additional validated examples of well-characterized gene regulatory networks; and 4) the need to connect gene network analysis to phenotype.

The last recommendation has particular relevance to understanding human disease. More than 90% of all genetic variants associated with human disease, as identified in genome-wide association studies (GWAS), reside outside of protein coding sequences, and are likely in regulatory sequences. Analysis of GWAS variants found in DNase hypersensitive sites revealed that about two-thirds of these GWAS variants appear to be at least 100 kb away from the target promoter to which they are linked (See: Science 337-1190,2012). A full understanding of how a gene's expression is controlled by its cognate regulatory elements would empower us with a much better understanding of how variation in non-coding functional elements can result in abnormal gene regulation as a cause of disease; it would also enable a much deeper understanding of basic biology, including the regulatory networks that control cellular functions and animal development.

This FOA solicits applications for research projects to initiate a new program, the Genomics of Gene Regulation (GGR). GGR will explore the use of genomic approaches to understanding the role of genomic sequence in the control of gene networks, the rules by which gene networks are regulated, and the use of these rules to predict the gene expression programs in cells of a given state.

To begin to address this challenge, this FOA will support a set of demonstration projects that explore the development of useful models for understanding how sets of functional elements work in concert to generate a gene expression profile. These demonstration projects will build gene regulatory network models that attempt to explain the changes in gene expression as cells transition from one physiological state to another. While many cellular processes would be expected to contribute to such a transition, the demonstration projects, being focused on the role of the genome, will use transcription as the primary genomic output, and regulatory events occurring on the DNA and RNA (genome-proximal events), such as transcription factor binding, changes in chromatin structure, RNA polymerase binding, physical interactions of RNA with protein and/or RNA, and physical interactions between DNA elements, as inputs to these models. Genome-wide data on functional elements, transcript amounts, and possibly transcript structure, will be combined in an unbiased manner in these networks. Given the small number of cell states that will be characterized, it is envisioned that these networks will only have power to explain the regulation of a subset of the genes during the cell state change, not all genes.

If successful, this approach should generate critical information about how genomic control elements interact and function to regulate the sets of genes involved in important cellular functions. This knowledgebase should provide a sufficient understanding of the general principles of gene network behavior to eventually enable prediction, from the genome sequence alone, of the expression patterns of genes in a given cell. Understanding genetic regulatory systems would be a highly significant advance that would facilitate interpretation of the phenotypic consequences (e.g., disease) of genetic variation that lies outside of protein-coding sequences.

The demonstration projects will be organized as a research network to take advantage of coordination of analytic strategies and methods and comparison of functional genomic data and to make more rapid progress.

This FOA will support demonstration projects to explore the development of testable models that predict how sets of functional genomic elements work together to regulate the expression of gene networks. Each project should select a well-established metazoan experimental model system that features at least one change in cell state that occurs in response to a defined stimulus (for example, an environmental stimulus or a change in cell fate during development). In this context, a cell state refers to a stable or metastable physiological condition of a cell, which may be characterized with respect to development, cell cycle, and cell activation at a particular point in time. A gene regulation network model that explains how gene expression and functional element usage change as the cell transitions from one state to the other should then be constructed. In this context, gene refers to protein-coding genes that initially produce mRNA, as well as genes for which the final product is RNA, such as miRNA, lncRNA, snRNA, and piRNA. These projects will require substantial generation of new data. Hypotheses derived from the model can be experimentally tested by measuring the biological effects of disruptions of identified cis- and trans-acting key regulators that are predicted by the model to be involved in regulation of the activity of the network. In all likelihood, analysis of the outcomes of the initial experiments would be used in an iterative process of modeling, prediction, and experimentation to refine the initial model. If successful, this approach should lead to a detailed understanding of the network under study.

The GGR demonstration projects will be organized into a collaborative research network (the GGR Network, GGRN) to promote the development and use of analytical methods that may be generally applicable, to share knowledge and insights about developing a genomic approach to understanding the regulation of gene networks, and to coordinate the use of functional genomics data, where feasible. Working together should accelerate the determination of whether it is feasible to decipher the general rules that determine gene regulation, the development of broadly applicable methods, and the identification of the data types with the highest utility for these kinds of studies. If successful, this approach may be adapted by other scientists, to study other important regulatory pathways and to use these new insights to understand the phenotypes of cells and organisms.

NHGRI anticipates that each of these genomic investigations of regulatory networks will have similar experimental strategies that involve several sequential components, as described below. However, this is presented as an example and other strategic approaches are welcomed.

First, the comprehensive set of functionally active sequence-based elements that comprises the chosen regulatory network will be determined in each of the relevant cell states. These elements may include, but are not limited to, RNA transcripts (gene expression profiles), histone modifications, DNase hypersensitive sites, transcription factor binding sites, and sites of DNA methylation. Thus, substantial collection of functional genomics data is likely to be part of each GGR application. Data generation methods should be state-of-the-art, high throughput, cost effective, and capable of generating high quality data. Applicants are encouraged to use all relevant existing data, including public resources such as ENCODE, modENCODE, GTEx, LINCS, TCGA, published data, or data obtained by the applicants in prior studies, in addition to generating new data. However, because the GGR initiative is focused on the subset of regulatory events that are genome-proximal and understanding the role of genome sequence in gene regulation, the generation of proteomic and metabolomic data is beyond the scope of this FOA.

Second, one or more gene regulatory network models will be developed that account for the changes in gene expression that occur during the transition from one cell state to another, utilizing the data and knowledge of the biology of the system in combination. A key feature of such gene regulatory network models is that testable hypotheses can be derived about the dynamics of the gene regulatory networks in the cell states, that is, how the stimulus affects the usage of the functional elements involved, resulting in the observed alterations in gene expression.

Third, experimental testing of hypotheses derived from the proposed model(s) will be performed. These experiments may involve the disruption (e.g., mutation, deletion or knock-down) of individual components of the regulatory circuit(s) in one state and determination of the effect on the transition of the cell to the second state. Factors should be chosen for disruption if they are likely to provide clearly interpretable results; they should be genome-proximal, and they could be trans-acting factors and/or cis-regulatory regions. The goal of these experiments is to test the hypotheses generated by the gene regulatory model. Substantial collection of data will likely be required for testing the hypotheses derived from the model(s) and should be obtained using high throughput, cost effective methods that result in high quality data.

Fourth, the regulatory model will be iteratively refined based on the additional information provided by each round of experimental testing. Rigorous assessment of the quality of the model requires quantifying the specificity and sensitivity of the model’s predictions of the system's response to changes in cell state.

It is anticipated that this process will provide a detailed understanding of the gene regulatory network under study in each GGR project. By investigating several gene regulatory networks this way, and organizing the projects in a collaborative research network, it is hoped that the GGR program will lead to an improved ability to decipher the grammar, or rules, that determine gene regulation, to determine if there are rules that are generalizable, and to establish the methodology to expand this approach to other regulatory pathways.

The choice of model systems for these proposed experiments will be a critical aspect of the applications, and must be strongly justified. In order to maximize the insight gained from these studies they must be performed in appropriate model systems, preferably ones that have been well studied and for which there is substantial existing knowledge. The genome sequence of the organism must be of sufficiently high quality to support genomic studies, and suitable reagents must be available, such as antibodies for chromatin proteins and transcription factors. It must be possible to obtain a sufficiently large number of cells of relatively pure cell populations to undertake the proposed genomic experiments, and it must be possible to efficiently disrupt the system to test the predictions about gene regulation. Some examples include the induction of fate-specific gene expression programs, differentiation of lymphoid, myeloid, neuronal, erythroid and adipose cells, and nuclear hormone receptor response to small molecules such as ecdysone. However, these are just examples for the purpose of illustration; applicants may propose any model system that meets the criteria described above and should describe the strengths of the model system employed, including the prior biological knowledge, existing resources, and experimental utility. This FOA is limited to the study of metazoan systems; prokaryotic, viral, single-cell eukaryote and plant systems will not be considered responsive to this FOA. The relevance to human health and disease, if any, should be discussed, although this is not a requirement of the program.

Funding Instrument	Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities.
Application Types Allowed	New The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	NHGRI intends to commit $10 million in total costs in FY 2014 and to make 5-8 awards, depending on the availability of funds and the receipt of a sufficient number of meritorious applications.
Award Budget	Application budgets are not limited, but need to reflect the actual needs of the proposed project.
Award Project Period	The total project period for an application submitted in response to this FOA may not exceed three years.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Institutions)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
• NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account and should work with their organizational officials to either create a new account or to affiliate an existing account with the applicant organization’s eRA Commons account. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

NIH will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (as described in the NIH Grants Policy Statement), except for submission:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

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

The letter of intent should be sent to:

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

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

All page limitations described in the SF424 Application Guide and must be followed, with the following exceptions or additional requirement:

• For this specific FOA, the Research Strategy section is limited to 30 pages.

The forms package associated with this FOA includes all applicable components, required and optional. Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate optional components.

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

The PD/PI and other members of the research team will be expected to participate in grantee meetings, held approximately annually, at grantee sites or near the NIH. Funds for travel of up to five people per grantee meeting should be included in the budget request. Grantees will be expected to host these meetings on a rotating basis, as determined by NIH staff. One of the grantees may be asked by NIH staff to serve as a coordinating center for conference calls and the annual meetings.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Research Strategy:

Applicants should propose to develop one or more gene regulatory network models that incorporate comprehensive gene expression data and genome-wide functional element analysis data (e.g., transcription factor binding sites, histone modifications and/or chromatin structure); the network model(s) could incorporate, but is (are) not limited to, statistical network modeling and/or mechanistic network modeling. The model derived from the experimental data must be capable of making experimentally testable, specific, biological predictions about cis- and/or trans-acting factors. The methods to develop the gene regulatory network model should constitute a substantial advance that will significantly improve on characterizing gene regulatory networks, rather than an incremental improvement on existing methods. Applications proposing to analyze the regulation of individual genes, and applications proposing to analyze only gene expression data and DNA sequence motifs, will not be considered responsive to this FOA.

Applicants should propose to collect comprehensive gene expression data and genome-wide functional element experimental data, perform computational modeling, and integrate the two approaches. Applications proposing only computational work or only experimental work will not be considered responsive to this FOA.

Applicants should propose to measure genome-proximal events, such as transcription factor binding and chromatin structure. Applicants might abstract the details of more distal events (such as the events regulating translocation of transcription factors from the cytoplasm to the nucleus) to simple on and off states. Applications focusing on membrane-proximal signaling events, such as transmembrane receptor activation, kinase cascades, and adaptor molecules will not be considered responsive to this FOA.

Applicants should justify the choice of experimental disruptions, including why they will be informative with respect to testing the proposed model(s) for the gene regulatory network, and how they will be used to test hypotheses generated by the gene regulatory network model(s).

Applicants should describe the expertise of the research team to conduct all components of the research project (for example, collection of the relevant data, analysis of gene regulatory networks, and knowledge of the particular biological system).

Applicants should describe the timeline for all major steps in the project, including initial assessment of at least two cell states, modeling the change(s) between cell states, and cycle(s) of testing the gene regulatory model(s).

Applicants should describe their approach to comprehensiveness. Datasets generated by these projects must be as comprehensive as necessary to allow understanding of the regulation of as many genes as possible in the cells being studied, rather than being focused on understanding the regulation of one or a few genes. However, it is likely that regulation of only a small number of genes will be explained by the specific gene regulatory network under study, given the small number of cell states examined.

Applicants should describe their approach to Data Quality. The approaches to data quality should be based on those that have been employed successfully in the ENCODE Projects (see: http://www.encodeproject.org/ENCODE/dataStandards.html). These standards are based on experimental reproducibility and evidence that the experimental platform(s) detect authentic biochemical events, and they are continually updated. Applicants should describe plans to follow these or develop more stringent standards, and to develop standards for any technologies that current lack useful standards.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R) Application Guide, with the following modifications:

Data release and resource sharing: The NHGRI is committed to the principle of rapid data, experimental protocol, model, and software release to the scientific community. GGR applicants are expected to provide a plan to release to the research community data, experimental protocols, models, and software in a timely fashion through an informatics platform. In addition, GGR awardees may also be asked to share data with the ENCODE Data Coordination and Analysis Center (EDCAC). GGR applicants may propose to utilize existing datasets that are not publicly shared at the start of the project as long as they describe their plan for sharing these datasets during the course of the project. The development of policies, methods, and standards for such sharing are critically important for GGR. The NHGRI expects that the GGR awardees, through the GGR Network Steering Committee of which they will be members, will develop such policies, methods, and standards in conjunction with NHGRI Staff. These policies, methods, and standards will need to remain consistent with NIH-wide policies on data and resource sharing.

In their grant applications, all applicants should provide specific plans for data, experimental protocol, model, and software release. Key elements that should be considered when developing such data sharing plans are detailed at: http://grants.nih.gov/grants/sharing_key_elements_data_sharing_plan.pdf.

Data Management: The applicants should describe their plan for broadly sharing the data collected in this project in public repositories. In addition, some of the data generated may be relevant to the ongoing ENCODE Project; thus, the GGR projects may also be asked to submit their data to the ENCODE Data Analysis and Coordination Center (EDCAC; see: RFA-HG-11-026).

Software: The proposed research project will likely include the development of software needed for the generation and analysis of gene regulatory networks. In that case, the application should include plans for the development and distribution of software and associated documentation that would allow others to use that software. For the same reason, software developed by awardees should be modular and robust, so that it can work as a stand-alone package. To facilitate sharing among the GGR projects, software development should, to the extent possible, use standard formats for data input and output. Such standard formats will preferably be ones that already are in use by the ENCODE Consortium (See: http://encodeproject.org/FAQ/FAQformat.html#ENCODE).

Consortium membership: Awardees funded in response to this FOA will be organized as the GGR Network (GGRN). All members of the GGRN will be expected to share information about experimental results, analysis activities and validated models with the other participants in the GGRN, with the goal of facilitating the development of a description of the grammar of gene regulation.The reviewers will provide their assessment of the proposed data and model sharing and software release plans; they will not factor it into the determination of scientific merit or the impact score.

After completion of the initial review, NHGRI program staff will be responsible for any additional administrative review of the data and model sharing and software release plans. The adequacy of these plans will be considered by NHGRI program staff when making recommendations about the funding of applications. The accepted data, experimental protocol, and model sharing and software release plans will become a condition of the award of the cooperative agreement. The applicant’s progress in implementing the data and model sharing and software release plan will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590). See Section VI.3. Reporting.

The applications are expected to include written statements from the officials responsible for intellectual property issues at all of the institutions (including subcontractors) participating in the proposed GGR project to the effect that the institution supports and agrees to abide by the software dissemination plans put forth in the application. Such letters will be considered to be clear expressions of commitment. A separate letter should be sent by each participating organization, including each subcontractor. Please note that institutional sign-off on the grant application signifies that all relevant components of the institution, including the technology transfer office, have reviewed and approved the document. The filing of patent applications and/or the enforcement of resultant patents in a manner that might restrict use of the method(s) could substantially diminish the utilization of it (them) to many disease areas and the potential public benefit they could provide. The goal of establishing a software sharing plan is to ensure the greatest possible public benefit from the development of this GGR application.

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission.

Organizations must submit applications to Grants.gov, the online portal to find and apply for grants across all Federal agencies. Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date. If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

This initiative is not subject to intergovernmental review.

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically.

Important reminders:
All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

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

In order to expedite review, applicants are requested to notify the NHGRI Referral Office by email at [email protected] when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030, with the following modification:

• Applicants may submit late-breaking research findings (maximum of 2 printed pages) 30 days before the review.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance

Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? Are the plans sufficiently bold to constitute a substantial advance, if they can be achieved? Do the computational methods propose new approaches that will significantly improve the ability to characterize gene regulatory networks, or does the computational work merely represent incremental improvements on existing methods?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project? Does the research team have the expertise to conduct all components of the research project, including data collection, analysis of gene regulatory networks, and knowledge of the particular biological system under study? Do the investigators have an appropriate plan to integrate the components of the project?

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed? Will the methods used to develop the gene regulatory network model(s) constitute a substantial improvement over existing methods, rather than an incremental improvement on existing methods?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Is the choice of model system well justified? Will the data generated be state-of-the-art, high throughput, cost effective, comprehensive, and of high quality? Are the choices for experimental disruptions logical and well justified? Is the use of the disruptions to test hypotheses generated by the gene regulatory network model(s) well-reasoned?

If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?

Environment

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Protections for Human Subjects

For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Children

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

Vertebrate Animals

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

Biohazards

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Applications from Foreign Organizations

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

Select Agent Research

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genome Wide Association Studies (GWAS).

Budget and Period of Support

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the NHGRI, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

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

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Council for Human Genome Research. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.
• Adequacy of the proposed data and resource sharing plans
• Synergy with other funded projects.
• Programmatic balance.
• Responsiveness to FOA.

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to the DUNS, SAM Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

The PD(s)/PI(s) will have the primary responsibility for:

• Defining the details for the project within the guidelines of this FOA and for performing the scientific activities.
• Ensuring that the appropriate analyses are developed, evaluated, and chosen for implementation.
• Sharing project activities within the collaborative research network (the GGR Network, GGRN).
• Fully disclosing algorithms, software source code, and experimental methods to the other members of the GGR Network for the purpose of scientific evaluation.
• Sharing results according to the data release and software release policy developed for and by this project.
• Openly and effectively participating in group activities, including attending periodic workshops to discuss the GGR Network’s progress, developing project policies such as data release, and coordinating publication of research results, as required.
• Serving as a member of the GGR Network Steering Committee.
• Not disclosing confidential information obtained from other members of the GGR Network.
• Adhering to NHGRI policies regarding intellectual property, data sharing, data release, and other policies that might be established during the course of this activity.
• Accepting and implementing the common guidelines and procedures approved by the Steering Committee and NHGRI.

Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

An NIH Project Scientist is a scientist of the NHGRI extramural staff who will have substantial scientific and programmatic involvement that is above and beyond the normal stewardship role in awards, including providing technical assistance, advice, and coordination for the GGR 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 GGR Network 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:

• Provide technical assistance, advice and coordination for the GGR Project and its component parts. However, the role of NIH staff will be to facilitate and not to direct the activities.
• Coordinate the activities of the Steering Committee 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.
• 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 GGR Network, including any other groups who may participate in the GGR Network but are not funded through this FOA.
• Attend all Steering Committee meetings as a voting member and assist in developing operating guidelines including quality control procedures, the data release policy, 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 GGR Project to the Director, NHGRI.
• Provide relevant expertise and overall knowledge of NIH-sponsored research to facilitate the selection of scientists not affiliated with the awardee institutions to serve on the External Consultants Panel.
• Serve as a liaison between the Steering Committee and the External Consultants Panel, attending External Consultants Panel meetings in a non-voting liaison member role.
• Serve on subcommittees of the Steering Committee and the External Consultants Panel, as appropriate.
• Assist awardees in the development, if needed, of policies for dealing with situations that require coordinated action.
• Provide advice in the management and technical performance of the investigation.
• Participate in data analyses, interpretations, and, where warranted, co-authorship of the publication of results of studies conducted through the GGR Research Network.

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 Official may also serve as an NHGRI Project Scientist.

An External Consultants Panel will be established by the NHGRI to evaluate the progress of the GGR Network. The External Consultants Panel will provide recommendations to the Director, NHGRI about the progress and scientific direction of all components of the program. The External Consultants Panel will be composed of four to eight senior scientists with relevant expertise, although the membership may be enlarged permanently or on an ad hoc basis as needed.

The External Consultants Panel will meet at least once a year; some meetings may be conducted by telephone conference. At least once a year, there will be a joint meeting with the Steering Committee to allow the members of the both the External Consultants Panel and the Steering Committees to interact directly with each other. Twice a year the External Consultants Panel will make recommendations regarding progress of the GGR Network and present advice to the Director of NHGRI about changes, if any, that may be necessary in the ENCODE Research Consortium program.

Areas of Joint Responsibility include:

The Steering Committee will serve as the main coordinating board of the GGR Network established under this FOA. 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 GGR Network. To address particular issues, the Steering Committee may establish working groups as needed, which will include representatives from the GGR Network and the NHGRI and possibly other experts. Such groups might include ones to: 1) address data management issues; 2) analyze Project data; 3) develop quality standards and methods to assess data quality; and 4) 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.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

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

A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Commons Help Desk (Questions regarding eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Web ticketing system: https://public.era.nih.gov/commonshelp
TTY: 301-451-5939
Email: [email protected]

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726

Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: [email protected]

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

Mike Pazin, Ph.D.
National Human Genome Research Institute (NHGRI)
Telephone: 301-496-7531
Fax: 301-480-2770
Email: [email protected]

Ken Nakamura, Ph.D.
National Human Genome Research Institute (NHGRI)
Telephone: 301-402-0838
Fax: 301-435-1580
Email: [email protected]

Dave Ruane
National Human Genome Research Institute (NHGRI)
Telephone: 301-451-7928
Fax: 301-451-5434
Email: [email protected]

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.