Part I Overview Information

Department of Health and Human Services

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

Components of Participating Organizations
This Funding Opportunity Announcement (FOA) is developed as a Common Fund initiative (http://commonfund.nih.gov/) through the NIH Office of the NIH Director, Office of Strategic Coordination (http://dpcpsi.nih.gov/osc/). This FOA will be administered by the
National Human Genome Research Institute (NHGRI, http://www.genome.gov/)on behalf of the NIH (http:www.nih.gov). Other participating Institutes include:
National Center for Research Resources (NCRR), (http://www.ncrr.nih.gov)
National Eye Institute (NEI), (http://www.nei.nih.gov)
National Heart, Lung, and Blood Institute (NHLBI), (http://www.nhlbi.nih.gov/)
National Institute on Aging (NIA), (http://www.nia.nih.gov)
National Institute on Alcohol Abuse and Alcoholism (NIAAA), (http://www.niaaa.nih.gov)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), (http://www.niams.nih.gov)
National Institute of Child Health and Human Development (NICHD), (http://www.nichd.nih.gov)
National Institute on Drug Abuse (NIDA), (http://www.nida.nih.gov)
National Institute of Deafness and Other Communication Disorders (NIDCD), (http://www.nidcd.nih.gov)
National Institute of Dental and Craniofacial Research (NIDCR), (http://www.nidcr.nih.gov)
National Institute of Environmental Health Sciences (NIEHS), (http://www.niehs.nih.gov)
National Institute of General Medical Sciences (http://www.nigms.nih.gov)
National Institute of Mental Health (NIMH), (http://www.nimh.nih.gov)
National Institute of Neurological Disorder and Stroke (NINDS), (http://www.ninds.nih.gov)

Title: Knockout Mouse Phenotyping (U54)

Announcement Type

New

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

• October 7, 2015 - This RFA has been reissued as RFA-RM-15-017.
• September 29, 2010 - See Notice NOT-RM-10-015 Notice of Pre-application Meeting and Correction.

Request For Applications (RFA) Number: RFA-RM-10-011

Catalog of Federal Domestic Assistance Number(s)
93.310, 93.172, 93.396, 93.389, 93.867, 93.837, 93.838, 93.839, 93.233, 93.866, 93.273, 93.846, 93.865, 93.859, 93.279, 93.173, 93.121, 93.114, 93.242, 93.853

Key Dates
Release Date: September 10, 2010
Letters of Intent Receipt Date(s): September 15, 2010
Application Receipt Dates(s): November 10, 2010
Peer Review Date(s): February, 2011
Council Review Date(s): May, 2011
Earliest Anticipated Start Date: July, 2011
Additional Information To Be Available Date (Url Activation Date): N/A
Expiration Date: November 11, 2010

Due Dates for E.O. 12372

Not Applicable

Additional Overview Content

Executive Summary

• Purpose. This FOA issued by the Office of Strategic Coordination, Office of the Director, National Institutes of Health, solicits grant applications from institutions/ organizations that propose to perform broad phenotyping of the International Knockout Mouse Consortium’s (IKMC) mutant mice. The overall objective of this FOA is to produce functional information for each protein-coding gene in the mammalian genome.
• Mechanism of Support. This FOA will utilize the U54 award mechanism and runs in parallel with two additional FOAs that solicit applications under the U54 and U42 award mechanisms (RFA-RM-10-012, RFA-RM-10-013).
• Funds Available and Anticipated Number of Awards. Up to $7.4 million in total costs per year for periods up to 5 years years may be requested. It is anticipated that 2-4 awards will be made contingent upon receiving scientifically meritorious proposals.
• Budget and Project Period. The total project period for an application submitted in response to this funding opportunity may not exceed five years. Total costs are limited to $7,400,000 per year for a five-year period.
• Application Research Strategy Length: The U54 Research Strategy section may not exceed 30 pages, including tables, graphs, figures, diagrams, and charts. .
• Eligible Institutions/Organizations. Institutions/organizations listed in Section III, 1.A. are eligible to apply. Non-domestic (non-U.S.) entities (Foreign Organizations) are not eligible to serve as primary applicants for this FOA. However, foreign components may submit a research project or subcontract within a domestic application, under this FOA.
• Eligible Project Directors/Principal Investigators (PDs/PIs). Individuals with the skills, knowledge, and resources necessary to carry out the proposed research are invited to work with their institution/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.
• Number of PDs/PIs. More than one PD/PI (i.e., multiple PDs/PIs), may be designated on the application.
• Number of Applications. Applicants may submit more than one application, provided they are scientifically distinct.
• Resubmissions. Resubmission applications are not permitted in response to this FOA.
• Renewals. Renewal applications are not permitted in response to this FOA.
• Special Date(s). This FOA uses non-standard due dates. See Receipt, Review and Anticipated Start Dates
• Application Materials. See Section IV.1 for application materials.
  Hearing Impaired. Telecommunications for the hearing impaired are 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, Review and Anticipated Start Dates
1. Letter of Intent
B. Sending an Application to the NIH
C. Application Processing
D. Application Assignment
4. Intergovernmental Review
5. Funding Restrictions
6. Other Submission Requirements

Section V. Application Review Information
1. Criteria
2. Review and Selection Process
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. Dispute Resolution 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

The purpose of this FOA is to solicit applications for research projects to make maximum progress toward the goal to producea null-mutant mouse phenotype resource for each gene in mouse strain C57BL/6, for the purpose of elucidating functional information for each protein coding gene in the mammalian genome. The goal of this FOA is to support high-throughput broad based phenotyping of 125 to 500 mouse knock-out (KO) lines per year, depending on the number of centers, with an overall goal of 500 lines per year for the KOMP² program. The mouse is the ideal mammalian system in which to produce a functional genomics resource because of the long history and depth of understanding of mouse genetics, the sophistication of ES cell technology in the mouse system, short generation times, and the low cost of working with mice in comparison to other mammals.

BACKGROUND: The mouse has long been an important mammalian model system for the study of gene function in human health and disease. Mouse mutants with phenotypes that mimic human traits have served as critical research tools in understanding the genetics underlying mammalian biology. Equally important, mouse mutants have been the tools used to begin to understand gene function and pathways as the field has moved from gene identification to mammalian functional genomics. Because of its importance to human biology, mapping and sequencing the genome of mouse strain C57BL/6 was carried out as part of the Human Genome Project. Another major genomic resource for mouse research was developed by the Mammalian Gene Collection (MGC) project (http://mgc.nci.nih.gov/), which as of December 2009 included 27,285 full-ORF (open reading frame) cDNA clones representing 17,701 individual mouse genes.

To complement the mouse genome sequence and full-length cDNA collection, a defined genetic resource that can be used to elucidate gene function is needed. To this end, a proposal was made during a meeting held in the fall of 2003 to establish a focused, large-scale international effort to produce a publicly available, comprehensive collection of mouse knockout mutants, i.e. a library containing a null mutation in every gene in the mouse genome (Austin, C.P., et al. Nature 36, 921-924 (2004)). The meeting attendees recommended that the plan under this proposal be accomplished in a phased production approach, beginning with the construction of a resource of ES cells comprising a comprehensive collection of null and conditional alleles. This would be followed by the construction of mice from the ES cells and then phenotyping the mice with an increasingly sophisticated set of tests. Tier 1, or basic phenotyping, would be done on nearly all of the mice created by the project. Tier 2, microarray and transcriptome based phenotyping, would be carried out on a subset of these mice. Subsequent specialized phenotyping and further in depth analyses on specific mice would then be pursued as part of individual research programs.

There followed a number of international efforts that further defined the proposed knockout mouse resource. Following a March 2005 workshop which endorsed the concept (http://www.genome.gov/15014549), the NIH launched the Knockout Mouse Program (KOMP) to generate knockout (null) mutations in 8,500 genes in C57BL/6 knockout mice lines by deleting all or most of the exons in target genes [Valenzuela, D.M., et al., Nature Biotechnology 6, 652-659 (2003)] or knockout-first conditional ready alleles [Testa, G., et al., Genesis 38, 151-158 (2004)]. As of the end of April 2010, KOMP had produced knockouts of about 5,500 genes and is on target to complete the goal of producing 8,500 knockout mutant ES cell lines by the end of 2011. In parallel, the European Conditional Mouse Mutagenesis Program (EuCOMM) and the North American Conditional Mouse Mutagenesis Program (NorCOMM) are on track to complete their goals of producing an additional 9,000 knockout mice by the end of 2011. The three programs will thus produce a comprehensive resource of mutant mouse ES cell lines. They have coordinated their efforts through the formation of the International Knockout Mouse Consortium (IKMC).

As part of KOMP, the NIH established a repository to archive, maintain, and distribute high quality ES cell clones, as well as live mouse lines, frozen embryos and sperm, and vectors (www.komp.org). As part of its quality control procedures, KOMP is generating live mice from a fraction of the ES cells as they are generated. The original goal was 500 and current efforts are exceeding that goal. To date, 413 lines of mice have been generated and, at current production rates, about 850 strains will be produced by the end of 2011.

Thus, the first phase of the proposed resource is on schedule to be completed by the Fall of 2011, and attention has now turned toward implementation of the second phase. Over the past year, there have been a number of discussions, and planning for a potential mouse phenotyping effort has begun. The NIH held a KOMP Phenotyping Conference in Bethesda, MD in October 2009, at which a group of researchers representing diverse scientific backgrounds expressed their unanimous enthusiasm and support for a proposed effort to conduct high-throughput and comprehensive phenotyping of the resource being produced by the members of the IKMC (meeting report available at www://www.komp.org). The meeting attendees were supportive of a proposed strategy to first convert ES cells into mice at one or more high-throughput facilities that can also efficiently conduct highly informative preliminary analyses (e.g., LacZ expression, stage of embryonic lethality, fecundity), followed by performance of a defined set of standard broad-based phenotype tests at KOMP phenotyping facilities. The phenotyping data would be rapidly and freely released to the public as they are generated, with the mice being archived for distribution to the research community. The meeting participants stressed that any U.S. phenotyping effort must be coordinated with comparable efforts elsewhere (similar discussions and plans are being made in Europe, Canada, and Asia). The standard phenotyping tests, analyses, and examinations that are included in the KOMP resource effort should be chosen primarily on the basis of their reliability, power, and likelihood to reveal disease and human clinical relevance. These recommendations were highly similar to those that have come from other efforts to solicit input from the US national research community.

There have been extensive pilot studies on mouse knockout phenotyping conducted over the past several years, such as the EUMORPHIA program, the current EUMODIC program, and several large-scale phenotyping programs in the commercial setting. The NIH and the Wellcome Trust have purchased mice and datasets from some of these companies. The NIH has deposited 251 lines at the Jackson Laboratories (http://www.informatics.jax.org) and the Mutant Mouse Regional Resource Centers (http://www.mmrrc.org/), whereas the Wellcome Trust resource of 87 lines is maintained by the EMMA repository (http://www.emmanet.org/projects/wt-kmr.php). The information available from all of these programs may help provide insight to applicants.

The first large-scale phenotyping effort using IKMC ES cells was funded by the European Commission (EC) in 2008. The European Mouse Disease Clinic (EUMODIC, http://www.eumodic.org/) program is comprised of 4 mouse phenotyping centers, whose goals are to provide phenotype information on 500 EUCOMM, NorCOMM and KOMP knockout mouse lines by 2011, using a common phenotyping protocol developed by the European Mouse Phenotyping Resource of Standardised Screens (EMPReSS, http://empress.har.mrc.ac.uk/) developed by the European Union Mouse Research for Public Health and Industrial Applications (EUMORPHIA) Program. This data is made accessible through a separately funded database, EUROPHENOME (http://www.europhenome.org/). It is expected that the NIH will ask successful applicants to this FOA to coordinate their efforts with the EUMODIC programs and the currently forming International Mouse Phenotyping Consortium (IMPC), to select knockout lines to be phenotyped, harmonize phenotyping platforms, and make use of prior know-how and experience. The basic protocol should include the observation of clinical signs (e.g., body weight, gait, activity level) and a complete necropsy of all normal and dead animals. The information available from all of these programs may help provide insight to applicants (http://commonfund.nih.gov/KOMP2/ipmc-policies.asp).

RESEARCH OBJECTIVE: The knockout mouse phenotyping program (KOMP²) is being implemented in several parts. This FOA calls for applications that propose to phenotype at least 2,500 mice over the course of five years, at the indicated funding level, or a proportionate number for less funding, but not less than 625 strains over 5 years. A companion FOA (RFA-RM-10-013) solicits applications for a program to convert IKMC knockout ES cells into mice for the phenotyping programs, therefore coordination with the production centers will be needed to obtain mice or germplasm. It is understood and acceptable that applicants may wish to apply to both FOAs either individually or in collaborations or using sub-contracts, to improve efficiencies and strengthen their applications. For any approach, the proposed plans must be based on realistic, documentable current capabilities (see SPECIAL GUIDANCE FOR APPLICANTS for information that may be useful for the applicant in describing and documenting past and planned activities), and may include a ramp-up period. Factors that will be considered in making funding decisions will include the timetable, the throughput, the cost, the type of phenotyping and the number of phenotyping tests employed. We expect the funded centers to work together to identify a common set of core assays that are performed similarly across all centers under harmonized husbandry conditions. The KOMP² program is envisioned as a fiver year pilot, which if successful, will be followed by 5 years of ramped-up production with some increased funds. Therefore, critical to the programs funded by all of the FOAs listed above, will be plans to improve the technology and decrease costs over the 5 years of the pilot phase.

The following components of the project should be addressed in detail:

(a) Past and current capabilities and efficiencies in the handling, importation, and expansion of mice or germplasm The applicant should present a sufficiently detailed plan and background information to demonstrate their ability to manipulate hundred(s) of mouse lines per year via importation, and/or internal production.

(b) Experience in large scale breeding of multiple mouse lines, high volume genotyping and allocation of cohorts to phenotyping experiments. If the applicant plans to receive germplasm or breeding pairs, then the applicant should present sufficiently detailed plans for setting up and maintaining a production pipeline for the large-scale generation of mouse lines for phenotyping programs.

(c) Animal husbandry and pathogen screening procedures and health status of mice. The applicant should describe the steps that are currently used in animal husbandry and those that will be taken to expand the mutant materials in compliance with international standards, as well as the protocol and procedures for assuring the health status of the mice.

(d) Phenotyping assays to be employed, experience and expertise. The applicant should describe in sufficient detail the phenotyping procedures that will be employed on the KO under study.

(e) Quality control of assays and data collection. The application should include QC procedures for each assay employed in the phenotyping platforms and the frequency of the QC.

(f) Formating of data to upload to centralized/other databases. A fundamental requirement of phenotyping centers is to provide the data in a standardized format on at least a weekly basis to a centralized database, yet to be defined.

The application should be organized such that each of these components is addressed clearly. It is also critical that applicants be willing to work with the International Mouse Phenotyping Consortium (IMPC) to maximize consistency and uniformity of phenotype data. Applicants who propose collaborations and/or subcontracts for specific components should describe how they would integrate their efforts with their collaborators or subcontractors.

In addition to the above strategy-specific issues, there are a number of production pipeline issues that must be addressed by applications for all approaches:

Information Technology. The applicant should discuss all pertinent informatics issues. 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 deposition. It is vital that the production data and phenotypic data be provided in a format that will be accessible to external databases. It is anticipated that the data uploads will occur on at least a monthly basis, and allow sufficient tracking information to assure that project goals are being met. There will be no holdback of data or moratorium on data release or its use.

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 the high-throughput phenotyping of mouse knockouts. NIH 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 on a per knockout basis.

Quality control. The applicant should discuss any additional means that will be taken to ensure the quality of, or otherwise validate, the phenotypic data that will be generated, beyond those mentioned above. Examples of appropriate quality control procedures include those for identification of the targeted allele, periodic validation of equipment and assays, data integrity, data validity, and testing the pathogen status of all biological reagents. Evidence of and experience in the effectiveness of the proposed quality control programs should be included.

Cost per gene knockout per assay should be addressed. The applicant should describe plans for determining and reducing the cost of analyzing knockout mice. All proposed costs and projected cost reductions should be given in terms of the total costs, i.e. the direct and indirect costs

In summary, applicants for awards under this FOA should:

• discuss the high throughput, cost efficient approaches or strategies to be used to make significant progress toward the creation of phenotype data from the mice produced under RFA RM-10-013;
• discuss the general approaches or strategies to be used for the phenotyping of knockout mice, including the applicant's past and current efforts (throughput and cost) in this area and how those efforts will ramp to achieve the proposed goals;
• discuss collaborations with other efforts and coordination of activities both among parties within the submitted application and with other participants who work towards the broader efforts of the IKMC and IMPC;
• describe how the applicant will improve the process of phenotyping mutant mice with the goal of reducing costs;
• present explicit production milestones and timelines when describing production and phenotyping goals;
• explicitly discuss the informatics infrastructure needed for the project;
• propose a plan for assessing the quality of the mouse produced;
• explicitly discuss project management and how various components of the center will be integrated;
• propose a comprehensive plan for the rapid release of data and materials so that the data are available to all users;
• discuss interactions, collaborations, or subcontracts that may be appropriate;
• provide information regarding the uniqueness of the resource or approach being proposed and a well documented data and resource release plan, if a subcontract to a non-U.S. institution is included.

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

Section II. Award Information

1. Mechanism of Support

This funding opportunity will use the U54 award mechanism(s).

This FOA uses Just-in-Time information concepts. It also uses non-modular budget formats described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/phs398/phs398.html).

This funding opportunity will use a cooperative agreement award mechanism. In the cooperative agreement mechanism, the Project Director/Principal Investigator (PD/PI) 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". The funding opportunity may be continued for an additional five year period, depending on the results of a program review in the 3rd or 4th year of the initial project.

2. Funds Available

• Up to $37 million in total costs over 5 years is to be awarded through this FOA;
• It is anticipated that 2-4 awards will be made;
• The expected total cost amount for individual awards will be $9.25-18.5 million over five years, or $1.85 3.7 million per year;

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. 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.

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.

Section III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

The following organizations/institutions are eligible to apply:

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education
• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Nonprofits 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)
• Small Businesses
• For-Profit Organizations (Other than Small Businesses)
• State Governments
• Other(s):
  • Eligible Agencies of the Federal Government

Foreign institutions are not eligible to apply in response to this FOA; however, subcontractual arrangements with foreign institutions are allowed.

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed research as the PD/PI is invited to work with his/her 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 program support.

More than one PD/PI, or multiple PDs/PIs, may be designated on the application for projects that require a team science approach and therefore clearly do not fit the single-PD/PI model. Additional information on the implementation plans, policies and procedures to formally allow more than one PD/PI on individual research projects is available at http://grants.nih.gov/grants/multi_pi. All PDs/PIs must be registered in the NIH eRA Commons prior to the submission of the application (see http://grants.nih.gov/grants/ElectronicReceipt/preparing.htm for instructions).

The decision of whether to apply for a grant with a single PD/PI or multiple PDs/PIs is the responsibility of the investigators and applicant organizations, and should be determined by the scientific goals of the project. Applications for grants with multiple PDs/PIs will require additional information, as outlined in the instructions below. When considering multiple PDs/PIs, please be aware that the structure and governance of the PD/PI leadership team as well as the knowledge, skills and experience of the individual PDs/PIs will be factored into the assessment of the overall scientific merit of the application. Multiple PDs/PIs on a project share the authority and responsibility for leading and directing the project, intellectually and logistically. Each PD/PI is responsible and accountable to the grantee organization, or, as appropriate, to a collaborating organization, for the proper conduct of the project or program, including the submission of required reports. For further information on multiple PDs/PIs, please see http://grants.nih.gov/grants/multi_pi.

Principal Investigator (P.I.) Effort. The effective management of a production project requires a significant commitment by the P.I. The P.I. of a large-scale project funded under this FOA is expected to devote at least 2.4 person months to the project. Additionally, the applicant should describe how he/she envisions managing 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 integration of the separate components to form an efficient pipeline, key personnel, section leaders, and reporting relationships. 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. It would be useful to discuss coordination of the awardee's activities with those of other international efforts to produce mouse knockouts.

2. Cost Sharing or Matching

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

3. Other-Special Eligibility Criteria

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

Resubmissions. Resubmission applications are not permitted in response to this FOA.

Renewals. Renewal applications are not permitted in response to this FOA.

Section IV. Application and Submission Information

1. Address to Request Application Information

The current 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

Prepare all applications using the PHS 398 application forms and in accordance with the PHS 398 Application Guide (http://grants.nih.gov/grants/funding/phs398/phs398.html).

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 in item (box) 2 only of the face page of the application form and the YES box must be checked.

Foreign Organizations (Non-domestic (non-U.S.) Entity)

Non-domestic (non-U.S.) entities (Foreign Organizations) are not eligible to serve as primary applicants for this FOA. However, foreign components may submit a research project or subcontract within a domestic application, under this FOA.

NIH policies concerning grants to foreign (non-U.S.) organizations can be found in the NIH Grants Policy Statement at: http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part12.htm#_Toc54600260.

Subcontractual arrangements from foreign organizations must:

• Request budgets in U.S. dollars.
• Contain detailed budgets. See NOT-OD-06-096.

In addition, for subcontracual arrangements from foreign organizations:

• Charge back of customs and import fees is not allowed.
• Every effort should be made to comply with the format specifications, which are based upon a standard U.S. paper size of 8.5 x 11 within each PDF.
• Funds for up to 8% Facilities and Administrative (F&A) costs (excluding equipment) may be requested. See NOT-OD-01-028, March 29, 2001.
• 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

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.

Applications with Multiple PDs/PIs

When multiple PD/PIs are proposed, use the Face Page-Continued page to provide items 3a 3h for all PD/PIs. NIH requires one PD/PI be designated as the contact PD/PI for all communications between the PD/PIs and the agency. The contact PD/PI must meet all eligibility requirements for PD/PI status in the same way as other PD/PIs, but has no special roles or responsibilities within the project team beyond those mentioned above. The contact PD/PI may be changed during the project period. The contact PD/PI should be listed in block 3 of Form Page 1 (the Face Page), with all additional PD/PIs listed on Form Page 1-Continued. When inserting the name of the PD/PI in the header of each application page, use the name of the Contact PD/PI, et. al. The contact PD/PI must be from the applicant organization if PD/PIs are from more than one institution.

All individuals designated as PD/PI must be registered in the eRA Commons and must be assigned the PD/PI role in that system (other roles such as SO or IAR will not give the PD/PI the appropriate access to the application records). Each PD/PI must include their respective eRA Commons ID in the eRA Commons User Name field.

Multiple PD/PI Leadership Plan: For applications designating multiple PDs/PIs, the section of the Research Plan entitled, Multiple PD/PI Leadership Plan , must be included. A rationale for choosing a multiple PD/PI approach should be described. The governance and organizational structure of the leadership team and the research project should be described, and should include communication plans, process for making decisions on scientific direction, and procedures for resolving conflicts. The roles and administrative, technical, and scientific responsibilities for the project or program should be delineated for the PDs/PIs and other collaborators.

If budget allocation is planned, the distribution of resources to specific components of the project or the individual PDs/PIs should be delineated in the Leadership Plan. In the event of an award, the requested allocations may be reflected in a footnote on the Notice of Award.

Additional information is available in the PHS 398 grant application instructions.

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
Letter of Intent Receipt Date(s): September 15, 2010
Application Receipt Date(s): November 10, 2010
Peer Review Date(s): February, 2011
Council Review Date(s): May, 2011
Earliest Anticipated Start Date(s): July, 2011

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 in Section IV.3.A.

The letter of intent should be sent to:

Colin Fletcher
Division of Extramural Research
National Human Genome Research Institute
5635 Fishers Lane
Suite 4076
Bethesda, MD 20892
Telephone: (301) 496-7531
Email: [email protected]

3.B. Sending an Application to the NIH

Applications must be prepared using the forms 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:

Ken Nakamura, Ph.D
Office of Scientific Review
National Human Genome Research Institute
5635 Fishers Lane
Bethesda MD 20892
Telephone: (301) 496-7531
Email: [email protected]

3.C. Application Processing

Applications must be received on or before the application receipt date described above (Section IV.3.A.). If an application is received after that date, the application may be delayed in the review process or not reviewed. Upon receipt, applications will be evaluated for completeness by the CSR and for responsiveness by the reviewing Institute. Incomplete and/or 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 NIH Grants Policy Statement.

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 award if such costs: 1) are necessary to conduct the project, and 2) 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 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

Special Guidance for Applicants

The NHGRI has conducted several competitions for large-scale projects and it has been our experience that there are specific information items and presentation formats that the reviewers have found to be critical for their ability to assess proposals for such efforts effectively. The following guidance summarizes that experience in the form of a format that the applicant may use to provide that information. If there is additional information, not addressed in this Guidance, that the applicant wishes to present, s/he is encouraged to provide it in a concise form, in addition to the information requested here. Following are specific instructions that may be used for writing the Report of Track Record and Research Plan for the approaches called for in this FOA.

6. Guidance for applications proposing mouse phenotyping:

6.I. Report of track record. The report of track record section should adequately describe the applicant's past experience in importation, production, husbandry, and phenotyping of mice. Brief, concise summaries are encouraged. The report of track record should represent the applicant's past accomplishments, rather than future plans.

This report of track record should include the following:

6.I.1. Importation of knockout mice and germplasm. The applicant should describe past and current efforts to import mice from outside sources. This description should include reanimation techniques and number of lines produced or imported per year and expansion capabilities. The applicant should also describe the throughput rate, quality, and cost, and should include, but not be limited to, the following information:

a. Throughput and quality rate:

i. The number of mice made in the most recent six months of activity, either by import of live mice or embryos or reanimation of cryopreserved germplasm. Describe the process used, based on tasks performed and individuals' efforts. For example, was the process organized by tasks or did each individual perform multiple steps?

ii. The generation of probes for confirming the genotype of the imported strain. Was the screening PCR based? What was the monthly success rate of genotyping during the most recent six month period?

iii. Any other metrics that the applicant has found to be useful in evaluating and managing mouse importation.

6.I.2. Mutant mouse breeding. The applicant should describe efforts over at least the most recent six months of activity in large scale breeding of multiple mouse lines, high volume genotyping, and allocation of cohorts to phenotyping experiments. The applicant should describe the rate of throughput, quality, and cost, and should include, but not be limited to, the following:

a. Throughput rate and quality:

i. The number of strains bred per month in the most recent six months of activity;

ii. The features of the database system used to track the mouse colony;

iii. The process for monitoring the identity and genetic integrity of the strains. Steps taken to ensure that genotyping was successful. What is the current success rate and how has it changed over the course of the past year?

iv. Any other internal metrics that the applicant has found to be useful in evaluating and managing the production of mice.

6.I.3. Animal husbandry and pathogen screening procedures and health status of mice. The applicant should describe the steps that are currently used in animal husbandry and those that will be taken to expand the mutant materials in compliance with international standards, as well as the protocol and procedures for assuring the health status of the mice.

a. Throughput rate and quality:

i. The number of strains bred per month in the most recent six months of activity;

ii. The health status monitoring program;

iii. Any training program in place for the veterinary and animal husbandry staff;

iv. Accreditation status of the facility.

6.I.4. Phenotyping assays to be employed, experience, and expertise. The applicants experience with each phenotyping assay, as well as any phenotyping pipeline flow pattern and methodologies should be discussed in detail.

a. Throughput rate and quality:

i. The number of phenotype assays performed per month in the most recent six months of activity;

ii Design of pipeline if used;

iii Rationale for cohort size of mutants and controls;

iv. Any other internal metrics that the applicant has found to be useful in evaluating and managing the phenotyping of mice.

v. Required expertise and training for staff to perform phenotyping assays (e.g., veterinary pathologist for necropsy and histopathology; radiologist for analysis of MRI or PET scan)

6.I.5. Quality control of assays and data collection. The application should describe QC procedures for each assay employed in the phenotyping platforms and the frequency of the QC.

6.I.6. Technology Development. The applicant should address any experience that s/he has had in developing and improving technology for mouse production and phenotyping. The discussion should describe, in quantitative terms, the effect that such technology improvements have had in process improvement and decreased production costs.

6.I.7. Prior experience in attaining milestones. The applicant should discuss his/her experience in defining and meeting useful milestones and budgets for a biological production effort.

6.II. The Research Proposal. This section comprises the applicant's description for a production project to provide phenotype information derived from broad-based phenotyping assays on hundred(s) of knockout mice lines per year developed from the IKMC program. The organization suggested below for this section of the application is based on the NIH staff's current understanding of the steps in these processes. The applicant is free to propose an alternative strategy but, in so doing, must address all of the issues raised below.

6.II.1. Knockout mouse importation. The applicant should present a sufficiently detailed plan and background information to demonstrate their ability to manipulate hundred(s) of mouse lines per year via importation and/or internal production. If the applicant cannot take in live mouse lines directly from qualified breeding and production centers, then a plan for and experience in reanimation/rederivation of germplasm should discussed in detail. The discussion should address the steps that will be used to handle the mice and/or germplasm provided by the KOMP² production centers (RFA-RM-10-013), the current throughput, projected expansion of capacity, the production goals and explicit milestones, and all other pertinent factors. A QC step and the method(s) for screening to confirm the correct genotype of the mouse lines should be included. Applicants must include convincing data that they can handle the high number of mouse lines anticipated and/or ramp to that level, in a cost efficient manner. All phases of the importation process must be addressed, as well as:

i. the overall projected throughput of the proposed center and how it will be attained;

ii. potential bottlenecks or other problems that can be anticipated, as well as proposed solutions;

iii. timelines and quantitative milestones where appropriate;

6.II.2. Large scale mouse breeding and genotyping. If the applicant does not plan to receive cohorts of live mice from the production centers, then the applicant should present sufficiently detailed plans for setting up and maintaining a production pipeline for the large-scale generation of mouse lines for phenotyping programs. The applicant should describe in detail the genotyping procedures that will be employed to confirm the KO lines under study, ensuring the correct identification of each KO under study. The SOPs and tracking systems employed are at the discretion of the applicant but the application should document both the cost analysis of generating lines from the systems employed and a detailed assessment of past and current success rates. It is anticipated that each line will be tested in 2-3 phenotyping pipelines that require ~7 KO males and ~7 KO females per pipeline. It is also expected that breeding KO (-/-) by KO (-/-) will be the most cost effective, followed by KO (-/-) by Het (+/-) and finally Het (+/-) by Het (-/+). The applicant’s current and projected production rates and costs for each breeding schema and costs per cohorts should be demonstrated in detail. All phases of the breeding process must be addressed, as well as:

i. the overall projected throughput of the proposed center and how it will be attained;

ii. potential bottlenecks or other problems that can be anticipated as well proposed solutions;

iii. timelines and quantitative milestones where appropriate;

6.II.3. Animal husbandry and pathogen screening procedures and health status of mice. The applicant should describe the steps that are currently used in animal husbandry and those that will be taken to expand the mutant materials in compliance with international standards, as well as the protocol and procedures for assuring the health status of the mice. All phases of the husbandry process must be addressed, as well as:

i. the overall projected throughput of the proposed center and how it will be attained;

ii. potential bottlenecks or other problems that can be anticipated as well proposed solutions;

iii. timelines and quantitative milestones where appropriate;

6.II.4. Phenotyping assays to be employed, experience, and expertise. The applicant should describe in sufficient detail the phenotyping procedures that will be employed on the KO under study. As a starting point, the EUMODIC pipeline (http://www.empress.har.mrc.ac.uk/viewempress/?map) may be used as a template for phenotyping but there must be flexibility in the future to add or drop tests as the project progresses. It is anticipated that the most efficient manner to phenotype mice will be to study mice as they reach the appropriate age and not require that all of a full cohort for a line be studied at the same time. In such a system, or in any system, it will be important to have a daily validation of the equipment and assays, as well an appropriate number of WT controls for the phenotyping. It is expected that a smaller number of WT mice can be used as a reference across phenotyping. For example, if 20 KO mice from 5 different lines are studied in an assay on a given day and a single cohort of 7 WT mice are run at the same time that might be sufficient to act as a control. The applicant should address the size of cohorts needed for each assay, the timing of the tests, the source and numbers of WT mice needed to validate the phenotyping assays. It is anticipated that the IMPC will provide guidance and recommendations at least yearly that can then be addressed by the KOMP Phenotyping Steering Committee. The ability to harmonize phenotyping platforms and cooperate with the international efforts will be important criteria for evaluation of the applications. The KOMP Phenotyping Workshop and Survey (report) strongly recommended the inclusion of more phenotyping screens employing challenge models in immunology, diet, and pharmacology. It was also recommended to include necropsy and histopathology images, LacZ staining of KO mice, and other imaging modalities. The applicants should address the process and/or ability to perform these types of phenotyping assays, as well as their ability to adopt new procedures. All phases of the phenotyping process must be addressed, as well as:

i. the overall projected throughput of the proposed center and how it will be attained;

ii. potential bottlenecks or other problems that can be anticipated as well proposed solutions;

iii. timelines and quantitative milestones where appropriate;

6.II.5. Quality control of assays and data collection. The application should include QC procedures for each assay employed in the phenotyping platforms and the frequency of the QC. It is strongly recommended that if the data are not currently collected automatically in a database, that the implementation plan for such a system be included in the application. The laboratory information management (LIM) systems for data collection are the responsibility of the applicant and these should be described in detail. All phases of the data collection process must be addressed, as well as:

i. the overall projected throughput of the proposed center and how it will be attained;

ii. potential bottlenecks or other problems that can be anticipated as well proposed solutions;

iii. timelines and quantitative milestones where appropriate;

6.II.6. Informatics. All production data and materials should be linked to the gene as the reference point. The informatics issues and requirements associated with mutant mouse production should be discussed in a manner such that all of the data will be integrated and linked to information on the gene of interest. The successful grantee will be expected to transfer all relevant data to the Data Coordination Center, which is to be funded under the companion RFA-RM-10-012. The applicant should propose how a plan to transfer data to that center will be developed and suggest elements of that plan if possible. This data exchange format should contain elements to describe data related to all steps in the process of generating knockout mutants and be in an explicitly defined, machine readable format. All phases of the data formatting/upload process must be addressed, as well as:

i. the overall projected throughput of the proposed center and how it will be attained;

ii. potential bottlenecks or other problems that can be anticipated as well proposed solutions;

iii. timelines and quantitative milestones where appropriate;

6.II.4. Technology development. The Research Plan should include a separate section describing plans for technology development efforts to improve the efficiency of the production pipeline for breeding and phenotyping mutant mice during the proposed project.

6.III. Budget Request. The budget requested must be described clearly and be well justified. Applicants should submit the Detailed Budget for the Initial Budget Period (page 4 of PHS-398) and the Budget for Entire Proposed Period of Support (page 5 of PHS-398)

Awardees must agree to the "Cooperative Agreement Terms and Conditions of Award" in Section VI.2.A "Award Administration Information".

PHS398 Research Plan Sections

All application instructions outlined in the PHS398 Application Instructions are to be followed, with the following additional requirements:

• Research Strategy, including tables, graphs, figures, diagrams, and charts is limited to 30 pages.

Budget

This FOA uses non-modular budget formats described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/phs398/phs398.html).

All subcontracual arrangements from foreign applicants must complete and submit budget requests using the Research & Related Budget component found in the application package for this FOA. See NOT-OD-06-096.

Appendix Materials

All paper PHS 398 applications submitted must provide appendix material on CDs only. Include five identical CDs in the same package with the application. See http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-031.html.

Do not use the Appendix to circumvent the page limitations. An application that does not observe the required page limitations may be delayed in the review process.

Resource Sharing Plan(s)

NIH considers the sharing of unique research resources developed through NIH-sponsored research an important means to enhance the value of, and advance research. When resources have been developed with NIH funds and the associated research findings published or provided to NIH, it is important that they be made readily available for research purposes to qualified individuals within the scientific community. If the final data/resources are not amenable to sharing, this should be explained in Resource Sharing section of the application. See http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm.

(a) Data Sharing Plan: Investigators seeking $500,000 or more in direct costs in any year are expected to include a brief 1-paragraph description of how final research data will be shared, or explain why data-sharing is not possible. Applicants are encouraged to discuss data-sharing plans with their NIH program contact. See Data-Sharing Policy or http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html.

(b) Sharing Model Organisms: Regardless of the amount requested, all applications where the development of model organisms is anticipated are expected to include a description of a specific plan for sharing and distributing unique model organisms and related resources, or state appropriate reasons why such sharing is restricted or not possible. See Sharing Model Organisms Policy, and NIH Guide NOT-OD-04-042.

(c) Genome-Wide Association Studies (GWAS): Regardless of the amount requested, applicants seeking funding for a genome-wide association study are expected to provide a plan for submission of GWAS data to the NIH-designated GWAS data repository, or provide an appropriate explanation why submission to the repository is not possible. A genome-wide association study is defined as any study of genetic variation across the entire genome that is designed to identify genetic associations with observable traits (such as blood pressure or weight) or the presence or absence of a disease or condition. For further information see Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies, NIH Guide NOT-OD-07-088, and http://grants.nih.gov/grants/gwas/.

All applications are expected to include a plan for sharing research data. The standard NIH data sharing policy is available at http://grants.nih.gov/grants/policy/data_sharing. All investigators responding to this funding opportunity should include a description of how final research data will be shared, or explain why data sharing is not possible. However, rapid release of the data would be of benefit to the scientific user community because of the scope of this community resource project as described in this FOA and because of the national and scientific investment that the NIH will make in KOMP². Accordingly, applicants should not feel constrained by the standard approach to data sharing but should display and promote innovative methods for achieving the maximum use of the KOMP² resource.

Data release. Applicants should be familiar with the NIH statements regarding sharing of resources developed with Federal funds (http://grants.nih.gov/grants/intell-property_64FR72090.pdf). In the case of phenotypic data, plans for the dissemination and access of the data to a centralized database is needed in line with the aims of the FOA. With regard to the present solicitation, NHGRI and the other participating Institutes have identified the goal of the KOMP² as the production of a community materials as described in the proceedings of the Meeting on Sharing Data from Large-Scale Biological Research Projects (http://www.wellcome.ac.uk/doc_wtd003208.html). Therefore, responses to this FOA should propose a specific and comprehensive plan for the rapid release of data resulting from the knockout mouse production and phenotyping effort to the appropriate databases. None of the funds of this project are intended to support the creation of a publically accessible database for each phenotyping center, as it is envisioned that a single separately funded database will provide public access to all phenotyping data. The quality of this plan will be an important criterion in the award of the cooperative, and an appropriate plan for release of data and materials will be made a condition of the awards made as a result of this FOA.

In presenting the data release plan, the release of data to the project's public website should be discussed and should include, but is not limited to: information as to the genes that have been assigned to the project, when the effort to study the mice is scheduled to begin or actually began, data that confirm a knockout mouse has been successfully made, date that data were collected and shipped to a central phenotyping database, and other pertinent data.

Additionally, the applicant's data release plan should address how software or technology improvements developed under this funding will be publicly released. It is highly likely that software solutions and LIMS system development would benefit the other IMPC phenotyping centers as well as other investigators.

The release plans are expected to fully address how the end users of the mice, embryos, data, and other materials generated by the funded activity, in both the public and private sectors, will be fully enabled to share and use the data, consistent with achieving the goals of this project.

The reviewers will assess the reasonableness of the data sharing plan or the rationale for not sharing research data. Program staff of the funding organization, when making recommendations about funding applications, will consider the adequacy of the resources sharing plan and any related data sharing plans. Section I. Research Objectives contains a section entitled Data and Materials Release that addresses the issues that can be used in a data-sharing plan for a KOMP² component.

Sharing Research Resources

NIH policy expects that grant awardee 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. However, as indicated in the previous section with respect to the data sharing plan, applicants should not feel constrained to propose a standard plan for sharing materials, given the scope of KOMP² as defined by the FOA and the NIH's investment in this project. Widespread dissemination and access to the materials generated through this program to the public and private research sectors are an aim of this FOA and will require innovative methods for achieving the maximum use of the resource to be produced under this project.

Program staff of the funding organization, when making recommendations about funding applications, will consider the adequacy of the resources sharing plan and any related data sharing plans. 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.

Material Transfer. A uniform MTA such as the Simple Letter Agreement (SLA), Material Transfer Agreement for the Transfer of Organisms (MTA-TO) will be used for all repositories which receive resources made by this effort to ensure that the resources made by this initiative are available in a manner consistent with the goals of this FOA and with no additional reach through rights to inventions[/discoveries] made by the end users. Although NIH Policy strongly discourages the patenting of research resources, applicants are free to patent their discoveries so long as the ES cells, embryos, mice, and data are made available for research purposes in a manner consistent with the NIH Data Sharing Policy, other NIH sharing policies (see http://sharing.nih.gov), and the goals of this FOA.

Specific Instructions for Foreign Applications

All subcontracual arrangements from foreign applicants must complete and submit budget requests using the Research & Related Budget component found in the application package for this FOA. See NOT-OD-06-096.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process.

2. Review and Selection Process

Review Process

Applications that are complete and responsive to the FOA will be evaluated for scientific and technical merit by an appropriate peer review group convened by NHGRI and in accordance with NIH peer review procedures (http://grants1.nih.gov/grants/peer/), using the review criteria stated below.

As part of the scientific peer review, all applications will:

• 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 impact/priority score.
• Receive a written critique.
• Receive a second level of review by an appropriate national advisory council or board.

The mission of the NIH is to support science in pursuit of knowledge about the biology and behavior of living systems and to apply that knowledge to extend healthy life and reduce the burdens of illness and disability. As part of this mission, applications submitted to the NIH for grants or cooperative agreements to support biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

Overall Impact

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

Scored Review Criteria

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

Significance. Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Investigator(s). Are the PD/PIs, 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?

Innovation. Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Approach. Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed?
If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?

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?

Additional Review Criteria

As applicable for the project proposed, reviewers will consider the following additional items in the determination of scientific and technical merit, but will not give separate scores for these items.

• The likelihood that the proposed center can obtain high-quality phenotype data for a set of mouse mutants.
• The quality of the plans for technology development and identifying and solving critical integration problems.
• The quality of the plans for bioinformatics, including infrastructure and laboratory information management systems.
• The quality of the plans for release of data and materials, including evidence that the systems are in place to support data release.
• The quality of the plans for release or distribution of other resources, software, or technologies developed under this award, including evidence that the systems are in place to support data release.
• The quality of the plans to coordinate efforts with other mouse mutagenesis projects in the U.S. and abroad, and with appropriate subcontractors or collaborators that may be needed.
• The track record of the Principal Investigator and other key personnel in producing and disseminating mouse knockouts.
• The reasonableness of the milestones, timelines, and goals proposed for the research project.

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.

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.

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, see http://grants.nih.gov/grants/olaw/VASchecklist.pdf.

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.

Resubmission Applications. Resubmissions are not applicable to this FOA.

Renewal Applications. Renewals are not applicable to this FOA.

Revision Applications. Revisions are not applicable to this FOA.

Additional Review Considerations

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

Applications from Foreign Organizations. Foreign institutions are not eligible to apply in response to this FOA; however, subcontractual arrangements with foreign institutions are allowed.

Select Agents 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 (http://grants.nih/gov/grants/policy/data_sharing/data_sharing_guidance.htm); 2) Sharing Model Organisms (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-04-042.html); and 3) Genome Wide Association Studies (GWAS) (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-088.html).

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

Selection Process

The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by peer review
• Availability of funds
• Relevance of the proposed project to program priorities
• Compliance with resource and resource sharing policies

NIH considers the following in evaluating Center grant applications:

• The scientific and technical merit of the proposed program;
• The qualifications and experience of the center director and other key personnel;
• The statutory and program purposes to be accomplished;
• The extent to which the various components of the proposed program would be coordinated into one multi-disciplinary effort within the center;
• The extent to which the center's activities would be coordinated with similar efforts by other organizations;
• The administrative and managerial capability of the applicant; and
• Other factors which the awarding IC considers appropriate in light of its particular statutory mission.

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.

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.

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 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.

2. A.1. Principal Investigator Rights and Responsibilities

The Principal Investigator will have the primary responsibility for defining the details for the gene knockout production project within the guidelines of FOA RFA-RM-10-011 and for performing the scientific activities. The P.I. will agree to collaboration with the other members of the KOMP² Research Network and to accept close coordination, cooperation, and participation of NIH staff and advisors in those aspects of scientific and technical management of the project as described under 2.A.2. NIH Responsibilities.

The P.I. will:

• Determine experimental approaches, design protocols, set project milestones and conduct experiments;
• Endeavor to meet or exceed stated milestones;
• Accept and participate in the cooperative nature of the KOMP² Research Network;
• Serve, along with the P.I. of each of the other funded KOMP² Research Network awards, on the Steering Committee for the KOMP² Research Network; the P.I. will have one vote on the Steering Committee;
• Provide goals for throughput, quality, and cost to the NHGRI as requested (usually at the outset of the award and in monthly progress reports to the Steering Committee, but also at other times as requested by NHGRI program staff);
• Ensure that the products of the production effort meet or exceed the quality standards and costs agreed upon at the time of award;
• Submit data for quality assessment in any manner specified by the Steering Committee or the Panel of Scientific Consultants;
• Submit periodic progress reports in a standard format, as agreed upon by the Steering Committee and the Panel of Scientific Consultants;
• Ensure that the data (sequence and quality assessment data and probes) are deposited in the appropriate public databases (e.g., the grantee to be funded by RFA-RM-10-012, as specified by NHGRI program staff), that resources developed as part of this project are made publicly available through an NIH-designated repository according to NIH policies;
• Adhere to the general NIH policies regarding sharing resources, data release, and resource sharing, as well as the specific data and resource-sharing policies proposed in the application, as modified by any negotiation prior to award or that might be established by the Steering Committee during the course of this activity;
• Accept and implement any other common policies, guidelines and procedures that are developed and approved for the KOMP² by the Steering Committee and the Panel of Scientific Consultants;
• Coordinate and collaborate with other U.S. and international groups producing mouse knockout mutants as a community resource;
• Inform the NHGRI Program Director of all major interactions with members of the Steering Committee;
  
• Attend a yearly Steering Committee meeting with the Panel of Scientific Consultants.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.
For the KOMP² Research Network, a Project Scientist will be appointed from each of the Institutes that is responsible for the participating cooperative agreements, that is, NHGRI and NCRR.

For RFA-RM-10-011 (this FOA), the NHGRI Project Scientist will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice and coordination. However, the role of the NHGRI Project Scientist will be to facilitate and not to direct the activities. It is anticipated that decisions in all collaborative activities will be reached by consensus of the KOMP² Steering Committee, of which the PI is a member, and that the NHGRI Project Scientist will participate in this process. The NHGRI Project Scientist shall participate as a member of the Steering Committee and will have one vote.

The Project Scientist will:

• Participate (with the P.I. and the other Steering Committee members) in the group process of setting research priorities for the KOMP² Research Network, 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 goals for throughput, quality, and cost with the awardee, as necessary;
• Serve as a liaison between the awardee and the Panel of Scientific Consultants, the National Advisory Council for Human Genome Research, other national advisory councils or boards;
• Coordinate the efforts of the awardee with other participants in the KOMP² and IMPC programs, including other awardees under this FOA, with any other large-scale knockout efforts in the U.S., with international mouse knockout projects, and with the larger biological research community;
• 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;
• Periodically report progress to the NIH Knockout Mouse Working Group, the Director of NHGRI, DPCPSI and the Directors of the NIH Institutes supporting the KOMP²;
• Lend relevant expertise and overall knowledge of NIH-sponsored research to facilitate the selection of scientists not affiliated with the awardee institutions who are to serve on the Panel of Scientific Consultants and the Steering Committee;
• Serve as liaison between the Steering Committee and the Panel of Scientific Consultants;
• Serve on subcommittees of the Steering Committee, as appropriate; to provide advice in the management and technical performance of the investigation;
• Assist in promoting the availability of the mouse knockout mutants and related materials and resources developed in the course of this project to the scientific research community-at large;
• Participate in data analyses, interpretations, and where warranted, authoring of the publication of results of studies conducted as part of the KOMP² Research Network;
• Assist awardees in the development, if needed, of policies for dealing with situations that require coordinated action;
• Retain the option to recommend, with the advice of the Panel of Scientific Consultants, the withholding or reduction of support from any cooperative agreement that substantially fails to achieve its goals according to the milestones agreed to at the time of award, or fails to maintain the state of the art in the production of mouse knockout mutants or fails to comply with the Terms and Conditions of the award. An NHGRI Program Director will be responsible for the normal stewardship of this award; this same Program Director may, in addition, be substantially involved as the NIH Project Scientist, as described above.
• Conduct an interim administrative review of the entire KOMP² in the 3rd or 4th year to assess whether the program is accomplishing its goal as a pilot to set the stage for an additional 5 year program to scale up in order to phenotype all the IKMC knockout mutants. This will be done in collaboration with the PSC.
• 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 KOMP² Research Network will involve three distinct activities (Knockout Mouse Production and Cryopreservation Centers, , a data coordination center, KOMP² phenotyping centers); funding of these activities will be solicited by a set of set of three FOAs [RM-10-011 (the current FOA), RFA-RM-10-012, RFA-RM-10-013]. All components of the KOMP² program will be funded by cooperative agreements and a single Steering Committee (section 2.A.3) and a single Panel of Scientific Consultants (section 2.A.3) will serve for all of the KOMP² activities. The Terms and Conditions described below are specific for this FOA (RM-10-011), but have been coordinated and made consistent with those described in the other FOAs soliciting components of the KOMP² Research Network.

The Steering Committee will serve as the main governing board of the KOMP² Research Network. The Steering Committee membership will include the P.I. of each awarded cooperative agreement and the NIH Project Scientist of each of the components of the KOMP² Research Network. Additional members may be added by action of the Steering Committee. Members of the KOMP² Working Group may attend the Steering Committee meetings. Government employees outside of KOMP² Working Group members may also attend, if their expertise is required for specific discussions.

The Steering Committee will:

• Discuss progress in meeting the goals of the KOMP² to provide a comprehensive collection of phenotyped null mutant mice to the research community;
• Discuss potential modifications of the goals of the KOMP² in light of developing technology and any changes in the scientific community's need for phenotyped mouse knockout mutants;
• Develop recommendations for uniform procedures and policies necessary to meet the goals of the KOMP², for example for data quality measures and assessment, nomenclature and annotation conventions for data deposition, for the KOMP² Research Network. Adoption of procedures and policies developed by the Steering Committee will require concurrence by the KOMP² Working Group and the Panel of Scientific Consultants;
• Serve as a venue for coordination on the improvement of mouse knockout phenotype production, for example by reporting progress, disseminating best practices and collectively evaluating new procedures, resources, and technologies.
• Interact as an active member with the IMPC

Each full member will have one vote; the total votes of the NIH Project Scientist-members of the Steering Committee will constitute a minority of the votes. Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee.

Panel of Scientific Consultants:

This program will be coordinated with and be a member of the IMPC. Because that program is in its formative stage, the degree of interactions of the KOMP² Steering committee with the IMPC and the nature of IMPC input into the oversight of the KOMP² is not yet known. The advisory structure may include:

A Panel of Scientific Consultants (PSC) will be responsible for reviewing and evaluating the progress of the members of the KOMP² Research Network toward meeting their individual and collective goals. The PSC will provide recommendations to the KOMP² Working Group, the Directors of NHGRI, NCRR, and DPCPSI as well as the Directors of the all other participating institutes, about continued support of the components of the KOMP² Research Network. The Panel will be composed of four to six senior scientists with relevant expertise who are not P.I.s of a cooperative agreement involved in the KOMP² Research Network. The Panel of Scientific Consultants will be appointed by the Directors of NHGRI, NCRR, and DPCPSI with concurrence from the Directors of all other participating Institutes. The membership of the Panel of Scientific Consultants may be enlarged permanently, or on an ad hoc basis, as needed.

The Panel of Scientific Consultants will meet at least once a year and by conference call 2 to 3 times per year. During part of this meeting, there will be a joint meeting with the Steering Committee to allow the PSC members to interact directly with the awardees. Annually, the PSC will make recommendations to the NIH regarding progress of the KOMP² Research Network and present advice about changes, if any, which may be necessary in the KOMP² Research Network program to the Directors of NHGRI NCRR, and DPCPSI and the Directors of the other participating institutes.

The KOMP² Working Group consists of program staff from each of the NIH institutes supporting the KOMP². The purpose of the KOMP² Working Group will be to disseminate information about the progress of the KOMP² Research Network to the participating Institutes and to provide a forum for the participating Institutes to discuss issues related to KOMP². The KOMP² Working Group members will report to the Director of their respective IC. The KOMP² Working Group will be chaired by the NHGRI Project Scientist for the knockout mouse phenotyping component of the KOMP².

2.A.4. Dispute Resolution 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 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 regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

3. Reporting

Awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.

Each awardee will be asked to define a set of monthly milestones at the time of the award and to update these milestones annually at the anniversary date. These will be made a condition of the award. In accord with the procedures described above, NHGRI may withhold or reduce funds for a project that substantially fails to meet its milestones or to maintain the state of the art in the field.

A final progress report, invention statement, and Financial Status Report are required when an award is relinquished when a recipient changes institutions or when an award is terminated.

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:

Colin Fletcher, Ph.D.
Division of Extramural Research
National Institute of Human Genome Research
5635 Fisher Lane
Suite 4076
Bethesda, MD 20892
Telephone: (301) 496-7531
FAX: (301) 480-2770
Email: [email protected]

2. Peer Review Contacts:

Ken Nakamura, Ph.D
Office of Scientific Review
National Human Genome Research Institute
5635 Fishers Lane
Bethesda MD 20892
Telephone: (301) 496-7531
Email: [email protected]

3. Financial or Grants Management Contacts:

Cheryl Chick
Grants Management Officer
Grants Administration Branch
5635 Fisher Lane
Suite 4076
Bethesda, MD 20892
Telephone: (301) 496-7531
FAX: (301) 402-1951
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).

Data and Safety Monitoring Plan:
Data and safety monitoring is required for all types of clinical trials, including physiologic toxicity and dose-finding studies (phase I); efficacy studies (Phase II); efficacy, effectiveness and comparative trials (Phase III). Monitoring should be commensurate with risk. The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risks to the participants (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

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.

Policy for Genome-Wide Association Studies (GWAS):
NIH is interested in advancing genome-wide association studies (GWAS) to identify common genetic factors that influence health and disease through a centralized GWAS data repository. For the purposes of this policy, a genome-wide association study is defined as any study of genetic variation across the entire human genome that is designed to identify genetic associations with observable traits (such as blood pressure or weight), or the presence or absence of a disease or condition. All applications, regardless of the amount requested, proposing a genome-wide association study are expected to provide a plan for submission of GWAS data to the NIH-designated GWAS data repository, or provide an appropriate explanation why submission to the repository is not possible. Data repository management (submission and access) is governed by the Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies, NIH Guide NOT-OD-07-088. For additional information, see http://grants.nih.gov/grants/gwas/.

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.

Inclusion of Women And Minorities in Clinical Research:
It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.

Inclusion of Children as Participants in Clinical Research:
The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all clinical research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them.

All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects (http://grants.nih.gov/grants/funding/children/children.htm).

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-09-116.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.

NIH Public Access Policy Requirement:
In accordance with the NIH Public Access Policy (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-033.html) investigators must submit or have submitted for them their final, peer-reviewed manuscripts that arise from NIH funds and are accepted for publication as of April 7, 2008 to PubMed Central (http://www.pubmedcentral.nih.gov/), to be made publicly available no later than 12 months after publication. As of May 27, 2008, investigators must include the PubMed Central reference number when citing an article in NIH applications, proposals, and progress reports that fall under the policy, and was authored or co-authored by the investigator or arose from the investigator’s NIH award. For more information, see the Public Access webpage at http://publicaccess.nih.gov/.

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 FOA 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. 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.