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 FOA is developed as a part of the NIH-wide Genes, Environment, and Health Initiative (GEI). All NIH Institutes and Centers participate in NIH-wide initiatives. This FOA will be administered by NIMH (http://www.nimh.nih.gov) on behalf of the NIH (http://www.nih.gov)

Title: Methods of Statistical Analysis of DNA Sequence Data for Studies Relating Variation to Disease (R01)

Announcement Type
New

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

NOTICE: Applications submitted in response to this Funding Opportunity Announcement (FOA) for Federal assistance must be submitted electronically through Grants.gov (http://www.grants.gov) using the SF424 Research and Related (R&R) forms and the SF424 (R&R) Application Guide

APPLICATIONS MAY NOT BE SUBMITTED IN PAPER FORMAT.

This FOA must be read in conjunction with the application guidelines included with this announcement in Grants.gov/Apply for Grants (hereafter called Grants.gov/Apply).

A registration process is necessary before submission and applicants are highly encouraged to start the process at least four weeks prior to the grant submission date. See Section IV.

Request for Applications (RFA) Number: RFA-MH-08-040

Catalog of Federal Domestic Assistance Number
93.242

Revised Key Dates (Per NOT-MH-07-120)
Opening Date: August 20, 2007(Earliest date an application may be submitted to Grants.gov)
Letters of Intent Receipt Date(s): December 7, 2007
NOTE: On time submission requires that applications be successfully submitted to Grants.gov no later than 5:00 p.m. local time (of the applicant institution/organization).
Application Receipt Date(s): January 8, 2008
Peer Review Date(s): March/April 2008
Council Review Date(s): August 2008
Earliest Anticipated Start Date(s): September 1, 2008
Additional Information To Be Available Date (Activation Date): N/A
Expiration Date(s): January 9, 2008

Key Dates (Original Dates)
Release/Posted Date: June 21, 2007
Opening Date: August 20, 2007 (Earliest date an application may be submitted to Grants.gov)
Letters of Intent Receipt Date(s): August 20, 2007
NOTE: On time submission requires that applications be successfully submitted to Grants.gov no later than 5:00 p.m. local time (of the applicant institution/organization).
Application Receipt Date(s): September 20, 2007
Peer Review Date(s): February 2008
Council Review Date(s): May 2008
Earliest Anticipated Start Date(s): July 1, 2008
Additional Information To Be Available Date (Activation Date): N/A
Expiration Date(s): September 21, 2007

Due Dates for E.O. 12372

Not Applicable

Additional Overview Content

Executive Summary

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

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

Section VI. Award Administration Information
1. Award Notices
2. Administrative and National Policy Requirements
3. Reporting

Section VII. Agency Contacts
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

Research in human genetics is about to be transformed by new methods to produce large amounts of DNA sequence data for relating genetic variation to health and disease. The human reference sequence, large collections of genetic variants, and maps of human haplotype structure provide the foundation for interpreting large-scale sequence data. Genome-wide association studies using genotyping are finding regions that are associated with disease phenotypes. These regions need to be examined more comprehensively by sequencing. The technology for sequencing is changing rapidly, and soon will allow the production of sequence in genomic regions and across the genome in many individuals. Despite the imminent production of large amounts of sequence data, it is very unclear how to use these data. This FOA aims to support the development of statistical methods for analysis of sequence data and how they relate to phenotype. Areas of interest include designing sequencing studies, and statistical methods for relating the variation to phenotype, assessing the significance of the associations, incorporating population genetic factors such as population history, admixture, and natural selection, and finding sets of variants that may include functional variants.

The Genes and Environment Initiative (GEI)

The Genes and Environment Initiative (GEI) is a four-year, NIH-wide program to support efforts to identify major genetic susceptibility factors for diseases of substantial public health impact and to develop technologies for reliable measurement of potentially causative environmental exposures. GEI is a multi-component program involving several related solicitations.

Background

Common diseases such as depression, diabetes, heart disease, and cancer are affected by multiple genetic and environmental factors. Finding genetic factors that contribute to a disease allows the prediction of risk for individuals and is the starting point for studies leading to a mechanistic understanding of the basis for the disease, including interactions among genes and interactions of genetic factors with environmental factors.

Until recently, because of the high cost of genotyping and the prohibitive cost of sequencing, studies of the genetic contributions to disease focused on linkage in families and on candidate genes that were suspected of being involved in the disease. However, although linkage studies are efficient for finding Mendelian variants, they are much less efficient than association studies of many unrelated individuals for finding common variants that affect common diseases, which generally have incomplete penetrance and modest contributions to disease risk, with odds ratios of 1.1 to 2. Studying candidate genes is a reasonable way of finding variants in genes known to affect a disease, but our knowledge of biological processes is incomplete enough that many important variants will be missed in such studies.

The majority of variants in the genome are single-nucleotide polymorphisms (SNPs, single-base differences in DNA sequence among individuals). In addition to SNPs, which are relatively easy to detect by current genotyping platforms, sequence variants include structural variants such as insertions, deletions, copy-number variants, microsatellites, segmental duplications, transposons, and inversions. They can be as small as one or a few bases or extend up to about a megabase. Sequence and array methods as well as some genotyping platforms can type structural variants, but the catalogue of structural variants is currently much less complete than for SNPs.

The recent production of the human haplotype map, the HapMap (www.hapmap.org), allows comprehensive studies of the genome for associations with disease. The HapMap shows regions where sets of SNPs are strongly associated with each other (strong linkage disequilibrium, LD). Sets of hundreds of thousands of tag SNPs can be chosen that describe most of the patterns of variation across the genome for the tens of millions of variants that exist. Although the cost of genotyping has dropped substantially in the last few years, it is still high enough that genotyping all known SNPs is impractical and thus the tag SNP approach to genotyping makes association studies feasible to do in thousands of individuals, as is needed to find variants with modest contributions to disease risk. The tag SNP approach finds regions associated with a disease, based on differences in allele frequencies of the tag SNPs in those regions between cases and controls. Any variants in LD with the tag SNPs could contribute to the association, so the method finds regions for further analysis but is not comprehensive in the characterization of variation in those regions.

Recently several genotyping companies have used the HapMap data to develop platforms with high coverage across the genome. These platforms are being used for many genome-wide association studies (GWAS). Already GWAS studies and candidate gene studies have found many regions and variants that are associated with diseases, such as macular degeneration, autism, type 1 and type 2 diabetes, and inflammatory bowel disease. Many more such studies are underway or will be soon. These studies have many technical and statistical issues; replication of results in several studies is generally needed for strong confidence that the gene regions found are associated with a disease.

It is difficult to identify any particular variant in a disease-associated region as being the causal one when others are in LD with it and are also associated with the disease. Variants found to be associated with disease include ones that change conserved amino acids, ones in coding regions that do not change the amino acid but may affect messenger RNA stability, ones at splice junctions that change the exon structure, and ones in regulatory regions that affect the expression of the protein. However, most variants, including ones that change the amino acid sequence, have unknown effects on function or do not differ in function.

Following up association hits from genotyping studies requires comprehensive characterization of the variation in the disease-associated regions. Sequencing of these regions will be needed in many individuals, probably hundreds to thousands. Sequence data show virtually all the variants in the samples in the regions examined, including rare variants, and their frequencies and LD relationships. Sequencing allows the discovery of variants not already known, including structural variants as well as SNPs. Although a large proportion of common SNP variants are already known, sequencing many individuals will allow discovery of less common variants, including ones that may contribute to disease in patient samples. Sequence data show the relationships of variants on chromosomes (haplotype phase), which is important for understanding protein function and regulation and the co-inheritance of variants, especially rare ones.

Currently sequencing is too expensive to be used across the entire genome of many individuals, so in the next couple of years sequencing will be used primarily in regions of association hits. In a few years the technology is expected to improve sufficiently that entire genomes of many individuals will be sequenced. For both types of sequencing the data will show many variants, most not in coding sequences. Some variants will look like smoking guns that would be expected to affect function, but most variants that do affect function probably will not be obvious among the many that have little effect on function.

Both types of sequencing raise many statistical issues of how to interpret the data. The LD among the variants, with complete sequencing in regions, means that sets of variants containing functional variants should be able to be identified, but the specific functional variants in these sets generally will not be able to be identified. However, statistical analyses of the data, such as of the frequency distribution of variants and the extent of LD, should provide clues about population history and how natural selection has acted. This information should be useful for prioritizing regions for functional analyses.

Sequence data provide much more detailed information than tag SNP genotype data do on how variants in a disease-associated region are related to the disease phenotypes. For example, a particular set of variants in LD may be associated with a phenotype, or there may be a disproportionate number of rare variants.

Statistical analysis of the sequence data should provide clues about which genes in a disease-associated region and which variants are good candidates for being causal. Some variants that change the protein structure (non-synonymous SNPs, slice site variants, stop codons) are obvious candidates for being causal. The disease associations may turn out to be with variants in the area of particular genes or genomic elements, such as a promoter region. There are also additional types of information; for example, the distribution of allele frequencies may provide information on how natural selection has acted on variation in the region.

Information from the sequence data provides clues about potentially causative genes and variants, and thus can be used to prioritize follow-up studies. To determine which genes and variants are actually causative requires experimental functional studies. These studies will find which variants in an associated set of variants are functional, and will provide an understanding of the mechanisms by which the variants result in the disease risk. The functional studies can include interactions with other variants and environmental factors.

Currently sequencing is most commonly done by the Sanger method, with reads of up to several hundred bases. Whole-genome shotgun sequence is easiest to produce, but PCR methods allow targeted sequencing of particular regions. New technologies promise highly parallel sequence production of millions of reads. In the next few years it will probably become feasible to sequence thousands of samples for particular genome regions, and soon after to sequence thousands of entire human genomes. As the costs decrease, presumably sequencing will replace genotyping for obtaining comprehensive information on variation and relating it to disease.

Objectives

The goal of this FOA is to support the development of statistical methods for designing sequencing studies, for analyzing the data to find associations with phenotypes, to narrow down and prioritize regions for further study, and to provide information on possible functional roles of the variation. Because of LD, statistical methods will generally allow the identification of sets of variants that possibly contain variants that affect function, without allowing the identification of the specific causal variants. This FOA supports the development of methods that statistically analyze the sequence data to identify sets of associated variants that contain functional variants, and to provide clues about function that will guide the choice of sets of variants for later functional studies and the types of functional studies to be done. There are several areas where such statistical analyses need to be developed.

The design and analysis of genome-wide association studies by genotyping is an active area of research. There may be ways that such studies could be designed that would facilitate sequencing studies. The results from genotyping studies, either of whole genomes or of candidate regions, will provide information on regions that are associated with the disease phenotypes; there may also be additional information that is useful for the design of sequencing studies.

A major question is how should sequencing studies be designed, to be done in the next few years or longer term. What should be the basis for choosing the number of samples and the specific samples and genomic regions to be sequenced, and what should be the extent of sequencing within regions?

Interpreting the results of sequencing studies in coding regions may be relatively straightforward. Some variants change the structure of proteins, although even these differences do not always result in a change in function. The functional interpretation of variants in non-coding regions is more difficult; features such as the distribution of allele frequencies may need to be considered.

Making associations between sets of variants and disease phenotypes raises many issues. The large number of variants and phenotypes means that there are multiple comparisons, and the LD patterns mean that many variants are not independent of each other. It can be difficult to establish phenotype associations for rare variants; methods will be needed that deal with many rare variants in regions.

Analysis of sequence data may require development of population genetics methods that provide neutral models and ways of testing the data for deviations from these models. Such deviations can arise from non-uniform mutation rates, population history, stratification, and admixture. Natural selection can also cause these deviations, with different results expected for negative selection against deleterious variants, positive selection for advantageous variants, balancing selection, and other modes of selection.

Sequence data may provide information on function when combined with other types of data, such as the patterns of genetic variation in other species, information on the location of coding and non-coding genetic elements, and patterns of expression and epigenetic marks.

The changing sequencing technologies and anticipated large increase in sequencing capacity are expected to be transformative, changing the scale and types of questions that can be asked. These will raise new statistical challenges for analyzing sequence data. Applicants are encouraged to address such issues.

This FOA will not support sample collection, sequencing, the development of algorithms for base-calling or assembly, phenotype collection, or functional studies. Simulated data may be used if appropriate. If needed for the methods development, applicants are expected to have sequence data and, if appropriate, phenotype and possibly exposure data available for analysis by the time they are needed during the development process. Data from model organisms may be used, as such data are frequently available for model organisms before they are available for humans, allowing methods development that can then be applied to human data. Applicants are encouraged to use publicly available data, or to provide data that can be broadly shared (consistent with human subjects protection and the consent processes). An update on available sequence data can be obtained from NIMH program staff (see Section VII below for contact).

Examples of questions that applicants may address include the following; applicants are also encouraged to address related questions:

1. What should be the criteria for choosing genomic regions from genome-wide or candidate region genotyping association studies for sequencing? How could genotyping studies be designed to better support sequencing studies? This includes the choice of samples, choice of tag SNPs, and choice of phenotypes.

2. How should sequencing studies be designed? What should be the criteria for choosing samples and regions to be sequenced? How extensive should the sequencing be? How far around an association peak? For what relative costs of different stages of sequencing would multi-stage designs be efficient?

3. How do technical issues of doing the sequencing--such as sequence accuracy, false positive and false negative variants, sequence assembly, stretches that are difficult to sequence, structural variants, polymorphisms in primers, and rare variants--relate to interpreting the associations with phenotypes and inferences about functional variants in regions?

4. What statistical analysis issues do the new sequencing technologies raise?

5. How can variants in coding regions (non-synonymous and synonymous) be associated with phenotypes and function?

6. How can variants in non-coding regions be associated with phenotypes and function?

7. How can associations be made with many rare variants? How can information about the frequency distribution of variants be used?

8. How can multi-marker information be used? How can haplotype information be used?

9. How should statistical significance be assessed, taking into account multiple comparisons and non-independence (LD) among the variants? How can the rates of false positive findings and false negative findings be estimated?

10. How can population genetics models be used to interpret the data?

11. How should admixture or population stratification be dealt with?

12. What patterns of data show evidence for non-neutral processes, such as natural selection?

13. How can comparisons with data from other species be useful (single genomic sequences or whole or regional genomic sequences from multiple individuals)?

14. How can sequence data be combined with other types of data to provide information on disease association or function?

15. What additional sequencing studies are needed to validate the sequencing results and to follow up on them?

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 Announcement (FOA) will use the NIH Research Project Grant (R01) award mechanism. The applicant will be solely responsible for planning, directing, and executing the proposed project.

This FOA uses Just-in-Time information concepts. It also uses the modular as well as the non-modular budget formats (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are a U.S. organization and are submitting an application with direct costs in each year of $250,000 or less (excluding consortium Facilities and Administrative [F&A] costs), which is the direct cost limit in this FOA, use the PHS398 Modular Budget component provided in the SF424 (R&R) Application Package and SF424 (R&R) Application Guide (see specifically Section 5.4, Modular Budget Component, of the Application Guide).

All 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, August 23, 2006.

2. Funds Available

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 Institutes and Centers (ICs) provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds and the submission of a sufficient number of meritorious applications.

The NIH has committed $2 million total costs in FY2008 ($6 million over the total project period of three years) to fund applications in response to this FOA. The total project period for an application submitted in response to this FOA may not exceed three years. Five to six awards are anticipated to be funded under this FOA, at up to $250,000 in direct costs per year per award, plus applicable Facilities and Administrative (F&A) costs. F&A costs requested by consortium participants are not included in the direct cost limitation. See NOT-OD-05-004, November 2, 2004.

The GEI includes an allocation of funds to the Intramural Research Program at the NIH, which does not diminish the funds allocated to this FOA for extramural applications. The awards to intramural scientists will be limited to the incremental costs required for participation. These awards will not include any salary or fringe benefits for federal employees with permanent appointments or any costs related to administrative or facilities support (equivalent to F&A costs).

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

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

http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-007.html
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-006.html

1.B. Eligible Individuals

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

More than one PD/PI, or multiple PDs/PIs, may be designated on the application for projects that require a team science approach that clearly does not fit the single-PD/PI model. Additional information on the implementation plans and 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://era.nih.gov/ElectronicReceipt/preparing.htm for instructions).

The decision of whether to apply for a single PD/PI or multiple PD/PI grant is the responsibility of the investigators and applicant organizations and should be determined by the scientific goals of the project. Applications for multiple PD/PI grants will require additional information, as outlined in the instructions below. The NIH review criteria for approach, investigators, and environment have been modified to accommodate applications involving either a single PD/PI or multiple PDs/PIs. 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 PD/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.

Investigators from the NIH Intramural Research Program (IRP) are eligible to participate in the NIH-wide Genes, Environment, and Health Initiative (GEI), including this FOA. This will expand the resources available to GEI, by encouraging participation of intramural investigators whose salaries are already supported by the NIH. NIH is seeking a broad range of studies for inclusion in GEI, and recognizes that potentially meritorious studies may be ongoing within the IRP. Expanding this program to include IRP investigators will help GEI meet its goals of including the most highly scientifically meritorious projects, accessing diverse population samples, and ensuring programmatic balance across disease areas. It will also assist in meeting goals for enhancing intramural-extramural collaborations as outlined in the 2003 Institute of Medicine Report, Enhancing the Vitality of the National Institutes of Health. IRP investigators will not directly compete for the R01 funds. They will submit requests to compete for the IRP funds allocated for GEI. Requests for the participation of the NIH IRP will be competitively reviewed.

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

Applicants may submit more than one application, provided each application is scientifically distinct.

Section IV. Application and Submission Information

To download a SF424 (R&R) Application Package and SF424 (R&R) Application Guide for completing the SF424 (R&R) forms for this FOA, link to http://www.grants.gov/applicants/apply_for_grants.jsp and follow the directions provided on that Web site.

A one-time registration is required for institutions/organizations at both:

PDs/PIs should work with their institutions/organizations to make sure they are registered in the eRA Commons.

Several additional separate actions are required before an applicant institution/organization can submit an electronic application, as follows:

1) Organizational/Institutional Registration in Grants.gov/Get Registered

2) Organizational/Institutional Registration in the eRA Commons

3) Project Director/Principal Investigator (PD/PI) Registration in the NIH eRA Commons: Refer to the NIH eRA Commons System (COM) Users Guide.

Both the PD/PI(s) and AOR/SO need separate accounts in the NIH eRA Commons since both are authorized to view the application image.

Note that if a PD/PI is also an NIH peer-reviewer with an Individual DUNS and CCR registration, that particular DUNS number and CCR registration are for the individual reviewer only. These are different than any DUNS number and CCR registration used by an applicant organization. Individual DUNS and CCR registration should be used only for the purposes of personal reimbursement and should not be used on any grant applications submitted to the Federal Government.

Several of the steps of the registration process could take four weeks or more. Therefore, applicants should immediately check with their business official to determine whether their organization/institution is already registered in both Grants.gov and the Commons. The NIH will accept electronic applications only from organizations that have completed all necessary registrations.

1. Request Application Information

Applicants must download the SF424 (R&R) application forms and the SF424 (R&R) Application Guide for this FOA through Grants.gov/Apply.

Note: Only the forms package directly attached to a specific FOA can be used. You will not be able to use any other SF424 (R&R) forms (e.g., sample forms, forms from another FOA), although some of the "Attachment" files may be useable for more than one FOA.

For further assistance, contact GrantsInfo: Telephone 301-710-0267, Email: GrantsInfo@nih.gov.

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

2. Content and Form of Application Submission

Prepare all applications using the SF424 (R&R) application forms and in accordance with the SF424 (R&R) Application Guide for this FOA through Grants.gov/Apply.

The SF424 (R&R) Application Guide is critical to submitting a complete and accurate application to NIH. There are fields within the SF424 (R&R) application components that, although not marked as mandatory, are required by NIH (e.g., the Credential log-in field of the Research & Related Senior/Key Person Profile component must contain the PD/PI’s assigned eRA Commons User ID). Agency-specific instructions for such fields are clearly identified in the Application Guide. For additional information, see Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

The SF424 (R&R) application has several components. Some components are required, others are optional. The forms package associated with this FOA in Grants.gov/APPLY includes all applicable components, required and optional. A completed application in response to this FOA includes the data in the following components:

Required Components:
SF424 (R&R) (Cover component)
Research & Related Project/Performance Site Locations
Research & Related Other Project Information
Research & Related Senior/Key Person
PHS398 Cover Page Supplement
PHS398 Research Plan
PHS398 Checklist
PHS398 Modular Budget or Research & Related Budget, as appropriate (See Section IV.6., Special Instructions, regarding appropriate required budget component.)
Research & Related Budget (required for foreign applications)

Optional Components:
PHS398 Cover Letter File
Research & Related Subaward Budget Attachment(s) Form

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

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.

Applications from foreign organizations must:

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.

SPECIAL INSTRUCTIONS

Applications with Multiple PDs/PIs

When multiple PDs/PIs are proposed, NIH requires one PD/PI to be designated as the "Contact PI, who will be responsible for all communication between the PDs/PIs and the NIH, for assembling the application materials outlined below, and for coordinating progress reports for the project. The contact PD/PI must meet all eligibility requirements for PD/PI status in the same way as other PDs/PIs, but has no other special roles or responsibilities within the project team beyond those mentioned above.

Information for the Contact PD/PI should be entered in item 15 of the SF424 (R&R) Cover component. All other PDs/PIs should be listed in the Research & Related Senior/Key Person component and assigned the project role of PD/PI. Please remember that all PDs/PIs must be registered in the eRA Commons prior to application submission. The Commons ID of each PD/PI must be included in the Credential field of the Research & Related Senior/Key Person component. Failure to include this data field will cause the application to be rejected.

All projects proposing Multiple PDs/PIs will be required to include a new section describing the leadership of the project.

Multiple PD/PI Leadership Plan: For applications designating multiple PDs/PIs, a new section of the research plan, entitled Multiple PD/PI Leadership Plan (Section 14 of the Research Plan Component in the SF424 (R&R)), 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, including 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.

Applications Involving a Single Institution

When all PDs/PIs are within a single institution, follow the instructions contained in the SF424 (R&R) Application Guide.

Applications Involving Multiple Institutions

When multiple institutions are involved, one institution must be designated as the prime institution and funding for the other institution(s) must be requested via a subcontract to be administered by the prime institution. When submitting a detailed budget, the prime institution should submit its budget using the Research & Related Budget component. All other institutions should have their individual budgets attached separately to the Research & Related Subaward Budget Attachment(s) Form. See Section 4.8 of the SF424 (R&R) Application Guide for further instruction regarding the use of the subaward budget form.

When submitting a modular budget, the prime institution completes the PHS398 Modular Budget component only. Information concerning the consortium/subcontract budget is provided in the budget justification. Separate budgets for each consortium/subcontract grantee are not required when using the Modular budget format. See Section 5.4 of the Application Guide for further instruction regarding the use of the PHS398 Modular Budget component.

3. Submission Dates and Times

See Section IV.3.A. for details.

3.A. Submission, Review, and Anticipated Start Dates (Revised, see NOT-MH-07-120)
Opening Date: August 20, 2007 (Earliest date an application may be submitted to Grants.gov)
Letters of Intent Receipt Date(s): August 20, 2007
NOTE: On time submission requires that applications be successfully submitted to Grants.gov no later than 5:00 p.m. local time (of the applicant
institution/organization).
Application Receipt Date(s): September 20, 2007
Peer Review Date(s): February 2008
Council Review Date(s): May 2008
Earliest Anticipated Start Date(s): July 1, 2008
Additional Information To Be Available Date (Activation Date): Not Applicable
Expiration Date: September 21, 2007

3.A.1. Letter of Intent

Prospective applicants are asked to submit a letter of intent that includes the following information:

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:

Thomas Lehner, Ph.D.
Division of Neuroscience and Basic Behavioral Science
National Institute of Mental Health
6001 Executive Boulevard, Room 7195, MSC 9643
Bethesda, MD 20892-9643
Telephone: (301) 443-1411
FAX: (301) 402-4720
Email: tlehner@mail.nih.gov

3.B. Submitting an Application Electronically to the NIH

To submit an application in response to this FOA, applicants should access this FOA via http://www.grants.gov/applicants/apply_for_grants.jsp and follow steps 1-4. Note: Applications must only be submitted electronically. PAPER APPLICATIONS WILL NOT BE ACCEPTED.

In order to expedite the review, applicants are requested to notify the NIMH Referral Office by email NIMHReferral@mail.nih.gov when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.

3.C. Application Processing

Applications may be submitted on or after the opening date and must be successfully received by Grants.gov no later than 5:00 p.m. local time (of the applicant institution/organization) on the application submission/receipt date(s). (See Section IV.3.A. for all dates.) If an application is not submitted by the receipt date(s) and time, the application may be delayed in the review process or not reviewed.

Once an application package has been successfully submitted through Grants.gov, any errors have been addressed, and the assembled application has been created in the eRA Commons, the PD/PI and the Authorized Organization Representative/Signing Official (AOR/SO) have two business days to view the application image.

Upon receipt, applications will be evaluated for completeness by the CSR and responsiveness by the NIMH. Incomplete and non-responsive applications will not be reviewed.

There will be an acknowledgement of receipt of applications from Grants.gov and the Commons. The submitting AOR receives the Grants.gov acknowledgments. The AOR and the PI receive Commons acknowledgments. Information related to the assignment of an application to a Scientific Review Group is also in the Commons.

Note: Since email can be unreliable, it is the responsibility of the applicant to check periodically on their application status in the Commons.

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.

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.

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

6. Other Submission Requirements

PD/PI Credential (e.g., Agency Login)

The NIH requires the PD/PI(s) to fill in his/her Commons User ID in the PROFILE Project Director/Principal Investigator section, Credential log-in field of the Research & Related Senior/Key Person Profile component.

Organizational DUNS

The applicant organization must include its DUNS number in its Organization Profile in the eRA Commons. This DUNS number must match the DUNS number provided at CCR registration with Grants.gov. For additional information, see Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

PHS398 Research Plan Component Sections

Items 2-5 of the PHS398 Research Plan component are limited to 25 pages. While each section of the Research Plan component needs to be uploaded separately as a PDF attachment, applicants are encouraged to construct the Research Plan component as a single document, separating sections into distinct PDF attachments just before uploading the files. This approach will enable applicants to better monitor formatting requirements such as page limits. All attachments must be provided to NIH in PDF format, filenames must be included with no spaces or special characters, and a .pdf extension must be used.

All application instructions outlined in the SF424 (R&R) Application Guide are to be followed, incorporating "Just-in-Time" information concepts, and with the following additional requirements:

Special Instructions for Modular Grant applications

R01 applications from U.S. institutions/organizations requesting up to $250,000 per year in direct costs (excluding consortium F&A costs) must be submitted in a modular budget format. Additional information on modular budgets is available at http://grants.nih.gov/grants/funding/modular/modular.htm. When submitting a modular budget, the applicant organization will include only the PHS398 Modular Budget component. See Section 5.4 of the SF424 (R&R) Application Guide for further instructions regarding the use of the PHS398 Modular Budget component.

Foreign organizations may not submit modular budgets. See NOT-OD-06-096.

Appendix Materials

NIH has published new limitations on grant application appendix materials to encourage applications to be as concise as possible while containing the information needed for expert scientific review. See http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-018.html.

Applicants must follow the specific instructions on Appendix materials as described in the SF424 (R&R) Application Guide (See http://grants.nih.gov/grants/funding/424/index.htm).

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

Note: While each section of the PHS398 Research Plan component needs to be uploaded separately as a PDF attachment, applicants are encouraged to construct the Research Plan component as a single document, separating sections into distinct PDF attachments just before uploading the files. This approach will enable applicants to monitor better formatting requirements such as page limits. All attachments must be provided to NIH in PDF format, filenames must be included with no spaces or special characters, and a .pdf extension must be used.

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

Special Application Requirements

Applicants are expected to document access to existing DNA sequence data, and if appropriate, to phenotype data and possibly exposure data. Applicants should describe all relevant phenotypic and environmental exposure measures from the study.

Applicants are expected to provide a plan to share analytical methods and tools with the scientific community in a timely manner, and should address any concerns regarding intellectual property. Any application that does not include this information will be considered non-responsive.

Applicants should include funds in their budget to attend a yearly meeting for this program in the Bethesda, MD, area for about three people from their research group.

Applications that include the recruitment of human subjects, collection of biological samples, large-scale sequencing, collection of phenotypic and other medical data, or functional studies will be considered non-responsive and returned to the applicant. The methods are intended to be applied to human data, but sequence data from other organisms may be considered with strong justification.

If selected, NIH intramural scientists will participate in GEI programs as Principal Investigators in accord with the Terms and Conditions of Award provided in this FOA.

Plan for Sharing Research Data

All applicants must include a plan for sharing research data and methods. The reasonableness of the data sharing plan or the rationale for not sharing research data and methods will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score.

NIH encourages the development of analysis tools based on data that are broadly available to the research community. These include datasets that are publicly available or available through databases such as dbGaP.

All participants in the GEI Sequence Analysis RFA are expected to promote the GEI Sequence Analysis Group policies on data access, publication, and intellectual property as summarized below, and describe their methods for doing so in the applications. NIH will establish mechanisms to monitor agreement with these policies.

The NIH expects that all GEI-supported data, results, methods, and tools will remain freely available, without licensing requirements, for uses such as, but not limited to, methods and tools for identifying markers that can be used for new potential targets for drugs, therapeutics, and diagnostics. The intent is to discourage the use of patents that would prevent use or block access to any methods or tools developed with GEI support. The NIH encourages broad use of GEI Sequence Analysis methods and tools that are consistent with a responsible approach to management of intellectual property derived from downstream discoveries as outlined in NIH’s Best Practices for the Licensing of Genomic Inventions and the NIH Research Tools Policy (http://grants.nih.gov/grants/intell-property_64FR72090.pdf).

Intellectual property will be managed in accord with established policy of the NIH in compliance with Executive Order 10096, as amended, 45 CFR Part 7; patent rights for inventions developed in NIH facilities are NIH property unless NIH waives its rights.

Sharing Research Resources

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

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

As the analysis components of the GEI are community resource projects, the NIH expects that the resources generated during the course of this program (e.g., analytic methods and tools) will be made rapidly available to the research community. The applicant should provide specific plans for resource sharing and distribution in the application.

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

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 NIMH in accordance with the review criteria stated below.

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

Undergo a selection process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed and assigned a priority score.

Applications submitted in response to this funding opportunity will compete for available funds with all other recommended applications. The following will be considered in making funding decisions:

The goals of NIH supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application.

Note that an application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward.

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

Approach: Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? For applications designating multiple PDs/PIs, is the leadership approach, including the designated roles and responsibilities, governance, and organizational structure, consistent with and justified by the aims of the project and the expertise of each of the PDs/PIs?

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

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

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

Additional Criteria:

2A. Additional Review Criteria

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

Protection of Human Subjects from Research Risk: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. See the Human Subjects Sections of the PHS398 Research Plan component of the SF424 (R&R).

While it is recognized that no new data collection will occur in applications in response to this RFA, this section should address issues of confidentiality of the existing data and availability or not of identifying information on the samples.

Inclusion of Women, Minorities and Children in Research: If Exemption 4 cannot be claimed for Human Subjects above, this section should also be included and addressed as appropriate. If Exemption 4 is claimed, this section need not be addressed.

The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated. See the Human Subjects Sections of the PHS398 Research Plan component of the SF424 (R&R)

2B. Additional Review Considerations

Data Sharing: The plans for data sharing should be evaluated by reviewers, but not included in the priority score for the application.

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

Applications from Foreign Organizations: Whether the project presents 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 will be assessed.

2C. Sharing Research Data

Data Sharing Plan: The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score. The presence of a data sharing plan will be part of the terms and conditions of the award. The funding organization will be responsible for monitoring the data sharing policy.

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

The NIH has identified the Methods of Statistical Analysis of DNA Sequence Data for Studies Relating Variation to Disease component of GEI as a community resource project. As such, the program aims to function openly by making all data (i.e., analysis methods and tools) available to the scientific community in a timely manner prior to publication, with suitable restrictions for protection of human research subjects. The applicant should provide specific plans for data release in the application.

2.D. Sharing Research Resources

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

Reviewers will be asked to assess the adequacy of the resources sharing plan. However, Program staff will be responsible for the administrative review of the plan for sharing research resources.

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

3. Anticipated Announcement and Award Dates

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 NIH 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 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 and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities.

3. Reporting

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

Section VII. Agency Contacts

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

1. Scientific/Research Contact(s):

Thomas Lehner, M.D., M.P.H.
National Institute of Mental Health
6001 Executive Boulevard, Room 7195, MSC 9643
Bethesda, MD 20892-9643
Telephone: (301) 443-1411
Fax: (301) 402-4740
Email: tlehner@mail.nih.gov

Lisa Brooks, Ph.D.
Division of Extramural Research
National Human Genome Research Institute
5635 Fishers Lane, Suite 4076, MSC 9305
Bethesda, MD 20892-9305
Telephone: (301) 435-5544
Email: lisa.brooks@nih.gov

Review Contact(s):

David Armstrong, Ph.D.
Division of Extramural Activities
National Institute of Mental Health
6001 Executive Boulevard, Room 6138, MSC 9606
Bethesda, MD 20892-9606
Telephone: (301) 443-3534
Email: armstrda@mail.nih.gov

3. Financial/Grants Management Contact(s):

Victoria Carper, MPA
Division of Extramural Activities
National Institute of Mental Health
6001 Executive Boulevard, Room 6118, MSC 9608
Bethesda, MD 20892-9608
Telephone: (301) 443-3858
Email: carpervictoria@mail.nih.gov

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 (45 CFR 46) 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. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score.

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

Sharing of Model Organisms:
NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm). At the same time the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with Federal funding pursuant to the Bayh Dole Act (see the NIH Grants Policy Statement. Beginning October 1, 2004, all investigators submitting an NIH application or contract proposal 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 SF424 (R&R) application; 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-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov/). It is the responsibility of the applicant to provide in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s) to be used in the proposed research. Applications that do not provide this information will be returned without review.

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

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

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

Standards for Privacy of Individually Identifiable Health Information:
The Department of Health and Human Services (HHS) 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 HHS 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) or PubMed Central (PMC) submission identification numbers must be used for publicly accessible on-line journal articles. Publicly accessible on-line journal articles or PMC articles/manuscripts accepted for publication that are directly relevant to the project may be included only as URLs or PMC submission identification numbers accompanying the full reference in either the Bibliography & References Cited section, the Progress Report Publication List section, or the Biographical Sketch section of the NIH grant application. A URL or PMC submission identification number citation may be repeated in each of these sections as appropriate. There is no limit to the number of URLs or PMC submission identification numbers that can be cited.

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 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 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 PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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

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