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
National Heart, Lung, and Blood Institute (NHLBI), (http://www.nhlbi.nih.gov)
National Human Genome Research Institute (NHGRI), (http://www.nhgri.nih.gov)
National Institute of Environmental Health Sciences (NIEHS), (http://www.niehs.nih.gov)
National Institute of General Medical Sciences (NIGMS), (http://www.nigms.nih.gov)

Title: Design and Analysis of Genome-wide Association Studies

Announcement Type
New

Request For Applications (RFA) Number: RFA-HL-05-011

Catalog of Federal Domestic Assistance Number(s)
93.837, 93.838, 93.839, 93.172, 93.859, 93.114

Key Dates
Release Date: May 13, 2005
Letters of Intent Receipt Date: June 24, 2005
Application Receipt Dates: July 21, 2005
Peer Review Date: November – December, 2005
Council Review Date: February 9, 2006
Earliest Anticipated Start Date: April 1, 2006
Expiration Date: July 22, 2005

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(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
   4. Intergovernmental Review
   5. Funding Restrictions
   6. Other Submission Requirements

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

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

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

 Section VIII. Other Information - Required Federal Citations

Part II - Full Text of Announcement
Section I. Funding Opportunity Description

1. Research Objectives

The purpose of this RFA is to develop and test innovative, informative, and cost-effective study designs and analytical strategies to perform genome-wide association studies on complex diseases. Developing new, analytic and computational strategies and tools for genome-wide association studies that can be used by the scientific community to find genes associated with disease is the ultimate goal of this RFA. The strategies obtained from this effort will contribute to determining the utility of genome-wide association studies to understand human genetic variation and its role in health and disease.

Nature of the research opportunity:

To assist in the discovery of the genes and gene variants involved in health and disease, the NIH is participating in an international project to develop a haplotype map of the human genome (HapMap) (http://www.nhgri.nih.gov/10001688; http://www.hapmap.org/). Sites in the genome where individuals differ in their DNA sequence at a single base are called single nucleotide polymorphisms (SNPs). A haplotype is a pattern of SNPs along a region of a chromosome that is transmitted together from generation to generation. The coinheritance of SNPs on these haplotypes leads to association of the SNPs in the human population, and this is known as linkage disequilibrium (LD). On February 22, 2005, the International HapMap Consortium released the genotypes, frequencies, and assays for 1 million SNPs for the initial HapMap, with a density of at least 1 SNP per 5 kb throught the genome. A map of the common haplotypes will provide an important resource to perform candidate-gene and genome-wide association studies. However, as scientists develop plans to perform genome-wide association studies, it is increasingly apparent that the major barrier to further progress and success of these studies is determining which study designs and analytical methods are most appropriate. Hence, as the resources, data, and pilot testing of genome-wide association strategies emerge, approaches to use these resources in the most efficient way are warranted.

Pertinent background information:

Many common diseases are multi-factorial and complex in their presentation, progression, and outcome. They are influenced by a combination of multiple genetic and environmental factors. However, the identification of genetic susceptibility factors for common disease remains a challenge. Genome-wide association is a method to obtain information on the association of SNPs across the entire genome. This strategy does not rely on a hypothesis-based approach, but does require detailed information on SNPs and their patterns of LD. Genome-wide association may offer the power to detect genetic variation for common disease and variable drug response.

As DNA variation discovery continues by a number of laboratories and collaborations and as technologies improve and become more reliable and cost efficient, the major barrier in executing genome-wide association studies is in the study design and analytical methods. The most informative and cost-effective study designs and analytical approaches for genome-wide association studies have not been elucidated. Novel strategies and methods are needed to analyze multiple SNP markers simultaneously while also considering multiple genetic loci for disease susceptibility.

Scientific knowledge to be achieved:

The ability to discover genetic variants associated with health and disease will facilitate our understanding of the genetic contribution to the pathogenesis and progression of disease. Further, the genes and pathways discovered through genome-wide association studies may lead to new treatment strategies to maintain and restore health and prevent disease. Identification of genetic susceptibility factors may additionally be used to determine individual risk of disease and responses to treatment.

Objectives of this research program:

This initiative will support investigators to bring their expertise, knowledge, and large-scale genome association data together in order to develop innovative strategies for planning, initiating, conducting, and analyzing genome-wide association studies. All strategies and tools developed through these awards will be made available to the scientific community.

The NIH supports a number of studies and programs that investigate the genetics of complex diseases, as well as programs to facilitate gene variation discovery. The current need is for investment in strategies to use these resources and data efficiently and effectively.

The National Heart, Lung, and Blood Institute (NHLBI) leads a national program in the causes, diagnosis, treatment, and prevention of diseases of the heart, vessels, lungs, and blood, and sleep disorders. Included in these efforts are a number of programs and resources geared to understand the genetic basis complex disease. Identifying the underlying genetic factors that influence common, yet complex, diseases is an important step in understanding the mechanisms of these diseases and in identifying appropriate treatment strategies. The NHLBI is interested in determining what analysis methods and resources can be successfully applied to genome-wide association for the detection of genetic susceptibility factors for cardiovascular, pulmonary, hematological, and sleep diseases and disorders. The ultimate goal of such studies is to develop approaches for individual disease prevention and treatment, novel therapeutics, and maintenance of health.

The mission of the National Institute of Environmental Health Sciences (NIEHS) is to reduce the burden of human illness and dysfunction from environmental causes by understanding the interaction of environmental factors, individual susceptibility and age. The Environmental Genome Project (see http://www.niehs.nih.gov/envgenom/home.htm) is based on the scientific concept that the genetic makeup of an individual is a major factor in human disease resulting from exposure to environmental agents. The long-term goal of the Environmental Genome Project is to characterize specific genetic variations that contribute to susceptibility of environmentally induced disease. As part of the Environmental Genome Project, NIEHS resequenced a panel of human samples to identify single nucleotide polymorphisms (SNPs) in environmentally responsive genes. All of this information is available in the GENESNPs database (http://www.genome.utah.edu/genesnps/) and is available as a public resource in order to facilitate research on human genetic variants that contribute to genetic susceptibility to environmentally induced diseases .

The National Institute of General Medical Sciences (NIGMS) supports research aimed at improving the molecular-level understanding of fundamental biological processes and discovering approaches to their control. Research supported by the Pharmacology, Physiology, and Biological Chemistry Division takes a multifaceted approach to selected problems in pharmacology and physiology, with particular emphasis on anesthesia, wound healing, trauma and burn injury, pharmacogenetics, and clinical pharmacology and toxicology. Topics of interest under this RFA would include patient responses to anesthesia, perioperative pain, factors associated with wound healing, sepsis, systemic inflammatory responses (SIRS), traumatic injury, burn injury, multiple organ failure (MODS), and shock. Additionally, pharmacogenetics and studies of drug action including absorption, distribution, metabolism, transport, bioavailability and interactions of molecules with their targets are of interest. NIGMS seeks the genetic analysis of datasets derived from genome-wide studies in these clinical areas.

This RFA requires the use of genotyping data already obtained to develop novel genome-wide association strategies for gene discovery and apply them to elucidate the genetics of complex disease. Applicants should propose analytical and computational genomic association strategies using existing pilot data sets derived from high-density SNP association studies of large regions (multimegabase up to the entire genome) or large sets of densely genotyped candidate genes.

Proposed methods of analyses should not be separated from proposed study data sets, as funding generally will not be awarded for the data set, or analysis strategy, alone. Proposed analysis methods involving simulated data sets only are non-responsive. This RFA expects that each awardee will share analytical strategies, methods, and tools with the other awardees in the Program, and that each analytical strategy proposed will be exchanged and tried on each dataset used in the Program. The purpose of this exchange is to allow for the development of tools and methods that are reliable, portable, and can be used to replicate results on data obtained from different resources.

Examples of research questions that would be relevant for the development of U01 applications under this RFA include, but are not limited to:

Program organization:

The grants funded under this RFA will be cooperative agreements (see Section VI.2.A. Cooperative Agreement Terms and Conditions of Award). Close interaction among the participating investigators will be required, as well as significant involvement from the NIH, over a three-year period to develop appropriate strategies and tools to design, perform, and analyze genome-wide association studies. The grantees will meet as a Steering Committee 2-3 times per year and monthly on conference calls to share information on data resources, methodologies, analytical tools, as well as data and preliminary results. Key co-investigators, and pre- and postdoctoral trainees, in addition to the PIs, are eligible to attend these meetings. The cost of attending these meetings, as well as the costs associated with monthly conference calls, should be included in the proposed research budget. All methods, strategies, and analyses will be made available to the scientific community through a public web site and publication. During the course of this program, the NHLBI will evaluate the strategies developed by this program and explore funding opportunities to implement and apply them to genome-wide association studies of complex diseases.

The awardee(s) will:

The Program Officer will:

The Steering Committee will be responsible for coordinating the efforts of the awardees in the Program and for advising NIH as to how this Program can help to determine a proper approach to genome-wide association studies within the stated goals of time and accuracy and within budget. To address particular issues, the Steering Committee may establish other groups as needed, and these groups will include representatives from the awardees and funding agencies and possibly other experts. Examples of such groups are a technology group to coordinate development of novel tools and resources (e.g., software) for data analysis; a presentation and publications committee to develop Program policies for presentations, data sharing, and data flow; and a data quality group to standardize strategies and methodologies for data analysis. Member of the Steering Committee will be required to accept and implement the common guidelines and procedures approved by the Steering Committee.

This Program will be a collaborative effort that will require frequent interactions of awardees among each other and with NIH staff.

Applicants should explicitly indicate their willingness to:

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

This initiative will not support the recruitment of human subjects, collection of human samples, collection of phenotypic or medical data, or studies using animal models or genotyping of these samples.

To be responsive to this RFA, each application must include: (1) projected semiannual project milestones for the duration of funding, (2) plans to cooperate closely and share analytical strategies and findings with the other investigators funded by this RFA, (3) plans to integrate methods on the various data sets involved in this RFA; and (4) plans to share research resources and data with the scientific community (see Section V. 2., Review and Selection Process, and Section VI.2.A. Cooperative Agreement Terms and Conditions of Award).

Section II. Award Information

1. Mechanism(s) of Support

This funding opportunity will use the U01 award mechanism.

This funding opportunity uses the just-in-time budget concepts. It also uses the non-modular budget format described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/phs398/phs398.html). A detailed categorical budget for the "Initial Budget Period" and the "Entire Proposed Period of Support" is to be submitted with the application.

The NIH U01 is a cooperative agreement award mechanism. In the cooperative agreement mechanism, the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the Section VI. 2. Administrative Requirements, "Cooperative Agreement Terms and Conditions of Award."

2. Funds Available

NHLBI intends to commit approximately $1.8 million dollars (total costs) in FY 2006 to fund 5-6 new grants in response to this RFA.

NIEHS intends to commit approximately $500,000 dollars (total costs) in FY 2006 to fund 1-2 new grants in response to this RFA.

NIGMS intends to commit approximately $300,000 dollars (total costs) in FY 2006 to fund 1 new grant in response to this RFA.

NHGRI will participate in the management of the program.

An applicant may request a project period of up to 3 years and a budget for direct costs up to $200,000 dollars per year. The anticipated start date for awards is April 1, 2006.

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 NHLBI, NIEHS, and NIGMS provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications.

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

Section III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

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

An applicant's failure to meet an eligibility criterion by the time of an application deadline will result in the return of the application without review or, even though the application may be reviewed, will preclude the agency from making an award. Collaborators at foreign institutions are allowed.  

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs.

2. Cost Sharing or Matching

As defined in the current NIH Grants Policy Statement, this program does not require cost sharing (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part2.htm).

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

3. Other-Special Eligibility Criteria

To be responsive to this RFA, applicants should have data sets, such as those derived from high-density SNP association studies of large genomic regions. This initiative will support the utilization of data already obtained to develop novel strategies for genome-wide association studies.

Section IV. Application and Submission Information

1. Address to Request Application Information

The PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. Applicants must use the currently approved version of the PHS 398. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.

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

2. Content and Form of Application Submission

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

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

Foreign Organizations

Several special provisions apply to applications submitted by foreign organizations:

Proposed research should provide a unique research opportunity not available in the U.S.

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: June 24, 2005
Application Receipt Date(s): July 21, 2005
Peer Review Date: November – December, 2005
Council Review Date: February 9, 2006
Earliest Anticipated Start Date: April 1, 2006

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 NHLBI staff to estimate the potential review workload and plan the review.

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

The letter of intent should be sent to:

Dina N. Paltoo, Ph.D., M.P.H.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive
Rockledge II, Room 9180
Bethesda, MD 20892
Telephone: (301) 435-0513
FAX: (301) 480-1336
Email: paltood@mail.nih.gov

3.B. Sending an Application to the NIH

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

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

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

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

Rudy Pozzatti
National Human Genome Research Institute
Suite 4076, MSC 9306
5635 Fishers Lane
Bethesda, MD 20852
Telephone: (301) 402-0838
FAX: (301) 435-1580
Email: pozzattr@exhange.nih.gov

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

3.C. Application Processing

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

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

Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within eight (8) weeks.

4. Intergovernmental Review
This initiative is not subject to intergovernmental review.

5. Funding Restrictions

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

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

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

6. Other Submission Requirements

Grantees funded under this RFA should plan to attend 2-3 investigator meetings per year for the purpose of sharing information on data resources, methodologies, analytical tools, as well as any other findings resulting from this RFA. Key co-investigators and pre- and postdoctoral trainees are eligible to attend these meetings. The cost of attending committee meetings and any other related travel, resource development, and monthly conference calls should be included in the proposed research budget.

Applicants are required to submit: (1) projected semiannual project milestones for the duration of funding, (2) plans to cooperate closely and share analytical strategies and findings with the other investigators funded by this RFA, (3) plans to integrate methods on existing data sets involved in this RFA, and (4) plans to share research resources and data with the scientific community (see Section V. 2., Review and Selection Process, and Section VI. 2.A. Cooperative Agreement Terms and Conditions of Award).

Projected semiannual milestones should include semiannual goals for the project, plans for achieving these goals, and a timeline. If an award is made from this RFA, then the investigators will additionally include in each report their progress based on the milestones described and achieved since the prior report.

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

Plan for Sharing Research Data

The precise content of the data-sharing plan will vary, depending on the data being collected and how the investigator is planning to share the data. Applicants who are planning to share data may wish to describe briefly the expected schedule for data sharing, the format of the final dataset, the documentation to be provided, whether or not any analytic tools also will be provided, whether or not a data-sharing agreement will be required and, if so, a brief description of such an agreement (including the criteria for deciding who can receive the data and whether or not any conditions will be placed on their use), and the mode of data sharing (e.g., under their own auspices by mailing a disk or posting data on their institutional or personal website, through a data archive or enclave). Investigators choosing to share under their own auspices may wish to enter into a data-sharing agreement. References to data sharing may also be appropriate in other sections of the application.

All applicants must include a plan for sharing research data in their application. The 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.

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 applicants must agree to abide by the data sharing policies developed by the Steering Committee. These policies will cover frequency and methods of data sharing, types of data to share, and how to make the data and results public. The goal will be to provide as open access to the data, results, and methods developed as possible in keeping with confidentiality and consent protections.

Informed consent and confidentiality for each dataset proposed for use in this program must be explained in the data sharing plan. The Program funded under this RFA requires the sharing of strategies, tools, and potentially data sets between funded investigators. These requirements should be addressed in the data sharing plan.

Plans for sharing research data should be described on two levels (1) among the other investigators funded under this RFA, and (2) dissemination to the scientific community.

Sharing Research Resources

NIH policy requires 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.

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

Consistent with the goals of this RFA, research methods, tools, and results developed from this Program will be placed on a public website for others to use and apply to their research on genome-wide association studies.

Section V. Application Review Information

1. Criteria

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

The following will be considered in making funding decisions:

2. Review and Selection Process

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

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

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? Is the data set appropriate for the work and relevant to the RFA goals? Does the applicant provide an appropriate plan to share analytical strategies (and potentially the data set) among the other investigators funded in the program? Has the applicant included a plan to share data and research resources to further the field? Has the applicant included projected semiannual milestones for the duration of the proposed project?

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? Does the applicant address any issues concerning intellectual property, and does the applicant agree to public dissemination of the results from the award?

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

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

2.A. Additional Review Criteria:

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

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

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

To be responsive to this RFA, sharing of analysis methods on existing data sets from awardees funded by this RFA are necessary. Reviewers will be asked to assess the adequacy of this plan.

2.B. Additional Review Considerations

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

2.C. Sharing Research Data

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

Reviewers will be asked to assess the adequacy of the plan for data sharing (1) amongst the other investigators funded by this RFA, and (2) to the scientific community. However, Program staff will be responsible for the administrative review of the plan for sharing research data and resources.

2.D. Sharing Research Resources

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

Reviewers will be asked to assess the adequacy of the sharing plan for research resources

(1) among the investigators funded by this RFA, and (2) to the scientific community. Program staff will be responsible for the administrative review of the plan for sharing research resources.

Program staff will be responsible for the administrative review of the plan for sharing research resources.

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

3. Anticipated Announcement and Award Dates
Not applicable

Section VI. Award Administration Information

1. Award Notices

After the peer review of the application is completed, the Principal Investigator will also receive a written critique called a Summary Statement.

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

A formal notification in the form of a Notice of Grant Award (NGA) will be provided to the applicant organization. The NGA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the Notice of Grant Award will be generated via email notification from the awarding component to the grantee business official (designated in item 14 on the Application Face Page). If a grantee is not email enabled, a hard copy of the Notice of Grant Award will be mailed to the business official.

Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NGA 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 notice of grant award. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part4.htm) and Part II Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part9.htm).

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

2.A. Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when state and local governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement (U01) , 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 above.

2.A.1. Principal Investigator Rights and Responsibilities

The Awardee(s) will have the primary responsibility for all aspects of the study, including any modification of study design, conduct of the study, quality control, data analysis and interpretation, preparation of publications, and collaboration with other investigators, unless otherwise provided for in these terms or by action of the Steering Committee.

During the course of the program, analytic methods, strategies, protocols, and tools, and possibly data sets, will be shared among investigators on the Steering Committee. The resulting analytic methods, strategies, protocols, and tools will be shared with scientific community. The NIH Project Scientists, on behalf of the NIH, will have the same access, privileges and responsibilities regarding the analytic methods, strategies, protocols, and tools as the other members of the Steering Committee.

Support or other involvement of industry or any other third party in the study -- e.g., participation by the third party; involvement of study resources or citing the name of the study or NIH support; or special access to study results, data, findings or resources -- may be advantageous and appropriate. However, except for licensing of patents or copyrights, support or involvement of any third party will occur only following notification of and concurrence by NIH.

Study investigators are encouraged to publish and to release publicly and disseminate results and other products of the study, in accordance with Steering Committee protocols and governance.

It is expected that all methods, analyses, software, and algorithms will be made available in a timely manner to the scientific community. A plan for dissemination will be developed by the Steering Committee and approved by NIH.

Study investigators are encouraged to publish and to release publicly and disseminate results and other products of the study, in accordance with Steering Committee protocols and governance.

It is expected that all methods, analyses, software, and algorithms will be made available in a timely manner to the scientific community. A plan for dissemination will be developed by the Steering Committee and approved by NIH.

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.

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

The NIH Project Scientists will serve on the Steering Committee; he/she or other NIH scientists may serve on other study committees, when appropriate. The NIH will have 1-2 voting members on the Steering Committee. The NIH Project Scientists (and other NIH scientists) may work with awardees on issues coming before the Steering Committee and, as appropriate, other committees (e.g., methods development, assessment of problems affecting the study design and analysis, data analysis and interpretation, preparation of publications, and development of solutions to major problems). Additionally, the NIH Project Scientists will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. There will be one Project Scientist assigned per award. The NIH reserves the right to terminate or curtail the study (or an individual award) in the event of (1) failure to develop or implement a mutually agreeable collaborative protocol, (2) substantial shortfall in Program participation and collaboration with other awardees, (3) major breach of the protocols and strategies or substantive changes in the agreed-upon methodologies with which NIH cannot concur, or (4) human subject ethical issues that may dictate a premature termination.

2.A.3. Collaborative Responsibilities

Awardee(s) agree to the governance of the study through a Steering Committee. Steering Committee voting membership shall consist of the principal investigators (i.e., cooperative agreement awardees), the NIH Project Scientists, and the Chairperson. The NIH will have 1-2 voting members on the Steering Committee. Meetings of the Steering Committee will ordinarily be held by telephone conference call or in the metropolitan Washington area.

Each full member will have one vote. Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee.

2.A.4. Arbitration Process

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to arbitration. An Arbitration Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

3. Reporting

All awardees in this Program will be asked to define semiannual milestones at the time of award and to update these milestones every 6 months. These reports will be made a condition of award. In accordance with the procedures described above, NIH may withhold or reduce funds for projects that substantially fail to meet their milestones or to maintain an updated status.

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

Section VII. Agency Contacts

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

1. Scientific/Research Contacts:

Dina N. Paltoo, Ph.D., M.P.H.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive
Rockledge II, Room 9180
Bethesda, MD 20892
Telephone: (301) 435-0513
FAX: (301) 480-1336
Email: paltood@mail.nih.gov

Rochelle M. Long, Ph.D.
Pharmacology, Physiology, & Biological Chemistry Division
National Institute of General Medical Sciences
45 Center Dr., Rm. 2AS-49G
Bethesda, MD 20892-6200
Telephone: (301) 594-3827
FAX: (301) 480-2802
Email: rochelle_long@nih.gov

Kimberly A. McAllister, Ph.D.
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233 (MD EC-21)
Research Triangle Park, NC 27709
Telephone: (919) 541-4528
FAX: (919) 316-4606
Email: mcallis2@niehs.nih.gov

2. Peer Review Contacts:

Rudy Pozzatti
National Human Genome Research Institute
Suite 4076, MSC 9306
5635 Fishers Lane
Bethesda, MD 20852
Telephone: (301) 402-0838
FAX: (301) 435-1580
Email: pozzattr@exhange.nih.gov

3. Financial or Grants Management Contacts:

Anthony Agresti
Grants Operations Branch
National Heart, Lung, and Blood Institute
Rockledge II, Room 7138
6701 Rockledge Drive
Bethesda , MD 20892
Telephone: (301) 435-0171
FAX: (301) 480-3310
Email: agrestia@nhlbi.nih.gov

Section VIII. Other Information

Required Federal Citations

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. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score.

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: (1) 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 (2) 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.

Public 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 public 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.

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. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site.

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

Authority and Regulations: This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

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

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


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