| Supplement Title: |
Administrative Supplements for Gene Identification Efforts: Replication and Fine-Mapping Studies: The Genes, Environment, and Health Initiative (GEI) |
| Available Funds: |
$2,000,000 |
| Request Receipt Deadline: |
May 1, 2008 |
| First Possible Award Date: |
September 1, 2008 |
Eligibility Requirements
On behalf of the NIH, the NCI is announcing the availability of administrative supplements for NIH-funded genetic association studies, aimed at identifying genetic factors involved in complex trait etiology. The purpose of this funding opportunity is to provide support for replication studies (with or without fine-mapping) of genetic regions putatively associated with the studied complex trait(s). This opportunity for eligible applicants to request administrative supplement support was developed as part of the NIH-wide Genes, Environment, and Health Initiative (GEI, http://www.gei.nih.gov/). All NIH Institutes and Centers participate in NIH-wide initiatives.
This opportunity to request administrative supplement support will be open to all current NIH awardees of R01, P01, and P50 grants and U01, U19, and U54 cooperative agreements provided that the following conditions are met:
- The "parent" award must be for a project or program involving genetic association studies (preferably involving a genome-wide association, or "GWA," component), well described and justified in terms of evidence for genetic factors contributing to disease susceptibility and/or trait variation, appropriateness of the proposed study design and study population, definition of case and control status (assuming population-based design), power of the sample set to detect a genetic effect, and analysis plan;
- Any phenotype can be proposed for investigation in the supplement request, provided it is related to the phenotype proposed and reviewed in the original award (NOTE: Acceptable phenotypes need not be cancer or cancer-related);
- The proposed replication study or fine-mapping effort must be clearly within the scope of the peer-reviewed "parent" award without duplication of efforts (NOTE: The proposed replication study or fine-mapping effort may not be currently supported by NIH or any other funding agency);
- The "parent" award must remain active during the entire funding period of this supplement; and
- The Principal Investigator (PI) for the supplement must be the PI of the "parent" award.
NOTE: Contracts are not eligible for supplements under this mechanism.
[Return to Top]
Research Objective
Recent advances in molecular technologies and the availability of the human genome sequence have revolutionized researchers’ ability to cost-effectively catalogue human genetic variation. In addition, the international HapMap project has provided researchers with invaluable information regarding the linkage disequilibrium structure within the genome, thereby allowing for the selection of haplotype tagging single nucleotide polymorphisms (SNPs). These considerable advances have made whole genome association studies a reality.
To date, numerous genome-wide association studies (GWAS) of complex traits have yielded promising results. However, follow-up studies are needed to eliminate false positives, extend the findings to diverse populations (diverse in terms of ethnicity or environmental exposures) and related phenotypes, and narrow the association interval. The purpose of this funding opportunity is to provide support to eligible NIH award holders for replication and fine-mapping studies of genetic regions putatively associated with the studied complex trait(s) (primarily those identified by GWA studies), with the aim of maximizing the productivity of NIH-funded GWAS. The overall goal of these efforts is to advance our understanding of the roles of genetic and environmental factors in complex disease etiology.
For this opportunity, "replication" is defined as assaying a subset of the most strongly associated SNPs or other genetic variants in one or more additional study populations. Fine-mapping is defined as additional genotyping of SNPs or other genetic variants not included in the original genotyping platform for a gene or region that has been replicated as associated with a disease or trait.
A replication study alone or a replication study plus a fine-mapping effort may be proposed. Fine-mapping alone would be considered non-responsive.
This funding opportunity includes support for:
- Genotyping of select genetic polymorphisms;
- Specimen preparation and transfer;
- Data analysis; and
- Modest amount of additional support for the PI and/or new collaborators, if needed to bring in the replication study populations.
This initiative will not support recruitment of human subjects, collection of human specimens, collection of medical or phenotype data, or studies using animal models. Applications that include recruitment of human subjects, collection of human specimens, collection of medical or phenotype data, or studies using animal models will be considered non-responsive and returned to the applicant.
NOTE: Priority in funding will be given to studies with one or more of the following characteristics:
- Synergy with NIH’s Gene Environment Association studies (GENEVA, RFA HG-07-014, http://www.genevastudy.org, see NIH press release at http://genome.gov/26022424);
- Breadth of available phenotypic (disease susceptibility or trait variation) and exposure measures for study participants and plans for sharing data with the research community through databases such as dbGAP (http://www.ncbi.nlm.nih.gov/sites/entrez?db=gap);
- Focus on replication in original discovery population, if little replication information is available to date (e.g., a study that focused on replicating "hits" in a recent GWAS using a similar study population); and
- Focus on populations not included in the initial GWAS or subsequent replication studies, such as a group with different exposures, as these environmental differences may be an important reason why some GWAS results do not replicate across studies;
- Focus on populations not included in the initial GWAS or subsequent replication studies, such as a different race/ethnic group (e.g., priority would be given to a study that focused on populations of African origin for associations that have been discovered and replicated in populations of European ancestry);
NOTE: These supplements are not intended to support discovery genome-wide association efforts; however, consideration may be given to trying to find resources within or outside GEI to perform such a study in very well-characterized participants in populations other than those studied to date. This possibility would depend on finding sufficient funds so as not to impede other GEI replication efforts, or on reprogramming GEI funds with the approval of the NIH GEI Coordinating Committee.
Investigators will be encouraged to accept genotyping support through an NIH GEI-funded genotyping center, but could have the option of accepting support through the investigator’s award, assuming they could provide adequate justification including data quality and cost-effectiveness.
If an award is made, the applicant institution would be expected to make de-identified individual-level genotype and phenotype data publicly available for approved research purposes within the NIH GWAS data repository, dbGAP, at the NIH National Center for Biotechnology Information (NCBI) (as described in NIH Guide Notice NOT-OD-07-088, Policy for Sharing of Data Obtained in NIH Supported or Conducted GWAS). Please note that the NIH policy for sharing of data obtained in NIH supported or conducted GWAS also addresses publication and intellectual property issues.
[Return to Top]
Funds Available
The NIH has committed $2,000,000 (total costs) in FY 2008 to fund five or six administrative supplements in response to this announcement. An applicant may request a project period of 1 year and a budget for total costs of up to $400,000.
Although the financial plans of the NIH provide support for the Genes, Environment, and Health initiative, administrative supplement awards pursuant to this announcement are contingent upon the availability of funds and the receipt of a sufficient number of meritorious requests.
[Return to Top]
Application Procedure
P01 and U19 grantees must identify the individual project for which they are seeking supplemental funds. Multiple requests from P01 and U19 grantees are acceptable. However, separate supplement requests must be submitted for individual components of the parent P01 or U19 grant and only one supplement per grant or cooperative agreement may be awarded.
If the "parent" award is a U01, U19, or U54 cooperative agreement award, explain briefly how the project will fit within the U01/U19/U54 cooperative agreement terms and conditions of award.
All applications should be submitted using the format of the PHS 398 application.
All requests must include the following:
- Cover letter:
Request the supplement and refer to notice number: NOT-CA-08-011.
- If applicable, state intent to submit a request for a no-cost extension.
- Include the following statement: "Per supplement instructions, a detailed budget request for the initial budget period is enclosed."
- PHS 398 Face page (PHS 398, Form Page 1):
- Item 1: The request should have the same title as the "parent" award. (Please include the number of the "parent" award.)
- Item 2: Identify as NOT-CA-08-011 "Administrative Supplements for Gene Identification Efforts: Replication and Fine-Mapping Studies for The Genes, Environment, and Health Initiative (GEI)."
- Item 3: The request must have the same PI as the "parent" award.
- Item 6: Request a single year of support. NOTE: There must be an active "parent" award during the entire funding period. Request a no-cost extension if necessary.
- PHS 398 Description, Project/Performance Sites, Senior/Key Personnel, Other Significant Contributors, and Human Embryonic Stem Cells (PHS 398, Form Page 2)
- PHS 398 Detailed Budget for Initial Budget Period (PHS 398, Form Page 4):
- All applicants can request up to $400,000 in total costs but must provide a detailed budget.
- Biographical sketches for NEW key personnel
- Research Plan (not to exceed 5 pages):
Provide a brief description of the proposed replication. Applicants should provide detailed summary information regarding the GWAS that identified the genetic regions as being associated with the disease or trait and why the regions should be a priority for a replication study. Applicants should summarize known/documented replication efforts, whether published, in progress, or planned. The replication study population should be well described in comparison to the origin of the original "discovery" study population. In addition, requests should address the power of the replication sample set to detect a smaller genetic effect than reported in the original study in order to address potential publication bias and the "winner’s curse" phenomenon.
- Relevant letters of support.
Requests should contain enough detail to allow assessment of the scientific merit of the proposed replication study and the appropriateness of the request for supplemental funding. Budgets should not exceed $400,000 in total costs for a time period not exceeding 12 months. All requests require an itemized budget and must be signed by the grantee institution's business office. Requests for administrative supplements under this program must comply with NIH policies for inclusion of women, minorities, and children in research involving human subjects.
The earliest anticipated award date for this program will be September 1, 2008.
[Return to Top]
Submission of Administrative Supplement Request
Requests for these administrative supplements must be submitted by May 1, 2008. If a request is received after this date, it will be returned to the applicant without review.
Please note that the NIH Center for Scientific Review (CSR) IS NOT involved in receipt and processing of these requests. The NCI will receive these administrative supplement requests directly.
Please submit a signed original request and five signed, single-sided photocopies, in one package to:
Elizabeth Gillanders, Ph.D.
Epidemiology and Genetics Research Program
Division of Cancer Control and Population Sciences
National Cancer Institute
6130 Executive Boulevard, EPN Room 5140, MSC 7324
Bethesda, MD 20892-7324 (for U.S. Postal Service express or regular mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: 301-594-5868
E-mail: lgilland@mail.nih.gov
NOTE: REQUESTS HAND-DELIVERED BY INDIVIDUALS TO THE NATIONAL CANCER INSTITUTE WILL NO LONGER BE ACCEPTED. This policy does not apply to courier deliveries (e.g., FEDEX, UPS, DHL, etc.) (http://grants.nih.gov/grants/guide/notice-files/NOT-CA-02-002.html).
[Return to Top]
Review Considerations
Upon receipt, requests will be reviewed for completeness and for responsiveness by the NCI. Incomplete and/or non-responsive requests will not be reviewed.
NIH program staff members (and appropriate outside consultants) who have expertise in genetic association studies, as well as the proposed phenotypes will evaluate administrative supplement requests that are complete and responsive to the supplement announcement. Only those requests that describe research deemed to have the highest scientific merit will be considered for funding.
[Return to Top]
Review Criteria
The goal of these NIH-supported administrative supplements for replication and fine mapping studies is to minimize false positive associations. The long-term goal of the Genes, Environment, and Health initiative is to “support research that will lead to the understanding of genetic contributions and gene-environment interactions in common disease.” NIH program staff and outside consultants will evaluate the following aspects of the administrative supplement requests in order to judge the likelihood that the proposed project will have a substantial impact on the pursuit of these goals. Each of the following criteria will be addressed and considered by the reviewers, weighting them as appropriate for each request. The administrative supplement request does not need to be strong in all categories in order for it to receive a favorable evaluation. 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.
The five categories of review criteria to be used in the evaluation of these administrative supplement requests are listed below.
1. Significance: Does this study address an important public health problem? Does the application address a significant and genetically complex trait and demonstrate the need for a replication study for this trait? 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?
2. Approach: Are the conceptual framework, design, methods, and analyses adequately developed? Are they well described, well integrated, well reasoned, well justified, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? Are the study design and population chosen well described and appropriate for the aims proposed? Have the sources and “representativeness” of study subjects been clearly described? Have any potential biases in subject selection been identified, and are the applicants’ approaches for minimizing these biases appropriate? When scientifically appropriate to the trait or disease being studied, are important exposures or covariates available for analysis? Are the phenotype and exposure measures of sufficient quality and completeness to provide maximal scientific value from the addition of targeted genotyping? Are the proposed plans to share data in a timely manner adequate?
3. Innovation: Are the aims original and innovative? Does the proposed 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? What advantages does the project offer for replication and fine-mapping studies of genetic regions putatively associated with the studied complex trait(s). What advantages does the study offer for discriminating true positive results from the large number of false positive results expected with genome wide association studies? What advantages does it offer for follow-up studies to identify causative genetic variants and develop diagnostic, preventive, or therapeutic strategies?
4. 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?
5. Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed studies take advantage of unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support? Is the bioinformatics infrastructure sufficient to accomplish the goals of the project?
In addition to the above criteria, the initial review also will examine the administrative supplement requests for demonstration of the following items: the appropriateness of the proposed project budget and duration; and the adequacy of plans to include both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Finally, the provisions for the protection of human subjects from risk relating to their participation in the proposed research and the safety of the study environment will be examined.
[Return to Top]
Award Criteria
Requests for administrative supplements will be considered for award based upon the following criteria: (a) scientific and technical merit of the proposed replication and fine-mapping study; (b) programmatic relevance and balance among diseases; (c) synergy with other funded projects; and (d) availability of funds.
Additional criteria for award will include:
- Public health significance of disease/trait to be studied;
- Potential for addressing minority health and health disparities relevant to the U.S. population;
- Quality and ease of use of the data set as assessed by NCBI; and
- Quality and quantity of DNA available for genotyping.
[Return to Top]
Required Federal Citations
ALL REQUIRED FEDERAL CITATIONS for PHS grants apply to this administrative supplement including the following:
Human Subjects Protection:
Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).
Sharing Research Data:
Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing).
Investigators should seek guidance from their institutions, on issues related to institutional policies and local institutional review board (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.
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 PA 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.
Inclusion of Women And Minorities in Clinical Research:
It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.
Inclusion of Children as Participants in Clinical Research:
The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all clinical research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them.
All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects (http://grants.nih.gov/grants/funding/children/children.htm).
Required Education on the Protection of Human Subject Participants:
NIH policy requires education on the protection of human subject participants for all investigators submitting NIH applications for research involving human subjects and individuals designated as key personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.
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 (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 funding opportunity 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.
[Return to Top]
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 2 years to the research. For further information, please see http://www.lrp.nih.gov.
[Return to Top]
Inquiries
Direct inquiries concerning the dissemination supplements and administrative review matters to:
Elizabeth Gillanders, Ph.D.
Epidemiology and Genetics Research Program
Division of Cancer Control and Population Sciences
National Cancer Institute
6130 Executive Boulevard, EPN Room 5140, MSC 7324
Bethesda, MD 20892-0001 (for U.S. Postal Service express or regular mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: 301-594-5868
E-mail: lgilland@mail.nih.gov
Direct inquiries regarding administrative and fiscal matters to:
Crystal Wolfrey
Office of Grants Administration
National Cancer Institute
6120 Executive Boulevard, EPS Room 243, MSC 7150
Bethesda, MD 20892-7150 (for U.S. Postal Service express or regular mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: 301-496-8634
E-mail: crystal.wolfrey@nih.gov
[Return to Top]
|
