THE ROLE OF GENE-ENVIRONMENTAL INTERACTIONS UNDERLYING THE HEALTH DISPARITY OF PREMATURE BIRTH RELEASE DATE: May 1, 2002 PA NUMBER: PA-02-102 EXPIRATION DATE: January 1, 2005, unless reissued. National Institute of Child Health and Human Development (NICHD) (http://www.nichd.nih.gov) National Institute of Environmental Health Sciences (NIEHS) (http://www.niehs.nih.gov) National Institute of Nursing Research (NINR) (http://www.ninr.nih.gov) THIS PA CONTAINS THE FOLLOWING INFORMATION o Purpose of the PA o Research Objectives o Mechanism of Support o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Submitting an Application o Peer Review Process o Review Criteria o Award Criteria o Required Federal Citations PURPOSE OF THIS PA The National Institute of Child Health and Human Development (NICHD), the National Institute of Environmental Health Sciences (NIEHS) and the National Institute of Nursing Research (NINR) are seeking research grant applications on the role of gene-environmental interactions underlying the health disparity of premature birth in the U.S. This solicitation specifically addresses the need to better understand how adverse societal, behavioral, and environmental conditions alter gene expression and interact with diverse genetic backgrounds to increase a woman's susceptibility for premature birth in high-risk racial and ethnic groups. The solicitation encourages multidisciplinary approaches to clarify the potential role of genetics in the increased risk of premature birth in these disadvantaged populations. RESEARCH OBJECTIVES Background Significant differences exist in health outcomes among different groups within the U.S. population. These differences in health outcomes, or health disparities, are particularly prominent when comparing the morbidity and mortality between and among various racial and ethnic populations. One of these health disparities is the incidence of premature birth, which is defined as birth prior to 37 weeks of gestation. In the U.S., approximately 10 percent of all births are premature. This accounts for approximately 400,000 infants born annually. Most of the infant mortality and morbidity of premature birth is associated with the one to two percent of infants born very premature (birth at less than 32 weeks of gestation). Excluding congenital malformations, premature birth accounts for approximately 70 percent of all neonatal deaths and results in nearly 50 percent of long-term neurological problems. The incidence of premature birth, however, is not equally distributed among races and ethnic groups. For example, African- Americans have the highest rate of premature birth, followed by Mexican- Americans, Asians, and Caucasians. Strikingly, African-Americans are 1.8 times more likely to deliver premature infants and 2.3 times more likely to deliver very premature infants than Caucasians. Consequently, premature birth is the leading cause of neonatal mortality and morbidity in African- Americans, surpassing congenital malformations. The majority of the health disparity of premature birth is commonly associated with racial and ethnic groups living under the burden of adverse societal, behavioral, and environmental conditions. These adverse factors include low social and economic status, racism, stress, sexually transmitted disease, tobacco/alcohol/drug use, and exposure to environmental toxins. Epidemiological studies indicate that over half of this health disparity can be attributed to these adverse conditions. However, it is unclear how these conditions alter a woman's biology to increase the risk of premature birth. Furthermore, not all women who live under the same adverse conditions deliver prematurely. Consequently, a genetic susceptibility may, in part, underlie the increased risk of premature birth in these high-risk populations. In the general population, there is suggestive evidence that genetics may contribute to premature birth. There is a familial tendency for premature birth, and the best predictor for a premature delivery is a prior premature delivery. It is unclear, however, if genetics play a major role in premature birth in these cases. It is argued that the familial tendency may be due to family members sharing similar living conditions. Similarly, it is posited that the increased tendency for recurring premature delivery may be due to exposure to the same environmental conditions that precipitated the first premature birth. The role of genetics in the health disparities of premature birth is also controversial. For example, 50 percent of the health disparity of premature birth in African-American women can be accounted for by correcting for adverse risk factors such as income, social status, psychological characteristics or medical diagnoses; nonetheless, it still remains higher than that of Caucasian women. The reason for this remaining health disparity is unclear, but a genetic component is speculated among other contributing factors, such as an increased rate of uterine infection. Although it is known that particular genetic traits that lead to disease may be more frequent in distinct population groups, the generalization of these findings to whole races or ethnic groups is suspect because of the lack of consideration given to the inherent genomic diversity contained within these populations. Furthermore, particular genetic traits, which increase susceptibility to disease, may be commonly shared between races and ethnic groups, but are only phenotypically manifested under certain environmental conditions generally associated with particular racial or ethnic populations. Therefore, the role of genetics in the health disparity of premature birth requires clarification. The major objective of this PA is to determine the role of gene-environmental interactions and genetic diversity in the health disparity of premature birth. This PA specifically addresses the need to better understand how adverse societal, behavioral, and environmental conditions alter gene expression and interact with diverse genetic backgrounds to increase a woman's susceptibility for premature birth in high-risk racial and ethnic groups in the U.S. Furthermore, the PA addresses the need for the identification and functional characterization of genetic markers that increase the risk of premature birth among these high-risk populations. Multidisciplinary applications linking biomedical scientists with social and behavioral scientists are highly encouraged. This PA is designed as a step in reducing one of the major disparities in health outcomes, one of the NIH Areas of Emphasis and incorporated in the FY 2001-2006 Department of Health and Human Services Strategic Plan, which is available at: http://aspe.hhs.gov/hhsplan/. Research Scope To address these research needs, this PA seeks research projects focused on one or more of the following goals: o Determine changes in gene or protein expression under adverse societal, behavioral or environmental conditions to identify candidate genes, or their corresponding proteins, that may be involved in increasing a woman's susceptibility for premature delivery in high-risk racial and ethnic populations in the U.S. Examples include, but are not limited to, studies utilizing gene or protein expression profiling by high-throughput platforms, such as DNA arrays, protein arrays, and protein capture/SELDI-TOF mass spectrometry. o Determine the functional relevance of an identified gene or protein for increasing a woman's susceptibility for premature delivery under adverse societal, behavioral or environmental conditions in high-risk racial and ethnic populations in the U.S. Examples include, but are not limited to, studies elucidating the function or mechanism of action of an identified gene or protein in precipitating premature delivery. o Determine genomic differences that serve as potential candidate markers for increasing a woman's susceptibility for premature delivery under adverse societal, behavioral or environmental conditions in high-risk racial and ethnic populations in the U.S. Examples include, but are not limited to, linkage studies using high-throughput genotyping platforms to uncover genomic differences, such as sequence repeats and multiple or single nucleotide polymorphisms. o Determine the functional relevance of candidate genomic markers associated with an increased risk for premature birth in high-risk racial and ethnic populations in the U.S. Examples include, but are not limited to, studies that determine the functional consequence of these markers as it relates to gene expression, function, or regulation. Special Considerations Applications identifying candidate genes and polymorphisms, as well as candidate proteins, associated with an increased susceptibility for premature delivery in the general population are acceptable, but should also contain a significant component(s) relating the research to the health disparity of premature birth in the U.S. In addition, relevant animal studies will not be excluded, but the proposed research should also include a translational component using human subjects that directly links the animal research to the health disparity of premature birth in the U.S. Applicants are encouraged to consider the complexity of issues surrounding the meaning and assessment of race and ethnicity, since an individual's identification with a particular racial or ethnic group may involve not only an individual's genetic background, but also an individual's cultural and geographical identity. As appropriate for their particular proposals, applicants should consider the following: the degree of genomic heterogeneity within racial and ethnic populations and that genetic differences may not apply broadly to a specific race or ethnic group; and the new Office of Management and Budget (OMB) directives on classifying race and ethnicity. NIH policy on reporting race and ethnicity data based on OMB directives was published in the NIH Guide for Grants and Contracts on August 8, 2001, and is available at: https://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-053.html. Since the NIEHS expanded its research agenda through the Environmental Genome Project, the NIEHS is particularly interested in applications that examine the complex interplay of genes and the environment. The understanding of the critical role of genetic susceptibility and sensitivity to environmental exposures will lead to more effective disease prevention and improved public health. Further information on the Environmental Genome Project can be found at http://www.niehs.nih.gov/envgenom/home.htm. MECHANISM OF SUPPORT This PA will use the NIH research project grant (R01) award mechanism. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. This PA uses just-in-time concepts. It also uses the modular as well as the non-modular budgeting formats (see https://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular format. Otherwise follow the instructions for non- modular research grant applications. ELIGIBLE INSTITUTIONS You may submit an application if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS 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. WHERE TO SEND INQUIRIES We encourage your inquiries concerning this PA and welcome the opportunity answer questions from potential applicants. Inquiries may fall into two areas: scientific/research and financial or grants management issues: o Direct your questions about scientific/research issues to: John V. Ilekis, Ph.D. Pregnancy and Perinatology Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 4B03, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 435-6895 FAX: (301) 496-3790 Email: ilekisj@mail.nih.gov Kimberly Gray Kamins, Ph.D. Chemical Exposures and Molecular Biology Branch National Institute of Environmental Health Sciences P.O. Box 12233 111 T.W. Alexander Drive, MD EC-21 Research Triangle Park, NC 27709 Telephone: (919) 541-0293 FAX: (919) 316-4606 Email: gray6@niehs.nih.gov Yvonne Bryan, Ph.D., R.N. Division of Extramural Activities National Institute of Nursing Research 45 Center Drive, Room 3AN-12, MSC 6300 Bethesda, MD 20892-6300 Telephone: (301) 594-6908 FAX: (301) 480-8260 Email: yvonne_bryan@nih.gov o Direct your questions about financial or grants management matters to: Christopher Myers Grants Management Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 8A17, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 435-6996 FAX: (301) 402-0915 Email: cm743g@nih.gov Dwight Dolby Grants Management Branch National Institute of Environmental Health Sciences P.O. Box 12233 111 T.W. Alexander Drive, MD EC-22 Research Triangle Park, NC 27709 Telephone: (919) 541-7824 FAX: (919) 541-2860 Email: dolby@niehs.nih.gov Cindy McDermott Chief, Office of Grants and Contracts Management National Institute of Nursing Research 45 Center Drive, Room 3AN-12, MSC 6300 Bethesda, MD 20892-6300 Telephone: (301) 594-6869 FAX: (301) 480-8260 Email: cindy_mcdermott@nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at https://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. APPLICATION RECEIPT DATES: Applications submitted in response to this program announcement will be accepted at the standard application deadlines, which are available at https://grants.nih.gov/grants/dates.htm. Application deadlines are also indicated in the PHS 398 application kit. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in a modular grant format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at https://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at https://grants.nih.gov/grants/funding/modular/modular.htm. SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR: Applications requesting $500,000 or more in direct costs for any year must include a cover letter identifying the NIH staff member within one of NIH institutes or centers who has agreed to accept assignment of the application. Applicants requesting more than $500,000 must carry out the following steps: 1) Contact the IC program staff at least six weeks before submitting the application, i.e., as you are developing plans for the study; 2) Obtain agreement from the IC staff that the IC will accept your application for consideration for award; and, 3) Identify, in a cover letter sent with the application, the staff member and IC who agreed to accept assignment of the application. This policy applies to all investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended or revised version of these grant application types. Additional information on this policy is available in the NIH Guide for Grants and Contracts, October 19, 2001, at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the checklist, and five 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 Bethesda, MD 20817 (for express/courier service) APPLICATION PROCESSING: Applications must be received by or mailed on or before the receipt dates described at https://grants.nih.gov/grants/funding/submissionschedule.htm. The CSR will not accept any application in response to this PA that is essentially the same as one currently pending initial review unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of a substantial revision of an application already reviewed, but such application must include an Introduction addressing the previous critique. PEER REVIEW PROCESS Applications submitted for this PA will be assigned on the basis of established PHS referral guidelines. An appropriate scientific review group convened in accordance with the standard NIH peer review procedures (http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific and technical merit. As part of the initial merit review, all applications will: o Receive a written critique o 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 o Receive a second level review by the appropriate national advisory council or board REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application's overall score, weighting them as appropriate for each application. Your 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, you may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) SIGNIFICANCE: Does your study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? What will be the effect of these studies on the concepts or methods that drive this field? (2) APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the Principal Investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: PROTECTIONS: The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. INCLUSION: 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. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below.) BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. AWARD CRITERIA Applications submitted in response to a PA will compete for available funds with all other recommended applications. The following will be considered in making funding decisions: o Scientific merit of the proposed project as determined by peer review o Availability of funds o Relevance to program priorities REQUIRED FEDERAL CITATIONS 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 AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (https://grants.nih.gov/grants/guide/notice- files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at https://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 RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. 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 that is available at https://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 proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts, dated June 5, 2000, at https://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 https://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. 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 Nos. 93.865 (NICHD), 93.361 (NINR), and 93.113 and 93.115 (NIEHS), and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies described at https://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 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.
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