RFA-HD-01-005: HEALTH DISPARITY IN PRETERM BIRTH: THE ROLE OF INFECTIOUS AND INFLAMMATORY PROCESSES

Department of Health
and Human Services (HHS)

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HEALTH DISPARITY IN PRETERM BIRTH: THE ROLE OF INFECTIOUS AND INFLAMMATORY PROCESSES Release Date: December 14, 2000 RFA: HD-01-005 National Institute of Child Health and Human Development (http://www.nichd.nih.gov) Letter of Intent Receipt Date: January 29, 2001 Application Receipt Date: March 12, 2001 THIS RFA USES THE MODULAR GRANT AND JUST-IN-TIME CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA. PURPOSE The purpose of this Request for Applications (RFA) is to determine the role of infectious and inflammatory processes leading to preterm birth and adverse neonatal outcomes in different ethnic populations. The research proposed in response to this solicitation should involve multidisciplinary investigations to clarify the potential role of infectious diseases and the associated immune response as a cause of early preterm birth and fetal and neonatal morbidity. 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 Request for Applications (RFA) is related to one or more of the priority areas. Potential applicants may obtain "Healthy People 2010" at http://www.health.gov/healthypeople/. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non- profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) Research Project Grant (R01) award mechanism. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. This RFA is a one-time solicitation. Future unsolicited competing continuation R01 applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. The anticipated award date is December 1, 2001. Specific application instructions have been modified to reflect MODULAR GRANT and JUST-IN-TIME streamlining efforts being examined by the NIH. Complete and detailed instructions and information on Modular Grant applications can be found at http://grants.nih.gov/grants/funding/modular/modular.htm. FUNDS AVAILABLE The NICHD intends to commit approximately $1.5 million in total costs [Direct plus Facilities and Administrative (F&A) costs] in FY 2001 to fund four to seven new grants in response to this RFA. An applicant may request a project period of up to five years and a budget for direct costs of up to $200,000 per year. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plans of the NICHD provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. RESEARCH OBJECTIVES Background Health disparities are major contributors to the morbidity and mortality associated with many disease conditions in the United States. Among the most striking of U.S. health disparities is the rate of preterm births among African American women. Preterm delivery accounts for 70 percent of perinatal mortality and nearly half of the long-term neurologic morbidity of newborns. Despite years of intense effort to reduce preterm delivery rates, approximately ten percent of all births in the United States are still preterm and the incidence of very early preterm births has been rising in recent years. Preterm births are twice as high among African American women as among any other group of women in the United States, with an even greater discrepancy in the rate of very early preterm birth. Our understanding of the underlying mechanisms of preterm birth is limited; less than half of all preterm births have an identifiable risk factor. Recent information suggests that infection/inflammation has an important, complex role in early preterm delivery and its sequelae. Up to 80 percent of early preterm births are associated with intrauterine infection that precedes the rupture of membranes; however, trials of antibiotic therapy in women with preterm labor and women with genital tract infections such as bacterial vaginosis have not been effective in preventing preterm delivery. A number of markers for delivery before 32 weeks, e.g., fetal fibronectin, cervical length, and bacterial vaginosis, also suggest a role for infection in preterm delivery. Intriguing preliminary information suggests that fetuses who are exposed to inflammation have an increased risk for arrested lung development and bronchopulmonary dysplasia, necrotizing enterocolitis, and cerebral palsy. The differences in distribution of preterm birth across U.S. population are unexplained; however, more African American women have bacterial vaginosis, histologic and clinical chorioamnionitis and postpartum endometritis, and genital tract infection. Some African American women also may have a low- grade chronic intrauterine infection before or between pregnancies that may be the cause of repeated spontaneous preterm births. These infections appear to be unrelated to age of onset of sexual activity or number of sexual partners. A history of a previous spontaneous preterm birth, especially in the second trimester, represents another important risk factor for preterm delivery The objectives of this RFA are to determine the role of infectious and inflammatory processes that result in preterm birth and adverse neonatal outcomes in different ethnic populations. The approach should involve multidisciplinary investigations to clarify the potential role of infectious diseases and the associated immune response as a cause of early preterm birth and fetal and neonatal morbidity. Because a large portion of the difference in infant mortality rates between African American and non-African American populations appears related to infection-induced preterm birth, this RFA 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. This RFA is intended to stimulate investigators interested in preterm birth/prematurity to focus on ethnic disparities and to create a body of data upon which future clinical trials may be developed. Research Scope To address these research needs, this RFA seeks research projects focused on one or more of the following goals: (a) To identify the determinants of the discrepancy among races in early preterm delivery associated with infectious/inflammatory disease, including infectious, immunologic, and genetic factors. (b) To examine mechanisms and timing of intrauterine infection/inflammation among racial/ethnic groups. Research topics that are responsive to the intent of this RFA include, but are not limited to, the following: o Potential mechanisms and timing of intrauterine infection/inflammation among racial/ethnic groups; o Potential mechanisms by which the mother and fetus respond to bacterial infection and the relative contributions of the maternal and fetal compartment to the overall inflammatory response, specifically evaluating the biology of the host response stratified along health disparities; o Identification of more discriminate markers for the diagnosis of subclinical maternal, fetoplacental, and neonatal infection and preterm delivery, including chronic uterine infection; o Research on the genetic component of very early preterm delivery associated with intrauterine infection/inflammation among different racial/ethnic groups; o Identification of susceptibility genes that may increase the risk of premature labor due to infectious/inflammatory stimuli; o Elucidation of the mechanism(s) by which inflammatory mediators (cytokines, chemokines, etc.) induce premature labor; o Identification of population-based differences in the local immune response to pathogens that result in uterine infection and/or inflammatory response; o Identification of mechanisms that result in a hyper-immune response to uterine or fetal infection/inflammation. Applications proposing solely epidemiologic and/or descriptive studies, or clinical trials on infection/inflammation as related to the racial disparities of preterm delivery, will not be considered responsive to this RFA. SPECIAL REQUIREMENTS Applicants are encouraged to consider the complexity of issues surrounding the meaning and assessment of race and ethnicity, and should consider collaborating with scientists in other disciplines when developing concepts and measures related to race and ethnicity. As appropriate for their particular proposals, applicants should consider the following: lack of congruence of biologic and social definitions of race and ethnicity; fluidity in racial and ethnic self-identification; and new Office of Management and Budget (OMB) directives on classifying race and ethnicity. In addition, community involvement in implementation of the proposed projects is strongly encouraged. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS 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 biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are 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 research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm. The revisions relate to NIH-defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to 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) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH 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 Inclusion of Children as Participants in Research Involving Human Subjects, published in the NIH Guide for Grants and Contracts, March 6, 1998, and available at: http://grants.nih.gov/grants/guide/notice-files/not98-024.html. Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. 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. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of this RFA. 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 NICHD staff to estimate the potential review workload and plan the review. The letter of intent is to be sent to Dr. Catherine Spong at the address listed under INQUIRIES, below, by January 29, 2001. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research, on the Internet at http://grants.nih.gov/grants/funding/phs398/phs398.html, and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892- 7910, telephone 301-710-0267, E-mail: grantsinfo@nih.gov. Application Instructions The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in- time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers, and NIH staff. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. For this RFA, Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $200,000 per year. The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $200,000) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period. Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD: Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT: Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION: Prepare a Modular Grant Budget Narrative page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the Total Direct Costs requested for each year. This is not a Form Page. Under Personnel, list all project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of Total Costs (Direct plus F & A) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of all personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the Letter of Intent to establish a consortium. Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH: The Biographical Sketch provides information used by reviewers in the assessment of each individual's qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm. - Complete the educational block at the top of the Form Page; - List position(s) and any honors; - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years; - List selected peer-reviewed publications, with full citations. o CHECKLIST: This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. o The applicant should provide the name and telephone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. Submission Instructions The RFA label available in the PHS 398 (rev. 4/98) application form must be stapled to the bottom of the face page of the application and must display the RFA number HD-01-005. A sample RFA label is available at http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. Please note this is in the pdf format. 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. 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 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application should be sent to: L. R. Stanford, Ph.D. Director, Division of Scientific Review National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 5E03, MSC 7510 Bethesda MD 20892-7510 Rockville MD 20852 (for express/courier service) Applications must be received by March 12, 2001. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA 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 substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and for responsiveness to this RFA by NICHD. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. 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 NICHD in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and may undergo a process in which only those applications deemed to have the highest scientific merit will be discussed, assigned a priority score, and receive a second level review by the National Advisory Child Health and Human Development Council. 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 the application 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 the 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. (1) Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? 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? Does the applicant acknowledge potential problem areas and consider alternative tactics? (3) Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (4) Investigator: Is the investigator 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 (if any)? (5) Environment: Does the scientific environment in which the 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? In addition, applications will be evaluated with respect to: o Justification of the definitions of race and ethnicity used in the proposal. o Discussion of the impact of the proposed definitions of race and ethnicity on the ability to interpret the findings and generalizability of the findings. o If appropriate, the applicability of animal models to the human model of infection-related preterm delivery. o The adequacy of the proposed plan to share data, if appropriate. In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research. o 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. Schedule Letter of Intent Receipt Date: January 29, 2001 Application Receipt Date: March 12, 2001 Peer Review Date: July 2001 Council Review: September 2001 Earliest Anticipated Start Date: December 1, 2001 AWARD CRITERIA Criteria that will be used to make award decisions include: o scientific and technical merit (as determined by peer review) o availability of funds o programmatic priorities. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or answer questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Catherine Y. Spong, M.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) 496-5577 FAX: (301) 496-3790 E-mail: spongc@exchange.nih.gov Or Linda Wright, M.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) 496-5577 FAX: (301) 496-3790 E-mail: wrightl@mail.nih.gov Direct inquiries regarding fiscal and administrative matters to: Douglas Shawver Grants Management Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 8A17E, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-1303 E-mail: shawverd@exchange.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.865. 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 and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-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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