PREVALENCE AND DIAGNOSIS OF CELIAC DISEASE Release Date: June 10, 1999 RFA: DK-99-015 P.T. National Institute of Diabetes and Digestive and Kidney Diseases Letter of Intent Receipt Date: June 22, 1999 Application Receipt Date: July 22, 1999 THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. THIS RFA INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING AN APPLICATION IN RESPONSE TO THIS RFA. PURPOSE The Division of Digestive Diseases and Nutrition of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) wishes to encourage experienced and new investigators to pursue research that will establish the prevalence and diagnosis of celiac disease in various at risk populations in the United States. This information should lead to increased awareness of the disorder and encourage proper diagnosis and treatment. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS led national activity for setting priority areas. This Request for Applications (RFA), PREVALENCE AND DIAGNOSIS OF CELIAC DISEASE, is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2000" at http://www.crisny.org/health/us/health7.html ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic 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. Foreign organizations are not eligible to apply; however, domestic organizations may have a foreign component, but it should not be the major research site. 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), interactive research project grants (IRPG), and the exploratory/developmental grant (R21) award mechanism. The total project period for a research project grant (R01) application submitted in response to this RFA may not exceed 5 years. The maximum dollar request for R01 applications is limited to $500,000 in direct costs for any one year. The Exploratory/Developmental Grant (R21) award provides funds for exploratory research projects (maximum of $100,000 in direct costs per year for two years). Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. These grants are non- renewable, but continuation of projects developed under this program can be supported by the investigator-initiated research project grant (R01). All applications submitted in response to this RFA must be submitted in the MODULAR GRANT and JUST-IN-TIME formats. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. 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 Institute staff. Complete and detailed instructions and information on Modular Grants can be found at http://www.nih.gov/grants/funding/modular/modular.htm. The IRPG mechanism encourages interaction and collaboration among independent scientists with common goals. It is intended to bring together research projects from investigators who wish to collaborate but who do not require extensive shared resources. There should be constructive interchange of ideas, data and/or materials. A minimum of two independent investigators are encouraged to submit concurrent, collaborative, cross-referenced individual regular research (R01) applications. These applications must be free-standing and contain independent hypotheses and aims. An application that provides only a service to other applicants is not acceptable. Applicants may be from one or several institutions. Potential applicants contemplating the submission of an IRPG should contact the program official listed under INQUIRIES as early as possible. Guidelines for preparing IRPG applications are available from the program official or from the internet at: https://grants.nih.gov/grants/guide/pa-files/PA-96-001.html Applicants will request direct costs in $25,000 modules, up to a total direct cost request of $500,000 per year for an R01 application and $100,000 per year for an R21 application. A typical modular grant application will request the same number of modules in each year. Applicants from institutions which have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC program director or principal investigator should be included with the application. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The anticipated award date is April 1, 2000. FUNDS AVAILABLE It is anticipated that for FY 2000, approximately $1,000,000 total costs will be available for the first year of support for this initiative. However, this funding level is dependent upon the receipt of a sufficient number of applications of high scientific merit. Although this program is provided for in the financial plans of the NIDDK, the award of grants pursuant to this RFA is also contingent upon the availability of funds for this purpose. It is anticipated that up to 3 to 5 new grants will be awarded under this program. RESEARCH OBJECTIVES Celiac disease (celiac sprue) is an autoimmune, gastrointestinal disorder characterized by intolerance to dietary gluten. The large majority of patients with celiac disease have at least one copy of the MHC type 2 HLA-DQ2 gene, but only a minority of persons with this genotype develop celiac disease. The "classic" presentation is among children who present with chronic diarrhea, bloating, anemia, and failure to gain weight. More recently, this disease has been diagnosed increasingly among adults, who may have minimal gastrointestinal symptoms and mild manifestations of malabsorption. Relatives of celiac patients are at increased risk as are persons with other autoimmune diseases such as type 1 diabetes mellitus and primary biliary cirrhosis. Celiac disease is commonly diagnosed in Western Europe, but is rarely identified in the United States, even among persons descended from European immigrants. The possible reasons for this difference in clinical recognition include: U.S. physicians may often fail to detect typical celiac disease; celiac disease may be common but causes atypical or mild symptoms; or the disease may actually be uncommon due to the influence of unknown environmental factors. Recently, specific and sensitive serological markers for celiac disease have been developed that allow for screening of patients and special populations. These tests include antigliadin antibody, IgA endomysium antibody, and the newer IgA tissue transglutaminase (tTG) antibody. Application of specific serological assays to particular patient populations should facilitate a better understanding of celiac disease in the U.S. The role of serological testing in either screening or evaluation of high-risk populations has not been defined. It is also not clear how HLA testing should be applied to diagnosis. Of primary interest are studies that will define the prevalence of celiac disease in high-risk groups. These groups could include, but are not limited to, relatives of patients with celiac disease, persons with autoimmune conditions such as insulin dependent diabetes mellitus and primary biliary cirrhosis, patients with diarrhea predominant functional bowel disease, persons with IgA deficiency, and persons with early onset osteoporosis. Such studies would require diagnostic confirmation of celiac disease using standard tests, including small bowel mucosal biopsy. For persons with antibody markers but not meeting criteria for diagnosis, despite full diagnostic evaluation, clinical characterization and natural history are of interest. Also of interest are population-based studies across the age range of different sex and ethnic groups that would determine antibody presence and association with other immunological markers, including HLA genotypes. It is anticipated that through systematic studies, this research will determine whether celiac disease is as rare as sometimes perceived in the United States and will define the utility of diagnostic testing in various populations. A goal of this RFA is to obtain information on celiac disease across as many identifiable groups as possible. 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 subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided 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 "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994 available on the web at the following URL address: http://www.nih.gov/grants/guide/1994/94.03.18/notice-nih-guideline008.html 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. 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 was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://www.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. LETTER OF INTENT Prospective applicants are asked to submit, by June 22, 1999, 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 the RFA in response to which the application may be submitted. 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 NIDDK staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be mailed or faxed to: Chief, Review Branch Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 6AS-37F, MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8885 FAX: (301) 480-3505 APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 4/98). Application kits are available at most institutional offices of sponsored research and may be obtained 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, email: GrantsInfo@nih.gov. The RFA label available in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of the application. 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 (PREVALENCE AND DIAGNOSIS OF CELIAC DISEASE) and number (DK-99-015) must be typed on line 2 of the face page of the application form and the YES box must be marked. 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 Institute 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. BUDGET INSTRUCTIONS 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: PHS 398 o FACE PAGE - Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $500,000) 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 - Use a Modular Grant Budget Narrative page. (See http://www.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. o PERSONNEL - Under Personnel, list key 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 facilities and administrative) 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 key 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. 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://www.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. It is important to identify all exclusions that were used in the calculation of the F&A costs for the initial budget period and all future budget years. o CONTACT - The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. APPLICATIONS NOT CONFORMING TO THESE GUIDELINES WILL BE CONSIDERED UNRESPONSIVE TO THIS RFA AND WILL BE RETURNED WITHOUT FURTHER REVIEW. 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 time of submission, two additional copies of the application must be sent to: Chief, Review Branch Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 6AS-37F, MSC 6600 Bethesda, MD 20892-6600 Applications must be received by July 22, 1999. If an application is received after that date, it will be returned to the applicant without review. Similarly, supplemental documents containing significant revision or additions will not be accepted after that date, unless applicants are notified by the Scientific Review Administrator. 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 previously 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 responsiveness by NIDDK. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive will be evaluated for scientific and technical merit by an appropriate scientific review group convened by the NIDDK in accordance with the standard NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed, assigned a priority score, and receive a second level review by the National Diabetes and Digestive and Kidney Diseases Advisory 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? All applications will also be evaluated for their ability to achieve the stated goals of the RFA. 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. The personnel category will be reviewed for appropriate staffing based on the requested percent effort. The direct costs budget request will be reviewed for consistency with the proposed methods and specific aims. Any budgetary adjustments recommended by the reviewers will be in $25,000 modules. The duration of support will be reviewed to determine if it is appropriate to ensure successful completion of the requested scope of the project. AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit as determined by peer review o Availability of funds o Programmatic priorities o The distinction from other meritorious proposals in regards to the study populations Schedule Letter of Intent Receipt Date: June 22, 1999 Application Receipt Date: July 22, 1999 Date of Initial Review: October - November 1999 Review by Advisory Council: February 2, 2000 Anticipated Award Date: April 1, 2000 INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: James Everhart, M.D., M.P.H. Division of Digestive Diseases and Nutrition National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 6AN-12J, MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8878 FAX: (301) 480-8300 Email: firstname.lastname@example.org Direct inquiries regarding fiscal matters to: Ms. Sharon Bourque Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 6AS-49, MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8846 FAX: (301) 480-3504 Email: email@example.com AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.848. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. 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 and contract 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, and 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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