TYPE 2 DIABETES IN THE PEDIATRIC POPULATION Release Date: December 1, 1999 RFA: DK-00-008 National Institute of Diabetes and Digestive and Kidney Diseases National Institute of Child Health and Human Development Letter of Intent Receipt Date: March 24, 2000 Application Receipt Date: April 25, 2000 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 National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Institute of Child Health and Human Development (NICHD) invite investigator-initiated research grant applications to study the epidemiology, natural history, pathophysiology, prevention and treatment of type 2 diabetes in children in the U.S. Type 2 diabetes has traditionally been viewed as a disease of adults. Recently, however, it has become apparent that an increasing number of cases of type 2 diabetes are being reported in children. This rise in type 2 diabetes in the pediatric population is presumed to be a consequence of widespread obesity and decreased physical activity among children. However, much of the available data concerning type 2 diabetes in children is anecdotal. This RFA is intended to stimulate epidemiologic, metabolic and clinical research into this important public health problem. The intent of this RFA is to intensify investigator-initiated research, to attract new investigators to the field and to encourage interdisciplinary approaches to research in this area. HEALTHY PEOPLE 2000 The Department of Health and Human Services (DHHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a DHHS-led national activity for setting priority areas. This RFA, Type 2 Diabetes in the Pediatric Population, is related to the priority area of diabetes and chronic disabling conditions. Potential applicants may obtain a copy of "Healthy People 2000" at http://odphp.osophs.dhhs.gov/pubs/hp2000 ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and nonprofit 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) and Exploratory/Development Research Grant (R21) award mechanisms. Except as otherwise stated in this announcement, awards will be administered under NIH grants policy as stated in the NIH Grants Policy Statement. The R21 awards are to demonstrate feasibility and to obtain preliminary data testing innovative ideas that represent clear departure from ongoing research interests. These grants are intended to 1) provide initial support for new investigators; 2) allow exploration of possible innovative new directions for established investigators; and 3) stimulate investigators from other areas to lend their expertise to research within the scope of this solicitation. Applicants for the R21 must limit their requests to $100,000 direct costs per year and are limited to two years. These R21 grants will not be renewable; continuation of projects developed under this program will be through the regular research grant (R01) program. 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. In such a case, 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 September 30, 2000. 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 Modular Grant applications will request direct costs in $25,000 modules. The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard NIH 398 application instructions. FUNDS AVAILABLE For FY 2000, the NIDDK intends to commit approximately $2 million, and the NICHD plans to commit $500,000 to fund 10-12 new and/or competing continuation grants in response to this RFA. An applicant may request a project period of up to 5 years for an R01. Because the nature and scope of the research proposed may vary, it is anticipated that the size of awards will also vary. Prospective applicants anticipating the submission of applications with direct cost budgets larger than $500,000 per year are encouraged to consult, at an early opportunity, with the appropriate program official listed under INQUIRIES. Although the financial plans of the NIDDK and 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 applications of outstanding scientific and technical merit. RESEARCH OBJECTIVES Background Type 2 diabetes is characterized by insulin resistance and impaired insulin secretion, although its precise etiology and pathogenesis are only incompletely understood. The public health impact of type 2 diabetes is enormous. Clearly associated with aging and obesity, type 2 diabetes has traditionally been considered a disease of adults. Children presenting with diabetes are usually assumed to have type 1 diabetes, an autoimmune disease. In recent years, however, it has become apparent that an increasing number of children who present with hyperglycemia actually have type 2 diabetes. Although many of the reports of type 2 diabetes in children are of an anecdotal nature, several published series have recently demonstrated a dramatic rise in the disorder in children. In general, population- based screening data are not available. However, data culled from diabetes clinics in several locations suggest that the percentage of children diagnosed with diabetes who are classified as having type 2 diabetes has risen from less than 5% (prior to 1994) to 20-30% (after 1994). The number of children being diagnosed with type 1 diabetes during this period has not changed substantially. Not surprisingly, the available published data reveal that one of the major risk factors for type 2 diabetes in children is obesity. Indeed, the increase in reports of type 2 diabetes among children parallels a similar rise in the adult population, as obesity has become a major public health concern. In children, the rise in the incidence in type 2 diabetes appears to be concentrated largely in minority populations African Americans, Hispanic Americans and Native Americans. Indeed, type 2 diabetes (in all age groups) is one of the major chronic diseases where significant racial/ethnic health disparities exist. Data from NHANES III suggests that up to 1/3 of adults who have type 2 diabetes may go undiagnosed. A similar situation may exist with children. Indeed, the diagnosis of type 2 diabetes in children is often made because of routine laboratory screening being conducted as part of a school physical and not because the child presents to a health care provider with specific complaints. Thus, many children who do not receive such screening may go undiagnosed until they become symptomatic, at which time they may have been hyperglycemic for many years and are at high risk for developing diabetic micro- and macrovascular complications. In addition, the incidence of type 2 diabetes in the pediatric population may be underestimated if all children with diabetes are assumed (but sometimes incorrectly) to have type 1 diabetes. Further confounding the situation are an increasing number of reports that many African American children with diabetes may present with ketoacidosis, traditionally considered the hallmark of type 1 diabetes, but subsequently can be managed without insulin. Thus, the emerging epidemic of type 2 diabetes in children also raises questions concerning the diagnostic criteria that have been used to distinguish type 1 and type 2 diabetes. The majority of children with type 2 diabetes are in the pre- adolescent or adolescent age range. The adolescent period presents special challenges to health care providers and families when attempting to promote behavior and life style changes. Treatment options are further restricted by the lack of data on the use of pharmacologic agents for type 2 diabetes in the pediatric population. Scope and Objectives New hypothesis-driven studies are needed to describe the epidemiology, refine the diagnosis, define the metabolic abnormalities and formulate treatment options for type 2 diabetes in children. Relevant topics listed below are examples and should not be construed as requiring or limiting. o Descriptive epidemiologic studies to define risk factors and metabolic or genetic markers for type 2 diabetes in children. These studies should have as a long-term goal the establishment of case definition. o Prospective screening studies in high-risk individuals to describe the incidence and prevalence of type 2 diabetes in specific sub- populations. o Studies to establish and validate practical screening programs for type 2 diabetes in children. o Metabolic studies to define early markers of insulin resistance and/or beta cell dysfunction in children. o Studies to examine the relative roles of insulin resistance and beta cell dysfunction in children with type 2 diabetes. o Studies to examine patterns of impaired glucose tolerance and determine the time course between the development of insulin resistance and clinical diabetes in children. o Studies to determine whether weight loss and/or exercise in children reverses insulin resistance. o Studies to define metabolic and/or genetic differences among various ethnic and/or racial groups which would predispose to the development of type 2 diabetes at a young age. o Studies to determine whether there are metabolic differences between children and adults with new-onset type 2 diabetes. o Studies to determine whether there are identifiable metabolic and/or genetic differences between ketosis-prone and typical type 2 diabetic children. o Single or multi-center clinical studies to determine the risks and benefits of pharmacologic treatment of type 2 diabetes in children. o Studies to describe the epidemiology of micro- and macrovascular complications in children with type 2 diabetes. o Studies to develop appropriate screening strategies for the micro- and macrovascular complications of type 2 diabetes in children. o Behavioral studies to define factors which impact on the pathogenesis of type 2 diabetes in children, and affect compliance with treatment and/or prevention programs. Also of interest would be studies to test strategies to improve and/or maximize compliance. o Studies to evaluate strategies for promoting weight loss, appropriate eating behavior, and increased exercise or physical activity in children and adolescents at risk for and/or with type 2 diabetes. 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 was 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: http://grants.nih.gov/grants/guide/notice-files/not94-100.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. 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 was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html Investigators may also 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 March 24, 2000, 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 sent to: Chief, Review Branch Division of Extramural Activities, NIDDK Natcher Building, Room 6AS-37F 45 Center Drive MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8885 FAX: (301) 480-3505 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 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: [email protected]. 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 Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $250,000 per year. (Applications that request more than $250,000 direct costs in any year must follow the traditional PHS 398 application 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 $250,000) 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. o 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. 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 phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. 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 and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The sample RFA label available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. 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, NIDDK Natcher Building, Room 6AS-37F 45 Center Drive MSC 6600 Bethesda, MD 20892-6600 Applications must be received by the application receipt date listed in the heading of the RFA. If an application is received after that date, it will be returned to the applicant without review. Supplemental documents containing significant revision or additions will not be accepted, 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 the NIDDK and 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 the NIDDK in accordance with the review criteria stated below. 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 the applications under review, will be discussed, assigned a priority score, and receive a second level review by the Advisory Councils of NIDDK and/or NICHD. 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, reviewer 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 to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o 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 to the proposed research. o The adequacy of the proposed protection of humans, animals, or the environment, to the extent that they may be adversely affected by the project proposed in the application. Schedule Letter of Intent Receipt Date: March 24, 2000 Application Receipt Date: April 25, 2000 Peer Review Date: June-July 2000 Council Review: September 2000 Earliest Anticipated Start Date: September 30, 2000. 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. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Barbara Linder, M.D., Ph.D. Division of Diabetes, Endocrinology and Metabolic Diseases NIDDK Building 45, Room 5AN18A 45 Center Drive MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-0021 FAX: (301) 480-3503 E-mail: [email protected] Gilman Grave, M.D. Center for Research for Mothers and Children NICHD 6100 Executive Blvd., Room 4B11 Bethesda, MD 20892-7510 Telephone: (301) 496-5593 FAX: (301) 480-9791 E-mail: [email protected] Direct inquiries regarding fiscal matters to: Nancy Dixon Division of Extramural Activities NIDDK 45 Center Drive MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8854 FAX: (301) 480-4237 E-mail: [email protected] E. Douglas Shawver Grants Management Branch NICHD 6100 Executive Blvd., Room 8A17 Bethesda, MD 20892-7510 Telephone: (301) 496-1303 FAX: (301) 402-0915 E-mail: [email protected] AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.847 and 93.865. Awards are 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 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 NIH 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, 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 NIH mission to protect and advance the physical and mental health of the American people.

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