Full Text CA-92-14 BIOMARKERS OF DIETARY FAT IN POST-MENOPAUSAL WOMEN NIH GUIDE, Volume 21, Number 32, September 4, 1992 RFA: CA-92-14 P.T. 34 Keywords: Nutrition/Dietetics Biological Markers Metabolism, Lipid National Cancer Institute Letter of Intent Receipt Date: October 7, 1992 Application Receipt Date: January 26, 1993 PURPOSE The Division of Cancer Prevention and Control (DCPC), National Cancer Institute (NCI), invites applications for cooperative agreements directed towards the identification and evaluation of potential biochemical/biological markers to assess total dietary fat intake in post-menopausal women and to monitor adherence to dietary interventions in cancer prevention clinical trials. A major challenge in studying the effects of diet on health and chronic disease risks is the difficulty of assessing dietary intake. Current methods for dietary assessment and adherence monitoring have different levels of precision and accuracy and all have the inherent limitation of relying on self-reported data. The availability of biochemical/biological markers for assessing dietary intake and adherence monitoring would greatly facilitate the design, conduct, and interpretation of cancer prevention clinical trials, analytical epidemiologic studies and diet-health survey studies on the relationship of diet and cancer risk. The specific objectives of this Request for Applications (RFA) are to encourage research on the identification and evaluation of biochemical/biological indicators of total fat intake in post-menopausal women on self-selected low- and high-fat diets and in controlled feeding and/or metabolic studies. 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 RFA, Cooperative Agreement for Biomarkers of Dietary Fat in Post-Menopausal Women, is related to the priority area of cancer prevention. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-0043-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). 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. Applications from minority individuals and women are encouraged. MECHANISM OF SUPPORT This RFA will support awards through the cooperative agreement (U01) mechanism. An assistance relationship will exist between the NCI and the awardees to accomplish the purpose of the activity. The planning, direction, and execution of the proposed research will be the responsibility of the awardees, with involvement of the NCI as described in SPECIAL REQURIREMENTS. In addition to the requirements stated in this RFA, awards will be administered under PHS grants policy as stated in Public Health Service Grants Policy Statement, DHHS Publication No. (OASH) 90- 50,000, revised October 1, 1990. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed by the Division of Research Grants (DRG). However, should the NCI determine that there is a sufficient continuing program need, the NCI may invite all funded recipients to submit competing continuation applications. FUNDS AVAILABLE Approximately $750,000 in total costs per year for three years will be committed to fund applications that are submitted in response to this RFA. It is anticipated that three to five awards will be made. This level of support is dependent on the receipt of a sufficient number of applications of high scientific merit. The total project period for applications submitted in response to the present RFA may not exceed three years. RESEARCH OBJECTIVES The purpose of this RFA is to encourage the submission of applications from qualified investigators interested in conducting investigations designed to identify, characterize, and evaluate biochemical/biological markers to assess dietary fat intake and adherence in post-menopausal women. This research initiative also seeks to promote the interactions of investigators with scientific expertise, facilities, and capabilities to conduct controlled feeding studies, metabolic studies, and field studies. Background Present knowledge of the relationship of diet to human health and chronic diseases has been derived from observational epidemiologic studies. There are marked variations in the international incidence and mortality rates of various cancers and in the per capita availability of fat, and correlations between these suggest that dietary intake is an important risk factor. Support for an etiologic relationship between dietary fat and breast cancer is provided by migrant population studies and by experimental animal studies which have shown that high fat diets enhance mammary tumor development and growth. The results of analytical epidemiologic studies (case-control and cohort) on the association of dietary fat with cancer incidence have been inconsistent. Some studies have shown a strong association of dietary fat with the incidence of some cancers whereas in others there is evidence of either a weak or no association. In the epidemiologic studies on dietary fat and cancer that have shown a positive association, the results generally indicate that higher intakes of total fat as well as saturated fat are associated with higher incidence and mortality rates of certain cancers. Inconsistent findings such as these are difficult to interpret. Measurement errors of dietary intake in general and of fat intake in particular, may in part account for these inconsistencies. Methods commonly used in epidemiologic research to assess dietary intake include per capita food availability, household food inventories, and food records and dietary recalls, both of which include diet histories and food frequency questionnaires. Per capita food availability provide useful leads for further research on the relationship of diet to chronic diseases because they enable investigators to compare rates of disease among countries with marked differences in mortality and incidence rates and in the availability of specific nutrients in their food supply. However, these cross-sectional comparisons do not control for confounding factors, nor can they be used to show associations between diet and disease in individuals. The choice of the dietary assessment method depends on whether the assessment pertains to the average intake of the group or to the usual intakes of individuals within a group, the level of detail (e.g., food groups, foods, or nutrients) desired, and the degree of precision needed in determining amounts of foods and nutrients consumed. Additional considerations include the costs, burden on respondents, and availability of trained interviewers. Diet history methods rely on interviewers or questionnaires to estimate the usual diet or habitual intake. Some diet histories are obtained through questionnaires, administered by an interviewer or completed independently by the respondent. This is often referred to as the foods frequency questionnaire in which the number of times each listed food is consumed and sometimes the portion sizes or amounts are reported. Often, many foods consumed may not be listed on the food frequency questionnaire. The 24-hour recalled method requires that respondents report the types and amounts of foods they consumed over the previous 24-hour period. Information is obtained by face-to-face interview or by telephone interview. The food record method requires participants to measure and record types and amounts of all foods and drinks consumed over a specified number of days, usually three to seven. In some studies, all foods are weighed, while in others, measuring cups and spoons and a ruler are used to assess dimensions. Food models, volume models, and photographs are sometimes used to estimate portion sizes. Accuracy can be reduced by many factors, such as poor memory of past dietary practices, inaccurate recall of foods eaten and the amounts, and the desire to please an interviewer. Therefore, true intake can only be determined with certainty if actual intakes are observed or measured and weighed. This has been feasible in only a few studies of small numbers of subjects conducted for a short time. Since true dietary intake can rarely be determined, investigators often try to assess the accuracy of a new or modified method by comparing results not with true intake but with results from some other accepted but possibly inaccurate method. Several types of errors may occur in the current state-of-the-art methods to assess dietary intake. These include sampling errors, reporting errors, errors due to wide day-to-day variation in dietary intake, interviewer bias, and errors due to use of food composition tables employed in estimating nutrient intakes. Assessing nutrient intake is also limited by the accuracy and completeness of standard food composition tables. There are sufficiently accurate data on the composition of protein and fat in most foods, but for dietary fiber, some vitamins, and trace values in food composition tables, averages of representative samples of a given food are used and do not indicate the nutrient content of any specific food sample. Two recent reports, "The Surgeon General's Report on Nutrition and Health" and the National Research Council's report "Diet and Health" have listed as specific research recommendations the need for identification and development of biochemical markers of dietary intake and of exposure to dietary fats. Identification of biochemical/biological indicators of dietary exposure would circumvent the current dietary assessment methodological short-comings that limit the interpretation of data and often prevent the derivation of precise conclusions about the association of dietary patterns and/or specific dietary components with the risk of cancer and other chronic diseases. The fatty acid composition of plasma and body tissues including erythrocytes, platelet, adipose tissue and cheek cells have been used to assess the types of fatty acids consumed. However, no single parameter or battery of biochemical/biological parameters have yet been identified to reflect total fat intake, to validate self-reported dietary intake, or to monitor adherence to low-fat diets. Specific and sensitive biochemical/biological indicators of dietary intake, in particular total dietary fat, would greatly facilitate the design, conduct, and interpretation of dietary intervention trials, epidemiologic studies and diet-health survey studies that attempt to determine the role of diet in cancer risk and prevention. In studies involving dietary modifications, the extent to which the results may be influenced by varying degrees of adherence is an aspect that is both important and difficult to evaluate. Thus, evaluation and validation of potential biochemical/biological indices of dietary intake will require controlled human feeding studies using well-defined diets and precise measures of actual intake. Studies of Special Interest Specifically, applications are solicited that will: (1) identify and evaluate potential biochemical/biological indicators of adherence in post-menopausal women on self-selected low- and high-fat diets, and/or (2) identify and evaluate biochemical/biological indicators of adherence to low-fat diets in post-menopausal women in controlled feeding and/or metabolic studies. Applicants may also propose to conduct a series of short-term (6-12 weeks) controlled clinical and/or metabolic studies and/or field studies. These studies should be designed to identify, characterize, and evaluate minimally invasive, specific, and sensitive biochemical/biological indicators for assessing total fat intake and/or for monitoring adherence to low-fat diets. Emphasis should be focused on dietary patterns that are nutritionally adequate and are characterized by reduced levels of total fat and saturated fat, increased levels of complex carbohydrates and fiber, and include a variety of foods typically present in the U.S. diet. In addition, the influence of varying the levels of fat intake while keeping fiber intake constant, weight loss, and energy balance may be taken into consideration in the study designs. Characteristics of an ideal biomarker may include the following, as well as others: (1) specimens for analyte measurements are readily accessible and involve minimally invasive procedures; (2) analyte is stable during prolonged storage; (3) analyte assays are precise, accurate and inexpensive; (4) analyte is sensitive to fat quantity and quality; (5) dose-response range is detectable; (6) minimal intra- and- inter-individual variation with defined intake; (7) minimal diurnal variation/seasonal variation; (8) minimal sensitivity to confounders; (9) defined time course of response and, (10) practical and low-cost. SPECIAL REQUIREMENTS Terms of Cooperation The cooperative agreement award mechanism requires establishment of a partnership and an assistance relationship between the NCI and award recipients. The role of the NCI will be to provide technical assistance and to assist in the coordination of certain activities of the award recipients as described below. The "partner role" of the NCI will be to facilitate, not to direct, the research activities. The Terms of Cooperation and other special requirements described below will be incorporated in the Notice of Grant Award and are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines; DHHS Grant Administration Regulations at 45 CFR 74; other DHHS, PHS, and NIH Grants Administration Policy Statements and other NCI administrative terms of award. A working group comprised of all Principal Investigators (PI) and the NCI Program Director will meet as soon as possible after awards are made to discuss approaches, to consider ways in which specific protocols might be improved, to facilitate the comparability of certain aspects of the research projects where desirable and feasible, to identify areas of cooperation, and to facilitate the exchange of information and material. Subsequently, the working group will meet annually to exchange information and to seek means of resolving problems that may have arisen. The cooperative approach allows for interactions among successful applicants and is designed to optimize the use of resources, biological specimens, and methodologies. The working group members may agree to share information and results in order to open avenues of cooperation between investigators and to keep abreast of the latest developments. However, each awardee institution will retain custody and primary rights to the data developed under these cooperative agreements. Responsibilities of NCI Program Director The role of the NCI Program Director, who is Chief of the Diet and Cancer Branch, DCPC, is to assist and facilitate, but not to direct, research activities. During the period of award the NCI Program Director will schedule, coordinate, and actively participate in the working group meetings. The NCI Program Director will serve as a liaison between the PIs and the NCI through annual meetings of the working group and provide appropriate assistance to the investigators, either individually or collectively as deemed necessary. Through telephone contacts, written correspondence, and meetings, the NCI Program Director will provide appropriate advice, assistance, and guidance in identifying areas of potential cooperation and will assist in facilitating the exchange of information and material. The NCI Program Director will assist the awardees with coordination of research activities such as the exchange of biological specimens, analytical methodologies, information, and results. The NCI Program Director will encourage standardization of analytical methodologies and sharing of data between investigators when this is in the mutual interest of all parties. Coordination activities may also include the NCI Program Director providing information on other ongoing studies and on NCI priorities. The NCI Program Director will monitor progress, review and evaluate technical performance, and will review and approve all requests for key personnel changes as appropriate during the project period. Key personnel are the PI and others specifically identified in the Notice of Grant Award. Responsibilities of Awardees Awardees are responsible for the planning, direction, and execution of the research projects, and for the dissemination and publication of results in a timely manner. The successful applicants will be responsible for obtaining approval by the Institutional Review Board (IRB) on all protocols with human subject involvement. Informed consent forms must comply with HHS Regulations and NIH guidelines. The awardees are expected to establish quality assurance/quality control procedures that will be an integral part of all laboratory activities and measurements, dietary data collection, and compliance to the dietary interventions. The awardees agree to conduct the study according to the IRB approved protocols and consent forms. The awardees are expected to cooperate with each other by making available information and results on a continuing basis and, where practical, sharing methodologies and materials. Data acquisition and analyses are the responsibilities of the awardees. Awardees are expected to participate in annual meetings of the working group to be held in Bethesda, MD. Applicants are advised to include travel expenses to attend working group meetings in the budget requests and to include a statement about willingness to participate in such activities in the applications. Copies of publications and major presentations are to be provided to the NCI Program Director. Publication of research results by the awardees is encouraged. The awardees will acknowledge NCI support in publications and oral presentations of work supported by this cooperative agreement. Arbitration Procedures An arbitration panel of external consultants will be created as needed to resolve any irreconcilable differences of opinion between the NCI Program Director and the awardee(s) related to scientific/programmatic matters or implementation of a proposed operating policy. The panel will include one award recipient designee, one NCI designee, and a third designee chosen by the other two members of the arbitration panel. Reporting Requirements Annual progress reports are to include a summary table of data and results for minority study participants and a summary table for all study participants combined. In addition to the required annual progress reports, the awardees will provide additional information requested by the NCI Program Director at the discretion of the affected PI(s). Other Required Applicant Information Applicants responding to the RFA will be expected to propose new and innovative approaches to this research area and are reminded to document the availability of multidisciplinary scientific expertise, appropriate facilities, and the ability to recruit volunteer human subjects including minorities. Specifically, the applicants should provide the following: (1) multidisciplinary scientific expertise; (2) appropriate facilities to conduct either controlled human feeding studies and/or metabolic studies or field studies; (3) access to existing cohorts of post-menopausal women with different dietary patterns, e.g., customary high- and low-fat diets or participants previously enrolled in other dietary modification research studies or diet programs; (4) ability to recruit and enroll volunteer post-menopausal women into controlled feeding studies and/or field studies, and (5) access to laboratory facilities with capabilities of performing analytical assays in biological specimens and foods. 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 PI must be included with the application. STUDY POPULATIONS SPECIAL INSTRUCTION TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF MINORITIES IN CLINICAL RESEARCH The following is a statement of NIH and ADAMHA policy regarding the inclusion of women and minorities in study populations. Applications that are responsive to this RFA will, be definition, meet the requirement for inclusion of women. The inclusion of minorities must be addressed in applications submitted responding to this RFA. NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical research grants and cooperative agreements will be required to include minorities and women in study populations so that research findings can be of benefit to all persons at risk of the disease, disorder or condition under study; special emphasis should be placed on the need for inclusion of minorities and women in studies of diseases, disorders and conditions which disproportionately affect them. This policy is intended to apply to males and females of all ages. If women or minorities are excluded or inadequately represented in clinical research, particularly in proposed population-based studies, a clear compelling rationale should be provided. The composition of the proposed study population must be described in terms of gender and racial/ethnic group. In addition, gender and racial/ethnic issues should be addressed in developing a research design and sample size appropriate for the scientific objectives of the study. This information should be included in the form PHS 398 in Sections 1-4, of the Research Plan AND Section 5, Human Subjects. Applicants are urged to assess carefully the feasibility of including the broadest possible representation of minority groups. However, the NIH recognizes that it may not be feasible or appropriate in all research projects to include representation of the full array of United States racial/ethnic minority populations (i.e., Native Americans (including American Indians or Alaskan Natives), Asian/Pacific Islanders, Blacks, Hispanics). The rationale for studies on single minority population groups should be provided. For the purpose of this policy, clinical research includes human biomedical and behavioral studies of etiology, epidemiology, prevention (and preventive strategies), diagnosis, or treatment of diseases, disorders or conditions, including but not limited to clinical trials. The usual NIH policies concerning research on human subjects also apply. Basic research or clinical studies in which human tissues cannot be identified or linked to individuals are excluded. However, every effort should be made to include human tissue from women and racial/ethnic minorities when it is important to apply the results of the study broadly, and this should be addressed by applicants. For foreign awards, the policy on inclusion of women applies fully; since the definition of minority differs in other countries, the applicant must discuss the relevance of research involving foreign population groups to the United States' populations, including minorities. If the required information is not contained within the application, the application will be returned. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of women or minorities in a study design is inadequate to answer the scientific question(s) addressed AND the justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and will be reflected in assigning the priority score to the application. All applications for clinical research submitted to NIH are required to address these policies. NIH funding components will not award grants or cooperative agreements that do not comply with these policies. LETTER OF INTENT Prospective applicants are asked to submit, by October 7, 1992, a letter of intent that includes a descriptive title of the proposed research, the name and address of the PI, the names of other key personnel, the 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 subsequent applications, it is requested in order to provide an indication of the number and scope of applications to be reviewed. The letter of intent is to be sent to: Postal mail address: Carolyn K. Clifford, Ph.D. Diet and Cancer Branch National Cancer Institute Division of Cancer Prevention and Control 9000 Rockville Pike Executive Plaza North, Room 212 Bethesda, MD 20892-6130 Overnight delivery address: Carolyn K. Clifford, Ph.D. Diet and Cancer Branch National Cancer Institute Division of Cancer Prevention and Control 6130 Executive Plaza Executive Plaza North, Room 212 Rockville, MD 20852 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 9/91) is to be used in applying for these grants. These forms are available at most institutional business offices; from the Office of Grants Inquiries, Division of Research Grants, National Institutes of Health, Room 449, Westwood Building, 5333 Westbard Avenue, Bethesda, MD 20892; and from the NCI Program Director named below. The RFA label available in the application form PHS 398 must be affixed to the bottom of the face page. Failure to use this label could result in delayed processing of your application such that it may not reach the review committee in time for review. In addition, the title of the application, "Biomarkers of Dietary Fat in Post-Menopausal Women", and the RFA number, CA-92-14, must be typed on line 2a of the face page of the application form. Submit a signed, typewritten original of the application, including the Checklist, and three signed, exact photocopies in one package to the DRG at the address listed below. The photocopies must be clear and single-sided. Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** At the time of submission, two additional copies of the application must be sent to: Referral Officer Division of Extramural Activities National Cancer Institute Westwood Building, Room 828 5333 Westbard Avenue Bethesda, MD 20892 Applications must be received by January 26, 1993. If an application is received after that date, it will be returned to the applicant. The Division of Research Grants (DRG) will not accept any application in response to this announcement that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The DRG 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 by the DRG for completeness. Incomplete applications will be returned to the applicant without further consideration. Evaluation for responsiveness to the program requirements and criteria stated in the RFA is an NCI program staff function. Applications that are judged non-responsive will be returned, but may be submitted as investigator-initiated research grants. Questions concerning the responsiveness of proposed research to the RFA should be directed to the Program Director indicated in the LETTER OF INTENT section. If the number of applications is large compared to the number of awards to be made, the NCI may conduct a preliminary scientific peer review (triage) to eliminate those applications that are clearly not competitive. The NCI will remove from competition those applications judged to be noncompetitive for award and notify the applicant and institutional business official. Those applications judged to be both competitive and responsive will be further evaluated according to the review criteria stated below for scientific and technical merit by an appropriate peer review group convened by the Division of Extramural Activities, NCI. The second level of review by the National Cancer Advisory Board considers the special needs of the NCI and the priorities of National Cancer Program. The following factors will be considered in evaluating the scientific merit of each response to this RFA: o Scientific merit, feasibility, and originality of the proposed research; o Appropriateness and adequacy of the experimental approach and methodology proposed to conduct the research; o Qualifications and research experience of the PI and key personnel; o Demonstration of availability of and access to potential study participants and/or study population(s); o Adequacy of plans for inclusion of minorities; o Adequacy of provisions for the protection of human subjects; o Scientific plans and timetable for implementing the proposed research and plans for effective interaction with other award recipients and with the NCI; o Availability of resources necessary to perform the research, and o Adequacy of the proposed budget and duration in relation to the proposed research. AWARD CRITERIA The anticipated date of award is September 30, 1993. Awards made pursuant to this RFA are contingent upon the availability of funds for this purpose and the scientific merit review. INQUIRIES Written and telephone inquiries concerning the objectives and scope of this RFA, and inquiries about specific proposed research are encouraged and should be directed to the Program Director listed below. The program staff welcome the opportunity to clarify any issues or questions from potential applicants. Direct inquiries regarding programmatic issues to: Carolyn K. Clifford, Ph.D. Chief and Program Director Diet and Cancer Branch Division of Cancer Prevention and Control National Cancer Institute 9000 Rockville Pike Executive Plaza North, Room 212 Bethesda, MD 20892-6130 Telephone: (301) 496-8573 FAX: (301) 402-0553 Direct inquiries regarding fiscal matters to: Eileen Natoli Team Leader, PC Team Grants Administration Branch National Cancer Institute 6120 Executive Boulevard Executive Plaza South, Room 243 Rockville, MD 20852 Telephone: (301) 496-7800, ext.56 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.399, Cancer Control. Awards will be made under the authority of the Public Health Services Act, Title IV, Section 301 (Public Law 78-410,;42 U.S.C. 241 and Section 412, as amended by Public Law 99-518, 42 U.S.C 258a-1); and administered under PHS grants policies and Federal Regulations 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12732 or Health Systems Agency review. .
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