Full Text CA-92-14


NIH GUIDE, Volume 21, Number 32, September 4, 1992

RFA:  CA-92-14

P.T. 34

  Biological Markers 
  Metabolism, Lipid 

National Cancer Institute

Letter of Intent Receipt Date:  October 7, 1992
Application Receipt Date:  January 26, 1993


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.


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).


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.


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

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.


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.


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.


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

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

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

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.


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

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

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

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.



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

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.


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


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

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.


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

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.


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.


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


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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