INTERDISCIPLINARY STUDIES IN THE GENETIC EPIDEMIOLOGY OF CANCER

Release Date: August 5, 1998

RFA:  CA-98-018

P.T.

National Cancer Institute
National Institute on Aging

Letter of Intent Receipt Date:  October 20, 1998
Application Receipt Date:  November 17, 1998

PURPOSE

The Epidemiology and Genetics Program, Division of Cancer Control and
Population Sciences, National Cancer Institute (NCI) and the National
Institute on Aging (NIA) invite investigator-initiated cooperative agreement
applications for collaborative and interdisciplinary genetic epidemiology
investigations designed to identify and evaluate the interactions of genetic
and epidemiologic risk factors leading to cancer susceptibility in
individuals, families and populations, and factors influencing the rate of
increase with age in cancer susceptibility.

The special feature of this Request for Applications (RFA) is to solicit the
submission of multi-site, cooperative research applications by multi-
disciplinary teams of investigators wishing to collaborate within the common
theme of the genetic epidemiology of cancer.  Particular emphasis is placed on
encouraging interdisciplinary, population-based research focusing on the
etiologic mechanisms underlying the interaction of genetic and epidemiologic
risk factors for cancer susceptibility. The effect on cancer susceptibility of
age-related changes over the lifespan, and the genetic factors leading to
older age at onset of cancer are also of interest.

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, Interdisciplinary Studies in
the Genetic Epidemiology of Cancer, is related to the priority area of cancer. 
Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: 
Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1)
through the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone 202-512-1800).

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.  Applications from minority and women investigators
are encouraged.

MECHANISM OF SUPPORT

The administrative and funding instrument to be used for this program will be
a cooperative agreement (U01), an "assistance" mechanism (rather than an
"acquisition" mechanism), in which substantial NIH scientific and/or
programmatic involvement with the awardee is anticipated during performance of
the activity.  Under the cooperative agreement, the NIH purpose is to support
and/or stimulate the recipient's activity by involvement in and otherwise
working jointly with the award recipient in a partner role, but it is not to
assume direction, prime responsibility, or a dominant role in the activity.
Details of the responsibilities, relationships and governance of the study to
be funded under cooperative agreement(s) are discussed later in this document
under the section "Terms and Conditions of Award."

The total project period for an application submitted in response to this
present RFA may not exceed 5 years.  The anticipated award date is July 1999. 
Because the nature and scope of the research proposed in response to this RFA
may vary, it is anticipated that the sizes of awards will vary also.  Awards
and level of support depend on receipt of a sufficient number of applications
of high scientific merit.  Although this program is provided for in the
financial plans of the NCI and NIA, awards pursuant to this RFA are contingent
upon the availability of funds for this purpose.  At this time, the NCI has
not determined whether or how this solicitation will be continued beyond the
present RFA.

FUNDS AVAILABLE

Approximately $5.0 million per year in total costs for five years will be
committed by the NCI to specifically fund applications submitted in response
to this RFA.  The expected number of awards is three to four.  The NIA will
commit up to $500,000 per year for five years in total costs for the support
of research on aging-relevant issues within funded projects.

RESEARCH OBJECTIVES

Background

During the last decade, the progressive identification of human genes
conferring susceptibility for complex diseases and the application of
increasingly sophisticated molecular technologies to the study of human
genetics have provided new ways to analyze the human genome and to look at the
relationship between phenotype and genotype in complex diseases such as
cancer.  Investigators in the genetic epidemiology of cancer can now attempt
to incorporate developments in molecular genetics into population studies, to
greatly increase insights into the genetic and environmental determinants of
this disease.  In addition, traditional statistical methods used in genetics
are yielding to new methodologies developed to encompass both genetic and
epidemiologic risk factors.

As genes are identified, mapped and cloned, the possibility of describing the
polymorphic frequency of various genes in the general population, as well as
the ways in which these genes and their polymorphisms interact with risk
factors influencing their penetrance to determine cancer susceptibility,
becomes feasible.  For example, germline mutations at the BRCA1 and BRCA2 loci
are thought to account for 5 to 10% of breast cancer incidence and 2 to 5% of
ovarian cancer incidence. Genetic and epidemiologic studies suggest that other
genes of markedly lower penetrance may also be important in determining breast
cancer risk. These genes may modulate individual response to environmental
factors and explain variability in risk associated with different exposures. 
This latter category of susceptibility genes may have very large attributable
risks for cancer and may be very common in the general population.  As a new
cancer susceptibility genes are mapped and cloned, and the role of
low-risk/high frequency candidate genes in cancer etiology is evaluated, it is
extremely important to consider what new research approaches will be necessary
to: (a) maintain the growth of scientific knowledge in this area; (b)
effectively and efficiently translate this growing knowledge into benefits for
affected and at-risk individuals and populations; and (c) develop strategies
for the resolution of ethical, social, and legal issues raised by the impact
of these discoveries on our society.

A current theory of carcinogenesis is that most forms of cancer result from
the variable effects of epidemiologic risk factors, some of which may be
modifiable (diet, physical activity, endogenous and exogenous hormones,
addictive substances such as tobacco and alcohol, radiation exposure, etc.),
on a broad range of genetic susceptibilities, in a multistage process that can
be delineated and modified at each step by exogenous and host-determined
factors.  Supportive evidence for this theory has been provided in recent
years by molecular, genetic and epidemiologic studies of specific cancers,
such as colon, breast and lung.  Because of the complex nature of these
diseases, it is important that genetic epidemiology studies be performed by
multi-disciplinary collaborative research groups capable of investigating both
epidemiologic risk factors and genetic determinants of cancer and their
complex interactions.  A continuum of familial and population-based studies
within a flexible research framework is necessary to identify high and low
frequency cancer susceptibility genes and characterize their interaction with
genetic and non-genetic effect modifiers.  Because of the extreme public
health relevance of such studies, the complexity of the scientific issues at
stake, and the ethical and legal implications confronting the individuals and
populations involved in such studies, such research is better conducted by
multi-disciplinary teams combining cutting edge approaches to epidemiologic
and genetics study design and analytical methodology, high throughput
molecular genetics techniques, and clinical sciences expertise.  Furthermore,
the analytical power required to confer validity to these studies, especially
for minority and underserved populations, will require collaborative studies
among national and possibly international sites.  Finally, cost-effectiveness
requirements would suggest the utilization, where appropriate, of existing
large cohorts, supported consortia or established research infrastructures.

Recommendations from a panel on Research Priorities for the Study of Genetic
Susceptibility to Cancer from the "Second International Conference Genetic
Epidemiology of Cancer: From Gene Cloning to Populations" sponsored by the
National Cancer Institute in 1996 suggest that there should be an increased
effort in establishing multi-site, cooperative research efforts for an
interdisciplinary approach to the type of genetic epidemiology studies
addressing the issues outlined above. This effort would facilitate the pooling
of data to increase power of needed analyses, the establishment of resources
appropriate for multi-disciplinary and translational research efforts in this
area, and the interdisciplinary training of genetic epidemiologists.  Such
cooperative efforts will be fostered and enhanced by the development of novel
epidemiologic approaches into the study of the interaction between genetic
susceptibility and epidemiologic risk factors in individuals and populations,
and the expeditious transfer of molecular and biostatistical methods and
technologies to population studies.  Support of studies on genetic and other
risk factors interplay leading to cancer susceptibility in understudied ethnic
and racial groups was particularly recommended.  Many genetic epidemiology
studies are on Caucasian populations, and the information derived may not be
applicable to ethnic and racial minorities. For example, few current studies
will contribute information on the distribution of polymorphisms and mutations
of the known cancer susceptibility genes in these populations. Genetic
epidemiology studies of geographically isolated/inbred populations were also
advocated.

Another important research objective of this RFA is the understanding of
genetic risk factors for cancer incidence in older populations, among whom the
incidence of many malignancies reaches the highest rates, and the interactions
between physiologic aging changes and genetic risk factors for cancer.

This Request for Applications is the re-issuance of a previous NCI-funded
initiative (RFA CA-93-020). Research supported under this initiative for the
past four years has provided a fundamental contribution to the identification
and characterization of breast, colon and ovarian cancer susceptibility genes
and to the understanding of the interaction of these genes with known
epidemiologic risk factors. The aim of the current RFA is to support multi-
site, interdisciplinary studies of the complex interaction between genetic and
other endogenous as well as exogenous risk factors in the etiology of cancer.
Special consideration is given to population-based research on the unique
aspects of cancer susceptibility genes (especially low relative risk, high
attributable risk because of wide distribution in the population under study)
in contrast to studies of major cancer susceptibility genes.

Objectives and Scope

The main goal of this initiative is to facilitate cross-disciplinary
technological, methodological and conceptual transfer in order to advance
research on the genetic epidemiology of cancer in families and populations. 
Inter- and Intra- institutional collaborations between epidemiologists,
laboratory scientists, clinical oncologists, human geneticists,
epidemiologists, biostatisticians, psychosocial and biobehavioral researchers,
geriatricians and gerontologists and experts in related disciplines working on
the same cancer site/syndrome are encouraged.  Although this research will
ultimately lead to more targeted prevention efforts and novel therapeutic
designs, the latter are beyond the scope of this RFA.

Collaborative proposals could include, but should not be limited to:

Identification and characterization of novel cancer susceptibility through
interdisciplinary genetic epidemiology studies;

Studies of complex genetic interactions in cancer etiology (gene modifiers,
gene-gene interaction);

Characterization of the interactions of cancer susceptibility genes with known
and suspected epidemiologic risk factors;

Development and validation of novel statistical models to evaluate
gene/environment interactions, genetic heterogeneity and alternative modes of
inheritance (e.g., gene imprinting) within existing cohort or family datasets;

Feasibility and validation studies to test the applicability of experimental
laboratory techniques to genetic epidemiology investigations;

Genetic epidemiology studies of precancerous lesions in familial clusters,
including the analysis of heritable and environmental factors affecting the
progression of the precursor state to malignancy;

Exploration of possible differences among age groups in the contributions of
specific genetic risk factors for incidence of cancers, and genetic factors
contributing to age-associated differences in aggressiveness and other
clinical properties of malignancies.

Studies of genetic factors affecting the rate of progression of precancerous
lesions in older populations and age of onset of malignancies;
and

Studies to evaluate the potential benefits, risks, and psychosocial impact of
testing and counseling for individuals at increased risk of developing cancer
and their families.

SPECIAL REQUIREMENTS

Each multi-site application must state clearly, in section 7 of the
application form PHS
398, how the sites plan to collaborate.  Applicants who already have ongoing
collaborations must indicate how their response to this RFA will augment their
current collaboration. Applicants are encouraged to establish collaborations
that will enable them to use established resources and facilities (e.g.,
familial cancer registries, SEER, SPORES, Cancer Centers, Cancer Genetics
Network, etc.) to facilitate the collection of patients and pedigrees and to
increase cost effectiveness.

Applicant institutions must demonstrate existing programs of scientific
excellence in areas related with the genetic and epidemiology of cancer.  All
applications must address the following questions in a clear and organized
manner, as described below:

What existing resources, capabilities, and expertise does the applicant bring
to the cooperative agreement?

How will the support requested for this cooperative agreement enhance the
applicant's ability to establish an interdisciplinary program to investigate
the mechanisms and nature of gene-gene and gene-epidemiologic risk factor
interactions in cancer susceptibility?

Will the proposed project utilize an existing resource or constitute a new
one?

Applications should include, at a minimum, descriptions of the following:

The source of recruitment (catchment area) for the population/families studied
and their expected age-ranges;

Capability and facilities to collect, process, and manage epidemiologic and
clinical data (data coordination unit);

Capability for establishing or previous existence of a biospecimen bank
related to the population studied and to the scientific aims of the
cooperative agreement;

Availability of laboratory and/or high throughput genotyping/sequencing
facilities, where needed;

Methods for assuring privacy and maintaining confidentiality of participant
records, including specific protections for Internet-based data systems.

Timetable: a detailed timetable for the proposed study must be included in the
application.

Unique Capabilities

Applicants should highlight unique expertise and/or unusual opportunities as
related to the purpose of this RFA.  Examples include, but are not limited to:

Expertise in specialized areas with potential applications to the
issues/questions considered in this RFA, such as molecular technology
applicable to large scale genetic epidemiology studies, or the development of
novel study design and analytical approaches in the genetic epidemiology of
complex diseases or cancer;

Access to special participant populations, such as ethnically diverse groups,
older age cohorts, populations that could be followed-up for long-term
longitudinal studies, cohorts with unique mutations or specific exposure to
known or potential risk factors for cancer;

Expertise in diagnosing and phenotyping of cancers highly prevalent in old
age, and in detection and characterization of premalignant changes
predisposing to such cancers; and /or in clinical and epidemiologic studies of
older people, or

Experience and/or expertise in state-of-the-art informatics technology.

Study Organization and Function

Successful grant awardees under this RFA should include in their budget
support for the participation of the Principal Investigator (P.I.) and at
least one Co-Principal Investigator in an annual program meeting of all
awardees with the Advisory Committee.  The meeting will be of one or two days
duration and may be held in Bethesda, Maryland, or in other convenient
locations.  The Project Scientist from NCI will coordinate the annual meetings
to review and assess overall progress and provide the opportunity for
investigators to exchange information and discuss research issues.

To demonstrate the feasibility of a successful multi-site collaboration, a
number of issues need to be addressed in the applications as discussed below. 
Applicants should document their ability to recruit a sufficient number of
study participants as related to the collaborative study aims, should discuss
their capability and willingness to participate in a collaborative, multi-site
study and discuss in detail the coordination and interaction among the groups
involved in the application groups.

Steering Committee

An single project Steering Committees (SC) will serve as the main governing
boards of each of the awarded multi-site cooperative agreements.  Each SC will
be responsible for the coordination and execution of the cooperative
agreement's proposed research in all its aspects.  SC membership will include
the Principal Investigator, the NCI Project Scientist, an NIA representative,
and a Co-Principal Investigator for each of the collaborating institutions. 
Additional members may be appointed by mutual agreement of the SC membership.

Advisory Committee

A single External Advisory Committee (EAC) will be composed of senior
scientists (not affiliated with the awarded Institutions) with multi-
disciplinary expertise in cancer genetics and epidemiology research, and other
areas relevant to the research supported.  The EAC will be responsible for
advising NCI, NIA and all the awardees on scientific matters related to the
overall initiative and to each single research project, and to review as
appropriate and consult with the NCI representative on the awardees'
scientific progress.  EAC members may be nominated by the Principal
Investigator of each awarded U01, and will be appointed by the NCI and NIA for
a two-year tenure.

The following terms and conditions will be incorporated into the award
statement and provided to the Principal Investigator(s) as well as the
institutional official at the time of award.

Terms and Conditions of Award

The Terms and Conditions of Award, below, will be incorporated in all awards
issued as a result of this RFA. It is critical that each applicant include
specific plans for responding to these terms.  These special Terms of Award
are in addition to and not in lieu of otherwise applicable OMB administrative
guidelines, HHS Grant Administration Regulations at 45 CFR Parts 74 and 92,
and other HHS, PHS, and NIH Grant Administration policy statements.  The
administrative and funding instrument used for this program is a cooperative
agreement (U01), an "assistance" mechanism (rather than an "acquisition"
mechanism) in which substantial NIH scientific and/or programmatic involvement
with the awardee is anticipated during performance of the activity.

Under the cooperative agreement, the NIH purpose is to support and/or
stimulate the recipient's activity by involvement in and otherwise working
jointly with the award recipient in a partner role, but it is not to assume
direction, prime responsibility, or a dominant role in the activity. 
Consistent with this concept, the dominant role and prime responsibility for
the activity resides with the awardee(s) for the project as a whole, although
specific tasks and activities in carrying out the studies will be shared among
the awardees and the NCI Project Scientist and/or the NIA representative where
appropriate, including the following.

1. Awardee Responsibility

a.  The Awardee is responsible for enrollment and follow-up of the study
participants, and for the establishment and maintenance of mechanisms to
ensure that data collection and management procedures have necessary quality
control and assure confidentiality of data.

b.  The Principal Investigator and the Co-Principal Investigator (s) will
serve as permanent members of their SC. The SC will determine the policy and
procedures pertinent to the study and meet yearly with the overall EAC and
with the other awardees.

c.  The Awardee must provide a semi-annual progress report to the NCI Project
Scientist.  This report should include progress during the reporting period
(including accrual and follow-up), staffing changes, a summary of project
expenditures, manuscripts prepared during the reporting period, and priorities
for the coming reporting period. Additional reports may be required by the NCI
Project Scientist as needed.

d.  The Awardee will cooperate in the scientific reporting of findings.  The
NCI will have access to and may periodically review all data generated under
an award.  Plans for joint publication with NCI extramural program staff of
pooled data will be reviewed and approved by the Steering Committee.  NIH
policies governing co-authorship of publications with NCI extramural program
staff will apply in all cases.

e.  The Awardee(s) will retain custody of and have primary rights to the data
developed under these awards, subject to Government rights of access
consistent with current HHS, PHS and NIH policies. However, publication or
oral presentation of results obtained under this Cooperative Agreement will
require appropriate acknowledgment of NCI support. Awardees will have primary
and lead responsibilities for the project as a whole, including research
design and protocol development and implementation, participant recruitment
and follow-up, data collection, quality control, interim data and safety
monitoring, final data analysis and interpretation and preparation of
publications, as well as collaboration with other awardees were needed, and
with assistance from and in collaboration with the NCI Project Scientist.

2.  NCI Staff Responsibilities

The NCI Project Scientist will have substantial scientific-programmatic
involvement during conduct of this activity, through technical assistance,
advice and coordination above and beyond normal program stewardship for
grants.

The NCI Project Scientist will:

a.  Serve as liaison from the NCI, helping to coordinate activities among the
Awardees;

b.  Serve as scientific liaison between the Awardees and other program staff
at NCI with experience in multi-center studies, cancer genetics and
epidemiology;

c. Provide expert consultation in the area of genetic epidemiology;

d.  Serve as a full participant and voting member of the SC, and, as
appropriate, SC subcommittee(s); serve as liaison between the SC and the EAC,
attending EAC meetings in a non-voting liaison member role; and

e.  Assist in the monitoring of field data collection, and assist in
developing operating guidelines, quality control procedures, and consistent
policies for dealing with recurrent situations that require coordinated
action.

f. Participate in the joint description of study findings for both the
scientific and public policy arena.

The NIA staff representative will review progress of the studies with
particular regard to aging-relevant issues, participating in Steering
Committee meetings, and consult with the NCI Program Coordinator on pertinent
issues.

The NCI reserves the right to reduce the budget, to withhold support, and to
suspend, terminate or curtail a study or an award in the event of substantial
shortfall in accrual, data reporting, inadequate quality control of data
collection, refusal to carry out the recommendations of the SC and EAC, or
substantial failure to comply with the terms of the award.  Periodic external
progress reviews of the program will be carried out as NCI deems appropriate.

3.  Collaborative Responsibilities

Steering Committees

Steering Committees will serve as the main governing boards for each of the
awarded multi-site cooperative agreement.  It will be responsible for the
coordination and execution of the proposed research in all its aspects, e.g.,
implementing the research designs, developing protocols and manuals as needed,
and reporting study results.  Its membership will include the Principal
Investigator (as Chairperson), the NCI Project Scientist, and the Co-Principal
Investigator for each of the collaborating institutions within a cooperative
agreement.  Additional members may be appointed by mutual agreement of the SC
membership.  Subcommittees will be established by the Steering Committee, as
it deems appropriate; the NCI Project Scientist will serve on or chair
subcommittees as deemed appropriate.  It is anticipated that awardees will
have lead responsibilities in all tasks and activities, except it is
anticipated that the NCI Project Scientist will have lead responsibilities in
providing programmatic guidance and in functioning as liaison between the
awardees of different cooperative agreements and the multi-disciplinary EAC. 
The NCI Project Scientist will have voting membership on the Steering
Committee and, as appropriate, its subcommittees.

4.  Arbitration

Any disagreement that may arise on scientific/programmatic matters (within the
scope of the award), between award recipients and the NCI may be brought to
arbitration.  An arbitration panel will be composed of three members -- one
selected by the Steering Committee (with the NCI member not voting) or by the
individual awardee in the event of an individual disagreement, a second member
selected by NCI, and the third member selected by the two prior selected
members. This special arbitration procedure in no way affects the awardee's
right to appeal an adverse action that is otherwise appealable in accordance
with the PHS regulations at 42 CFR Part 50, Subpart D and HHS regulation at 45
CFR Part 16.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of 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 s 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 or 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, Volume 23,
Number 11, March 18, 1994.

NIH POLICY AND GUIDELINES ON THE 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 clear and compelling 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 the policy 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 October 20, 1998, a letter of
intent that includes a descriptive title of the proposed research, name,
address, and telephone number of the Principal Investigator, identities of
other key personnel and participating institutions, and 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, the information allows NCI
staff to estimate the potential review workload and to avoid conflict of
interest in the review.

The letter of intent is to be sent to:

Daniela Seminara, Ph.D., M.P.H.
Division of Cancer Control and Population Sciences
National Cancer Institute
6130 Executive Boulevard, Room 535, MSC 7395
Bethesda, MD  20892-7395
Telephone:  (301) 496-9600
FAX:  (301) 402-4279
Email:  ds79k@nih.gov

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 5/95) is to be used in
applying for these cooperative agreements.  Applications 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
301/435-0714, E-mail: grantsinfo@nih.gov.  Applications are also available on
the web at http://grants.nih.gov/grants/funding/phs398/forms_toc.html.

The RFA label available in the PHS 398 (rev. 5/95) 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.

A detailed timetable for the proposed study must be included in the
application.

Submit a signed, typewritten original of the application, including the
Checklist, and three signed photocopies, in one package to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

At the time of submission, two additional copies of the application must also
be sent to:

Referral Officer
Division of Extramural Activities
National Cancer Institute
6130 Executive Boulevard, Room 636
Bethesda, MD  20892
Rockville, MD  20850 (for express/courier service)

Applications must be received by November 17, 1998.  If an application is
received after that date, it will be returned to the applicant without review. 
The Center for Scientific Review (CSR) will not accept any application in
response to this RFA that is essentially the same as one currently pending
initial review, unless the applicant withdraws the pending application.  The
CSR will not accept any application that is essentially the same as one
already reviewed.  This does not preclude the submission of a substantial
revision of an application already reviewed, but such an application must
follow the guidance in the PHS Form 398 application instructions for the
preparation of revised applications, including an introduction addressing the
previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR and
responsiveness by the NCI.  Incomplete and/or non-responsive applications will
be returned to the applicant without further consideration.  Those
applications that are complete and responsive, and judged to be competitive,
will undergo further scientific merit review in accordance with the criteria
stated below for scientific/technical merit by an appropriate peer review
group convened by the NCI.  The second level of review will be provided by the
National Cancer Advisory Board and the National Aging Advisory Council.

All applications will be judged on the basis of the scientific merit of the
proposed project and the documented ability of the investigators to meet the
RESEARCH OBJECTIVES of the RFA.  Although the technical merit of the proposed
protocol is important, it will not be the sole criterion for evaluation of a
study.  Other considerations, such as the importance and timeliness of the
proposed study, access to the study population, and the interdisciplinary
nature of the studies, will be part of the evaluation criteria.

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 appropriate national advisory council.

Review Criteria

Applicants are encouraged to submit and describe their own ideas about how
best to meet the goals of the cooperative study and their specific protocols,
and are expected to address issues identified under SPECIAL REQUIREMENTS of
the RFA. The review group will assess the scientific merit of the protocols
and related factors as follows:

Significance:  Does this study address an important problem in the genetic
epidemiology of cancer?  If the aims of the applications 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?

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?

Innovation:  Does the project employ novel concepts, approaches, or methods?
Are the aims original and innovative?  Does the project challenge existing
paradigms or develop new methodologies or technologies?

Investigators: Are the Principal Investigator, Co-Principal Investigators and
their teams appropriately trained and have adequate experience to carry out
this work?  Is the work proposed appropriate to the experience level of the
principal investigator and his/her collaborators?

Environment:  Does the scientific environment in which the work will be done
significantly 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?

Is a suitable population(s) available for this study?

In addition to the above criteria, in accordance with NIH policy, all
applications will also be reviewed with respect to the following:

The reasonableness of the proposed budget and duration in relation to the
proposed research.

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.

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.

Availability of special opportunities for furthering research programs through
the use of unusual talent resources, populations, or environmental conditions
in other countries which are not readily available in the United States, or
which provide augmentation of existing U.S. resources.

The application of creative and innovative (high risk/high impact)
experimental approaches and the development of interactive strategies and
collaborative teams are integral to the research goals of this RFA and are
encouraged.

AWARD CRITERIA

Applications recommended by the NCI Advisory Board and the NIA Advisory
Council will be considered for award based upon (a) scientific and technical
merit; (b) program balance, including in this instance, sufficient
compatibility of features to make a successful collaborative program a
reasonable likelihood; and (c) availability of funds.

Schedule

Letter of Intent Receipt Date:  October 20, 1998
Application Receipt Date:       November 17, 1998
Review by NCAB Advisory Board:  May 1999
Anticipated Award Date:         July 1999

INQUIRIES

Written and telephone 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:

Daniela Seminara, Ph.D., M.P.H.
Division of Cancer Control and Population Sciences
National Cancer Institute
6130 Executive Boulevard, Room 535, MSC 7395
Bethesda, MD  20892-7395
Telephone:  (301) 496-9600
FAX:  (301) 402-4279
Email:  ds79k@nih.gov

Direct inquiries regarding aging-related topics to:

Rosemary Yancik, Ph.D.
Cancer Section
National Institute on Aging
Gateway Building, Suite 3E-327
Bethesda, MD  20892-9205
Telephone:  (301) 496-5278
FAX:  (301) 402-1784
Email:  ry3e@nih.gov

Direct inquiries regarding fiscal matters to:

Catherine E. Blount
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Room 243
Bethesda, MD  20892
Telephone:  (301) 496-7800 Ext. 262
FAX:  (301) 496-8601
Email:  cb136g@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance
No.93.393.  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 Parts 52 and 45 CFR Part 74 [and Part 92 when applicable
for State and Local governments]. 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, any portion of a facility) in which
regular or routine education, library, day care, health care or early
childhood development services are provided to children.  This is consistent
with the PHS mission to protect and advance the physical and mental health of
the American people.


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