CANCER INTERVENTION AND SURVEILLANCE MODELING NETWORK (CISNET)

Release Date:  August 18, 1999

RFA:  CA-99-013 (see reissue RFA-CA-05-018)

National Cancer Institute

Letter of Intent Receipt Date:  October 21, 1999
Application Receipt Date:  November 18, 1999

PURPOSE

The Division of Cancer Control and Population Sciences (DCCPS), National
Cancer Institute (NCI), invites applications from domestic and foreign
applicants to support collaborative research using simulation and other
modeling techniques to describe the impact of interventions (i.e., primary
prevention, screening, and treatment) in population-based settings in the
United States or in non-US settings that will shed light on US population-
based trends.  It is well known that great progress can be made in the war
against cancer by the complete use and adequate delivery of existing
modalities of cancer control.  The goal of this research is to help:  (1)
answer the "why" questions in the analysis of cancer incidence and mortality
trends, (2) determine if recommended interventions are having their expected
population impact, and (3) predict the potential of new interventions on
national trends.  It is not the purpose of this RFA to support analysis of
hypothetical or trial-based cohorts, but rather to support analysis based on
realistic scenarios of population impact.  The first round of funding will be
limited to prostate, breast and colorectal cancers.  To keep applications
focused, each will be limited to a single cancer site.  The cooperative
agreement mechanism will allow the development of site-specific working groups
that will: (1) facilitate comparative analyses, (2) allow modeling groups
access to a broader array of data resources and multidisiplinary expertise and
(3) provide a forum for discussions of validation and other methodologic
issues.  The diversity and originality of modeling approaches which can be
compared using uniform criteria is an inherent strength of this cooperative
agreement.  The Division of Cancer Control and Population Sciences, which
fulfills a federal-level function to respond to evolving surveillance
questions of national policy relevance, will help focus research questions and
act as a conduit to national data resources necessary for parameter
estimation, model calibration, validation and population trends. An emergent
property of this collaborative agreement is progress towards a comprehensive
understanding of the determinants of cancer site specific trends at the
population level.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2000," a PHS-led national
activity for setting priority areas.  This Request for Applications (RFA),
Cancer Intervention Surveillance Modeling Network (CISNET), is related to the
Priority area of cancer surveillance and data systems.  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), or at
http://www.crisny.org/health/us/health7.html.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign for-profit and
non-profit organizations, public and private, such as universities, colleges,
medical centers, units of State and Local governments, and eligible agencies
of the Federal Government.  Applications from minority individuals, women, and
persons with disabilities, are encouraged to apply.

Each Principal Investigator (PI) is limited to only one application per cancer
site, and thus up to three applications are possible by one PI.  If a PI, or
an institution, is submitting several applications that share a common
structure (e.g., models for breast and prostate cancer share a similar
computing framework), funds to develop or enhance that common structure should
be included separately in each application, and overlapping funding of
activities will be considered at the time of award (see Special Requirements -
Budget).

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 applications submitted in response to the present
RFA may not exceed four years.  Awards and level of support depend on receipt
of a sufficient number of applications of high scientific merit.  The
anticipated award date is July 2000.

At this time the Division of Cancer Control and Population Sciences
anticipates that there will be a renewed competition after two years.  It is
anticipated that the second submission will broaden the range of cancer sites,
and a high priority for inclusion will be tobacco related sites. If the
Division does not continue the program, awardees may submit grant applications
through the usual investigator-initiated grants program.

FUNDS AVAILABLE

The NCI intends to commit approximately $1,500,000 in total costs (direct and
indirect) in FY 2000 to fund 5 to 9 new grants in response to this RFA.  An
applicant may request a project period of up to four years.  It is anticipated
that the award for each application for modeling of a single cancer site will
be between $75,000 - $300,000 total cost for the first year.  It is
anticipated that several modeling centers will submit applications for more
than one cancer site.  Because the nature and scope of the research proposed
may vary, it is anticipated that the size of each award will also vary. 
Applications on the lower end of range (e.g., $75,000 - $125,000) are
encouraged for smaller more focused efforts, while those at the higher end of
the range ($125,000-$300,000) are for more comprehensive population-based
applications which consider the entire spectrum of the disease process and/or
model multiple interventions simultaneously.  Although the financial plans of
the NCI provide support for this program, awards pursuant to this RFA are
contingent upon the availability of funds and the receipt of a sufficient
number of applications of outstanding scientific and technical merit.

RESEARCH OBJECTIVES

Background

Modeling is the use of mathematical and statistical techniques within a
logical framework to integrate and synthesize known biological,
epidemiological, clinical, behavioral, genetic and economic information.
Simulation and other modeling techniques have been utilized to describe the
impact of cancer interventions (i.e., primary prevention, screening, and
treatment) for hypothetical cohorts or in trial and other clinical settings. 
The goal of this concept is to promote the application and extension of these
models to population-based settings in order to help answer "why" questions in
the analysis of cancer trends.  These questions are of importance to the
National Cancer Institute because of the necessity of understanding: (1) if 
recommended interventions are having their expected population impact, and (2)
to help predict the potential impact of new interventions on national trends. 
These studies will often involve extrapolation of controlled cancer
intervention studies to estimates of U.S. population and community
effectiveness.  This type of modeling addresses issues of population based
policies and programs, and is distinct from individual level models of risk
and models of clinical decision making used at the individual patient-
physician level. An additional goal of this concept is to advance methodology
for modeling and to develop more uniform criteria for model validation in the
population setting.

The National Cancer Institute (NCI) has a long standing need to provide
answers to critical research questions which cannot be obtained from direct
observation because of expense, ethical, or other reasons. For example, a
trial is only conducted in a limited study population under limited study
conditions and extrapolation to other settings and conditions may only be
feasible through modeling.  Lead time, the time which a diagnosis is advanced
through screening, often may only be estimated through modeling because it is
unethical to leave a screen detected patient untreated until clinical symptoms
develop.  NCI has supported a variety of small efforts in this area through
in-house work, contracts and grants.  The majority of extramural efforts have
been directed at the analysis of specified cancer control interventions using
a variety of modeling approaches applied to a hypothetical cohort or in the
context of a trial or other limited settings, while the in-house work has
mainly been directed toward addressing cancer surveillance issues at the
national level.  There has been growing recognition that much can be gained by
integration of these two approaches.

Models increasingly have been used in recent years to inform public health
policy decisions at the national level.  In Europe, the cervical and breast
cancer screening models  have been used to design, monitor and evaluate
national screening programs in several countries [1].  Models have been used
in the United States to help understand the implication of dramatic changes in
national cancer statistics, such as patterns of increasing incidence related
to screening in breast and prostate cancer [2-4] , improving survival due to
the dissemination of breakthrough treatment approaches in Hodgkin's Disease
and Testicular cancer [5-6].

Macro-level models use estimates of standard population-based statistics
(i.e., birth rates, incidence, stage-distribution, relative survival, and
mortality from causes other than cancer) as parameter estimates to model the
life-process in terms of birth, the development of cancer, and death from
cancer or other causes.  The impact of cancer control interventions aimed at
primary prevention, screening, and treatment are estimated by changing the
model parameters.  This approach has proven useful in evaluating the potential
costs and benefits of specific cancer control strategies, and exploring the
impact of these interventions on population-based cancer incidence and
mortality statistics.  For example, CAN*TROL (a computer program developed by
Dr. David Eddy for cancer control planning for the World Heath Organization
and adapted for use at NCI) [7] is a tool which has been used to examine the
cost-effectiveness of various strategies for breast cancer screening, and
models of this type are currently being used to evaluate the impact of the
introduction of adjuvant therapy on breast cancer mortality as well as the
impact of changes in modifiable risk factors on colon cancer incidence.

CAN*TROL has proven to be an effective tool for responding to policy questions
from Congress and other sources addressed to NCI.

Macro-level models have their limitations.  For example, macro-level models do
not capture individual disease history, especially the pre-clinical phase, and
how early detection might alter that history. These dynamics are  captured in
models of specified cancer control interventions using microsimulation and
other modeling techniques.  While these modeling efforts have been invaluable
in providing insight into the cost and effectiveness of specific intervention
strategies, they are not designed to directly address the question of how
trends in screening dissemination at the national level affect trends in
cancer incidence, survival, mortality, and cost.  Recent efforts have been
made to adapt these models to address population level surveillance questions.
While in the past these models have been utilized to model hypothetical
cohorts in an organized screening program, the NCI has facilitated efforts to
model opportunistic screening for multiple cohorts reflecting the varying
cancer risk of U.S. population over time.  For example current efforts are
underway to model the impact of the dissemination of the PSA screening test in
the US population on prostate cancer incidence and mortality [8].  By
validating against current population trends we can provide further clues
about lead time, overdiagnosis, and the timing and size of potential mortality
declines.

In conjunction with the development of these models, there have been various
methodologic spin-offs that have broad uses in a variety of modeling settings. 
For example, NCI researchers, in collaboration with extramural researchers,
have investigated the issue of obtaining variability of estimates from
microsimulations [9], estimation techniques have been developed for the
incidence of pre-clinical prostate cancer from autopsy prevalence data [10],
and issues related to model validation have been explored.

Objectives and Scope

The objective of this RFA is to enhance research on the development and use of
models to evaluate the impact of cancer control interventions on population
level statistics.  NCI sponsored efforts to date in this area have been
productive, yet modest in scope and exploratory in nature.  Based on this
experience, it seems clear that a more systematic approach will tap the
potential of this area.  Funding will consist of two rounds, two years apart,
and in the first round applications will be restricted to breast, prostate and
colorectal cancer.  These are three major cancer control sites where there is
substantial modeling experience and, for the most part, interest in the
population impact of all three modalities of cancer control (screening,
treatment and primary prevention).  Depending upon our experience in the first
round, the second round will include other cancers, especially tobacco control
cancer sites.  To keep applications focused, each will be limited to a single
cancer site.  Models will focus on one or more of the following areas:

(1) Dissemination patterns, e.g., modeling national patterns of the adoption
and repeat use of mammography, PSA testing, etc. and diagnostic follow-up 
Data for such models are commonly obtained from national survey data and
longitudinal case studies.  Ties to social and behavioral models of change
would allow model parameters to be tied to specific cancer control
interventions.

(2) The impact of interventions on observed national trends in measures such
as incidence, mortality, quality of life costs, resource use, etc.:

(A) Using estimates of the impact of interventions in controlled settings
(e.g., meta-analysis of clinical trials or epidemiologic studies) and
dissemination patterns, e.g., a model of the impact of adjuvant chemotherapy
on colon cancer mortality starting in 1989.

(B) Using a model of disease natural history and operating characteristics of
an intervention (validated against clinical trial and controlled observational
experience) extrapolated to the population setting, e.g., model breast cancer
screening trials and/or demonstration projects, and extrapolate the results to
the U.S. screening experience.

(C) Using discrepancies between modeled and observed population trends to
study U.S. population and community effectiveness, i.e., study discrepancies
between model predictions and observed data to better understand how community
screening practices differ from trials (e.g., sensitivity of screening test
may be better than in a trial because of improved technology, or worse because
of less expert application of technology compared to the trial setting)

(3) Predicting the impact of new interventions on national trends, e.g., model
the impact of the preventative use of tamoxifen in high risk women on
projected US trends in breast cancer incidence and mortality.

(4) Determining the impact of targeted cancer control interventions on
population outcome, e.g., model the population impact of targeting different
age groups, risk groups, adherence to initial versus repeat screening
guidelines.

The focus of these efforts is on modeling the impact of the dissemination of
cancer control interventions in the population, rather than using trends to
help identify new risk factors.  However, these models can include components
which model the impact of population changes in both modifiable and non-
modifiable risk factors.  Models which include the impact of multiple
interventions simultaneously, e.g., the synergistic effects of screening and
treatment, are desirable.  Models can be of the entire US population, a region
of the country, or some specific identified population where unique data
exists on the implementation of an intervention, or in a subpopulation of
specific interest (e.g., rural poor).  Models can be developed for non-US
populations, but should be justified based on their applicability to
understanding US cancer trends.  Models can focus on one aspect of a disease
(e.g., in Situ breast cancer), although justification must be given as to how
one part of the disease process can be modeled separately, and how this model
can be integrated into the complete disease picture.  It is not the purpose of
this RFA to support analysis of hypothetical or trial-based cohorts, but
rather to support analysis based on realistic scenarios of population impact.

Applications should demonstrate modeling capability, and propose a specific
research plan.  However, applications should be flexible enough to accommodate
further refinement and integration with other efforts.

SPECIAL REQUIREMENTS

Terms and Conditions of Award

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.

Under this cooperative agreement, a partnership will exist between the
recipient of the award and the NCI. 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, 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 NCI scientific and/or
programmatic involvement with the awardee is anticipated during performance of
the activity. Under the cooperative agreement, the NCI 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  Scientific Staff.

1.  Definitions:

AWARDEES: Institutions receiving cooperative agreements through this RFA.

NCI PROGRAM DIRECTOR: Scientist administrator from the NCI extramural staff,
the Program Director will not only provide normal stewardship for the U01
grants awarded under this RFA, but will also be involved in the scientific
coordination and collaboration within the Network and will coordinate
interaction between the research groups.

PRINCIPAL INVESTIGATOR (PI): The investigator who is designated by the
applicant organization to direct the project to be supported by the U01 grant. 
The PI will assume the responsibility and accountability to the applicant
organization officials and to the NCI for the performance and proper conduct
of the research supported by the U01 mechanism.  Each institution may have
more than one CISNET PI, and a single person may be the PI for applications
for more than one cancer site.

NCI  SCIENTIFIC COORDINATORS: Scientists from the NCI extramural staff
designated by the Program Director to coordinate the activities for one of the
three cancer sites or the methodology working group.  NCI scientific
coordinators will have substantial scientific involvement with the working
groups and will help refine research questions.

NCI SCIENTIFIC STAFF: Scientific staff from NCI's extramural and intramural
programs called upon to provide their expertise to the CISNET efforts.

EXTRAMURAL SCIENTIFIC INVESTIGATORS: Scientific staff named in the application
from the participating institutions and their subcontractors.

CANCER-SITE WORKING GROUPS: There will be three cancer site specific working
groups (breast, prostate and colorectal cancer).  Voting members of each
working groups will be the PI's of each site specific grant project, and the
NCI Scientific Coordinator.  Other project and NCI Scientific Staff will
attend at the discretion of the voting members. The co-chairs of the working
groups will be the NCI Scientific Coordinator and one of the PI's (chosen by
mutual consent of the PI's for that cancer site).  Other subcommittees will be
formed by the working groups as needed.

METHODOLOGY WORKING GROUP: A group comprised of interested methodologists
among the extramural scientific investigators and NCI Scientific Staff.  The
chairs of the methodology working groups will be one Extramural Scientific
Investigator (chosen by mutual consent of the Extramural Scientific
Investigators on the Methodology Working Group) and an NCI Scientific
Coordinator designated by the NCI Program Director. Other subcommittees will
be formed by the working group as needed.

STEERING COMMITTEE: A committee consisting of the four non-NCI chairs of the
Working groups, the NCI Program Director, and one NCI Scientific Coordinator
as designated by the NCI Program Director.  The Chair of the Steering
Committee will be one of the PI's as selected by the Steering Committee.  The
Steering Committee can admit additional non-federal members as they deem
necessary.  The Steering Committee will provide overall direction for the
CISNET project and provide oversight to procedures and policies.

2.  Awardee Rights and Responsibilities

The award recipients must join the NCI CISNET project for the purpose of
planning, developing, and conducting collaborative projects to address high
priority surveillance research objectives.  Within this framework, awardees
have primary authorities and responsibilities to define objectives and
approaches, and to plan, conduct, analyze, and publish results,
interpretations, and conclusions of their studies.

Awardees will be expected to attend working group meetings and are obligated
to adhere to joint decisions for publication and research direction decided on
by the Steering Committee and the Working Groups.  The first cancer-site
working group meetings will be held shortly after the initiation of the award.

Awardees will be expected to share information about model structure and
assumptions at working group meetings, as well as strategies and data
resources for parameter estimation.

Awardees will be expected to engage in efforts coordinated by the Working
Groups for calibration, validation, and comparison of model results.

Awardees will retain custody of and have primary rights to the models and
model results developed under these awards, subject to Government rights of
access consistent with current HHS, PHS, and NIH policies.

3.  NCI Staff Responsibilities

The NCI  Program Director and his designees 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 Program Director will serve as a member of the Steering Committee.

The NCI Program Director will designate an NCI Scientific Coordinator for each
cancer site and for the methodology group who will serve as a co-chair of the
Working Groups.

The NCI Scientific Coordinators will provide information about a wide range of
data resources which will be used for parameter estimation and population
trends, and will serve as a conduit to the potential utility, access, and use
of these resources.  In addition, the NCI Scientific Coordinators will call
upon other NCI Scientific Staff to provide advice on specific scientific and
technical issues as needed.

The NCI reserves the right to reduce the budget, withhold support, or suspend,
terminate or curtail a study or an award in the event of substantial lack of
collaborative participation, failure to make satisfactory progress in
fulfilling the stated goals of the project, refusal to carry out the
recommendations of the Working Groups or the Steering Committee, or
substantial failure to comply with the terms of award.

4.  Collaborative Responsibilities

A. Steering Committee

The Steering Committee will:

Be the ultimate decision making body for CISNET, unless a disagreement is
brought to arbitration.

Review, approve, and provide comments on the written reports of the Cancer
Site-Specific Working Groups.  This approval process should ensure that the
proposed activities are consistent with the objectives and scope as specified
in the RFA.

Review, approve, comment on, and provide directives for implementation based
on the written recommendations from the Methodology Working Group.

Set publication procedures and policies.

Coordinate communication between the Working Groups.

Meet at least twice a year, and schedule additional meetings and conference
calls as needed.

B. Working Groups

Meet at least twice a year.

Refine research questions that are consistent with high priority surveillance
research needs.

Identify key potential determinants and confounders of population based
trends, and to identify useful data resources to inform these models.

Collaborate to identify and select common data resources for conducting
calibration and independent model validation.

Consider the development of common modules that supply intermediate inputs to
the central simulation models (e.g., screening histories supplied by a
dissemination module, survival improvements in a screening model supplied by a
treatment dissemination module).

Consider the use of common input data for dissemination, costs, and other
parameters based on the best available national estimates.

Facilitate comparative analyses which will improve the credibility of
individual models.

Evolve into an expert knowledge base to provide technical advise on policy
relevant surveillance questions.

Will provide written reports to the Steering Committee after each Working
Group Meeting summarizing research priorities, directions, and method of
implementation.

Responsibilities of the chairs of the Working Groups will be to:

Convene working meetings.

Set meeting agendas.

Coordinate communication within the Working Group,

Set (in consultation with the working group) the publication agenda and
schedule.

The PI Co-Chair of the Working Group will serve as a voting member of the
Steering Committee, and will represent their Working Group to the Steering
Committee.

C. The Methodology Working Group will:

Meet once a year, mainly for the purpose of scientific presentation and
exchange of ideas, and to coordinate research plans where necessary.

Provide a forum for the discussion of methods development associated with the
application of microsimulation and other models to population-based questions.

At the discretion of the group, provide written recommendations to the
steering committee for common methodologic approaches and validation
strategies and development of common model components.

5.  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 recipient group, 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 the NIH that women and members of minority groups and
their subpopulations must be included in all NIH supported biomedical and
behavioral research projects involving human subjects, unless a clear and
compelling rationale and justification is provided that inclusion is
inappropriate with respect to the health of the subjects or the purpose of the
research.  This policy results from the NIH Revitalization Act of 1993
(Section 492B of Public Law 103-43).

All investigators proposing research involving human subjects should read the
"NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical
Research," which have been published in the Federal Register of March 28, 1994
(FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23,
Number 11, March 18, 1994, available on the web at the following URL address:
http://grants.nih.gov/grants/guide/notice-files/not94-100.html

Investigators may also obtain copies of the policy from the program staff
listed under INQUIRIES.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them. 
This policy applies to all initial (Type 1) applications submitted for receipt
dates after October 1, 1998.

All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjects" that was published in the NIH Guide for
Grants and Contracts, March 6, 1998, and is available at the following URL
address: http://grants.nih.gov/grants/funding/children/children.htm

LETTER OF INTENT

Prospective applicants are asked to submit, by October 21, 1999, 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
interests in the review.

The Letter of Intent is to be sent to the program staff listed under INQUIRES
by the letter of intent receipt date listed in the heading of this RFA.

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used in
applying for these grants.  All instructions apply unless otherwise noted.
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.  For those applicants with internet access, the 398 kit
may be found at http://grants.nih.gov/grants/funding/phs398/forms_toc.html

Special Requirements

Budget

First year costs may include funds for such activities as model development,
model validation, acquisition of data for parameter estimation, methods
development, and/or use or purchase of high-speed computer systems. 
Activities may involve the acquisition and/or consolidation of data necessary
for parameter estimation, model calibration, or validation, and subcontracts
may be employed if necessary to make these efforts possible.  For purposes of
budgeting, funds should be requested for up to three persons to travel to up
to two cancer-site specific working group meetings, and one methodology
meeting per year for each of the four years of the award.  Because it is
anticipated that the same individuals may be participating in the activities
for more than one cancer site, site-specific meetings will be held
consecutively whenever possible.  Investigators should state their willingness
to participate in these meetings, be willing to share methods and data
resources, and to embark on collaborative efforts to decide overall research
direction.

If a PI, or an institution, are submitting several applications which share a
common structure (e.g., models for breast and prostate cancer share a similar
computing framework), funds to develop or enhance that common structure should
be included separately in each application, and overlapping funding of
activities will be considered at the time of award. Likewise, travel funds for
each application should be considered separately, and overlapping funding will
be considered at the time of award.  Finally, a submission from one
institution may contain subcontracts for consultation from another
institution, although if both institutions are funded the subcontract may be
superfluous.  Areas of potential overlapping funds across multiple
applications should be clearly identified.

Research Plan

Applications in response to the RFA must address the following areas:

Specific Aims/Background and Significance - Surveillance research question or
questions which this application is designed to address and the importance of
these issues for cancer control in the US.  If the proposal includes the
modeling of trends outside of the US, justification must be given as to what
special insights this will give in understanding of US trends, how these
results will be related to US trends, and why the same models could not be
applied directly to US data.

Preliminary Studies/Research Design and Methods -  Nature and characteristics
of the model to be employed. How the model will be adapted to address
population-based surveillance questions?  Proposed data resources for model
development and validation.. Description of Areas of potential collaboration
with other grantees in this Cooperative Agreement. Strategies for identifying
and characterizing differences between modeled and observed population trends,
and general approach towards developing a comprehensive understanding of the
determinants of cancer site specific trends at the population level.

Contractual Arrangements - Description of contractual arrangement necessary
for acquisition and/or consolidation of data necessary for parameter
estimation.  Any other contractual arrangements should also be described.

In addition, investigators should state their willingness to participate in
joint meetings, be willing to share methods and data resources, and to embark
on collaborative efforts to decide overall research direction.

The RFA label available in the PHS 398 (rev. 4/98) application form must be
affixed to the bottom of the face page of the application.  The RFA label and
line 2 of the application should both indicate the RFA number.  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.

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:

Ms. Toby Friedberg
Division of Extramural Activities
National Cancer Institute
6130 Executive Boulevard, Room 636, MSC-7407
Bethesda, MD 20892-7407
Rockville, MD 20852 (express courier)

Applications must be received by November 18, 1999.  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 398 application instructions for the
preparation of revised applications, including an introduction addressing the
previous critique.

REVIEW CONSIDERATIONS

Applicants are encouraged to submit and describe their own ideas about how
best to meet the general research goals outlined in this RFA, and are expected
to address issues identified under SPECIAL REQUIREMENTS of the RFA.

Upon receipt, applications will be reviewed for completeness by CSR and
responsiveness by the National Cancer Institute.  Incomplete and/or non-
responsive applications will be returned to the applicant without further
consideration.

Applications that are complete and responsive to the RFA will be evaluated for
scientific and technical merit by an appropriate peer review group convened by
the Division of Extramural Activities of the National Cancer Institute in
accordance with the review criteria stated below.  As part of the initial
merit review, a process will be used by the initial review group in which
applications 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 National Cancer
Advisory Board.

Review Criteria

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  The
reviewers will comment on the following aspects of the application in their
written critiques in order to judge the likelihood that the proposed research
will have a substantial impact on the pursuit of these goals.  Each of these
criteria will be addressed and considered by the reviewers in assigning the
overall score weighting them as appropriate for each application.  Note that
the application does not need to be strong in all categories to be judged
likely to have a major scientific impact and thus deserve a high priority
score.  For example, an investigator may propose to carry out important work
that by its nature is not innovative but is essential to move a field forward.

1.  Significance.  Does this study address an important population-based
surveillance problem? If the aims of the application are achieved, how will
surveillance research and cancer control be advanced?  What will be the
potential effect of these studies on policy of health care practices that
could ultimately improve the health of the American public?

2.  Approach.  What is the nature and characteristics of the model to be
employed.  How will the model be adapted to address population-based
surveillance questions.  What are the strategies for identifying and
characterizing differences between modeled and observed population trends, and
general approach towards developing a comprehensive understanding of the
determinants of cancer site specific trends at the population level. Are the
conceptual framework, design, methods, and analyses adequately developed,
well-integrated, and appropriate to the aims of the project?  Does the
applicant acknowledge potential problem areas and consider alternative
tactics?

3.  Innovation.  Does the project employ novel concepts, approaches or method? 
Are the aims original and innovative? Since the application of models of
cancer interventions to population based trends is a relatively new area,
applicants should describe in detail their approach to adaptation of current
models, and demonstrate an understanding of the problems inherent in working
with population based data.

4.  Investigator.  Is the investigator appropriately trained and well suited
to carry out this work?  Do the investigators have extensive modeling
experience? Is the work proposed appropriate to the experience level of the
principal investigator and other researchers (if any)?  Do the investigators
comprise a multi-disciplinary team that is adequate to carry out the proposed
work?

5.  Environment.  Does the scientific environment in which the work will be
done contribute to the probability of success?  Is modeling activities an
established element of the research environment? Do the proposed modeling
efforts take advantage of unique features of the scientific environment or
employ useful collaborative arrangements? Is there evidence of institutional
support?

6. Collaboration.  Do the investigators state their willingness to participate
in joint meetings, be willing to share methods and data resources, and to
embark on collaborative efforts to decide overall research direction?  Do the
investigators have a documented history of engaging in collaborative modeling
research with: (a) colleagues at their own institution, (b) modeling groups at
other institutions, (c) providers of primary data sources, and (d) policy
oriented organizations or agencies?  Documentation could include letters of
support from prior collaborations.

The initial review group will also examine: the appropriateness of proposed
project budget and duration; the adequacy of plans to include both genders,
minorities and their subgroups, and children  as appropriate for the
scientific goals of the research; and the safety of the research environment.

AWARD CRITERIA

Applications recommended by the National Cancer Advisory Board will be
considered for award based upon (a) scientific and technical merit; (b)
program balance, including in this instance, a reasonable representation of
projects across all three cancer sites, and 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 21, 1999
Application Receipt Date:         November 18, 1999
Review by NCAB Advisory Board:    May 2000
Earliest Anticipated Start Date:  July 2000

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:

Dr. Eric Feuer
Division of Cancer Control and Population Sciences
National Cancer Institute
6130 Executive Boulevard, Room 313, MSC 7344
Bethesda, MD  20892-7344
Telephone:  (301) 496-5029
Fax: (301) 435-3710
Email: rf41u@nih.gov

Direct inquiries regarding review issues to:

Ms. Toby Friedberg
Division of Extramural Activities
National Cancer Institute
6130 Executive Boulevard, Room 636, MSC-7407
Bethesda, MD  20892-7407
Rockville, MD  20852 (for express/courier service)
Telephone:  (301) 496-3428
Fax: (301) 402-0275
Email: tf12w@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Crystal Wolfrey
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Room 243
Bethesda, MD  20892-7510
Telephone:  (301) 496-8634
Fax: (301) 496-8601
Email: crystal.wolfrey@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.399. Awards are made under authorization of Sections 301 and 405 of the
Public Health Service Act as amended (42 USC 241 and 284) and administered
under NIH grants policies and Federal Regulations 42 CFR Parts 52 and 45 CFR
Parts 74 and 92. This program is not subject to the intergovernmental review
requirements of Executive Order 12372 or Health Systems Agency review.

The 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.

REFERENCES

1.  van den Akker-van Marle E, de Koning H, Boer R, van der Maas P. Reduction
in breast cancer mortality due to the introduction of mass screening in the
Netherlands: comparison with the United Kingdom.  J Med Screen 1999;6:30-34.

2.  Feuer, E.J., Wun, L.M. "How Much of the Recent Rise in Breast Cancer
Incidence Can be Explained by Increases in Mammography Utilization:  A Dynamic
Population Approach," American Journal of Epidemiology, 1992; 136, 1423-1436.

3.  Wun, L.M. Feuer, E.J., Miller, B.A. "Are Increases in Mammographic
Screening Still a Valid Explanation for Trends in Breast Cancer Incidence in
the United States?" Cancer Causes and Control, 1995; 6, 135-144.

4.  Legler, J.M., Feuer, E.J., Potosky, A.L., Merrill, R.M., Kramer, B.S.,
"The Role of Prostate-Specific Antigen Testing Patterns in the Recent Prostate
Cancer Incidence Decline," Cancer Causes and Control, 1998; 9, 519-527.

5.  Feuer, E.J., Kessler, L.G., Triolo, H.E., Baker, S.G., Green, D.T.  "The
Impact of Breakthrough Clinical Trials on Survival in Population Based Tumor
Registries," Journal of Clinical Epidemiology, 1991; 44, 141-153.

6.  Weller, E.A., Feuer, E.J., Frey, C.M., Wesley, M.N., "Parametric Relative
Survival Modeling Using Generalized Linear Models with Application to
Hodgkin's Lymphoma,"  Applied Statistics, 1999; 48, 79-89.

7.  Levin DL, Gail MH, Kessler LG, Eddy DM, "A Model for Projecting Cancer
Incidence and Mortality in the Presence of Prevention, Screening, and
Treatment Programs,"  NCI Monographs, 2:83-93, 1986.

8. Etzioni, R, Legler, JM, Feuer, EJ, Merrill, RM, Cronin, KA, Hankey, BF,
"Cancer Surveillance Series: Interpreting Trends in Prostate Cancer - Part
III: Quantifying the Link Between Population Prostate-Specific Antigen Testing
and Recent Declines in Prostate Cancer Mortality," JNCI , 91: 1033-1039, 1999.

9.  Cronin KA, Legler, JM, Etzioni RD, "Assessing Uncertainty in
Microsimulation Modeling with Application to Cancer Screening Applications,"
Statistics in Medicine, 1998; 17:2509-23.

10. Etzioni, R., Cha, R, Feuer, E.J., Davidov, O.  "Asymptomatic Incidence and
Duration in Prostate  Cancer,." American Journal of Epidemiology, 1998; 148,
775-785.


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