Full Text HG-94-001

STUDIES OF GENETIC TESTING AND COUNSELING FOR HERITABLE BREAST,
OVARIAN AND COLON CANCER RISKS

NIH GUIDE, Volume 23, Number 5, February 4, 1994

RFA:  HG-94-001

P.T.


Keywords: 


National Center for Human Genome Research
National Cancer Institute
National Institute of Mental Health
National Institute of Nursing Research

Letter of Intent Receipt Date:  March 1, 1994
Application Receipt Date:  April 22, 1994

PURPOSE

This Request for Applications (RFA) will solicit projects designed to
examine the psychosocial and clinical impact of using gene-based
diagnostic tests in families with heritable forms of breast, ovarian,
and colon cancer to identify those individuals who have an increased
risk of developing cancer and those who do not; and to gather
information needed to establish clinical protocols for the optimum
use of these risk assessment technologies in the future.

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,
Studies of Genetic Testing and Counseling for Heritable Breast,
Ovarian, and Colon Cancer Risks, is related to the priority areas of
health promotion and cancer prevention.  Potential applicants may
obtain a copy of "Healthy People 2000" (Full Report:  Stock No.
017-001-00474-0) or "Healthy People 2000" (Summary Report:  Stock No.
017-001-00473-1) through the Superintendent of Documents, Government
Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign for-profit and
non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State or local
governments, and eligible agencies of the Federal government.
Applications from minority individuals and women are encouraged.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) individual
research grant (R01) and small research grant mechanisms (R03).
Responsibility for the planning and direction of the proposed project
will be that of the applicant.  However research teams supported
under this RFA will be asked to work together to coordinate their
efforts in order to assure that as many of the research questions are
answered as possible and to reduce duplication of research efforts.
Awards will be administered under PHS grants policy as stated in the
Public Health Service Grants Policy Statement.

This RFA is a one-time solicitation.  Future unsolicited competing
continuation applications will be reviewed according to the customary
peer review procedures and compete with all other unsolicited
investigator-initiated applications.  The total project period for
applications submitted in response to the present RFA may not exceed
three years.  The anticipated award date will be September, 1994.

FUNDS AVAILABLE

It is anticipated that $2,400,000 (direct and indirect costs) per
year for up to three years will be available beginning in fiscal year
1994 for approximately eight to ten studies.  This level of support
is dependent upon the receipt of a sufficient number of applications
of high scientific merit.  Although this program is provided for in
the financial plans of the participating institutes, awards pursuant
to this RFA are contingent upon the availability of funds for this
purpose.  The amount of funding for these projects may be increased
if a large number of highly meritorious applications are received and
if funds are available.

RESEARCH OBJECTIVES

Background and Significance

Cancer is the second leading cause of death in the United States,
accounting for one out of every five, or more than 500,000 deaths
each year.  More than 1,000,000 individuals are identified to have
cancer each year.  One in three Americans now living will develop
cancer in his or her lifetime.  Colorectal cancer accounts for 15
percent of all cancers diag-nosed and 12 percent of all
cancer-related deaths, while breast cancer (which occurs primarily in
women) accounts for 14 percent of all cancers diagnosed and 18
percent of cancer related deaths in women.  Ovarian cancer accounts
for approximately two percent of all cancers diagnosed and 2.5
percent of all cancer related deaths.  Early detection and
intervention have the potential to significantly reduce morbidity and
mortality in these forms of cancer.

For years, it has been known that human cancers tend to cluster in
families.  Whether these clusters are due to chance, inherited cancer
susceptibility genes, or shared environments is only now beginning to
be understood.  The genetic contribution to human cancers is being
identified, notably with the discovery or the imminent discovery of
such genes as the p53 gene (associated with the Li-Fraumeni
syndrome), the familial adenomatous polyposis coli (APC) gene
(correlated with colon cancer), the hereditary non-polyposis colon
cancer (HNPCC) gene, called MSH2 (associated with genetic instability
in tumors), and the breast cancer gene termed BRCA1 (associated with
breast and ovarian cancers).  As the Human Genome Project moves
forward there will be a continuous improvement in the ability to
localize and sequence genes, some of which will be determined to have
a major role in the development of various forms of cancer.  In some
families with heritable forms of cancer, genetic tests can now
identify those individuals who are at increased risk for cancer to
develop and those who are not.  Until now, these tests have been
available only in research settings involving studies on several
familial cancer syndromes.

As the mapped genes are cloned, such testing will become technically
feasible not only in families with heritable forms of cancer, but
also in a much wider population where cancer has sporadically
occurred.  Identifying individuals who have a genetic risk for
developing cancer may allow an opportunity to provide counseling and
early interventions to reduce the risk of associated morbidity and
mortality.  Well designed clinical protocols for the use of these
tests are urgently needed to ensure the professionally responsible
integration of such tests into clinical practice for optimal outcome
with minimal associated risks.  The anticipated availability of
genetic tests for cancer risks has the potential to launch genetic
testing out of genetic specialty areas and into mainstream health
care practice in the very near future.  Because cancer affects a
significant proportion of the population and the potential benefits
associated with early detection of possible genetic contributions to
various forms of cancer are substantial, it is anticipated that as
cancer-causing genes are discovered, there may be considerable
professional as well as public demand to offer testing for identified
mutations to a much wider population than families with heritable
forms of cancer.

As a result of recent breakthroughs in molecular biology and the
potential to offer such testing in the relatively near future, issues
related to whether, when, and how best to offer genetic testing and
counseling to assess heritable cancer risks have been widely
discussed.  There is consensus that there is an urgent need to
examine both professional and public knowledge and attitudes about
genetic testing for cancer risks; to establish the parameters of
genetic testing for cancer risks, including to whom such testing
should be offered; to identify the optimum providers, settings and
timing for genetic testing for cancer risks; to determine the optimum
mechanisms for pretest education and counseling for people
considering genetic testing for cancer risks; to explore the
psychosocial impact of identifying that an individual has a genetic
risk factor for cancer, as well as finding that other individuals,
who may have previously thought they had an increased risk for
cancer, do not actually have such a genetic risk factor; to define
the optimum forms of post-test counseling and follow up care for
individuals found to have genetic risk factors for cancer; to develop
policies about management of genetic information and cancer risk
status; and to investigate the impact of identifying genetic risk
factors in individuals on longevity, quality of life, and adherence
to health promotion and disease prevention strategies.  Research is
also urgently needed to further define any unanticipated consequences
of genetic testing for heritable cancer risks.

Since the genetics (including genetic linkage or direct DNA mutation
testing for alleles), natural histories, and clinical management
options for some forms of heritable breast, ovarian, and colon
cancers are in the process of being elucidated, this research
initiative will focus on this group of disorders.  This spectrum of
conditions displays enough variety to raise a wide range of
questions, while remaining similar enough to make cross comparisons
practical.  While applications regarding hereditary non-polyposis
colorectal cancer (HNPCC) are welcome in response to this RFA,
applications on familial adenomatous polyposis (FAP) will not be
accepted because there exist well established protocols for the
diagnosis of FAP (without gene testing) as well as an effective
treatment for this disorder.

Objectives

The goal of these studies is to identify clinical practices that best
increase individual and provider understanding of genetic testing for
cancer risks; the meaning and implications of test results; and
strategies to promote health, prevent the development of cancer, and
reduce the risk for test-related psychological harm, stigmatization
and discrimination in individuals tested and their families.
Multidisciplinary research teams are encouraged to respond to this
RFA.  Research questions that may be appropriately addressed in
applications responding to this RFA include, but are not limited to:

1.  Identifying individuals who are most likely to benefit from
genetic testing for heritable cancer risks.

2.  Determining optimum ways to educate individuals considering
having genetic tests for cancer risk assessment, including public
education and education through support groups.

3.  Establishing mechanisms to assess individual readiness for
genetic testing for cancer risks (including minors and other
individuals with diminished autonomy, in whom testing may be
recommended) and determining factors that influence the decision to
be tested.

4.  Defining issues that should be addressed in the informed consent
process for individuals in families considering genetic testing and
counseling for cancer risks, including the potential for the use of
persuasion within families, changes in family dynamics, and
stigmatization or discrimination.

5.  Examining diverse models (including a variety of settings and
providers) of delivery for providing genetic testing and counseling
for cancer risks.

6.  Identifying and evaluating strategies for providing post-test
counseling and follow up for individuals who have had genetic tests
for cancer risks (for both those individuals who were found to have
an increased risk and those who were not).

7.  Determining what the psychosocial impact is on individuals who
learn through genetic testing that their risk to develop cancer is
either substantially increased above or no greater than that of the
general population (especially as it pertains to family
relationships, subsequent health behavior, reproductive intentions,
and quality of life).

8.  Defining the impact of genetic diagnosis for cancer risk on
subsequent interactions with health professionals and third party
payers.

9.  Examining the behavior and actions of non-test-takers, including
women, men and non-tested minors.

10.  Ascertaining attitudes, levels of understanding and interest in
genetic testing to determine cancer risk in provider populations by
whom testing might be offered in the future, distinguishing
discipline, training, gender and ethnocultural differences.

11.  Ascertaining attitudes, levels of understanding and interest in
genetic testing for cancer risks in individuals and families with
diverse ethnocultural backgrounds to whom genetic testing for cancer
risks may be offered in the future.

12.  Examining the economic impact and technical accuracy of various
genetic testing strategies for determining cancer risks in families
and other populations, including analysis of associated health care
costs placed in the context of health outcomes related to early
detection and interventions to reduce risks.

SPECIAL REQUIREMENTS

Applicants do not need to respond to all of the above research
questions, but may respond to a subset of the questions or single
research question.  In order to adequately evaluate the several
variables involved in the use of genetic cancer risk assessments, the
NIH will develop a consortium of studies, each addressing some subset
of the overall research agenda in cooperation with the others.  In
addition to potentially increasing the scope and pace of the
research, such an arrangement allows some features of the research,
such as evaluation measures and tools, laboratory quality control,
and human subjects protections to be standardized across the
participating investigations.  This mechanism also allows for more
reliable comparisons between studies.  To facilitate such
coordination, grantee workshops will be arranged on an annual basis
in the Bethesda area.  The initial meeting of the consortium will
take place shortly after the grants are funded.  Funds for travel to
this meeting for as many as two investigators per year may be
requested.

In addition to the coordination of funded studies, initiatives should
be interdisciplinary in nature.  Research design should consider
surveys of individuals affected with cancer, health care providers,
and public knowledge and attitudes of genetic testing for cancer
risks, using standard survey research methodology, to address study
questions or gather baseline information.  Structured interviews,
focus groups, or other sociologic techniques may also be appropriate.
Applications that address issues limited to specific aspects of
knowledge and attitudes should utilize the R03 mechanism, which
provides total direct costs up to $50,000 per year for a maximum
period of two years.

Applications that include testing and counseling or educational
interventions and those which address knowledge and attitudes with
complex study designs, should consider the R01 application mechanism.
However, funding for R01 application in response to the RFA is
limited to a three-year period.  For applications that test specific
interventions, an experimental design is the preferred approach;
however, the individual person or provider may not necessarily be the
appropriate unit of randomization.  A quasi-experimental design may
be considered in some circumstances.  The intervention must be
clearly described in the application.  Evaluation of outcomes should
include endpoints that reflect quality of life (QOL) and/or specific
QOL domains, assessed with valid and reliable techniques.  Additional
endpoints of adherence to prevention programs (including early
detection strategies and life-style changes) and utilization of
health services should be considered as appropriate for the research
questions.  Qualitative, ethnographic approaches to the study of
family dynamics and psychosocial impact are encouraged.

In applications in which the gene has not yet been cloned and genetic
testing by linkage analysis will be utilized, applicants should
explain in their research plans, how they would accommodate the
cloning of any genes involved in their study proposal and how they
would adapt their protocols from linkage analysis studies to direct
DNA mutation detection.  For projects involving testing for HNPCC,
applicants should describe how the recent cloning of the MSH2 gene
will affect their plan, acknowledging the trade-off between the
advantages of actual mutation detection in allowing individual
testing vs. the increased cost and technical complexities of scanning
a large gene for all possible mutations.  Applicants must also detail
their laboratory quality control procedures for review, if they are
proposing clinical studies involving linkage analysis or DNA testing.
The laboratory component of the research proposal does not have to be
on site.  The laboratory costs associated with these studies are
allowable if required by the research protocol.  However, because of
limitations in the availability of funds, investigators are
encouraged to seek other sources of funding for associated laboratory
costs.  The costs and budget justification for the laboratory
component should be clearly identified, described, and justified in
the budget section of the application.

All applicants should describe, in detail, plans for the protection
of the rights and interests of any individual and/or family involved
in any clinical testing protocol.  Specific plans for recruitment of
subjects should be clearly summarized.  Any plans for sharing of data
and storage of DNA samples for other purposes must be outlined.
While it is foreseeable that there may be some research situations in
which it would be appropriate to involve minors as subjects, studies
proposing to perform gene-based risk assessments involving minors
have the potential to result in a "greater than minimal risk," and
thus applicants need to explicitly address any potential benefits and
risks to minor subjects, in whom such testing would be carried out.
Applicants proposing to carry out clinical protocols should review
the OPRR publication, 1993 Protecting Human Research Subjects:
Institutional Review Board Guidebook, Chapter 5, Section H, Human
Genetic Research.  If funded, applicants may wish to consider
applying for a Certificate of Confidentiality from the Department of
Health and Human Services in order to attempt to provide further
protection for research subjects.  For further information regarding
Certificates of Confidentiality, communicate with Mr. John Fanning at
(202) 690-5896 or Internet and Bitnet jfanning@oash.ssw.dhhs.gov.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements are required to include minorities and women
in study populations so that research findings can be of benefit to
all persons at risk to develop the disease, disorder or condition
under study; special emphasis must 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 must 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 must be addressed in developing a research
design and sample size appropriate for the scientific objectives of
the study.  This information must be included in the form PHS 398 in
Sections 1-4 of the Research Plan AND summarized in Section 5 Human
Subjects.  Applicants are urged to assess carefully the feasibility
of including the broadest possible representation of minority groups.
However, 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 is defined as 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.

DHHS policies concerning research involving 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 tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including
minorities.

If the required information is not contained within the application,
the application will be returned.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies. If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the
selected study population is inadequate, it will be considered a
scientific weakness or deficiency in the study design and reflected
in assigning the priority score to the application.

All applications for clinical research submitted to NIH are required
to address these policies.  NIH funding components will not award
grants or cooperative agreements that do not comply with these
policies.

LETTER OF INTENT

Prospective applicants are asked to submit, by March 1, 1994, a
letter of intent to respond to this RFA that includes a descriptive
title of the proposed research, the name, address, and telephone
number of the Principal Investigator, the identities of other key
personnel and participating institutions, and the number and title of
the RFA in response to which the application may be submitted.
Although a letter of intent is not required, is not binding, and does
not enter into the review of subsequent applications, the information
that it contains is helpful in planning for the review of
applications.  It allows NIH 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:

Elizabeth J. Thomson, M.S., R.N.
Ethical, Legal, and Social Implications Branch
National Center for Human Genome Research
Building 38A, Room 617
Bethesda, MD  20892
Telephone:  (301) 402-4997
FAX:  (301) 480-2770

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these grants.  These forms are available at most
institutional offices of sponsored research; from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892,
telephone (301)435-0714; and from the NIH program administrator
listed under INQUIRIES.

The RFA label available in the PHS 398 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 2a 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:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

To expedite the review process, at the time of submission, send two
additional copies of the application to:

Office of Scientific Review
National Center for Human Genome Research
Building 38A, Room 604
Bethesda, MD  20892

Applications must be received by April 22, 1994.  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 revisions of applications already reviewed, but
such applications must include an introduction addressing the
previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed by DRG for completeness
and by NCHGR program staff for responsiveness to the RFA.  Incomplete
applications will be returned to the applicant without further
consideration.  If the R01 application is not responsive to the RFA,
NIH staff will contact the applicant to determine whether to return
the application to the applicant or submit it to the Division of
Research Grants (DRG) for review in competition with unsolicited
applications at the next review cycle.

Applications may be triaged by an NIH peer review group on the basis
of relative competitiveness.  The NIH will withdraw from further
competition those applications judged to be non-competitive for award
and notify the applicant Principal Investigator and institutional
official.  Those applications judged to be competitive will undergo
further scientific merit review.  Those applications that are
complete and responsive will be evaluated by an appropriately
constituted initial review group in accordance with the criteria
stated below for scientific/technical merit by an appropriate peer
review group convened by NCHGR. The second level of review will be
provided by the appropriate National Advisory Councils.

o  originality, innovativeness of proposed project;

o  potential of the proposed work to attain the objectives outlined
in the RFA;

o  scientific, technical, medical, educational or counseling
significance and originality of proposed project;

o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the project;

o  qualifications and experience of the Principal Investigator and
staff, particularly but not exclusively in the area of the proposed
project;

o  availability of resources necessary to perform the project;

o  appropriateness of the proposed budget and duration in relation to
the proposed project;

o  adequate gender and minority representation; and

o  adequate protections for human subjects, if involved in the
project.

AWARD CRITERIA

The anticipated date of award approximately September 30, 1993.  The
following criteria will be considered in making funding decisions:

o  the quality of the proposed project as determined by peer review;
o  the responsiveness of the proposed project to achieve the goals of
this RFA;
o  balance among the projects to respond to the questions included in
the RFA; and
o  availability of funds.

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:

Elizabeth J. Thomson, M.S., R.N.
Ethical, Legal, and Social Implications Branch
National Center for Human Genome Research
Building 38A, Room 617
Bethesda, MD  20892
Telephone:  (301) 402-4997
FAX:  (301) 480-2770

Direct inquiries regarding fiscal matters to:

Jean M. Cahill
Grants and Contracts Management Section
National Center for Human Genome Research
Building 38A, Room 613
Bethesda, MD  20892
Telephone:  (301) 402-0733

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.172, Human Genome Research.  Awards are under
authorization of the Public Health Service Act, Title IV, Part A
(Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and
285) and administered under PHS grants policies and Federal
Regulations 42 CFR 52 and 45 CFR Part 74.  This program is not
subject to the intergovernmental review requirements of Executive
Order 12372 or Health Systems Agency review.

References

Biesecker, B.B., Boehnke, M., Calzone, K, Markel, D., Garber, J.,
Collins, F., and Weber, B. Genetic counseling for families with
inherited susceptibility to breast and ovarian cancer.  JAMA 269:15,
1970-1974, 1993.

Department of Health and Human Services.  Healthy People DHHS
Publication No. PHS 91-50212, 1991.

Fishel, R., Lescoe, M.K., Rao, M.R.S., Copeland, N.G., Jenkins, N.
A., Garber, J., Kane, M., Kolodner, R. The human mutator gene homolog
msh2 and its association with hereditary nonpolyposis colon cancer.
Cell 75, 1027-1038, 1993.

King, M.C., Rowell, S., and Love, S. Inherited breast and ovarian
cancer:  what are the risks?  what are the choices? JAMA 269:15,
1975-1980, 1993.

Leach, F. S., Nicolaides, N.C., Papadopoulos, N., Liu, B., Jen, J.,
Parsons, R., Peltomaki, P., Sistonen, P., Aaltonen, L.A.,
Nystrom-Lahti, M., Guan, X-Y, Zhang, J., Meltzer, P.S., Yu, J.W.,
Kao, F.T., Chen, D.J., Cerosaletti, K.M., Fournier, R.E., Todd, S.,
Lewis, T., Leach, R.J., Naylor, S.L., Weissenbach, J., Mecklin, J.
P., Jarvinen, H., Petersen, G. M., Hamilton, S.R., Green, J., Jass,
J., Watson, P., Lynch, H.T., Trent, J.M., de la Chapelle, A.,
Kinzler, K.W., Vogelstein, B. Mutations of a muts homolog in
hereditary non-polyposis colorectal cancer.  Cell (in press) 1993.

Lerman, C., Rimer, B., and Engstrom, P. Cancer risk notification:
psychosocial and ethical implications.  J Clin Oncol 9:7, 1275-1282,
1991.

Li, F., Garber, J., Friend, S., Strong, L., Patenaude, A., Juengst,
E., Reilly, P., Correa, P., and Fraumeni, J. Recommendations on
predictive testing for germ line p53 mutations among cancer-prone
individuals.  JNCI 84:15, 1156-1160, 1992.

Parsons, R., Li, G.M., Longley, M.J., Fang, W., Papadopoulos, N.,
Jen, J., de la Chapelle, A., Kinzler, K. W., Vogelstein, B., Modrich,
P. Hypermutability and mismatch repair deficiency in rer+ tumor
cells.  Cell (in press) 1993.

.

Return to RFAs Index

Return to NIH Guide Main Index


Office of Extramural Research (OER) - Home Page Office of Extramural
Research (OER)
  National Institutes of Health (NIH) - Home Page National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS)
  USA.gov - Government Made Easy


Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.