STATISTICAL METHODS IN HIV/AIDS RESEARCH

Release Date:

PA NUMBER:  PA-98-054

P.T.

National Institute of Allergy and Infectious Diseases
National Institute of Mental Health

PURPOSE

The National Institute of Allergy and Infectious Diseases (NIAID), and the
National Institute of Mental Health (NIMH), National Institutes of Health
(NIH), invite applications for the development of original statistical methods
to advance the understanding, treatment, and prevention of human
immunodeficiency virus (HIV) disease/AIDS.

NIH Support of Research on this Topic

Although this Program Announcement is being issued by NIAID and NIMH, the
other components of NIH listed below also have an interest in and support
research on the topics covered.  Applicants may wish to contact each of these
NIH components listed in INQUIRIES to find out about other funding
opportunities.  Institutes and Centers at NIH use different grant mechanisms
to support their portfolio of research; the components listed here may not use
all of the mechanisms specified for this Program Announcement.

NCRR:   Mathematical models of basic biological processes.
NCI:    Epidemiology of AIDS/retroviral-associated cancers.
NICHD:  Statistical methods and designs for analyzing the determinants of
sexual behavior related to HIV risk and the impact of interventions to modify
sexual behavior, including techniques to improve the accuracy of self-report
data; demographic approaches to modeling the spread and impact of HIV within
the population.
NIDA:   Mathematical models of transmission related to drug abuse and effects
of behavioral prevention programs.

Applications submitted in response to Program Announcements are assigned
according to established PHS referral guidelines.  When the subject of an
application is of interest to more than one component of NIH, dual assignments
are made.

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 PA, Statistical Methods in HIV/AIDS
Research, is related to the priority areas of HIV infection, sexually
transmitted diseases, immunization and infectious diseases, and 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).

ELIGIBILITY

Applications may be submitted by domestic and foreign, for-profit and non-
profit organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of State and local governments, and eligible
agencies of the Federal government.  Racial/ethnic minority individuals,
women, and persons with disabilities are encouraged to apply as Principal
Investigators.

MECHANISM OF SUPPORT

Traditional research project grant (R01) applications may be submitted in
response to this program announcement.  Applications for R01 grants may
request up to five years of support.

R01 applicants who wish to collaborate may apply for a Interactive Research
Project Grant (IRPG).  Further information may be found via the WWW at
http://www.nih.gov/grants/guide/pa-files/PA-96-001.html

RESEARCH OBJECTIVES

Background

The AIDS epidemic has posed unique challenges for the design of therapeutic
and prevention trials, and epidemiologic and basic science studies, and for
the analysis of data resulting from each of these. New statistical methods
have been developed to handle such problems as the tracking and prediction of
number of AIDS cases, the use and assessment of immunologic and virologic
measurements, and the analysis and monitoring of clinical trials with censored
and missing data. Recent years have seen an increasing array of available
drugs, diversity of affected populations and viral characteristics, and an
increased appreciation of the dynamic, multivariate, and multiphasic nature of
HIV disease. Research in this changing and ever more complex environment
presents great methodological challenges.

Research Objectives and Scope

Innovative statistical methods are expected to continue to play an important
role in the investigation of new AIDS therapies and prevention strategies. 
Such methods need to be attuned to the particular features of HIV/AIDS biology
and epidemiology.  The evolving circumstances of the epidemic and the
expanding set of research tools also need to be considered.  For instance, new
statistical methods are needed for the effective utilization of recently
developed immunologic and virologic measures (for example, HIV RNA assays and
HIV genotypic data). Such measures provide new opportunities for the
evaluation of HIV therapies and vaccines, and the study of HIV transmission
and pathogenesis. Recent NIH guidelines for the use of antiretroviral agents
provide a backdrop for the design of ethical clinical and prevention trials,
but questions remain in the use of highly, though not universally, effective
treatment regimens.  Little is known, for instance, on how to optimally use
virologic and other laboratory measures in decisions about when to start and
when to switch therapy and the sequence of regimens.  The appropriate and
efficient utilization of multiple endpoints, clinical as well as laboratory,
in efficacy studies needs further consideration.  Mathematical models have
provided some clues for effective treatment strategies, but further
development is required to capture enough features of disease dynamics to
produce reliable and relevant inferences.

The areas of research listed below are not all-inclusive, but are intended to
provide guidance as to the types of research that are of interest.

1.  Design and analysis of novel clinical trials involving, for example,
multiple or combined endpoints, treatment changes or multicomponent treatment
strategies, or sequential evaluation of therapies;

2.  Trial designs for the evaluation of HIV vaccine candidates and other
interventions such as STD diagnosis and treatment, behavioral counseling,
microbicides, chemoprophylactic agents, and antiretroviral therapy which
assess the indirect as well as direct effects of intervention;

3.  Statistical methods for assessing the impact of HIV genetic and antigenic
variation on the effectiveness of HIV vaccines;

4.  Design and analysis of explanatory clinical studies, for example, nested
studies within clinical trials to explore questions regarding HIV pathogenesis
or to assess the validity of biological markers such as viral load as
surrogate endpoints;

5.  Statistical methods to assess the timing and correlates of HIV perinatal
transmission and to address unique features of pediatric HIV disease;

6.  Design and analysis of early stage therapy studies (including preclinical
studies and Phase I and II clinical trials) for the efficient screening and
evaluation of drugs, drug combinations, or doses;

7.  Mathematical or statistical modeling of HIV pathogenesis including acute
infection, resistance, interactions among multiple pathogens, and the course
of HIV disease.

8.  Mathematical or statistical modeling of the potential population-level
effects of HIV vaccination programs and other prevention strategies on the
control of HIV transmission;

9.  Design of animal challenge studies for assessing the effects of HIV (or
analogous) vaccines and chemoprophylactic strategies;

10.  Methods for the statistical evaluation of data quality in large,
multicentered clinical trials;

11.  Mathematical or statistical modeling of HIV transmission and spread
within at-risk populations;

12.  Design and analysis of Phase I and II safety and immunogenicity studies
of HIV vaccine candidates;

13.  Improved methods for obtaining self-report data and use of multiple
methods (e.g., behavioral and biological) to establish psychometrics;

14.  Improved methods for assessing family systems and social networks, and
data analysis strategies for multiple data points in longitudinal studies of
family and social systems; and,

15.  Mathematical models using available seroincidence data for linking
behavioral change with reduction in HIV transmission at different levels of
seroprevalence and social mixing.

To address these issues, a multidisciplinary approach is strongly encouraged. 
The mathematical/statistical modeling of the potential impact of HIV
vaccination, for example, would benefit from a research team which includes
persons with expertise in demography, STD control, behavioral science, and
vaccine development, in addition to statistics and/or mathematics.

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 are provided that demonstrate inclusion
is inappropriate with respect to the health of the subjects for 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 the NIH Guide for Grants and Contracts, Vol. 23, No.
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 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://www.nih.gov/grants/guide/notice-files/not98-024.html

Statistical modeling approaches proposed in response to this Program
Announcement should take the NIH Guidelines on Women and Minorities and
Children (above) into consideration, as appropriate.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev.
5/95) and will be accepted on the standard AIDS application deadlines as
indicated on the application kit.  Application 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) 710-0267, email: asknih@od.nih.gov.

For purposes of identification and processing, item 2 on the face page of the
application must be marked "YES".  The PA number and the PA title must also be
typed in section 2.

The completed, signed original and five legible, single-sided copies of the
application must be sent or delivered to:

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

APPLICANTS REQUESTING $500,000 OR MORE IN ANNUAL DIRECT COSTS.  The NIH Policy
Update on Acceptance for Review of Unsolicited Applications that Request More
Than $500,000 Direct Cost for Any One Year applies to applications in response
to this PA.  The Policy Update was published in the NIH Guide for Grants and
Contracts, March 20, 1998.

Applicants from institutions that have a General Clinical Research Centers
(GCRC) funded by the NIH National Center for Research Resources may wish to
identify the Center as a resource for conducting the proposed research.  If
so, a letter of agreement from the GCRC Program Director must be included in
the application material.

REVIEW CONSIDERATIONS

Review Procedures

Applications will be assigned on the basis of established PHS referral
guidelines. Upon receipt, applications will be reviewed for completeness by
the NIH Center for Scientific Review.  Incomplete applications will be
returned to the applicant without further consideration.

Applications will be reviewed for scientific and technical merit by study
sections of the Center for Scientific Review, NIH, in accordance with the
standard NIH peer review procedures.  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

The five criteria to be used in the evaluation of grant applications are
listed below.  To put those criteria in context, the following information is
contained in instructions to the peer reviewers.

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 problem? If the aims
of the application 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?

2.  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?

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

4.  Investigator.  Is the investigator appropriately trained and well suited
to carry out this work?  Is the work proposed appropriate to the experience
level of the principal investigator and other researchers (if any)?

5.  Environment.  Does the scientific environment in which the work will be
done 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?

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

AWARD CRITERIA

Applications will compete for available funds with all other favorably
recommended applications.  The following will be considered when making
funding decisions: quality of the proposed project as determined by peer
review, program balance among research areas of the program announcement, and
availability of funds.

INQUIRIES

Written and telephone inquiries are encouraged.  The opportunity to clarify
any issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Jeffrey M. Albert, Ph.D.
Division of AIDS
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 2A26-A
Bethesda, MD  20892-7640
Telephone:  (301) 435-3752
FAX:  (301) 480-5703
Email:  ja24o@nih.gov

Willo Pequegnat, Ph.D.
Office on AIDS Research
National Institute of Mental Health
Parklawn Building, Room 18-101
Rockville, MD  20857
Telephone:  (301) 443-6100
FAX:  (301) 443-9719
Email:  WPEQUEGN@nih.gov

Direct inquiries regarding fiscal matters to:

Mary Ledford
Grants Management Branch
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4B24
Bethesda, MD  20892-7610
Telephone:  (301) 402-6446
FAX:  (301) 480-3780
Email:  ml28g@nih.gov

Other NIH Institutes and Centers with related research interests:

Christine A. Bachrach, Ph.D.
Center for Population Research
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8B13
Bethesda, MD  20892-7510
Telephone:  (301) 496-1174
FAX:  (301) 496-0962
Email:  cbachrach@nih.gov

Sandra L. Melnick, Dr.P.H.
Epidemiology and Genetics Program
National Cancer Institute
Executive Plaza North, Room 535
Bethesda, MD  20892-7395
Telephone:  (301) 435-4914
FAX:  (301) 402-4279
Email:  sm33k@nih.gov

Steven W. Gust, Ph.D.
Office on AIDS
National Institute on Drug Abuse
Parklawn Building, Room 10-05
Rockville, MD  20857
Telephone:  (301) 443-6480
FAX:  (301) 443-9582
Email:  sgust@nih.gov

Jill L. Carrington, Ph.D.
Biological Models and Materials Research
National Center for Research Resources
6705 Rockledge Drive, Room 6164, MSC 7865
Telephone:  (301) 435-0776
FAX:  (301) 480-3659
email:  jillc@ep.ncrr.nih.gov

AUTHORITY AND REGULATIONS

This program is supported under authorization of the Public Health Service
Act, Sec. 301(c), Public Law 78-410, as amended.  The Catalogue of Federal
Domestic Assistance Citations are No. 93.855 - Immunology, Allergy, and
Transplantation Research and No. 93.856 - Microbiology and Infectious Disease
Research.  Awards will be administered under PHS grants policies and Federal
Regulations 42 CFR Part 52 and 45 CFR Part 74.  This program is not subject to
the intergovernmental review requirements of Executive Order 12372 or Health
Systems 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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