COGNITION AND BEHAVIOR IN DOWN SYNDROME

Release Date:  March 27, 1998

RFA:  HD-98-007

P.T.

National Institute of Child Health and Human Development
National Institute of Neurological Disorders and Stroke

Letter of Intent Receipt Date:  May 1, 1998
Application Receipt Date:  June 11, 1998

PURPOSE

The Mental Retardation and Developmental Disabilities Branch (MRDD), Center for
Research for Mothers and Children (CRMC), of the National Institute of Child
Health and Human Development (NICHD), and the Division of Fundamental
Neuroscience and Developmental Disorders (DFNDD) of the National Institute of
Neurological Disorders and Stroke (NINDS), in collaboration with the National 
Down Syndrome Society (NDSS), invite research grant applications that address
various aspects of cognition and behavior in individuals with Down Syndrome (DS). 
Areas of interest include the developmental and neurological mechanisms
underlying characteristic loss of function, approaches toward preserving or
improving level of function, and methods to assess effects of interventions.  Six
to seven awards may be funded under this grant solicitation subject to the
availability of funds.

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, Cognition and Behavior in Down
Syndrome, is related to the priority areas on chronic disabling conditions,
nutrition, and educational and community-based programs. Potential applicants may
obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017001-00474-0 or
Summary Report:  Stock No. 017-001-00473-1) through the Superintendent of
Documents, Government Printing Office, Washington, DC 20402-9325  (telephone
202-512-1800).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit and non-profit
organizations, public and private, such as universities, colleges, hospitals,
laboratories, and units of state or local governments, and eligible agencies of
the Federal government.  Applicants may collaborate, through consultation or
contractual arrangements, with foreign investigators. Applications from minority
individuals, women and persons with disabilities are encouraged.

MECHANISM OF SUPPORT

This RFA will use the NIH research project (R01) and small research grants (R03)
(NICHD only) mechanisms.  Responsibility for the planning, direction, and
execution of the proposed project will be solely that of the applicant. The total
project period for an application submitted in response to this RFA may not
exceed five years. For R03s, the total project period may not exceed two years.
The anticipated date of award is September 30, 1998.

This RFA is a one-time solicitation. Future unsolicited competing continuation
applications will compete with all investigator-initiated applications and will
be reviewed according to the customary NIH peer review procedures.

FUNDS AVAILABLE

Research grant applications submitted in response to this RFA will compete for
$1.3 million in total costs that will be made available for the first year of
support. Through a partnership agreement, the NDSS in New York will contribute
$200,000 and NICHD $800,000.  NINDS will contribute $300,000.  It is anticipated
that six to seven awards will be made. The number of awards depends on the
overall scientific merit of the applications and the availability of funds in
fiscal year 1998.

RESEARCH OBJECTIVES

Background

The MRDD Branch, NICHD supports research that relates to the biological,
behavioral and social processes that contribute to, or influence the development
of mental retardation and developmental disabilities. Prevention of mental
retardation and developmental disabilities, and amelioration of the clinical
manifestations of those afflicted constitute areas of special emphasis within the
MRDD Branch.  DFNDD, NINDS supports research on developmental neurological
disorders.  The mechanisms underlying inherited neurological disorders are of
particular interest.  

Genetic disorders have become increasingly prominent in the etiology of mental
retardation. With aggressive use of antimicrobial agents to treat infectious
diseases, widespread immunization programs to protect against bacterial and viral
infectious agents, better nutrition, and surgical correction of congenital
abnormalities, those with genetic disorders, many of them with mental
retardation, who otherwise would have succumbed are able to survive longer.

Trisomy is the most commonly recognized chromosome abnormality in humans,
occurring in at least 4% of all clinically recognized pregnancies. Some trisomies
are compatible with postnatal life; however, most trisomic fetuses do not survive
to term. They are associated either with clinically recognized spontaneous
abortions, where they account for approximately 25% of all such fetuses, or they
terminate as subclinical spontaneous abortions.

DS is the most common genetic cause of mental retardation, affecting 1 in 800
live-born infants, and is due to triplication of a portion of the long arm of
chromosome 21 (2lq22).  In addition to mental retardation, the following
associated defects have been described in children with DS: congenital heart
defects, duodenal stenosis or atresia, keratoconus, astigmatism, and myopia.  In
addition, they are susceptible to repeated bouts of infection, and they have a
10-20 fold increased risk to develop leukemia. Neuropathological examination of
the brain demonstrates decreased weight especially in the cerebellum and brain
stem.  Moreover, neuronal number is reduced in many regions of the brain.
Magnetic imaging studies have shown that the frontal and temporal regions of the
brain are proportionally diminished in DS, but the volumes of the subcortical
nuclei are similar to those in control subjects. It has been known for a long
time that there exists a disparity in the neuropsychological profile of children
with DS.  In comparison with children with mental retardation resulting from
other etiologies, verbal short-term memory skills of children with DS are
diminished. Conversely, visual-motor skills are comparatively well preserved.

Scope

This RFA focuses on cognition and behavior in individuals with DS.  Applications
may address one or more of the following topics: 

o  Cognitive development and function; including learning and memory, language
development, speech intelligibility, literacy development, motor development,
social behavior and emotional development

o  Intervention strategies (behavioral, educational, pharmacological,
nutritional, etc.) to improve cognitive development or to prevent cognitive
decline and dementia or amelioration of maladaptive behaviors

o  Development of methodologies to assess effects of intervention

o  Assessment of the applicability of imaging, electrophysiology, pharmacology,
molecular biology and behavior in following the developmental trajectories of
different brain functions onto developing cognitive and motor skills

o  Characterization and evaluation of the cognitive, physiological, and molecular
mechanisms of cognitive dysfunction

o  Examination of the mechanisms by which DS genetic status affects the
development, function, and dysfunction of the nervous system, particularly with
respect to cognition and behavior, including dementia

o  Development and use of animal models to evaluate the genetic, molecular, and
physiological bases of cognitive dysfunction and to assess the potential clinical
efficacy of therapeutic interventions

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 protocols 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 10.1-
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 2 3,
Number 11, March 18, 1994.

For the purpose of this policy, clinical research is defined as human biomedical
and behavioral studies of etiology, epidemiology, prevention (and prevention
strategies), diagnosis, or treatment of diseases, disorders or conditions,
including, but not limited to, clinical trials.

LETTER OF INTENT

Prospective applicants are asked to submit, by May 1, 1998, a letter of intent
that includes a descriptive title of the proposed research, address, and
telephone number of the Principal Investigator, names of other key personnel and,
if applicable, participating institutions, and the number and title of the RFA
in response to which the application may he 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 allows Institute staff
to estimate the potential review workload and to avoid possible conflict of
interest in the review.

The letter of intent is to be sent to:

Felix F. de la Cruz, M.D., M.P.H.
Center for Research for Mothers and Children
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 4B09, MSC 7510
Bethesda, MD  20892-7510
Telephone: (301) 496-1383
FAX: (301) 496-3791
Email:  fd14a@NIH.GOV

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev.
5/95). 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, E-mail: ASKNIH@od.nih.gov;
and from the program administrators listed under INQUIRIES. The RFA label
available in the PHS 398 (rev. 5/95) application form must be affixed to the
bottom of the face page of the application. Failure to use this label could
result in delayed processing of the application such that it may not reach the
review committee in time for review.  In addition, the RFA title and number must
be typed on line 2 of the face page of the application form and the YES box must
be marked.

The applications must be prepared in a manner consistent with the instructions
provided in PHS 398 (rev. 5/95) and, for small research grant applications
assigned to NICHD, guidelines outlined in the NICHD Small Grants Program (NIH
Guide, Volume 25, Number 3, February 9, 1996, PA-96-025) should be followed. 
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 DR, 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 be sent
to:

Scott F. Andres, Ph.D.
Division of Scientific Review
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 5E-03, MSC 7510
Bethesda, MD 20892-7510
Rockville, MD 20852 (for express/courier service)
Telephone: (301) 496-1485

Applications must be received by June 11, 1998. If an application is received
after this 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 substantial revisions of applications already
reviewed, but such applications must include an introduction addressing the
previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by CSR and
responsiveness by NICHD staff. 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 the NICHD Division of Scientific Review in accordance with the review
criteria stated below.

As part of the initial merit review, a process may be used by the initial review
group in which applications will be determined to be competitive or
non-competitive based on their scientific merit relative to other applications
received in response to the RFA.  Applications judged to be competitive will be
discussed and assigned a priority score. Applications determined to be non-
competitive will be withdrawn from further consideration, and the Principal
Investigator and the official signing for the applicant organization will be
notified. The second-level review will be made by the National Advisory Child
Health and Human Development Council at its September 1998 meeting. The
anticipated date of award is September 30, 1998.

REVIEW CRITERIA

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  In the
written review, comments on the following aspects of the application will be made
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 in the assignment of the overall score.

(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?

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

o The adequacy of plans to include both genders, minorities, and their subgroups
as appropriate for the scientific goals of the research. Plans for the
recruitment and retention of subjects will also be evaluated

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

o The adequacy of the proposed protection for humans, animals or the environment,
to the extent they may be adversely affected by the project proposed in the
application

AWARD CRITERIA

In addition to the scientific and technical merit of the applications, other
factors will be considered in making the awards. Among these are:

o  Relevance to mental retardation and its neurological origins
o  Access to unique populations
o  Institutional commitment and support

INQUIRIES

Written and telephone requests for the RFA, and the opportunity to clarify any
issues or questions from the potential applicants are welcome.

Inquiries regarding programmatic and scientific issues may be directed to;

Felix F. de la Cruz, M.D., M.P.H.
Center for Research for Mothers and Children
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 4B-09
Bethesda, MD 20892
Telephone: (301) 496-1383 
FAX: (301) 496-3791 
Email: fd14a@NIH.GOV

Sarah H. Broman, Ph.D.
Division of Fundamental Neurosciences and Developmental Disorders
National Institute of Neurological Disorders and Stroke
7550 Wisconsin Avenue, Room 8C06
Bethesda, MD 20892-9170
Telephone: (301) 496-5821
FAX: (301) 402-1501
Email: sb73f@nih.gov

Direct inquiries regarding fiscal matters to:

Mr. Edgar D. Shawver
Grants Management Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8 A-17
Bethesda, MD 20892
Telephone: (301) 496-1303
FAX: (301) 402-0915
E-mail: es65o@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.865 Research for Mothers and Children. Awards are made under the authority 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.

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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