NIH Guide, Volume 26, Number 39, December 5, 1997

RFA:  HL-98-004


National Heart, Lung, and Blood Institute
National Institute of Dental Research
National Institute of Child Health and Human Development

Letter of Intent Receipt Date:  April 30, 1998
Application Receipt Date:  June 23, 1998



The primary goal of this initiative is to define abnormalities in airway
structure and function responsible for obstructive sleep apnea (OSA) in children
(3-12 years of age) and to identify  physiological and clinical measures
associated with increased morbidity.  Specific objectives include the
identification of neural and soft tissue factors increasing airway
collapsibility; soft tissue and craniofacial features that elevate airway
resistance; defects in ventilatory control reflexes that compromise airway
patency; the genetic and epidemiological risk factors for OSA; and the
neuropsychological, cognitive, and behavioral consequences of OSA in children. 
It is anticipated that these studies will provide new strategies for the
diagnosis and treatment of OSA in children.


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),
Obstructive Sleep Apnea in Children, is related to the priority areas of heart
disease and stroke, chronic disabling conditions, mental health and disorders,
oral health, maternal and infant health, and clinical prevention services. 
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).


Applications may be submitted by domestic for-profit and non-profit
organizations, public and private, such as universities, colleges, hospitals,
laboratories, units of State and local governments, and eligible agencies of the
Federal government.  Foreign institutions may not apply.  However, subcontracts
to foreign institutions may be allowed if justified.  Ethnic minority
individuals, women, and persons with disabilities are especially encouraged to
apply as principal investigators.

Institutions submitting multiple applications in response to this RFA must ensure
that each application is independent and does not have scientific overlap with
other applications from the same institution.


This RFA will use the National Institutes of Health (NIH) individual research
project grant (R01) mechanism of support.  Awards will be made and managed by the
National Heart, Lung, and Blood Institute (NHLBI), the National Institute on
Dental Research (NIDR), and/or the National Institute of Child Health and Human
Development (NICHD). Policies that govern the research grants programs of the NIH
will apply. However, specific application instructions have been modified to
reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts currently being
examined by the NIH.  The modular grant concept establishes specific modules in
which direct costs may be requested as well as a maximum level for requested
budgets.  Only limited budgetary information is required in the application under
this approach.  The just-in-time concept allows applicants to submit certain
information only when there is a possibility for an award.  It is anticipated
that these changes will reduce the administrative burden for the applicants,
applicant institutions, reviewers, and Institute staff.

For this RFA, funds must be requested in $25,000 direct cost modules up to a
maximum of 10 modules ($250,000 direct costs) per year.  A feature of the modular
grant concept is that no escalation is provided for future years, and all
anticipated expenses for all years of the project must be included within the
number of modules being requested.  Only limited budget information will be
required in the application.  Any budget adjustments made by the Initial Review
Group will be in modules of $25,000.  Instructions for completing the
Biographical Sketch have also been modified.  In addition, Other Support
information and the application Checklist page are not required as part of the
initial application.  If there is a possibility for an award, the necessary
budget, Other Support and Checklist information will be requested by staff at
NHLBI and/or NIDR and/or NICHD following the initial review.  The APPLICATION
PROCEDURES section of this RFA provides specific details of these modifications
to standard PHS 398 application kit instructions.  This RFA is a one time
solicitation.  Future requests for continuation beyond this initial award period
will compete with all investigator initiated applications and be reviewed
according to customary peer review procedures.


It is anticipated that during fiscal year 1999, support will be available for
total costs of approximately $1,800,000 from the NHLBI, $600,000 from NIDR, and
$200,000 from NICHD for the first year of this initiative. Award of grants
pursuant to this RFA is contingent upon the receipt of such funds for this
purpose.  It is anticipated that approximately five to seven grants will be
awarded under this program. Applicants may request up to four years of support. 
However, the specific number of awards will depend on the merit and scope of the
applications received, overall program balance, and on the availability of funds. 
Direct costs will be awarded in modules of $25,000, less any overlap or other
necessary administrative adjustments. Facilities and administrative (indirect)
costs will be awarded based on the negotiated rates.



Obstructive sleep apnea (OSA) is widely recognized as a potentially serious
medical condition in adults.  However, we do not know the prevalence of OSA in
children or whether the OSA syndrome in children and adults represents the same
disease process.  Limited epidemiological data suggests that the prevalence of
OSA may follow a bimodal distribution, with peaks in childhood and in later life,
and that, unlike the syndrome in adults, obesity or daytime sleepiness may not
be a reliable indicator of childhood OSA.  Studies also suggest that ethnicity
may be a significant risk factor, because African-American children appear to be
two to three-fold more likely to have OSA than Caucasian children.  However,
without clearly established guidelines or thresholds to define clinically
significant OSA in children, the use of adult criteria probably underestimates
the true prevalence of OSA in this population.

The lack of systematically collected data on the pathogenesis of OSA in children
has contributed to inconsistencies in identifying and treating children at risk. 
For instance, children with OSA symptoms are routinely subjected to procedures
modifying craniofacial and soft tissue features (e.g., tonsillectomy and
adenoidectomy) without the benefit of definitive diagnostic tools or substantive
evidence that surgery reduces health risks associated with sleep-disordered
breathing or improves long-term outcome.  OSA is most likely a manifestation of
multiple risk factors including anatomical, neuromuscular, and hormonal factors. 
In children, the relative contribution of these factors to OSA may differ from
that in adults and influence the effectiveness of specific therapies.

Extrapolating from findings in adults, unrecognized OSA may predispose children
to cardiovascular and cerebrovascular disease, learning/performance deficits, and
decrements in several quality of life measures.  For adults, OSA could be a
modifiable risk factor for hypertension.  However, very little is actually known
about the specific risks associated with OSA in children including its effects
on cardiovascular and respiratory control mechanisms; problem sleepiness; and
cognitive, behavioral, and neuropsychological development.  Adult data suggests
that the successful treatment of OSA reduces some risks but the efficacy or
appropriateness of these treatments in children is unclear.

Research Scope

Substantial data in adults indicate that precise interactions between airway
anatomy and the control of pharyngeal dilator muscles are necessary to maintain
airway patency.  Sleep negatively impacts these interactions in some adults
leading to airway collapse.  However, these physiological interrelationships need
to be investigated in children.  How development affects airway anatomy,
pharyngeal neuromuscular control, and regulation during sleep has been minimally
studied in children.  Whether pharyngeal muscles respond to similar stimuli in
children as adults and are affected by sleep in a similar manner is unknown. 
Gender and obesity influences on airway anatomy and motor control also need to
be explored in children. The mechanisms terminating apneas during sleep are
reasonably well-defined in adults but have not been studied at all in children. 
The neural and chemosensory mechanisms controlling ventilation during sleep have
been minimally studied in children particularly as they relate to development of
sleep apnea.  Arousal responses to obstructive events in children could have a
different threshold and functional relationship to sleep compared to adults.
Fundamental research is needed to establish indices in children for measures such
as respiratory disturbance frequency, arousal, and oxygen desaturation and to
define the natural history and pathophysiological mechanisms responsible for
airway abnormalities and OSA during childhood.

Precise definitions of OSA phenotypes are essential to conduct studies into the
genetic basis of childhood abnormalities in ventilation.  Among the traits that
are likely to be responsible for OSA in children, are differences in craniofacial
structure, soft tissue structures, obesity, and neural control of the airway. 
A number of genetic disorders, such as Down's syndrome and Treacher Collins
syndrome, may induce changes in craniofacial or soft tissue growth and increase
the risk of OSA in children.  Studies are needed to determine the genes and
nature of genetic abnormalities affecting craniofacial structure/function, airway
size, and sleep in order to develop appropriate therapeutic strategies for OSA.

Criteria for identifying children with clinically significant OSA need to be
established to better associate health risks, and to determine whether procedures
used in the diagnosis and treatment of OSA in adults are applicable to OSA in
children.  There is a need for studies to investigate whether OSA impairs the
function of sleep in children and if there are cardiovascular, ventilatory,
neuroendocrine, neuropsychological, cognitive, or behavioral consequences to
apnea-induced hypoventilation and sleep fragmentation.  For instance, it is not
known whether OSA may cause emotional or behavioral difficulties; or impairs the
learning ability, linguistic function, or working memory of children.  Whether
children may experience adverse health effects even when there is no evidence of
sleep disruption needs to be studied.  New techniques, such as functional
magnetic resonance imaging, can facilitate studies of the intermittent changes
in brain metabolism and neural behavior of OSA in children. There is evidence
that abnormal neural endocrine growth hormone function in children with OSA may
lead to growth retardation.  Whether upper airway obstruction influences physical
development or the growth of craniofacial features affecting airway function
needs to be studied. Whether OSA influences the severity of other childhood
respiratory disorders, such as asthma, is also an area in need of investigation.

These topics serve as examples and are not a comprehensive or exclusive list of
the areas that could be considered under this initiative.  Not all areas are
required in an application.  Applicants are encouraged to propose other topics
consistent with the goals of this program.


Proposed studies must focus on defining the abnormalities in airway structure and
function responsible for OSA in children (3-12 years of age) or on identifying
physiological and clinical measures associated with increased morbidity.  Studies
should provide strategies for either the diagnosis or treatment of OSA in
children by determining risk factors or evaluating therapeutic approaches (e.g.,
tonsillectomy and adenoidectomy).  However, large clinical studies or trials and
the establishment of large descriptive epidemiological cohorts that collect data
for future studies are not within the scope of this RFA.  Applications that do
not propose hypothesis-driven studies or are limited to measuring the efficacy
of potential treatments will be considered unresponsive to this RFA.  Studies
that focus on animal or in vitro models to test hypotheses must provide a strong
rationale for relevance to airway abnormalities and apnea in children. 
Applications directed at the development of model systems alone will not be

Collaborations and consortia promoting interdisciplinary approaches between
pulmonologists, neurologists, epidemiologists, neuroendocrinologists,
psychologists, otolaryngologists, and other clinical or basic disciplines are
strongly encouraged.  In such cases, each participant's contribution should be
identified and well-integrated into the overall experimental design.

Upon initiation of the program, the NHLBI, NIDR, and NICHD may co-sponsor
periodic meetings to encourage exchange of information among investigators who
participate in this program.  Travel funds for a one day meeting each year, most
likely to be held in Bethesda, Maryland, should be included in the module
calculation.  Applicants should also include a statement indicating their
willingness to participate in these meetings.


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 of
March 18, 1994, Volume 23, Number 11.

Investigators may obtain copies of the policy from these sources or from the
program staff listed under INQUIRIES.  Program staff may also provide additional
relevant information concerning the policy.


Prospective applicants are asked to submit, by April 30, 1998, a letter of intent
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, 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
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 faxed or sent to Dr.
C. James Scheirer, at the address listed under INQUIRIES.


Applications are to be submitted on the grant application form PHS 398 (rev.
5/95).  These forms are available at most institutional offices of sponsored
research and 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.  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, to identify the application as a response to this
RFA, check "YES" in item 2 of page 1 of the application and enter the title
"Obstructive Sleep Apnea in Children, HL-98-004".

The following modifications are made to the standard PHS 398 application


The total direct costs must be requested in accordance with the program
guidelines and modifications made to the standard PHS 398 application
instructions as described below:

As a reminder, Item 7 should be completed to indicate Modular Direct Costs
requested and Item 8 should reflect Total Costs (Modular Direct plus facilities
and administrative costs).

Do not complete Form Page 4 of the PHS 398 (rev 5/95).  It is not required nor
will it be accepted at the time of application.

Do not complete the categorical budget tables on Form page 5 of the PHS 398 (rev.
5/95).  Only the requested total direct costs line for each year must be
completed based on the number of $25,000 modules being requested.  Applicants may
not request a change in the amount of each module.  A maximum of 10 modules
($250,000 direct costs) per year may be requested and each applicant may request
up to four years of support for this RFA.  Equipment is included in the budget
limitation.  If an application includes research activities that involve
institutions other than the application institution, the activity is considered
a consortium effort. The total cost (direct costs and facilities and
administrative) of consortium arrangements are included in the budget limitation.

If there is a possibility of an award, applicants will be asked to confirm that
the salary budgeted for any one project member does not exceed an annual rate cap
of $125,000 per year in any budget period.

Direct cost budgets will remain constant throughout the life of the project (i.e.
the number of modules will not be subject to escalation).  However, in the event
that the number of modules required to accomplish the proposed research changes
in any future year, appropriate justification must be provided.  Total Direct
Costs for the Entire Proposed Project Period should be shown in the box provided
on Form Page 5.

 -Budget justifications should be provided under "Justifications" on Form Page
5 of the PHS 398.
-List the names, role on the project and proposed percent effort for all project
personnel (salaried or unsalaried) and provide a narrative justification for each
person based on their role on the project. -Identify all consultants by name and
organizational affiliation and describe the services to be performed.
-Provide a general narrative justification for individual categories (equipment,
supplies, etc.) required to complete the work proposed.  More detailed
justifications should be provided for high cost items.  Any large one-time
purchases, such as large equipment requests, must be accommodated within the
budget limitations.
-Separate justification should be provided for the use of grant funds to support
a scientific element of the project outside the United States or its territories
including but not limited to travel, surveying, and data or sample collection.

If collaborations or subcontracts are involved that require transfer of funds
from the grantee to other institutions, it is necessary to establish formal
subcontract agreements with each collaborating institution.  A letter of intent
from each collaborating institution should be submitted with the application. 
Only the percentage of the consortium/contractual TOTAL COSTS (direct plus
facilities and administrative costs) relative to the total DIRECT COSTS of the
overall project needs to be stated at this time.  The following example should
be used to indicate the percentage cost of the consortium, "The consortium
agreement represents 27% of overall $175,000 direct costs requested in the first
year".  A budget justification for the consortium should be provided as described
in the "Budget Justification" section above (no Form Page 5 required for the
consortium). Please indicate whether the consortium will be in place for the
entire project period and identify any future year changes in the percentage
relative to the parent grant.  If there is a possibility for an award, the
applicant will be requested to identify the actual direct and facilities and
administrative costs for all years of the consortium.

Please note that total subcontract costs are not to be calculated in $25,000
modules.  However, when subcontract funds are added to the parent grant budget,
the total cost of the consortium or contract must be included in the number of
$25,000 modules requested.

-Biographical sketches are required for key personnel, following the modified
instructions below.  Do not exceed the two-page limit for each person.
-Complete the educational block at the top of the form page; -List current
position(s) and those previous positions directly relevant to the application;
-List selected peer-reviewed publications directly relevant to the proposed
project, with full citation;
-The applicant has the option to provide information on research projects
completed and/or research grants participated in during the last five years that
are relevant to the proposed project.

Do not complete the "Other Support" pages (Form Page 7).  Selected other support
information relevant to the proposed research may be included in the Biographical
Sketch as indicated above.  Complete Other Support information will be requested
by the staff of NHLBI or collaborating Institutes if there is a possibility for
an award

No "Checklist" page is required as part of the initial application.  A completed
Checklist including a breakdown of facilities and administrative cost
calculations (rate, base, and base exclusions) will be requested by the staff of
NHLBI or collaborating Institutes if there is a possibility for an award.

o  The applicant should provide the name and phone number of the individual to
contact concerning fiscal and administrative issues if additional information is
necessary following the initial review.


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

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 be sent
to Dr. C. James Scheirer, at the address listed under INQUIRIES. Applications
must be received by June 23, 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 also 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.

A sample budget is available upon request from Mr. Raymond Zimmerman at the phone
number listed under INQUIRIES.


Upon receipt, applications will be reviewed for completeness by the CSR and for
responsiveness to this RFA by the collaborating Institutes. 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
receive primary assignment to NHLBI and receive secondary assignment to NIDR and
NICHD.  Applications will be evaluated for scientific and technical merit by an
appropriate peer review group convened by the Division of Extramural Affairs,
NHLBI.  Final Institute primary assignments will be determined by the
collaborating Institutes.

As part of the initial merit review, all applications will receive a written
critique and undergo a review in which only those applications deemed to have the
highest scientific merit of the applications under review (usually two to three
times the number of applications that the NHLBI and participating Institutes
anticipate being able to fund under the program) will be discussed, assigned a
priority score, and receive a second level review by the National Heart, Lung,
and Blood Advisory Council and the Advisory Councils of NIDR and/or NICHD.

The following criteria will be considered when assessing the scientific and
technical merit of a research grant application:

(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

(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 key personnel?

(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 personnel category will be reviewed for appropriate staffing based on the
requested percent effort.  The direct costs budget request will be reviewed for
consistency with the proposed methods and specific aims. Any budgetary
adjustments recommended by the reviewers will be in $25,000 modules.  The
duration of support will be reviewed to determine if it is appropriate to ensure
successful completion of the requested scope of the project.


The anticipated date of award is March 1, 1999.  Factors that will be taken into
consideration in making awards include the scientific merit of the proposed
program as evidenced by the priority score, the availability of funds, relevance
to the scientific programs of the participating Institutes, and overall
programmatic balance.  Subject to the availability of necessary funds and
consonant with the priorities of this RFA, the NHLBI and/or NIDR and/or NICHD
will provide funds for a project period up to four years.


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:

Michael J. Twery, Ph.D.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 7024, MSC-7952
Bethesda, MD  20892-7952
Telephone:  (301) 435-0202
FAX:  (301) 480-3557
Email:  TweryM@nih.gov

James P. Kiley, Ph.D.
National Center on Sleep Disorders Research
National Heart, Lung, Blood Institute
6701 Rockledge Drive, Suite 7024, MSC-7920
Bethesda, MD  20892-7920
Telephone:  (301) 435-0199
FAX:  (301) 480-3451
Email:  KileyJ@nih.gov

Linda A. Thomas, Ph.D.
Inherited Diseases and Disorders Program
National Institute of Dental Research
45 Center Drive, Room 4AN24J
Bethesda, MD  20892-6402
Telephone:  (301) 594-2425
FAX:  (301) 480-8138
Email:  ThomasL@DE45.nidr.nih.gov

G. Reid Lyon, Ph.D.
Child Development and Behavior Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 4B05, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-9849
FAX:  (301) 480-7773
Email:  LyonR@hd01.nichd.nih.gov

Direct inquiries regarding review matters and address the letter of intent to:

C. James Scheirer, Ph.D.
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7220, MSC 7924
Bethesda, MD  20892-7924
Telephone:  (301) 435-0266
FAX:  (301) 480-3541
Email:  ScheireJ@nih.gov

Direct inquiries regarding fiscal matters to:

Raymond L. Zimmerman
Grants Operations Branch
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7154
Bethesda, MD  20892-7926
Telephone:  (301) 435-0171
FAX:  (301) 480-3310
Email:  ZimmermR@gwgate.nhlbi.nih.gov

Martin R. Rubinstein
Grants Management
National Institute of Dental Research
45 Center Drive, Room 4AN44A
Bethesda, MD  20892-6402
Telephone:  (301) 594-4800
FAX:  (301) 480-8301
Email:  Martin.Rubinstein@nih.gov

Edgar D. Shaver
Grants Management Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8A17, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-1303
FAX:  (301) 402-0915
Email:  ShawverD@hd01.nichd.nih.gov


This program is described in the Catalog of Federal Domestic Assistance No.
93.838.  Grants are made under the authorization of the Public Health Service
Act, Title III, Section 301 (Public Law 78-410, as amended by Public Law 99-158,
42 US 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 to a review by
a Health Systems Agency.

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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