ROLE OF SLEEP AND SLEEP-DISORDERED BREATHING IN METABOLIC SYNDROME

RELEASE DATE:  October 16, 2002  

RFA:  RFA-HL-03-008

National Heart, Lung, and Blood Institute (NHLBI)
 (http://www.nhlbi.nih.gov/)
National Institute on Aging (NIA)
 (http://www.nia.nih.gov/)
 
Letter of Intent Receipt Date:  January 13, 2003

Application Receipt Date:  February 11, 2003

THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism(s) of Support 
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements (if included)
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations:

PURPOSE OF THIS RFA 

The goal of this Request for Applications (RFA) is to elucidate the 
relationship of sleep deprivation and sleep-disordered breathing (SDB) to 
characteristics of the metabolic syndrome including obesity, high blood 
pressure, dyslipidemia, insulin resistance, and vascular inflammation. 
Specific objectives include identifying the pathophysiological mechanisms and 
genetic risk factors linking sleep deprivation and SDB to these 
characteristics. 

RESEARCH OBJECTIVES

Background

The high prevalence of metabolic syndrome, SDB, and sleep deprivation has 
major public health implications. Recent estimates suggest that 20-25% of the 
U.S. population exhibit symptoms of the metabolic syndrome and are at 
increased risk of cardiovascular complications. SDB including loud snoring, 
increased upper airway resistance, and repetitive pauses or decrements in 
breathing during sleep, is estimated to affect 5-10% of middle-age adults and 
20-30% of the elderly. Children with academic difficulty exhibit an unusually 
high prevalence of SDB symptoms. Sleep deprivation due to lifestyle and 
chronic illness is thought to be widespread in all age groups. Average sleep 
duration of the normal working population has decreased from about 9 hours per 
night in 1910 to about 7.5 hours currently, a trend that is inverse to that of 
obesity. Both SDB and sleep deprivation are associated with excessive daytime 
sleepiness, impaired cognitive performance, and an increased risk of 
accidents. Recent findings suggest that SDB and sleep deprivation are 
associated with specific molecular, anatomical, and pathophysiological 
abnormalities affecting brain, kidney, and vascular function. However, the 
relationship of SDB and sleep deprivation to other physiological systems 
contributing to normal health and development are not well understood.

Recent findings suggest that the metabolic syndrome, SDB, and sleep 
deprivation may share similar pathophysiological, prothrombotic and 
proinflammatory states. SDB has been identified as a potentially important 
risk factor for cardiovascular abnormalities including overactivity of the  
sympathetic nervous system, decreased nocturnal dipping of blood pressure, 
blunted heart rate variability, and possibly arrhythmia. SDB produces 
repetitive episodes of blood oxygen desaturation (hypoxemia) and sleep 
disturbance (electroencephalographic arousal) that disturb restorative 
physiological patterns linked to cycles of sleep and wakefulness. Several 
lines of evidence indicate a relationship between sleep disturbance, 
abnormalities in the circadian secretion of neuroendocrine hormones, and a 
diminished ability to regulate blood glucose that characterizes pre-diabetic 
conditions. Improving sleep quality in patients with heart failure seems to 
reduce sympathetic outflow and preserve myocardial function. Fasting glucose 
and insulin levels are higher than normal in patients with SDB, and SDB 
severity correlates with indices of glucose metabolism. Proinflammatory 
cytokines associated with insulin resistance and vascular disease are also 
higher in patients with SDB. SDB patients with diabetes exhibit significantly 
less deep (REM) sleep; and there is a close association between the prevalence 
of diabetes and SDB severity. SDB treatment using nasal continuous positive 
airway pressure (CPAP) seems to improve insulin sensitivity in some obese 
diabetic patients  but it is unclear whether SDB is independently associated 
with insulin resistance. 

Chronic sleep restriction may increase susceptibility to the metabolic 
syndrome independent of SDB or other sleep disorders. Sleep deprivation in 
normal healthy young adults results in marked alterations of glucose 
metabolism in the absence of breathing abnormalities. The state of "sleep 
debt" per se is associated with increased sympathetic nervous activity and 
abnormalities in endocrine function. Chronic partial sleep deprivation 
decreases the normal nocturnal rise in thyrotropin, increases cortisol 
secretion, and decreases nocturnal growth hormone secretion, similar to 
patterns seen in older adults. Alterations in the pattern of growth hormone 
and cortisol exposure may play a role in weight gain and the development of 
insulin resistance. 

Obesity is associated with depressed respiratory control. SDB patients have 
greater amounts of visceral fat compared to obese non-SDB patients, and 
indices of SDB correlate with visceral fat. Women appear less susceptible to 
the development of SDB compared to men, and this may be related to a higher 
preponderance of subcutaneous versus visceral fat for a given level of 
obesity. Emerging evidence suggests that circulating factors secreted 
primarily from visceral fat link SDB and cardiovascular disease. Leptin, a fat 
cell-secreted hormone, influences food intake by signaling energy balance, and 
may have opposing effects on vascular tone by stimulating both central 
sympathetic tone to vascular beds leading to vasoconstriction and peripheral 
vascular nitric oxide production leading to vasodilatation. SDB patients 
exhibit higher leptin levels than expected based on the severity of obesity, 
and treatment of SDB with CPAP appears to normalize leptin levels independent 
of weight changes. A relative deficiency in leptin, or leptin resistance, may 
play a role in the pathophysiology of SDB and cardiovascular disease. Other 
circulating fat-secreted factors, such as TNF-alpha and interleukin-6, promote 
sleep, and seem to exacerbate symptoms of poor sleep when elevated in 
association with SDB. Elevated levels of TNF-alpha can also stimulate leptin 
secretion and contribute to dyslipidemia. Apolipoprotein E epsilon4 (APOE e4), 
a polymorphism of a key protein in lipid metabolism, and linked to  
cardiovascular disease, diabetes, and Alzheimer=s disease, appears to be 
associated with increased severity of SDB symptoms in some populations, 
suggesting a possible common pathophysiological pathway involving lipid 
metabolism.

Abnormalities in endothelial function are associated with SDB. Frequent 
intermittent episodes of hypoxia and reoxygenation associated with SDB are a 
potent stimulus for oxidative stress. The production of reactive oxygen 
species (ROS) has been implicated in vascular complications such as 
retinopathy, nephropathy, cardiovascular disease, and pathologies associated 
with aging. ROS levels are elevated in SDB and lowered by CPAP treatment. 
Whether SDB can account for the elevated levels of ROS associated with obesity 
is unclear. Nitric oxide signaling is a potent regulator of vascular tone 
altered by intermittent hypoxia. SDB is associated with  a decreased level of 
circulating nitric oxide and blunted endothelium-dependent vasodilator 
responsiveness to acetylcholine and bradykinin. This endothelial dysfunction 
appears to be reversed by CPAP therapy. Abnormalities in vascular reactivity 
associated with SDB may predict atherosclerosis and its complications. 
Alterations in circulating levels of ROS and nitric oxide can also affect 
chemosensitivity to hypoxia and hypercapnia, respiratory control, and sleep. 

Concomitant with diminished vasodilator responsiveness, SDB patients exhibit 
increased levels of the vasoconstrictor, endothelin-1, and vascular 
endothelial growth factor (VEGF), an angiogenic cytokine implicated in 
diabetic vascular complications, with reductions in both after CPAP therapy. 
The VEGF gene is mainly stimulated by hypoxia through the mediation of 
hypoxia-inducible factor (HIF). HIF may be responsible for inducing an array 
of hypoxia-sensitive genes as a result of SDB and intermittent hypoxia 
including those encoding erythropoietin and glycolytic enzymes. 

Thrombotic events believed to a major cause of heart attack are more likely to 
occur during sleep. SDB-induced hypoxic stress and metabolic abnormalities 
stemming from sleep deprivation may modulate circulating inflammatory 
mediators causing accelerated atherogenesis. SDB is associated with increased 
expression of pro-inflammatory mediators, adhesion molecules, and increased 
ROS production in some monocyte and granulocyte subpopulations. CPAP appears 
to decrease platelet activation and aggregation suggesting that SDB 
contributes to a prothrombotic environment. 

Research Scope 

This RFA seeks to develop a better understanding of relationships between 
sleep deprivation, SDB, and the metabolic syndrome with the goal of reducing 
the risk of cardiovascular complications and age-associated pathologies. 
Listed below are examples of studies that would be responsive to this program. 
These are only illustrative examples and applicants are encouraged to consider 
other topics consistent with the goals of this program. Not all areas need to 
be addressed in a single application. 

o Elucidate the effects of partial sleep deprivation or SDB on 
pathophysiological mechanisms of lipid and glucose metabolism that influence 
the risk of obesity, diabetes, or neurodegenerative disorders in human 
subjects or in well-characterized animal models.

o Determine whether SDB plays a role in the pathophysiological mechanism by 
which insulin resistance increases endothelial dysfunction, which leads to 
hypertension, all hallmarks of the metabolic syndrome.

o Characterize the effect of sleep deprivation or SDB on cardiovascular 
disease or neurocognitive outcomes using existing epidemiological cohorts 
(nested case-control study) in which risk factors for the metabolic syndrome 
were determined as a major focus of the parent investigation. 

o Elucidate the relative role of SDB-related intermittent hypoxia and sleep 
disturbance in producing abnormalities in atherogenesis, prothrombotic or  
proinflammatory mediators, sympathetic neural activity, or causing  
cardiovascular disorders, such as hypertension, that contribute to the 
metabolic syndrome.

o Identify genetic, racial, ethnic, gender, or age-dependent factors 
influencing the pathophysiological effects of partial sleep deprivation or SDB 
on potential risk for the metabolic syndrome. 

o Elucidate the mechanisms through which sleep deprivation or SDB affect fat-
secreted factors contributing to the risk of the metabolic syndrome.

o Elucidate effects of sleep deprivation or SDB occurring during critical 
phases of early development and leading to increased risk for the metabolic 
syndrome in older children or older adults. 

o Elucidate potential links between abnormalities in chemosensitivity or the 
regulation of breathing and disorders characteristic of the metabolic 
syndrome.

o Elucidate functions of the biological clock or other neural mechanisms 
regulating sleep that influence the relationship between individual or age-
dependent susceptibility to sleep deprivation and risk factors for the 
metabolic syndrome.

MECHANISM OF SUPPORT
 
This RFA will use the NIH research project (R01) award mechanism. As an 
applicant you will be solely responsible for planning, directing, and 
executing the proposed project. This RFA is a one-time solicitation. Future 
unsolicited, competing-continuation applications based on this project will 
compete with all investigator-initiated applications and will be reviewed 
according to the customary peer review procedures. The anticipated award date 
is September 30, 2003.

This RFA uses just-in-time concepts. It also uses the modular budgeting 
format. (see http://grants.nih.gov/grants/funding/modular/modular.htm). 
All applications must be in the modular format.

FUNDS AVAILABLE
 
The NHLBI intends to commit approximately $3 million, and the NIA intends to 
commit approximately $375,000 in FY2003 to fund six to eight new grants in 
response to this RFA. An applicant may request a project period of up to four 
years and a budget for direct costs of up to $250,000 per year. Because the 
nature and scope of the proposed research will vary from application to 
application, it is anticipated that the size and duration of each award will 
also vary. Although the financial plans of the NHLBI and NIA provide support 
for this program, awards pursuant to this RFA are contingent upon the 
availability of funds and the receipt of a sufficient number of meritorious 
applications.

Since the total costs for a subcontract or consortium are included in the 
direct cost request, one or more additional modules of $25,000 above the cap 
may be requested for the facilities and administrative costs associated with 
third party agreements. Modules requested for this purpose must be clearly 
identified in the budget justification section of the application, and will be 
restricted for this purpose only at the time of award.
 
ELIGIBLE INSTITUTIONS
 
You may submit (an) application(s) if your institution has any of the 
following characteristics: 

o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, hospitals, 
and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign
 
INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS   

Any individual with the skills, knowledge, and resources necessary to carry 
out the proposed research is invited to work with their institution to develop 
an application for support. Individuals from under-represented racial and 
ethnic groups as well as individuals with disabilities are encouraged to apply 
for NIH programs. 

SPECIAL REQUIREMENTS

Restrictions and Exclusions

To be responsive to this announcement, applications must propose hypothesis-
driven studies that focus on elucidating the effects of sleep deprivation or 
SDB on characteristics of the metabolic syndrome and related cardiovascular or 
cerebrovascular outcomes. For the purpose of this RFA, the metabolic syndrome 
includes emerging risk factors such as lipoprotein, homocysteine, 
prothrombotic and proinflammatory factors, impaired glucose metabolism, and 
subclinical atherosclerotic disease. Sleep deprivation is defined as sleep 
restriction independent of other sleep disorders or sources of disturbed 
sleep. Studies focused on partial sleep deprivation and having the potential 
to facilitate epidemiological studies of life-habit risk factors are 
encouraged. Studies to identify genetic markers of this interrelationship will 
also be responsive. Studies proposing the use of nonmammalian species or in 
vitro preparations should clearly establish the relationship of these models 
to the goals set forth in this RFA. 

The elucidation of environmental and psychosocial factors that cause sleep 
deprivation such as life-style behaviors, shift work, rapid time zone changes, 
stress, cultural and socioeconomic factors will not be supported under this 
RFA. Studies of sleep deprivation secondary to chronic illness, alcohol abuse, 
pain syndromes, cancer, mental disorders, and the relationship of sleep to 
behavioral endpoints such as workplace performance would also be unresponsive 
to this RFA. Applications focused on the development of methodology, 
interventions, large clinical studies, or the establishment of large 
epidemiological cohorts that collect data for future studies are not within 
the scope of this program. 

Collaborations and consortia promoting interdisciplinary approaches between 
scientists studying cardiology, vascular biology, pulmonology, sleep medicine, 
hematology, neuroimmunobiology, infectious disease, endocrinology, genetics, 
and neurophysiology are strongly encouraged. In such cases, each participant's 
contribution should be identified and well-integrated into the overall 
experimental design.

Investigator Coordination Meetings

Upon initiation of the program, periodic meetings may be organized to 
encourage the exchange of information among investigators who participate in 
this program. Travel funds for the principal investigator to attend a two-day 
meeting each year, most likely to be held in Bethesda, Maryland, must be 
included in the module calculation. Applicants must include a statement 
indicating their willingness to participate in these meetings. Applicants are 
encouraged to contact the program officials listed under INQUIRIES for further 
information.

General Clinical Research Centers

Applicants from institutions that have a General Clinical Research Center 
(GCRC) funded by the NIH National Center for Research Resources may wish to 
identify the GCRC as a resource for conducting the proposed research. If so, a 
letter of agreement from either the GCRC program director or principal 
investigator should be included with the application.

WHERE TO SEND INQUIRIES

We encourage inquiries concerning this RFA and welcome the opportunity to 
answer questions from potential applicants. Inquiries may fall into three 
areas:  scientific/research, peer review, and financial or grants management 
issues:

o Direct your questions about scientific/research issues to:

Michael Twery, Ph.D.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
National Institutes of Health
6701 Rockledge Drive, MSC 7952
Bethesda, Maryland  20892-7952
Telephone:  (301) 435-0202
Fax:  (301) 480-3557
Email:  Twerym@nhlbi.nih.gov 

Winnie Barouch, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 10193, MSC 7956
Bethesda, MD  20892-7956
Telephone: (301)435-0560
FAX: (301)480-2849
Email: BarouchW@nhlbi.nih.gov 

Paul Sorlie, Ph.D.
Division of Epidemiology and Clinical Applications
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 8176, MSC 7934
Bethesda, MD  20892-7934
Phone: (301) 435-0707
Fax: (301) 480-1455
Email: ps46f@NIH.GOV 

Carl E. Hunt, M.D.
National Center on Sleep Disorders Research
National Heart, Lung, and Blood Institute
Rockledge II, Suite 10138
6701 Rockledge Drive
Bethesda, MD  20892
Phone: (301) 443-0199 
Fax: (301) 480-3557
E-mail: HuntC@nhlbi.nih.gov 

Andrew A. Monjan, Ph.D., M.P.H.
National Institute on Aging
7201 Wisconsin Avenue, Suite C3C07 
Bethesda, MD  20892
Telephone:  (301) 496-9350 
FAX:  (301) 496-1494
Email:  am39m@nih.gov

o Direct your questions about peer review issues to:

Anne Clark, Ph.D.
Chief, Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Dr., Room 7214 (MSC 7924)
Bethesda, MD 20892-7924 (20817 for express/courier service)
Telephone:  (301) 435-0270
FAX:  (301) 480-0730
Email: clarka@nhlbi.nih.gov

o Direct your questions about financial or grants management matters to:

Robert Pike
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
National Institutes of Health
6701 Rockledge Drive, MSC 7926
Bethesda, Maryland  20892-7926
Telephone:  (301) 435-0171
Fax:  (301) 480-3310
Email: rp182p@NIH.GOV 

Linda Whipp
Grants and Contracts Management Officer
National Institute on Aging
Gateway Building, Suite 2N212
7201 Wisconsin Avenue, MSC 9205
Bethesda, MD  20892-9205
Telephone: (301) 496-1472
FAX: (301) 402-3672
Email: whippl@nia.nih.gov
 
LETTER OF INTENT
 
Prospective applicants are asked to submit a letter of intent that includes 
the following information:

o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel 
o Participating institutions
o Number and title of this RFA 

Although a letter of intent is not required, is not binding, and does not 
enter into the review of a subsequent application, the information that it 
contains allows IC staff to estimate the potential review workload and plan 
the review.
 
The letter of intent is to be sent by the date listed at the beginning of this 
document. The letter of intent should be sent to Dr. Anne Clark at the address 
listed under WHERE TO SEND INQUIRIES.

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001). The PHS 398 is available at 
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive 
format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, 
Email: GrantsInfo@nih.gov.
 
SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS:  All applications 
submitted to this RFA must use the modular budget format. Facilities and 
administrative costs associated with subcontract or consortium third party 
agreements can be requested with additional modules, using the modular budget 
format. The modular grant format simplifies the preparation of the budget in 
these applications by limiting the level of budgetary detail. Applicants 
request direct costs in $25,000 modules. Section C of the research grant 
application instructions for the PHS 398 (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step 
guidance for preparing modular grants. Additional information on modular 
grants is available at 
http://grants.nih.gov/grants/funding/modular/modular.htm

USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) 
application form must be affixed to the bottom of the face page of the 
application. Type the RFA number on the label. 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 RFA label is also available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.
 
SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of 
the application, including the Checklist, and three signed, photocopies, in 
one package to:
 
Center For Scientific Review
National Institutes Of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)
 
At the time of submission, two additional copies of the application and all 
five collated sets of Appendix material must be sent to Dr. Anne Clark at the 
address listed under WHERE TO SEND INQUIRIES.
 
APPLICATION PROCESSING: Applications must be received by the application 
receipt date listed in the heading of this RFA. If an application is received 
after that date, it will be returned to the applicant without review.
 
The Center for Scientific Review (CSR) will not accept any application in 
response to this RFA that is essentially the same as one currently pending 
initial review, unless the applicant withdraws the pending application. The 
CSR will not accept any application that is essentially the same as one 
already reviewed. This does not preclude the submission of substantial 
revisions of applications already reviewed, but such applications must include 
an Introduction addressing the previous critique.

PEER REVIEW PROCESS  
 
Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NHLBI. If an application is not responsive to the RFA, 
staff may contact the applicant to determine whether to return the application 
to the applicant or submit it for review in competition with unsolicited 
applications at the next appropriate NIH review cycle.

Applications that are complete and responsive to the RFA will be evaluated for 
scientific and technical merit by an appropriate peer review group convened by 
the NHLBI in accordance with the review criteria stated below. As part of the 
initial merit review, all applications will:

o Receive a written critique
o 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 and assigned a priority score
o Receive a second level review by the NHLBI and/or NIA National Advisory 
Council
 
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 comments, reviewers will be asked to discuss the following aspects of 
your application in order to judge the likelihood that the proposed research 
will have a substantial impact on the pursuit of these goals: 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
  
The scientific review group will address and consider each of these criteria 
in assigning your application's overall score, weighting them as appropriate 
for each application. Your application does not need to be strong in all 
categories to be judged likely to have major scientific impact and thus 
deserve a high priority score. For example, you 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 your study address an important problem? If the aims 
of your application are achieved, how do they advance scientific knowledge?  
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?  Do you acknowledge potential problem areas and consider alternative 
tactics?

(3) INNOVATION:  Does your project employ novel concepts, approaches or 
methods? Are the aims original and innovative?  Does your project challenge 
existing paradigms or develop new methodologies or technologies?

(4) INVESTIGATOR: Are you appropriately trained and well suited to carry out 
this work?  Is the work proposed appropriate to your experience level as the 
principal investigator and to that of other researchers (if any)?

(5) ENVIRONMENT:  Does the scientific environment in which your 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?

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your 
application will also be reviewed with respect to the following:

o PROTECTIONS:  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.

o INCLUSION:  The adequacy of plans to include subjects from both genders, all 
racial and ethnic groups (and subgroups), and children as appropriate for the 
scientific goals of the research. Plans for the recruitment and retention of 
subjects will also be evaluated. (See Inclusion Criteria included in the 
section on Federal Citations, below)

o DATA SHARING:  The adequacy of the proposed plan to share data.

o BUDGET:  The reasonableness of the proposed budget and the requested period 
of support in relation to the proposed research.

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date: January 13, 2003
Application Receipt Date: February 11, 2003
Peer Review Date: June/July, 2003
Council Review: September, 2003
Earliest Anticipated Start Date: September 30, 2003

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o Scientific merit (as determined by peer review)
o Availability of funds
o Programmatic priorities.
 
REQUIRED FEDERAL CITATIONS 

MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components 
involving Phase I and II clinical trials must include provisions for 
assessment of patient eligibility and status, rigorous data management, 
quality assurance, and auditing procedures. In addition, it is NIH policy that 
all clinical trials require data and safety monitoring, with the method and 
degree of monitoring being commensurate with the risks (NIH Policy for Data 
Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html). 

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of 
the NIH that women and members of minority groups and their sub-populations 
must be included in all NIH-supported clinical research projects unless a 
clear and compelling justification is provided indicating 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 clinical research should read the AMENDMENT "NIH 
Guidelines for Inclusion of Women and Minorities as Subjects in Clinical 
Research - Amended, October, 2001," published in the NIH Guide for Grants and 
Contracts on October 9, 2001 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html);
a complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. 
The amended policy incorporates: the use of an NIH definition of clinical 
research; updated racial and ethnic categories in compliance with the new OMB 
standards; clarification of language governing NIH-defined Phase III clinical 
trials consistent with the new PHS Form 398; and updated roles and 
responsibilities of NIH staff and the extramural community. The policy 
continues to require for all NIH-defined Phase III clinical trials that: a) 
all applications or proposals and/or protocols must provide a description of 
plans to conduct analyses, as appropriate, to address differences by 
sex/gender and/or racial/ethnic groups, including subgroups if applicable; and 
b) investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 
differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: 
The NIH maintains a policy 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 is available at 
http://grants.nih.gov/grants/funding/children/children.htm. 

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy 
requires education on the protection of human subject participants for all 
investigators submitting NIH proposals for research involving human subjects. 
You will find this policy announcement in the NIH Guide for Grants and 
Contracts Announcement, dated June 5, 2000, at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on 
hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm and at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only 
research using hESC lines that are registered in the NIH Human Embryonic Stem 
Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). 
It is the responsibility of the applicant to provide the official NIH 
identifier(s)for the hESC line(s)to be used in the proposed research. 
Applications that do not provide this information will be returned without 
review. 

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The 
Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances. Data that are (1) first produced in a project 
that is supported in whole or in part with Federal funds and (2) cited 
publicly and officially by a Federal agency in support of an action that has 
the force and effect of law (i.e., a regulation) may be accessed through FOIA. 
It is important for applicants to understand the basic scope of this 
amendment. NIH has provided guidance at 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this PA in a public archive, 
which can provide protections for the data and manage the distribution for an 
indefinite period of time. If so, the application should include a description 
of the archiving plan in the study design and include information about this 
in the budget justification section of the application. In addition, 
applicants should think about how to structure informed consent statements and 
other human subjects procedures given the potential for wider use of data 
collected under this award.

URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals 
for NIH funding must be self-contained within specified page limitations. 
Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) 
should not be used to provide information necessary to the review because 
reviewers are under no obligation to view the Internet sites. Furthermore, we 
caution reviewers that their anonymity may be compromised when they directly 
access an Internet site.

HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving 
the health promotion and disease prevention objectives of "Healthy People 
2010," a PHS-led national activity for setting priority areas. This RFA is 
related to one or more of the priority areas. Potential applicants may obtain 
a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal 
Domestic Assistance No. 93.837, 93.838, 93.839, 93.233, and 93.866 and is not 
subject to the intergovernmental review requirements of Executive Order 12372 
or Health Systems Agency review. Awards are made under authorization of 
Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 
and 284)(or other authorizations) and administered under NIH grants policies 
described at http://grants.nih.gov/grants/policy/policy.htm (cite other 
relevant policies) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 
and 92 (cite other relevant regulations). 

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and discourage the 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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