and Human Services (HHS)
EXPIRED
RESEARCH ON ALCOHOL AND SLEEP
Release Date: April 25, 2000
RFA: AA-00-005
National Institute on Alcohol Abuse and Alcoholism
Letter of Intent Receipt Date: August 14, 2000
Application Receipt Date: September 14, 2000
THIS REQUEST FOR APPLICATIONS (RFA) USES THE "MODULAR GRANT" AND "JUST-IN-TIME"
CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION
INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS
RFA.
PURPOSE
The National Institute on Alcohol Abuse and Alcoholism (NIAAA) is seeking grant
applications to conduct research on alcohol"s effects on sleep. It is well
documented that acute and chronic alcohol consumption cause sleep disturbances.
In those with alcoholism, sleep patterns may never return to normal, and
continuing sleep problems may be a core factor in alcohol relapse. Despite the
adverse effects of alcohol on sleep and the serious implications for alcoholism
treatment, the topic of alcohol and sleep is currently an understudied area.
The purpose of this Request for Applications (RFA) is to stimulate research on
alcohol and sleep in areas that are of particular interest because of the
potential contribution to our understanding of the etiology and treatment of
alcoholism. These research areas include the neural mechanisms of alcohol-
induced sleep disturbances, persistent poor sleep as a risk marker for
development of alcoholism in adolescents and non-alcoholic young adults, sleep
disorders as a predictor of relapse in abstinent alcoholics, and the health
consequences of alcohol"s disruptive effects on sleep particularly the
interaction with age, ethnicity, and gender. NIAAA strongly encourages
collaboration between experts in sleep research and established alcohol
researchers to facilitate the development of research proposals in the area of
alcohol and sleep.
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 Request for Applications (RFA),
Research on Alcohol and Sleep, 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/.
ELIGIBILITY REQUIREMENTS
Applications may be submitted by domestic and foreign, for-profit and non-profit
organizations, public and private, such as universities, colleges, hospitals,
laboratories, units of State 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
This RFA will use the National Institutes of Health (NIH) Research Project Grant
(R01) and the NIAAA Exploratory/Developmental Grant (R21) 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 5 years for the R01
mechanism and 3 years for the R21 mechanism. Under the R21 mechanism, direct
costs are limited to $100,000 per year (See Program Announcement PA-99-131,
"NIAAA Exploratory/Developmental Grant Program,"
http://grants.nih.gov/grants/guide/pa-files/PA-99-131.html for a complete
description of the R21 mechanism). This RFA is a one-time solicitation. Future
unsolicited competing continuation applications will compete with all
investigator-initiated applications and be reviewed according to the customary
peer review procedures. The earliest anticipated award date is March 1, 2001.
Applicants may also submit applications for Investigator-Initiated Interactive
Research Project Grants (IRPG). Interactive Research Project Grants require the
coordinated submission of related research project grants (R01) from
investigators who wish to collaborate on research, but do not require extensive
shared physical resources. These applications must share a common theme and
describe the objectives and scientific importance of the interchange of, for
example, ideas, data, and materials among the collaborating investigators. A
minimum of two independent investigators with related research objectives may
submit concurrent, collaborative, cross- referenced individual R01 applications.
Applicants may be from one or several institutions. Further information on these
and other grant mechanisms may be obtained from the program staff listed in the
INQUIRIES section of this RFA or from the NIAAA Web site
http://www.niaaa.nih.gov/ under Research Programs/Program Announcements.
Applicants who want to request direct costs exceeding $500,000 in any one year
must obtain written agreement from the NIAAA that the application will be
accepted for consideration of award. Applicants who want to request a waiver
for exceptional circumstances should contact the program staff listed in the
INQUIRIES section of this RFA.
FUNDS AVAILABLE
The NIAAA intends to commit approximately $3 million in FY 2001 to fund eight to
ten new and/or competitive continuation grants in response to this RFA. Because
the nature and scope of the research proposed might vary, it is anticipated that
the size of awards will also vary. Although the financial plans of the NIAAA
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.
RESEARCH OBJECTIVES
Background
In the 1960"s and 1970"s, research in the area of alcohol and sleep provided the
basic foundations of our knowledge concerning the acute and chronic effects of
alcohol on sleep (1-3). In later decades, it was found that alcohol"s
disruptive effects on sleep can have serious health consequences including
impaired breathing and associated cardiovascular abnormalities. Excessive
daytime sleepiness caused by alcohol-induced sleep disturbances can result in
memory deficits, impaired social and occupational function, and car crashes.
However, research on alcohol and sleep has been modest over the past 20 years,
despite the potential ramifications of impairments resulting from the effects of
alcohol on sleep, and the fact that failure to normalize sleep following
withdrawal from alcohol may be predictive of relapse. Therefore, it is
important that an effort be made to renew interest in research on alcohol and
sleep particularly in areas that have implications for the etiology and
treatment of alcoholism.
1. Insomnia as a Pathway to Alcoholism
In healthy subjects, acute alcohol in doses of .16 - 1.0 g/kg suppresses REM
sleep and increases deep non-rapid eye movement sleep (nonREM). Initial latency
to sleep is reduced, but paradoxically, wake time during the latter half of the
sleep period is increased (2). The reduced time to fall asleep produced by
alcohol may encourage continued use of alcohol at bedtime.
Epidemiological studies have found that 28 percent of those who complain of
insomnia reported using alcohol to help them sleep, and further, individuals who
reported having two weeks or more of insomnia were more likely to have met
diagnostic criteria for alcoholism at one year follow-up (4). A recent study
found that insomniacs were more likely to self-administer ethanol before bedtime
than non-insomniacs (5). Furthermore, a low dose of ethanol before bedtime made
subtle improvements in the insomniacs" sleep and mood, suggesting that ethanol
may be more reinforcing for insomniacs. Therefore, the degree to which ethanol
use in insomniacs extends beyond the therapeutic context into daytime use is an
important line of research. Tolerance development to low doses of alcohol in
insomniacs is also a possibility, which could lead to increased doses, although
this has not been investigated. Finally, for the elderly who use alcohol at
bedtime to counteract insomnia, there is increased risk for falls during the
night. Thus, whether insomnia precedes the development of alcohol abuse, and the
clinical significance of the sequencing of these two disorders particularly with
respect to age and gender are important research questions.
2. Sleep Disorders as a Pathway to Relapse
Chronic actively drinking alcoholics take longer to fall asleep, have poor sleep
efficiency, and show marked disorganization of sleep patterns with frequent
awakenings, shortened REM periods, and reduced nonREM sleep. Sleep is severely
disturbed during withdrawal, and the severe REM deprivation leads to "pressure"
for REM sleep (1-3). Sleep in abstinent alcoholics is also
characterized by delayed sleep onset, frequent awakenings, and reduced amounts
of nonREM sleep. Thus, a major question is whether the sleep disturbances may
predict relapse during withdrawal and long-term abstinence. Recent studies (6-
7) shed some light on this issue. Increased REM density at the time of
admission to a 1-month inpatient alcohol treatment program predicted relapse in
primary alcoholics with and without secondary depression by 3 months following
hospital discharge.
However, many questions remain regarding the nature of the sleep disruption
following prolonged abstinence, whether sleep parameters as predictors of
relapse change during different phases of the abstinent withdrawal syndrome, and
what factors may mediate it such as diagnostic heterogeneity, age, gender,
severity and other consequences of alcohol. Finally, the role of treatments for
the withdrawal syndrome (e.g., the benzodiazepine receptor agonists) in possibly
exacerbating the alcohol-induced sleep disturbance, or the ability of naltrexone
and other therapeutic agents (e.g., SSRIs) in reducing sleep disturbances and
relapse rates, remains to be explored. Further therapeutic trials using new
treatments that target sleep or circadian dysfunction (e.g., L-tryptophan,
bright light therapy) and that include subjective and objective sleep
measurements, relapse rates, and psychiatric states are clearly needed. In
addition to humans, animal models of alcohol relapse (8) are now available to
study the relationship among effects of chronic alcohol on sleep, new drug
treatments, and relapse outcomes.
3. Biological Mechanisms of Alcohol-Related Sleep Disturbances
Neurotransmitters, Neuropeptides, Cytokines: Sleep disturbances have been
described in alcoholic patients during active drinking and during different
stages of recovery, however little is known about the underlying biological
mechanisms. Research on the basic mechanisms of sleep has implicated circuits
involving multiple neurotransmitters in the generation of sleep-wake states
(9), and changes in these same neurotransmitters that modulate sleep could
contribute to ethanol"s effects on the sleep-wake cycle. For example, serotonin
has a prominent role in regulation of certain aspects of REM sleep and
modulation of onset of nonREM sleep. Loading with 5-hydroxytryptophan (5-HTP),
a serotonin precursor, decreased REM fragmentation and stabilized REM sleep in
abstinent alcoholics, suggesting that serotonin dysfunction is involved in
alcohol-induced sleep disorders (10). NMDA antagonists reduced REM sleep
frequency in rats in a manner similar to ethanol (11), implicating glutamate as
a selective modulator of sleep. Adenosine is another neurotransmitter affected
by alcohol that is also an important modulator of sleep/wake control (12).
However, there is no research to date connecting disrupted sleep with alcohol-
adenosine interactions.
Disturbances in the sleep of abstinent alcoholics could also have a
neurohormonal basis. Reduction in slow wave sleep is one of the hallmarks of
long-term alcohol administration. Growth hormone releasing factor (GHRF)
increases slow wave sleep in several species, whereas corticotropin releasing
factor (CRF) produces hyperarousal, reductions in slow wave sleep, insomnia, and
delayed sleep onset (3). Hypothalamic-pituitary-adrenal (HPA) and hypothalamic-
pituitary-somatotropic (HPS) systems are disrupted in acute alcohol intoxication
and in abstinent alcoholics (3,13). However, few studies in humans or animals
have examined whether sleep dysregulation in alcoholism and hormonal
disturbances are causally related.
Cytokines such as interleukin-1 (IL1) beta and tumor necrosis factor (TNF) alpha
induce increases in duration of nonREM sleep (14). These same somnogenic growth
factors are also involved in alcohol toxicity (15-16). However, the mechanistic
relationship among cytokines, alcohol toxicity and sleep dysfunction is
virtually unexplored. In sum, there have been very few animal or human studies
that have attempted to link brain mechanisms important in the regulation of
sleep and sleep pathologies associated with long-term effects of alcohol. The
specific target neurochemical systems could include but are not limited to
serotonin, acetylcholine, adenosine, specific neuropeptides such as GHRF, CRF,
and neuropeptide Y, and cytokines such as IL-1, TNF.
Alcohol-Induced Brain Structural Damage and Sleep: It is well known that chronic
alcohol use produces structural brain changes particularly in frontal regions of
the brain. Therefore, some investigators have hypothesized that chronic alcohol
exposure disrupts sleep through its direct toxic effects on brain areas that
regulate sleep (17-18). New imaging technologies such as MRI
and SPECT combined with EEG measures of sleep could determine whether structural
or functional changes in brain sleep circuits are responsible for sleep
disturbances in chronic alcoholics.
Alcohol and Circadian Rhythms: Circadian rhythms, generated by an internal
clocklike mechanism and synchronized by external cues (e.g., light, food,
temperature) and internal hormonal signals (e.g., melatonin), are important
determinants of the ability to sleep. Furthermore, an individual"s
acquisition, response, and continuation of alcohol use may be entrained to
circadian rhythms, and in turn, alcohol may affect the underlying circadian
mechanism itself. For example, alcohol"s sedative effects differ depending on
whether the same dose is given in the morning or the evening (19), and night
shiftworkers are more likely to consume alcohol and use alcohol as a sleep aid
than day shift workers (20). Alcohol disrupts hormonal and behavioral circadian
rhythms in humans and animals (21-23), and recently chronic alcohol exposure in
rats was found to produce an irreversible depression of peptide immunoreactivity
and mRNA levels in the suprachiasmatic nucleus, which is considered the
biological clock in rodents (3). Thus, disturbed circadian
processes could be a mechanism of sleep disruption in alcoholics. Sophisticated
studies are needed to dissociate homeostatic (need for sleep) and circadian
(temporally-related) processes to determine the mechanisms by which ethanol is
having its major effects. Other important issues relate to
ethanol"s potential as a chronobiotic, i.e., a substance that can alter
circadian phase, and the effect of phase advances or delays on alcohol
consumption.
4. Alcohol, Sleep Development, Adolescence, and Predispositional Factors
Alcohol and Sleep Development: Although there is extensive literature on
prenatal effects of alcohol on brain development, very little is known about
alcohol"s effects on fetal and early neonatal (i.e., during breast feeding)
sleep development, including the circadian clock systems. A recent study (24)
found that infants tend to fall asleep sooner, but sleep for significantly
shorter periods of time, immediately after consuming alcohol through mothers"
milk. In addition, infants are more active during wakefulness after consuming
alcohol through mothers" milk, although the
mechanisms underlying the reduction in sleep remains to be elucidated.
Investigators have demonstrated that perturbations of the serotonergic system
early in development has long lasting effects on adult sleep behavior (25).
Furthermore, the same cytokines that enhance sleep (e.g., IL-1, TNFalpha and
TNFbeta) are present in developing brain, affect developmental events (26), and
are implicated in alcohol toxicity. Thus, the relationship among fetal alcohol
exposure, neurotransmitter function, cytokine production, and trajectories of
sleep development is an important area of investigation.
Adolescence, Sleep, and Alcoholism Risk: Developmental changes in sleep and
sleep patterns occur during adolescence. There is a gradual decrease in the
amount of REM sleep, and a significant drop-off in delta sleep around the time
of adolescence. Other sleep changes during adolescence include greater daytime
sleepiness, greater tendency to sleep in the morning, and a
predisposition toward shifting to late-night schedules (27-28). Adolescent
sleep patterns are influenced by intrinsic sleep/wake control mechanisms and
circadian timing systems, although the exact biological mechanism for the phase
delays is unknown. Extrinsic factors such as parental control, peers, homework,
extracurricular activities and athletics, jobs and school starting
times also play a role in the delayed sleep time of adolescents. A recent study
found an association among later and more irregular sleep schedules, perceived
daytime tiredness, and increased use of cigarettes and alcohol, particularly in
boys (age 15)(29). However, the relationship of this
association to biological or social factors is unknown. More importantly,
increased alcohol use combined with sleep deprivation could have serious health
consequences including impaired cognitive and motor performance, and increased
risk for car crashes.
We know that during adolescence, the brain continues to undergo development,
particularly in the prefrontal cortex, an area thought to mediate higher
cognitive functions. The prefrontal cortex has connections with the mesolimbic
reward circuit, sleep circuits, and is a target of alcohol"s toxic
effects. Thus, increased alcohol use associated with sleep deprivation may
alter these developing systems, making an individual more susceptible to sleep
disturbances, alcohol abuse or dependence, or both. Conversely, an inborn
neurotransmitter abnormality that provokes a sleep disorder may trigger a cycle
of increased alcohol intake that injures the developing brain system
further. Recent evidence in nonhuman primates suggests that abnormal sleep
patterns and serotonergic activity may be risk markers for alcoholism. That is,
low 5-HIAA concentrations in infancy, which are predictive of excessive alcohol
consumption during adolescence, are also associated with delayed sleep onset and
increased daytime activity (30). However, more research is needed in humans and
animals to determine whether sleep disturbances are a predictor of heavy
drinking or alcoholism in adolescents at differing genetic risk, and/or whether
susceptibility to the effects of alcohol on sleep may vary during adolescence.
Alcohol, Sleep and Genetics: Recent advances in sequencing the mouse genome
offer new opportunities for discovering genes that may be involved in complex
behaviors such as alcoholism and sleep. One technique, random mutagenesis,
could help determine whether sleep and alcoholism are genetically related. For
example, using different strains of mice, animals can be "pre-screened" for
abnormal alcohol preference and/or sleep architecture in offspring of
mutagenized mice, yielding a "few" animals to be more intensely evaluated for
abnormal alcohol preference and/or sleep architecture. Once genetic
transmission of an abnormal phenotype is found, it is possible to use a variety
of genetic and molecular techniques to determine the gene involved in regulation
of the behavior under study, and to characterize the genetic alteration that led
to the mutant phenotype. Such an approach could yield new insights into the
genetic mechanisms that are involved in the regulation of sleep, alcohol
consumption, and circadian rhythmicity as well as how these complex behaviors
influence each other.
5. Health Consequences of Alcohol-Induced Sleep Disturbances
Alcohol and Sleep-Disordered Breathing. Alcohol facilitates the occurrence of
obstructive sleep apneas (OSA) during sleep by relaxing upper airway dilator
muscles and depressing the central nervous system response to airway occlusion.
As a result, alcohol use in the evening is associated with an of increased risk
of OSA, increased severity of hypoxemia in individuals with OSA, increased risk
of stroke, cardiovascular morbidity, and functional consequences of disrupted
sleep such as motor vehicle crashes (31). Males, elderly, snorers, and
individuals with OSA are at particularly high risk for this alcohol
administration effect. Abstinent alcoholics have increased
prevalence of obstructive sleep apnea, hypoxemia, and sleep-related breathing
and movement disturbances. Of interest is that sleep disordered breathing is
not seen in alcoholic women. Even though the association between alcohol and
OSA is well documented, the occurrence of OSA in non-alcoholics and sober
alcoholics is an important clinical problem. Many questions remain as to the
daytime consequences of drinking and sleep apnea (including motor vehicle
accidents, impaired psychomotor, cognitive performance) and medical consequences
such as a stroke, hypertension, and myocardial infarction as they interact with
gender and age. Also the reversibility of OSA following abstinence, or the
development of OSA in non-alcoholic drinkers is also unknown.
Research Areas of Interest
This RFA is soliciting applications on alcohol and sleep in an effort to
increase research in this understudied area. While previous clinical studies
have provided basic information on alcohol-induced sleep disorders, they relied
on small numbers of subjects and manual scoring of EEG sleep records. New
methodologies using quantitative measures of EEG such as spectral analysis or
period/amplitude analysis are now available and can be applied to analysis of
sleep disturbances in alcohol dependence and potentially link that disturbance
to underlying neural activity. Forced desynchrony techniques could be used to
dissociate alcohol"s effects on circadian vs. homeostatic processes. Animal
models of alcohol dependence and relapse are now available that could be used
for controlled studies of alcohol-induced sleep disturbances, the underlying
neural mechanisms of these disturbances, and their contribution to relapse.
Longitudinal studies would be useful in studying the developmental trajectories
of sleep disorders in adolescents and their relationship to onset of alcohol
problems in adulthood, as well as the reversibility vs. persistence of sleep
disorders and sleep-disordered breathing with abstinence.
Areas needing further research include, but are not limited to:
o Studies on the nature, degree, specificity, and duration of sleep disruption
that occurs with alcohol withdrawal (e.g., are the changes sleep-stage
specific?), and what factors influence it (e.g., is the degree and nature of REM
rebound related to age, gender, ethnicity, alcohol dose or duration of
drinking?).
o Use of sleep deprivation techniques to characterize sleep disorders in
alcoholic patients.
o Studies on the nature of the relationship among sleep disturbance, the
development of alcohol- use disorders and the likelihood of relapse after
alcoholism treatment.
o Studies, including clinical trials, on pharmacologic and nonpharmacologic
treatments of insomnia in patients with alcohol abuse and alcoholism, and
whether treatment of sleep disorders in alcoholics prevents relapse.
o Use of standardized criteria for diagnosing insomnia in alcoholic individuals,
and development of sleep-related rating scales for alcoholic individuals.
o Studies on chronological sequencing of insomnia and alcoholism (primary
insomnia/secondary alcoholism and vice versa) and how sequencing of these
disorders relates to age, gender, demographic, clinical, familial, and
biological factors.
o Studies on biological and genetic mechanisms that may predispose to both sleep
disturbance and alcoholism.
o Studies on nature of sleep disturbances in adolescence, whether these sleep
disturbances are the precursor or result of heavy drinking in adolescents, and
determination of personality, emotional, and sleep characteristics of
adolescents who may be at risk for later alcoholism.
o Studies on whether disruption of circadian or homeostatic processes is the
source of alcohol-induced sleep disturbances.
o Studies of whether waking EEG phenotypes are reflected in the sleep EEG of
alcoholics, and whether waking EEG may be predictive of sleep disturbance.
o Studies of alcohol"s effects on basic mechanisms of sleep circuits including
the role of neurotransmitters, neuropeptides, and cytokines in alcohol-induced
sleep disturbances.
o Studies on the daytime and medical consequences of drinking and sleep apnea,
as well as parameters that increase risk of developing OSA.
o The effects of fetal and early neonatal alcohol exposure on sleep development.
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 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 was published in the Federal Register of March 28, 1994 (FR 59
14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11,
March 18, 1994, available on the Web at
http://grants.nih.gov/grants/guide/notice-files/not94-100.html.
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://grants.nih.gov/grants/guide/notice-files/not98-024.html .
Investigators also may obtain copies of these policies from the program staff
listed under INQUIRIES. Program staff may also provide additional relevant
information concerning the policy.
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 a 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.
Reviewers are cautioned that their anonymity may be compromised when they
directly access an Internet site.
LETTER OF INTENT
Prospective applicants are asked to submit 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 and
participating institutions, and the number and title of the RFA in response to
which the application may be submitted. Although a letter of intent is not
required, is not binding, and does not enter into the review of a subsequent
application, the information that it contains allows Institute staff to estimate
the potential review workload and avoid conflict of interest in the review.
The letter of intent is to be sent to
RFA-AA-00-005
Extramural Project Review Branch
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 409, MSC 7003
Bethesda, MD 20892-7003
by the letter of intent receipt date listed in the heading of this RFA.
APPLICATION PROCEDURES
The research grant application form PHS 398 (rev. 4/98) is to be used in
applying for these grants. 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, email:
[email protected].
SPECIFIC APPLICATION INSTRUCTIONS FOR MODULAR GRANTS
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 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, reviewers, and Institute staff. The
research grant application form PHS 398 (rev. 4/98) is to be used in applying
for these grants, with the modifications noted below.
BUDGET INSTRUCTIONS
Modular Grant applications will request direct costs in $25,000 modules, up to a
total direct cost request of $250,000 per year. (Applications that request more
than $250,000 direct costs in any year must follow the traditional PHS 398
application instructions.) The total direct costs must be requested in
accordance with the program guidelines and the modifications made to the
standard PHS 398 application instructions described below:
PHS 398 FACE PAGE - Items 7a and 7b should be completed, indicating Direct Costs
(in $25,000 increments up to a maximum of $250,000) and Total Costs [Modular
Total Direct plus Facilities and Administrative (F&A) costs] for the initial
budget period. Items 8a and 8b should be completed indicating the Direct and
Total Costs for the entire proposed period of support.
DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 of
the PHS 398. It is not required and will not be accepted with the application.
BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the
categorical budget table on Form Page 5 of the PHS 398. It is not required and
will not be accepted with the application.
NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative page.
(See http://grants.nih.gov/grants/funding/modular/modular.htm. for sample
pages.) At the top of the page, enter the total Direct Costs requested for each
year. This is not a Form page. Under Personnel, list key project personnel,
including their names, percent of effort, and roles on the project. No
individual salary information should be provided. However, the applicant should
use the NIH appropriation language salary cap and the NIH policy for graduate
student compensation in developing the budget request. For
Consortium/Contractual costs, provide an estimate of total costs (Direct plus
F&A) for each year, each rounded to the nearest $1,000. List the
individuals/organizations with whom consortium or contractual arrangements have
been made, the percent effort of key personnel, and the role on the project.
Indicate whether the collaborating institution is foreign or domestic. The total
cost for a consortium/contractual arrangement is included in the overall
requested Modular Direct Cost amount. Include the letter of intent to establish
a consortium. Provide an additional narrative budget justification for any
variation in the number of modules requested.
BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by
reviewers in the assessment of each individual"s qualifications for a specific
role in the proposed project, as well as to evaluate the overall qualifications
of the research team. A biographical sketch is required for all key personnel,
following the instructions below. No more than three pages may be used for each
person. A sample biographical sketch may be viewed at:
http://grants.nih.gov/grants/funding/modular/modular.htm. - Complete the
educational block at the top of the Form page, - List position(s) and any
honors, - Provide information, including overall goals and responsibilities, on
research projects ongoing or completed during the last three years, and, - List
selected peer-reviewed publications, with full citations.
CHECKLIST - This page should be completed and submitted with the application. If
the F&A rate agreement have been established, indicate the type of agreement and
the date. All appropriate exclusions must be applied in the calculation of the
F&A costs for the initial budget period and all future budget years. 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.
The RFA label available in the PHS 398 (rev. 4/98) 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 sample RFA label available at:
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to
allow for this change. Please note this is in pdf format.
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 must be sent
to:
RFA :AA-00-005
Extramural Project Review Branch
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 409, MSC 7003
Bethesda, MD 20892-7003
Rockville, MD 20852 (for express/courier service)
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.
REVIEW CONSIDERATIONS
Upon receipt, applications will be reviewed for completeness by the CSR and
responsiveness by the NIAAA. Incomplete applications will be returned to the
applicant without further consideration. If the application is not responsive
to the RFA, CSR 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 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 NIAAA in accordance with the review criteria stated below. 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 NIAAA 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 the
application 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 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 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? (For the R21 mechanism, a strong rationale and conceptual
framework are normally sufficient for establishing the feasibility of the
project, in lieu of extensive preliminary data.)
(3) Innovation: Does the project employ novel concepts, approaches, or methods?
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, and children 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.
Additional consideration pertinent to the review of Exploratory/Developmental
Grant (R21) applications:
o Pilot/feasibility studies may contain little or no preliminary data. Review
should focus on whether the rationale for the study is well developed and
whether the proposed research is likely to generate data that will lead to a
regular research project grant or full-scale clinical trial. Adequate
justification for the proposed work may be provided through literature
citations, data from other sources, or investigator-generated data.
Schedule
Letter of Intent Receipt Date: August 14, 2000
Application Receipt Date: September 14, 2000
Peer Review Date: Fall 2000
Council Review: February 8, 2001
Earliest Anticipated Start Date: March 1, 2001
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
INQUIRIES
Inquiries concerning this RFA are encouraged. The opportunity to clarify any
issues or questions from potential applicants is welcome.
Direct inquiries regarding programmatic issues on neuroscience and basic
research to:
Ellen D. Witt, Ph.D.
Division of Basic Research
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 402, MSC 7003
Bethesda, MD 20892-7003
Telephone: (301) 443-6545
FAX: (301) 594-0673
Email: [email protected]
Direct inquiries regarding programmatic issues on clinical/treatment research
to:
Joanne Fertig, Ph.D.
Division of Clinical and Prevention Research
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 505, MSC 7003
Bethesda, MD 20892-7003
Telephone: (301) 443-0635
Fax: (301) 443-8774
Email: [email protected]
Direct inquiries regarding fiscal matters to:
Linda Hilley
Office of Planning and Resource Management
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 504, MSC 7003
Bethesda, MD 20892-7003
Telephone: (301) 443-4703
FAX: (301) 443-3891
Email: [email protected]
AUTHORITY AND REGULATIONS
This program is described in the Catalog of Federal Domestic Assistance No.
93.273. Awards are made under authorization of the Public Health Service Act,
Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241
and 285) and administered under NIH 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 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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