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 301/435-0714, email: 
GrantsInfo@nih.gov.

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: ewitt@willco.niaaa.nih.gov

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:  jfertig@willco.niaaa.nih.gov

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:  lhilley@willco.niaaa.nih.gov

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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