Full Text HL-94-009

CARDIOVASCULAR CONSEQUENCES OF SLEEP APNEA

NIH GUIDE, Volume 23, Number 7, February 18, 1994

RFA:  HL-94-009

P.T. 34

Keywords: 
  Cardiovascular Diseases 
  Sleep Disorders 
  Clinical Medicine, General 


National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date:  April 1, 1994
Application Receipt Date:  May 23, 1994

PURPOSE

The Division of Lung Diseases, Division of Epidemiology and Clinical
Applications, and the National Center on Sleep Disorders Research are
undertaking the development of a collaborative clinical study of
cardiovascular consequences of sleep apnea, to be conducted in well
characterized, existing population-based cohorts.  Goals include
determining the degree to which sleep apnea and milder degrees of
sleep-related breathing disorders (SRBD) are independent or
contributing risk factors for the development of cardiovascular and
cerebrovascular disease, as well as examining possible associations
with other cardiovascular risk factors.

This request for applications (RFA) is both for clinical centers and
the data coordinating center.  It is estimated that the study will
involve five to six clinical centers, each recruiting approximately
900 to 1,000 participants for in-depth studies of sleep apnea and
SRBD from existing epidemiological cohorts; there will be a single
Data Coordinating Center.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This RFA,
Cardiovascular Consequences of Sleep Apnea, is related to the
priority areas of heart disease and stroke, clinical prevention
services, diabetes and chronic disabling diseases.  Potential
applicants may obtain a copy of "Healthy People 2000" (Full Report:
Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary Report:
Stock No. 017-001-00473-1) through the Superintendent of Documents,
Government Printing Office, Washington, DC 20402-9325 (telephone
202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic, for-profit, and non-profit
organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of state and local governments, and
eligible agencies of the Federal government.  Foreign organizations
are not eligible to apply and any international component of a
domestic application must be minor in its magnitude and critical in
what it would contribute.  Applications from minority individuals and
women are encouraged.

Awards for a Clinical Center and a Data Coordinating Center under
this RFA will not be made to the same Principal Investigator (PI) to
ensure that data analysis is done independently of data acquisition.
The same institution may apply for both a Clinical Center and the
Data Coordinating Center award, but the applications for each must be
from different individuals.  Data coordinating centers currently
participating in epidemiology cohort studies are eligible.

MECHANISM OF SUPPORT

The administrative and funding instrument to be used for this program
will be a cooperative agreement (U01), an assistance mechanism, in
which substantial NIH scientific and/or programmatic involvement with
the awardee is anticipated during performance of the activity.  Under
the cooperative agreement, the NIH purpose is to support and/or
stimulate the recipient's activity by involvement in and otherwise
working jointly with the award recipient in a partner role, but it is
not to assume direction, prime responsibility or a dominant role in
the activity.  Details of the responsibilities, relationships, and
governance of the study to be funded under cooperative agreement(s)
are discussed later in this document under the section Terms and
Conditions of Award.

The total project period for applications submitted in response to
the present RFA may not exceed five years.  The anticipated award
date is September 30, 1994.

Awards and level of support depend on receipt of a sufficient number
of applications of high scientific merit.  Although this program is
provided for in the financial plans of the NHLBI, awards pursuant to
this RFA are contingent upon the availability of funds for this
purpose.  Because the nature and scope of the research proposed in
response to this RFA may vary, it is anticipated that the sizes of
awards will also vary.

At this time, the NHLBI anticipates that there may be a renewed
competition after five years.  However, the final decision will
depend upon experience with the program during the first five years
as well as financial considerations.

FUNDS AVAILABLE

An estimated five to six awards for Clinical Centers and one award
for a Data Coordinating Center will be made under this RFA.  A
maximum of about $16.3 million (including direct and indirect costs)
over a five-year period will be awarded for the Clinical Centers and
the Data Coordinating Center.  Approximately $3.0 million will be
available for the first year, $3.1 million for the second year, $3.3
million for the third year, $3.4 million the fourth year and $3.5
million for the last year.  It is anticipated that the award for each
Clinical Center will be about $400,000 total costs for the first year
and the award for the Data Coordinating Center will be about $600,000
total costs for the first year.

RESEARCH OBJECTIVES

Background

Snoring, the most common symptom of sleep disordered breathing, has
been implicated as a risk factor for the development of hypertension,
ischemic heart disease and cerebral infarction.  Many of these
adverse cardiovascular effects of snoring have been attributed to the
substantial prevalence of obstructive sleep apnea among habitual
snorers.

Obstructive sleep apnea is characterized by loud snoring and
disrupted breathing during sleep.  It is associated with a number of
adverse clinical consequences, including daytime sleepiness, impaired
performance, accidents and cardio/cerebrovascular morbidity and
mortality.  The relative risks of cerebrovascular accidents, ischemic
heart disease, and myocardial infarctions range from 1.5 to 4 in
snorers as compared to non-snorers.  Hypertension is common in
patients with sleep apnea, with studies suggesting that up to 40
percent of hypertensive patients may have significant sleep apnea.
Improvement in hypertension control has been reported to occur in
patients with both conditions following treatment of their apnea.
Vascular mortality may be significantly higher among untreated or
conservatively treated patients with sleep apnea compared to patients
treated aggressively.

In addition, patients with sleep apnea or heavy snoring may have up
to a 50 percent decrease in brain blood flow during rapid eye
movement (REM) sleep and as high as a 50 percent increase in the
incidence of stroke.  These findings raise the intriguing possibility
of a potential etiologic relationship between sleep apnea and
thrombotic stroke.  Sleep apnea may be an independent vascular
disease risk factor, a concomitant of established vascular or
cerebral diseases or other risk factors (such as obesity or
hypertension), but this remains to be determined.  Similarly, little
is known regarding potential interactions between sleep apnea and
other risk factors, or whether specific population subgroups may be
particularly susceptible to adverse cardiovascular and
cerebrovascular consequences potentially associated with sleep apnea.

Further elucidation of the relationship between sleep apnea and
hypertension in African-Americans may be particularly important.
Severe hypertension is more common and its consequences more severe
in African-Americans than in whites, but the reasons for this are not
clear.  Risk factors for sleep apnea such as obesity and macroglossia
are also common in African-Americans, and preliminary data suggest
that, among young subjects, sleep apnea may be more prevalent among
African-Americans than among whites.  Sleep apnea could help
elucidate the marked racial differences in hypertension and its
consequences.  Sleep apnea is also known to increase markedly in
prevalence following menopause.  Examining cardiovascular disease
events and sleep apnea in post-menopausal women may provide insight
into any possible changes in cardiovascular disease risk among women.

Sleep apnea has been described in 30 percent or more of elderly
subjects.  The bases for strong relationships between aging and
increased apneic activity are not understood, but may be related to
changes in sleep quality, cerebral function, muscle tone, obesity,
cardiac function and lung function with aging.  Due to their reduced
functional reserves and co-existing morbidity, elderly persons may be
at greatest risk for exacerbation of underlying cardiovascular and
cerebrovascular disease when exposed to the physiologic stresses
associated with apnea and arousal from sleep.

The profound physiological derangements (hypoxemia, severe
hypertension, tachycardia, fragmentation of sleep, arrhythmias) that
often occur in association with sleep disordered breathing provide
biologically plausible explanations for associations between sleep
apnea and cardiovascular morbidity.  The increased risk of
cardiovascular events shortly after awakening has been linked to
sympathetic discharge associated with arousal, which can occur dozens
of times each night in patients with sleep apnea.  The use of
cardiovascular medications may also be an important effect modifier
on the relationship of CVD, its risk factors, and SRBD, since some of
these agents have known side effects related to sleep and breathing.

Identification of factors that predispose to increased risk for SRBD
is important for public health policy, potentially enabling specific
high risk populations to be targeted, as well as for developing an
improved understanding of disease pathogenesis that may include
interactions among a number of risk factors in causing morbidity.
This program seeks to accomplish this with an interactive,
coordinated group of clinical centers working under a common protocol
in a multidisciplinary setting.  A separate Data Coordinating Center
will support protocol development, sample size calculations, common
questionnaires, complete data analysis, data management,
standardization of procedures, quality control and overall study
coordination.

Objectives and Scope

The overall objective of this program (sleep study) is to
utilize existing, well characterized, established
population-based epidemiologic cohorts (parent studies) to
determine the degree to which sleep apnea is an independent
or contributing risk factor for the development of
cardiovascular and cerebrovascular disease.  It is also
aimed at examining possible associations between sleep
apnea, hypertension and stroke among different age, gender
and ethnic groups.

This program has five specific aims; however, other important areas
may be appropriate for inclusion into this program and it is not
restricted to only these five aims:

o  Determining the risk of CVD associated with sleep apnea and other
sleep related breathing disorders independent of other cardiovascular
disease risk factors;

o  Assessing potential interactions between sleep apnea, SRBD, and
other vascular disease risk factors, particularly obesity and
hypertension, in relation to CVD risk;

o  Examining the contribution of sleep apnea and SRBD to the
development of other CVD risk factors, particularly hypertension;

o  Identifying population subgroups at greatest risk for adverse
clinical outcomes from sleep apnea and SRBD, including those defined
by age, gender and race;

o  Estimating the extent of medical care utilization, health care
costs, and measures of quality of life associated with sleep apnea
and SRBD.

Although these five aims are identified, others may be appropriate.
The design of the experimental protocol and identification of
specific populations targeted for this program remain in the hands of
the investigators.  A number of possible components are listed for
illustrative purposes.

Study Population and Design

This program is to be built upon established epidemiologic programs.
It is anticipated that the sleep study would make use of data
previously collected in existing cohort studies as well as any
outcome information.  For example, a number of studies supported by
NHLBI, other components of NIH, National Center for Health Statistics
and other agencies have already collected much of the baseline
information on hypertension, obesity, and other cardiovascular risk
factors needed to examine relationships with sleep apnea and SRBD.
These studies together cover a wide age span, concentrated in single
communities or distributed among multiple sites.  Information on
cardiovascular outcomes and development of risk factors such as
obesity and hypertension is also being collected.  Several
epidemiology studies also include questionnaires on snoring and
sleep-related breathing disorders, which could be used to identify
persons at high risk of sleep apnea.

Sleep Study Cohort

A total population of approximately 6,000 participants (50 percent
women and appropriate minority representation) is anticipated.  The
sleep study population may include a wide range of samples.  For
example, for ages 40 years and above:  (a) subjects at increased risk
for CVD because of other known risk factors (e.g., family history,
hypertension, obesity, etc.); (b) subjects at risk for sleep apnea
(but without severe apnea at entry); and/or (c) subjects with mild to
moderate levels of apnea, but without known CVD.  It is not essential
that all Clinical Centers have access to the full age range of
subjects since certain established cohorts may be particularly suited
to provide a unique aspect (age, gender, race) of their population
for this program.  For data that are already collected or planned to
be collected in the parent study, applicants should demonstrate
availability, adequacy of the data set, standardization and
reliability of data on the cohort to be included in the sleep study.

Study Design

It is envisioned that the sleep study will require approximately 900
to 1,000 well characterized participants recruited from established
cohort studies or clinical trials in each of five to six clinical
sites, which may themselves consist of more than one site.  It is
possible for one or more sites from a multicenter study to
collaborate in recruiting a subset of their participants into the
sleep study.

It is expected that the sleep study design would include, as a
minimum, baseline and repeated measures, as needed, of
sleep-disordered breathing, sleep state, pulmonary and cardiac
function, oxygen saturation, lipid and lipoprotein levels, endocrine
function, blood pressure, obesity, and other cardiopulmonary risk
factors.  Given the cost of conducting laboratory polysomnography in
the number of participants needed for this study and the difficulty
with participants accepting additional measurements, applicants
should probably utilize ambulatory measurements of sleep disordered
breathing in non-laboratory settings.  Polysomnography may be used to
validate the ambulatory measurements in a subset of the population or
in selected cases.

Morbid outcomes may be defined with the use of several measures, such
as evidence of left ventricular dysfunction, sustained hypertension,
atherosclerosis, cognitive impairment, hospital admissions for
treatment of ischemic heart disease, health care expenditures
associated with CVD and cerebrovascular disease, measures of
functional status, quality of life, and death.

For any activities to be conducted through subcontracts, applicants
should develop and describe such operational factors as access to
subjects, organization of the facility, means of assuring quality
control, data entry, plans for coordination, and a process for filing
human subject assurances.

Applicants should also provide all details of the experimental
design, methods and procedures to be used in the proposed sleep
studies.

The proposed studies of successful applicants will be submitted to
the Steering Committee for further consideration once the cooperative
agreements have been awarded.  It is anticipated that the final sleep
protocol (including standardized data collection procedures) will be
developed from among the highly meritorious studies proposed by the
successful applicants.  However, a decision to fund a particular
Clinical Center will not commit the steering committee to conduct
that Center's specific protocol.

Timetable

The timetable for the sleep study may be roughly subdivided into
three phases over a five year period.  There may be some overlap of
functions within each of the phases, and the time estimates are only
approximations.  The purpose of the phases is to provide broad
guidelines for the collaborative endeavor.

Phase I:    Planning and protocol           months 0-12
             development

Phase II:   Subject recruitment, protocol   months 12-48
             implementation, examinations,
             and follow-up.

Phase III:  Data analysis and report        months 48-60
             preparation

The first twelve months of the study may be devoted to planning and
protocol development, for example, to determine participant
eligibility criteria; train staff in diagnostic procedures and sleep
studies; help set up data acquisition and consent forms; define terms
and outcome measures; develop a manual of operations, standardized
protocol, questionnaires, forms, and procedures for quality control;
and pretest data collection forms and procedures.

The Data Coordinating Center will also play a key role in the
planning and protocol development stage.  Possible objectives in
addition to assisting Clinical Centers in their planning and
organization of the steering committee, are to help develop the study
protocol and analytic plans; select a data acquisition, transfer, and
management system; plan for any subcontracts for chemical analysis;
establish a reading center for evaluating and interpreting sleep
records collected or validated by ambulatory methods and
polysomnography; develop procedures for quality control, training,
standardization of procedures and certification; print the protocols
and data forms; develop and produce a Manual of Operations, and take
the lead for the orderly accumulation and transmission of data for
the sleep study.

In Phase II, the Clinical Centers will proceed with subject
recruitment, protocol implementation, examinations and follow-up.
The Data Coordinating Center will assist the Clinical Centers with
respect to implementing the protocol, subject recruitment, data
acquisition, and ongoing quality control.

In Phase III, Clinical Centers and the Data Coordinating Center will
conduct data analysis and prepare reports.

SPECIAL REQUIREMENTS

Characteristics of Existing Epidemiological Cohorts

To promote and facilitate development of a collaborative program
among the award recipients, and to permit assessment according to
review criteria, a number of issues discussed below need to be
addressed in each application for a Clinical Center.

Applicants must have access to established, well characterized
populations that include measures of CVD risk factors and outcomes.
These may include studies supported by the National Institutes of
Health or other federal, state, or private agencies.  This program is
primarily aimed at cohorts in ongoing epidemiological studies.
However, those from recently completed studies may be proposed if
they are in every way suitable for the study as specified in this
RFA, including considerations of cost as discussed earlier under
FUNDS AVAILABLE and subsequently under Budget and Related Issues, as
well as under Review Criteria and Award Criteria.

Applicants must describe plans for providing data from the parent
study to the sleep study Data Coordinating Center and the concurrence
of the parent study data source with these plans.  Applicants should
describe and document access to study participants and provide a
brief, clear description of the characteristics, age distribution,
other relevant baseline information of the potential population, and
any unique features for use of their particular cohort in the sleep
study.  Applicants should also describe current procedures for
collecting and classifying information on deaths, cardiovascular
events, and other health outcomes.

As described under study design, it is expected that the sleep study
will require a number of cardiopulmonary and sleep measurements.
Therefore, it is expected that the subjects of the established
epidemiology cohort will have had measurements of certain minimum
characteristics, such as blood lipids, glucose, insulin, cholesterol,
hematocrit, blood pressure, ECG, body size and fatness, smoking
status, medical/family history, as well as outcome measures such as
left ventricular dysfunction, myocardial infarction, sustained
hypertension, atherosclerosis, stroke, hospital admissions for
treatment of ischemic heart disease, and cause specific mortality.
The existing study should also have the means to re-contact and
follow-up the identified cohort for CVD events.

The parent study data that will be utilized in the sleep study should
have been collected according to up-to-date and standard methods
within five years of Phase II (on or about September 30, 1995) of the
sleep study, as agreed to during protocol development.  If such data
are not available from the parent study or if certain minor baseline
measurements are missing, investigators may propose methods for
collecting these data as part of the sleep study.  It is the
responsibility of the principal investigators to provide
documentation from appropriate parent study Steering Committees, Data
and Safety Monitoring Boards and sponsoring agencies for use of their
population for this program.

Additional Material to Include in the Application

It is envisioned that the Principal Investigator (PI) will be an
established investigator in cardiovascular, pulmonary or sleep
disorders research.  Either the PI or a co- investigator should have
demonstrated experience in sleep disorders research.  For example, it
would be desirable for the PI and Co-PI to have combined expertise in
CVD risk factors, epidemiology and sleep disorders medicine.  It is
not essential that this investigative team be from the same
institution.  However, if applications involve investigators from
different institutions there must be well documented plans for
adequate communication, interactions and facilities to conduct the
sleep aspects of the protocol.

Clinical Center applicants must be able to interact effectively with
the Data Coordinating Center to transmit and edit data and should
discuss their capability to participate in a distributed data entry
system if this approach is selected.  Clinical Center applicants
should also state their willingness, and that of the institutions
involved, to participate in a cooperative and interactive manner with
other Clinical Centers, the NHLBI and the Data Coordinating Center
within the context of this collaborative research program.

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.

Data Coordinating Center applicants should discuss various aspects of
study design that would be important in developing the sleep study
protocol, their familiarity with sleep disorders and cardiopulmonary
risk factors and diseases, eligibility criteria, important
considerations for making sample size and power calculations,
baseline and outcome measures, methods and frequency of data
collection and entry, monitoring accuracy of data collection, methods
of data acquisition and transfer, quality control procedures
including training and certification, chemical analysis of blood
samples, centralized reading of sleep records, and plans for
statistical analysis of results.

Budget and Related Issues

Applicants are expected to be able to complete the sleep study with
the funding available through this RFA in conjunction with any
already committed funding.  A decision to award a sleep study
application does not constitute a continued commitment to the parent
study beyond its current project and budget period.

Applications for the Clinical Centers and the Data Coordinating
Center should present five budget periods of 12 months each.
Applicants should provide adequate budget justification for each
phase of the study and all applicable direct and indirect costs
should be included.

Estimates of staffing needs, including the Principal Investigator,
Co-Investigator, other professional and support staff must be
included.  The suggested level of commitment for the Principal
Investigator and Co-Investigator should be not less than 20 percent
each.  Other personnel such as clinic coordinator, sleep technician,
research assistants and secretary should be carefully outlined and
justified in the application.  Travel costs for approximately three
to four trips to Bethesda for two people should be included in the
first year budget with reductions to two trips for two people in
subsequent years.  Any major equipment items should be well
justified.  If collaborations or subcontracts are involved which
require transfer of funds from the grantee to other institutions, it
is necessary to establish formal subcontract agreements with each
collaborating institution.  Budgets for subcontracts should be
prepared using the same guidelines as for the main grant.  Budgets
can be escalated four percent for the remaining future years.

Future year awards may be redistributed based on the final protocol,
enrollment of subjects into the sleep protocol during a specified
time frame and overall performance.  The individual clinics are
expected to project subject enrollment into the sleep protocol.

Applicants for the Data Coordinating Center should prepare budgets
that allow for roughly the standard coordinating center activities
and responsibilities related in timing and scope to the above
mentioned phases.

Terms and Conditions of Award

These special Terms of Award are in addition to and not in lieu of
otherwise applicable OMB administrative guidelines, HHS Grant
Administration Regulations at 45 CFR part 74, and other HHS, PHS, and
NIH Grant Administration policy statements. [Part 92 applies when
state and local governments are eligible to apply as a "domestic
organization."]

The administrative and funding instrument used for this program is a
cooperative agreement (U01), an assistance mechanism (rather than an
acquisition mechanism) in which substantial NIH scientific and/or
programmatic involvement with the awardee is anticipated during
performance of the activity.  Under the cooperative agreement, the
NIH purpose is to support and/or stimulate the recipient's activity
by involvement in and otherwise working jointly with the award
recipient in a partner role, but it is not to assume direction, prime
responsibility or a dominant role in the activity.  Consistent with
this concept, the dominant role and prime responsibility for the
activity resides with the awardee(s) for the project as a whole,
although specific tasks and activities in carrying out the studies
will be shared among the awardees and the NHLBI Project Scientist.

Awardees will have the usual responsibilities of award recipients,
including protocol development, participant recruitment and
follow-up, data collection, quality control, interim data and safety
monitoring, final data analysis and interpretation, and preparation
of publications, as well as responsibilities for collaboration with
other awardees, and collaboration with the NHLBI Project Scientist.

The NHLBI Project Scientist (Branch Chief, Airways Diseases Branch,
Division of Lung Diseases), in addition to the usual stewardship
responsibilities, will have responsibilities in protocol development,
quality control, interim data and safety monitoring, final data
analysis and interpretation, preparation of publications,
collaboration with awardees, and project coordination.

Awardees will have lead responsibilities for the project as a whole
and it is anticipated that the awardees will have lead
responsibilities in all joint tasks and activities, except it is
anticipated that the NHLBI Project Scientist will have lead
responsibilities in quality control and catalyzing interim monitoring
of data and safety and may, consistent with publication policy to be
adopted by the Steering Committee, have lead responsibilities in the
preparation of some publications.

A Steering Committee, composed of the principal investigator(s) of
each Clinical Center, the principal investigator(s) of the
Coordinating Center, and the NHLBI Project Scientist will be the main
governing body of the study and will have primary responsibility for
developing common protocols, facilitating the conduct and monitoring
of studies, and reporting study results.  Each Field Site, the
Coordinating Center and the NHLBI Project Scientist will have one
vote.  The Chairperson, who will be someone other than an NHLBI staff
member, will be selected by the Steering Committee.  Subcommittees
will be established by the Steering Committee, as it deems
appropriate; an NHLBI scientist (or where necessary, scientists) will
serve on subcommittees as deemed appropriate by the NHLBI Project
Scientist.

The collaborative protocol will be developed by the Steering
Committee.  This protocol may be reviewed by an external committee
convened by NHLBI.  The protocol will be implemented only with the
concurrence of the awardees and NHLBI.  Data will be submitted
centrally to the Coordinating Center.  The protocol will define rules
regarding access to data and publications.  An independent Data and
Safety Monitoring Board, to be appointed by NHLBI, will review
progress at least annually and report to NHLBI.

Awardees will retain custody of and have primary rights to their data
developed under these awards, subject to Government rights of access
consistent with current HHS, PHS, and NIH policies.

The NHLBI reserves the right to terminate or curtail the study (or an
individual award) in the event of (a) failure to develop or implement
a mutually agreeable collaborative protocol, (b) substantial
shortfall in participant recruitment, follow-up, data reporting,
quality control, or other major breach of the protocol, (c)
substantive changes in the agreed-upon protocol with which NHLBI
cannot concur, (d) reaching a major study endpoint substantially
before schedule with persuasive statistical significance, or (e)
human subject ethical issues that may dictate a premature
termination.

Any disagreement that may arise in scientific/programmatic matters
(within the scope of the award), between award recipients and the
NHLBI may be brought to arbitration.  An arbitration panel will be
composed of three members--one selected by the Steering Committee
(with the NHLBI member not voting) or by the individual awardee in
the event of an individual disagreement, a second member selected by
NHLBI, and the third member selected by the two prior members.  This
special arbitration procedure in no way affects the awardee's right
to appeal an adverse action that is otherwise appealable in
accordance with the PHS regulations at 42 CFR part 50, Subpart D and
HHS regulation at 45 CFR part 16.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements are required to include minorities and women
in study populations so that research findings can be of benefit to
all persons at risk of disease, disorder, or condition under study;
special emphasis must be placed on the need for inclusion of
minorities and women in studies of diseases, disorders, and
conditions which disproportionately affect them.  This policy is
intended to apply to males and females of all ages.  If women or
minorities are excluded or inadequately represented in clinical
research, particularly in proposed population-based studies, a clear
compelling rationale must be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues must be addressed in developing a research
design and sample size appropriate for the scientific objectives of
the study.  This information must be included in the form PHS 398
(rev. 9/91) in Sections 1-4 of the Research Plan, and summarized in
Section 5, Human Subjects.  Applicants are urged to assess carefully
the feasibility of including the broadest possible representation of
minority groups.  However, NIH recognizes that it may not be feasible
or appropriate in all research projects to include representation of
the full array of United States racial/ethnic minority populations
(i.e., Native Americans [including American Indians or Alaskan
Natives], Asian/Pacific Islanders, Blacks, Hispanics).

The rationale for studies on single minority population groups should
be provided.

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

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are not subject to
these policies.  However, every effort should be made to include
human tissues from women and racial/ethnic minorities when it is
important to apply the results of the study broadly, and this should
be addressed by applicants.

If the required information is not contained within the application,
the application will be returned.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies. If the representation of
women in a study design is inadequate to answer the scientific
question(s) addressed AND the justification for the selected study
population is inadequate, it will be considered a scientific weakness
or deficiency in the study design and will be reflected in assigning
the priority score to the application.

All applications for clinical research submitted to NIH are required
to address these policies.  NIH funding components will not award
grants or cooperative agreements that do not comply with these
policies.

LETTER OF INTENT

Prospective applicants are asked to submit, by April 1, 1994, 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 subsequent applications, the information
that it contains is helpful in planning for the review of
applications.  It allows NHLBI staff to estimate the potential review
workload and to avoid conflict of interest in the review.

The letter of intent is to be sent to:

C. James Scheirer, Ph.D.
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 648
Bethesda, MD  20892
Telephone:  (301) 594-7452
FAX:  (301) 594-7407

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these grants.  These forms are available at most
institutional offices of sponsored research; from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892,
telephone (301) 710-0267; and from the NIH Project Scientist(s)
listed under INQUIRIES.

The RFA label available in the PHS 398 application form must be
affixed to the bottom of the face page of the application.  Failure
to use this label could result in delayed processing of the
application such that it may not reach the review committee in time
for review.  In addition, the RFA title and number must be typed in
line 2a of the face page of the application form and the YES box must
be marked.  Send or deliver the original, signed application and
three legible complete photocopies to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

Send two additional copies of the application to:

C. James Scheirer, Ph.D.
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 648
Bethesda, MD  20892
Telephone:  (301) 594-7452

It is important to send these two copies at the same time as the
original and three copies are sent to the division of research
grants.  Otherwise, the NHLBI cannot guarantee that the application
will be reviewed in competition for this RFA.

Applications must be received by May 23, 1994.  If an application is
received after this date it will be returned to the applicant without
review.  The Division of Research Grants (DRG) 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 DRG 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
reviewed, but such applications must include an introduction
addressing the previous critique.

REVIEW CONSIDERATIONS

General Considerations

All applicants will be judged on the basis of the scientific
merit of their proposed research project and their
documented ability to conduct the essential study components
as broadly outlined in the RESEARCH OBJECTIVES of this RFA.

Review Method

Upon receipt, applications will be reviewed by the DRG for
completeness and by NHLBI staff for responsiveness to this RFA.
Incomplete applications will be returned to the applicant without
further consideration.  If the application is judged unresponsive,
the applicant will be contacted and given an opportunity to withdraw
the application.  If the application submitted in response to this
RFA is substantially similar to a grant application already submitted
to the NIH for review, but has not yet been reviewed, the applicant
will be asked to withdraw either the pending application or the new
one.  Simultaneous submission of identical applications will not be
allowed, nor will essentially identical applications be reviewed by
different review committees.  Therefore, an application cannot be
submitted in response to this RFA that is essentially identical to
one that has already been 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.

Applications judged to be responsive by NHLBI staff will be reviewed
for scientific and technical merit by an initial peer review group,
which will be convened by the Division of Extramural Affairs, NHLBI,
solely to review these applications.  The initial review will include
a preliminary evaluation to determine scientific merit relative to
the other applications received in response to this RFA (triage); the
NIH will remove from further consideration applications judged to be
noncompetitive and promptly notify the Principal Investigator and the
official signing for the applicant organization.  Those applications
judged to be competitive will be further evaluated for
scientific/technical merit by the usual peer review procedures,
including, if deemed appropriate, an applicant interview in or near
Bethesda at the applicant's expense.  Subsequently, they will be
reviewed by the National Heart, Lung, and Blood Advisory Council.

Review Criteria

Applicants are encouraged to submit and describe their own ideas on
how best to meet the goals of the RFA and their specific protocol,
but they are expected to address issues identified under SPECIAL
REQUIREMENTS of this Request for Applications.  Applications will be
judged primarily on the scientific quality of the application, the
appropriateness, facilities and access to subjects from existing,
established epidemiology studies, adequacy of existing data,
multidisciplinary nature of the study and group, approach to cost
containment, the discussion of considerations relevant to this RFA,
expertise of the investigators, their capability to perform the work
proposed, and a demonstrated willingness to work as part of the
collaborative group and with the NHLBI Project Scientist.

The review group will assess the scientific merit of the applications
and related factors, including:

Clinical Centers

o  Ability to utilize existing, established epidemiological cohorts
to address the goals of this program; adequacy of the population,
data set, and access to recruit the required numbers of subjects,
including appropriate representation of minorities and women.

o  Importance and scientific merit of the proposed sleep study
protocol, including adequacy of the methodology to carry out the
proposed research plan.

o  Availability of adequate facilities and other resources including
a plan for the administrative structure within the Clinical Center.

o  Rationale and cost-effectiveness of the research approach proposed
and appropriateness of the budget.

o  Adequacy of data collection, preliminary analysis, reporting
procedures, monitoring of study recruitment and subject follow-up,
ability to process the volume of data expected within their Center
and manage the individual study databases.  Plans to ensure quality
control of data.

o  Expertise, training, and experience of the investigators and
staff, including the scientific and administrative abilities of the
PI and co-investigators; their potential to accomplish the proposed
research goals; the time they plan to devote to the program for the
effective conduct of the study; their previous experience conducting
clinical or population based research; their ability, experience and
willingness to participate collaboratively with other Clinical
Centers, the Data Coordinating Center, and the NHLBI in the manner
summarized in the RFA.

o  Facilities, equipment, and organizational structure to effectively
implement the proposed research.

Data Coordinating Center

o  Understanding of the scientific, statistical, logistical, and
technical issues underlying multicenter studies, including taking a
leadership role in the area of study design, statistics, logistics,
data acquisition and management, quality control, data analysis, and
overall coordination.

o  Adequacy of the proposed plans for acquisition, transfer,
management, and analysis of data; sleep reading center; quality
control of data collection and monitoring, and overall coordination
of Center activities.

o  The expertise, training, and experience of the investigators and
staff, including the administrative abilities of the Principal
Investigator and co-investigators, and the time they plan to devote
to the program for effective coordination.

o  The administrative, supervisory, and collaborative arrangements
for achieving the goals of the program, including willingness to
cooperate with the participating Clinical Centers and the NHLBI.

o  Facilities, equipment, subcontracts, and organizational structure
to effectively assist Clinical Centers in implementing the protocol
and in data collection procedures and in overall coordination of
study-wide activities.

o  Appropriateness of the budget for the work proposed.

AWARD CRITERIA

Applications recommended by the National Heart, Lung, and Blood
Advisory Council will be considered for award based on (a) scientific
and technical merit; (b) program balance, including in this instance,
sufficient compatibility of features to make a successful
collaborative program a reasonable likelihood; and (c) availability
of funds.

Letter of Intent Receipt Date:     April 1, 1994
Application Receipt Date:          May 23, 1994
Review by NHLBI Advisory Council:  September 1-2, 1994
Anticipated Award Date:            September 30, 1994

INQUIRIES

Written and telephone inquiries are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.
Inquiries regarding programmatic issues may be directed to:

James P. Kiley, Ph.D.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
Westwood Building, Room 6A15
Bethesda, MD  20892
Telephone:  (301) 594-7443
FAX:  (301) 594-7487

Inquiries regarding review and application procedures may be directed
to:

C. James Scheirer, Ph.D.
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 648
Bethesda, MD  20892
Telephone:  (301) 594-7452
FAX:  (301) 594-7407

Inquiries regarding fiscal and administrative matters may be directed
to:

Mr. Raymond Zimmerman
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 4A11C
Bethesda, MD  20892
Telephone:  (301) 594-7420
FAX:  (301) 594-7492

AUTHORITY AND REGULATIONS

This project is described in the Catalog of Federal Domestic
Assistance No. 93.837.  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 PHS grants policies and Federal Regulations 42 CFR 52 and 45
CFR 74.  This project is not subject to the intergovernmental review
requirements of Executive Order 12372 or Health Systems Agency
review.

.

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	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
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