Full Text HL-94-011

GENETIC DETERMINANTS OF HIGH BLOOD PRESSURE

NIH GUIDE, Volume 23, Number 10, March 11, 1994

RFA:  HL-94-011

P.T. 34

Keywords: 
  Genetics 
  Hypertension 


National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date:  June 17, 1994
Application Receipt Date:  September 16, 1994

PURPOSE

The Division of Heart and Vascular Diseases and the Division of
Epidemiology and Clinical Applications invite cooperative agreement
applications to establish networks that, with the assistance of the
National Heart, Lung, and Blood Institute (NHLBI), will participate
in a coordinated effort to elucidate the major genetic factors
involved in the etiology and pathogenesis of hypertension.

The objective of this request for applications (RFA) is to establish:

(1) Genetic Networks of collaborating investigators to exploit modern
molecular genetic tools to map and identify the major genetic
determinants of high blood pressure, and

(2) Genetic Epidemiology Networks that, in addition to gene mapping
and identification described above, will also study interactions
between genetic and non-genetic determinants of hypertension in
defined populations.  Support for Genetic Epidemiology Networks will
not be provided for de novo recruitment of probands who have not
previously been examined and had their blood pressures measured and
family histories of high blood pressure ascertained.

An essential feature of these collaborative research efforts, both
within and among networks, is the sharing of technology, data,
skills, biological materials, as well as population resources.  The
studies may employ a variety of genetic strategies using family
configurations, including linkage analysis of affected sib-pairs and
extended families.  Case-controlled allelic association studies are
considered responsive to this RFA only when the investigator
expresses a clear intent to confirm any positive findings with
evidence from other sorts of studies (e.g., linkage analysis).
Approaches may incorporate candidate genes and/or anonymous genetic
markers.  As the intent of this RFA program is to map and identify
genetic factors in humans, mapping studies using animal models will
only be considered responsive if they meet the criteria outlined
later in this document under the section titled "Role of an Animal
Mapping Center."

Although each network will be fully capable of pursuing all necessary
facets to map and identify genetic factors responsible for high blood
pressure, each network may differ in terms of strategy, design, and
methodology.  Hence, in order to achieve the goals of this RFA in the
most effective manner possible, there will be a Program Steering
Committee to ensure collaborative efforts among networks, assure
comparability of results within and across networks, promote and
coordinate collaboration among networks, develop uniform protocols
and standard methods, facilitate sharing of resources, and plan and
evaluate changes in research design as developments warrant.

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,
Genetic Determinants of High Blood Pressure, is related to the
priority area of heart disease and stroke.  Potential applicants may
obtain a copy of "Healthy People 2000" (Full Report:  Stock No.
017-001-00474-0 or Summary Report:  Stock No. 017-001-00473-1)
through the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone 202-783-3238).

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.  However, under exceptional circumstances,
a foreign component, which is critical to the success of the network
and minor in its magnitude, may be included as part of a domestic
application.  Applications from minority individuals and women are
encouraged.

MECHANISM OF SUPPORT

The administrative and funding instrument to be used for this program
will be a cooperative clinical research agreement (U10), an
"assistance" mechanism, in which substantial National Institutes of
Health (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 sections titled
"Special Requirements" and "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 April 1, 1995.

The number of 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
amount of funds to establish each network will also vary.

This RFA is a one-time solicitation.  Future unsolicited competing
continuation applications may compete with all investigator-initiated
applications and be reviewed according to the customary peer review
procedures.

FUNDS AVAILABLE

Up to four networks may be funded under this RFA, depending upon
availability of funds for this purpose.  A network will be comprised
of components.  Each component will be directed by a Principal
Investigator and will receive a separate award.  As network tasks can
be organized according to a number of different organizational
strategies, each network could be comprised of four to seven
components (awards).  Hence, if four networks are funded, the total
number of awards might vary from 12 to 28.

A maximum of about $30 million (including direct and indirect costs)
over a five-year period will be awarded.  Approximately $4.50 million
may be available for the first year, $6.00 million for the second
year, $6.24 million for the third year, $6.50 million the fourth year
and $6.76 million for the last year.

RESEARCH OBJECTIVES

Background

Hypertension, a complex disease that involves the interplay of
genetic and environmental factors, affects an estimated 50 million
Americans and is a major predisposing factor for myocardial
infarction, vascular disease, stroke, and renal failure.  It has been
estimated from segregation analysis and twin studies that
approximately 45 percent of the interindividual differences in blood
pressure are accounted for by genetic differences.  The
identification of the genes whose variants contribute to high blood
pressure will have far-reaching effects on our understanding of the
pathophysiology of the circulation and may suggest new preventive
measures and rational therapeutic approaches.

One of the principal advantages of the genetic approach is that it
identifies primary molecular defects.  The division of the general
hypertensive population into subgroups, defined by genotypes, may
allow the evaluation of therapies in more homogeneous groups.  On the
one hand, knowledge of these defects may provide new targets for
specifically-designed therapies.  On the other hand, it may prove
possible to use existing approaches in a more directed way to treat
individuals with specific genotypes.

Similar considerations apply to the evaluation of preventive
measures.  In a complex and heterogeneous disease, the use of a
preventive measure that produces no obvious benefit when applied to
the whole patient group may be effective in a subgroup with a
particular etiology.  Subdivision of hypertension according to the
genotypes of major contributing genes is likely to provide one of the
most powerful means of defining etiologically homogeneous groups.

It may not be necessary to negate the effects of all the genes
contributing to hypertension to treat the disease in an individual
case.  It is likely that many genetic effects are additive and that
neutralizing one or two of the genetic determinants operating in an
individual may be sufficient to reduce blood pressure to a level that
has no associated risk.

The identification of hypertension genes provides the basis for an
understanding of the interactions between genes and environmental
factors.  It is very likely that particular environmental variables
exert effects only in the presence of certain genotypes.  Moreover,
the effects of certain environmental factors may be "lost" in a
genetically heterogeneous group.  Some of these factors have large
effects in some genetically-defined populations.

Until recently, the techniques for dissecting the genetic
determinants of high blood pressure were not available or were not
developed to an extent that would make the proposed project feasible.
Several recent advances in technology and analytical methods,
together with the rapid construction of genetic maps, have
substantially improved the chances of detecting these genetic
factors.  These techniques have already been applied with
considerable success to single-gene disorders, such as Duchenne
muscular dystrophy, retinoblastoma, cystic fibrosis,
neurofibromatosis, and many others.

Examples of developments that make the use of genetic strategies in
the study of hypertension timely include:  The Human Genome Project
has developed (and continues to develop) physical and high-resolution
genetic maps; genes encoding proteins important in controlling blood
pressure are being isolated at an unprecedented pace, providing a set
of "candidate genes"; genomic localization of newly cloned genes is
now routine, so that the locations of many physiologically important
genes are becoming known; the construction of comparative human/mouse
maps allows information gained from studies of the mouse to be
applied rapidly to humans; automated methods of studying genetic
polymorphism and mutation are being developed at an accelerated pace,
and; there are several new techniques for the identification of
single-base changes, such as single-stranded conformational
polymorphism, denaturing gradient gel electrophoresis, chemical
cleavage, and direct sequencing by machine, that allow candidate
genes to be screened rapidly.

The confluence of these methodological, analytical, and technological
developments makes it an opportune time for a comprehensive and
coordinated program that will systematically map and identify the
genetic factors involved in complex polygenic disorders, such as
hypertension.

Objectives and Scope

The goal is to identify the genes involved in hypertension by using
an alliance of talented investigators skilled in the appropriate
scientific disciplines who will use the most sophisticated and modern
molecular genetic approaches.  In addition to gene mapping and
identification, investigators may also apply to study interactions
between genetic and non-genetic determinants of hypertension in
defined populations.  Consequently, support will be provided to
collect and characterize appropriate family configurations, to
phenotypically and genotypically characterize members of these
configurations, and to perform genetic and statistical analyses to
localize and identify genetic factors responsible for high blood
pressure.  Studies utilizing genetic inbred animal models (especially
rats) may also be included under special circumstances, as presented
below ("Role of the Animal Mapping Center").

Study Design, Methodology, and Analysis

There are a number of feasible study designs that could achieve the
objectives of this program, depending upon the varying degrees of
certainty regarding the true modes of inheritance, the understanding
of underlying physiology of disease processes, and the availability
of appropriate intermediate phenotypes.   Therefore, the exact study
design(s), methodology, and analytical tools employed may differ
among networks.  Regardless of the particular strategy chosen, it is
absolutely critical for the applicants to carefully justify the
methodology, strengths, and limitations of the study design,
analytical strategies, statistical tools, and the selection of the
population.  For example, the research plan should specify the
numbers and relationships of individuals and families to be studied
and specify their age, sex, and race composition, as well as their
hypertensive status.  Sample size estimates and power calculations
should be provided.  Clinic procedures and laboratory assays and
methods should be described.  In addition, the research plan must
include a scheme to address the ethical, legal, and social aspects of
conducting genetic research.  Examples include informed consent,
confidentiality, access to information, and privacy.

As an example of a substantive issue that needs to be addressed,
genetic heterogeneity may substantially increase the difficulty of
identifying genes involved in high blood pressure.  The extent of
genetic heterogeneity cannot be accurately determined and is likely
to become apparent only when the molecular determinants of the trait
have been elucidated.  There are, however, ways to reduce the impact
of heterogeneity.  One way is to subdivide the population by defining
intermediate phenotypes.  Another way is to study populations which
have probably originated from a restricted founder population or have
been isolated in some other manner so that the number of genetic
variants present in the population is limited.  A different approach
is to sample many small families and perform linkage mapping using a
"simultaneous search strategy".  Another strategy is to utilize high
resolution genetic maps and high quality genetic markers that allow
genetic analysis of smaller and therefore more homogeneous
populations.

A number of different genetic methodologies may be used that employ
family configurations, such as the sib-pair method and other
combinations of affected related individuals, genetic linkage
analysis of pedigrees, and nonparametric analyses and refinements.
The development and application of new methods to extract mapping
information in the presence of genetic heterogeneity is highly
desirable.  Case-controlled allelic association studies are
considered responsive to this RFA only when the investigator
expresses a clear intent to confirm any positive findings with
evidence from other sorts of studies (e.g., linkage analysis).
Examples of responsive strategies include generalized linkage
entailing a whole genome search using anonymous highly-informative
genetic markers spread throughout the genome or within "candidate"
genes.  Regardless of strategy, there are a number of different
methods for characterizing DNA polymorphisms that are suitable.  It
is anticipated that polymerase chain reaction (PCR) typing of
microsatellite repeats will be a major approach, which may be
supplemented by more effective methods as they become available.
Genotyping may use currently existing and/or generate new highly
polymorphic markers as needed to better define the chromosomal region
of a genetic marker by refined genetic and physical mapping to
determine the disease locus.

In addition, a Genetic Epidemiology Network would be capable of
performing analyses that will address:  distributions of blood
pressure and related characteristics in individuals and families;
correlations and clustering of determinants of blood pressure and of
clinical attributes associated with hypertension, genetic and
environmental contributions to phenotypic variance, measures of
association of determinants of blood pressure with blood pressure
levels and clinical manifestations of hypertension in related and
unrelated individuals, as well as other genetic analyses.

Purpose and Characteristics of a Network

The most effective way to achieve the objectives of this RFA program
is to establish highly interactive networks that will pursue the
requisite tasks and provide the essential tools and infrastructure.
A network will link the best people and resources in several
locations and provide essential cohesion and coordination.  Effective
genetic research requires the help of collaborators from many
disciplines, such as genetics, epidemiology, biostatistics, clinical
and laboratory science, and expertise in the molecular techniques of
gene mapping, characterization and cloning.  Additional skills
include genotyping, data management, and informatics.  In order to
effectively perform research, a network will also need to establish
and share the requisite resources, including technology, data,
biological materials, and population resources.  The collection of
adequate numbers of well characterized subjects is central to the
success of the genetic approach.  However, it is inevitable that the
subjects will be geographically dispersed and that more than one
location will be required to establish, in a timely fashion, a sample
of sufficient size to provide statistical power appropriate for the
study design.  It is anticipated that, although some existing
research centers may have access to all necessary resources, many of
the investigators critical to the success of the project will be
located in institutions that lack important elements.  Hence, a
network will allow a group of investigators at distinct geographical
locations to interact and share resources.

Each application to establish a network must be submitted by a group
of investigators who are capable of forming a dynamic, highly
interactive, cohesive, coordinated network that is fully capable of
independently pursuing all necessary facets required to map and
identify genetic factors responsible for high blood pressure,
including recruitment, phenotyping, genotyping, and data management
and analysis.  These tasks can be organized according to a variety of
schemes and rationales to form a network, as long as all requisite
activities essential to achieving the objectives of this RFA are
included.  In addition, a network must have the appropriate areas of
expertise and infrastructure, include mechanisms to achieve
coordination and communication within a network, and be willing to
participate in multi-network activities.

Key members who desire to establish a network and who are expert in
the necessary tasks must be involved in the preparation of the
research plan, study design, and all other crucial aspects of the
application that is submitted to the NHLBI.

For purposes of illustration only, these network tasks and activities
could be organized into the following components: Field Centers,
Laboratory Center, Genotyping Center, Data Coordinating Center (DCC),
and Animal Mapping Center.  This model is not meant to limit other
organizational strategies.  It is used solely to help articulate
specific functions necessary to build a successful network and to
simplify the description of the terms, conditions, governance, and
other requirements of this RFA program.

Role of Field Centers:

Network Field Centers could be used to implement its plan for subject
selection and recruitment, ascertainment, characterization, and
classification of hypertension and related characteristics.
Identification and characterization of participants might be
accomplished through questionnaires, extensive interviewing (e.g.,
about risk factors and medical history), clinical examinations and
procedures, and laboratory studies, including biological measures of
phenotypic characteristics relevant to genetic studies of
hypertension.  These Centers should be able to maintain contact with
study participants, follow subjects longitudinally, propose and
implement criteria and procedures for referring participants for
further investigation and medical care, if needed, and track changes
in critical parameters.  All Field Centers would employ a common,
comprehensive set of standardized, reliable, and valid assessment
protocols and instruments.  In addition, Field Centers will need a
plan to enter collected data and transmit it to the DCC.  Field
Centers might also be used to collect, prepare, and ship samples for
measurement, quality control, and storage (e.g., blood samples for
laboratory analysis, DNA extraction, and isolation and transformation
of lymphocytes into permanent cell lines).  Central training of Field
Center staff within each network (and possibly across all networks),
plus certification of staff and monitoring of performance at each
site, is an approach that would ensure uniformity, reproducibility,
and comparability of data and results.  If the use of ECGs,
echocardiography, Holter monitors, and other similar devices is
proposed, then their measurement, reading, and interpretation could
also be the responsibility of the Field Centers, either directly or
by subcontract.  Expertise in diagnosis and characterization of
hypertensives should also be available at the Field Center.

Role of a Laboratory Center

A Laboratory Center could be used to perform blood, urine, and other
essential biological and biochemical measures, and ensure quality
control.  Measurements that may serve as intermediate phenotypes
could be performed here as well.  Sample assays might include plasma
renin activity, cortisol and aldosterone, angiotensin II, sodium and
potassium, erythrocyte Na/Li countertransport, kallikrein, and
creatinine.

A Laboratory Center would assure standardization of measurements
through the use of an operating quality control program to assess and
control within-run and between-run variability, accuracy and
long-term drift for all measurements.  In addition, the Laboratory
Center could coordinate efforts with the Field Centers such that
there is uniform collection, preparation, storage, and shipping of
samples.

In addition, the Laboratory Center can collaborate with the DCC to
develop and utilize mechanisms to transmit data generated by this
study to the DCC.  Also in conjunction with the DCC, the Laboratory
Center would develop a record keeping and catalogue system for stored
materials, which could be then maintained and updated at the DCC.

Role of a Genotyping Center:

A Genotyping Center could be used to slow freeze lymphocytes for
storage, transform lymphocytes and store them as permanent cell
lines, extract and store DNA, and analyze DNA for variations in
structure.  The latter information can be used to test for linkage or
association with phenotypic markers, depending upon the study design.
In addition, the Genotyping Center would work with the DCC to develop
and utilize mechanisms to transmit genotypic data generated by this
study to the DCC.  Also in conjunction with the DCC, the Genotyping
Center may develop a record keeping and catalogue system for stored
materials (DNA, cell lines), which could then be maintained and
updated at the DCC.

Role of an Animal Mapping Center (optional)

Gene mapping efforts in humans can be greatly facilitated by
judicious use of inbred animal models.  Advantages include short
generation times, availability for thorough measurement of
quantitative risk factors under controlled conditions, and the
ability to control and alter environmental factors.  Therefore, for
the purposes of this RFA, animals (especially rats) can be used for
direct mapping of genes responsible for hypertension (e.g., searching
for quantitative trait loci, either by a total genomic search or
candidate gene strategy, followed by synteny conservation mapping) as
long as they are an integrated part of a network in which the results
are expeditiously exploited for comparative gene mapping efforts
directed toward the identification of the corresponding genes in
humans.  If animal mapping studies are included, a plan to this
effect must be presented by the applicant.

Role of a Data Coordinating Center

The DCC would supply critical, specialized data management and
statistical and analytical expertise and participate fully with the
other key network components to conceive and develop the research
plan and study design that form the basis of an application submitted
to the NHLBI to establish a Genetic or Genetic Epidemiology Network.
Hence, close interaction of the DCC and other members of the network
team is strongly encouraged in order to submit an application in
response to this RFA.  The strongest network applications would
involve key members who are independently recognized scientists with
a track record of publications in relevant areas, such as the
analysis of genetic data and population genetics.

A DCC could receive, edit, and store all relevant research data
collected in a network, including data pertinent to ascertainment and
assessment, genetic and phenotypic information, family structures,
blood and urine samples stored and analyzed at the Laboratory Center,
cell lines and DNA stored at the Genotyping Center, and other data
required for the analyses to be undertaken by the network.  In
addition, the DCC would possess the capabilities for implementing
remote site data entry and for interacting with all other performance
sites [eg., Field Centers, Laboratory Center, Genotyping Center,
Animal Mapping Center (if included)] of the network.  The DCC could
also be responsible for providing appropriate access by participant
investigators and for distribution of information to investigators
both internal and external to the network, as appropriate.

The DCC could recommend and, after approval by the Internal Network
Coordinating Committee, purchase hardware and software for use at
each Field and Laboratory Center.  Other relevant responsibilities
could include setting up data entry and transmission at each site,
training and monitoring performance of personnel at each site,
preparing forms and data entry screens, and integrating and producing
multi-network protocols and manuals of procedures.

Multi-network Activities

Although the networks funded by this program may differ in strategies
and design, there will be numerous beneficial and exciting
opportunities for collaboration among the different networks that
will expedite and enhance the specific aims of each network and the
overall objectives of this RFA.  Consequently, a Program Steering
Committee will be used to facilitate the establishment and conduct of
multi-network activities, such as develop and initiate collaborative
studies, develop uniform protocols, standardize methods, share data
and resources, generate new ideas and strategies that result from new
research findings, and ensure a minimum of research and budgetary
duplication.  Because genetic studies of complex, quantitative traits
like hypertension require great care with respect to the methods used
to characterize subjects, a Program Steering Committee will also
serve as a mechanism to help ensure comparability of results within
and across networks.

Timetable

In order to assist applicants in preparing a budget, broad guidelines
of the total scope and objectives for this RFA are presented in the
approximate timetable presented below.  There may be some overlap of
functions within each of the three stages, and the time estimates are
only approximate. Because different networks may be at different
stages upon initiation of this program, due to differences in such
elements as study design or prior recruitment and characterization of
study participants, budgets proposed by different networks will vary.
However, all networks must anticipate the time required in the first
year to develop multi-network standard procedures and collaborative
protocols.

Year 1: Develop multi-network study protocols specifying objectives,
organizational structure, and study designs; prepare manuals of
operation detailing standardized methods and procedures including
questionnaires, examination and laboratory procedures, diagnostic
criteria, quality control, data management and analysis; recruit and
train personnel; select study individuals and families; animal
genetic mapping studies (if proposed); select Program Steering
Committee chairperson; organize subcommittees of the Program Steering
Committee.

Years 2 - 3: Pilot test examination and laboratory procedures;
recruit, examine and follow-up study participants; perform laboratory
assays and genotyping; store specimens; perform data analysis;
continue animal genetic mapping studies (if proposed).

Years 4 - 5: Continue laboratory assays and genotyping; follow-up
study participants; examine selected pedigrees, if indicated; data
analysis; report results; continue animal genetic mapping studies (if
proposed).

SPECIAL REQUIREMENTS

Internal Network Coordinating Committees:

Each network will use an Internal Network Coordinating Committee to
govern its own activities.  An Internal Network Coordinating
Committee will be used to achieve suitable coordination within a
network, and should be comprised of the Network Director, the PIs of
its various components (eg., Field Centers, Laboratory Center, DCC,
Genotyping Center, and Animal Mapping Center), and one NHLBI
representative.  An application must also indicate who would be
responsible for assisting the Network Director with the day-to-day
administrative details, program coordination, and with the planning
and evaluation of the program.  The Network Director must exercise
great diligence in preserving the interactions of the participants
and the integration of its components in order to maintain
cohesiveness and synergism.

Inter-network Governance by the Program Steering Committee

A Program Steering Committee will be the main governing body of
multi-network studies and activities.  Membership will consist of two
representatives from each network, one of whom must be the Network
Director, and the two NHLBI Project Scientists.  The Chairperson, who
will be someone other than an NHLBI staff member, will be selected by
the Program Steering Committee. Recommendations regarding all
scientific issues will be decided by majority vote.

As it is responsible for the overall guidance of multi-network
coordination, the Program Steering Committee will: establish and
encourage well focused collaborations among the different networks;
develop uniform protocols, standard methods, and the manner and
extent of data sharing; facilitate the sharing of resources, and;
plan and evaluate changes in research design and strategies as
developments warrant.  The extent of standardization, uniformity of
protocols, and sharing of data, reagents, and specimens will be
determined on the basis of feasibility and greatest promise from the
approved research scope of the networks awarded.  THOSE ASPECTS OF A
NETWORK THAT DO NOT INVOLVE SHARING AND COLLABORATION BETWEEN
NETWORKS MAY BE PURSUED INDEPENDENTLY.

Because of the magnitude and complexity of this program, it is
anticipated that the Program Steering Committee will convene
subcommittees to cover specific cross-cutting areas, such as
diagnosis and subject ascertainment, human subjects protection,
family design and recruitment, quality control, genetic analysis and
mapping strategies, phenotypic measurements, genotyping, longitudinal
follow-up, data collection, data analysis, sharing of study data and
materials, ethics, legal and social issues, intellectual property
rights, publication policies and procedures, and the rights to
authorship.  Although the Program Steering Committee will develop
procedures and assign responsibilities for preparation of
publications resulting from collaboration among networks, this does
not abrogate each network's ability to publish its own findings.
Publication and ancillary study policies should be included in the
protocol and agreed to by all awardees.  Membership of subcommittees
will be determined by the Program Steering Committee and consist of
scientists engaged in the network and others as needed to ensure
appropriate coverage of subject matter and balance.  An NHLBI
scientist (or where necessary, scientists) will serve on
subcommittees as deemed appropriate by the NHLBI Project Scientists.

Program Steering Committee meetings, which will be held in Bethesda,
MD, will take place at approximately one month intervals during the
first six months, at three month intervals during the second six
months, and at intervals of six months throughout the remainder of
the study. Additional communication will be made by telephone
conference calls, approximately monthly, as needed.

Willingness to Collaborate

As described above, representatives of network components and the
NHLBI Project Scientists will collaborate to develop common
protocols, standard procedures, and centralized training for
multi-network efforts.  Hence, prospective network representatives,
such as the PIs of the Field Centers, Genotyping Center, Laboratory
Center, DCC, and the Animal Mapping Center, must agree to serve on
the Internal Network Coordinating Committee, express willingness to
collaborate in multi-network studies, and be willing to serve on the
Program Steering Committee.

Budget and Related Issues

Applications should present five budget periods of 12 months each.
Applicants should provide adequate budget justification and all
applicable direct and indirect costs should be included.  Estimates
of staffing needs, including the PIs, other professional and support
staff must be included.  The suggested minimum level of effort for
Network Directors, PIs (and Co- Investigators, if applicable) is 20
percent each.  Other personnel such as clinic coordinator,
technicians, research assistants and secretary should be carefully
outlined and justified in the application.  Travel costs for Program
Steering Committee meetings, as detailed under the section titled
"Inter-network Governance by the Program Steering Committee," must be
budgeted, along with statements indicating willingness to participate
in these meetings.

These awards will be subject to administrative review annually.
Future year awards may be redistributed based on the final protocols
and standardized procedures, actual recruitment, and overall
performance.

Requests for expensive special equipment may be permitted on a
case-by-case basis following staff consultation.  Such equipment
requires in-depth justification.  Final decisions will depend on the
nature of the justification and the Institute's fiscal situation.

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 PI should be included with the application.

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 Grants 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
the cooperative clinical research agreement (U10), 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 Scientists.

Awardees will have the usual responsibilities of award recipients,
including protocol development, participant recruitment and
follow-up, data collection, quality control, interim data 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 Scientists.

The NHLBI Project Scientists (the Associate Director,
Arteriosclerosis, Hypertension, and Lipid Metabolism Program,
Division of Heart and Vascular Diseases; and the Associate Director,
Epidemiology and Biometry Program, Division of Epidemiology and
Clinical Applications), in addition to the usual stewardship
responsibilities, will have responsibilities in protocol development,
quality control, interim data 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 Scientists will have lead
responsibilities in quality control and catalyzing interim monitoring
of data and may, consistent with publication policy to be adopted by
the Program Steering Committee, have lead responsibilities in the
preparation of some publications.

A Program Steering Committee will be the main governing body of
multi-network studies and activities, and will have primary
responsibility for developing common protocols, facilitating the
conduct and monitoring of studies, and reporting study results.
Membership will consist of two representatives from each network, one
of whom must be the Network Director, and the two NHLBI Project
Scientists.  The Chairperson, who will be someone other than an NHLBI
staff member, will be selected by the Program 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 Scientists.

Collaborative protocols will be developed by the Program Steering
Committee.  These protocols may be reviewed by an external committee
convened by NHLBI.  These protocols will be implemented only with the
concurrence of the awardees and NHLBI.  The protocols will define
rules regarding access to data and publications.

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 breech 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 Program 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 June 17, 1994 a letter
of intent that includes a descriptive title of the proposed research,
the name, address, and telephone number of the Network Director, the
identities of other key personnel and participating institutions, and
the number and title of this RFA.

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 selection of
reviewers.

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) 402-1660

The Network Application

Investigators who wish to establish a collaborative network will
submit concurrent, cross-referenced individual research grant
applications together as a package.  Each network component (e.g.,
Field Center, Laboratory Center, Genotyping Center, Data Coordinating
Center, Animal Mapping Center) will be directed by a Principal
Investigator (PI).  In addition, the application submitted by the
Network Director, who will be responsible for organizing and
maintaining effective integration and interaction, must also include
a clear description of the relationship among the various network
components; describe plans for collaboration, interaction,
communication, and sharing among investigators in the network; and
indicate the mechanisms for handling day-to-day administrative
details, program coordination, planning and evaluation.  A separate
award will be issued to each  successful applicant in a network.

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 and from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892,
telephone (301) 435-0714; and from the NIH Project Scientists 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 that 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 September 16, 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 announcement 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 activities as broadly outlined in 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.

Those applications that are complete and responsive will be evaluated
for scientific and technical merit by an appropriate peer review
group convened by the NHLBI.  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, applications
recommended for further consideration will receive a second level of
review by the National Heart, Lung, and Blood Advisory Council.

A network application must include all requisite functions organized
into appropriate components.  Each network component will receive a
priority score.  In addition, each network will receive an overall
priority score.  Inclusion of weaker components will compromise the
enthusiasm for the overall network and may seriously jeopardize its
establishment.  Under certain, highly special cases, weaker
components that are not critical to the success of a network may be
removed (eg., a poorly integrated Animal Mapping Center or a Field
Center not required for appropriate statistical power).

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 protocols,
but they are expected to address all issues identified in this
Request for Applications.

Major factors to be considered in the evaluation of applications
include:

o  Scientific merit of the hypotheses, methodology, study design,
analytical strategies, statistical tools, and the selection of the
study population.

o  Adequacy of the environment for performance of the proposed
research including access to study participants; laboratory
facilities; instrumentation; data management systems; and
institutional research and administrative support and commitment.

o  Leadership, scientific stature, research experience, and level of
commitment of the Network Program Director and PIs of network
components; competence of the investigators to accomplish the
proposed research goals and their time commitment to the program; and
availability of all areas of expertise necessary to accomplish all
facets of the proposed network.

o  The plans for coordination, cooperation, and sharing of biological
and informational resources, both within a network and across
networks.

o  Adequacy of plans to implement the "Special Requirements" and
"Terms and Conditions of Award" sections, including provisions for
involvement of Institute staff and willingness to participate in
multi-network efforts, as well as any other conditions and
specifications stipulated elsewhere in the RFA.

o  Appropriateness of the budget for the proposed network.

o  Adequacy of the provisions for the protection of human subjects
and the welfare of animal subjects, as applicable.

o  Evidence of inclusion of appropriate numbers of women and
minorities.

AWARD CRITERIA

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

Letter of Intent Receipt Date:     June 17, 1994
Application Receipt Date:          September 16, 1994
Review by NHLBI Advisory Council:  February 9-10, 1995
Anticipated Award Date:            April 1, 1995

INQUIRIES

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

Stephen C. Mockrin, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
Federal Building, Room 4C10
Bethesda, MD  20892
Telephone:  (301) 496-1613
FAX:  (301) 402-2044
EMAIL:  SM60D@NIH.GOV

Millicent Higgins, M.D.
Division of Epidemiology and Clinical Applications
National Heart, Lung, and Blood Institute
Federal Building, Room
Bethesda, MD  20892
Telephone:  (301) 496-2327
FAX:  (301) 402-1624

Direct inquiries regarding review and application procedures 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) 594-7363
FAX:  (301) 402-1660

Direct inquiries regarding fiscal and administrative matters to:

Ms. Jane Davis
Division of Extramural Affairs
National Heart, Lung and Blood Institute
Westwood Building, Room 4A15C
Bethesda, MD  20892
Telephone:  (301) 594-7436
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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