INTERACTION OF GENES AND ENVIRONMENT IN SHAPING RISK FACTORS FOR HEART, LUNG, 
BLOOD, AND SLEEP DISORDERS

Release Date:  October 4, 2001

RFA:  RFA-HL-02-010 (Notice of Limited Competition, see NOT-HL-06-123)

National Heart, Lung, and Blood Institute
 (http://www.nhlbi.nih.gov)

Letter of Intent Receipt Date:  February 20, 2002
Application Receipt Date:       March 22, 2002

PURPOSE

Applications are being sought to identify novel genes which interact with 
specific environmental exposures to modify risk factors for heart, lung, 
blood, and sleep (HLBS) disorders.  The genetic aspects of response to 
environmental change, and related biological mechanisms, will be studied using 
short term, focused interventions in families.  The goal of this Request for 
Applications (RFA) is to identify subgroups based on genotype who are most 
likely to benefit from targeted environmental changes designed to reduce the 
development or progression of HLBS diseases.

HEALTHY PEOPLE 2010								

The Public Health Service (PHS) is committed to achieving the health promotion 
and disease prevention objectives of "Healthy People 2010," a PHS-led national 
activity for setting priority areas.  This Request for Applications (RFA), 
Interaction of Genes and Environment in Shaping Risk Factors for Heart, Lung, 
and Blood Diseases, is related to one or more of the priority areas.  
Potential applicants may obtain a copy of "Healthy People 2010" at 
http://www.health.gov/healthypeople/

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit and non-
profit organizations, public and private, such as universities, colleges, 
hospitals, laboratories, units of State and local governments, and eligible 
agencies of the Federal government.  Racial/ethnic minority individuals, 
women, and persons with disabilities are encouraged to apply as Principal 
Investigators.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) cooperative 
agreement (U01) grant mechanism. Under the cooperative agreement, the NIH 
assists, supports and/or stimulates, and is substantially involved with 
recipients in conducting the study by facilitating performance of the effort 
in a partner role.  Individually funded grants under this RFA are requested to 
collaborate in areas which have broad applicability across all funded studies, 
such as recruitment, informed consent, adherence, data analysis methodology 
and data sharing policies.  Details of responsibilities, relationships, and 
governance of research funded through this cooperative agreement are discussed 
under SPECIAL REQUIREMENTS.  

The total project period for an application submitted in response to this RFA 
may not exceed four years.  This RFA is a one-time solicitation.  Future 
unsolicited competing continuation applications will compete with all 
investigator-initiated applications and be reviewed according to the customary 
peer review procedures.  The anticipated award date is September 30, 2002.

FUNDS AVAILABLE 

The NHLBI intends to commit approximately $9,000,000 in FY 2002 to fund 3 to 5 
new grants in response to this RFA.  Up to $36,000,000 (total cost) over the 
entire project period is available to support this initiative.  Because the 
nature and scope of the research proposed may vary, it is anticipated that the 
size of each award will also vary. Although the financial plans of the NHLBI 
provide support for this program, awards pursuant to this RFA are contingent 
upon the availability of funds and the receipt of a sufficient number of 
meritorious applications. At this time, there is no plan to reissue this RFA.

RESEARCH OBJECTIVES

Background

Complex diseases, such as coronary heart disease, asthma, anemias, sleep 
disordered breathing, and their antecedent risk factors (e.g., dyslipidemia, 
bronchial reactivity, iron binding capacity, and obesity), are by definition 
influenced by multiple genes interacting with each other and with the 
environment.  Deciphering the underlying genetics of such diseases and their 
risk factors can be extremely difficult when these complex interactions are 
not adequately assessed and not understood.  To date the search for new genes 
affecting HLBS disease risk has produced many inconsistent results.  One 
reason is that the influence of environmental factors on measured phenotypes 
can vary by genotype.  Blood pressure response to a low sodium diet, for 
example, has been shown to vary by polymorphisms of renin-angiotensin system 
genes.  In addition, LDL-cholesterol response to the National Cholesterol 
Education Program (NCEP) Step II diet has been shown to differ by variants in 
the ApoA1 gene.  Failure to consider such interactions often results in the 
inability to detect or accurately quantify the underlying genetic contribution 
to phenotypic variability.

Elucidation of the genetic architecture of complex HLBS diseases and their 
risk factors will require meticulous assessment of environmental exposures and 
consideration of their influences on gene expression.  However, even well 
defined environmental exposures, such as smoking, have been difficult to 
accurately measure in observational studies.  It is possible that substantial 
short-term modifications of the environment, such as dramatic changes in 
dietary composition or exposure to bronchoconstricting or dilating agents, may 
be needed to unmask variation in response to environmental factors.  Such 
responses, and their relationships to genotypic variation, may not be 
detectable given the range of environmental variation normally seen in 
observational studies.

Identifying genes that interact significantly with modifiable environmental 
factors will have significant public health and clinical implications.  
Genotypic characterization of individuals who respond favorably to a short-
term intervention may enable targeted interventions to reduce risk factors and 
may help to identify the most effective treatments in clinical practice.  For 
example, the identification of genotypes that predispose individuals to 
thrombosis (such as Factor V Leiden mutations) in physically inactive 
individuals might lead to the recommendation for individuals with that 
genotype to maintain a strict exercise program.  From a public health 
standpoint, individuals with modifiable genetic risk of disease could be 
identified prior to disease development.  Effective, appropriate interventions 
tailored to the unique genotypic characteristics of an individual could then 
be initiated to reduce the likelihood of developing the disease or modify its 
outcome.  Identification of environmental modifiers of gene expression will 
permit direct application of human genome sequence information to improve the 
health of the public in the future.  Advances in this area could significantly 
enhance the effectiveness of clinical care and particularly of risk factor 
modification.

Research Plan

This initiative will support several studies to examine genetic influences on 
response to short term, focused interventions or environmental modifications 
with, prior evidence of efficacy, in families at risk of HLBS diseases.  
Studies of genetic variation are increasingly being used in clinical trials 
and intervention studies to evaluate the impact of polymorphisms in known 
candidate genes on the response to intervention in unrelated individuals.  
However, intervention methodologies have not been widely applied to families. 
The primary advantage of studying families is the ability to localize novel 
genes related to response to environmental change, through genetic linkage 
methodologies, as well as testing candidate genes.  In addition, 
identification of novel genes related to response to environmental change will 
be facilitated by studying them on a more homogeneous genetic and 
environmental background than is typical of clinical or population-based 
studies of individuals.  Such "background" variation is reduced among families 
and in more discrete racial/ethnic groups.  In addition, interventions adopted 
by family units may be more successful than when applied to individuals.  For 
example, interventions involving allergen reduction, changes in diet, 
exercise, smoking cessation, or reduction in chronic sleep deprivation may 
have higher adherence when there is support from other family members who are 
also adopting healthy habits or changing the home environment.  

Examples of proposals responsive to this RFA include, but are not limited to:

A) A proposal designed to localize novel genes contributing to change in lipid 
profile after exposure to NCEP Step II diet.

B) A proposal to localize genes influencing change in blood pressure in 
response to short term mental stress.

C) A proposal to search for genes influencing change in hemostasis in response 
to antithrombotic drugs, such as aspirin.

D) A proposal to localize novel genes contributing to change in lung function 
in response to decreased exposure to allergens and/or viral  triggers of 
asthma.  

E) A proposal to search for genes influencing weight loss and change in sleep 
disordered breathing (SDB) in response to exercise.  

1.  Recruitment and Ascertainment of families

The group of families adopting a given intervention will ideally be 
ascertained from a single site and will all belong to the same racial/ethnic 
group to minimize environmental and genetic heterogeneity.  However, 
recruitment of families may occur at several different geographic sites.  
Applicants proposing recruitment over several geographic sites must 
demonstrate adequate quality control and oversight of recruitment, examination 
and intervention phases of the study.  Furthermore, the applicant may wish to 
subcontract with field centers or make collaborative agreements with field 
centers for recruitment, examination and intervention phases to ensure that 
all activities are encompassed within a single grant application.

If appropriate for the intervention and scientific hypotheses, families 
recruited as part of a pre-existing study may be enrolled in the current 
intervention.  The application must demonstrate the appropriateness of the 
existing families for the protocol and provide assurance that all additional 
recruitment will occur in a consistent manner.

For all proposed study sites, applicants must demonstrate the ability to 
recruit families, implement examination and intervention procedures, and 
provide evidence of ability to maintain high rates of followup throughout the 
intervention.

Families may be ascertained based on an index member whose risk profile is 
appropriate for the short-term intervention.  For example, in a protocol 
designed to raise HDL-C in response to an intensive exercise regimen, the 
index family member would have a low to moderate HDL-C level.  If a random 
ascertainment strategy is adopted, the applicant must justify the 
appropriateness of the sample in terms of variability of response to 
intervention and power to detect gene by environment interactions.

Adequate representation of racial and ethnic minorities will be required for 
the program as a whole.  

2.  Sample Size and Power Calculations

To ensure acceptable statistical power, the recruitment design should include 
an adequate number of families of sufficient size to detect gene - environment 
interactions.  Families may be randomized into intervention and control 
groups.  In addition, the intervention chosen must be of proven efficacy, and 
of sufficient magnitude and duration to produce a response in the quantitative 
risk factor of interest.  Applicants must justify family size, ascertainment 
strategies, intervention protocol and their choice with respect to 
randomization.  For example, if moderate to large nuclear families (family 
size of 6 or more) are ascertained, the total sample size for interventions in 
which a control group is required is estimated to be approximately 2,500 
individuals (420 families randomized equally to intervention and control 
groups). 

3.  Clinical Examinations and Intervention

Baseline measurements of multiple risk factors, medical and sleep history, 
environment, and lifestyle, as appropriate, will be made prior to 
intervention.  Applicants should carefully assess risk factors and 
environmental exposures which may impact the outcome of the intervention.  
Although all such confounders can not be completely assessed, the applicant 
should demonstrate that the baseline risk profile and environmental exposures 
are measured to the best of their ability and are considered in the analysis 
of the resulting data.

Interventions will be of short duration, and some could be given as a single 
challenge, the exact length will depend on the type of intervention.  Multiple 
short-term interventions might be undertaken sequentially in identified 
families.  The type of intervention should be one that is known to produce 
measurable outcomes over a short period of time and that is feasible to 
implement in families.  Examples include exercise training and/or calorie 
restriction for changes in body composition or sleep disordered breathing, 
decreased salt intake for changes in blood pressure, or aspirin for changes in 
coagulation parameters.  Interventions could also take the form of an 
environmental perturbation or challenge, such as a high-fat meal, mental 
stress, cold pressor test, or exposure to a bronchoconstricting or dilating 
agent.  Outcome variables should be quantitative risk factors for HLBS 
diseases, such as serum LDL-C or blood pressure, or disease manifestations 
such as degree of bronchodilation.   Families will be reassessed for the same 
phenotypes after the intervention as in the baseline exam.

Applicants must demonstrate that the proposed intervention has a proven impact 
on the phenotypes of interest and is feasible to implement in families, 
including those members not affected by the disorder.  Studies implementing 
interventions that impact multiple quantitative outcomes are encouraged.  
Applicants who choose to implement multiple interventions in the same families 
must demonstrate that the initial interventions will not impact the outcome of 
subsequent interventions.

4.  Data Analyses

Novel approaches to the identification of genes that influence response to 
specific interventions is encouraged. Data analyses can include, but are not 
restricted to gene localization using linkage based analyses, combined linkage 
and association analysis, polymorphism testing in candidate genes by family 
based association analyses and haplotype-based analyses.  Applicants are 
encouraged to make full use of the longitudinal nature of the data and the 
family structure in their analytic plan.  A program-wide committee will be 
formed to discuss and promote new analytic methods for the analysis of gene-
environment interaction.

Applications are limited to four years and each should consist of a single 
application demonstrating the capacity for recruiting families, performing 
clinical examinations, delivering the intervention(s), assessing the 
appropriate response variables, conducting the laboratory work, managing data 
and conducting the analysis.  Subcontracts or collaborative agreements may be 
used for specialized services or recruitment off site.  Each application must 
specify the research questions to be addressed, the interventions to be 
delivered, power calculations and the proposed genetic and statistical 
analyses to be conducted.  The cost of recruiting families may be offset by 
utilizing existing cohort studies.  This initiative proposes to fund 3-5 such 
applications, aiming for programmatic balance across cardiovascular and/or 
sleep disorders, blood disease, and lung disease.

SPECIAL REQUIREMENTS

To be responsive investigators must propose to localize and/or identify genes 
contributing to response to specific environmental perturbations using short 
term interventions in families.  Applicants must justify the proposed study 
design and sample size and provide power calculations.

Program Organization

1.  Administrative Coordinating Center

The Administrative Coordinating Center functions will be performed by one of 
the study centers.  The Administrative Coordinating Center will coordinate 
activities across the three to five studies funded in this RFA and assist in 
the organization and monitoring of committees and issues that have broad 
applicability across all funded studies, such as recruitment, informed 
consent, analysis methodology and data sharing.  The Administrative 
Coordinating Center will also be responsible for monitoring membership of 
Program wide committees, tracking and scheduling of committee meetings and 
conference calls, and planning DSMB meetings. 

Applicants who are interested in fulfilling the role of the Administrative 
Coordinating Center for this RFA should include a section in their application 
describing their anticipated activities as the Administrative Coordinating 
Center and a separate budget for these activities in their applications.  
Applicants should include costs of monthly Steering Committee conference calls 
and travel funds for 8-10 DSMB members to attend meetings in Bethesda twice a 
year.  Travel funds should also be included for the Steering Committee 
Chairman to attend two annual meetings in Bethesda.

2.  Internal Governance of Each Study

Each study will establish an internal organization by which they govern and 
oversee various components of the study.  This organization will oversee and 
approve all protocols and procedures involved in the performance of the 
research and publication of findings.  Applicants should include a description 
of the organization, as well as a budget to cover monthly meetings and/or 
conference calls.

3.  Steering Committee

The Steering Committee, comprised of each PI, a Co-PI from each study, and 
NHLBI Scientific staff, will identify issues that have broad applicability 
across the program.  Initial recommendations regarding program level 
organization, consistency across studies in areas which would benefit from a 
coordinated research effort will be made by the Steering Committee.  Such 
recommendations might involve areas such as standardized aspects of informed 
consent, data analysis techniques, data sharing and publications policy, 
recruitment, protocol development and adherence.  Applicants should budget for 
meetings to be held twice a year in Bethesda.

4.  Data Safety and Monitoring Board

An independent program - wide Data Safety and Monitoring Board will be 
appointed by the Director of NHLBI.  Descriptions of the board membership, 
scheduling, responsibilities and authority are listed under "TERMS AND 
CONDITIONS OF AWARD".  Each study should budget for the PI and one Co-PI to 
travel to Bethesda twice a year to attend DSMB meetings.

Data Sharing

Studies within the Program are expected to utilize a collaborative approach to 
data analysis and interpretation.  It is expected that a program-wide Analysis 
Committee, consisting of at least one member from each study and at least one 
NHLBI Scientist, will explore methods for analyzing family based intervention 
data.  The activities of the Analysis Committee will at the minimum involve 
identification of the best existing statistical methods for analysis and if 
needed, development of new statistical methodologies.  If appropriate, the 
activities of the Analysis Committee may involve joint analysis and 
interpretation of unpublished results.  Applicants should budget for an annual 
meeting in Bethesda.

Each study must provide a policy for sharing data collected with funds from 
this RFA with the scientific community.  Applicants should outline how 
collaboration with the scientific community will be facilitated, for example 
review policies for ancillary study or collaborative proposals that may arise 
from the scientific community, description of publicly available information 
and methods of dissemination.  The adequacy of the applicant=s plan to share 
data with the outside community will be evaluated in the review of the 
application.  

Applicants should plan to provide a limited access data set to the NHLBI 
within three years following the close of this grant period (end of the fiscal 
year 2009). Limited access data refers to trial or study data, with certain 
deletions and recoding (to ensure participants= privacy and confidentiality), 
that are released to requesting institutions and investigators for specific 
purposes and with certain restrictions and conditions.  Limited access data 
will be made available to the public in accordance with the NHLBI Policy for 
Distribution of Data (http://www.nhlbi.nih.gov/resources/deca/policy.htm).  
In brief, the limited access data sets are stripped of all obvious and 
inadvertent personal identifiers and the data may be grouped or modified 
slightly to prevent identification of individuals in the study.  The limited 
access data would include baseline measures and outcome data, pedigrees and 
genotypes.  Furthermore, stored samples should be made available upon request. 
 Individuals requesting data must adhere to the requirements of a Distribution 
Agreement and submit an approval from their Institutional
Review Board (IRB). 

TERMS AND CONDITIONS OF AWARD

The cooperative agreement is an award instrument establishing an assistance 
relationship between NHLBI and a recipient, in which substantial NHLBI 
scientific and/or programmatic involvement with the recipient is anticipated 
during the performance of the activity.  The NHLBI purpose is to support or 
stimulate the activity in a "partner" role, but avoiding a dominant role, 
direction or prime responsibility.  The terms and conditions outlined below 
elaborate on these actions and responsibilities, and the awardee agrees to 
these collaborative actions with the NHLBI Project Scientist toward achieving 
the project objectives.  It is expected that these terms and conditions will 
enhance the relationship between the NHLBI staff and the principal 
investigator(s), and will facilitate successful conduct and completion of the 
study.  These agreements will be in addition to, and not in lieu of, the 
relevant NIH procedures for grants administration.  The terms will be as 
follows:

1.  The awardee(s) will have lead responsibilities in all aspects of the 
study, including study design, conduct of the study, quality control, data 
analysis and interpretation, preparation of publications, and collaboration 
with other investigators, unless otherwise provided for in these terms or by 
action of the Steering Committee.

2.  The NHLBI Project Scientist will serve on the Steering Committee, NHLBI 
scientist (s) may serve on other study committees, when appropriate.  The 
NHLBI Project Scientist (and other cited NHLBI scientists) may work with 
awardees on issues before the Steering Committee, and as appropriate, other 
committees, for example: recruitment, intervention, quality control, data 
analysis and publication, and preparation and development of solutions to 
major problems such as insufficient participant enrollment.

3.  Awardee(s) agree to governance of the program through a Steering 
Committee.  Steering Committee voting membership shall consist of the 
principal investigators (i.e., the cooperative agreement awardees)  and the 
NHLBI Project Scientist.  Monthly meetings of the Steering Committee will 
ordinarily be held by telephone conference call.  In person meetings should be 
held biannually in Bethesda.

4.  A Program - wide Data Safety and Monitoring Board (DSMB), consisting of 8-
10 members, will be appointed by the Director, NHLBI to provide overall 
monitoring of interim data and safety issues for all studies awarded through 
this RFA.  Biannual meetings of the Data Safety and Monitoring Board will 
ordinarily be held in Bethesda.  An NHLBI Scientist will serve as Executive 
Secretary to the DSMB.

5.  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 collaborative protocol 
and governance policies will call for procedures for data analysis, reporting 
and publication, and procedures to protect and ensure the privacy of 
individual medical records and genetic data.  The NHLBI Project Scientist, on 
behalf of the NHLBI, will have the same access, privileges and 
responsibilities regarding the data as the other members of the Steering 
Committee.

6.  Support or other involvement of industry or other third party in the study 
C- e.g., participation by the third party, involvement of study resources or 
citing the name of the study or NHLBI support, or special access to study 
results, data or resources B- may be advantageous or appropriate.  However, 
except for licensing of patents or copyrights, support or involvement of a 
third party will occur only following notification of and concurrence by 
NHLBI.

7.  Awardees are encouraged to publish and to publicly disseminate results, 
data and other products of the study, concordant with the study protocol and 
governance, and the approved plan for making data and materials available to 
the scientific community and NHLBI.  However, during or within three years 
beyond the end date of the project period of NHLBI support, unpublished data, 
unpublished results, data sets not previously released, or other study 
materials or products are to be made available to any third party only with 
the approval of the Steering Committee and in accordance with paragraph 6.

8.  The NHLBI reserves the right to terminate or curtail the study 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 protocol, 
(c) substantive changes in the protocol with which NHLBI can not concur, (d) 
human subject ethical issues that may dictate a premature termination.

9.  Any disagreement that may arise in scientific/programmatic matters (within 
the scope of the award), between recipients and the NHLBI may be brought to 
arbitration.  An arbitration panel will be composed of three membersBone 
selected by the Steering Committee (with the NHLBI member not voting), or by 
the awardee in the event of an individual disagreement, a second member 
selected by NHLBI, and a third 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, 
or the rights of NHLBI under applicable statues, regulations and terms of the 
award.

10.  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.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and 
their sub-populations must be included in all NIH-supported biomedical and 
behavioral research projects involving human subjects, unless a clear and 
compelling rationale and justification are provided indicating that inclusion 
is inappropriate with respect to the health of the subjects or the purpose of 
 the research.  This policy results from the NIH Revitalization Act of 1993 
(Section 492B of Public Law 103-43). 

All investigators proposing research involving human subjects should read the 
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research," published in the NIH Guide for Grants and Contracts on 
August 2, 2000 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), 
a complete copy of the updated Guidelines are available at  
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm:  The 
revisions relate to NIH defined Phase III clinical trials and require: a) all 
applications or proposals and/or protocols to provide a description of plans 
to conduct analyses, as appropriate, to address differences by sex/gender 
and/or racial/ethnic groups, including subgroups if applicable, and b) all 
investigators to report accrual, and to conduct and report analyses, as 
appropriate, by sex/gender and/or racial/ethnic group differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21) 
must be included in all human subjects research, conducted or supported by the 
NIH, unless there are scientific and ethical reasons not to include them.  
This policy applies to all initial (Type 1) applications submitted for receipt 
dates after October 1, 1998.

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines" on the Inclusion of Children as Participants in 
Research Involving Human Subjects that was published in the NIH Guide for 
Grants and Contracts, March 6, 1998, and is available at the following URL 
address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html

Investigators also may obtain copies of these policies from the program staff 
listed under INQUIRIES.  Program staff may also provide additional relevant 
information concerning the policy.

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS

NIH policy requires education on the protection of human subject participants 
for all investigators submitting NIH proposals for research involving human 
subjects.  This policy announcement is found in the NIH Guide for Grants and 
Contracts Announcement dated June 5, 2000, at the following website: 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

URLS IN NIH GRANT APPLICATIONS OR APPENDICES

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

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT

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

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

Prospective applicants are asked to submit a letter of intent that includes a 
descriptive title of the proposed research, the name, address, and telephone 
number of the Principal Investigator, the identities of other key personnel 
and participating institutions, and the number and title of the RFA in 
response to which the application may be submitted.  Although a letter of 
intent is not required, is not binding, and does not enter into the review of 
a subsequent application, the information that it contains allows IC staff to 
estimate the potential review workload and plan the review.

The letter of intent is to be sent to Dr. Deborah Beebe listed under Inquiries 
no later than February 20, 2002.

APPLICATION PROCEDURES

The PHS 398 research grant application instructions and forms (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html are to be used in 
applying for these grants. This version of the PHS 398 is available in an 
interactive, searchable PDF format.  Beginning January 10, 2002, the NIH will 
return applications that are not submitted on the 5/2001 version.  For further 
assistance contact GrantsInfo, Telephone 301/435-0714, Email: 
GrantsInfo@nih.gov.

The RFA label available in the PHS 398 (rev. 5/2001) application form must be 
affixed to the bottom of the face page of the application.  Type the RFA 
number on the label.  Failure to use this label could result in delayed 
processing of the application such that it may not reach the review committee 
in time for review.  In addition, the RFA title and number must be typed on 
line 2 of the face page of the application form and the YES box must be 
marked. The RFA label is also available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.

Submit a signed, typewritten original of the application, including the 
Checklist, and three signed, photocopies, in one package to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710

BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

At the time of submission, two additional copies of the application as well as 
all five collated sets of Appendix material must be sent to Dr. Deborah Beebe 
at the address listed under inquiries.

Applications must be received by the application receipt date listed in the 
heading of this RFA.  If an application is received after that date, it will 
be returned to the applicant without review.
 
The Center for Scientific Review (CSR) will not accept any application in 
response to this RFA that is essentially the same as one currently pending 
initial review, unless the applicant withdraws the pending application.  The 
CSR will not accept any application that is essentially the same as one 
already reviewed. This does not preclude the submission of substantial 
revisions of applications already reviewed, but such applications must include 
an Introduction addressing the previous critique.

Principal investigators should not send supplementary material without first 
contacting the Scientific Review Administrator (SRA).  The SRA will be 
identified in the letter sent to you indicating that your application has been 
received.  If you have not yet received such a letter within three weeks after 
submitting the application, contact Dr. Deborah Beebe at the address listed 
under inquiries.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NHLBI.  Incomplete and/or non-responsive applications 
will be returned to the applicant without further consideration.

Applications that are complete and responsive to the RFA will be evaluated for 
scientific and technical merit by an appropriate peer review group convened by 
the NHLBI in accordance with the review criteria stated below.  As part of the 
initial merit review, all applications will receive a written critique and 
undergo a process in which only those applications deemed to have the highest 
scientific merit, generally the top half of the applications under review, 
will be discussed, assigned a priority score, and receive a second level 
review by the National Heart, Lung, and Blood Advisory Council.

Review Criteria

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments reviewers will be asked to discuss the following aspects 
of the application in order to judge the likelihood that the proposed research 
will have a substantial impact on the pursuit of these goals.  Each of these 
criteria will be addressed and considered in assigning the overall score, 
weighting them as appropriate for each application.  Note that the application 
does not need to be strong in all categories to be judged likely to have major 
scientific impact and thus deserve a high priority score.  For example, an 
investigator may propose to carry out important work that by its nature is not 
innovative but is essential to move a field forward.

(1) Significance:  Does this study address an important problem? If the aims 
of the application are achieved, how will scientific knowledge be advanced?  
What will be the effect of these studies on the concepts or methods that drive 
this field?

(2) Approach:  Are the conceptual framework, design, methods, and analyses 
adequately developed, well-integrated, and appropriate to the aims of the 
project?  Does the applicant acknowledge potential problem areas and consider 
alternative tactics?

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

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

(5) Environment:  Does the scientific environment in which the work will be 
done contribute to the probability of success?  Do the proposed experiments 
take advantage of unique features of the scientific environment or employ 
useful collaborative arrangements?  Is there evidence of institutional 
support?

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

o  The adequacy of plans to include both genders, minorities and their 
subgroups, and children as appropriate for the scientific goals of the 
research.  Plans for the recruitment and retention of subjects will also be 
evaluated.

o  The reasonableness of the proposed budget and duration in relation to the 
proposed research.

o  The adequacy of the proposed protection for humans, animals or the 
environment, to the extent they may be adversely affected by the project  
proposed in the application.

o  The adequacy of the proposed plan to share data.

Schedule

Letter of Intent Receipt Date:    February 20, 2002
Application Receipt Date:         March 22, 2002
Peer Review Date:                 June 2002
Council Review:                   September 2002
Earliest Anticipated Start Date:  September 30, 2002

AWARD CRITERIA

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

o  scientific merit (as determined by peer review)
o  availability of funds
o  programmatic priorities.

INQUIRIES

Inquiries concerning this RFA are encouraged.  The opportunity to clarify any 
issues or answer questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Cashell E. Jaquish, Ph.D.
Division of Epidemiology and Clinical Applications
National Heart, Lung and Blood Institute
Rockledge II, Room 8170
MSC 7934
6701 Rockledge Drive
Bethesda, MD  20892-7934
Telephone:  (301) 435-0447
FAX:  (301) 480-1455
Email: jaquishc@nhlbi.nih.gov

Mariana Gerschenson, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
Rockledge II, Room 9180
MSC 7940
6701 Rockledge Drive
Bethesda, MD  20892-7940
Phone: 301-435-0515
FAX: 301-480-1336
Email: gerschem@nhlbi.nih.gov

Charles Peterson, M.D.
Division of Blood Diseases Research
National Heart, Lung, and Blood Institute
Rockledge II, Room 10158
MSC 7950
6701 Rockledge Drive
Bethesda, MD  20892-7950
Phone: 301-435-0050
FAX: 301-480-0868
Email: petersoc@nhlbi.nih.gov

Susan Banks-Schlegel, Ph.D.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
Rockledge II, Room 10018
MSC 7952
6701 Rockledge Drive
Bethesda, MD  20892-7952
Phone: 301-435-0202
FAX: 301-480-3557
Email: schleges@nhlbi.nih.gov

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

Direct inquiries regarding review issues and send letters of intent to:

Deborah Beebe, Ph.D.
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7178, MSC 7924
Bethesda, MD  20892-7924
Telephone: (301) 435-0270
FAX: (301) 480-3541
Email: beebed@nhlbi.nih.gov

Direct inquiries regarding fiscal matters to:

Leslie Boggs
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7142,MSC 7924
Bethesda, MD  20892-7924
Telephone: (301) 435-0177
FAX:  (301) 480-3310
Email: boggsl@nhlbi.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No. 
93.839.  Awards are made under authorization of Sections 301 and 405 of the 
Public Health Service Act as amended (42 USC 241 and 284) and administered 
under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 
74 and 92.  This program is not subject to the intergovernmental review 
requirements of Executive Order 12372 or Health Systems Agency review.

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and promote the non-use of all tobacco products.  In addition, 
Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain 
facilities (or in some cases, any portion of a facility) in which regular or 
routine education, library, day care, health care, or early childhood 
development services are provided to children.  This is consistent with the 
PHS mission to protect and advance the physical and mental health of the 
American people.



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Bethesda, Maryland 20892
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