THE ROLE OF GENE-ENVIRONMENTAL INTERACTIONS UNDERLYING THE HEALTH DISPARITY 
OF PREMATURE BIRTH

RELEASE DATE:  May 1, 2002

PA NUMBER: PA-02-102

EXPIRATION DATE:  January 1, 2005, unless reissued.
 
National Institute of Child Health and Human Development (NICHD) 
 (http://www.nichd.nih.gov)
National Institute of Environmental Health Sciences (NIEHS)
 (http://www.niehs.nih.gov)
National Institute of Nursing Research (NINR)
 (http://www.ninr.nih.gov)

THIS PA CONTAINS THE FOLLOWING INFORMATION

o Purpose of the PA
o Research Objectives
o Mechanism of Support 
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements 
o Where to Send Inquiries
o Submitting an Application
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS PA

The National Institute of Child Health and Human Development (NICHD), the 
National Institute of Environmental Health Sciences (NIEHS) and the National 
Institute of Nursing Research (NINR) are seeking research grant applications 
on the role of gene-environmental interactions underlying the health 
disparity of premature birth in the U.S.  This solicitation specifically 
addresses the need to better understand how adverse societal, behavioral, and 
environmental conditions alter gene expression and interact with diverse 
genetic backgrounds to increase a woman's susceptibility for premature birth 
in high-risk racial and ethnic groups.  The solicitation encourages 
multidisciplinary approaches to clarify the potential role of genetics in the 
increased risk of premature birth in these disadvantaged populations.

RESEARCH OBJECTIVES

Background

Significant differences exist in health outcomes among different groups 
within the U.S. population.  These differences in health outcomes, or health 
disparities, are particularly prominent when comparing the morbidity and 
mortality between and among various racial and ethnic populations.  One of 
these health disparities is the incidence of premature birth, which is 
defined as birth prior to 37 weeks of gestation.  In the U.S., approximately 
10 percent of all births are premature.  This accounts for approximately 
400,000 infants born annually.  Most of the infant mortality and morbidity of 
premature birth is associated with the one to two percent of infants born 
very premature (birth at less than 32 weeks of gestation).  Excluding 
congenital malformations, premature birth accounts for approximately 70 
percent of all neonatal deaths and results in nearly 50 percent of long-term 
neurological problems.  The incidence of premature birth, however, is not 
equally distributed among races and ethnic groups.  For example, African-
Americans have the highest rate of premature birth, followed by Mexican-
Americans, Asians, and Caucasians.  Strikingly, African-Americans are 1.8 
times more likely to deliver premature infants and 2.3 times more likely to 
deliver very premature infants than Caucasians.  Consequently, premature 
birth is the leading cause of neonatal mortality and morbidity in African-
Americans, surpassing congenital malformations.

The majority of the health disparity of premature birth is commonly 
associated with racial and ethnic groups living under the burden of adverse 
societal, behavioral, and environmental conditions.  These adverse factors 
include low social and economic status, racism, stress, sexually transmitted 
disease, tobacco/alcohol/drug use, and exposure to environmental toxins. 
Epidemiological studies indicate that over half of this health disparity can 
be attributed to these adverse conditions.  However, it is unclear how these 
conditions alter a woman's biology to increase the risk of premature birth.  
Furthermore, not all women who live under the same adverse conditions deliver 
prematurely.  Consequently, a genetic susceptibility may, in part, underlie 
the increased risk of premature birth in these high-risk populations.

In the general population, there is suggestive evidence that genetics may 
contribute to premature birth.  There is a familial tendency for premature 
birth, and the best predictor for a premature delivery is a prior premature 
delivery.  It is unclear, however, if genetics play a major role in premature 
birth in these cases.  It is argued that the familial tendency may be due to 
family members sharing similar living conditions.  Similarly, it is posited 
that the increased tendency for recurring premature delivery may be due to 
exposure to the same environmental conditions that precipitated the first 
premature birth.

The role of genetics in the health disparities of premature birth is also 
controversial.  For example, 50 percent of the health disparity of premature 
birth in African-American women can be accounted for by correcting for 
adverse risk factors such as income, social status, psychological 
characteristics or medical diagnoses; nonetheless, it still remains higher 
than that of Caucasian women.  The reason for this remaining health disparity 
is unclear, but a genetic component is speculated among other contributing 
factors, such as an increased rate of uterine infection.  Although it is 
known that particular genetic traits that lead to disease may be more 
frequent in distinct population groups, the generalization of these findings 
to whole races or ethnic groups is suspect because of the lack of 
consideration given to the inherent genomic diversity contained within these 
populations.  Furthermore, particular genetic traits, which increase 
susceptibility to disease, may be commonly shared between races and ethnic 
groups, but are only phenotypically manifested under certain environmental 
conditions generally associated with particular racial or ethnic populations.  
Therefore, the role of genetics in the health disparity of premature birth 
requires clarification. 

The major objective of this PA is to determine the role of gene-environmental 
interactions and genetic diversity in the health disparity of premature 
birth.  This PA specifically addresses the need to better understand how 
adverse societal, behavioral, and environmental conditions alter gene 
expression and interact with diverse genetic backgrounds to increase a 
woman's susceptibility for premature birth in high-risk racial and ethnic 
groups in the U.S.  Furthermore, the PA addresses the need for the 
identification and functional characterization of genetic markers that 
increase the risk of premature birth among these high-risk populations.  
Multidisciplinary applications linking biomedical scientists with social and 
behavioral scientists are highly encouraged.  This PA is designed as a step 
in reducing one of the major disparities in health outcomes, one of the NIH 
Areas of Emphasis and incorporated in the FY 2001-2006 Department of Health 
and Human Services Strategic Plan, which is available at: 
http://aspe.hhs.gov/hhsplan/. 

Research Scope

To address these research needs, this PA seeks research projects focused on 
one or more of the following goals:

o  Determine changes in gene or protein expression under adverse societal, 
behavioral or environmental conditions to identify candidate genes, or their 
corresponding proteins, that may be involved in increasing a woman's 
susceptibility for premature delivery in high-risk racial and ethnic 
populations in the U.S.  Examples include, but are not limited to, studies 
utilizing gene or protein expression profiling by high-throughput platforms, 
such as DNA arrays, protein arrays, and protein capture/SELDI-TOF mass 
spectrometry.
 
o  Determine the functional relevance of an identified gene or protein for 
increasing a woman's susceptibility for premature delivery under adverse 
societal, behavioral or environmental conditions in high-risk racial and 
ethnic populations in the U.S.  Examples include, but are not limited to, 
studies elucidating the function or mechanism of action of an identified gene 
or protein in precipitating premature delivery.

o  Determine genomic differences that serve as potential candidate markers 
for increasing a woman's susceptibility for premature delivery under adverse 
societal, behavioral or environmental conditions in high-risk racial and 
ethnic populations in the U.S.  Examples include, but are not limited to, 
linkage studies using high-throughput genotyping platforms to uncover genomic 
differences, such as sequence repeats and multiple or single nucleotide 
polymorphisms.

o  Determine the functional relevance of candidate genomic markers associated 
with an increased risk for premature birth in high-risk racial and ethnic 
populations in the U.S.  Examples include, but are not limited to, studies 
that determine the functional consequence of these markers as it relates to 
gene expression, function, or regulation.

Special Considerations

Applications identifying candidate genes and polymorphisms, as well as 
candidate proteins, associated with an increased susceptibility for premature 
delivery in the general population are acceptable, but should also contain a 
significant component(s) relating the research to the health disparity of 
premature birth in the U.S.  In addition, relevant animal studies will not be 
excluded, but the proposed research should also include a translational 
component using human subjects that directly links the animal research to the 
health disparity of premature birth in the U.S.  

Applicants are encouraged to consider the complexity of issues surrounding 
the meaning and assessment of race and ethnicity, since an individual's 
identification with a particular racial or ethnic group may involve not only 
an individual's genetic background, but also an individual's cultural and 
geographical identity.  As appropriate for their particular proposals, 
applicants should consider the following:  the degree of genomic 
heterogeneity within racial and ethnic populations and that genetic 
differences may not apply broadly to a specific race or ethnic group; and the 
new Office of Management and Budget (OMB) directives on classifying race and 
ethnicity.  NIH policy on reporting race and ethnicity data based on OMB 
directives was published in the NIH Guide for Grants and Contracts on August 
8, 2001, and is available at: 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-053.html. 

Since the NIEHS expanded its research agenda through the Environmental Genome 
Project, the NIEHS is particularly interested in applications that examine 
the complex interplay of genes and the environment.  The understanding of the 
critical role of genetic susceptibility and sensitivity to environmental 
exposures will lead to more effective disease prevention and improved public 
health.  Further information on the Environmental Genome Project can be found 
at http://www.niehs.nih.gov/envgenom/home.htm.

MECHANISM OF SUPPORT 

This PA will use the NIH research project grant (R01) award mechanism.  As an 
applicant, you will be solely responsible for planning, directing, and 
executing the proposed project. 

This PA uses just-in-time concepts.  It also uses the modular as well as the 
non-modular budgeting formats (see 
http://grants.nih.gov/grants/funding/modular/modular.htm).  Specifically, if 
you are submitting an application with direct costs in each year of $250,000 
or less, use the modular format.  Otherwise follow the instructions for non-
modular research grant applications.

ELIGIBLE INSTITUTIONS 

You may submit an application if your institution has any of the following 
characteristics: 

o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, hospitals, 
and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS

Any individual with the skills, knowledge, and resources necessary to carry 
out the proposed research is invited to work with their institution to 
develop an application for support.  Individuals from underrepresented racial 
and ethnic groups as well as individuals with disabilities are always 
encouraged to apply for NIH programs.

WHERE TO SEND INQUIRIES

We encourage your inquiries concerning this PA and welcome the opportunity 
answer questions from potential applicants.  Inquiries may fall into two 
areas:  scientific/research and financial or grants management issues:

o Direct your questions about scientific/research issues to:

John V. Ilekis, Ph.D.
Pregnancy and Perinatology Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 4B03, MSC 7510
Bethesda, MD 20892-7510
Telephone:  (301) 435-6895
FAX:  (301) 496-3790
Email:  ilekisj@mail.nih.gov

Kimberly Gray Kamins, Ph.D.
Chemical Exposures and Molecular Biology Branch
National Institute of Environmental Health Sciences
P.O. Box 12233
111 T.W. Alexander Drive, MD EC-21
Research Triangle Park, NC 27709
Telephone:  (919) 541-0293
FAX:  (919) 316-4606
Email:  gray6@niehs.nih.gov

Yvonne Bryan, Ph.D., R.N.
Division of Extramural Activities
National Institute of Nursing Research
45 Center Drive, Room 3AN-12, MSC 6300
Bethesda, MD 20892-6300
Telephone:  (301) 594-6908
FAX:  (301) 480-8260
Email:  yvonne_bryan@nih.gov

o Direct your questions about financial or grants management matters to:

Christopher Myers
Grants Management Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8A17, MSC 7510
Bethesda, MD 20892-7510
Telephone:  (301) 435-6996
FAX:  (301) 402-0915
Email:  cm743g@nih.gov 

Dwight Dolby
Grants Management Branch
National Institute of Environmental Health Sciences
P.O. Box 12233
111 T.W. Alexander Drive, MD EC-22
Research Triangle Park, NC 27709
Telephone:  (919) 541-7824
FAX:  (919) 541-2860
Email:  dolby@niehs.nih.gov

Cindy McDermott
Chief, Office of Grants and Contracts Management
National Institute of Nursing Research
45 Center Drive, Room 3AN-12, MSC 6300
Bethesda, MD 20892-6300
Telephone:  (301) 594-6869
FAX:  (301) 480-8260
Email:  cindy_mcdermott@nih.gov 

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  The PHS 398 is available at 
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive 
format.  For further assistance contact GrantsInfo, Telephone (301) 435-0714, 
Email: GrantsInfo@nih.gov.

APPLICATION RECEIPT DATES:  Applications submitted in response to this 
program announcement will be accepted at the standard application deadlines, 
which are available at http://grants.nih.gov/grants/dates.htm.  Application 
deadlines are also indicated in the PHS 398 application kit.

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS:  Applications 
requesting up to $250,000 per year in direct costs must be submitted in a 
modular grant format.  The modular grant format simplifies the preparation of 
the budget in these applications by limiting the level of budgetary detail.  
Applicants request direct costs in $25,000 modules.  Section C of the 
research grant application instructions for the PHS 398 (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step 
guidance for preparing modular grants.  Additional information on modular 
grants is available at 
http://grants.nih.gov/grants/funding/modular/modular.htm.

SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR: 
Applications requesting $500,000 or more in direct costs for any year must 
include a cover letter identifying the NIH staff member within one of NIH 
institutes or centers who has agreed to accept assignment of the application.   

Applicants requesting more than $500,000 must carry out the following steps:

1) Contact the IC program staff at least six weeks before submitting the 
application, i.e., as you are developing plans for the study; 

2) Obtain agreement from the IC staff that the IC will accept your 
application for consideration for award; and,
  
3) Identify, in a cover letter sent with the application, the staff member 
and IC who agreed to accept assignment of the application.  

This policy applies to all investigator-initiated new (type 1), competing 
continuation (type 2), competing supplement, or any amended or revised 
version of these grant application types.  Additional information on this 
policy is available in the NIH Guide for Grants and Contracts, October 19, 
2001, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. 

SENDING AN APPLICATION TO THE NIH:  Submit a signed, typewritten original of 
the application, including the checklist, and five 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)

APPLICATION PROCESSING:  Applications must be received by or mailed on or 
before the receipt dates described at 
http://grants.nih.gov/grants/funding/submissionschedule.htm.  The CSR will 
not accept any application in response to this PA 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 a substantial revision of an application already reviewed, but 
such application must include an Introduction addressing the previous 
critique.

PEER REVIEW PROCESS

Applications submitted for this PA will be assigned on the basis of 
established PHS referral guidelines.  An appropriate scientific review group 
convened in accordance with the standard NIH peer review procedures 
(http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific 
and technical merit.  

As part of the initial merit review, all applications will:

o Receive a written critique
o Undergo a selection process in which only those applications deemed to have 
the highest scientific merit, generally the top half of applications under 
review, will be discussed and assigned a priority score
o Receive a second level review by the appropriate national advisory council 
or board

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 your application in order to judge the likelihood that the 
proposed research will have a substantial impact on the pursuit of these 
goals: 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
  
The scientific review group will address and consider each of these criteria 
in assigning your application's overall score, weighting them as appropriate 
for each application.  Your 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, you 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 your study address an important problem?  If the aims 
of your application are achieved, how do they advance scientific knowledge?  
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?  Do you acknowledge potential problem areas and consider alternative 
tactics?

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

(4) INVESTIGATOR: Are you appropriately trained and well suited to carry out 
this work?  Is the work proposed appropriate to your experience level as the 
Principal Investigator and to that of other researchers (if any)?

(5) ENVIRONMENT:  Does the scientific environment in which your 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?

ADDITIONAL REVIEW CRITERIA:  In addition to the above criteria, your 
application will also be reviewed with respect to the following:

PROTECTIONS:  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.

INCLUSION:  The adequacy of plans to include subjects from both genders, all 
racial and ethnic groups (and subgroups), and children as appropriate for the 
scientific goals of the research.  Plans for the recruitment and retention of 
subjects will also be evaluated.  (See Inclusion Criteria included in the 
section on Federal Citations, below.)

BUDGET:  The reasonableness of the proposed budget and the requested period 
of support in relation to the proposed research.

AWARD CRITERIA

Applications submitted in response to a PA will compete for available funds 
with all other recommended applications.  The following will be considered in 
making funding decisions:  

o Scientific merit of the proposed project as determined by peer review
o Availability of funds 
o Relevance to program priorities

REQUIRED FEDERAL CITATIONS 

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH:  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 clinical research projects unless a 
clear and compelling justification is 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 clinical research should read the AMENDMENT "NIH 
Guidelines for Inclusion of Women and Minorities as Subjects in Clinical 
Research - Amended, October, 2001," published in the NIH Guide for Grants and 
Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-
files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is 
available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. 
The amended policy incorporates:  the use of an NIH definition of 
clinical research; updated racial and ethnic categories in compliance with 
the new OMB standards; clarification of language governing NIH-defined Phase 
III clinical trials consistent with the new PHS Form 398; and updated roles 
and responsibilities of NIH staff and the extramural community.  The policy 
continues to require for all NIH-defined Phase III clinical trials that:  a) 
all applications or proposals and/or protocols must 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) investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 
differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: 
The NIH maintains a policy 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 is available at 
http://grants.nih.gov/grants/funding/children/children.htm. 

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.  You will find this policy announcement in the NIH Guide for Grants 
and Contracts, dated June 5, 2000, at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

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 PA 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 think about how to structure 
informed consent statements and other human subjects procedures given the 
potential for wider use of data collected under this award.

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.  Furthermore, 
we caution reviewers that their anonymity may be compromised when they 
directly access an Internet site.

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 
PA 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.

AUTHORITY AND REGULATIONS:  This program is described in the Catalog of 
Federal Domestic Assistance Nos. 93.865 (NICHD), 93.361 (NINR), and 93.113 
and 93.115 (NIEHS), and is not subject to the intergovernmental review 
requirements of Executive Order 12372 or Health Systems Agency review.  
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 described at http://grants.nih.gov/grants/policy/policy.htm 
and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and discourage the 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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