RELEASE DATE:  January 28, 2004
PA NUMBER:  PA-04-052 (Reissued as PA-07-419)

EXPIRATION DATE:  February 15, 2007, unless reissued

Department of Health and Human Services (DHHS)

National Institutes of Health (NIH) 
National Institute of Child Health and Human Development (NICHD) 



o Purpose of this 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


The purpose of this PA is to support new, innovative, multidisciplinary, 
interactive, and synergistic program projects that integrate basic, 
translational, and clinical approaches to understanding the developmental 
biology and genetic basis of congenital human malformations. Each program 
must consist of at least three component projects. At least one project must 
be clinical or translational in nature. The component projects must share a 
common central theme, focus, or objective on a specific developmental defect 
or malformation that is genotypically, mechanistically, biologically, or 
phenotypically analogous or homologous in both animal models and humans. Any 
non-mammalian or mammalian animal model may be used, as long as it 
contributes to the common overall theme or objective of the program project. 
If the component projects do not share a common developmental gene, process, 
mechanism, pathway, or phenotype, the application will be considered 
nonresponsive to this PA.



Annually, about four percent of all live births in the United States involve 
babies with significant structural birth defects (more than 150,000 babies). 
Next to accidents, birth defects are the leading cause of death in children; 
they account for half of all pediatric hospitalizations. In terms of the 
economic costs, billions of dollars are spent over the lifetimes of children 
born with any of 17 major, severe, nonfatal birth defects. In sum, structural 
birth defects have a great impact on public health, socioeconomics, and 
family life. A high priority goal of NICHD's strategic plan is to address the 
problem of human structural birth defects. 

The clinical and epidemiological aspects of human malformations were 
addressed at a workshop in 1997. As a result of that workshop, NICHD, NIEHS, 
NIDCR, and the EPA issued RFA HD-99-002, "Genetic Susceptibility and 
Variability of Human Malformations." That initiative funded several R01s and 
established a basis for a network of investigators focused on the use of 
molecular genetic approaches to the study of genetic susceptibility and 
epidemiology of human malformations. 

A second workshop was held in 1998 and its recommendations served as the 
basis for RFA HD-99-008, "Developmental Mechanisms of Human Malformations", 
from which NICHD and NIEHS funded several P01s. An important feature of those 
P01s was the emphasis on integrating basic, translational, and clinical 
research. Combined with the R01s funded under the first initiative, these 
projects expanded the network of researchers focused on the study of 
structural birth defects.

By issuing this PA, "Developmental Mechanisms of Human Structural Birth 
Defects," the NICHD plans to increase the number of basic scientists and 
clinicians involved in this network. Now that the sequencing of the human 
genome is complete, it is time to capitalize on the rapid advances being made 
in functional genomics and proteomics. Broadening the base of PIs involved in 
this research effort will promote the translation of these advances from the 
bench to the bedside. 


The purpose of this PA is to support new, innovative, multidisciplinary, 
interactive and synergistic program projects that integrate basic, 
translational, and clinical approaches to understand the developmental 
biology and genetic basis congenital human malformations. 

Of particular interest to the NICHD are applications proposing to study 
embryonic developmental defects of generalized body patterning and localized 
anomalies of the skeletal, nervous, and visceral systems that lead to 
clinically significant congenital structural malformations. 

While applications focusing on developmental disorders that result in mental 
retardation and related neurobehavioral disabilities are of interest to the 
NICHD, they are outside the scope of this PA. 

The basic science component projects may include studies to: 1) identify and 
characterize the genes, gene products, mutations, polymorphisms, multigene 
and gene/environment interactions that play a role in normal and abnormal 
embryonic patterning and organogenesis; 2) elucidate the developmental 
biological processes and pathways, the biochemical, cellular, molecular, 
genetic mechanisms, and spatial and temporal gene expression patterns which 
are involved in dysmorphogenesis; and 3) examine how teratogens and 
nutritional deficiencies disrupt or modify gene expression and basic 
developmental processes. 

The translational/clinical component projects may include studies to: 1) 
characterize and classify genotypes and phenotypes of human malformations 
that are comparable in the animal models being examined; 2) develop physical, 
genetic, and comparative maps for genes involved in human malformations; 3) 
identify the developmental genetic processes and molecular pathogenesis of 
human malformations utilizing animal models; and 4) develop innovative 
molecular genetic methods, technologies, and strategies to enhance the 
diagnosis and methods for intervention of the human malformations. 

Applicants are encouraged to incorporate the recent scientific advances in 
developmental biology and genetics in their projects and to utilize the many 
research resources, bioinformatic databases, and biotechnological tools in 
their research cores. The research cores should be structured to share work 
effort and research resources (e.g., biotechnology, high-throughput 
instrumentation, microarrays, oligonucleotide chips, animal model 
development, and technical assistance) among the research projects. The aim 
of the core is to enhance the progress, productivity, cost-effectiveness, and 
outcome of the research projects. 

Applications may include new and innovative approaches to investigate: 1) 
genetic defects, nutritional deficiencies, teratogens that perturb, modify, 
or alter gene expression during early development; 2) the identity and 
function of transcription and growth factors in normal and abnormal 
gastrulation, embryogenesis, organogenesis, and patterning, as well as their 
modification by environmental agents; and 3) defective embryonic 
developmental processes and pathways that ultimately lead to malformations. 

Research projects responsive to this PA include, but are not limited to, the 

o Investigations on the identity, characteristics, and mechanisms of growth 
factors and growth factor receptors that function in embryonic development 
and dysmorphogenesis of the skeletal, nervous, and visceral systems; 

o Studies of transcription factors regulating gene expression and temporal 
and spatial expression patterns during normal and abnormal embryonic 

o Studies of developmental genes, gene products, transcription factors, and 
growth factors that function and interact to regulate cell proliferation, 
cell differentiation, apoptosis, cell migration, and cell fate in embryonic 

o Examination of genes and molecular mechanisms and interactions that control 
normal and abnormal body axes and symmetry during development; 

o Studies to identify, map, and characterize genes that play a role in: 
signal transduction and biochemical pathways, cell fate determination, 
gastrulation, embryogenesis, organogenesis, body patterning and how 
developmental defects, mutations, or susceptible polymorphisms lead to 

o Investigations of pharmaceutical, nutritional, and teratogenic agents and 
factors that alter genes and developmental processes and pathways that result 
in dysmorphologies; 

o Investigations to characterize and classify genotype/phenotypes of 
hereditary human malformations and correlate them to homologs in animal 

o Efforts to define pleiotropic effects that genes and their modifiers have 
in the spatial and temporal development of embryonic and/or fetal anomalies; 

o Development and validation of new and/or improved animal models to study 
the genes, mutations, mechanisms, and developmental processes and pathways 
that cause human malformations; 

o Imaging and gene expression studies to investigate and monitor the 
developmental pathogenesis of dysmorphic features; 

o Investigations of the role of imprinting and epigenetic factors in the 
development of major congenital malformations; 

o Studies on nutritional factors (e.g., folic acid deficiency) and teratogens 
(e.g., retinoids and valproic acid) affecting gene/gene, gene/receptor, 
gene/modifier, and gene/teratogen interactions that lead to neural tube or 
other structural defects; 

o Examination of the role and developmental biology of neural crest cells in 
normal embryonic development and how defects in cell proliferation, 
differentiation, migration, and patterning may result in major structural 
birth defects; 

o Elucidation of the underlying genetic and molecular mechanisms that alter 
normal developmental processes in drug-induced (e.g., Accutane, Thalidomide) 

o Identification and characterization of polymorphisms/mutations of metabolic 
genes that function in the development of structural birth defects. 

The topics listed above are only examples, are not in priority order, and are 
not intended to be all-inclusive. Investigators are encouraged to explore and 
develop new, innovative projects and research cores that are consistent with 
the overall objectives of this PA.

Research Cores

Applicants are encouraged to incorporate the recent scientific advances in 
developmental biology and genetics in their projects and to utilize the many 
research resources, bioinformatic databases, and biotechnological tools in 
their research cores.  The research cores should be structured to share work 
effort and research resources (e.g., biotechnology, high-throughput 
instrumentation, microarrays, oligonucleotide chips, animal model 
development, and technical assistance) among the research projects.  The aim 
of the cores is to enhance the progress, productivity, cost-effectiveness, 
and outcome of the research projects.


This PA will use the NIH Program Project Grant (P01) award mechanism. The P01 
supports broadly based multidisciplinary research programs that have a well-
defined central research focus or objective. An important feature is that the 
interrelationships among the individual projects will result in a greater 
contribution to the overall program goals than if each project were pursued 
independently. The P01 grant requires a minimum of three interrelated 
individual research projects that contribute to the overall program 
objective. At least one component project must be translational or clinical 
in nature. The application may request support for certain common core 
resources. As an applicant you will be solely responsible for planning, 
directing, and executing the proposed project.

Guidelines for the NICHD Program Project (P01) Grant may be found at  


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

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 institutions/organizations
o Foreign institutions are not eligible to apply


Any individual with the skills, knowledge, and resources necessary to carry 
out the proposed research is invited to work with his/her 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.   


The Program Director for the overall grant and the principal investigator for 
each component project should plan to attend an annual NIH-sponsored two-day 
meeting in Bethesda, MD. In addition, this meeting will be attended by 
investigators supported through the two previous RFAs (HD-99-002, Genetic 
Susceptibility & Variability of Human Malformations, and HD-99-008, 
Developmental Mechanisms of Human Malformations). The meeting will provide an 
opportunity for all the investigators to communicate, discuss the progress of 
their research, exchange ideas and information, share resources, and foster 
collaborations that are relevant to the research goals of the NICHD birth 
defects initiative. This requirement is designed to establish an interactive 
network of investigators who are interested in multidisciplinary approaches 
to enhancing our understanding of the epidemiology, etiology, pathogenesis, 
and developmental biology and genetics of structural birth defects.

All applications should include a request for funds to support attendance of 
the Program Director and project principal investigators at the annual 
meetings, as well as a statement of agreement to participate in these 
meetings and to cooperate with investigators at other program project sites.

A data-sharing plan must be included as outlined in the recent NIH Guide 


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:  

Lorette Javois, Ph.D.
Developmental Biology, Genetics and Teratology Branch, Center for 
Developmental Biology and Perinatal Medicine
National Institute of Child Health and Human Development
6100 Executive Blvd., 4B01 MSC 7510
Bethesda, MD  20892-7510
Telephone: (301) 496-5541
FAX: (301) 480-0303

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

Annette Hanopole
Grants Management Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, 8A17, MSC 7510
Bethesda, MD  20892-7510
Telephone: (301) 435-6975
FAX: (301) 402-0915


Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001). Applications must have a Dun and 
Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the 
Universal Identifier when applying for Federal grants or cooperative 
agreements. The DUNS number can be obtained by calling (866) 705-5711 or 
through the web site at The DUNS number 
should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 
is available at in an 
interactive format.  For further assistance contact GrantsInfo, Telephone 
(301) 710-0267, Email:

The title and number of this program announcement must be typed on line 2 of 
the face page of the application form and the YES box must be checked.

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

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 

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 mailed on or before the receipt 
dates described at 

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.

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and funding 
assignment within eight weeks.


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 
( will evaluate applications for scientific 
and technical merit.  

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

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 written critique
o Receive a second level review by the appropriate national advisory council 
or board.


Applications assigned to NICHD will be evaluated for scientific and technical 
merit according to the review criteria outlined in the NICHD Program Project 
(P01) Grant Guidelines (

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following 
items will be considered in the determination of scientific merit and the 
priority score:

subjects and protections from research risk relating to their participation 
in the proposed research will be assessed.  (See criteria included in the 
section on Federal Citations, below.)

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 will be assessed.  Plans for the recruitment and retention of 
subjects will also be evaluated. (See Inclusion Criteria in the sections on 
Federal Citations, below.)

be used in the project, the five items described under Section f of the PHS 
398 research grant application instructions (rev. 5/2001) will be assessed.


SHARING RESEARCH DATA:  Applicants requesting more than $500,000 in direct 
costs in any year of the proposed research are expected to include a data 
sharing plan in their application. The reasonableness of the data-sharing plan 
or the rationale for not sharing research data will be assessed by the 
reviewers. However, reviewers will not factor the proposed data sharing plan 
into the determination of scientific merit or priority score. 

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


Applications submitted in response to a PAR 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


HUMAN SUBJECTS PROTECTION:  Federal regulations (45CFR46) require that 
applications and proposals involving human subjects must be evaluated with 
reference to the risks to the subjects, the adequacy of protection against 
these risks, the potential benefits of the research to the subjects and 
others, and the importance of the knowledge gained or to be gained 

SHARING RESEARCH DATA:  Starting with the October 1, 2003 receipt date, 
investigators submitting an NIH application seeking $500,000 or more in direct 
costs in any single year are expected to include a plan for data sharing or 
state why this is not possible  
(  Investigators should seek 
guidance from their institutions, on issues related to institutional policies, 
local IRB rules, as well as local, state and Federal laws and regulations, 
including the Privacy Rule. Reviewers will consider the data sharing plan but 
will not factor the plan into the determination of the scientific merit or the 
priority score.

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 "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 
a complete copy of the updated Guidelines is available at  
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 

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

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 Announcement, dated June 5, 2000, at

HUMAN EMBRYONIC STEM CELLS (hESC):  Criteria for federal funding of research 
on hESCs can be found at and at  Only 
research using hESC lines that are registered in the NIH Human Embryonic Stem 
Cell Registry will be eligible for Federal funding (see   
It is the responsibility of the applicant to provide, in the project 
description and elsewhere in the application as appropriate, the official NIH 
identifier(s)for the hESC line(s)to be used in the proposed research.  
Applications that do not provide this information will be returned without 

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

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.

Department of Health and Human Services (DHHS) issued final modification to 
the “Standards for Privacy of Individually Identifiable Health Information,” 
the “Privacy Rule,” on August 14, 2002.  The Privacy Rule is a federal 
regulation under the Health Insurance Portability and Accountability Act 
(HIPAA) of 1996 that governs the protection of individually identifiable 
health information, and is administered and enforced by the DHHS Office for 
Civil Rights (OCR). Those who must comply with the Privacy Rule (classified 
under the Rule as “covered entities”) must do so by April 14, 2003 (with the 
exception of small health plans which have an extra year to comply).  

Decisions about applicability and implementation of the Privacy Rule reside 
with the researcher and his/her institution. The OCR website 
( provides information on the Privacy Rule, including 
a complete Regulation Text and a set of decision tools on “Am I a covered 
entity?”  Information on the impact of the HIPAA Privacy Rule on NIH processes 
involving the review, funding, and progress monitoring of grants, cooperative 
agreements, and research contracts can be found at

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

AUTHORITY AND REGULATIONS:  This program is described in the Catalog of 
Federal Domestic Assistance at and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.  Awards are made under the authorization of Sections 
301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) 
and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.  All 
awards are subject to the terms and conditions, cost principles, and other 
considerations described in the NIH Grants Policy Statement.  The NIH Grants 
Policy Statement can be found at  

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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