GENETIC BASIS OF RECOVERY AND REHABILITATION

RELEASE DATE:  August 12, 2003

RFA Number:  RFA-HD-03-025

National Institute of Child Health and Human Development (NICHD)       
 (http://www.nichd.nih.gov/)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S):  93.929

LETTER OF INTENT RECEIPT DATE:  November 15, 2003

APPLICATION RECEIPT DATE:  December 15, 2003

THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism of Support
o Funds Available
o Eligible Institutions
o Individuals Eligible to become Principal Investigators
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS RFA

The ultimate purpose of this initiative is to use molecular genetic 
approaches to better understand the basis for rehabilitation and recovery.  A 
screening of genomic alleles among affected individuals could help identify 
genes in key neurodevelopmental or musculoskeletal pathways that correlate 
with rehabilitative outcome.  It is also possible that studies of known 
allelic differences in other physiological systems would have particular 
relevance when examined in the context of rehabilitative outcomes.  Genomic 
screening may suggest novel targets for therapeutic interventions and would 
have significant prognostic value in targeting rehabilitative therapies to 
the individual, improving clinical efficacy and avoiding rare idiosyncratic 
contraindications.  

RESEARCH OBJECTIVES

Background

Medical rehabilitation strives to improve function and reduce disability for 
conditions that result from developmental, acquired, or degenerative 
conditions.  In some cases, patients can have very different outcomes, 
despite similarities in the extent of the initial insult and in clinical 
management.  Some of this variation may be due to subtle differences in the 
initial pathology, prior state of health, or even differences in compliance 
during rehabilitation.  However, there is increasing evidence that one's 
genetic constitution may have a significant role in clinical outcome and 
recovery.  Although the molecular genetic basis of regeneration, plasticity, 
and adaptation are areas of intense study, these finding have not translated 
to improving the efficacy and specificity of rehabilitative strategies.

Scope

This initiative will support hypothesis-driven genomic studies of individuals 
with physical disabilities in order to identify genetic factors that drive 
rehabilitative outcome.  While animal studies may provide the background for 
certain proposals, this initiative is primarily aimed at clinical studies in 
humans.  Applications submitted must have direct relevance to improving 
rehabilitation prognosis, refining rehabilitative therapies, or defining 
novel targets for therapeutic intervention.  While studies of developmental 
and degenerative conditions may have relevance to this RFA, research that 
predominantly focuses on the genetic basis of these conditions per se is 
likely supported by other parts of the NIH and beyond the scope of this 
solicitation.  

Examples of appropriate studies include, but are not limited to:

o  Hypothesis-driven screens and focused genetic studies of rehabilitative 
outcomes in defined clinical populations involving acquired disorders (e.g., 
stroke, brain or spinal cord injury, hypoxic-ischemic insult, orthopedic 
injuries).

o  Studies of specific neurological genes (e.g., apolipoprotein E, dopamine 
transporter) that have allelic variation in the general population and may 
play a role in regeneration, plasticity or other neurological processes, 
provided they are studied in the context of rehabilitative outcomes.  

o  Studies of allelic variation in genes of the immune system (e.g., 
interleukins, platelet antigens) that have relevance to understanding 
differences in inflammatory reactions or other neuroimmune processes relevant 
to rehabilitation and long-term recovery.

o  Genomic studies of angiogenesis, revascularization, extracellular matrix, 
or other aspects of tissue support relevant to rehabilitative outcomes.

o  Studies of modifying genes, risk factors, and other genomic elements that 
influence the extent of disability, rehabilitation, and recovery associated 
with developmental or degenerative conditions; also, genomic studies relevant 
to the progression of secondary complications arising from these conditions.  

o  Genomic studies of muscle, bone, connective tissue, and other aspects of 
musculoskeletal function that have particular relevance for understanding 
rehabilitative outcome and recovery.  

o  Studies of mitochondrial genetics and metabolic activity in the 
progression of secondary complications and sustaining rehabilitative 
outcomes.

o  Studies of genes that influence exercise capacity, cardiovascular 
function, activity-mediated processes, and compliance with physical therapies 
in rehabilitative settings.

o  Genomic studies of hormonal factors, neuroendocrine function, and other 
trophic interactions relevant to rehabilitative therapies.

o  Studies of allelic variation that have particular relevance for 
understanding differences in rehabilitative outcome in specific racial and 
ethnic groups.

o  Pharmacogenetic studies that have direct relevance to refining drug and 
other exogenous treatments used in rehabilitative settings.

MECHANISM OF SUPPORT

This RFA will use the NIH Research Project Grant (R01) and 
Exploratory/Developmental Grant (R21) award mechanisms.  As an applicant you 
will be solely responsible for planning, directing, and executing the 
proposed project.  This RFA is a one-time solicitation.  Future unsolicited, 
competing-continuation applications based on this project will compete with 
all investigator-initiated applications and will be reviewed according to the 
customary peer review procedures.  The anticipated award date is July 01, 
2004.  Applications that are not funded in the competition described in this 
RFA may be resubmitted as NEW investigator-initiated applications using the 
standard receipt dates for NEW applications described in the instructions to 
the PHS 398 application.

The R21 mechanism is used for support of creative, novel, and/or high 
risk/high payoff approaches that could produce innovative advances in this 
field.  This includes feasibility studies, protocol planning, and the 
incorporation of new disciplines and technologies.  The R21 provides the 
means to acquire the necessary pilot information, to attract talented new 
investigators from related disciplines, and to foster the development of 
interdisciplinary, inter-institutional collaborative efforts among 
investigators with diverse training and expertise.  R21 grants are non-
renewable and may not be used to supplement an ongoing project.  For further 
information on the R21 mechanism, go to 
https://grants.nih.gov/grants/guide/pa-files/PA-03-107.html.  

This RFA uses just-in-time concepts.  It also uses the modular budgeting 
format (see https://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.  This program does not 
require cost sharing as defined in the current NIH Grants Policy Statement at 
https://grants.nih.gov/archive/grants/policy/nihgps_2001/part_i_1.htm.

FUNDS AVAILABLE

The NICHD intends to commit approximately $2 million in total costs [Direct 
plus Facilities and Administrative (F & A) costs] in FY 2004 to support six 
to 10 new and/or competing continuation grants in response to this RFA.  An 
applicant for an R01 may request a project period of up to five years and a 
budget for direct costs of up to $250,000 per year (including F & A costs on 
subcontracts).  An applicant for an R21 may request a project period of up to 
two years with a combined budget for direct costs of up $275,000 for the two 
year period.  For example, you may request $100,000 in the first year and 
$175,000 in the second year.  The request should be tailored to the needs of 
the project.  Normally, no more than $200,000 may be requested in any single 
year.  Because the nature and scope of the proposed research will vary from 
application to application, it is anticipated that the size and duration of 
each award will also vary.  Although the financial plans of the NICHD 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. 

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 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.   

WHERE TO SEND INQUIRIES

We encourage inquiries concerning this RFA and welcome the opportunity to 
answer questions from potential applicants.  Inquiries may fall into three 
areas:  scientific/research, peer review, and financial or grants management 
issues:  

o Direct your questions about scientific/research issues to:  

Ralph Nitkin, Ph.D.
National Center for Medical Rehabilitation Research
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 2A03, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 402-4206
FAX:  (301) 402-0832
Email:  rn21e@nih.gov 

o Direct your questions about peer review issues to:  

Robert Stretch, Ph.D.
Director, Division of Scientific Review
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 5B01, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-1485
FAX:  (301) 402-4104
Email:  stretchr@mail.nih.gov 
 
o Direct your questions about financial or grants management matters to:  

Kathy Hancock
Grants Management Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, 8A17, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-5482
FAX:  (301) 402-0915
Email:  kh246t@nih.gov 

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent that includes 
the following information:  

o Descriptive title of the proposed research 
o Name, address, and telephone number of the Principal Investigator 
o Names of other key personnel 
o Participating institutions 
o Number and title of this RFA 

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 NICHD staff to estimate the potential review workload and 
plan the review.

The letter of intent is to be sent by the date listed at the beginning of 
this document.  The letter of intent should be sent to:  

Ralph Nitkin, Ph.D.
National Center for Medical Rehabilitation Research
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 2A03, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 402-4206
FAX:  (301) 402-0832
Email:  rn21e@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 
https://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive 
format.  For further assistance contact GrantsInfo, Telephone (301) 710-0267, 
Email:  GrantsInfo@nih.gov.  

SUPPLEMENTAL INSTRUCTIONS: Specific instructions for preparing an R21 
application can be found at 
https://grants.nih.gov/grants/guide/pa-files/PA-03-107.html.

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 
https://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 
https://grants.nih.gov/grants/funding/modular/modular.htm.

USING THE RFA LABEL:  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: 
https://grants.nih.gov/grants/funding/phs398/label-bk.pdf.

SENDING AN APPLICATION TO THE NIH:  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 must be 
sent to:  

Robert Stretch, Ph.D.
Director, Division of Scientific Review
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 5B01, MSC 7510
Bethesda, MD  20892-7510
Rockville, MD  20852 (for express/courier service)

APPLICATION PROCESSING:  Applications must be received on or before 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.

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.

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.  
However, when a previously unfunded application, originally submitted as an 
investigator-initiated application, is to be submitted in response to an RFA, 
it is to be prepared as a NEW application.  That is, the application for the 
RFA must not include an Introduction describing the changes and improvements 
made, and the text must not be marked to indicate the changes.  While the 
investigator may still benefit from the previous review, the RFA application 
is not to state explicitly how.

PEER REVIEW PROCESS

Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NICHD.  Incomplete 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 NICHD in accordance with the review criteria stated below.  
As part of the initial merit review, all applications will: 

o Receive a written critique
o 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 and assigned a priority score
o Receive a second level review by the National Advisory Child Health and 
Human Development 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:

o Significance
o Approach
o Innovation
o Investigator
o Environment 

The scientific review group will address and consider each of these criteria 
in assigning the application's overall score, weighting them as appropriate 
for each application.  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.

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?

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?

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

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)?

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?

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:

PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK:  The involvement of human 
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.)

INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH:  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 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.)

CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH:  If vertebrate animals are to 
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.

ADDITIONAL CONSIDERATIONS

DATA SHARING:  The adequacy of the proposed plan to share data. 

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

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date:  November 15, 2003
Application Receipt Date:  December 15, 2003
Peer Review Date:  February/March 2004
Council Review:  June 2004
Earliest Anticipated Start Date:  July 01, 2004

AWARD CRITERIA

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

REQUIRED FEDERAL CITATIONS

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.
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm

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 "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 
(https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); 
a complete copy of the updated Guidelines is available at
https://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 
https://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 Announcement, dated June 5, 2000, at 
https://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 
https://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 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.

STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION:  The 
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 
(http://www.hhs.gov/ocr/) 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 
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.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.  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 
RFA 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 at http://www.cfda.gov/ 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 
https://grants.nih.gov/grants/policy/policy.htm.

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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