GENE EXPRESSION STUDIES IN ARTHRITIS AND MUSCULOSKELETAL AND SKIN
DISEASES
RELEASE DATE: December 4, 2002
RFA: AR-03-007
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
(http://www.niams.nih.gov/)
LETTER OF INTENT RECEIPT DATE: February 17, 2003
APPLICATION RECEIPT DATE: March 17, 2003
THIS RFA CONTAINS THE FOLLOWING INFORMATION
o Purpose of this RFA
o Research Objectives
o Mechanism(s) of Support
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements
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
This solicitation is intended to facilitate the use of comprehensive
gene expression analysis technology in basic and clinical research
relevant to arthritis and musculoskeletal and skin diseases. The NIAMS
invites two types of applications. First, Principal Investigators who
are currently supported by research project grants from the NIAMS are
invited to submit competing supplement applications, proposing the
expansion of the scope of the projects to include use of comprehensive
gene expression analysis technology. Second, scientists with
established expertise in arthritis or musculoskeletal or skin diseases
are invited to propose new projects in which comprehensive gene
expression analysis technology is a major and essential component, and
in which new insights are likely to be obtained that would not arise
from the use of conventional analytical techniques.
RESEARCH OBJECTIVES
Background and Rationale
In recent years, a variety of techniques have been developed that allow
for the assessment of messenger RNA levels for very large numbers of
genes in a single procedure. The most commonly used tools are high-
density arrays of hybridization probes, which have been produced using
either synthetic oligonucleotides or cloned DNA fragments. High-
throughput sequencing of concatenated DNA fragments has also shown
promise. The adoption of these techniques has presented a number of
challenges, both technical and conceptual. Technical problems include
the specialized and costly nature of the required equipment, the
substantial degree of skill and experience required to make use of the
techniques, the limited availability of standardized probe collections,
and the bioinformatic problems of analyzing very large datasets.
Conceptually, it has been difficult to frame rigorous hypotheses and
models that integrate the enormous amount of detail obtained in these
experiments with broader questions in biology and medicine. This
solicitation is intended to focus available resources on those
applications of gene expression analysis that hold the most immediate
promise of contributing to rigorous investigations in areas within the
NIAMS mission.
Objectives and Scope
Proposed research must support the NIAMS mission as detailed in the
NIAMS World Wide Web home page, which can be found at
http://www.niams.nih.gov/rtac/funding/faq.htm. In brief, the NIAMS
supports research in: rheumatic diseases; cartilage biology and
diseases; bone biology and diseases (e.g., osteoporosis, Paget's
disease); skin biology and skin diseases; autoimmune diseases (e.g.,
lupus, rheumatoid arthritis); connective tissue diseases;
musculoskeletal diseases (e.g., osteoarthritis); musculoskeletal
imaging; injuries and disorders of the musculoskeletal system; muscle
biology and diseases (e.g., muscular dystrophy); exercise physiology
and musculoskeletal fitness; sports injuries; occupational diseases and
injuries; and orthopaedic and bioengineering topics.
Applications will be accepted across the spectrum of biological models
and diseases within the NIAMS mission. The primary objective of this
initiative is to focus resources on specific biological and medical
problems for which the immediate application of comprehensive gene
expression analysis technology has the potential to yield significant
new insights. For example, characterizing gene knockout or transgenic
mouse strains, in which genetic variation from controls is limited and
known, should produce manageable datasets, and may indicate the
downstream targets of inactivated or introduced genes. In more complex
situations, computational approaches such as hierarchical clustering
can group genes into subsets showing coordinated expression patterns,
presumably reflecting related functions. However, such an approach must
be firmly grounded in established biology.
A second objective is to direct support to groups that are in the best
position to make use of comprehensive gene expression analysis
technology at this time. These are likely to be groups with access to
necessary equipment, and with substantial previous experience in the
use of the technology. Alternatively, investigators may establish
collaborations with other scientists having the requisite expertise, or
make use of commercial products and services that standardize aspects
of the technology.
Examples of situations in which a response to this RFA may be
appropriate include, but are not limited to, the following:
o On-going NIAMS-funded projects in which comprehensive gene expression
analysis was not originally included in the research design, but in
which such analysis can be justified in pursuit of the original aims.
o On-going NIAMS-funded projects in which results to date justify
expansion of the scope to include new but related aims requiring
comprehensive gene expression analysis.
o On-going NIAMS-funded projects in which comprehensive gene expression
analysis was included in the original design, but in which the
originally budgeted funds have proven inadequate to support rigorous
application of the technology.
o New projects in which existing comprehensive gene expression data,
(e.g., from publicly accessible data resources) will be analyzed to
achieve aims relevant to the NIAMS mission.
o New projects requiring comprehensive gene expression analysis, and
making use of existing patient cohorts or specimen archives, whether the
original development of the resource was NIAMS-supported or not.
o New projects that would have been impractical to undertake with older
analytical methods, but which may be tractable with the application of
comprehensive gene expression analysis techniques.
MECHANISM OF SUPPORT
This RFA will use NIH competing supplement and investigator-initiated
research project grant (R01) 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 September 2003.
Competing supplement applications are subject to the requirements
stated in the Form 398 instructions (see
ftp://ftp.grants.nih.gov/forms/phs398.pdf.) Briefly, a competing
supplement application may be submitted to request support for a
significant expansion of a project's scope or research protocol. The
principal investigator must be the same as the principal investigator
of the parent application. Supplemental applications must include both
a Progress Report for the current grant and an Introduction, providing
an overall description of the nature of the supplement and how it will
influence the specific aims, research design, and methods of the
current grant. Only R01, P01, R37, P30, P50, P60, and U01 awards are
eligible for supplements under this initiative. In order to be
considered for a supplement, the current grant must have at least two
years of funding remaining at the time of the supplement award. A
supplement request may not extend beyond the parent grant. Applicants
must identify supplemental applications by checking the "Supplement"
box on the Checklist page and entering the number of the currently
funded grant for which the supplement is being requested.
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.
FUNDS AVAILABLE
The NIAMS intends to commit approximately $2 million in FY 2003 to fund
ten to fifteen supplements and/or new awards in response to this RFA.
Supplement applications may request up to $100,000 per year in direct
costs. A supplement may not extend beyond the parent project award
period. Research project (R01) grants may not exceed $250,000 per year
in direct costs. The total project period for an R01 application
submitted in response to this RFA may not exceed four years. 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 NIAMS 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(s) 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
Individuals with the skills, knowledge, and resources necessary to
carry out the proposed research are 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 particularly encouraged to apply for support from
NIAMS programs.
SPECIAL REQUIREMENTS
Data Sharing Plan
Because comprehensive gene expression analysis methods can record
expression levels for thousands of genes, data may be useful for
purposes beyond those prompting their original collection. Thus,
applicants responding to this RFA must describe plans for making data
available to other investigators. For example, they may identify
existing publicly accessible data repositories, such as the NCBI Gene
Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) to which data
will be submitted. Data sharing plans must include a timetable
specifying when data will be shared, relative to collection, analysis,
and publication. Peer reviewers will be asked to comment on the
adequacy of the plan. The requirement for data sharing will be
incorporated as a condition of any award made under this RFA.
Annual meetings
The technology of comprehensive gene expression analysis presents new
challenges and is still changing rapidly. It is important for
investigators applying this technology to exchange information
regularly. The NIAMS plans to organize annual meetings of investigators
supported under this initiative, to facilitate this exchange of
information. In preparing budget requests, applicants should anticipate
expenses for annual travel to Bethesda, Maryland for this purpose.
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:
William J. Sharrock, Ph.D.
Musculoskeletal Diseases Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
One Democracy Plaza
6701 Democracy Blvd., Suite 800
Bethesda, MD 20892-4872
Telephone: (301) 594-5055
FAX: (301) 480-4543
Email: ws19h@nih.gov
o Direct your questions about peer review issues to:
Richard Bartlett, Ph.D.
Review Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
One Democracy Plaza
6701 Democracy Blvd, Suite 800
Bethesda, MD 20892-4872
Telephone: 301-594-4956
Fax: 301-402-2406
Email: bartletr@mail.nih.gov
o Direct your questions about financial or grants management matters
to:
Michael G. Morse
Deputy Chief, Grants Management Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
One Democracy Plaza
6701 Democracy Blvd. Suite 800
Bethesda, MD 20892-4872
Telephone: (301) 594-3535
FAX: (301) 480-5450
Email: nelsonm@mail.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 IC 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:
William J. Sharrock, Ph.D.
Musculoskeletal Diseases Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
One Democracy Plaza
6701 Democracy Blvd., Suite 800
Bethesda, MD 20892-4872
Telephone: (301) 594-5055
FAX: (301) 480-4543
Email: ws19h@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.
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:
Richard Bartlett, Ph.D.
Review Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
One Democracy Plaza
6701 Democracy Blvd, Suite 800
Bethesda, MD 20892-4872
Telephone: 301-594-4956
Fax: 301-402-2406
Email: bartletr@mail.nih.gov
APPLICATION PROCESSING: 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.
PEER REVIEW PROCESS
Upon receipt, applications will be reviewed for completeness by the CSR
and responsiveness by the NIAMS. Incomplete applications will be
returned to the applicant without further consideration. And, if the
application is not responsive to the RFA, CSR staff may contact the
applicant to determine whether to return the application to the
applicant or submit it for review in competition with unsolicited
applications at the next appropriate NIH review cycle.
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 NIAMS 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 Arthritis and
Musculoskeletal and Skin Diseases 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 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:
o 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.
o 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)
o DATA SHARING: The adequacy of the proposed plan to share data.
o 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: February 17, 2003
Application Receipt Date: March 17, 2003
Peer Review Date: June/July 2003
Council Review: September 2003
Earliest Anticipated Start Date: September 2003
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.
REQUIRED FEDERAL CITATIONS
MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research
components involving Phase I and II clinical trials must include
provisions for assessment of patient eligibility and status, rigorous
data management, quality assurance, and auditing procedures. In
addition, it is NIH policy that all clinical trials require data and
safety monitoring, with the method and degree of monitoring being
commensurate with the risks (NIH Policy for Data Safety and Monitoring,
NIH Guide for Grants and Contracts, June 12, 1998:
https://grants.nih.gov/grants/guide/notice-files/not98-084.html).
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
(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.
HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of
research on hESCs can be found at
https://grants.nih.gov/grants/stem_cells.htm and at
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.
Only research using hESC lines that are registered in the NIH Human
Embryonic Stem Cell Registry will be eligible for Federal funding (see
http://escr.nih.gov). It is the responsibility of the applicant to
provide 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 review.
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.
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 No. 93.846, 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 https://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.