NEW RESEARCH STRATEGIES FOR EVALUATION AND ASSESSMENT OF BONE QUALITY

Release Date:  December 31, 2001

RFA:  RFA-AR-02-002

National Institute of Arthritis and Musculoskeletal and Skin Diseases
 (http://www.niams.nih.gov/)
National Institute of Dental and Craniofacial Research
 (http://www.nidr.nih.gov/)

Letter of Intent Receipt Date:  February 21, 2002
Application Receipt Date:       March 21, 2002


THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  MODULAR  
INSTRUCTIONS MUST BE USED FOR RESEARCH GRANT APPLICATIONS UP TO $250,000 PER 
YEAR.  MODULAR BUDGET INSTRUCTIONS ARE PROVIED IN SECTION C OF THE PHS 398 
(REVISION 5/2001) AVAILABLE AT
http://grants.nih.gov/grants/funding/phs398/phs398.html.
                    
PURPOSE

The National Institute of Arthritis and Musculoskeletal and Skin Diseases 
(NIAMS) invites research applications that provide novel means to assess bone 
quality and elucidate the relationships among disease- and aging-related 
changes in bone quality, gender-related variations  in bone quality, and 
increased bone fragility and fracture susceptibility. Current tools for the 
precise assessment of fracture risk are limited.  In order to target high 
risk populations for preventive or therapeutic interventions, it is necessary 
to have tools that are able to assess bone strength and quality.  
Applications may be in the form of individual research projects (R01) or 
exploratory/developmental research grants (R21).

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, "New Research 
Strategies for Evaluation and Assessment of Bone Quality," is related to the 
priority area of chronic diseases.  Potential applicants may obtain a copy of 
"Healthy People 2010" at http://www.health.gov/healthypeople.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign for-profit and non-
profit organizations, public and private, such as universities, colleges, 
hospitals, laboratories, units of State and local governments, and eligible 
agencies of the Federal government. Applicants also may collaborate, through 
consultation or contractual agreements, with investigators at foreign 
institutions. Racial/ ethnic minority individuals, women, and persons with 
disabilities are encouraged to apply as Principal Investigators. 
Participation in the program by investigators at minority institutions is 
strongly encouraged.

MECHANISMS OF SUPPORT

The mechanisms of support will include the investigator-initiated research 
project grant (R01) and the exploratory/developmental research grant (R21). 

R01 Applications.  The individual research grant (R01) is a specific, 
circumscribed project to be performed by the named investigator(s) who has a 
specific interest and competency in an area of interest to this RFA. The 
total project period for an R01 application submitted in response to this RFA 
may not exceed 5 years.  Future unsolicited competing continuation 
applications will compete with all investigator-initiated applications and be 
reviewed according to the customary peer review procedures.  Because the 
nature and scope of the research proposed in response to this RFA may vary, 
it is anticipated that the size of an R01 award will vary also.  Modular 
budgeting procedures apply to grants up to $250,000.  Specific R01 
application instructions have been modified to reflect "modular grant" and 
"just-in-time" streamlining efforts.  Complete instructions and information 
on modular grants can be found at 
http://grants.nih.gov/grants/funding/modular/modular.htm.  Direct costs will 
be awarded in modules of $25,000, less any overlap or other necessary 
administrative adjustments.  F and A costs will be awarded based on the 
negotiated rates.

R21 Applications.  The purpose of the R21 projects solicited under this RFA 
is to gather preliminary data leading to the development of an investigator-
initiated research project (R01). Use of this mechanism is recommended by 
investigators experienced in bone structure/imaging /osteoporosis research 
who wish to adapt or apply novel methodologies to study bone quality.  It is 
also recommended for investigators with relevant expertise (e.g., imaging of 
other tissues, engineers, or others) interested in developing a program for 
assessment of bone quality.  Exploratory/developmental research grants (R21) 
may not exceed $100,000 per year (4  modules) in direct costs, not including 
facilities and administrative (F&A) costs for collaborating institutions, if 
any.  The total project period for an R21 application submitted in response 
to this RFA may not exceed 3 years.  These grants are nonrenewable and 
continuation of projects developed under the R21 program should be through 
the traditional unsolicited (R01) grant programs.  Exploratory/ developmental 
studies are not intended for large-scale undertakings or to support or 
supplement ongoing research.  Instead, investigators are encouraged to 
explore the feasibility of an innovative research question or approach that 
may not be at a stage advanced enough to compete as a standard research 
project grant (e.g., R01).

FUNDS AVAILABLE

It is anticipated that for FY 2002, approximately $1.2 million (total costs)  
will be available for the first year of support for this initiative.  The 
specific number of grants to be awarded will depend upon the merit and scope 
of the applications received and on the availability of funds for this 
purpose. An applicant using the R01 mechanism may request a project period of 
up to 5 years and a budget for direct costs of up to $250,000 per year. 
Exploratory/developmental research grants using the R21 mechanism may not 
exceed $100,000 per year in direct costs, not including F and A costs for 
collaborating institutions, if any.  Total project period for an R21 
application submitted in response to this RFA may not exceed 3 years.  Awards 
pursuant to this RFA are contingent upon the availability of funds and the 
receipt of a sufficient number of meritorious applications of interest to 
NIAMS.  At this time, it is not known if this RFA will be reissued.

RESEARCH OBJECTIVES

The progressive or sudden loss of bone very commonly leads to osteoporosis, a 
condition characterized by increased skeletal fragility and susceptibility to 
fracture.  Osteoporosis and its consequences are a significant cause of 
frailty, morbidity, and even mortality among the elderly.  However, while 
reduced bone mass is important both in contributing to and predicting an 
enhanced risk of fracture, low bone mass alone is not a sufficient 
explanation for osteoporotic fractures.  This is exemplified by the 
substantial overlap in bone density between normal individuals and those who 
sustain hip and other osteoporotic fractures. Recently, gender-related 
differences in fracture susceptibility have been identified that cannot be 
explained by simple differences in bone size.  It has become apparent that 
the conceptual basis of skeletal integrity must be broadened to include, in 
addition to bone mineral content, qualitative factors that may impact on bone 
strength such as geometry, macro and micro-structural organization, 
distribution of material within bone, biochemical composition, and the burden 
of unrepaired microdamage.

This RFA is directed towards:  (1) stimulating research aimed at elucidating 
mechanisms of bone fragility and its measurement and (2) developing 
strategies and methodologies aimed at better identifying those at risk of 
osteoporosis-related fractures and in need of therapeutic intervention to 
prevent such fractures.  Specifically, this RFA seeks applications for basic 
and clinical research to identify and evaluate the relationship between 
measures of bone density and bone quality and/or strategies to modify the 
bone quality to reduce skeletal fragility and decreased fracture 
susceptibility.  Topics of interest include, but are not limited to:

o  Changes in architecture, mechanical properties, and strength of bone with 
disease and aging and non-invasive means to determine these properties

o  Evaluation of changes in bone matrix and mineralization and their impact 
on strength and resistance to microdamage

o  Assessment of the consequences of the accumulation of cortical and 
trabecular microdamage and their relationship to bone strength and fracture 
biomechanics

o  Development and application of new technologies for bone quality 
assessment to be used in monitoring craniofacial development and alveolar 
bone loss.

o  Development and application of techniques such as histomorphometry, 
ultrasound, MRI, and QCT to evaluate changes in architecture, bone strength 
and fracture susceptibility 
http://odp.od.nih.gov/consensus/cons/111/111_intro.htm.

Specific Objectives

This initiative will support studies in areas that have the potential to 
elucidate the nature and consequences of disease- and age-related changes in 
bone quality and the relationship of such changes to increased bone fragility 
and fracture susceptibility.  The specific objectives of this solicitation 
are to address the following questions:

o  What changes in bone mineral density, bone matrix, and bone architecture 
significantly affect the biomechanical properties of bone?

o  Are there non-invasive, reproducible imaging markers/methodologies that 
can be used to assess longitudinal, age-related, and gender-related changes 
in bone quality with regard to fracture risk?

o  Do these non-invasive, reproducible imaging markers/methodologies for bone 
quality assessment provide a means to explain the discrepancy between bone 
mineral density and fracture reduction with anti-resorptive therapy?

o  How do measurement site and regional heterogeneity influence these non-
invasive, reproducible imaging markers/methodologies for assessment of 
bone quality?

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and 
their sub-populations must be included in all NIH-supported 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 are 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

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

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

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

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS

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

URLS IN NIH GRANT APPLICATIONS OR APPENDICES

All applications and proposals for NIH funding must be self-contained within 
specific page limitations.  Unless otherwise specified in an NIH 
solicitation, internet addresses (URLs) should not be used to provide 
information necessary to the review because reviewers are under no obligation 
to view the Internet sites.  Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site.
 
 PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT
 
The Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances.  Data that are (1) first produced in a 
project that is supported in whole or in part with Federal funds and (2) 
cited publicly and officially by a Federal agency in support of an action 
that has the force and effect of law (i.e., a regulation) may be accessed 
through FOIA.  It is important for applicants to understand the basic scope 
of this amendment.  NIH has provided guidance at: 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this RFA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application should 
include a description of the archiving plan in the study design and include 
information about this in the budget justification section of the 
application. In addition, applicants should 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.

LETTER OF INTENT

Prospective applicants are asked to submit, by February 21, 2002, a letter of 
intent that includes a descriptive title of the proposed research; the name, 
address, and telephone number of the Principal Investigator; the identities 
of other key personnel and participating institutions; and the number and 
title of this RFA. Although a letter of intent is not required, is not 
binding, does not commit the sender to submit an application, 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 avoid 
conflict of interest in the review. The letter of intent is to be sent (e-
mail, fax or post) to Dr. Tommy Broadwater at the address listed under INQUIRIES.

APPLICATION PROCEDURES

Specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME" streamlining efforts that have been adopted by the 
NIH. Complete and detailed instructions and information on Modular Grant 
applications have been incorporated into the PHS 398 (rev. 5/2001). 
Additional information on Modular Grants can be found at 
http://grants.nih.gov/grants/funding/modular/modular.htm.

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.

Modular grant applications will request direct costs in $25,000 modules, up 
to a total direct cost request of $250,000 per year for R01 mechanisms and up 
to a total direct cost of $100,000 per year for R21 mechanisms.  A typical 
modular grant application will request the same number of modules in each 
year.  The total direct costs must be requested in accordance with the 
program guidelines and the modifications made to the standard PHS 398 
application instructions described below:

In preparing the R21 application, the Background and Significance Section of 
application should specifically state how the project represents a new 
direction for the work performed at the PI's laboratory. This should include 
a brief section (one page or less) entitled "Qualifications for High Risk" in 
which the PI specifically addresses the following concerns:

o  Innovation & Novelty: Does the proposed project represent a high degree of 
innovation and novelty?
o  Departure from current work:  Does the proposed project specifically 
overlap with work  from the PI during the last five years?  How does the 
proposed work represent a significant departure from the PI's current line of 
work?
o  High risk: Explain how the high gain potential of the project, if 
successful, offsets the high  risk of failure.

A Preliminary Data section is not required for the R21 applications but if 
included, it should not exceed one page. 

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

Submit a signed typewritten original of the application 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 and all 
five sets of any appendix materials must be sent to:

Dr. Tommy L. Broadwater
Scientific Review Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
45 Center Drive, Room 5AS-25U - MSC 6500
Bethesda, MD  20892-6500

Applications must be received by March 21, 2002.  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 the RFA that is essentially the same as on 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.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by CSR and 
responsiveness by NIAMS.  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 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 receive a written 
critique and under a process in which only those applications deemed to have 
the highest scientific merit, generally the top half of the applications 
under review, will be discussed, assigned a priority score, and receive a 
second level review by the NIAMS Advisory Council.

REVIEW CRITERIA

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments, reviewers will be asked to discuss the following 
aspects of the application in order to judge the likelihood that the proposed 
research will have a substantial impact on the pursuit of these goals.  Each 
of these criteria will be addressed and considered in assigning the overall 
score, weighing them as appropriate for each application.  Note that the 
application does not need to be strong in all categories to be judged likely 
to have major scientific impact and thus deserve a high priority score.  For 
example, an investigator may propose to carry out important work that by its 
nature is not innovative but is essential to move a field forward.  R21 
applications will be judged by the criteria listed in the "High Risk 
Arthritis and Musculoskeletal and Skin Diseases Research" solicitation, 
AR-01-008, found at 
http://grants.nih.gov/grants/guide/rfa-files/RFA-AR-01-008.html.

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

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

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

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

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

(6) Protection of Human Subjects.  Are there adequate provisions for the 
protection of human  subjects?  Is there sufficient attention given to the 
extent they may be adversely affected by the project proposed in the 
application?  Applications that fail to comply with this requirement will be 
designated as incomplete and will constitute grounds for the return of the 
application without peer review.

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

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

o  The adequacy of the provisions for the protection of animal subjects, the 
safety of the research environment, to the extent they may be adversely 
affected by the project proposed in the application.  

o  The appropriateness of staffing based on the requested percent effort and 
the personnel budget.  The direct costs budget request will be reviewed for 
consistency with the proposed methods and specific aims.  Any budgetary 
adjustments recommended by the reviewers will be in $25,000 modules.  The 
duration of support will be reviewed to determine if it is appropriate to 
ensure successful completion of the requested scope of the project.

SCHEDULE

Letter of Intent Date:            February 21, 2002
Application Receipt Date:         March 21, 2002
Council Review:                   September 25, 2002
Earliest Anticipated Start Date:  September 30, 2002

AWARD CRITERIA

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  Programmatic priorities

INQUIRIES

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

Direct inquiries regarding programmatic issues to one of the following:

Gayle E. Lester, Ph.D.
Musculoskeletal Diseases Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
45 Center Drive, Room 5AS-43C
Bethesda, MD  20892-6500
Telephone:  (301) 594-5055
FAX:  (301) 480-4543
Email:  gl83g@nih.gov

Guo Zhang, Ph.D.
Program Director
Division of Extramural Research
National Institute of Dental and Craniofacial Research
Natcher Building, Room 4AN-18C
Bethesda, MD  20892-6402
Telephone:  (301) 594-0618
FAX:  (301) 480-8318
Email:  gio.zhang@nih.gov

Direct inquiries regarding review issues to:

Tommy L. Broadwater, Ph.D.
Scientific Review Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
45 Center Drive, Room 5AS-25U - MSC 6500
Bethesda, MD  20892-6500
Telephone:  (301) 594-4953
FAX:  (301) 480-4543
Email:  broadwat@mail.nih.gov

Direct inquiries regarding fiscal matters to one of the following:

Melinda Nelson
Grants Management Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
45 Center Drive, Room 5AS-49F, MSC 6500
Bethesda, MD  20892-6500
Telephone:  (301) 594-3535
FAX:  (301) 480-5450
Email:  nelsonm@mail.nih.gov

Mr. Martin Rubinstein
Office of Grants Management
National Institute of Dental and Craniofacial Research
Natcher Building, Room 4AN-44A
Bethesda, MD  20892-6402
Telephone:  (301) 594-4800
FAX:  (301) 480-8301
Email:  Martin.Rubinstein@nih.gov


AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance 
No. 93.846.  Awards are made under authorization of the Public Health 
Service Act, Title IV, Part A (Public Law 78-410), as amended by Public 
Law 99-158, 42 USC 241 and 285) and administered under PHS grants 
policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74.  This 
program is not subject to the intergovernmental review requirements of 
Executive Order 12372 or Health Systems Agency review.

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


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