This Program Announcement expires on November 1, 2004, unless reissued.

STRATEGIES TO IDENTIFY THE GENETIC BASIS OF DIABETIC RETINOPATHY

Release Date:  November 26, 2001

PA NUMBER:  PA-02-020

National Eye Institute
 (http://www.nei.nih.gov)
National Institute of Diabetes and Digestive and Kidney Diseases
 (http://www.niddk.nih.gov)

THIS PA 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 PROVIDED IN SECTION C OF THE PHS 398 
(REVISION 5/2001) AVAILABLE AT 
http://grants.nih.gov/grants/funding/phs398/phs398.html.

PURPOSE

Diabetic retinopathy, a complication of diabetes mellitus, is a debilitating 
condition which often results in visual impairment, and in some cases 
blindness.  Data from family studies suggest a genetic component to the 
development of diabetic retinopathy.  The purpose of this Program Announcement 
(PA) is to encourage investigator-initiated research to advance scientific 
understanding of the genetic predisposition underlying the initiation or 
progression of diabetic retinopathy.  Major areas of research interest 
include, but are not limited to:  (1) gene discovery; (2) genetic 
epidemiology; (3) methodological studies of phenotypic assessment of 
retinopathy, including possible surrogate markers; and, (4) the development 
and application of novel statistical methods relevant to analyzing genetic 
data on diabetic retinopathy.

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 Program Announcement, Strategies to 
Identify the Genetic Basis of Diabetic Retinopathy, 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/.

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.  Racial/ethnic minority individuals, 
women, and persons with disabilities are encouraged to apply as principal 
investigators.

MECHANISM OF SUPPORT

This PA will use the National Institutes of Health (NIH) R01 award mechanism.  
Responsibility for the planning, direction, and execution of the proposed 
project will be solely that of the applicant.  The total project period for an 
application submitted in response to this PA may not exceed five years.

RESEARCH OBJECTIVES

Diabetic retinopathy is one of the most common causes of severe vision loss in 
the world.  Despite advances in screening, diagnosis, and treatment, the 
pathogenesis of diabetic retinopathy is not well understood, and opportunities 
to improve our understanding of the pathophysiology of this complication of 
diabetes have been limited.  Results from epidemiologic studies of diabetic 
persons suggest that there are familial predispositions to diabetes and to 
diabetic retinopathy.

In September 2000, the National Eye Institute (NEI) convened a 
multidisciplinary group of clinicians, epidemiologists, statistical 
geneticists, and molecular geneticists to discuss recent developments in human 
molecular genetics and the opportunities created for studying the genetic 
predisposition underlying the development and progression of diabetic 
retinopathy.  Several key areas were identified as important to advance 
scientific knowledge of the genetics of diabetic retinopathy (see 
http://www.nei.nih.gov/funding/wrkshop.htm)  Some of these recommendations 
form the basis of this PA.  It is hoped that increased understanding of the 
genetics underlying the development or progression of retinopathy will have an 
impact on future diagnostic, prevention and intervention strategies.

Summary

A broad range of specific research questions and methodological approaches are 
relevant to this PA.  Applicants are strongly encouraged to develop 
collaborative interdisciplinary team approaches involving clinicians, 
epidemiologists, molecular geneticists, and statistical geneticists to study 
the complex genetic basis underlying diabetic retinopathy.  Applicants can 
focus on one or more key areas of interest.  Examples include, but are not 
limited to, those outlined below:

o	Gene discovery:  Genetic linkage studies and/or candidate gene studies 
relevant to diabetic retinopathy.

o  Genetic epidemiology:

(a)  Population-based and/or family-based approaches that consider complex 
interactions among genes and non-genetic factors, e.g. those incorporating the 
effects of cofactors likely involved in the expression of retinopathy as well 
as those underlying diabetes and potential co-occurring complications such as 
nephropathy.

(b)  The addition of a retinopathy phenotype component to a study where 
genotyping information is available.

(c)  The addition of a genotyping component to a study analyzing stored or 
newly-collected specimens where retinopathy phenotypic data are available.

o	Methodological studies on phenotypic assessment:

(a)  Development of quantitative, objectively-assessed phenotypic measures, 
including possible surrogate markers to use as endpoints for earlier diagnosis 
of retinopathy.

(b)  Development and validation of novel technology-driven methods as cost-
effective, scientifically valid and logistically feasible alternatives to a 
comprehensive dilated eye examination with fundus photography so as to 
facilitate large-scale epidemiologic studies.

o	Statistical methods:  Development and application of novel statistical 
approaches to analyze complex interrelationships between genetic and non-
genetic factors predisposing to diabetes, diabetic retinopathy, and other 
diabetic complications 

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 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 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 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 policy.

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 
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.  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 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.

APPLICATION PROCEDURES

The PHS 398 research grant application instructions and forms (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html must be used in 
applying for these grants and will be accepted at the standard application 
deadlines (http://grants.nih.gov/grants/dates.htm) as indicated in the 
application kit.  This version of the PHS 398 is available in an interactive, 
searchable format.  For further assistance contact GrantsInfo, Telephone 
301/435-0714, Email: GrantsInfo@nih.gov.

Applicants planning to submit an investigator-initiated new (type 1), 
competing continuation (type 2), competing supplement, or any amended/revised 
version of the preceding grant application types requesting $500,000 or more 
in direct costs for any year are advised that he or she must contact the 
Institute or Center (IC) program staff at least six weeks before the 
application receipt date, i.e., as plans for the study are being developed.  
Furthermore, the application must obtain agreement from the IC staff that the 
IC will accept the application for consideration for award.  Finally, the 
applicant must identify, in a cover letter sent with the application, the 
staff member and Institute or Center who agreed to accept assignment of the 
application.

This policy requires an applicant to obtain agreement for acceptance of both 
any such application and any such subsequent amendment.  Refer to the NIH 
Guide for Grants and Contracts, March 20, 1998 at 
http://grants.nih.gov/grants/guide/notice-files/not98-030.html 

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS

The modular grant concept establishes specific modules in which direct costs 
may be requested as well as a maximum level for requested budgets. Only 
limited budgetary information is required under this approach.  The 
just-in-time concept allows applicants to submit certain information only when 
there is a possibility for an award. It is anticipated that these changes will 
reduce the administrative burden for the applicants, reviewers and NIH staff.  
The research grant application form PHS 398 (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html is to be used in 
applying for these grants, with modular budget instructions provided in 
Section C of the application instructions.  

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

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)

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established PHS referral 
guidelines.  Applications will be evaluated for scientific and technical merit 
by an appropriate scientific review group convened in accordance with the 
standard NIH peer review procedures.  As part of the initial merit review, all 
applications will receive a written critique and undergo a process in which 
only those applications deemed to have the highest scientific merit, generally 
the top half of applications under review, will be discussed, assigned a 
priority score, and receive a second level review by the appropriate national 
advisory council or board.

Review Criteria

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments reviewers will be asked to discuss the following aspects 
of 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, 
weighting 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.

(1) 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?

(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 method? 
Are the aims original and innovative?  Does the project challenge existing 
paradigms or 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?

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.  Plans for the recruitment and retention of subjects will also be 
evaluated.

o  The reasonableness of the proposed budget and duration in relation to the 
proposed research.

o  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  The adequacy of the proposed plan to share data, if appropriate.

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.

INQUIRIES

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

Direct inquiries regarding programmatic issues to:

Peter A. Dudley, Ph.D.
Division of Extramural Research
National Eye Institute
Executive Plaza South, Suite 350, MSC 7164
Bethesda, MD  20892-7164
Telephone:  (301) 496-0484
FAX:  (301) 402-0528
Email:  pad@nei.nih.gov

Dr. Thomas L. Eggerman
Division of Extramural Activities
National Institute on Diabetes and Digestive and Kidney Diseases
2 Democracy Plaza, Room 697
6707 Democracy Blvd, MSC 5456
Bethesda, MD  20892-5456
Telephone:  (301) 594-8813
FAX:  (301) 480-3503
Email:  eggermant@extra.niddk.nih.gov

Direct inquiries regarding fiscal matters to:

Grants Management Officer
Division of Extramural Research
National Eye Institute
Executive Plaza South, Suite 350, MSC 7164
Bethesda, MD  20892-7164
Telephone:  (301) 496-5884
FAX:  (301) 496-9997
Email:  wwd@nei.nih.gov

Grants Management Officer
Division of Extramural Activities
National Institute on Diabetes and Digestive and Kidney Diseases
2 Democracy Plaza, Room 654
6707 Democracy Blvd, MSC 5456
Bethesda, MD  20892-5456
Telephone:  (301) 594-8854
FAX:  (301) 480-4237
Email:  de30z@nih.gov

AUTHORITY AND REGULATIONS 

This program is described in the Catalog of Federal Domestic Assistance No. 
93.867.  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 and Federal Regulations 42 CFR 52 and 45 CFR Parts 
74 and 92.  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, and 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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