DIABETIC AND NON-DIABETIC NEPHROPATHY SUSCEPTIBILITY GENES

Release Date:  January 20, 1999

RFA:  DK-99-005

P.T.

National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date:  March 12, 1999
Application Receipt Date:  April 12, 1999

PURPOSE

The Division of Kidney, Urologic and Hematologic Diseases (DKUHD) of the National
Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) invites
Cooperative Agreement Applications for a Genetic Analysis and Data Coordinating
Center (GADCC) and for Participating Investigating Centers (PICs) to participate
in the development and implementation of studies to identify genes which are
associated with the development and progression of renal diseases, especially
diabetic nephropathies.  The Centers will work together as a Consortium.

The goals of the study include recruitment and clinical characterization of
subjects and special populations of patients with renal disease and appropriate
control populations, data coordination, and genetic analyses. The GADCC and the
PICs will jointly propose and finalize the initial study protocol(s), and methods
of genetic analyses, which will employ cost-effective strategies to recruit
prospectively the appropriate number and variety of subjects and families. The
PICs will recruit subjects and control populations, taking advantage of their
individual geographic locations and access to special patient populations.  It
is anticipated that the PICs will conduct independent analyses and will have
exclusive access to data from their study populations for a period of time.  The
GADCC will be responsible for the collection, management and analysis of both the
genetic and the clinical data. The GADCC will perform genotyping for all the
PICs.  The GADCC may perform studies proposed by the individual PICs, or groups
of PICs.  The end-stage renal disease (ESRD) population presents investigators
with an extraordinary potential study population.

The primary objective(s) of this investigation will be identification of genes
or genomic regions that are associated with differential risks for the expression
and progression of renal disease, or high risk of development of ESRD, especially
diabetic nephropathies.  To that end, identification and recruitment of patients
from specific, homogeneous ethnic backgrounds, with well characterized renal
diseases, including treatment profiles and responses, especially patients with
diabetic nephropathy, and use of family recruitment techniques and appropriate
control patient populations will be critical.  In addition, these studies will
serve to establish, maintain and make available a database of uniformly and
accurately collected genetic and phenotypic information reflecting underlying
susceptibility to variable courses and outcomes of renal diseases identified by
the GADCC and the PICs, especially diabetic nephropathy.  It is the intent of
this solicitation to focus primarily on renal diseases which often progress to
ESRD, and are at high prevalence in the ESRD population.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2000," a PHS-led national
activity for setting priority areas. This RFA, Diabetic and Non-diabetic
Nephropathy Susceptibility Genes, relates to the priority areas of chronic
disabling conditions and prevention services.  Potential applicants may obtain
a copy of "Healthy People 2000" at http://www.crisny.org/health/us/health7.html.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic, 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.  Foreign institutions are not eligible to apply. 
Racial/ethnic minorities, women, and persons with disabilities are encouraged to
apply as Principal Investigators.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) cooperative agreement
(U01) mechanism of support. The cooperative agreement is an assistance mechanism
in which substantial NIDDK scientific and programmatic involvement is anticipated
during performance of the activity.  Under the cooperative agreement, the NIDDK
purpose is to support and encourage the recipient's activities by working jointly
with the awardees in a partnership role, but not to assume direction, primary
responsibility, or dominance.  Details of the responsibilities, relationships,
and governance of a study funded under a cooperative agreement are described
under the section entitled "Terms and Conditions of Award."

The total project period for an application submitted in response to this RFA may
not exceed five years.  The anticipated award date is September 30, 1999.

It is anticipated that the awards for the GADCC and the PICs will be
approximately $4,000,000 total cost, per year.

At this time, the NIDDK has not determined whether or how this solicitation will
be continued beyond the present RFA.

FUNDS AVAILABLE

The NIDDK intends to commit approximately $4,000,000 in total costs (direct plus
indirect costs) in FY 1999, to fund up to six awards for the PICs and one award
for a GADCC, in response to this RFA. An applicant for a GADCC may request a
project period of up to five years and a budget for total costs of up to
$1,500,000 per year for its core functions.  An applicant for a PIC may request
a project period of up to five years. It is anticipated that the PICs will
conduct independent studies and analyses, using the facilities of the GADCC, but
will have exclusive access to data from their study populations for a period of
time.  Individual PIC studies performed by the GADCC will be funded from the PIC
budget.  The award for each PIC could be up to $500,000 total costs, depending
on the scope of the work proposed, for the first year of the award. Because the
nature and scope of the research proposed in response to this RFA may vary, it
is anticipated that the size of each award will also vary.

The number of awards to be made is dependent on the receipt of a sufficient
number of applications of high scientific merit and availability of funds. 
Although the financial plans of the NIDDK provide support for this program,
awards pursuant to this RFA are contingent upon the availability of funds and the
receipt of sufficient number of applications of outstanding scientific and
technical merit.

RESEARCH OBJECTIVES

A.  Background

Kidney disease is a serious and costly disease. More than 300,000 people in the
USA have ESRD. Renal disease due to diabetes mellitus and hypertension accounts
for the majority of incident cases of ESRD.  This is thought to represent a small
minority of the number of patients with kidney disease at less advanced stages,
including chronic renal insufficiency.  The early stages of kidney disease may
be undetected, unless screening is employed to detect hypertension, proteinuria
and renal insufficiency.

Previous studies have demonstrated that there is an increased prevalence of renal
disease in family members of patients with diabetic renal disease (familial
clustering). Limited studies suggest a higher risk of a variety of different
renal diseases in family members of African-American patients with ESRD. There
is also an increased incidence and prevalence of both diabetic and non-diabetic
renal disease in selected subpopulations within the US, such as African-
Americans, Hispanic-Americans, and Native Americans. Variations in specific
genomic regions have been associated with the differential prevalence of diabetic
nephropathy and IgA nephropathy in populations. Approximately 10% of human
immunodeficiency virus infected people develop an associated nephropathy, but the
vast majority of those affected are African-American men. These findings suggest
an inherited susceptibility to the development of renal disease, which may be
independent of the predisposition to developing diabetes mellitus.

Although studies show similarity of glomerular findings in patients with Type 1
and Type 2 diabetes mellitus and diabetic nephropathy, recent findings have
demonstrated the heterogeneity of renal histologic patterns in patients with Type
II diabetes mellitus and renal disease.  Such heterogeneity, and variations in
response to different pharmacologic therapies,  must be considered in planning
studies of the genetic susceptibility to renal disease in patients with diabetes
mellitus.

A salient characteristic of renal disease is that its progression is variable
among patients, but may follow a predictable course in an individual patient over
time.  Such variation is particularly striking in patients with polycystic kidney
disease (PKD), but early studies suggested onset of ESRD is similar in family
members, suggesting heritable factors exist which modify the course of disease. 
More recent genetic analyses suggest variants at both PKD gene and other loci
modify the course of the decline in renal function. Some populations experience
hypertension for many years, without developing renal disease (essential
hypertension), while other people at risk develop hypertensive nephropathy.
Finally, controversy regarding the differential susceptibility of the kidney to
end-organ damage in different populations also suggests a role for genetic
determinants in the pathogenesis of diabetic and non-diabetic renal diseases.

The focus of this research initiative is the discovery of disease specific and
non-specific genetic renal disease susceptibility and modifying factors, which
may be critical to the development of nephropathy in humans. Current state-of-
the-art methods make possible the identification of specific genomic regions that
may vary among populations. Two approaches to the identification of specific gene
sequences in populations have emerged: candidate gene strategies and genome wide
screening methods.  Although cohort studies are likely to be less costly,
ultimately, family studies will be necessary to establish associations and reduce
possible confounds.  There are several strategies for using families to establish
the necessary and sufficient gene sequences involved in the pathogenesis of renal
disease.  There is, however, very limited experience in applying these techniques
to identify groups with specific renal diseases, or with unusually fast or slow
rates of disease progression.

The ESRD population presents an opportunity to apply such techniques to the
search for nephropathy susceptibility genes.  A large number of patients with
well-established renal diagnoses is available for investigation, and incident
patients number over 70,000 persons. The latter group represents an ideal
population in which to perform family studies.  The United States Renal Data
System and the regional system of ESRD Networks established by the Health Care
Financing Administration are potential institutional partners in implementation
of large scale molecular epidemiologic studies in this population.  Nationwide
dialysis providers may have unique access to patient populations of interest. 
Investigators partnering with dialysis providers may increase their access to
large numbers of subjects.

Identification of gene sequences associated with susceptibility to the
development of renal disease, or with slow progression of nephropathy might
provide markers for patients at risk for the development of ESRD, allow the early
implementation of proved therapies, and provide rationales for the development
of novel therapeutic strategies to treat renal disease.  Although the cost of
these techniques has diminished recently with advances in automation, genotyping
large populations and assessment of many gene sequences is likely to be costly. 
Strategies for reducing costs will enhance the power of such studies.

B. Research Goals and Scope

It is the intent of this solicitation to invite applications from investigators
with diverse scientific interests, who wish to apply their expertise to the
discovery of gene sequences associated with the development of nephropathy,
especially diabetic renal disease, and the variability of its progression. It is
the overall goal of this solicitation to identify genetic pathways that may be
critical for the development of nephropathy, and lead to candidates amenable to
therapeutic strategies to prevent the onset or progression of nephropathy.  Such
data might aid identification of people at risk for the development of
progressive renal disease.  The specific goals of this solicitation are to be
able  (1) to facilitate the recruitment of representative patients and families
with well-characterized renal diseases, especially the diabetic nephropathies,
to delineate genomic regions associated with the development and progression of
renal disease(s); (2) to improve outcomes, provide protection and slow
progression of renal disease in people at risk;  (3) to help establish a resource
for genetic studies of kidney disease by creating a family collection repository;
and (4) to encourage studies of the genetics of progressive renal disease.

It is anticipated that the study will take place in up to six PICs over a period
of five years.  It is envisioned that the PIC will need to develop realistic
estimates of the appropriate number of well-characterized selected patient,
family and control subjects to achieve the goals of the study.

The data collection activities of the PICs will be supported by a single GADCC.

C.  Study Design

It is anticipated that over the five-year period, several cohorts of patients,
families and control subjects will be studied by the Principal Investigators. 
The individual PICs and the GADCC participating in the cooperative study should
conduct mutually agreed upon protocols for characterization of study subjects and
for genetic analytic strategies.  The PICs will also conduct independent
analyses, and will have exclusive access to data from their study populations for
a period of time, to be determined by the Steering and Planning Committee (see
below).

The design of the final research protocol for implementation, including the
eligibility criteria for the final study population and the studies to be
undertaken, will be effected by the Steering and Planning Committee (see below),
based on protocols submitted and approved by the Scientific Review Group during
the review process.

D.  Study Components

1.  Participating Investigating Centers (PICs)

A PIC is an institution that is actively involved in the recruitment and
evaluation of patients, family members and control subjects as appropriate study
subjects, and the initiation of individual, center-specific genetic studies
taking advantage of special patient populations.  The PIC should consist of an
interdisciplinary team of clinical investigators and appropriate personnel, such
as a research coordinator and clerical staff.

PICs will be required to submit familial, phenotypic, diagnostic, medical
therapeutic and genetic data expeditiously.  The PIC must work in concert with
the GADCC to implement procedures for uniform data collection, handling and
transmittal of data, as well as data audits and other data quality control
procedures, as established by the study protocol.  The PIC will be required to
share data and patient specimens derived from collaborative studies.  The
Principal Investigator and Co-Investigators in each PIC should be skilled in
collaborative clinical investigation. It is anticipated that the PICs will
conduct independent analyses and will have exclusive access to data from their
study populations for a period of time to be determined by the Steering and
Planning Committee.  Individual, center-specific projects may be conducted
through the auspices of the GADCC.  The PICs and GADCC will develop uniform
procedures and data sharing policies, and independently and collectively allocate
resources and personnel for the performance of independent, center-specific
analyses and studies.

2. Genetic Analysis and Data Coordinating Center (GADCC)

The GADCC will have primary responsibility for collecting, storing, and analyzing
data generated by the PICs, for establishing and implementing data auditing and
quality control procedures for each aspect of the study, and for providing final
study analyses. The GADCC should establish a core facility for clinical specimen
handling and analyses.  The GADCC will also have primary responsibility for
proposing the development of the initial study protocol for the collective
studies, and will be responsible for the collection and analysis of the clinical
and genetic data.  Sub-contracting of various aspects of the GADCC to other
institutions with special expertise may be included in the application.  The
GADCC should be prepared to assume a key role in overseeing implementation and
adherence to the study protocols, and assuring quality control of the data
collected.  The GADCC will be expected to provide appropriate molecular biologic,
biostatistical, data management, and coordination expertise, as well as
supporting the special independent studies proposed by the individual PICs and
approved by the Steering and Planning Committee (see below).  The GADCC also will
be expected to generate appropriately detailed reports to the Steering and
Planning Committee and to the External Advisory Committee (see below) at regular
intervals, and will be responsible for the logistics and planning of the meeting
of these committees and their subcommittees.

3.  Steering and Planning Committee

The primary governing body of the study will be the Steering and Planning
Committee comprised of each of the Principal Investigators of the PICs and the
GADCC, the Chairperson of the Steering and Planning Committee, and the NIDDK
Project Coordinator (described in detail under Terms and Conditions).

4.  External Advisory Committee

An independent committee supported by the NIDDK and composed of experts in
nephrology, biostatistics, genetics, and bioethics who are not otherwise involved
in the study, will be established to review periodically the progress of the
study (described in detail under Terms and Conditions).  This Committee will also
be responsible for reviewing the acceptability of initial data quality monitoring
plans established by the Steering and Planning Committee and the subsequent
monitoring of data quality by means of reports prepared by the GADCC.

5.  Project Coordinator

The NIDDK will appoint a Project Coordinator, within the Division of Kidney,
Urologic and Hematologic Diseases, to assist the Steering and Planning Committee
and External Advisory Committee in carrying out the study (described in detail
under Terms and Conditions).  The Project Coordinator will provide scientific
support to awardees activities, including protocol development, quality control,
interim data monitoring, final data analysis and interpretation, preparation of
publications, and overall performance monitoring.

6.  Study Phases

It is anticipated that the study will be implemented in three phases over a five-
year period.  There may be some overlap in functions within each of the phases,
and the time estimates are only approximations.  The purpose of the phases is to
provide broad guidelines regarding the total scope of work to be accomplished for
this RFA.

Phase I: Development of the study infrastructure, completion of the study
protocol(s), including informed consent procedures, and development of a manual
of operations.  This phase should take approximately six months.

The first six months of the study will be devoted to finalizing the study
protocol(s), the clinical studies infrastructure and committees' structure. Goals
for the Steering and Planning Committee will be to finalize the study protocol,
including determination of patient, family and control subject eligibility
criteria; train staff in procedures; help set up data acquisition and consent
forms; develop a manual of operations, diagnostic and familial questionnaires,
and procedures for quality control.

The GADCC will play a key role in the logistics of the planning and development
stage. It is anticipated that in the proposal, criteria for standardization of
patient, family member and control population selection criteria and genetic
studies, and data collection for the investigations to be performed will be
outlined.  In addition to assisting the PICs in finalizing the study protocols,
the GADCC will establish the data acquisition, transfer, and management system;
develop procedures for ensuring subject and control confidentiality and safety;
develop procedures for quality control, training, and certification; develop and
produce a manual of operations; and supervise the orderly collection and
transmission of data.

Phase II: Patient recruitment, protocol implementation and further protocol
refinement.  This phase should take approximately 48 months.

In Phase II, the PICs will have full responsibility for training of pertinent PIC
staff, and for implementing data auditing and quality control procedures, as
established.  The GADCC will also support the joint and independent studies of
the PICs with the central processing and analysis of genetic, laboratory and
clinical data.  The GADCC will assist with formulation of strategies to enhance
patient recruitment, and it will assist with the overall protocol implementation
and refinement, as necessary. The PICs will have full responsibility for
identifying, recruiting and enrolling the necessary number of study participants
to meet the study goals and bring the study to completion.  The PICs will collect
and transmit genetic, familial and clinical data as delineated in the Manual of
Operation.

Phase III: Data analysis and reporting of study findings.  This phase should take
approximately six months.

After the last patients in the studies have been recruited and the sample
collection is completed, the PICs will review the data and assist the GADCC in
the close-out of the study. The GADCC will continue with its activities in data
management, editing, and molecular biologic and statistical analysis.  The GADCC
will support manuscript preparation through data analysis, statistical
consultation, editorial tasks, and coordination of meetings.

SPECIAL REQUIREMENTS

Terms and Conditions of Award

The following terms and conditions will be incorporated into the award statement
and provided to each Principal Investigator as well as to the institutional
officials at the time of the award.  These terms are in addition to, not in lieu
of, otherwise applicable Office of Management and Budget (OMB) administrative
guidelines, HHS Grant Administration Regulations at 45 CFR Part 74 and 92, and
other HHS, PHS, and NIH Grants Administration policy statements.

The administrative and funding instrument used for this program is the
cooperative agreement (U01), an "assistance" mechanism (rather than an
"acquisition" mechanism), in which substantial NIH scientific and/or programmatic
involvement with the awardee is anticipated during the performance of the
activity.  Under the cooperative agreement, the NIH purpose is to support and/or
stimulate the recipient's activity by involvement in and otherwise working
jointly with the award recipient in a partner role, but it is not to assume
direction, prime responsibility, or a dominant role in the activity. Consistent
with the cooperative agreement concept, the dominant role and prime
responsibility for the planned activity resides with the awardees for the project
as a whole, although specific tasks and activities in carrying out the activity
will be shared among the awardees and NIDDK Project Coordinator.

A.  Awardee Rights and Responsibilities

Awardees will have substantial and lead responsibilities in all tasks and
activities.  These include protocol development, patient recruitment, insurance
of patient and subject safety and confidentiality, data collection, quality
control, final data analysis and interpretation, and preparation of publications. 
The awardee agrees to work cooperatively with the other PICs and the GADCC,
agrees to share data and patient specimens derived from collaborative studies,
and agrees to follow the common protocol and Manual of Operations developed by
the Steering Committee.  The awardee also agrees to transmit all study data to
a central GADCC for combination and analysis.  Awardees will retain custody of
and have primary rights to their data developed under these awards, subject to
Government (e.g., NIDDK, NIH, or PHS) rights or access consistent with current
HHS, PHS, and NIH policies.

B.  NIDDK Staff Responsibilities

The NIDDK will name a Project Coordinator from within the Division of Kidney,
Urologic and Hematologic Diseases, whose function will be to assist the Steering
and Planning Committee and External Advisory Committee in carrying out the study. 
The Project Coordinator will be a voting member of all key study group
subcommittees and will serve as Executive Secretary of the External Advisory
Committee.  The Project Coordinator will have substantial scientific programmatic
involvement in the overall management of the study, in protocol development,
quality control, interim data analysis, safety monitoring, and final data
analysis and interpretation, preparation of publications, and coordination and
performance monitoring.  The dominant role and prime responsibility for these
activities resides with the awardees for the project as a whole, although
specific tasks and activities in carrying out the studies will be shared among
the awardees and the NIDDK Project Coordinator.

The NIDDK Project Coordinator will have voting membership on the Steering and
Planning Committee and, as determined by that committee, its subcommittees.

The NIDDK reserves the right to terminate or curtail the study (or an individual
award) in the event of substantial shortfall in participant recruitment, data
reporting, quality control, or other major breach of the protocol, or if human
subject ethical issues dictate a premature termination. 

C. Collaborative Responsibilities

A Steering and Planning Committee, composed of the Principal Investigators of
each PIC, the Principal Investigator of the GADCC, and the NIDDK Project
Coordinator will be the main governing board of the study and will have primary
responsibility for developing common study designs, protocols, and manuals;
facilitating the conduct and monitoring of studies, and reporting study results. 
Each Principal Investigator from a PIC and the GADCC as well as the NIDDK Project
Coordinator, will have one vote.  The Chairperson, who will be someone other than
an NIDDK staff member, will be selected by the Steering and Planning Committee.

Subcommittees will be established by the Steering and Planning Committee, as it
deems appropriate; the Project Coordinator will serve on subcommittees as he/she
deems appropriate.

The final collaborative protocols will be developed by the Steering and Planning
Committee.  Individual, center-specific PIC studies will be approved by the
Steering and Planning Committee.  Patient, family and control subject data and
laboratory specimens, as determined, will be submitted to the central GADCC. 
Protocols will define access to data and publications, and the time period during
which the PIC will have exclusive access to their individual data.  An
independent External Advisory Committee, to be appointed by the NIDDK, will
review progress at least annually and report to the NIDDK.

Awardees will be required to accept and implement the common protocol(s) and
procedures approved by the Steering and Planning Committee, and be willing to
share data and patient specimens derived from collaborative studies.

D.  Arbitration

Any disagreement that may arise on scientific/programmatic matters (within the
scope of the award) between recipients and the NIDDK may be brought to
arbitration.  An arbitration panel will be composed of three members - one
selected by the Steering and Planning Committee (with the NIDDK member not
voting) or by the individual awardee in the event of an individual disagreement,
a second member selected by NIDDK, and the third member selected by the two
previously selected members. This special arbitration procedure in no way affects
the awardee's right to appeal an adverse action that is otherwise appealable in
accordance with the PHS regulations at 42 CFR Part 50, Subpart D and HHS
regulation at 45 CFR Part 16.

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 biomedical and behavioral
research projects involving human subjects, unless a clear and compelling
rationale and justification is provided 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 1003-43).

All investigators proposing research involving human subjects should read the
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical
Research" which have been published in the Federal Register of March 28, 1994 (FR
59 14508-14513), and in the NIH Guide for Grants and Contracts of March 18, 1994,
Volume 23, Number 11, available on the web at:
http://grants.nih.gov/grants/guide/notice-files/not94-105.html.

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 subject 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 this policy.

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent that includes a
descriptive title of the proposed research, the name, address, and telephone
number of the Principal Investigator, and identities of other key personnel and
participating institutions, and number and title of the RFA in response to which
the application may be submitted.  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 the NIDDK staff to estimate the potential
review workload and avoid conflict of interest in the review.

The letter of intent is to be sent to:

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney
45 Center Drive, Room 6AS-37F - MSC 6600
BETHESDA, MD  20892-6600
Telephone:  (301) 594-8885
FAX:  (301) 480-3505

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used in applying
for these grants. Application kits are available at most institutional offices
of sponsored research and may be obtained from the Division of Extramural
Outreach and Information Resources, National Institutes of Health, 6701 Rockledge
Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301) 435-0714, email:
GrantsInfo@nih.gov.

The RFA label in the form PHS 398 must be affixed to the bottom of the face page. 
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.  For purposes
of identification and processing, item 2 of the face page of the application must
be marked "YES" and the RFA number and title,  "Nephropathy Susceptibility Genes"
must be typed in.

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:

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes, Digestive, and Kidney Diseases
45 Center Drive, Room 6AS-37F MSC 6600
Bethesda, MD 20892-6600

Applications must be received by the application receipt date listed in the
heading of this RFA.  If an application is received after this date it will be
returned to the applicant without review.  Supplemental documents containing
significant revisions or additions to submitted applications will not be accepted
unless applicants are contacted by the Scientific Review Administrator.

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.

Information to be Included in Applications

Provision should be made for meeting the required appropriate representation of
genders, minorities and children, as required for successful accomplishment of
study goals.

Applicants for both the PICs and the GADCC should respond with research protocols
involving multicenter participation to address the objectives of the study and
to reach the study goals.  It is anticipated that applicants will develop
criteria for studying both patients at high risk of progression, and homogenous
populations with well-characterized renal diseases, representing study
populations of particular interest.  Applicants should outline the rationale and
background of the proposed studies, study design and protocols, eligibility
criteria, type of patients, family members and control subjects to be included
in the studies, and initial power analyses in their applications.  For each of
the clinical protocols, the PIC applicants should discuss the characteristics and
number of potential participants that would be available from their own
geographic region.  It is anticipated that PIC applicants will propose a varying
number of studies, but the submitted research plan should remain within the 25
page limit.

Genetic studies involving individual subjects and groups of people necessarily
involve information that should be kept highly confidential.  It will be critical
that at all phases of the study, the investigators understand and minimize the
risks involved in such genetic research,  protecting both individual subjects and
research participants in groups, and optimize procedures for obtaining informed
consent.

An application for a PIC should provide evidence that the investigators are
capable of recruiting a sufficient number of participants for the proposed
studies, and initiating and completing independent studies consistent with the
overall goals of this RFA.  Applicants for PICs should describe the target
population from which they expect to recruit the required number of patients,
family members and control subjects as study participants, and plans for
recruitment of women, minorities, and children, as required. In addition,
applicants for a PIC will submit proposals and power analyses for cost-effective
strategies to address their individual study questions, taking advantage of their
particular geographic locations and patient populations.  Proposed provisions to
ensure confidentiality and to optimize informed consent procedures must be
presented in the application.

There should be evidence of strong institutional support for the PIC, including
adequate space in which to conduct clinic activities and office space for staff. 
An organizational structure for the PIC should be set forth in the application,
delineating lines of authority and responsibility for dealing with problems in
all general areas as well as stated willingness to follow commonly agreed upon
protocols.

The applicant should include a succinct discussion of previous relevant research
efforts.  Applicants for PICs should consider the economies of scale to be gained
and cost effectiveness of strategies of research plans involving large numbers
of patients, such as those treated for ESRD.  Suitable partnership strategies and
relationships with dialysis providers may be desirable.  The applicant should
also discuss in detail the recruitment strategies to procure the expected number
of study participants.  Specific plans for recruitment of minority participants
and children must also be discussed.

Applicants for the GADCC should provide a detailed description of prior
experience in multicenter and genetic clinical studies. Proposed provisions to
ensure subjects' confidentiality and to optimize informed consent procedures must
be presented in the application.

It is anticipated that in the GADCC application, criteria for standardization of
patient, family member and control population selection criteria and genetic
studies, and data collection for the investigations to be performed will be
outlined.

Applications for the PICs and the GADCC must include a year-by-year budget that
is adequately justified.

For the PICs, the proposed budget should include a minimum number of full-and
part-time staff to successfully carry out the proposed studies.  Typical
personnel at a PIC might include part-time effort of a Principal Investigator,
Co-Investigator, and the full time effort of a Study Coordinator.  The budget
should include support for travel for up to two key study personnel to attend
monthly Steering and Planning Committee Meetings during Phase I, quarterly
meetings during Phase II, and bi-monthly meetings during Phase III of the study.
Steering and Planning Committee Meetings will be held in the Washington, D.C.,
area.  The budget also should include travel support for the Principal
Investigator to attend the External Advisory Committee Meetings, to be held, at
the completion of Phase I, one meeting per year in Phase II, and one meeting at
the completion of Phase III of the study.

The PIC should also budget for the costs of the contemplated independent studies,
to be performed by the GADCC.

For applications for the GADCC, the proposed budget should include the time and
effort of a Principal Investigator and Co-Investigator, and key personnel needed
to conduct the studies. The proposed budget should also include the costs of
transport of clinical specimens for central processing and analysis.  The budget
should include support for travel for three to four investigators to attend
monthly Steering and Planning Committee Meetings during Phase I; quarterly
meetings during Phase II; and bi-monthly meetings during Phase III of the study. 
Meetings of the Steering and Planning Committee will be held in the Washington
D.C., area. The budget should include costs to travel to Washington, D.C., for
External Advisory Committee Meetings.  Meetings of the External Advisory
Committee will be held at the completion of Phase I; one meeting per year during
Phase II; and one final meeting at the completion of Phase III of the study. 
Site visits (one visit for years 2-5) should also be included in the budget.  The
GADCC should also budget for travel for the Chairperson of the Steering and
Planning Committee to attend monthly meetings during Phase I, quarterly meetings
during Phase II, and bi-monthly meetings in Phase III of the study.

The GADCC should budget for the costs of the common analyses approved by the
Steering and Planning Committee, and for the individual PIC projects, approved
by the Steering and Planning Committee.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR and
responsiveness by the NIDDK. Incomplete and/or non-responsive 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 NIDDK in
accordance with the review criteria stated below.  As part of the initial merit
review, a process will be used by the initial review group in which applications
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 the
applications under review, will be discussed, assigned a priority score, and
receive a second level review by the NIDDK National Advisory Council.

In addition to the scientific and technical merit, all applications will be
judged on the documented ability of the investigators to meet the research
objectives of the RFA, including for PICs, the availability of study
participants, the ability to recruit minority participants and children, and the
geographic location, which will be part of the evaluation criteria.

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 the field forward.

(1) Significance:  Does this study address an important problem?  If the aims of
the application are achieved, how will scientific knowledge be advance?  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 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 sub-
groups, and children, as appropriate for the scientific goals of the research.

o  Plans for recruitment and retention of study participants.

o  The reasonableness of the proposed budget and the duration of the proposed
research.

o  The adequacy of the proposed protection for humans, or the environment, to the
extent they may be adversely affected by the project proposed in the application.

Additional scientific/technical merit criteria, specific to the objectives of the
RFA, to be used in the review are as follows:

Applicants are encouraged to submit and describe their own ideas about how best
to meet the goals of the cooperative study and their specific protocols. The
evaluation of applications for PICs and the GADCC will be based primarily on the
scientific merit of the proposed studies, as defined above.  Specific criteria
for review of applications will be as follows:

For both Participating Investigating Centers and the Genetic Analysis and Data
Coordinating Center:

1.  The scientific merit of the proposed study design(s) to address the
objectives of the RFA, including strategies for patient identification and
recruitment, and data collection and management, as outlined in the RFA.

2.  Adequacy of the facilities and space.

Understanding and awareness of the scientific, ethical, and practical issues
underlying the proposed studies and appropriateness of plans to deal with them.

4.  Evidence of the degree of institutional commitment and support for the
proposed program, including the relative position of the proposed project staff
within the applicant's organizational structure.

5.  Willingness to carry out a commonly agreed upon study protocol, and to share
patient data and specimens derived from collaborative studies.

6.  Adequacy of plans to ensure accurate collection, confidentiality and timely
transmission of study data.

7.  The organizational and administrative structure of the proposed program.

For Participating Investigating Centers:

1.  Documentation of the specific competence and previous experience of
professional, technical, and administrative staff pertinent to the operation of
a PIC in previous collaborative clinical investigations. Evaluation will include
the following: familiarity with and experience in recruiting participants in a
study; handling laboratory specimens; working in collaboration with other
investigators under a common protocol; ability to implement study procedures; and
meticulous and expeditious handling of study data.

2.  Documentation of access to patient population(s) from which a substantial
number of participants can be recruited in sufficient numbers to meet the goals
specified in the RFA.

3.  Ability to recruit representative minority populations and children, as
required.

4.  Adequacy of proposed sample sizes and strategies for cost effective patient
recruitment and data collection.

For the Genetic Analysis and Data Coordinating Center:

1.  Documentation of the specific competence and private experience of
professional, technical, and administrative staff pertinent to both the molecular
biologic, biostatistical and data coordination aspects of the proposed study. 
Prior experience in similar studies, in the collection of data and patient
specimens from multiple locations, as well as experience in monitoring the
quality and timeliness of such data, should be demonstrated.

2.  Demonstrable knowledge of the potential problems associated with the conduct
of this study and possible solutions must be demonstrated.

3.  Suitability of proposed data management and data analytic plans.

4.  Ability to design, implement and maintain a distributed data entry system for
the PICs.

5.  The approach to and likelihood of soliciting cooperation from the
participating PICs and exercising appropriate leadership in matters of study
design and protocol revisions, and data acquisition, management, and analysis. 
Specific plans for ensuring standardization and quality control of data
collection across all study sites are required.

6.  The adequacy of the proposed technical hardware.

7.  Provision of cost-effective strategies for genotyping large populations and
reliable estimates of genotyping costs for the contemplated joint and independent
large-scale, high-throughput studies.

SCHEDULE

Letter of Intent Receipt Date:  March 12, 1999
Application Receipt Date:       April 12, 1999
Special Review Committee:       June/July, 1999
NIDDK Advisory Council:         September 1999
Anticipated Award Date:         September 30, 1999

AWARD CRITERIA

Applications recommended by the National Diabetes and Digestive and Kidney
Diseases Advisory Council will be considered for award based upon (a) scientific
and technical merit (as determined by peer review); (b) programmatic priorities;
(c) program balance, including in this instance sufficient compatibility of
features to make a successful collaborative program a reasonable likelihood; (d)
availability of funds; (e) appropriate representation of minorities, genders, and
children in the trial, as required; and (f) geographic balance among clinical
centers.

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:

Gladys Hirschman, M.D., or Paul L. Kimmel, M.D.
Division of Kidney, Urologic and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AS-13, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-7717
FAX:  (301) 480-3510
Email:  hirschmang@ep.niddk.nih.gov
Email:  kimmelp@extra.niddk.nih.gov

Direct inquiries regarding fiscal and administrative matters to:

Aretina Perry-Jones
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AN-38B, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8862
FAX:  (301) 480-3504
Email:  perrya@ep.niddk.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No
93.849.  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 work place 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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