PROSPECTIVE COHORT STUDY OF CHRONIC RENAL INSUFFICIENCY

Release Date:  September 21, 2000

RFA:  DK-01-005 (Reissued as RFA-DK-07-502)

National Institute of Diabetes and Digestive and Kidney Diseases

Applicant Information Forum Date:  December 11, 2000
Letter of Intent Receipt Date:     February 28, 2001
Application Receipt Date:          March 28, 2001

PURPOSE

The Division of Kidney, Urologic, and Hematologic Diseases (DKUHD) of 
the National Institute of Diabetes and Digestive and Kidney Diseases 
(NIDDK) has a longstanding interest in supporting epidemiological 
studies of end-stage renal disease (ESRD) patients.  A substantial 
number of these studies, many emanating from the United States Renal 
Data System (URSRDS), has led to significant improvements in the 
treatment and quality of life of ESRD patients.  In contrast, our 
understanding of the epidemiology of chronic renal disease prior to 
ESRD, during a period of reduced renal function or chronic renal 
insufficiency, is far less advanced.  The NIDDK invites cooperative 
agreement applications for investigators to establish Clinical Centers 
to conduct a seven-year prospective cohort study of patients with 
chronic renal insufficiency.  This Request for Applications (RFA) also 
seeks a Data Coordinating Center to assist the Clinical Centers in 
carrying out this cohort study.  The primary goals of the cohort study 
in persons with chronic renal insufficiency with mild to moderately 
reduced levels of renal function are two-fold, to determine the risk 
factors for accelerated decline in renal function, and to determine the 
incidence and identify risk factors for cardiovascular disease.  
Because of the relative and increasing importance of diabetes as a 
cause of ESRD, approximately one-half of the study participants in the 
cohort study will be diabetic.

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, 
 Prospective Cohort Study of Chronic Renal Insufficiency , 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, for-profit and non-profit 
institutions, public and private organizations, such as universities, 
colleges, hospitals, units of State and local government, 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.  

An institution or organization may apply for both a Clinical Center and 
a Data Coordinating Center.  However, separate applications are 
required for each of these study components.  The same person may not 
serve as the Principal Investigator of a Clinical Center and the Data 
Coordinating Center.  

MECHANISM OF SUPPORT

The administrative and funding instrument to be used for these awards 
will be the cooperative agreement (U01).  The cooperative agreement is 
an assistance mechanism in which substantial NIDDK scientific and 
programmatic involvement is anticipated during the performance of the 
activity.  Under the cooperative agreement, the NIDDK’s 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, 
prime 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 applications 
submitted in response to this RFA is seven years.  The anticipated 
award date is September 30, 2001.  At this time, the NIDDK has not 
determined whether or how this solicitation will be continued beyond 
the present RFA.

FUNDS AVAILABLE

The NIDDK plans to make six awards for Clinical Centers and one award 
for a Data Coordinating Center.  Approximately $4,000,000 total cost 
(direct plus facilities and administrative costs) is expected to be 
available during year one of the study.  In all subsequent years 
$6,000,000 will be available under this RFA.  It is anticipated that 
the award for each Clinical Center will be about $500,000 total cost in 
year one and $650,000 total cost in all subsequent years.  The award 
for the Data Coordinating Center will be about $1,000,000 total cost in 
year one and approximately $2,100,000 total cost in all subsequent 
years of the program.  If the budget for either a Clinical Center or 
Data Coordinating Center exceeds the amount specified above the 
applicant must contact the Clinical Trials Program Director (contact 
information in the section, INQUIRIES), DKUHD, NIDDK, prior to 
submitting the grant application. 

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 this program is provided for in the 
financial plans of the NIDDK, awards pursuant to this RFA are 
contingent upon the availability of funds and the receipt of a 
sufficient number of applications of outstanding scientific and 
technical merit.

RESEARCH OBJECTIVES

Background

End-stage renal disease is an important medical and public health 
problem in the United States that disproportionately affects racial and 
minority populations.  According to the USRDS, at the end of 1997 over 
300,000 patients were receiving treatment for ESRD and nearly 80,000 
new patients started ESRD treatment during the same year.  The number 
of ESRD patients is steadily increasing.  The absolute number of ESRD 
patients has more than doubled and the incidence rate has doubled from 
1988 to 1997.  Two important factors associated with this dramatic rise 
are the increasing prevalence of diabetes and the continuing high rates 
of uncontrolled high blood pressure observed in this country.  Despite 
the prominence of diabetes and hypertension in increasing the risk of 
developing chronic renal disease the factors responsible for 
accelerating decline in renal function once chronic renal disease has 
been established are considerably less well defined. While there has 
been substantial interest during the past two decades to better 
understand the risk factors for progression of chronic renal disease 
(i.e., accelerated decline in renal function), there have been only a 
small number of epidemiological studies examining this issue.  Of the 
studies conducted, all of them have had important shortcomings.  Their 
major limitations include retrospective study design, small sample 
size, short-term follow-up, use of select populations such as clinical 
trial participants, lack of ethnic and racial diversity of the study 
populations, exclusion or low rates of participation of women, use of 
crude measures of renal function, limited assessment of potential risk 
factors, and inclusion of only select causes of renal disease, among 
others.  Therefore, it is not surprising that the demographic, 
clinical, and laboratory factors examined in these studies explain only 
a small percentage of the variability in renal function decline between 
patients.  This suggests that there remains a significant number of 
important but as of yet unidentified patient, genetic, environmental, 
and health care utilization related risk factors for rapid loss of 
renal function in persons with established chronic renal disease.  

The survival of ESRD patients is significantly poorer when compared to 
patients with other major illnesses such as prostate and colon cancer.  
In 1996 the adjusted (for age, race, sex, and primary cause of ESRD) 
death rate for all incident ESRD patients was 19.8 per 100 patient 
years at risk for patients in the first year of ESRD therapy.   The 
death rate for ESRD patients with renal disease due to diabetes is even 
higher.  Strikingly, cardiovascular disease mortality rates among all 
ESRD patients are approximately 10 to 20 times those in the general 
population with cardiac arrest of unknown cause, acute myocardial 
infarction, and all other cardiac causes accounting for nearly one-half 
of the deaths in hemodialysis patients greater than 20 years of age.  
In contrast to the many studies of cardiovascular disease in ESRD 
patients, most notably in those undergoing hemodialysis, there is a 
noticeable lack of epidemiological studies documenting the occurrence 
of and risk factors for cardiovascular disease in persons with chronic 
renal insufficiency in the U.S.  However, several small retrospective 
and prospective studies conducted in Europe suggest that the incidence 
rate of cardiovascular disease is at least three times more frequent 
among patients with chronic renal insufficiency resulting primarily 
from non-diabetic renal disease compared to the general population.  In 
contrast, a recent report from the Framingham Heart Study found that 
among women, mild chronic renal insufficiency was not associated with 
an increased risk for cardiovascular events or all-cause mortality in 
men and in women, whereas in men there was an increase in all-cause 
mortality but not cardiovascular events.  The impact of chronic renal 
disease on morbidity and mortality in diabetic patients is especially 
striking.  For example, in insulin-dependent diabetic patients with 
overt nephropathy, the excess mortality may be up to one hundred times 
that of an otherwise matched normal population.  Much of this mortality 
burden is due to an excess of cardiovascular deaths, which is over 
several hundred times higher in young insulin-dependent diabetic 
patients on renal replacement therapy compared with a normal 
population.  Likewise, the impact of cardiovascular disease among non-
insulin dependent diabetics with nephropathy is substantial.  The 
reasons for the increased risk for cardiovascular disease among 
diabetic and non-diabetic patients with nephropathy are unclear.  
Although traditional risk factors such as hypertension, hyperlipidemia, 
hyperglycemia, tobacco use, and physical inactivity are considered 
important risk factors for cardiovascular disease in patients with 
chronic renal insufficiency, the relative importance of each of these 
risk factors compared to nontraditional risk factors (i.e., chronic 
inflammation, infection, oxidative stress, elevated homocysteine 
levels, fibrinogen, etc.), is not known.  Thus, further studies are 
needed to determine the risk factors for cardiovascular disease and the 
relative magnitude of their effects in persons with chronic renal 
insufficiency and to evaluate the contribution of uremia to the 
pathophysiology of cardiovascular disease.  These studies, however, 
must include ethnically and racially diverse populations with chronic 
renal diseases representing the major causes of ESRD in the United 
States.  

Research Goals and Scope of the Activity

The purpose of this RFA is to solicit applications from investigators 
proposing to serve as a Clinical Center or a Data Coordinating Center 
to develop and conduct a multi-institution, prospective cohort study of 
patients with chronic renal insufficiency.  Investigators will 
collaborate to develop a protocol with primary emphasis on assessing 
risk factors for both the accelerated loss of renal function and the 
occurrence of cardiovascular disease.  Patients with chronic renal 
disease and decreased renal function are most likely to be identified 
in a time-efficient and cost-effective manner from established sources 
of medical care such as outpatient clinics and health maintenance 
organizations where information on serum creatinine is readily 
available.  This RFA does not intend to support large-scale screening 
programs utilizing tests of renal function (i.e. serum creatinine) to 
recruit cohort study participants.  However, there may be certain 
circumstances where specialized screening may be performed by the 
Clinical Centers to recruit minority or other participants at high risk 
for accelerated decline in renal function into the cohort study that 
otherwise would not be identified via traditional sources of medical 
care.  Potentially eligible participants with a serum creatinine value 
suggesting that they would meet the glomerular filtration rate (GFR) 
eligibility range (see below) will be further assessed during a period 
of baseline screening.  Upon entry into the cohort study, participants 
will be regularly followed and assessed by Clinical Center staff for a 
period, on average, of approximately 5 years.  Baseline and follow-up 
measurements will be standardized across the Clinical Centers.  Central 
Laboratories and Central Reading Centers will be utilized to maintain 
strict quality control of selected tests and procedures.  A Central 
Repository will be established by the NIDDK to genetic and other 
material.

The two primary goals of this solicitation are as follows:

To determine risk factors for rapid progression of chronic renal 
disease.

To determine the incidence of and risk factors for cardiovascular 
disease.

The following are examples of the types of secondary goals that should 
be planned for the cohort study.

To describe the relationship between baseline and follow-up levels of 
microalbuminuria (urinary albumin excretion > 30 mg/24 hours), 
proteinuria (urinary albumin excretion > 1g/24 hours) and subsequent 
loss of renal function, treatment for ESRD, cardiovascular disease 
morbidity, and cardiovascular disease mortality in different gender and 
ethnic groups.

To examine factors associated with worsening of cardiovascular disease.

To plan and conduct gender and racial/ethnic subgroup analyses as 
warranted by the evidence.

To describe patterns of nutrition and the development of malnutrition.

To assess the rates and causes of hospitalization, and the prevalence 
and incidence of other important co-morbid events and diseases.

To document overall and cause-specific mortality rates.

To describe patterns and levels of use of health services resources.

To measure quality of life and psychological factors that may be 
associated with decline in renal function and the development of 
cardiovascular disease.

To identify practice patterns of physicians with respect to chronic 
renal insufficiency patients.

To obtain biological specimens (to be maintained in a central 
repository) for concurrent and future evaluation of genetic and 
biochemical risk factors for accelerated decline in renal function and 
development/progression of cardiovascular disease and other diseases.

To collect and evaluate information on family members of the cohort 
study participants that may be useful in studies of genetic factors 
associated with increased susceptibility to chronic renal disease and 
cardiovascular disease.

To determine the incidence of cardiovascular disease, other co-morbid 
medical conditions, hospitalization, and mortality in patients after 
treatment for ESRD has been initiated.

To describe the patterns of access to chronic renal insufficiency and 
ESRD therapy.

To conduct subgroup analyses by cause of renal disease, gender, and 
ethnicity for renal disease progression and cardiovascular disease.

The purpose of this RFA is to establish a cohort of patients with 
chronic renal insufficiency whose distribution of clinically and 
pathologically diagnosed causes of renal disease represents, as much as 
feasible, the major causes of ESRD found in the U.S.  The goal of this 
RFA is to recruit a cohort of study participants whose racial, ethnic, 
and gender composition reflects the United States end-stage renal 
disease patient population.  It is envisioned that diabetic patients 
will comprise approximately 50% of the cohort.  The total sample size 
for the cohort study is projected to be approximately 3,000.  It is 
anticipated that this number of participants will permit subgroup 
analyses of the major outcomes (renal function decline, ESRD, incidence 
of cardiovascular disease) of the study among diabetic compared to non-
diabetic patients and by other primary causes of renal disease.  
Currently there are no widely accepted and standardized definitions for 
mild and moderate chronic renal insufficiency.  For the purposes of 
this RFA and to provide guidelines for targeting populations for 
further screening for entry into the cohort study, the lower value for 
serum creatinine in women and men with mild chronic renal insufficiency 
is suggested as 1.4 mg/dl and 1.7 mg/dl, respectively.  It is 
envisioned that the range of renal function as assessed by the 
glomerular filtration rate  (GFR) will be approximately 30   70 
ml/min/1.73m2.  It is anticipated that GFR will be measured twice during 
baseline and once annually during follow-up.  Although levels of serum 
creatinine to be considered for initial screening and a study 
eligibility GFR range are suggested in this RFA, investigators may wish 
to propose their own criteria for these renal function parameters.  
However, it is important to note that any recommendations for study 
entry based on GFR must be accompanied by evidence from the published 
literature that a sufficient number of cohort study participants will 
not only have renal function decline at an accelerated rate but also 
experience the necessary number of cardiovascular disease events during 
the period of time specified in this RFA to achieve the goals of the 
study. 

Because cardiovascular disease imposes such a significant burden on 
ESRD patients, a major emphasis of the cohort study will be observing 
the treated natural history of cardiovascular disease.  Evidence of 
cardiovascular disease will be carefully assessed during baseline and 
during follow-up.  A major effort will be placed on identifying risk 
factors for incident cases of cardiovascular disease and worsening of 
established disease.  To that end the following tests and procedures to 
assess cardiovascular disease status may be considered in the design of 
the cohort study protocol: electrocardiogram, echocardiography, 
ultrasound measurement of the carotid arteries, and electron-beam 
computed tomography of the heart.  Other measurements of cardiovascular 
disease may also be proposed for implementation in the entire cohort 
study population or defined subgroups.  However, these recommendations 
must be supported by published literature and their utility and 
practicality in a multi-center study as described in this RFA must be 
considered.   

Because little is known about the natural history of cardiovascular 
disease in patients undergoing renal replacement therapy, the cohort 
study will continue to follow participants after they reach end-stage 
renal disease.

The information obtained from this prospective cohort study of chronic 
renal insufficiency will serve to identify the point at which promising 
interventions could be evaluated in clinical trials.  In addition, 
professional and public education programs to prevent ESRD and to 
reduce the burden of cardiovascular disease in patients with chronic 
renal insufficiency and ESRD in the U.S. will benefit from these 
findings.

Study Phases

The timetable for the cohort study may be subdivided into four phases 
over a seven-year period.

Phase I  (Months 1-6):  Protocol Development.  Work to be performed 
during this phase includes the development of the study protocol, 
including forms for data collection, for the cohort study by the 
Steering and Planning Committee. Central Laboratories, and Reading 
Centers.  A Central Repository for genetic and other material will be 
established and supported directly by the NIDDK. The Data Coordinating 
Center will begin computer programming to establish the database for 
the study.  Prior to implementation of the cohort study, the protocol 
will be reviewed and must be approved by external advisors.  

Phase II (Months 7-24):  Recruitment of Cohort Study 
Participants/Initiate Follow-up and Clinic Visit Assessment.  Over this 
period of 18 months potentially eligible participants will be 
identified, invited to the Clinical Centers for baseline assessment, 
and those found eligible will be asked to enter into the cohort study.  
Concurrent with recruitment, follow-up of all study participants will 
be conducted in a standardized fashion over regular intervals.  The 
external advisors will review the progress of recruitment at its mid-
point (about Month 16 in Phase II) and recommend to the NIDDK whether 
the cohort study should continue.  Preparation of manuscripts 
describing recruitment of the cohort, baseline demographic and clinical 
characteristics of the participants, and the cross-sectional 
relationships between level of renal function and cardiovascular 
disease status using clinical, demographic, and laboratory measurements 
will begin to be developed in the latter months (Months 18 to 24) of 
this phase.
 
Phase III (Months 25-78):  Follow-up of Cohort Study Participants and 
Participants Post-ESRD Treatment.  The major activity during this 
period will be follow-up clinic visits.  Questionnaires will be 
administered to assess various demographic, nutritional and quality of 
life factors, renal function will be measured, cardiovascular studies 
will be performed, and will be laboratory tests performed in all cohort 
study participants.  Follow-up and data collection on cohort study 
participants who reach ESRD will be performed after initiation of renal 
replacement therapy (renal transplantation, hemodialysis, peritoneal 
dialysis) with modification of data collection, measurements, and 
follow-up visit schedule, as necessary and described in the study 
protocol.  Follow-up assessment of patients who have reached ESRD 
includes determining the incidence of cardiovascular disease, other co-
morbid medical conditions, frequency and cause of hospitalization, 
overall and cause-specific mortality, selected laboratory measurements 
and procedures to evaluate cardiovascular disease.  Manuscripts will be 
prepared and submitted for publication on the cross-sectional and 
initial longitudinal findings from the study.  The last follow-up visit 
of cohort study participants will be scheduled during the final four 
months of this phase.  Data collection for persons who previously 
reached ESRD will also be terminated at that time.
 
Phase IV (Months 79-84):  Final Data Analysis and Close-out of the 
Clinical Centers and the Data Coordinating Center.  During the final 
six months of the program, the activities include final data analysis 
and preparation of manuscripts on the findings from the cohort study, 
including the morbidity and mortality experience in persons treated for 
ESRD.  The Clinical Centers, the Data Coordinating Center, and all 
central facilities (excluding the Central Repository) will be closed-
out in the last two months of this phase of the study.  It is 
anticipated that the National Institutes of Health will maintain the 
Central Repository for genetic and other material beyond the seven 
years of this program.

Study Outline

STUDY COMPONENTS	

Clinical Centers

The Clinical Center investigators will have direct responsibility for 
developing the study protocol and uniform data collection forms, 
identifying potentially eligible study participants, assessing their 
eligibility to participate in the cohort study, conducting baseline and 
follow-up visits, obtaining blood, urine, and other biological samples, 
performing renal function and other measurements, collecting data, and 
transmitting it in a timely fashion to the Data Coordinating Center.  
They, along with staff from the Data Coordinating Center and the 
various central laboratories and reading centers, will also be 
responsible for making presentations at scientific meetings and writing 
and publishing manuscripts on the findings of their studies.

Data Coordinating Center

The Data Coordinating Center will be responsible for assisting the 
Clinical Center investigators through the Steering and Planning 
Committee in developing the cohort study protocol.  The Data 
Coordinating Center will create data collection forms based on input 
from the Steering and Planning Committee. The Data Coordinating Center 
will be responsible for establishing a database to accommodate data 
sent by the Clinical Centers, developing a web-based data transmission 
system, assessing data quality and completeness throughout the study, 
and provide general assistance to the Clinical Centers to maintain 
long-term participation of the cohort study subjects.  The Data 
Coordinating Center will also perform analyses as suggested by the 
Clinical Centers, Central Laboratories and Central Reading Centers, as 
well as propose original analyses to the collaborative group for their 
consideration.  The Data Coordinating Center will prepare periodic 
reports on the progress of the study, including data quality control, 
and interim and final results to the Steering and Planning Committee, 
the NIDDK and the group of external advisors.  The Data Coordinating 
Center will be responsible for arranging meetings and conference calls 
of the Steering and Planning Committee, meetings of the external 
advisors, and will perform other administrative functions necessary to 
coordinate the efficient operation of the collaborative study group.  
The Data Coordinating Center will establish, via subcontracts, Central 
Laboratories and Reading Centers, as deemed necessary by the study 
protocol.  They will also provide administrative coordination for the 
Central Repository to be established and directly supported by the 
NIDDK to store genetic material and other biological specimens obtained 
from cohort study participants.

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 Clinical Centers and the Principal Investigator of the Data 
Coordinating Center, the Chairperson of the Steering and Planning 
Committee, and the NIDDK Project Scientist (described in detail under 
Terms and Conditions).  The Steering and Planning Committee will 
develop policies for the study pertaining to access to patient data and 
specimens, ancillary studies, performance standards, and publications 
and presentations.  They will meet initially to develop the study 
protocol and subsequently to discuss the progress of the study and to 
consider problems arising during its conduct. The Steering and Planning 
Committee may establish subcommittees on such topics as recruitment, 
measurement of renal function, risk factor assessment for renal disease 
and cardiovascular disease, cardiovascular studies, quality control, 
and publications and ancillary studies.  Small working groups may be 
established to prepare manuscripts and presentations.

External Advisors

An independent group of experts in areas such as nephrology, 
cardiology, preventive medicine, epidemiology, nutrition, ethics, 
health economics, and biostatistics who are not otherwise involved in 
the study will be recruited by the NIDDK to evaluate the proposed 
protocol and review periodically the progress of the study (described 
in detail under Terms and Conditions).

Project Scientists

The NIDDK will identify two Project Scientists for the study.  The 
Project Scientists will assist the Steering and Planning Committee and 
external advisors in carrying out the study (described in detail under 
Terms and Conditions).

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 and NIH Grants 
Administration policy statements.

Responsibilities of the Clinical Centers:  The participating Clinical 
Centers will have primary responsibility for developing the study 
protocol, recruiting a sufficient number of study participants, 
maintaining high rates of follow-up and data collection, obtaining data 
of high quality, and interpreting, presenting, and publishing findings 
from the study. 

Responsibilities of the Data Coordinating Center:  The Data 
Coordinating Center will assist in protocol development and preparation 
of scientific publications.  The Data Coordinating Center has the major 
responsibility of creating a database and data collection systems for 
the Clinical Centers, ongoing evaluation of data quality and 
performance monitoring of the Clinical Centers, and statistical 
analyses of the data.

(1) Awardees  Rights and Responsibilities  

Awardees will have substantial and lead responsibilities in all tasks 
and activities.  These include protocol development, enrollment of 
study participants, data collection, data quality control, final data 
analysis and interpretation, and preparation of publications.  The 
awardees agree to work cooperatively with the other Clinical Centers 
and agree to follow the common protocol developed by the Steering and 
Planning Committee.  The awardees agree also to transmit the agreed 
upon study data in a timely manner according to study protocol to the 
Data Coordinating Center for combination and analysis.  Awardees will 
retain custody of and have primary rights to their data developed under 
these awards for the duration of the awards, subject to Government 
(e.g., NIDDK, NIH, or PHS) rights or access consistent with current HHS 
and NIH policies.

(2) NIDDK Staff Responsibilities

The NIDDK will name two Project Scientists from within the Division of 
Kidney, Urologic and Hematologic Diseases whose function will be to 
assist the Steering and Planning Committee in carrying out the study.  
The Project Scientists will have experience in nephrology and the 
development and conduct of multi-center clinical studies.  The Project 
Scientists will have substantial scientific-programmatic involvement in 
protocol development, quality control, interim data analysis, final 
data analysis and interpretation, preparation of publications, and 
coordination and performance monitoring.  The NIDDK Project Scientists 
will have voting membership on the Steering and Planning Committee and 
will have one vote.  One of the NIDDK Project Scientists will also 
serve as Executive Secretary of the external advisors.  The NIDDK 
reserves the right to terminate or curtail the study (or an individual 
award) in the event of difficulties in recruiting participants to the 
cohort study, maintaining high rates of follow-up and data 
collection/completion of participants tests, in timely data reporting, 
achieving high levels of data quality, working cooperatively or other 
major breaches of the protocol, or human subject ethical issues that 
may dictate a premature termination.  The NIDDK Project Scientists will 
establish the Central Repository for genetic and other material.

(3) Collaborative Responsibilities  

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 awardees 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 reside 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 Scientist.

The Steering and Planning Committee, composed of each of the Principal 
Investigators of the Clinical Centers, the Principal Investigator of 
the Data Coordinating Center, the NIDDK Project Scientists, and the 
Chairman of the Steering and Planning Committee, will be the main 
governing board of the study.  This committee will have the primary 
responsibility for developing the study protocol, facilitating the 
conduct of participant follow-up and testing, monitoring completeness 
of data collection and timely transmission to the Data Coordinating 
Center, and reporting the study results.  It will also be responsible 
for establishing study policies in such areas as access to patient data 
and specimens, ancillary studies, publications and presentations, and 
performance standards. Each member of the Steering and Planning 
Committee will have one vote (NIDDK will have one vote), and all major 
scientific decisions will be determined by a majority vote of the 
Steering and Planning Committee.  A Chairperson will be chosen by the 
NIDDK from among the Steering and Planning Committee members (but not 
the NIDDK Project Scientist) or alternatively, from among experts in 
the field of nephrology, cardiology, preventive medicine, nutrition, or 
epidemiology who are not participating directly in the study.  An 
independent group of external advisors, selected by the Director, 
NIDDK, will review periodically the progress of the study.  This group 
will include experts in the relevant medical, epidemiological, 
statistical, and ethics fields who are not otherwise involved in the 
study.  The external advisors will review the study protocol and 
evaluate results, monitor data quality, participant safety, and provide 
operational and policy advice to the Steering and Planning Committee 
and to the NIDDK regarding the status of the study.  One of the NIDDK 
Project Scientists will serve as Executive Secretary of the group.  The 
members of the group will review progress and report to the NIDDK at 
least once each year, or more often if necessary. 

(4) 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 prior 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 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 are 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 research involving human subjects should 
read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities 
as Subjects in Clinical Research," published in the NIH Guide for 
Grants and Contracts on August 2, 2000 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a 
complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: 
The revisions relate to NIH defined Phase III clinical trials and 
require: a) all applications or proposals and/or protocols to 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) all investigators to report accrual, 
and to conduct and report analyses, as appropriate, by sex/gender 
and/or racial/ethnic group differences.

Investigators should consider the available evidence and discuss the 
NIH Phase III Clinical Trial requirements for planning analyses of 
gender or subgroup differences in their applications and protocols, and 
conducting and reporting on these analyses in reports to NIH and in 
manuscripts for publication.

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 and ethical 
reasons not to include them.  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/not98-025.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.

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.

INFORMATION FOR PROSPECTIVE APPLICANTS

Open Forum

A one-day open information forum will be held for prospective 
applicants on December 11, 2000, from 1 p.m. to 4 p.m. (EST) in 
Building 1, Room 151, on the campus of the National Institutes of 
Health.  At this forum NIDDK program staff will address any questions 
that prospective applicants might have regarding the 
clinical/scientific concepts of the RFA.  Attendance is not required 
and is not a pre-condition for submission of an application.  
Applicants planning to attend this meeting should submit their 
questions in writing (electronic mail is acceptable) to John W. Kusek, 
Ph.D. at the address listed under INQUIRIES at least two weeks in 
advance of the forum.  

Information on the Web

For those who cannot attend the December 11 forum, a website will 
contain a summary of that meeting.  It will also contain questions of 
general interest asked by prospective applicants and their answers.  
Prospective applicants are encouraged to check this website frequently 
while preparing an application.  The website can be reached through the 
following URL:  http://www.niddk.nih.gov/fund/crfo/rfas.htm.

LETTER OF INTENT

Prospective applicants are asked to submit, by February 28, 2001, a 
letter of intent that includes a descriptive title of the proposed 
research, name, address, and telephone number of the Principal 
Investigator, 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 it contains allows the NIDDK 
staff to estimate the potential review workload and plan the review.  
The letter of intent is to be sent to:

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes, Digestive, and Kidney Diseases
6707 Democracy Boulevard
Room 653, MSC 5452
Bethesda, Maryland 20892-5452 (for courier service use 20817)
Telephone:  (301) 594-8885
Fax:  (301) 480-3505
Email:  hagana@extra.niddk.nih.gov

APPLICATION PROCEDURES

Applications must be submitted on the standard research grant 
application form PHS 398 (rev. 4/98).  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, Maryland 20892-7910, telephone (301) 710-0267, E-mail: 
GrantsInfo@nih.gov.

The RFA label available 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 the words  Prospective Cohort Study 
of Chronic Renal Insufficiency  must be typed in.

The RFA label and line 2 of the application should both indicate the 
RFA number.  The RFA label 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.

The sample RFA label available at:  
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been 
modified to allow for this change.  Please note this is in pdf format.

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
6707 Democracy Boulevard
Room 653 MSC 5452
Bethesda, Maryland 20892-5452 (For express/courier service, use 20817)

Applications must be received by March 28, 2001.  If an application is 
received after this date it will be returned to the applicant without 
review.  The Center for Scientific Review (CSR) will not accept any 
application in response to this RFA that is essentially the same as one 
currently pending initial review, unless the applicant withdraws the 
pending application.  The CSR will not accept any application that is 
essentially the same as one already reviewed.  This does not preclude 
the submission of a substantial revision of an application already 
reviewed, but such an application must follow the guidance in the PHS 
398 applications instructions for the preparation of revised 
applications, including an introduction addressing the previous 
critique.

Information to be Included in Applications

Details of the Proposed Study Protocol:  Applicants for a Clinical 
Center should describe a research plan involving multi-center 
participation to address the objectives of the study and to reach the 
study goals.  Applicants should outline the rationale and background of 
the proposed prospective cohort study and follow-up data collection of 
participants after they have reached ESRD.  Major entry and exclusion 
criteria, including measures of renal function, should be described and 
justified.  The type of laboratory and medical tests, questionnaires, 
and other data collection should be specified and the frequency of 
assessment during follow-up must be specified.  Particular emphasis 
should be given to measurement of renal function and tests to determine 
prevalence of cardiovascular disease at baseline and its incidence 
and/or progression during follow-up.  An application for a Clinical 
Center must provide credible evidence of the size of the potential pool 
of participants based on an objective measure of renal function, an 
estimate of the proportion of persons with mild to moderate chronic 
renal insufficiency who will be willing to come to the Clinical Center 
to participate in a screening visit to assess cohort study eligibility, 
and a reasonable projection of the proportion who were screened and 
found eligible that would be willing to commit to participation in a 
long-term follow-up study as described in this RFA.  A detailed 
description of the gender and racial/ethnic composition of the 
population of chronic renal insufficiency patients targeted for 
recruitment as well as a comprehensive plan to recruit a cohort of 
patients reflecting the make-up of the U.S. end-stage renal disease 
patient population must be provided.  Realistic rates of study drop-
outs and out migration from the study should be proposed.  Efforts to 
maintain follow-up of cohort study participants must also be described.  
Applicants must consider the sample size proposed in this RFA and 
include a discussion of event rates (ESRD, incident cardiovascular 
disease), the expected rate of decline in renal function (GFR) 
anticipated in the cohort, and the statistical power of the study for 
subgroup analyses (diabetics vs. non-diabetics, within major causes of 
renal disease, gender, and racial/ethnic subgroup).  Recommendations 
for serum creatinine values for screening and GFR eligibility range for 
the cohort study differing from those included in the RFA must be 
justified with published information.  Applications for the Data 
Coordinating Center should also include a proposed design for a 
prospective cohort study of chronic renal insufficiency patients as 
described in this RFA, a plan for the study of cohort study 
participants post-initiation of renal replacement therapy, plans for 
data collection, and overall quality control of the study. Information 
on proposed plans for study-wide data analysis should be included, 
including the analysis of the cohort study phase and the post-ESRD 
treatment follow-up phase. Applicants must also consider the sample 
size proposed in this RFA and include a discussion of event rates 
(ESRD, incident cardiovascular disease), the expected rate of decline 
in renal function (GFR) anticipated in the cohort, and the statistical 
power of the study for subgroup analyses (diabetics vs. non-diabetics, 
within major causes of renal disease). An administrative plan to 
coordinate the activities of the Central Laboratories and Central 
Reading Centers, including quality control and data transmission to the 
Data Coordinating Center must be included in the application.  The 
identification and access of genetic material and other biological 
specimens stored in the Central Repository must also be delineated.  A 
description of anticipated problems in carrying out this study and 
their proposed solutions should be included in the application.

Institutional Support:  There should be evidence of strong 
institutional support for the study, including adequate space in which 
to conduct participant follow-up (Clinical Centers) and data 
analysis/management (for the Data Coordinating Center) activities.  An 
organizational structure for the study should be set forth in the 
application, delineating lines of authority and responsibility for 
dealing with anticipated problems in all general areas as well as 
stated willingness to follow the commonly agreed-upon protocol.

Previous Experience:  The applicant should include a succinct 
discussion of previous relevant research efforts in epidemiological 
population studies, multi-center clinical trials, and any relevant 
experience/success in working collaboratively with investigators 
outside their own research institution.  Experience in the recruitment 
and retention of participants for long-term studies should be 
described.  Previous participation in studies of racial and ethnic 
minority populations should be included.

Suggested Personnel Requirements:  The application must describe the 
expertise of key scientific, technical and administrative personnel and 
include a mechanism for replacing key professional or technical 
personnel should the need arise.  For the Clinical Centers, expertise 
in nephrology, cardiology, and epidemiology is required.  Personnel may 
be full-time or part-time and may serve in more than one capacity, as 
appropriate. A suggested Clinical Center study team may include besides 
a Principal Investigator, a co-investigator (M.D. or Ph.D.), study 
coordinators, GFR technician, appointment scheduler/administrative 
assistant and data entry clerk.  Expertise required for the Data 
Coordinating Center must also include expertise in biostatistics, 
epidemiology, data management, computer programming and database 
development.  Experience in the use of web-based data collection 
systems in a multi-center study setting is also necessary.  Consultants 
in nephrology, cardiology, nutrition, quality of life, and health 
resource utilization assessment are also advisable.

Budget Preparation by Year

Applicants for the Clinical Centers and the Data Coordinating Center 
must include an adequately justified year-by-year budget, reflecting 
the major changes in proposed activities as the study progress through 
its various phases.  Note that budgets are not to be prepared in 
modules.  Also note that the Central Repository established for the 
cohort study will be supported directly by the NIDDK and not via a 
subcontract to the Data Coordinating Center.

Phase I (First 6 months of Year 1). The budget will be for development 
of the protocol by the Clinical Centers in collaboration with the Data 
Coordinating Center.  The Data Coordinating Center will establish the 
database necessary to accommodate the data transmitted by the Clinical 
Centers.  A web-based technology for data transmission will be 
established in Phase I that will protect study participant privacy.  
The Data Coordinating Center will identify and establish subcontracts 
with Central Laboratories and Central Reading Centers as specified by 
the study protocol. It is expected that the Data Coordinating Center 
will purchase the hardware and software necessary for data transmission 
from the Clinical Centers.  The proposed study protocol will also be 
reviewed by the external advisors and must be approved prior to its 
implementation.  The travel budget for Phase I should be estimated 
based on travel for two key investigators to attend two-day, every two 
months meetings of the Steering and Planning Committee in the 
Washington, D. C. area.

Phase II (Months 7-24).  The budget for the Clinical Centers should 
reflect the level of effort necessary to recruit the entire study 
cohort and perform baseline and follow-up studies. Follow-up data will 
also be collected by the Clinical Centers.  Costs should be included 
for specialized studies of renal function (GFR measurement) and 
cardiovascular studies (echocardiography, carotid ultrasound, electron 
beam computed tomography).  The Data Coordinating Center will receive 
and store the data transmitted by the Clinical Centers, assess its 
completeness, provide feedback to the Clinical Centers regarding data 
quality, and prepare progress reports for the Steering and Planning 
Committee and the group of external advisors on the progress of the 
cohort study.  The budget should include costs associated with a 
Central Biochemistry Laboratory, a Central GFR Laboratory, and central 
facilities for reading the echocardiography, carotid ultrasound, and 
electron beam computed tomogaphy).  Costs associated with a Central 
Repository for genetic and biochemical material will be borne directly 
by the NIDDK.  However, the Data Coordinating Center should budget 
staff to coordinate the activities of the Central Repository as it 
pertains to quality control.  This phase of the program will require 
meeting approximately every four months in the Washington, D.C. area.  
The travel budget for Phase II should be estimated based on travel for 
the Principal Investigator and the Study Coordinator as well as any 
other key personnel for both the Clinical Centers and the Data 
Coordinating Center.  Budgets for the Data Coordinating Center should 
include travel for any consultants.  Travel for key staff at the 
Clinical Centers and the Data Coordinating Center should be budgeted 
each year for central training.

Phase III (Months 25-78).  The major activities in this phase are 
follow-up and assessment of cohort study participants.  Initially, data 
analysis of the recruitment experience and baseline characteristics of 
the cohort study participants will be undertaken.  The first 
manuscripts will focus on cross-sectional findings.  Subsequently, the 
manuscripts will deal with longitudinal changes in renal function and 
occurrence of cardiovascular disease in the cohort and other outcomes 
of interest.  Data analysis will be conducted and papers addressing the 
secondary goals of the cohort study will also be prepared. Renal 
function measurements and studies of cardiovascular disease will 
continue during follow-up.  A Central Biochemistry Laboratory, Central 
GFR Laboratory, and Central Reading Facilities for echocardiography, 
ultrasound, and electron beam computed tomography continue to operate 
to handle follow-up data.  The Central Repository will receive, 
process, and store specimens from cohort study participants.  In-clinic 
visit follow-up of the cohort study participants, including those 
followed post-ESRD treatment, will be terminated during the last 
several months of Phase III.  

Three meetings of the investigators should be budgeted for each year of 
this phase of the study.  Central training will occur annually and key 
staff should be budgeted to travel to the Washington, D. C. area.

For a Clinical Center, the budget should request support for the 
minimum number of full and/or part-time staff to successfully carry out 
the proposed cohort study.  A Clinical Center personnel list could 
include a principal investigator, co-investigator, study coordinators, 
GFR technician, appointment scheduler/administrative assistant, and 
data entry clerk.

For applications for the Data Coordinating Center, the budget should 
include the time and effort of key personnel for database management, 
programming, data analysis, and administrative functions to support the 
collaborative group.  The budget should also include subcontracts for a 
Central GFR Laboratory, Central Biochemistry Laboratory, 
Echocardiography Reading Center, Ultrasound Reading Center, and 
Electron Beam Computed Tomography Reading Center.  As noted previously, 
funding for the Central Repository will be directly from the NIDDK.  
Travel by Data Coordinating Center staff to Washington, D.C. for a 
meeting with the group of external advisors should be planned and 
budgeted for annually.

Phase IV (Months 79-84). Final Data Analysis and Close-out of the 
Clinical Centers, the Data Coordinating Center, Central Biochemistry 
Laboratory, the Central GFR Laboratory and Central Reading Facilities 
for Echocardiography, Ultrasound, and Electron Beam Computed 
Tomograpghy.  The major activities include final data analysis of the 
cohort study.  Final data analysis will also be conducted on the post-
ESRD treatment experience of the cohort study participants.  
Manuscripts describing these findings will be prepared and submitted to 
peer-reviewed scientific journals for publication.  The Clinical 
Centers, the Data Coordinating Center, the Central Laboratories, and 
Central Reading Centers will be closed-out during the last two months 
of this phase of the program.  Two meetings of the Steering and 
Planning Committee and one meeting of the group of external advisors 
will be held in Phase IV.
  
The following is a list of yearly major activities to assist in the 
preparation of budgets for each of the five years of the program.

Year 1 (Months 1-6).  Develop the study protocol and data collection 
forms for the collaborative studies by means of meetings every two 
months.  The database will be established by the Data Coordinating 
Center.  A web-based data transmission system will also be developed by 
the Data Coordinating Center.  Central Laboratories, and Reading 
Centers will be identified and established by the Data Coordinating 
Center.  Recruitment plans are further developed by the Clinical 
Centers. Computer hardware and software will be purchased by the Data 
Coordinating Center for use by the Clinical Centers.  The Central 
Repository will be identified by the NIDDK.

Year 1 (Months 7-12):  The Clinical Centers begin recruitment and 
screening of cohort study participants.  Participant follow-up 
assessment begins. Database development is continued by the Data 
Coordinating Center. The Central Biochemistry Laboratory, the Central 
GFR Laboratory, the Central Repository, and Central Facilities for 
Echocardiography, Ultrasound, and Electron Beam Computed Tomography 
will begin functioning. The Central Repository will become operational.

Year 2 (12 months):  Recruitment of cohort study participants continues 
and is completed at the end of year two.  Participant follow-up 
assessment by the Clinical Centers continues.  Reports on recruitment 
rates, data quality, and baseline characteristics of study participants 
prepared by the Data Coordinating Center.  Plans for data analysis on 
the recruitment experience and baseline findings are established by the 
Data Coordinating Center.

Year 3 (12 months):  Participant follow-up assessment by the Clinical 
Centers continues.  Reports on data quality, and follow-up studies 
generated by the Data Coordinating Center.  Manuscripts describing the 
recruitment experience, baseline clinical and demographic 
characteristics of the participants, and unique aspects of this cohort 
study are prepared based on analyses from the Data Coordinating Center.

Year 4 (12 months):  Participant follow-up by the Clinical Centers 
continues.  Manuscripts describing short-term changes in renal 
function, changes in cardiovascular disease risk factors, and other 
findings from the study are prepared based on data analysis from the 
Data Coordinating Center.  The Clinical Centers and the Data 
Coordinating Center, and whenever appropriate the Central Reading 
Centers and Central Laboratories, will participate in special 
epidemiological studies such as nested case-control studies of risk 
factors for renal disease progression and occurrence of cardiovascular 
disease.

Year 5 (12 months): Participant follow-up assessment by the Clinical 
Centers continues.  Data analysis and manuscripts prepared addressing 
secondary goals of the cohort study.  

Year 6 (12 months):  Participant follow-up assessment by the Clinical 
Centers continues.  Continued data analysis by the Data Coordinating 
Center and preparation of manuscripts by the Clinical Centers and 
investigators from the Central Reading Centers on primary and secondary 
goals of the study. Plans will be established for study close-out.

Year 7 (First 6 months):  Final follow-up clinic visit is conducted.  
Data collection for patients receiving treatment for ESRD is concluded.  
Plans will be established for final data analysis by the Data 
Coordinating Center and Clinical Centers.

Year 7 (Last 6 months):  Final data analysis will be performed and 
major reports and manuscripts prepared.  The Data Coordinating Center, 
the Clinical Centers, the Central Laboratories, and the Central Reading 
Center, will be closed-out.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR 
and for 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, 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 the applications under review, will be 
discussed, assigned a priority score, and receive a second level review 
by the National Diabetes and Digestive and Kidney Diseases Advisory 
Council.

Review Criteria

Applicants are encouraged to submit and describe their own ideas about 
how best to meet the goals of the cooperative study as outlined in this 
RFA, and are expected to address issues identified under INFORMATION TO 
BE INCLUDED IN APPLICATIONS.  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.

Review Criteria for Clinical Centers

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

Approach:  Does the applicant propose a sound study design and methods 
to achieve the aims of the RFA? Is the potential pool of cohort study 
participants available to the investigator outlined clearly?  Have 
realistic estimates been made regarding the number of participants who 
will prove to be eligible for the cohort study based on level of renal 
function?  Among persons found eligible during screening have realistic 
participation rates been applied to meet the sample size goals stated 
in the RFA?  Has the racial, ethnic, and gender composition of the 
proposed cohort been adequately described, and plans described for 
appropriate analyses?  Has information on the distribution of renal 
disease of the population targeted for recruitment been discussed?  
What plans have been presented to ensure high rates of follow-up and 
high rates of participation in answering questionnaires and undergoing 
tests mandated by the study protocol?  What risk factors (i.e., 
demographic, clinical, and laboratory measurements) are proposed to be 
included in the study protocol to explain decline in renal function and 
development of cardiovascular disease?  What measurements will be used 
to assess cardiovascular disease status at baseline and during follow-
up?  Have the sample size and power calculations and proposed subgroup 
analyses been adequately addressed?  What steps are planned for data 
quality control?  The applicant must provide plans to ensure the 
complete, reliable, and timely transmission of study data to the Data 
Coordinating Center.  Knowledge of the possible problems associated 
with the conduct of multi-center epidemiological studies and any 
potential issues of importance in this study should be described.

Investigators:  Is the Principal 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?  Are the Principal Investigator and her/his co-
investigators experienced in collaborating with other investigators in 
a multi-center study?  Are the investigators willing to participate in 
establishing and conducting a common protocol?  Does the Principal 
Investigator and the proposed study team possess experience in 
recruiting participants to long-term follow-up studies?

Necessary Expertise:  Documented experience in nephrology, cardiology, 
and epidemiology is required.  Demonstrated knowledge of clinical 
aspects of chronic renal disease and cardiovascular disease is 
required.  

Staff Qualifications:  Documented specific competence and relevant 
experience of professional, technical, and administrative staff 
pertinent to the operation of a Clinical Center are required.

Environment:  Does the scientific environment in which the work will be 
done contribute to the probability of success?  Documented adequacy of 
the proposed facility and space is necessary.  Is there evidence of 
institutional support and commitment for the proposed program? 

Access to Large Patient Databases:  Evidence of the ability to access 
large patient databases containing information on level of renal 
function and/or diagnoses of chronic renal disease from which potential 
cohort study participants will be recruited is necessary.  
Documentation must be provided on the ability to contact patients 
identified in these databases in order to invite them to a more 
detailed, in-clinic assessment of their eligibility to participate in 
the cohort study.  The necessary administrative arrangements to access 
these databases and to contact individual patients must also be 
included in the application.
 
Recruitment of Minority Participants:  Has the applicant described in 
detail, the distribution of minority participants to be recruited?  Is 
the racial and ethnic composition of the proposed recruited population 
similar to the U.S. end-stage renal disease patient population?

Review Criteria for a Data Coordinating Center:

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

Approach:  A design for a cohort study should be included in the 
application for a Data Coordinating Center.  Is a sound design proposed 
for the cohort study and are the planned follow-up studies and 
examinations reasonable to achieve the goals of the RFA. Are the 
conceptual framework, design, and methods adequately developed, well 
integrated, and appropriate to the aims of the project?  Does the 
applicant acknowledge potential problem areas and consider alternative 
tactics?  Experience in developing protocols, developing web-based 
technology for data collection, establishing and maintaining large 
databases for data from the Clinical Centers, plans for analysis of the 
combined data, and efforts to ensure high quality data collection, and 
ensuring study participant confidentiality will be evaluated.  Have the 
sample size estimates and power calculations been described in detail?  
Have adequate statistical plans been included for subgroup analyses?  
What is the approach to handle missing follow-up data?

Investigators:  Is the Principal 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?  Are the Principal Investigator and her/his co-
investigators experienced in collaborating with other investigators in 
a multi-center study?  Documented experience in epidemiology and 
biostatistics is required.  Does the applicant have expertise in 
longitudinal data analysis, including renal function measurements?  
Demonstrated knowledge of clinical aspects of chronic renal disease and 
cardiovascular disease from either a co-investigator or consultant will 
be judged.  The level of expertise of consultants in nephrology, 
cardiology, quality of life and health resource utilization will be 
considered.  Experience in database development, data management, and 
statistical analysis is required.  The ability of the investigators 
from the Data Coordinating Center to take the lead in developing a 
cooperative relationship among the participating Clinical Centers, the 
Central Laboratories, and the Central Reading Centers and exercise 
appropriate leadership in matters of study design, data acquisition, 
data management, data quality, data analysis, and administration and 
coordination of Steering and Planning Committee will be considered.

Environment:  Does the scientific environment in which the work will be 
done contribute to the probability of success?  Documented adequacy of 
the proposed facility and space is necessary.  Is there evidence of 
institutional support and commitment for the proposed program? 

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

The reasonableness of the proposed budget for each year of the program.

The adequacy of the proposed protection for humans and the environment, 
to the extent they may be adversely affected by the studies described 
in this RFA.  The scientific review group will also examine the safety 
of the research environment.

Schedule

Applicant Information Forum Date:  December 11, 2000
Letter of Intent Receipt Date:     February 28, 2001
Application Receipt Date:          March 28, 2001
Special Review Committee:          June/July 2001
NDDK Advisory Council:             September, 2001
Anticipated Award Date:            September, 2001

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 Cost

o The distribution of the causes of renal disease, racial and ethnic 
composition of the population targeted for recruitment

o Geographic distribution of the Clinical Centers 

INQUIRIES

Written and telephone inquiries concerning this RFA are strongly 
encouraged.  The opportunity to clarify any issues or questions form 
potential applicants is welcome.

For information relating to the NIDDK, programmatic inquiries may be 
made to:

John W. Kusek, Ph.D.
or Paul L. Kimmel, M.D.
Division of Kidney, Urologic, and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
Room 617 (J. Kusek, Ph.D.) or Room 607 (P.L. Kimmel, M.D.) MSC 5458
6707 Democracy Boulevard
Bethesda, Maryland 20892-5458 (for express or courier service use 
20817)
Telephone:  (301) 594-7717
FAX:  (301) 480-3510 
Email:  kusekj@ep.niddk.nih.gov
kimmelp@ep.niddk.nih.gov

Fiscal and administrative inquiries may be directed to:

Teresa A. Farris
Grants Management Specialist
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Room 630 MSC 5456
6707 Democracy Boulevard
Bethesda, Maryland 20892-5456 (for express/courier service use 20817)
Telephone:  (301) 594-7682
FAX:  (301) 480-3504
Email:  farrist@ep.niddk.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance 
Nos. 93.849 and 93.864.  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 Public Health Service 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 Public Health Service 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 Public Health Service mission to protect and advance the physical 
and mental health of the American people.

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