STUDY OF HEALTH OUTCOMES OF WEIGHT-LOSS (SHOW): DATA COORDINATING CENTER

Release Date:  November 18, 1998

RFA:  DK-98-020 (ORWH now participating, see NOT-DK-05-019)
                (Notice of limited competition for competing applications, see NOT-DK-05-016)

P.T.

National Institute of Diabetes and Digestive and Kidney Diseases
National Institute of Environmental Health Sciences
National Heart, Lung, and Blood Institute
National Institute of Nursing Research
Office of Research on Women"s Health
Centers for Disease Control and Prevention

Letter of Intent Receipt Date:  February 10, 1999
Application Receipt Date:       March 24, 1999

PURPOSE

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the
National Institute of Environmental Health Sciences (NIEHS), the National Heart,
Lung, and Blood Institute (NHLBI), the National Institute of Nursing Research
(NINR), the Office of Research on Women"s Health (ORWH), and the Centers for
Disease Control and Prevention invite cooperative agreement applications for a
Data Coordinating Center to assist in the design and conduct of a multicenter,
randomized clinical trial to study two primary research questions: 1) Do
interventions designed to produce sustained weight loss in obese individuals with
type 2 diabetes improve health?  2) How do the benefits and risks of
interventions designed to produce weight loss compare with the benefits and risks
related to treatment of obesity-related comorbid conditions in the absence of
weight loss intervention?  The Study of Health Outcomes of Weight-Loss (SHOW) is
expected to recruit approximately 6000 patients over a three-year period with
four additional years of treatment and follow-up.  Midway during recruitment, an
independent assessment will be made to determine the feasibility of continuing
the trial.

The NINR is interested in encouraging applications that include nurse researchers
as principal investigators or co-investigators.  The NINR also is interested in
the role of psychosocial variables on health outcomes in the SHOW trial
population and the relationship of these variables to physiologic outcomes.

NIEHS is interested in understanding if sustained weight loss impacts on the
response of individuals to environmental agents by providing support to research
grant applications responsive to this Request for Applications (RFA).  For
example, research on the effects, if any, of weight loss on the deposition of
environmental agents such as fat stored toxicants may be important in the context
of the SHOW trial.  In addition, research that addresses the effects of sustained
weight loss on the expression of enzymes involved in the metabolism of
environmental agents is also considered important.  Applicants to this RFA are
invited to address these issues in their applications.

The ORWH is interested in providing support to a research grant application
responsive to this RFA that specifically addresses research into sex and gender
related issues and the effects of hormonal status in the context of the SHOW
trial.  The ORWH also wishes to help ensure that there are adequate numbers of
women included, as well as representation from appropriate minority groups. 
Applicants to this RFA are invited to address these issues in their applications.

The Data Coordinating Center will participate with the NIDDK and approximately
15 Clinical Centers in all phases of this clinical trial.  A separate request for
the Clinical Centers has been issued (RFA DK-98-019). 

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, Study of Health Outcomes of
Weight-Loss: Data Coordinating Center, is related to one or more of the priority
areas.  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 for-profit and non-profit domestic
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 for this award. 
Racial/ethnic minority individuals, women, and persons with disabilities are
encouraged to apply as Principal Investigators.

The expertise appropriate for this research program includes biostatistics,
knowledge of the clinical and epidemiological aspects of diabetes and obesity,
and expertise in data coordination and analysis for multi-center clinical trials.

The Data Coordinating Center and a participating Clinical Center may be located
in the same institution, however, each must be administratively and fiscally
distinct from the other.

MECHANISM OF SUPPORT

The administrative and funding mechanism to be used to undertake this project
will be the cooperative agreement (U01), which is an assistance mechanism, rather
than an acquisition mechanism.  Under the cooperative agreement, the NIDDK"s
purpose is to support and/or stimulate the recipient"s activity by collaborating
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 this concept, the tasks and activities in carrying out
the studies will be shared among the awardees and the NIDDK Project Coordinator. 
Details of the responsibilities, relationships and governance of this study
funded under a cooperative agreement are discussed under the section "Terms and
Conditions of Award."  Except as otherwise stated in this announcement, awards
will be administered under NIH grants policy as stated in the NIH Grants Policy
Statement.

The total project period for applications submitted in response to this RFA will
be seven years.  Since the trial design is expected to require nine years
(including planning and close-out phases), it is anticipated that a second RFA
will be issued to support the continuation of the trial beyond seven years.  The
anticipated award date is September 30, 1999.  It is anticipated that the Fiscal
Year 99 award for the Data Coordinating Center will be approximately $3.4 million
(direct costs).  This figure includes approximately $1 million (direct costs) for
activities of the Data Center itself (levels of effort anticipated to remain at
approximately this amount throughout the study), plus $2.4 million (direct costs)
provided through the Data Coordinating Center for subcontracts to support
centralized laboratory activities and resources to develop recruitment materials
and clinical communications.  Funding for the Data Coordinating Center is
expected to gradually increase to approximately $5.1 million per year (direct
costs) by the end of study recruitment, reflecting the increased costs of
subcontracts to support centralized resources and outcome analyses for additional
patients.  In years subsequent to completion of recruitment into the trial,
funding for the Data Coordinating Center is expected to decline to approximately
$4.3 million dollars per year (direct costs), reflecting lower subcontract costs
due to the end of recruitment activities and the reduced intensity of
intervention and monitoring after the most intensive initial stages of the
lifestyle interventions have been completed.  Funds to support the subcontract
aspects of the trial will largely cease during the final year of closeout, data
analysis, and reporting.

FUNDS AVAILABLE

For Fiscal Year (FY) 1999, approximately $4.75 million (total costs) will be
committed to fund one Data Coordinating Center under this RFA.  The NIDDK also
has planned for the projected fiscal requirements of the study beyond FY 1999,
consistent with the direct costs of the Data Coordinating Center and associated
subcontracts as described above and with the projected budgets of the Clinical
Centers for the study (recruited under a separate RFA, DK-98-019).  Although this
program is provided for in the financial plans of the NIDDK and other sponsoring
organizations, the awards pursuant to this RFA also are contingent upon the
availability of funds and the receipt of a sufficient number of applications of
outstanding scientific and technical merit.

RESEARCH OBJECTIVES

A. Background

Overweight and obesity now affect more than 50% of adult Americans, with 22.5%
classified as obese (BMI greater than or equal to 30) (Flegal et al, 1998). This
major public health problem stems from the dramatic increase in obesity that has
occurred during the past ten years, a trend that continues.  Obesity is
associated with significant morbidity and mortality, and the direct and indirect
costs attributable to obesity are estimated to approach  $100 billion per year
in the U.S. (Wolf and Colditz, 1998). It is well established that the prevalence
of type 2 diabetes increases with increasing weight (National Diabetes Data
Group, 1995).  Data from NHANES III indicate that minority populations,
particularly African American and Mexican American women, are disproportionately
affected by obesity.  For example, 37.4% of non-Hispanic black women and 34.2%
of Mexican American women are obese (BMI greater than or equal to 30), compared
with 22.4% of Caucasian women.

Numerous studies show that short term reductions in body weight improve obesity-
related risk factors, including dyslipidemia, hyperinsulinemia, hypertension, and
elevated plasma glucose (Maggio and Pi-Sunyer, 1997). Consistent with these
observations, current public health policy recommends weight loss for obese
individuals (BMI greater than or equal to 30) and for overweight individuals (BMI
25.0 - 29.9) with two or more comorbid conditions (NHLBI and NIDDK, 1998). 
Despite the compelling data for the benefits of short-term weight loss, there is
little information regarding the health effects of long-term intentional weight
loss in obese individuals. 

Increasingly, critics in both the lay press (Johannes and Stecklow, 1998) and
professional literature (Kassirer and Angell, 1998) have questioned the safety,
efficacy, and desirability of recommending weight loss to obese individuals. 
This controversy has stemmed in large part from observational studies suggesting
that weight loss (Andres et al, 1993) or weight fluctuation (Williamson, 1996)
are associated with increased morbidity and mortality.  However, such studies
have a number of limitations, such as the inability to distinguish intentional
from unintentional weight loss and the possibility of confounding due to effects
of underlying illness or smoking status on weight change.  One prospective 12-
year study has examined the issue of intentional weight loss in non-smokers by
utilizing the American Cancer Society"s Cancer Prevention Study (CPS-1) cohort
(Williamson et al, 1995).  This study found that intentional weight loss among
overweight, never-smoking women aged 40-64 years with obesity-related
comorbidities was associated with increased longevity, but that among overweight
women with no preexisting illness, the association was ambiguous.  

In April of 1997 the National Task Force on Prevention and Treatment of Obesity
convened a workshop with the support of the NIDDK, the National Heart, Lung and
Blood Institute, the National Institute on Aging, and the Centers for Disease
Control and Prevention to consider the need for and feasibility of a randomized
clinical trial to assess the long-term health effects of intentional weight loss
in obese persons (Yanovski et al, in press).  The workshop participants confirmed
the paucity of evidence demonstrating that intentional weight loss improves long-
term health outcomes and recommended that a well-designed randomized clinical
trial be undertaken to answer a number of important questions necessary for
development of a rational clinical and public health policy for management of
obese individuals.  Subjects with obesity-related comorbid conditions were felt
to be a useful target population, because the presence of comorbidities would
increase the event rate of the chosen outcome(s) in the control populations, thus
enhancing the feasibility of conducting a study to detect changes in health risk
and disease progression with weight loss.  Additional recommendations from the
workshop included: 1) the focus should be on health effects of weight loss,
rather than efficacy of specific interventions, 2) a range of outcomes should be
assessed, and 3) questions of public health importance, such as cost
effectiveness of weight loss intervention in comparison with treatment of
comorbidities in the absence of weight loss intervention, should be considered.

Individuals with type 2 diabetes are highly suitable as subjects for a trial of
the benefits and risks of intentional sustained weight loss.  Diabetes is a
common condition - over six percent of individuals aged 45-64 have diagnosed
diabetes, primarily type 2 (National Diabetes Data Group, 1995).  Over one third
of all persons with type 2 diabetes are obese, and 70 percent are overweight
(National Diabetes Data Group, 1995).  Obesity in type 2 diabetes increases
mortality, exacerbates hyperglycemia, hyperinsulinemia and dyslipidemia, and also
causes increased insulin resistance (Maggio and Pi-Sunyer, 1997).  Weight loss
has been shown to improve glycemic control and other risk factors over the short
term in obese individuals with type 2 diabetes, but little information is
available on the long-term benefits of weight loss in this group.

Macrovascular complications of type 2 diabetes are the major cause of morbidity
and mortality in individuals with type 2 diabetes, with coronary heart disease
(CHD) the leading cause of death.  Diabetic individuals have over twice the death
rate from coronary heart disease as individuals without diabetes (National
Diabetes Data Group, 1995).  A recent study in Finnish patients with type 2
diabetes demonstrates that the rate of CHD mortality in diabetic subjects with
no history of myocardial infarction is as high as that in nondiabetics with a
history of previous myocardial infarction (Haffner et el., 1998).  Obesity is
linked to cardiovascular risk factors and also is an independent predictor of
coronary atherosclerosis (Eckel, 1997).  In a multivariate simulation model,
simultaneous interventions for cardiovascular disease risk factors (smoking
cessation and correction of systolic blood pressure, cholesterol, and HDL
cholesterol to the non-diabetic reference range) are projected to eliminate only
half of the excess cardiovascular disease risk associated with type 2 diabetes
(Eastman and Keen, 1997).  Particular aspects of weight loss interventions, such
as changes in diet composition and/or physical activity, may have benefits with
respect to this residual cardiovascular disease risk that are independent of the
effects of weight loss on lipid levels and hypertension.

In addition to the long-term benefits and risks of intentional weight loss, the
efficacy of long-term weight loss interventions in sustaining weight loss is of
concern.  Recently, lifestyle interventions for weight loss have demonstrated the
ability to elicit sustained modest weight loss.  These interventions are capable
of producing a loss of 8 to 10 percent of initial body weight over a six-month
period, with gradual regain over several years.  In the Trial of Nonpharmacologic
Interventions in the Elderly (TONE), a mean weight loss of more than 4.5 kg at
30 months was reported in overweight older adults who received instruction in
diet, physical activity, and behavioral skills (Whelton et al, 1998).  Limited
data suggest that in some circumstances diabetic patients can succeed in
sustaining weight loss long-term.  In the Diabetes Treatment Study, a small
uncontrolled prospective trial in Northern Ireland, obese patients with recently
diagnosed diabetes were able to lose an average of 9 kg in 6 months and to
sustain this loss for up to 6 years, with 71% of patients able to control their
diabetes by diet alone at 6 years (Hadden et al, 1986).

Studies also have demonstrated that pharmacological treatment confers a modest,
but significant, increase in weight loss compared with that obtained by
behavioral treatment alone, and may assist in longer-term maintenance of weight
loss (National Task Force on Prevention and Treatment of Obesity, 1996, Sjostrom
et al, 1998, Hollander et al, 1998).  The availability of lifestyle interventions
that can sustain some degree of weight loss for an extended period, as well as
the potential use of pharmacological agents to help sustain weight loss, has
enhanced the feasibility of conducting a randomized clinical trial to address the
questions surrounding long-term weight loss, as recommended by the 1997 workshop.

The cost-effectiveness of weight loss interventions as a means of diminishing
obesity-related comorbid conditions in comparison to the cost-effectiveness of
treating comorbid conditions in the absence of weight loss has not been
systematically documented (Williamson et al, 1998).  A randomized clinical study
of interventions to produce sustained weight loss in diabetic patients compared
with community care of comorbid conditions offers an opportunity to
systematically assess the incremental cost-effectiveness of weight loss
interventions, as well as their efficacy in improving health.

B. Research Goal and Scope of the Activity

The objective of this RFA is to select a Data Coordinating Center to participate
in planning and implementing a randomized, controlled, multicenter clinical trial
in obese type 2 diabetic patients.  The trial will examine the effects of
interventions designed to produce sustained weight loss on a range of health
outcomes.  The primary outcome is anticipated to be differences in progression
of atherosclerosis.  This study also will examine the effects of the
interventions on cardiovascular and cerebrovascular event rates, cardiovascular
and all-cause mortality, cardiovascular risk factors, glycemic control, and other
outcomes.

Several anticipated features of this study are cited below so that applicants
have a common understanding of factors necessary for the collaborative effort.

It is anticipated that two-thirds of the patients recruited to the study will be
randomly assigned to enrollment in weight loss interventions and one-third to
community care.  The SHOW trial is likely to have three arms, as follows:

1) Community Care -- Patients will receive medical care for their obesity and
obesity-related comorbid conditions (e.g., diabetes, hypertension, dyslipidemia)
from their primary care physician.  The primary care physician will be given
standard of care recommendations for treatment of obesity and comorbid conditions
(e.g., guidelines from the American Diabetes Association) and will be provided
with results of diagnostic tests carried out at study sites.

2) Intensive Lifestyle Intervention -- Patients will undergo a long-term
behavioral treatment program that includes dietary modification, increased
physical activity, and behavioral therapies designed to enhance weight loss and
weight maintenance.  This intervention is anticipated to be conducted in groups. 
Obesity-related comorbid conditions will be treated by the primary care physician
as in Group 1.

3) Intensive Lifestyle Intervention plus Weight-Loss Medication -- Medication
will be added to the intensive lifestyle intervention in an attempt to enhance
long-term weight maintenance.  Comorbid conditions will be treated by the primary
care physician as in Group 1.

Applicants may propose other designs (for instance, a two-arm design with the
potential for addition of obesity medications to the lifestyle intervention). 
In all cases, applicants should include a discussion of their rationale and
should address the pros and cons of utilizing obesity medications in the study.

Because maintenance of weight loss for extended periods of time has been
difficult to achieve, applicants may propose a subrandomization of study
participants to more than one approach to weight loss maintenance.  Applicants
incorporating such a substudy should address the rationale for alternative
maintenance strategies to be tested, specific aims, design, and assessment
features.

Primary outcome: The SHOW trial is intended to be of sufficient size and duration
to detect differences in the rate of progression of atherosclerosis. Applicants
are invited to submit applications utilizing the development or progression of
atherosclerosis, as assessed by quantitative B-mode ultrasound, as the primary
outcome of the study.  NOTE: If an applicant wishes to propose an alternative
primary cardiovascular outcome, this should be accompanied by a detailed
justification, including discussion of projected progression or event rates for
the proposed outcome, sample sizes, statistical assumptions underlying the
design, and potential advantages and disadvantages.

Secondary outcomes:  This study also will examine the effects of the
interventions on cardiovascular and cerebrovascular event rates, cardiovascular
and all-cause mortality, and cardiovascular risk factors, as well as glycemic
control.

Other outcomes of interest include, but are not limited to: costs and cost-
effectiveness of the interventions, health-related psychosocial measures (e.g.,
health-related quality of life, social support, self-efficacy), changes in body
fat and body fat distribution, diabetes-specific microvascular outcomes,
musculoskeletal outcomes, such as bone density, change in use of medications,
fitness measures, such as cardiovascular fitness and flexibility, and development
of gallbladder disease.  It is the intention of the NIDDK to study these and
other possible outcomes as funds permit.  Applicants are invited to identify
their highest priorities for other outcome measures that can reasonably be
budgeted within the resources available, and to include these additional high-
priority outcome measures in their study designs and budgets.

Other questions of clinical and public health importance about which this trial
may provide information include:  1) To what extent can weight loss be sustained
over the long term in persons with type-2 diabetes using the best currently
available non-surgical interventions?  2) Does weight fluctuation impact on the
outcomes listed above?  3) Is there a difference in the effectiveness or benefit
of the intervention(s) by age, sex, or ethnicity?

C.  Study Phases

Phase 1 (Planning phase, approximately 12 months):  This phase will encompass
collaborative development of the protocol and the manual of operations by a
Steering Committee composed of the Principal Investigators of the Clinical
Centers, the Chairperson of the study, the Principal Investigator of the Data
Coordinating Center, and the NIDDK Project Coordinator.  The Data Center will
coordinate these activities and provide statistical guidance for the protocol
design.  The Steering Committee-approved protocol and manual of operations will
be subject to review by an NIDDK-appointed expert group, the Data Safety and
Monitoring Board, that will serve to advise the Institute on subject safety, data
quality and other issues.  The study will move into its operational phase only
following the recommendation of the Data Safety and Monitoring Board and the
final approval of the NIDDK.

Phase 2 (Recruitment phase, 36 months): The protocol for the study will be
initiated in Phase Two.  Clinical Centers will recruit and randomize 6000
participants over this period, implement the protocol according to the manual of
operations, collect the outcome data specified in the protocol, and provide study
data to the Data Coordinating Center.  The Data Center will coordinate these
activities, and will manage the collection, editing, storage and analysis of
data.

Midway in Phase Two, the NIDDK will assess the feasibility of continuing the
trial.  Criteria that will influence the decision to continue enrollment or to
terminate the trial include: 1) Ability of at least one weight-loss intervention
to achieve and sustain a clinically meaningful weight difference from the
community care arm (clinically meaningful weight difference will be defined by
the Steering Committee as part of the trial design), and 2) Satisfactory
recruitment and retention of participants.

Phase 3 (Treatment and Follow-up phase, 48 months):  Clinical Centers will no
longer recruit patients, but will continue to implement the protocol, collect
outcome data, ship specimens, and provide study data to the Data Coordinating
Center during this period.  All patients will continue to be studied throughout
Phase 3 (average duration of intervention 5.5 years, range 4-7 years).  The Data
Center will coordinate these activities, and will manage the collection, editing,
storage and analysis of data.

Phase 4 (Close-out phase, 12 months):  The final phase of the study will be for
close-out of Clinical Center activities, final data analysis, and reporting of
results.

SPECIAL REQUIREMENTS

A. Participation in a Collaborative Program

The Data Coordinating Center will be involved in collaborations with the NIDDK
and the Clinical Centers during all phases of the trial.  Thus the applicant is
expected to demonstrate experience in working cooperatively with Clinical Centers
and sponsoring organizations in a multi-center trial and in overseeing the
implementation of and adherence to a common protocol, as well as assuring quality
control of the data collected.  An explicit statement of willingness to
participate in a collaborative program should be included in the application. 
In addition to organizing and attending regular meetings, the Data Center will
be expected to maintain close communications with the NIDDK Project Coordinator
and the Clinical Centers.

B. Personnel

A Director and a Deputy Director for the Data Coordinating Center must be
designated.  The Director of the Data Coordinating Center should be an
biostatistician, epidemiologist, or other professional with experience in
directing a coordinating center for a large scale collaborative multi-center
clinical trial or other large scale epidemiological research project involving
multiple institutions.  The Deputy Director should be fully qualified to carry
out the responsibilities of the Director.

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.  Staff needs may be modified as the
trial progresses, however, statisticians, systems analysts, computer programmers,
statistical assistants, clerks, and administrative assistants must be available. 
Adequate support staff should be designated to manage routine tasks.  It is
expected that senior statistical staff will devote time to developing data
analysis methods for use in the trial.  The Data Coordinating Center should
possess expertise in obesity/diabetes or have access to consultants in these
areas.

C. Study Outline

While the final design for the SHOW trial will be determined by the Steering
Committee, applicants should address the potential requirements of the study by
providing a description of projected tasks likely to be performed by the Data
Coordinating Center and the centralized facilities, consistent with resources
projected to be available for this study.

The application should be structured around the requirements of a projected study
design that addresses likely outcomes to be determined and likely eligibility
requirements for study participation, including patient age, gender,
racial/ethnic background and exclusion criteria.  The overall ethnic and racial
composition of the recruited patient populations is expected to reflect the
prevalence rates of diabetes in the U.S.  Based on NHANES III data, for adults
aged 20 years or older with type 2 diabetes, 74.4% are non-Hispanic White, 15.0%
are non-Hispanic Black, 5.8% are Mexican-American, and 4.8% are other race-ethnic
groups.  The study population mix at any one center may vary from this overall
distribution based on local demography.  The overall study population may
include, but is not limited to, Caucasians, Native Americans and Alaskan Natives,
African Americans, Hispanics, and Asian or Pacific Islanders.  Issues related to
oversampling of minority populations should be considered in developing the
design.

Potential differential effectiveness of lifestyle interventions with respect to
racial/ethnic background of the participants should be considered.  It is
anticipated that group lifestyle interventions will be selected for reasons of
efficacy and cost-effectiveness.  Many aspects of proposed lifestyle
interventions are anticipated to be similar to those of the Diabetes Prevention
Program (DPP).  The protocol for the DPP will be available on the SHOW website
at http://www.niddk.nih.gov/fund/fund.htm as a resource for
applicants.  Alternative lifestyle interventions may also be proposed.  NOTE:
Inclusion and exclusion criteria and recruitment and screening strategies are
expected to differ from the DPP.  Potential use of obesity medications in the
study should be addressed.

In addition to the primary and secondary outcome measures listed in RESEARCH
OBJECTIVES, which should be included in the study design, applicants should
indicate other outcome measures proposed for assessment (e.g., computed
tomography scans for assessment of body composition, dual energy absorptiometry
studies of bone density, quality of life assessments), identifying those they
consider the highest priority that can be accommodated within the funds
available.

Plans for collection and handling of data and samples consistent with the
projected needs of the study should be discussed.  Part of the proposed study
design also should address the means for communicating results of patient
laboratory tests and guidelines for treatment of comorbidities to primary care
physicians.

D. Study Components

1) Clinical Centers.  Clinical Centers in the SHOW trial will be expected to:

o  Design the study protocol and write the manual of operations.

o  Develop operational plans for the Recruitment phase and the Treatment and
Follow-up phase of the trial in close collaboration with the communities they
serve.

o  Participate in a full-scale clinical trial.

o  Participate in ancillary studies of trial subjects, as appropriate.

A Clinical Center is an institution that is actively involved in the recruitment,
evaluation, treatment, and follow-up of study participants.  For this trial it
will consist of a core team of researchers who are skilled in delivery of
behavioral/lifestyle interventions for obesity and have experience in
collaborative clinical investigation. The NIDDK expects that the average number
of patients per center will be approximately 400, of whom two-thirds will receive
a lifestyle intervention

2) Data Coordinating Center

The Data Coordinating Center will have primary responsibility for collecting,
editing, storing, and analyzing data provided by the Clinical Centers.  It should
be prepared to assume a key role in developing the manual of procedures for the
trial, overseeing implementation and adherence to the study protocol, and
assuring quality control of the data collected.  The Data Coordinating Center
will be expected to provide appropriate biostatistical, data management, and
coordination expertise.  Applicants for the Data Coordinating Center must provide
a detailed description of prior experience in multicenter studies, and should
address the aspects of the Data Coordinating Center described below.

The Data Coordinating Center will have a central role in statistical aspects of
the trial, including sample size determination, estimates of event rates, interim
analyses for quality control, analyses of trial outcomes, and full statistical
oversight.  The application should include a discussion of statistical issues and
potential problems likely to arise in the design and conduct of this clinical
trial.  The Data Coordinating Center will provide the support and guidance
necessary to maintain the scientific integrity of the trial through Coordinating
Center staff or procurement of consultants as necessary.

The Data Coordinating Center will have the primary responsibility for developing
and implementing systems necessary for intra-study communications. The Center
will facilitate the design and refinement of all protocols, manuals of operation,
and forms.  The Center will establish a system for electronic submission of data
in a standard format from the clinical centers, process all data transmitted,
monitor the quality of the data and the performance of the Clinical Centers in
the implementation of the protocols, and prepare periodic reports to Clinical
Centers on data quality problems identified.  The Data Coordinating Center will
be responsible for developing plans for the Data Safety and Monitoring Board. 
The Center will perform analyses necessary for interim publications and
presentations, and prepare appropriately detailed reports to the NIDDK, the
Steering Committee, and to the Data Safety and Monitoring Boards at regular
intervals and as dictated by the study needs.  During Phase Four, the Data
Coordinating Center will prepare outcome analyses of the data from the clinical
trial and will collaborate with the investigators of the Clinical Centers and the
NIDDK to prepare final reports of the study for publication.

The Data Coordinating Center will be responsible for acquiring and administering
subcontracts for central laboratory and clinical resources. Examples of the types
of centralized laboratory functions that may be required include analyses such
as blood glucose determination, measures of renal function, and measurement of
blood lipid and lipoprotein subtypes.  Centralized reading centers will be needed
for interpretation of projected outcome measures, such as B-mode ultrasound of
the carotid artery, computed tomography scans, and electrocardiograms.  The NIDDK
also intends that a central repository contracted by the Data Coordinating Center
will store patient samples in a manner suitable for future DNA and molecular
analyses.  A central laboratory supported by a subcontract from the Data
Coordinating Center must adhere to all NIH policies and procedures governing
consortium grants.

Staff of the Data Coordinating Center will be required to travel to meetings
during the planning phase for the development of study design, protocols,
manuals, and forms.  Phases 2 and 3 will require personnel to attend Steering
committee meetings, to travel to the Clinical Centers as necessary to monitor
quality control procedures, and to conduct training programs for clinic staff. 
Additionally, the Data Coordinating Center will be required to assist in managing
the logistics of all committee and sub-committee meetings during the course of
the trial and will be responsible for taking minutes of the various meetings. 
The Data Coordinating Center also will make logistical arrangements for meetings
of the Data Safety and Monitoring Board, but the NIDDK Project Coordinator will
serve as executive secretary of this group.

The Data Coordinating Center will assist the NIDDK Project Coordinator in
written, telephone, and electronic communications with Clinical Centers and with
various committees as requested.

3) Steering Committee.  The primary governing body of the study will be the
Steering Committee, which will have responsibility for overall study design and
policy decisions (described in more detail under Terms and Conditions).

4) Executive Committee.  An Executive Committee also will be convened to
facilitate the monitoring and conduct of the study between meetings of the
Steering Committee (described in more detail under Terms and Conditions).

5) Data Safety and Monitoring Board.  An independent committee will be
established by the Director, NIDDK, to review the progress of the study on a
regular basis (described in more detail under Terms and Conditions).

6) NIDDK Project Coordinator.  The NIDDK will name an NIDDK Project Coordinator
whose function will be to assist the other components as appropriate in all
aspects of the study (described in more detail under Terms and Conditions).

E.  Budget Preparation by Year

Applicants for the Data Coordinating Center should submit adequately justified
budgets for each 12-month period of the trial, reflecting the major changes in
proposed activities that occur as the trial progresses through its phases.

NOTE:  Budgets for this application should be based on the applicant"s best
judgment of likely activities projected to be included in a final protocol. 
Final budgets will be determined following the design of the study protocol and
writing of the manual of operations during Phase One.

The Phase 1 budget (Year 1) should include costs of establishing the Data
Coordinating Center staff, as required to carry out the Coordinating Center"s
functions.  Phase 1 also will involve development of the protocol and manual of
operations in conjunction with the Steering Committee for the study and creation
of a database for the trial.  During this phase the collaborating centralized
laboratory facilities and other centralized facilities needed to analyze outcome
measures will be identified.  Budgets should include the costs of organizing
eight Steering Committee meetings, and providing for attendance of necessary Data
Coordinating Center staff.

During Phase 2 (Years 2,3, and 4), the budgets should include projected data
handling costs, reporting functions, meetings and other communications costs, and
the projected expense of performing interim analyses requested by the Data Safety
and Monitoring Board.  The applicant also should address the potential
requirements of the study by budgeting for tasks likely to be performed by
centralized facilities and other subcontractors, consistent with the funds
available for the study.  These should include activities such as central
laboratory functions, centralized reading of projected outcome measures (e.g.,
carotid ultrasound), periodic on-site monitoring/data audits, development of a
repository to store patient samples, and centralized screening/recruitment
materials development costs.  It should, however, be understood that the specific
centralized facilities required and their final budgets will be determined
following the design of the study protocol and the writing of the manual of
operations by the Steering Committee.  Budgets should include costs of organizing
three Steering Committee meetings per year and providing for attendance of
necessary Data Coordinating Center staff.

During Phase 3 (Years 5,6,7 and 8), budgeted activities of the Data Coordinating
Center should include all data handling costs, reporting functions, meetings and
other communications costs, projected expense of performing interim analyses
requested by the Data Safety and Monitoring Board, and the cost of the
subcontracts to carry out laboratory and other central functions projected to be
needed during the Treatment and Follow-up phase.  Budgets should include costs
of organizing three Steering Committee meetings per year and providing for
attendance of necessary Data Coordinating Center staff.

The Phase 4 budget (Year 9) should be concerned with study close-out, analysis
of study data, and reporting of results in collaboration with the Clinical
Centers.  Budgets should include the costs of organizing two meetings of the
Steering Committee and providing for attendance of necessary Data Coordinating
Center staff.

NOTE:  Since actual meeting locations have not been selected, each meeting may
be assumed to cost $1500 per person.  Each Clinical Center will budget for the
travel of its own staff members.  It is estimated that approximately one third
of the meetings will be held in the Washington D.C. area.  The Data Coordinating
Center also will be responsible for organizing meetings of the Data Safety and
Monitoring Board at least once a year and for supporting the travel of these
individuals to meeting sites and their lodging. These costs should be included
in the budget.

F. Terms and Conditions of Award

The following special terms of award (1-5) are in addition to, and not in lieu
of, otherwise applicable OMB administrative guidelines, HHS grant administration
regulations at 45 CFR Parts 74 and 92, and other HHS, PHS, and NIH grant
administration policies.

1) Collaborative Responsibilities.  The administrative and funding mechanism to
be used to undertake this project will be the cooperative agreement (U01), which
is 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 NIDDK purpose is to support and/or stimulate the recipient"s
activity by collaborating 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 this concept, the tasks and
activities in carrying out the studies will be shared among the Clinical Center
awardees, the Data Coordinating Center awardee and the NIDDK Project Coordinator.

2) Awardee Rights and Responsibilities.  The tasks or activities in which
awardees for the Clinical Centers and the Data Coordinating Center of the SHOW
trial will have substantial and lead responsibilities include protocol
development, patient recruitment and follow-up, data collection, quality control,
final data analysis and interpretation, and preparation of publications.  The
Data Coordinating Center awardee agrees to work cooperatively with the other
Clinical Centers and agrees to follow the common protocol and manual of
operations developed in Phase One of the study by the Steering Committee.

Awardees will retain custody of and have primary rights to their data developed
under these awards, subject to Government policies regarding rights of access.

3) NIDDK Responsibilities.  The NIDDK will name the Director, Obesity Special
Projects, Division of Digestive Diseases and Nutrition, NIDDK, to be the NIDDK
Project Coordinator.  The Project Coordinator"s function will be to assist the
Steering Committee, Executive Committee, Data Safety and Monitoring Board, and
other subcommittees in carrying out the study, including quality control, interim
data and safety monitoring, final data analysis and interpretation, preparation
of publications, and coordination and performance monitoring.  The NIDDK Project
Coordinator will have voting membership on the Steering Committee, the Executive
Committee, and, as appropriate, other subcommittees of the Steering Committee. 
The NIDDK Project Coordinator also will serve as executive secretary of the
independent Data Safety and Monitoring Board.

Other NIDDK scientists may, as appropriate, serve on study committees and work
with awardees on issues coming before the Steering Committee or its
subcommittees.  However, in all cases, the NIDDK will have only a single vote on
study committees, either of the whole or on subcommittees.  In addition, the
NIDDK may invite non-voting representatives from other sponsoring Institutes and
agencies, as appropriate.

The NIDDK reserves the right to terminate or curtail the study (or an individual
award) in the event of (a) a major breach in the protocol or substantial changes
in the agreed-upon protocol with which the Institute does not agree or (b) human
subject ethical issues that may dictate a premature termination or (c) failure
to achieve and sustain a clinically meaningful difference in weight loss between
the control and at least one weight loss intervention, or (d) substantial
shortfall in recruitment and/or retention of subjects.

4) Governance.

a) The Steering Committee, comprised of each of the Principal Investigators of
the Clinical Centers, the Principal Investigator of the Data Coordinating Center,
the NIDDK Project Coordinator, and the Study Chairperson, will have primary
responsibility for developing common clinical protocols, facilitating the conduct
and monitoring of the studies, and reporting the study results.  Each member of
the Steering Committee will have one vote, and all major scientific decisions
will be determined by majority vote of the Steering Committee.  A Chairperson
will be chosen from among the Steering Committee members (but not the Project
Coordinator or Data Coordinating Center director), or alternatively, from among
experts in the field of obesity clinical research who are not participating
directly in the study.  Subcommittees appointed by the Steering Committee and
comprised of Principal Investigators and appropriate staff from the Clinical
Centers and the Data Coordinating Center will be involved in design of the
protocol and the manual of operations, and in ongoing functions of the trial,
such as review of ancillary studies and preparation of publications.  Not all
Clinical Centers will necessarily be represented on all subcommittees.

b) An Executive Committee comprised of the Study Chairperson, the Principal
Investigator of the Data Coordinating Center and the NIDDK Project Coordinator
also will be convened to effect management decisions required between Steering
Committee meetings, as needed for efficient progress of the trial.  The Executive
Committee will report its actions to the Steering Committee on a regular basis. 
Meetings of the Executive Committee will generally be held in the Washington,
D.C. metropolitan area or by conference call.

c) An independent Data Safety and Monitoring Board will be appointed by the
Director, NIDDK, to review periodically the progress of the SHOW trial.  It will
be comprised of experts in relevant medical, psychological, statistical,
operational, and bioethical fields who are not otherwise involved in the study. 
The Data Safety and Monitoring Board will oversee participant safety, evaluate
results, monitor data quality, and provide operational and policy advice to the
Steering Committee and to the NIDDK regarding the status of the study.  The
Principal Investigator of the Data Coordinating Center, the NIDDK Project
Coordinator, and the Director of the Division of Digestive Diseases and Nutrition
(or representative) may participate as ex-officio, non-voting members of the
Board. The NIDDK Project Coordinator will serve as executive secretary of the
Data Safety and Monitoring Board.  The Data Safety and Monitoring Board will
review progress and report to the NIDDK at least once per year.

5) Arbitration.  Any disagreement that may arise in scientific-programmatic
matters between award recipients and NIDDK may be brought to arbitration.  An
arbitration panel will be composed of three members - one selected by the
Steering Committee (with the NIDDK member not voting) or by the individual
awardees in the event of an individual disagreement, a second member selected by
NIDDK, and a third member selected by the preceding two members.  These special
arbitration procedures in no way affect 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 regulations 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 103-43).

All investigators proposing research involving human subjects should read the
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical
Research," which was published in the Federal Register of March 28, 1994 (FR 59
14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11,
March 18, 1994, available on the web at:
http://www.nih.gov/grants/guide/1994/94.03.18/notice-nih-guideline008.html.

Investigators may also obtain copies from these sources or from the program staff
or contact person listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.

NIH POLICY AND GUIDELINES ON THE INCLUSION OF CHILDREN AS PARTICIPANTS IN
RESEARCH INVOLVING HUMAN SUBJECTS

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

However, the NIDDK has determined that the SHOW trial does not require inclusion
of children for the following reasons.  One of the trial arms will likely include
weight-loss medications that have not been studied in individuals under the age
of 18 years for any length of time.  Because the risks of taking these
medications have not been assessed in phase II studies in children or
adolescents, it is not known if the risks of medication use outweigh any
potential benefits.  Thus, for pediatric subjects, the proposed study has greater
than minimal risk without the prospect of direct benefit.  Further, since the
cardiovascular disease endpoints that are the primary focus of this study will
not be evident in young individuals, the study does not present an opportunity
to prevent a serious problem affecting the health or welfare of children. 
Therefore, this research cannot be approved for subjects under the age of 18
years on the basis of federal regulation 45-CFR-46 Subpart D.

LETTER OF INTENT

Prospective applicants are asked to submit, by February 10, 1999, a letter of
intent that includes a descriptive title of the proposed research, the name,
address, and telephone number of the Principal Investigator, the identities of
other key personnel and participating institutions, and the number and title of
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 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:

Ann A. Hagan, Ph.D.
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
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. 5/95) is to be used in applying
for these grants.  These forms are available at most institutional offices of
sponsored research and 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 available in the PHS 398 (rev. 5/95) application form must be
affixed to the bottom of the face page of the application.  Failure to use this
label could result in delayed processing of the application such that it may not
reach the review committee in time for review.  In addition, the RFA title and
number must be typed on line 2 of the face page of the application form and the
YES box must be marked.

Applicants must describe plans to accommodate the stated program requirements,
criteria, and staff involvement.  Applicants must address points discussed in the
SPECIAL REQUIREMENTS section of this RFA.

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:

Ann A. Hagan, Ph.D.
Division of Extramural Activities 
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AS-37F, MSC 6600
Bethesda, MD 20892-6600

Applications must be received by March 24, 1999.  If an application is received
after that date, it will be returned to the applicant without review.  The Center
for Scientific Review (CSR) will not accept any application in response to this
RFA that is essentially the same as one currently pending initial review, unless
the applicant withdraws the pending application.  The CSR will not accept any
application that is essentially the same as one already reviewed.  This does not
preclude the submission of substantial revisions of applications previously
reviewed, but such applications must include an introduction addressing the
previous critique.

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 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 SPECIAL REQUIREMENTS.  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.

o Significance:  Does this 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?

o 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?

Since the final study design will be developed collaboratively by the Steering
Committee for the trial, the peer review group will focus on evidence that the
applicant has carefully thought about the issues involved and possesses the
knowledge necessary to contribute meaningfully to the final design, including
understanding of the scientific, ethical, and practical issues underlying the
proposed study.

o 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)?  

For the SHOW trial this criterion will focus on the following questions:  Is
there documented evidence of the investigators" training, experience, and
specific competence relevant to the operation of a data coordinating center in
a multicenter clinical trial as described in this RFA?  Is there evidence of
successful collaborative interactions with other investigators under a common
protocol in a multi-center clinical trial?

o Environment:  Does the scientific environment in which the work will be done
contribute to the probability of success?  Is there evidence of institutional
support?

Review of applications for the Data Coordinating Center will also be based on the
following specific criteria:

o  Scientific and technical merit of the proposed approach to managing the
requirements of the study as outlined in the RFA.

o  Staff Qualifications:  Documented specific competence and relevant experience
of professional, technical, and administrative staff pertinent to the operation
of a Data Coordinating Center for a collaborative clinical trial.  Prior
experience collecting data and patient specimens from multiple clinical sites,
monitoring the data quality, and developing and utilizing statistical methods for
analysis of data should be demonstrated.  Experience of Data Center personnel in
utilizing procedures that insure the safety and confidentiality of all records
should be documented.

o  Data and Sample Management:  Adequacy of the proposed plans and experience
relating to data collection, management, editing, processing, analysis, and
reporting, as well as management of samples.

o  Centralized Support Functions:  Demonstrated ability to identify, enlist, and
coordinate the efforts of central laboratories and clinical facilities to carry
out centralized support functions for the Clinical Centers.  Adequacy of plans
to recruit central laboratories, clinical facilities, and/or other central
support functions.

o  Resources:  Adequacy of the proposed facility, technical hardware, and space. 
Appropriateness of the organizational and administrative structure of the
proposed coordinating center.  Evidence of institutional support and commitment
for the proposed program should be provided.

o  Knowledge of Problems:  Demonstrable knowledge of the potential problems
associated with the conduct of this study and possible solutions.

o  Cooperative Experience and Approach:  Adequacy of the approach to developing
a cooperative relationship among the participating clinical centers and
exercising appropriate leadership in matters of study design, data acquisition,
data management, and data analysis.  Evidence of experience in and willingness
to participate appropriately in a collaborative study as described in this RFA.

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

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

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

o  The adequacy of the proposed protection for humans or the environment, to the
extent they may be adversely affected by the project proposed in the application. 
The initial review group will also examine the safety of the research
environment.

Schedule

Letter of Intent Receipt Date:    February 10, 1999
Application Receipt Date:         March 24, 1999
Peer Review Date:                 June-July 1999
Council Review:                   September 8-9, 1999
Earliest Anticipated Start Date:  September 30, 1999

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

INQUIRIES

Inquiries concerning this RFA are strongly encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.  A website
on the NIDDK homepage containing information pertaining to this RFA is located
at http://www.niddk.nih.gov/fund/fund.htm.  Answers to
frequently asked questions and other information updates concerning this RFA and
the companion RFA for the Clinical Centers (DK-98-019) will be posted on the site
as they are developed.  Applicants are strongly encouraged to visit this website
on a regular basis in the course of preparing their applications.

Direct inquiries regarding programmatic issues that are not addressed at the
website to:

Barbara Harrison, M.S.
Division of Digestive Diseases and Nutrition
National Institute on Diabetes and Digestive and Kidney Diseases
45 Center Drive, MSC 6600, Room 6AN-18C
Bethesda, MD  20892-6600
Telephone:  (301) 594-8858
FAX:  (301) 480-8300
Email:  HarrisonB@extra.niddk.nih.gov

Michael J. Galvin, Ph.D.
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233, EC-23
111 T.W. Alexander Drive, EC-23 (for express/courier service)
Research Triangle Park, NC  27709
Telephone:  (910) 541-7825
FAX:  (919) 541-5064
Email:  galvin@niehs.nih.gov

Robin Hill, Ph.D.
Division of Epidemiology and Clinical Applications
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 8122, MSC-7936
Bethesda, MD  20892-7936
Telephone:  (301) 435-0407
FAX:  (301) 480-1773
Email:  robin_hill@nih.gov

Nell Armstrong, Ph.D., RN
Division of Extramural Activities
National Institute of Nursing Research
45 Center Drive, MSC 6300, Room 3AN-12
Bethesda, MD  20892-6300
Telephone:  (301) 594-5973
FAX:  (301) 480-8260
Email:  nell_armstrong@nih.gov

Direct inquiries regarding fiscal and administrative matters to:

Nancy Dixon
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, MSC 6600, Room 6AN-44C
Bethesda, MD  20892-6600
Telephone:  (301) 594-8854
FAX:  (301) 480-4237
Email:  DixonN@extra.niddk.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.847 and 93.848.  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 recipients to provide a smoke-free
workplace and promote the non-use of all tobacco products.  In addition, Public
Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain
facilities (or in some cases, any portion of a facility) in which regular or
routine education, library, day care, health care or early childhood development
services are provided to children.  This is consistent with the PHS mission to
protect and advance the physical and mental health of the American people.

References

Andres R, Muller DC, and Sorkin JD.  Long-term effects of change in body weight
on all-cause mortality: A review.  Ann Int Med 1993 119 (7 pt 2): 737-43.

Eastman RC and Keen H.  The impact of cardiovascular disease on people with
diabetes:  the potential for prevention.  Lancet 1997, 350: S129-32.

Eckel R, American Heart Association Science Advisory:  Obesity and Heart Disease. 
Circulation 1996, 96(9): 3248-50.

Flegal KM, Carroll MD, Kuczmarski RJ, and Johnson CL.  Overweight and Obesity in
the United States:  prevalence and trends, 1960-1994.  Int J of Obesity 1998, 22:
3947.

Hadden DR, Blair ALT, Wilson EZ, et al. Natural history of diabetes presenting
age 40-69 years:  a prospective study of the influence of intensive dietary
therapy.  Quart J Med 1986, 59: 579-98.

Haffner SM, Lehto S, Ronnemaa T, et al.  Mortality from Coronary Heart Disease
in Subjects with Type 2 Diabetes and in Nondiabetic Subjects with and without
Prior Myocardial Infarction.  N Eng J Med 1998, 339(4): 229-34.

Hollander PA, Elbein SC, Hirsch IB, et al.  Role of Orlistat in the Treatment of
Obese Patients with Type 2 Diabetes.  Diabetes Care 1998, 21(8): 1288-1294.

Johannes L and Stecklow S.  Dire Warnings About Obesity Rely on a Slippery
Statistic.  Wall Street Journal, Feb. 9,1998.

Kassirer J and Angell, M.  Losing Weight - An Ill-Fated New Year"s Resolution. 
N Eng J Med 1998, 338(1): 52-4.

Maggio CA and Pi-Sunyer FX.  The Prevention and Treatment of Obesity.  Diabetes
Care 1997, 20(11): 1744-1766.

National Diabetes Data Group.  Diabetes in America 2nd edition 1995, National
Institutes of Health Publication Number 95-1469, Chapter 19 and Appendix 7.11.

NHLBI and NIDDK.  Clinical Guidelines on the Identification, Evaluation, and
Treatment of Overweight and Obesity in Adults. 1998. Available at
http://www.nhlbi.nih.gov/nhlbi/cardio/obes/prof/guidelns/ob_home.htm

National Task Force on Prevention and Treatment of Obesity.  Long-term
Pharmacotherapy in the Management of Obesity.  JAMA 1996, 276(23): 1907-1915.

Sjostrom, L, Rissanen A, Andersen T, et al.  Randomized placebo-controlled trial
of orlistat for weight loss and prevention of weight regain in obese patients. 
Lancet 1998, 352: 167-72.

Whelton PK, Appel LJ, Espeland MA, et al.  Sodium reduction and weight loss in
the treatment of hypertension in older persons:  a randomized controlled trial
of nonpharmacologic interventions in the elderly (TONE).  JAMA. 1998, 279: 839-
46.

Williamson DF, Pamuk E, Thun M, et al.  Prospective Study of Intentional Weight
Loss and Mortality in Never-Smoking Overweight US White Women Aged 40-64 Years. 
Am J Epidemiol 1995, 141(12): 1128-41.

Williamson DF.  Weight Cycling and Mortality:  How do the Epidemiologists Explain
the Role of Intentional Weight Loss?  J Amer Coll Nutr 1996: 15(1): 6-13.

Williamson DF, Venkat Narayan KM, and Teutsch SM.  The Economic Impact of Obesity
in the United States:  Whither?  Obesity Research 1998, 6(2): 173-5.

Wolf AM, Colditz GA.  Current estimates of the economic cost of obesity in the
United States.  Obesity Research 1998, 6: 97-106.

Yanovski, SZ, Bain RP and Williamson, DF.  Report of the NIH-CDC workshop on the
feasibility of conducting a randomized clinical trial to evaluate the long-term
health impact of intentional weight loss in obese persons.  Am J Clin Nutr, in
press.



Weekly TOC for this Announcement
NIH Funding Opportunities and Notices


Office of Extramural Research (OER) - Home Page Office of Extramural
Research (OER)
  National Institutes of Health (NIH) - Home Page National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS)
  USA.gov - Government Made Easy


Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.