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Youth
SEARCH Phase 3 Protocol
Table of Contents
Section 1
Executive Summary
Section 2
Center Descriptions
Section 3
Study Organization
Section 4A
Registry Study Objectives
Section 4B
Cohort Study Objectives
Section 5A
Registry Study Case Ascertainment & Data Collection
Section 5B
Cohort Study Data Collection
Section 6A
Registry Study Statistical Considerations
Section 6B
Cohort Study Statistical Considerations
Section 7
Data Management
Section 8A
Registry Study Human Subjects
Section 8B
Cohort Study Human Subjects
Section 1 - Executive Summary (Phase 3 - 12/2010)
Section 1 - Page 1
SEARCH Phase 3 Protocol - Section 1
Executive Summary
Background
Diabetes mellitus (DM) is one of the most common chronic diseases in children and adolescents.
Although in some racial/ethnic groups (e.g., American Indians) the majority of cases in children
may be type 2 diabetes (T2D), in most populations, type 1 diabetes (T1D) is the predominant
form of the disease. T1D results primarily from the autoimmune destruction of the insulin
producing β-cells of the pancreas. T2D, once rarely observed in youth, is becoming more
common, especially among youth of racial/ethnic minority groups in the US. Although the
pathophysiology of T2D in the pediatric population has not been well-studied, emerging
evidence
(1-3)
suggests that it is similar to that seen in adults, in whom insulin resistance and
progressive beta cell failure results in T2D
(4)
.
Recent estimates of the prevalence and incidence of diabetes by type in the US population aged
<20 years have been provided by the population-based, multi-center SEARCH for Diabetes in
Youth study. SEARCH estimated that in 2002-2003 among children <10 years of age, the
incidence of T1D was 23/100,000/year non-Hispanic whites. 13/100,000/year in African
Americans, 12/100,000/year in Hispanics, 5.2/100,000/year in American Indians, and
6.9/100,000/year Asian/Pacific Islanders
(5)
. In older youth, there was a similar pattern: the
incidence of T1D (per 100,000 person-years) among youth aged 10-14 and 15 to 19 years, was
highest among non-Hispanic white children (32.9 and 15.1, respectively), followed by African
American (19.2 and 11.1, respectively) and Hispanic youth (17.6 and 12.1, respectively), and
lowest among American Indian (7.1 and 4.8, respectively) and Asian/Pacific Islander youth (8.3
and 6.8, respectively). In all racial/ethnic groups in the age group 0-9 years, T1D represented the
majority of cases. However, in the 10-19 year old group, the proportion of cases due to T1D
ranged from 85% in non-Hispanic whites to 14% in American Indians
(5)
.
Worldwide, an annual increase of 2.8% in T1D incidence has been reported
(6)
, especially among
young children aged below 5 years (4.0% per year). In Europe, recent findings from the
EURODIAB study, a population-based T1D registry of children diagnosed before age 15 years,
showed an annual increase of 3.9% during 1989-2003, and that the increase was highest in the
age group 0-4 years (5.4%)
(7)
. The underlying factors of this increase have not yet been
identified. An internationally collaborative observational study aimed at identifying potential
environmental factors of T1D is now underway.
In parallel to the increase in T1D, T2D is becoming more common in adolescents. This has been
linked to the increase in obesity among youth observed in the last two decades in the U.S.
(8)
and
around the world. Very limited data are available on the temporal trends in the incidence of
T2D. Data from SEARCH estimates that T2D represented 86% of diabetes cases in American
Section 1 - Executive Summary (Phase 3 - 12/2010)
Section 1 - Page 2
Indians, 70% in Asian/Pacific Islanders, 58% in African Americans and 46% of cases in
Hispanic youth.
In order to study trends in both T1D and T2D incidence, it will require long-term continuous
monitoring of these two major forms of diabetes in diverse populations of youth less than 20
years of age. In addition to providing the population burden of the disease over time,
surveillance is also pivotal for identifying potential risk factors, evaluating diabetes prevention
strategies, and prioritizing the allocation of limited health care resources.
In children and adolescents with diabetes, acute complications are more common than chronic
complications and, at this age, they carry a greater risk of morbidity and mortality
(9, 10)
. The
most common acute DM complications observed in youth are diabetic ketoacidosis (DKA) and
hypoglycemia. DKA is a serious, costly, and potentially preventable complication caused by
insulin deficiency. If left untreated, it can lead to coma and death. DKA may be the clinical
presentation of both T1D and T2D
(11)
or can occur in individuals with an established diabetes
diagnosis. Recent findings from the SEARCH study demonstrated that this complication is
present at diabetes onset in 1 out of 4 youth and 93% of these are hospitalized
(11)
.
Data on the occurrence of diabetes acute complications are crucial to evaluate the effectiveness
of diabetes awareness campaigns and education programs, disease management and to identify
sub-groups of the youth population at increased risk for these serious complications.
Large clinical trials have indicated that glycemic, blood pressure, and lipid control can prevent or
delay the onset of diabetes-related complications. Very little is known about the natural history
of youth-onset T2D. Data from the Pima Indian longitudinal study indicated that among
individuals with early-onset T2D (before age 20), by age 30, 45% developed retinopathy and
57% nephropathy, and they had a higher risk of developing end-stage renal disease and of dying
by middle age
(12, 13)
. Furthermore, the life expectancy of individuals diagnosed with diabetes at
age 10 years is reduced, on average, by 19 years
(14)
. These findings warrants further research to
identify the factors that confer the elevated risk of these complications associated with early-
onset T2D.
The SEARCH study brings together major and timely facets of childhood diabetes research: an
epidemiologic component that assesses temporal trends in the incidence of diabetes in youth; a
pathophysiologic component addressing the natural history of diabetes in youth; a health services
research component to evaluate the processes and quality of care for youth with diabetes; and a
public health perspective on case classification of diabetes in youth.
Section 1 - Executive Summary (Phase 3 - 12/2010)
Section 1 - Page 3
Methods
SEARCH Phases 1 and 2
SEARCH Phases 1 and 2 involved six centers, coordinated in Cincinnati, Ohio; Denver,
Colorado; Seattle, Washington; Columbia, South Carolina (and Chapel Hill, North Carolina);
Honolulu, Hawaii; and Pasadena, California, that have identified prevalent and incident cases of
diabetes (excluding gestational diabetes) in youth less than 20 years of age in defined
populations for specific calendar years. Four centers (Ohio, Colorado, Washington, South
Carolina) were geographically based - newly diagnosed diabetes cases were identified from a
geographically defined population. Two centers (Hawaii and California) were membership-
based - diabetes cases were identified among members of participating health plans.
The study identified diabetes cases that were prevalent in 2001 and 2009 and cases incident from
January 1, 2002 through September 29, 2010. At all six SEARCH centers, the primary approach
to identification of incident cases was a rapid reporting network of clinics and health care
providers, including in some instances diabetes educators and school nurses.
In SEARCH Phase 1 and 2, approximately 6,400 prevalent 2001 cases were identified under the
SEARCH Phase 1 protocol and 6600 prevalent 2009 cases were identified under the SEARCH
Phase 2 protocol. For 2002 - 2010, approximately 11,000 incident cases were identified. Data
collection in SEARCH Phases 1 and 2 included, at baseline, both for prevalent 2001 and incident
2002 - 2010 cases, questionnaire surveys and an invitation to an in-person visit (excluding
incident 2007 and 2009 cases). For 2006 and 2008 cases, the in-person visit was an abbreviated
“Typology” visit. For incident cases and a subset of prevalent 2001 cases, data collection also
included medical record review. Incident 2002 - 2005 cases were asked to return for a follow-up
visit at 12, 24 and 60 months after their baseline visit.
Table 1-1. Participation in SEARCH Phases 1 and 2 By Cohort
2001
Prevalent
2002 - 2005
Incident
2006 - 2009
Incident
2009 Prevalent
2010 Incident
Case
Registration
x x
x
x x
Initial
10>20>
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