Microsoft Word search phase 3 Title Page Amendment

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S
SEARC
CH for 
Phase
Decem
 
 
Diabet
 
e 3 Proto
 
mber 20
tes in Y
ocol 
010 
 
 
 
 
 
 
 
 
Youth 

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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 
 

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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 

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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.
 

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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