Microsoft Word search phase 3 Title Page Amendment

Severity at Onset of T1D: The onset of T1D is heterogeneous, ranging from severe 
diabetic ketoacidosis (DKA) requiring hospitalization to a relatively gradual onset.  
Younger age at onset is usually associated with a more severe onset, more need for 
hospitalization, a greater chance of DKA, lower C peptide levels and higher HbA
1c
.   
As onset age is decreasing, the presentation of diabetes in very young children is 
increasing, and can be particularly difficult for parents to recognize 
(65)
.  SEARCH 
found an increasing prevalence of DKA at onset of T1D with younger age: 15% of 
children 15-19; 27% of children 5-9; 25% of children 10-14; and 37% of children age 
0-4 
(19)
.  This study also revealed that the incidence of DKA at diagnosis of T1D has 
not changed significantly over the past two decades, despite efforts to improve 
awareness regarding diabetes symptoms to facilitate the earlier diagnosis and 
treatment of diabetes in children.  By continuing to assess the presence of DKA at 
onset of T1D, SEARCH will be positioned to document potential temporal trends in 
the severity of T1D onset and to explore potential determinants of such trends.  
Other characteristics which differ by age at onset include fasting C peptide (FCP) 
levels, and level and type of autoantibodies.  A study examining FCP at diagnosis of 
T1D found that higher levels were associated with older age at onset, less 
hyperglycemia, and a reduced insulin requirement 
(60)
.  SEARCH also found that, 
among youth with T1D and positive DA, older onset age and lower HbA
1c
 levels 
were associated with preservation of FCP within the first year of diagnosis 
(17)
.  It is 
not known if the percent of youth with T1D and preserved beta cell function is 
changing over time.  Such knowledge may have important implications for clinical 
care and clinical trials. 
The presence of islet cell (ICA), insulin (IAA), 65-kDa isoform of glutamic acid 
decarboxylase (GAD65), insulinoma-associated protein 2 (IA-2) or islet zinc 
transporter (ZnT8) autoantibodies is highly predictive of T1D risk.  It is believed that 

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Section 4A - Study Objectives/Background and Significance (Phase 3 - 11/2010) 
Section 4A - Page 9 
 Registry 
Study
 
 
seroconversion occurs early in life 
(66)
; however, autoimmunity can occur at any age 
(67)
.  The Diabetes Prevention Trial - Type 1 recently confirmed that not only 
presence, but number of DA, type and titers are also predictive for T1D risk 
(67)
.  
Differences in the levels of DA have also been reported by onset age.  Zimmet et al 
reported a higher frequency of GAD65 positive antibodies among patients who were 
diagnosed with T1D at age 10+ compared to those diagnosed before age 10 
(68)
.  
Similarly, SEARCH reported a higher prevalence of GAD65 antibodies in T1D youth 
age 10+ compared with those < 10 years old at diagnosis (65.6% vs. 56.4%) 
(5)
.  Data 
on trends in autoimmunity at presentation with T1D are very limited.  It is unknown if 
autoimmunity is shifting to younger ages over time as seen with T1D onset age.  Such 
knowledge of a potential shift in DA seroconversion would narrow the exposure 
window and help in identifying potential environmental triggers.