OBJECTIVE: To utilize islet
autoantibody titers to improve the estimation of future type 1 diabetes risk in
children.
<p>RESEARCH DESIGN AND METHODS:
Prospective cohort studies in Finland, Germany, Sweden and the US followed
24,662 children at increased genetic or familial risk to develop islet
autoimmunity and diabetes. For 1,604 children with confirmed positivity, titers
of autoantibodies against insulin (IAA), glutamic acid decarboxylase (GADA) and
insulinoma-associated antigen-2 (IA-2A) were harmonized for diabetes risk analyses.</p>
<p>RESULTS: Survival analysis from
time of confirmed positivity revealed markedly different 5-year diabetes risks
associated with IAA (n=909), GADA (n=1076) or IA-2A (n=714), when stratified by
quartiles of titer, ranging from 19% (GADA 1<sup>st</sup> quartile) to 60%
(IA-2A 4<sup>th</sup> quartile). The minimum titer associated with a maximum
difference in 5-year risk differed for each autoantibody, corresponding to the
58.6<sup>th</sup>, 52.4<sup>th</sup> and 10.2<sup>nd</sup> percentile of
children specifically positive for each of IAA, GADA and IA-2A, respectively.
Using these autoantibody type-specific titer thresholds in the 1,481 children
with all autoantibodies tested, the 5-year risk conferred by single (n=954) and
multiple (n=527) autoantibodies could be stratified from 6%
to 75% (p<0.0001). The thresholds effectively identified children with 50%
or higher 5-year risk when considering age-specific autoantibody screening
(57-65% positive predictive value and 56-74% sensitivity for ages 1-5 years).
Multivariable analysis confirmed the significance of associations between the
three autoantibody titers and diabetes risk, informing a childhood risk
surveillance strategy.</p>
<p>CONCLUSIONS: This study defined
islet autoantibody type-specific titer thresholds that significantly improved
type 1 diabetes risk stratification in children.</p>