1IBM Research, Cambridge MA and Yorktown Heights, NY.
2Department of Pediatrics, PEDEGO Research Unit, University of Oulu and Oulu University Hospital, Oulu, Finland.
Diabetes Care. 2022 Jan 1;45(1):160-168. doi: 10.2337/dc21-0878.
To use islet autoantibody titers to improve the estimation of future type 1 diabetes risk in children.
Prospective cohort studies in Finland, Germany, Sweden, and the U.S. 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), GAD antibodies (GADA), and insulinoma-associated antigen 2 (IA-2A) were harmonized for diabetes risk analyses.
Survival analysis from time of confirmed positivity revealed markedly different 5-year diabetes risks associated with IAA (n = 909), GADA (n = 1,076), and IA-2A (n = 714), when stratified by quartiles of titer, ranging from 19% (GADA 1st quartile) to 60% (IA-2A 4th quartile). The minimum titer associated with a maximum difference in 5-year risk differed for each autoantibody, corresponding to the 58.6th, 52.4th, and 10.2nd 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 a ≥50% 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.
This study defined islet autoantibody type-specific titer thresholds that significantly improved type 1 diabetes risk stratification in children.
利用胰岛自身抗体滴度提高对儿童 1 型糖尿病未来风险的评估。
在芬兰、德国、瑞典和美国进行的前瞻性队列研究，对 24662 名有遗传或家族史易发生胰岛自身免疫和糖尿病的儿童进行随访。对于 1604 名确证阳性的儿童，对胰岛素自身抗体（IAA）、谷氨酸脱羧酶抗体（GADA）和胰岛瘤相关抗原 2（IA-2A）的抗体滴度进行了协调，用于糖尿病风险分析。
从确证阳性时的生存分析显示，与 IAA（n=909）、GADA（n=1076）和 IA-2A（n=714）相关的 5 年糖尿病风险明显不同，按滴度四分位距分层，范围从 19%（GADA 第 1 四分位距）到 60%（IA-2A 第 4 四分位距）。与 5 年风险差异最大相关的最小滴度，因每种自身抗体而异，分别对应于 IAA、GADA 和 IA-2A 特异性阳性儿童的第 58.6、52.4 和 10.2 百分位数。在检测了所有自身抗体的 1481 名儿童中，使用这些自身抗体类型特异性滴度阈值，可以将单（n=954）和多（n=527）种自身抗体的 5 年风险分层为 6-75%（P<0.0001）。这些阈值在考虑年龄特异性自身抗体筛查时（1-5 岁时阳性预测值为 57-65%，敏感性为 56-74%），有效地确定了 5 年风险≥50%的儿童。多变量分析证实了三种自身抗体滴度与糖尿病风险之间的关联具有显著意义，为儿童风险监测策略提供了信息。
本研究确定了胰岛自身抗体类型特异性滴度阈值，可显著改善儿童 1 型糖尿病的风险分层。
