Jaeger C, Hatziagelaki E, Stroedter A, Becker F, Scherer S, Petzoldt R, Federlin K, Bretzel R G
Third Medical Department, Justus-Liebig University, Giessen, Germany.
Exp Clin Endocrinol Diabetes. 1999;107(8):496-505. doi: 10.1055/s-0029-1232558.
To determine the value of a combined antibody screening for prediction of type I diabetes in a low incidence cohort, we prospectively studied 882 first-degree relatives (485 parents, 382 siblings and 15 offsprings) for up to 11 years who were not preselected for islet cell antibody (ICA) status. During the observation period, 16 individuals developed diabetes. The first serum sample obtained at study entry was analyzed for ICA and antibodies to insulin (IAA), glutamic acid decarboxylase (GADA) and anti-IA-2ic. A multivariate analysis, according to the Cox proportional hazard model considering the joint effects of all baseline variables, selected the four antibodies and the specific family history as significant risk confounding factors (p < 0.05). Further analysis by Kaplan-Meier Life-table methods confirmed a significantly increasing risk of diabetes with the number of autoantibodies present (p < 0.001). In accordance with the Cox model, relatives with more than one affected family member (a multiplex pedigree) and siblings and offsprings vs. parents were at increased risk of IDDM (p < 0.05). In addition to technical problems, a screening strategy based on initial ICA testing has the potential of missing ICA negative subjects among future cases of type I diabetes (19% were ICA negative in the present study) and we therefore set out to evaluate an alternative approach using a dual step strategy with a combination of GADA and anti-IA-2ic for initial screening followed by retesting of positive individuals for ICA and IAA. The combination of GADA and anti-IA-2ic for primary screening (step 1) proved to be more sensitive, identifying 94% of future cases of type I diabetes compared to 81% using ICA as initial test and this antibody combination identified 93% of those individuals with ICA of 20 JDF or more. Retesting of positive individuals for ICA and IAA (step 2) significantly improved the positive predictive value confering a risk of diabetes for siblings and offsprings with more than 2 antibodies within 5 years of 67% (95%CI: 39-90). We conclude that the prognosis of contracting IDDM in relatives is strongly related to the number of autoantibodies present, but the family history should be additionally considered for individual risk assessment. The proposed screening strategy could overcome the inherent problems of the ICA and IAA assays for large-scale screening. In the present study it allows 5-year risk estimates of up to 67% identifying 94% of future cases of type I diabetes.
为了确定联合抗体筛查在低发病率队列中预测1型糖尿病的价值，我们对882名一级亲属（485名父母、382名兄弟姐妹和15名后代）进行了长达11年的前瞻性研究，这些亲属未根据胰岛细胞抗体（ICA）状态进行预先选择。在观察期内，有16人患糖尿病。对研究开始时采集的第一份血清样本进行ICA、胰岛素抗体（IAA）、谷氨酸脱羧酶抗体（GADA）和抗IA-2ic抗体分析。根据Cox比例风险模型进行多变量分析，考虑所有基线变量的联合效应，选择这四种抗体和特定家族史作为显著的风险混杂因素（p<0.05）。通过Kaplan-Meier生存表方法进一步分析证实，随着自身抗体数量的增加，患糖尿病的风险显著增加（p<0.001）。根据Cox模型，有多个受影响家庭成员的亲属（多重家系）以及兄弟姐妹和后代与父母相比，患IDDM的风险增加（p<0.05）。除技术问题外，基于初始ICA检测的筛查策略有可能在未来1型糖尿病病例中遗漏ICA阴性个体（本研究中19%为ICA阴性），因此我们着手评估一种替代方法，即采用两步策略，先用GADA和抗IA-2ic联合进行初始筛查，然后对阳性个体进行ICA和IAA复测。结果表明，GADA和抗IA-2ic联合用于初次筛查（第一步）更为敏感，可识别94%的未来1型糖尿病病例，而以ICA作为初始检测时这一比例为81%，且这种抗体组合可识别93%的ICA为20 JDF或更高的个体。对阳性个体进行ICA和IAA复测（第二步）显著提高了阳性预测值，对于有超过2种抗体的兄弟姐妹和后代，5年内患糖尿病的风险为67%（95%CI：39-90）。我们得出结论，亲属患IDDM的预后与自身抗体数量密切相关，但在进行个体风险评估时还应考虑家族史。所提出的筛查策略可克服ICA和IAA检测在大规模筛查中的固有问题。在本研究中，它可实现高达67%的5年风险估计，识别94%的未来1型糖尿病病例。
