Department of Clinical Sciences, Lund University CRC, Malmö, Sweden.
Department of Cell and Molecular Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
EBioMedicine. 2024 Jun;104:105144. doi: 10.1016/j.ebiom.2024.105144. Epub 2024 May 8.
Two or more autoantibodies against either insulin (IAA), glutamic acid decarboxylase (GADA), islet antigen-2 (IA-2A) or zinc transporter 8 (ZnT8A) denote stage 1 (normoglycemia) or stage 2 (dysglycemia) type 1 diabetes prior to stage 3 type 1 diabetes. Automated multiplex Antibody Detection by Agglutination-PCR (ADAP) assays in two laboratories were compared to single plex radiobinding assays (RBA) to define threshold levels for diagnostic specificity and sensitivity.
IAA, GADA, IA-2A and ZnT8A were analysed in 1504 (54% females) population based controls (PBC), 456 (55% females) doctor's office controls (DOC) and 535 (41% females) blood donor controls (BDC) as well as in 2300 (48% females) patients newly diagnosed (1-10 years of age) with stage 3 type 1 diabetes. The thresholds for autoantibody positivity were computed in 100 10-fold cross-validations to separate patients from controls either by maximizing the χ-statistics (chisq) or using the 98th percentile of specificity (Spec98). Mean and 95% CI for threshold, sensitivity and specificity are presented.
The ADAP ROC curves of the four autoantibodies showed comparable AUC in the two ADAP laboratories and were higher than RBA. Detection of two or more autoantibodies using chisq showed 0.97 (0.95, 0.99) sensitivity and 0.94 (0.91, 0.97) specificity in ADAP compared to 0.90 (0.88, 0.95) sensitivity and 0.97 (0.94, 0.98) specificity in RBA. Using Spec98, ADAP showed 0.92 (0.89, 0.95) sensitivity and 0.99 (0.98, 1.00) specificity compared to 0.89 (0.77, 0.86) sensitivity and 1.00 (0.99, 1.00) specificity in the RBA. The diagnostic sensitivity and specificity were higher in PBC compared to DOC and BDC.
ADAP was comparable in two laboratories, both comparable to or better than RBA, to define threshold levels for two or more autoantibodies to stage type 1 diabetes.
Supported by The Leona M. and Harry B. Helmsley Charitable Trust (grant number 2009-04078), the Swedish Foundation for Strategic Research (Dnr IRC15-0067) and the Swedish Research Council, Strategic Research Area (Dnr 2009-1039). AL was supported by the DiaUnion collaborative study, co-financed by EU Interreg ÖKS, Capital Region of Denmark, Region Skåne and the Novo Nordisk Foundation.
针对胰岛素（IAA）、谷氨酸脱羧酶（GADA）、胰岛抗原-2（IA-2A）或锌转运蛋白 8（ZnT8A）的两种或更多种自身抗体表示 1 型糖尿病的 1 期（正常血糖）或 2 期（糖调节受损），然后才是 3 期 1 型糖尿病。通过在两个实验室中比较自动化多重抗体检测的凝集-PCR（ADAP）检测与单plex 放射配体结合检测（RBA），确定诊断特异性和敏感性的阈值水平。
在基于人群的对照组（PBC）中分析了 1504 名（54%为女性）患者、456 名（55%为女性）医生办公室对照组（DOC）和 535 名（41%为女性）献血者对照组（BDC）的 IAA、GADA、IA-2A 和 ZnT8A，以及 535 名（41%为女性）新诊断的 3 期 1 型糖尿病患者（1-10 岁）。通过最大程度地增加卡方检验（chisq）或使用特异性的第 98 百分位数（Spec98），在 100 次 10 倍交叉验证中计算了自身抗体阳性的阈值，以将患者与对照组区分开来。呈现了阈值、敏感性和特异性的平均值和 95%置信区间。
四个自身抗体的 ADAP ROC 曲线在两个 ADAP 实验室中具有可比的 AUC，并且高于 RBA。与 RBA 相比，使用 chisq 检测两种或更多种自身抗体的 ADAP 显示 0.97（0.95，0.99）的敏感性和 0.94（0.91，0.97）的特异性，而 RBA 显示 0.90（0.88，0.95）的敏感性和 0.97（0.94，0.98）的特异性。使用 Spec98，ADAP 显示 0.92（0.89，0.95）的敏感性和 0.99（0.98，1.00）的特异性，而 RBA 显示 0.89（0.77，0.86）的敏感性和 1.00（0.99，1.00）的特异性。与 DOC 和 BDC 相比，PBC 的诊断敏感性和特异性更高。
ADAP 在两个实验室中是可比的，均与 RBA 相当或优于 RBA，以确定将两种或更多种自身抗体定义为 1 型糖尿病的阶段的阈值水平。
得到了利昂娜·M. 和哈里·B. 赫尔姆斯利慈善信托基金（资助号 2009-04078）、瑞典战略研究基金会（IR 15-0067）和瑞典研究理事会战略研究领域（资助号 2009-1039）的支持。AL 得到了 DiaUnion 合作研究的支持，该研究由欧盟 INTERREG ÖKS、丹麦首都大区、斯科讷地区和诺和诺德基金会共同资助。
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