College of Medicine, QU Health, Qatar University, PO Box 2713, Doha, Qatar.
Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, PO Box 34110, Doha, Qatar.
Mol Psychiatry. 2024 Mar;29(3):653-659. doi: 10.1038/s41380-023-02357-9. Epub 2023 Dec 22.
Autism Spectrum Disorder (ASD) is a common neurodevelopmental disorder in children. It is currently diagnosed by behaviour-based assessments made by observation and interview. In 2018 we reported a discovery study of a blood biomarker diagnostic test for ASD based on a combination of four plasma protein glycation and oxidation adducts. The test had 88% accuracy in children 5-12 years old. Herein, we present an international multicenter clinical validation study (N = 478) with application of similar biomarkers to a wider age range of 1.5-12 years old children. Three hundred and eleven children with ASD (247 male, 64 female; age 5.2 ± 3.0 years) and 167 children with typical development (94 male, 73 female; 4.9 ± 2.4 years) were recruited for this study at Sidra Medicine and Hamad Medical Corporation hospitals, Qatar, and Hospital Regional Universitario de Málaga, Spain. For subjects 5-12 years old, the diagnostic algorithm with features, advanced glycation endproducts (AGEs)-N-carboxymethyl-lysine (CML), N-carboxymethylarginine (CMA) and 3-deoxyglucosone-derived hydroimidazolone (3DG-H), and oxidative damage marker, o,o'-dityrosine (DT), age and gender had accuracy 83% (CI 79 - 89%), sensitivity 94% (CI 90-98%), specificity 67% (CI 57-76%) and area-under-the-curve of receiver operating characteristic plot (AUROC) 0.87 (CI 0.84-0.90). Inclusion of additional plasma protein glycation and oxidation adducts increased the specificity to 74%. An algorithm with 12 plasma protein glycation and oxidation adduct features was optimum for children of 1.5-12 years old: accuracy 74% (CI 70-79%), sensitivity 75% (CI 63-87%), specificity 74% (CI 58-90%) and AUROC 0.79 (CI 0.74-0.84). We conclude that ASD diagnosis may be supported using an algorithm with features of plasma protein CML, CMA, 3DG-H and DT in 5-12 years-old children, and an algorithm with additional features applicable for ASD screening in younger children. ASD severity, as assessed by ADOS-2 score, correlated positively with plasma protein glycation adducts derived from methylglyoxal, hydroimidazolone MG-H1 and N(1-carboxyethyl)lysine (CEL). The successful validation herein may indicate that the algorithm modifiable features are mechanistic risk markers linking ASD to increased lipid peroxidation, neuronal plasticity and proteotoxic stress.
自闭症谱系障碍（ASD）是一种常见的儿童神经发育障碍。目前，它是通过观察和访谈进行的基于行为的评估来诊断的。2018 年，我们报告了一项基于四种血浆蛋白糖基化和氧化加合物组合的 ASD 血液生物标志物诊断测试的发现性研究。该测试在 5-12 岁的儿童中具有 88%的准确性。在此，我们提出了一项国际多中心临床验证研究（N=478），该研究应用了类似的生物标志物，将年龄范围扩大到 1.5-12 岁的儿童。在卡塔尔的锡德拉医学和哈马德医疗公司医院和西班牙马拉加的马尔瓦利亚医院，招募了 311 名 ASD 儿童（247 名男性，64 名女性；年龄 5.2±3.0 岁）和 167 名发育正常的儿童（94 名男性，73 名女性；4.9±2.4 岁）进行这项研究。对于 5-12 岁的儿童，具有特征、晚期糖基化终产物（AGEs）-N-羧甲基赖氨酸（CML）、N-羧甲基精氨酸（CMA）和 3-脱氧葡萄糖衍生的氢咪唑酮（3DG-H）以及氧化损伤标志物 o,o'-二酪氨酸（DT）、年龄和性别的诊断算法的准确性为 83%（CI 79-89%），敏感性为 94%（CI 90-98%），特异性为 67%（CI 57-76%），接收器操作特征图的曲线下面积（AUROC）为 0.87（CI 0.84-0.90）。纳入额外的血浆蛋白糖基化和氧化加合物可将特异性提高到 74%。对于 1.5-12 岁的儿童，具有 12 种血浆蛋白糖基化和氧化加合物特征的算法是最佳的：准确性为 74%（CI 70-79%），敏感性为 75%（CI 63-87%），特异性为 74%（CI 58-90%），AUROC 为 0.79（CI 0.74-0.84）。我们得出结论，ASD 诊断可以使用在 5-12 岁儿童中具有血浆蛋白 CML、CMA、3DG-H 和 DT 特征的算法，以及具有适用于 ASD 筛查的其他特征的算法来支持。ASD 严重程度，由 ADOS-2 评分评估，与来自甲基乙二醛的血浆蛋白糖基化加合物、氢咪唑酮 MG-H1 和 N（1-羧乙基）赖氨酸（CEL）呈正相关。在此成功验证可能表明，算法可修改的特征是将 ASD 与增加的脂质过氧化、神经元可塑性和蛋白毒性应激联系起来的机制风险标志物。
