Gesundheit Benjamin, Zisman Philip David, Hochbaum Leah, Posen Yehudit, Steinberg Avraham, Friedman Gerald, Ravkin Hersh D, Rubin Eitan, Faktor Ouriel, Ellis Ronald
Cell-El Ltd., Jerusalem, Israel.
Shaare Zedek Medical Center, Jerusalem, Israel.
Front Pediatr. 2023 Feb 21;11:967954. doi: 10.3389/fped.2023.967954. eCollection 2023.
Children with autism spectrum disorder (ASD) present with distinctive clinical features. No objective laboratory assay has been developed to establish a diagnosis of ASD. Considering the known immunological associations with ASD, immunological biomarkers might enable ASD diagnosis and intervention at an early age when the immature brain has the highest degree of plasticity. This work aimed to identify diagnostic biomarkers discriminating between children with ASD and typically developing (TD) children.
A multicenter, diagnostic case-control study trial was conducted in Israel and Canada between 2014 and 2021. In this trial, a single blood sample was collected from 102 children with ASD as defined in Diagnostic Statistical Manual of Mental Disorders [DSM)-IV (299.00) or DSM-V (299.00)], and from 97 typically developing control children aged 3-12 years. Samples were analyzed using a high-throughput, multiplexed ELISA array which quantifies 1,000 human immune/inflammatory-related proteins. Multiple logistic regression analysis was used to obtain a predictor from these results using 10-fold cross validation.
Twelve biomarkers were identified that provided an overall accuracy of 0.82 ± 0.09 (sensitivity: 0.87 ± 0.08; specificity: 0.77 ± 0.14) in diagnosing ASD with a threshold of 0.5. The resulting model had an area under the curve of 0.86 ± 0.06 (95% CI: 0.811-0.889). Of the 102 ASD children included in the study, 13% were negative for this signature. Most of the markers included in all models have been reported to be associated with ASD and/or autoimmune diseases.
The identified biomarkers may serve as the basis of an objective assay for early and accurate diagnosis of ASD. In addition, the markers may shed light on ASD etiology and pathogenesis. It should be noted that this was only a pilot, case-control diagnostic study, with a high risk of bias. The findings should be validated in larger prospective cohorts of consecutive children suspected of ASD.
自闭症谱系障碍（ASD）患儿具有独特的临床特征。目前尚未开发出用于确诊ASD的客观实验室检测方法。鉴于已知的ASD免疫关联，免疫生物标志物或许能够在未成熟大脑具有最高可塑性的早期阶段实现ASD的诊断与干预。本研究旨在识别能够区分ASD患儿与发育正常（TD）儿童的诊断生物标志物。
2014年至2021年间，在以色列和加拿大开展了一项多中心诊断性病例对照研究试验。在该试验中，从102名符合《精神疾病诊断与统计手册》（DSM）-IV（299.00）或DSM-V（299.00）定义的ASD患儿以及97名3至12岁发育正常的对照儿童中采集了一份血样。使用高通量多重ELISA阵列对样本进行分析，该阵列可定量检测1000种人类免疫/炎症相关蛋白。采用多重逻辑回归分析，通过10倍交叉验证从这些结果中获得一个预测指标。
识别出12种生物标志物，在阈值为0.5时，其诊断ASD的总体准确率为0.82±0.09（敏感性：0.87±0.08；特异性：0.77±0.14）。所得模型的曲线下面积为0.86±0.06（95%CI：0.811 - 0.889）。在纳入研究的102名ASD患儿中，13%对该特征呈阴性。所有模型中包含的大多数标志物据报道都与ASD和/或自身免疫性疾病有关。
所识别的生物标志物可作为早期准确诊断ASD的客观检测方法的基础。此外，这些标志物可能有助于揭示ASD的病因和发病机制。需要注意的是，这只是一项初步的病例对照诊断研究，存在较高的偏倚风险。这些发现应在更大规模的疑似ASD连续儿童前瞻性队列中进行验证。
