Table3_Urine Organic Acids as Metabolic Indicators for Global Developmental Delay/Intellectual Disability in Chinese Children.DOCX

Objective: The purpose of this study was to search for differential metabolites in urine organic acids, and to characterize metabolic features that can be used to identify metabolites for exploration of global developmental delay (GDD)/intellectual disability (ID) etiology and pathogenesis.
Methods: We screened positive test results that could explain GDD/ID from 1,253 cases, and the major differential metabolites in 132 urine organic acids from the 1,230 cases with negative results (863 GDD cases, 367 ID cases), and 100 typically developing children (TD). Non-supervisory principal component analysis and orthogonal partial least squares discriminant analysis were used to develop models to distinguish GDD/ID from TD children, and to detect major differential metabolites.
Results: We get 23 positive results that could identify the cause of GDD/ID from 1253 cases diagnosed with GDD/ID. Among 1,230 negative results, we get the differential metabolites of the GDD group and the ID group had the same trend compared with the TD group. Twenty four differential metabolites were obtained from the GDD group, and 25 from the ID group (VIP > 1.0, p < 0.01). These differential metabolites were mainly related to the following pathways: the synthesis and degradation of ketone bodies, citrate cycle, alanine, aspartate and glutamate metabolism, pyrimidine metabolism, butanoate metabolism, pyruvate metabolism, fatty acid biosynthesis, valine, leucine and isoleucine degradation.
Conclusion: The use of metabolomics research methods to detect urine organic acids of children with GDD/ID can discover differential metabolites, which might be valuable for future research on the etiology, pathogenesis, prognosis and possible interventions of GDD/ID. The significantly altered differential metabolites indicators could therefore be potential diagnostic biomarkers for GDD/ID.

研究目的：本研究旨在筛查尿液有机酸中的差异代谢物，并刻画代谢特征，以筛选可用于探究全面发育迟缓（Global Developmental Delay, GDD）/智力障碍（Intellectual Disability, ID）病因与发病机制的潜在代谢标志物。
研究方法：本研究从1253例疑似全面发育迟缓（GDD）/智力障碍（ID）的病例中，筛选出可明确其病因的阳性检测结果；同时针对1230例检测结果阴性的病例（其中863例GDD病例、367例ID病例）的132份尿液有机酸样本，以及100例正常发育儿童（Typically Developing, TD）的样本，开展主要差异代谢物筛选工作。本研究采用无监督主成分分析与正交偏最小二乘判别分析构建模型，以区分GDD/ID患儿与正常发育儿童，并识别核心差异代谢物。
研究结果：本研究从1253例确诊GDD/ID的病例中，筛选出23例可明确其病因的阳性检测结果。在1230例检测结果阴性的病例中，GDD组与ID组的差异代谢物相较于TD组均呈现一致的变化趋势。本研究分别从GDD组与ID组中筛选得到24种与25种差异代谢物（变量重要性投影值VIP（Variable Importance in Projection）>1.0，P<0.01）。上述差异代谢物主要参与以下代谢通路：酮体合成与降解、三羧酸循环（citrate cycle）、丙氨酸-天冬氨酸和谷氨酸代谢、嘧啶代谢、丁酸代谢、丙酮酸代谢、脂肪酸生物合成以及缬氨酸、亮氨酸与异亮氨酸降解通路。
研究结论：采用代谢组学研究方法检测GDD/ID患儿的尿液有机酸，可筛选得到差异代谢物，该结果可为未来GDD/ID的病因、发病机制、预后及潜在干预手段的相关研究提供参考。上述发生显著变化的差异代谢物指标，有望成为GDD/ID潜在的诊断生物标志物（biomarker）。