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A Metabolomics Approach to Screening for Autism Risk in the Children's Autism Metabolome Project.

儿童自闭症代谢组项目中筛查自闭症风险的代谢组学方法。

  • 影响因子:3.94
  • DOI:10.1002/aur.2330
  • 作者列表:"Smith AM","Natowicz MR","Braas D","Ludwig MA","Ney DM","Donley ELR","Burrier RE","Amaral DG
  • 发表时间:2020-06-18
Abstract

:Autism spectrum disorder (ASD) is biologically and behaviorally heterogeneous. Delayed diagnosis of ASD is common and problematic. The complexity of ASD and the low sensitivity of available screening tools are key factors in delayed diagnosis. Identification of biomarkers that reduce complexity through stratification into reliable subpopulations can assist in earlier diagnosis, provide insight into the biology of ASD, and potentially suggest targeted interventions. Quantitative metabolomic analysis was performed on plasma samples from 708 fasting children, aged 18 to 48 months, enrolled in the Children's Autism Metabolome Project (CAMP). The primary goal was to identify alterations in metabolism helpful in stratifying ASD subjects into subpopulations with shared metabolic phenotypes (i.e., metabotypes). Metabotypes associated with ASD were identified in a discovery set of 357 subjects. The reproducibility of the metabotypes was validated in an independent replication set of 351 CAMP subjects. Thirty-four candidate metabotypes that differentiated subsets of ASD from typically developing participants were identified with sensitivity of at least 5% and specificity greater than 95%. The 34 metabotypes formed six metabolic clusters based on ratios of either lactate or pyruvate, succinate, glycine, ornithine, 4-hydroxyproline, or α-ketoglutarate with other metabolites. Optimization of a subset of new and previously defined metabotypes into a screening battery resulted in 53% sensitivity (95% confidence interval [CI], 48%-57%) and 91% specificity (95% CI, 86%-94%). Thus, our metabolomic screening tool detects more than 50% of the autistic participants in the CAMP study. Further development of this metabolomic screening approach may facilitate earlier referral and diagnosis of ASD and, ultimately, more targeted treatments. LAY SUMMARY: Analysis of a selected set of metabolites in blood samples from children with autism and typically developing children identified reproducible differences in the metabolism of about half of the children with autism. Testing for these differences in blood samples can be used to help screen children as young as 18 months for risk of autism that, in turn, can facilitate earlier diagnoses. In addition, differences may lead to biological insights that produce more precise treatment options. We are exploring other blood-based molecules to determine if still a higher percentage of children with autism can be detected using this strategy.

摘要

: 自闭症谱系障碍 (ASD) 具有生物学和行为异质性。ASD 的延迟诊断是常见的和有问题的。ASD 的复杂性和可用筛查工具的低敏感性是延迟诊断的关键因素。通过分层到可靠的亚群来降低复杂性的生物标志物的鉴定可以帮助早期诊断,提供对 ASD 生物学的洞察,并可能建议有针对性的干预措施。对参加儿童孤独症代谢组项目 (CAMP) 的 708 例 18 ~ 48 个月禁食儿童的血浆样本进行定量代谢组学分析。主要目标是确定有助于将 ASD 受试者分层为具有共同代谢表型 (即代谢型) 的亚群的代谢改变。在 357 例受试者的发现集中确定了与 ASD 相关的代谢型。在 351 例 CAMP 受试者的独立复制集中验证了代谢型的可重复性。确定了区分 ASD 亚群与典型发育参与者的 34 种候选代谢型,敏感性至少为 5%,特异性大于 95%。根据乳酸或丙酮酸盐、琥珀酸盐、甘氨酸、鸟氨酸、 4-羟脯氨酸或 α-酮戊二酸与其他代谢物的比例,34 个代谢型形成了 6 个代谢簇。将新的和以前定义的代谢型子集优化到筛选电池中,获得了 53% 的灵敏度 (95% 置信区间 [CI],48%-57%) 和 91% 的特异性 (95% CI, 86%-94%)。因此,我们的代谢组学筛查工具在 CAMP 研究中检测到超过 50% 的自闭症参与者。这种代谢组学筛查方法的进一步发展可能有助于 ASD 的早期转诊和诊断,并最终提供更有针对性的治疗。LAY 总结: 分析自闭症儿童和典型发育中儿童血样中的一组选定代谢物,确定了约一半自闭症儿童代谢的可重复差异。检测血样中的这些差异可以用来帮助筛查 18 个月大的儿童患自闭症的风险,这反过来又可以促进早期诊断。此外,差异可能会导致产生更精确的治疗选择的生物学见解。我们正在探索其他基于血液的分子,以确定使用这种策略是否仍然可以检测到更高比例的自闭症儿童。

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DOI:10.1038/s41380-020-0649-0
作者列表:["Li C","Meng F","Garza JC","Liu J","Lei Y","Kirov SA","Guo M","Lu XY"]

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影响因子:5.83
发表时间:2020-01-22
DOI:10.1523/JNEUROSCI.0786-19.2019
作者列表:["Torretta S","Rampino A","Basso M","Pergola G","Di Carlo P","Shin JH","Kleinman JE","Hyde TM","Weinberger DR","Masellis R","Blasi G","Pennuto M","Bertolino A"]

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影响因子:6.22
发表时间:2020-01-17
DOI:10.1038/s41386-020-0614-2
作者列表:["Chadha R","Meador-Woodruff JH"]

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