Validation of a salivary miRNA diagnostic test for autism spectrum disorder

自闭症谱系障碍唾液 miRNA 诊断测试的验证

• 批准号: 9202372
• 负责人: Frank A. Middleton
• 金额: $ 22.5万
• 依托单位: QUADRANT BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9202372
• 关键词: 21 year old; 3 year old; Accounting; Adaptive Behaviors; Affect; Age; Algorithms; American; Anoxic Encephalopathy; Autistic Disorder; Autopsy; Behavior; Biological Assay; Biological Markers; Blinded; Blood; Brain; Cells; Cephalic; Cerebrum; Characteristics; Child; Child Development; Clinical; Clinical Trials; Collection; Communication; Data; Data Set; Databases; Detection; Development; Diagnosis; Diagnostic; Diagnostic Procedure; Diagnostic tests; Disease; Docking; Early Diagnosis; Early treatment; Electroencephalography; Enrollment; Environmental Risk Factor; Epigenetic Process; Exhibits; Extracellular Fluid; Extracellular Space; Eye; Foundations; Gender; Gene Cluster; Gene Expression; Genes; Genetic; Genetic Materials; Gold; Heterogeneity; Hormonal; Incidence; Individual; Intelligence; Interview; Knowledge; Leukocytes; Link; Liquid substance; Magnetic Resonance Imaging; Measures; Medical; Methods; MicroRNAs; Mitochondria; Modeling; Motion; Motor; Nerve; Neuraxis; Neurologic; Neurons; Oral cavity; Oxidative Stress; Pain; Painless; Patient Care; Patient-Focused Outcomes; Patients; Pattern; Peripheral; Pharmaceutical Preparations; Phenotype; Pilot Projects; Plasma; Predictive Value; Prevalence; Public Health; RNA; RNA Degradation; Research; Research Personnel; Saliva; Salivary; Sample Size; Sampling; Schedule; Sensitivity and Specificity; Sensory; Severities; Social Interaction; Societies; Specificity; Study of serum; Symptoms; Techniques; Testing; Toddler; Training; Transcriptional Activation; Validation; abstracting; accurate diagnosis; autism spectrum disorder; base; biomarker identification; brain tissue; clinical Diagnosis; clinical application; clinical practice; diagnostic biomarker; diagnostic screening; differential expression; economic impact; epigenetic marker; exosome; extracellular; functional outcomes; gene environment interaction; genetic risk factor; genetic variant; improved; interest; lymphoblast; microRNA biomarkers; microvesicles; minimally invasive; neurodevelopment; neuron development; neuropsychological; phase 1 study; programs; prospective; reduce symptoms; screening; sex; symptom management; tool; validation studies

Project Summary/Abstract Autism spectrum disorder (ASD) is a continuum of neurodevelopmental characteristics that includes deficits in communication and social interaction, as well as restrictive, repetitive interests and behaviors. ASD is an increasing public health concern, with about 1 in 45 American children diagnosed with ASD in 2014, a 10-fold increase in prevalence over the past 40 years. The effect of ASD on both society and the economy is a large burden, estimated at more than $286 billion per year in the U.S. alone. While a single direct link to ASD diagnosis has not been determined, studies have identified genetic, epigenetic, neurological, hormonal, and environmental factors that affect outcomes for patients with ASD. In order to effectively treat patients with ASD, timely detection is crucial for implementation of early treatment options. Using knowledge of these preexisting factors for ASD, doctors can begin treatment while the patient is still young, even if the child has not begun to exhibit typical ASD symptoms. Studies suggest that earlier treatment results in better functional outcomes and reductions in symptoms of ASD. These models, medications and programs have proven to be effective in managing the symptoms of ASD, and may remove some patients from the ASD spectrum entirely. Unfortunately, current diagnostic methods for ASD are not very accurate for young children; the average age of diagnosing ASD is three years old, and about half of those are false positives. Development of accurate diagnostic biomarkers for ASD would thus represent a valuable addition to patient care. Motion Intelligence is developing an approach to diagnose ASD by measuring brain-related micro ribonucleic acids (miRNAs) in saliva. Extracellular transport of miRNA via exosomes and other microvesicles is an established epigenetic mechanism for cells to alter gene expression in nearby cells. The microvesicles are extruded into the extracellular space, where they can dock and enter neighboring cells, and alter gene expression. These microvesicles are present in various bodily fluids, such as saliva. This has enabled Motion Intelligence to measure genetic material that may have originated from the central nervous system simply by collecting saliva. This method minimizes many of the limitations associated with analysis of post-mortem brain tissue (e.g., anoxic brain injury, RNA degradation, post-mortem interval, agonal state), or peripheral leukocytes (relevance of expression changes, painful blood draws) employed in previous studies. Thus, extracellular miRNA quantification in saliva provides an attractive and minimally invasive technique for biomarker identification in children with ASD. This Phase I study will include a prospective clinical trial that will characterize the expression pattern of salivary miRNAs in children with ASD and age- and gender-matched controls with typical development. Data from half of the subjects will be used as a training dataset to create an algorithm of relevant miRNA biomarkers, and the other half will be used in a validation study to determine the efficacy of this algorithm.

项目概要/摘要 自闭症谱系障碍 (ASD) 是一系列神经发育特征，包括以下方面的缺陷： 沟通和社交互动，以及限制性、重复性的兴趣和行为。自闭症谱系障碍 (ASD) 是一种 公众对健康的关注日益增加，2014 年，大约每 45 名美国儿童中就有 1 人被诊断患有自闭症谱系障碍 (ASD)，这一比例增加了 10 倍 过去 40 年来患病率有所增加。自闭症谱系障碍对社会和经济的影响是巨大的 据估计，仅美国每年的负担就超过 2860 亿美元。虽然与 ASD 的单个直接链接 诊断尚未确定，研究已确定遗传、表观遗传、神经、激素、 以及影响 ASD 患者预后的环境因素。为了有效治疗患者 自闭症谱系障碍（ASD）的及时发现对于实施早期治疗方案至关重要。利用这些知识 由于自闭症谱系障碍 (ASD) 已有的因素，医生可以在患者还年轻时就开始治疗，即使孩子患有自闭症谱系障碍 (ASD) 尚未开始表现出典型的 ASD 症状。研究表明，早期治疗可带来更好的功能 ASD 症状的结果和减少。这些模型、药物和项目已被证明是 可以有效控制自闭症谱系障碍的症状，并可能将一些患者完全从自闭症谱系障碍中剔除。 不幸的是，目前的 ASD 诊断方法对于幼儿来说并不是很准确。平均年龄 自闭症谱系障碍的诊断已有三年历史，其中大约一半是误报。开发精准 因此，自闭症谱系障碍（ASD）的诊断生物标志物将成为对患者护理的宝贵补充。运动智能是 开发一种通过测量大脑相关微核糖核酸（miRNA）来诊断自闭症谱系障碍（ASD）的方法 唾液。通过外泌体和其他微泡进行 miRNA 的细胞外转运是一种已确定的表观遗传学 细胞改变附近细胞基因表达的机制。微泡被挤出到 细胞外空间，它们可以停靠并进入邻近细胞，并改变基因表达。这些 微泡存在于各种体液中，例如唾液。这使得运动智能能够 只需收集唾液即可测量可能源自中枢神经系统的遗传物质。 这种方法最大限度地减少了与死后脑组织分析相关的许多限制（例如， 缺氧性脑损伤、RNA 降解、死后间隔、痛苦状态）或外周白细胞（相关性 先前研究中使用的表达变化、痛苦的抽血）。因此，细胞外 miRNA 唾液定量为生物标志物鉴定提供了一种有吸引力的微创技术 患有自闭症谱系障碍的儿童。这项 I 期研究将包括一项前瞻性临床试验，该试验将描述 自闭症谱系障碍 (ASD) 儿童和具有典型特征的年龄和性别匹配对照儿童唾液 miRNA 的表达模式 发展。来自一半受试者的数据将用作训练数据集，以创建相关算法 miRNA 生物标志物，另一半将用于验证研究以确定其功效 算法。