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.

项目摘要/摘要 自闭症谱系障碍(ASD)是一系列神经发育特征的连续体，包括 交流和社会互动，以及限制性、重复性的兴趣和行为。ASD是一种 公共卫生问题日益受到关注，2014年约每45名美国儿童中就有1人被诊断为自闭症，是 在过去的40年里，患病率增加了。ASD对社会和经济的影响是巨大的 据估计，仅在美国每年就超过2,860亿美元。而与ASD的单一直接链接 诊断尚未确定，研究已确定遗传、表观遗传学、神经学、激素、 以及影响ASD患者预后的环境因素。为了有效地治疗患有癌症的患者 对于ASD，及时检测对于实施早期治疗方案至关重要。利用这些方面的知识 如果已经存在ASD的因素，医生可以在患者还小的时候就开始治疗，即使孩子有 没有开始表现出典型的ASD症状。研究表明，早期治疗会带来更好的功能 ASD的转归和症状的减轻。这些模式、药物和计划已被证明是 有效地控制ASD的症状，并可能完全将一些患者从ASD谱中移除。 不幸的是，目前对自闭症的诊断方法对幼儿不是很准确； 诊断ASD已经有三年的历史了，其中大约一半是假阳性。精确度的发展 因此，ASD的诊断生物标志物将是对患者护理的有价值的补充。运动智能是 建立一种通过测量脑相关微核糖核酸(MiRNAs)诊断自闭症的方法 唾液。通过外切体和其他微囊进行miRNA的细胞外运输是一种既定的表观遗传学。 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，在那里它们可以停靠并进入邻近的细胞，并改变基因表达。这些 微泡存在于各种体液中，如唾液中。这使运动智能能够 仅仅通过收集唾液就可以测量可能来自中枢神经系统的遗传物质。 该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、死亡状态)或外周血白细胞(相关性 表情变化，痛苦的抽血)在以前的研究中使用。因此，胞外miRNA 唾液中的定量提供了一种有吸引力的微创技术用于生物标志物鉴定 患有自闭症的儿童。这项I期研究将包括一项前瞻性临床试验，该试验将描述 唾液miRNAs在自闭症儿童和年龄性别匹配的典型自闭症儿童中的表达 发展。来自一半受试者的数据将被用作训练数据集，以创建相关的算法 MiRNA生物标志物，另一半将用于验证研究，以确定这一方法的有效性 算法。