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; 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）是神经发育特征的连续体，包括缺陷 沟通和社会互动，以及限制性，重复的利益和行为。 ASD是一个 增加公共卫生的关注点，2014年被诊断出ASD的45名美国儿童中有1个，这是10倍 在过去40年中的患病率增加。 ASD对社会和经济的影响是很大的 估计，仅在美国就估计每年超过2860亿美元。而单个直接链接到ASD 尚未确定诊断，研究已经确定了遗传，表观遗传学，神经系统，激素， 以及影响ASD患者预后的环境因素。为了有效治疗患者 ASD，及时检测对于实施早期治疗方案至关重要。使用这些知识 ASD的先前存在因素，医生可以在患者还年轻的时候开始治疗，即使孩子有 没有开始表现出典型的ASD症状。研究表明，较早的治疗可提高功能性更好 ASD症状的结果和减少。这些模型，药物和计划已被证明是 有效地管理ASD的症状，并可能完全将某些患者从ASD谱系中删除。 不幸的是，对于幼儿而言，当前的ASD诊断方法不是很准确。平均年龄 诊断ASD已有三年历史，其中约有一半是假阳性。制定准确 因此，ASD的诊断生物标志物将代表患者护理的宝贵补充。运动智能是 通过测量与脑相关的微核糖酸（miRNA）中的ASD诊断方法 唾液。 miRNA通过外泌体和其他微囊泡的细胞外转运是一种已建立的表观遗传学 细胞改变附近细胞中基因表达的机制。将微泡挤进 细胞外空间，可以在其中停靠并进入相邻细胞，并改变基因表达。这些 微泡中存在于各种体液中，例如唾液。这使运动智能得以 仅通过收集唾液来测量可能起源于中枢神经系统的遗传物质。 这种方法最大程度地减少了与分析后脑组织分析相关的许多局限性（例如， 缺氧性脑损伤，RNA降解，验尸间隔，激动状态）或周围白细胞（相关性 表达变化，疼痛的抽血）在先前的研究中使用。因此，细胞外miRNA 唾液中的量化为生物标志鉴定提供了一种有吸引力的侵入性技术 有ASD的孩子。这一I阶段研究将包括一项前瞻性临床试验，该试验将以特征 ASD和年龄和性别匹配的对照的儿童唾液miRNA的表达模式 发展。一半受试者的数据将用作培训数据集，以创建相关算法 miRNA生物标志物，另一半将用于验证研究中，以确定其功效 算法。