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: 10001004
• 负责人: Qian Du
• 金额: $ 62.2万
• 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 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001004
• 关键词: 3 year old; Adaptive Behaviors; Adopted; Affect; Age; Algorithms; American; Anoxic Encephalopathy; Autopsy; Behavior; Biological Markers; Biological Process; Biological Sciences; Blood; Brain; Cells; Characteristics; Child; Clinical; Clinical Trials; Collection; Communication; Communities; Consumption; DNA Sequence Alteration; Data; Detection; Development; Developmental Delay Disorders; Diagnosis; Diagnostic; Diagnostic Procedure; Diagnostic tests; Early Intervention; Early treatment; Elements; Enrollment; Ensure; Environmental Risk Factor; Epigenetic Process; Etiology; Exhibits; Family; Future; Gene Expression; Genes; Genetic; Genetic Materials; Genetic Risk; Genetic Transcription; Genomics; Geography; Goals; Grant; Heterogeneity; Hormonal; Human; Human Microbiome; Incidence; Individual; Knowledge; Lead; Learning; Leukocytes; Link; Measurement; Measures; Medical; Methodology; Methods; MicroRNAs; Microbe; Mitochondria; Modeling; Monitor; Neuraxis; Neurodevelopmental Deficit; Neurologic; Neuropsychology; Only Child; Outcome; Oxidative Stress; Pain; Patient Care; Patient-Focused Outcomes; Patients; Performance; Peripheral; Pharmaceutical Preparations; Phase; Phenotype; Prevalence; Primary Care Physician; Process; Public Health; RNA; RNA Degradation; Research; Saliva; Salivary; Sampling; Screening procedure; Sensitivity and Specificity; Small Business Technology Transfer Research; Social Interaction; Socialization; Societies; Specialist; Specificity; Stimulus; Symptoms; Techniques; Technology; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Toddler; Training; United States; Untranslated RNA; Validation; Work; accurate diagnosis; autism diagnostic observation schedule; autism spectrum disorder; autistic children; biomarker identification; brain tissue; clinical practice; cohort; combinatorial; commercialization; diagnostic accuracy; diagnostic biomarker; differential expression; endophenotype; exosome; extracellular; functional outcomes; improved; insight; interest; magnetic resonance imaging/electroencephalography; microbial community; microbiota; microvesicles; minimally invasive; multiple omics; neurodevelopment; next generation sequencing; peer; phase 1 study; phase 2 study; primary outcome; prognostic; programs; prospective; response; secondary outcome; standard of care; symptom management; tool; trait; treatment response; visual tracking; 3 year old; Adaptive Behaviors; Adopted; Affect; Age; Algorithms; American; Anoxic Encephalopathy; Autopsy; Behavior; Biological Markers; Biological Process; Biological Sciences; Blood; Brain; Cells; Characteristics; Child; Clinical; Clinical Trials; Collection; Communication; Communities; Consumption; DNA Sequence Alteration; Data; Detection; Development; Developmental Delay Disorders; Diagnosis; Diagnostic; Diagnostic Procedure; Diagnostic tests; Early Intervention; Early treatment; Elements; Enrollment; Ensure; Environmental Risk Factor; Epigenetic Process; Etiology; Exhibits; Family; Future; Gene Expression; Genes; Genetic; Genetic Materials; Genetic Risk; Genetic Transcription; Genomics; Geography; Goals; Grant; Heterogeneity; Hormonal; Human; Human Microbiome; Incidence; Individual; Knowledge; Lead; Learning; Leukocytes; Link; Measurement; Measures; Medical; Methodology; Methods; MicroRNAs; Microbe; Mitochondria; Modeling; Monitor; Neuraxis; Neurodevelopmental Deficit; Neurologic; Neuropsychology; Only Child; Outcome; Oxidative Stress; Pain; Patient Care; Patient-Focused Outcomes; Patients; Performance; Peripheral; Pharmaceutical Preparations; Phase; Phenotype; Prevalence; Primary Care Physician; Process; Public Health; RNA; RNA Degradation; Research; Saliva; Salivary; Sampling; Screening procedure; Sensitivity and Specificity; Small Business Technology Transfer Research; Social Interaction; Socialization; Societies; Specialist; Specificity; Stimulus; Symptoms; Techniques; Technology; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Toddler; Training; United States; Untranslated RNA; Validation; Work; accurate diagnosis; autism diagnostic observation schedule; autism spectrum disorder; autistic children; biomarker identification; brain tissue; clinical practice; cohort; combinatorial; commercialization; diagnostic accuracy; diagnostic biomarker; differential expression; endophenotype; exosome; extracellular; functional outcomes; improved; insight; interest; magnetic resonance imaging/electroencephalography; microbial community; microbiota; microvesicles; minimally invasive; multiple omics; neurodevelopment; next generation sequencing; peer; phase 1 study; phase 2 study; primary outcome; prognostic; programs; prospective; response; secondary outcome; standard of care; symptom management; tool; trait; treatment response; visual tracking

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. Quadrant Biosciences is developing an approach to diagnose ASD by measuring brain-related and other ribonucleic acids (micro, circular, and bacterial) 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. This has enabled Quadrant 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. Alterations in the human microbiome (i.e., microbial communities) have also been shown to correlate with ASD. Thus, extracellular RNA quantification in saliva provides an attractive and minimally invasive technique for biomarker identification in children with ASD. This Phase II study will test the hypothesis that a pre-defined panel of human and non- human RNAs will accurately determine ASD status in a cohort of 1600 children ages 18 months to 6 years. Using prospective clinical trial methodology, with input from FDA, the project will provide data essential to the commercialization of Quadrant’s ASD diagnostic technology, further testing the algorithm with the inclusion of additional children and following children who are flagged with the currently utilized ASD to determine their ultimate diagnosis.

自闭症谱系障碍（ASD）是神经发育特征的连续体，其中包括定义 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 伯恩（Burnen）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，荷尔蒙和 影响ASD患者预后的环境因素。为了有效治疗ASD患者， 及时检测对于实施早期治疗方案至关重要。利用这些先前存在的知识 ASD的因素，医生可以在患者还年轻的时候开始治疗，即使孩子尚未开始 表现出典型的ASD症状。研究表明，较早的治疗会导致更好的功能结果，并且 ASD症状的减少。这些模型，药物和计划已被证明有效 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。象限生物科学 正在通过测量脑相关和其他核糖核酸（微型，微核酸）来开发一种诊断ASD的方法 唾液中的圆形和细菌）。 miRNA通过外泌体和其他微泡的细胞外转运是一种 建立了细胞改变附近细胞基因表达的表观遗传机制。这已启用 仅通过 收集唾液。这种方法最大程度地减少了与验尸后大脑分析相关的许多局限性 组织（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 （表达变化的相关性，抽血的疼痛）在先前的研究中进行。人类的改变 微生物组（即微生物群落）也已显示与ASD相关。那是细胞外RNA 唾液中的数量为生物标志鉴定提供了一种有吸引力且微创的技术 有ASD的孩子。这项II期研究将检验以下假设： 人类RNA将准确地确定1600名18个月至6岁的儿童组中的ASD状态。 使用前瞻性临床试验方法，随着FDA的投入，该项目将为该项目提供必不可少的数据 象限ASD诊断技术的商业化，进一步测试算法 其他孩子和追随当前使用ASD的孩子的孩子来确定他们的 最终诊断。