Article(id=1325500679686594708, tenantId=1146029695717560320, journalId=1256213402557890569, issueId=1325500677975318675, articleNumber=null, orderNo=null, doi=10.16835/j.cnki.1000-9817.2025038, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1725811200000, receivedDateStr=2024-09-09, revisedDate=1731513600000, revisedDateStr=2024-11-14, acceptedDate=null, acceptedDateStr=null, onlineDate=1793953588648, onlineDateStr=2026-11-06, pubDate=1740412800000, pubDateStr=2025-02-25, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1793953588648, onlineIssueDateStr=2026-11-06, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1793953588648, creator=13701087609, updateTime=1793953588648, updator=13701087609, issue=Issue{id=1325500677975318675, tenantId=1146029695717560320, journalId=1256213402557890569, year='2025', volume='46', issue='2', pageStart='153', pageEnd='304', issueExtLink='null', onlineDate='null', pubDate='1740412800000', pubDateStr='2025-02-25', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1793953588241, creator='13701087609', updateTime=1793953588241, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext=null, issueFiles=null, downloadFileDto=null}, startPage=157, endPage=161, ext={EN=ArticleExt(id=1325500680860999830, articleId=1325500679686594708, tenantId=1146029695717560320, journalId=1256213402557890569, language=EN, title=Overview and implications of the cohort construction for autism spectrum disorders based on Internet recruitment, columnId=1325500680437375125, journalTitle=Chinese Journal of School Health, columnName=Expert Viewpoint, runingTitle=null, highlight=null, articleAbstract=

The construction of autism spectrum disorders (ASD) specialty cohorts in China is still in its infancy, and the cost-effectiveness is insufficient when relying on diagnostic and treatment processes of child health care to collect ample and high-quality data. After 2000, the United States Simons Foundation's ASD Research Initiative, the Early ASD Risk Longitudinal Investigation (EARLI), and the British ASD Study of Infant Siblings (BASIS), which have been built based on Internet recruitment, have provided new insight for the construction of large-sample ASD specialty cohorts in China. Future research can further explore and optimize the methods of Internet recruitment, and establish a more comprehensive and accurate ASD specialty cohorts.

, authors=Xin CHEN1, Hui GAO1, 2, *, De WU1, Fangbiao TAO2, authorsList=Xin CHEN, Hui GAO, De WU, Fangbiao TAO, authorCompany=null, correspAuthors=Hui GAO, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2025 Chinese Journal of School Health. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, fund=null), CN=ArticleExt(id=1325500687102124186, articleId=1325500679686594708, tenantId=1146029695717560320, journalId=1256213402557890569, language=CN, title=基于互联网招募的孤独症谱系障碍专病队列建设概况及启示, columnId=1325500682912014487, journalTitle=中国学校卫生, columnName=专题笔谈, runingTitle=null, highlight=null, articleAbstract=

中国孤独症谱系障碍(ASD)专病队列的建设尚在起步阶段,依托儿童保健等诊疗过程采集的数据使其成本-效益不足。2000年后,基于互联网招募建设的美国西蒙斯推动ASD研究、美国早期ASD风险纵向调查和英国婴幼儿ASD同胞研究等,为中国建设ASD大样本专病队列提供了新思路。未来的研究可进一步探索和优化互联网招募的方法,建立更全面、准确的ASD专病队列。

, authors=陈鑫1, 高慧1, 2, *, 吴德1, 陶芳标2, authorsList=陈鑫, 高慧, 吴德, 陶芳标, authorCompany=null, correspAuthors=高慧, authorNote=

陈鑫(1999-),男,安徽省人,在读硕士,主要研究方向为环境污染物暴露与儿童健康

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高慧,E-mail:
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注:A为SPARK队列相关研究,B为EARLI队列相关研究。

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基于互联网招募的孤独症谱系障碍专病队列建设概况及启示
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陈鑫 1 , 高慧 1, 2, * , 吴德 1 , 陶芳标 2
中国学校卫生 | 专题笔谈 2025,46(2): 157-161
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中国学校卫生 |专题笔谈 2025 , 46 (2) : 157 -161
基于互联网招募的孤独症谱系障碍专病队列建设概况及启示
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陈鑫1, 高慧1, 2, * , 吴德1, 陶芳标2
作者信息
  • 1安徽医科大学第一附属医院儿科,合肥 230022
  • 2安徽医科大学公共卫生学院出生人口健康教育部重点实验室/环境与人口健康重点实验室
通讯作者:
高慧,E-mail:
作者简介:

陈鑫(1999-),男,安徽省人,在读硕士,主要研究方向为环境污染物暴露与儿童健康

Overview and implications of the cohort construction for autism spectrum disorders based on Internet recruitment
Xin CHEN1, Hui GAO1, 2, * , De WU1, Fangbiao TAO2
Affiliations
  • 1Department of Pediatrics, First Affiliated Hospital of Anhui Medical University, Hefei (230022), Anhui Province, China
出版时间: 2025-02-25 doi: 10.16835/j.cnki.1000-9817.2025038
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中国孤独症谱系障碍(ASD)专病队列的建设尚在起步阶段,依托儿童保健等诊疗过程采集的数据使其成本-效益不足。2000年后,基于互联网招募建设的美国西蒙斯推动ASD研究、美国早期ASD风险纵向调查和英国婴幼儿ASD同胞研究等,为中国建设ASD大样本专病队列提供了新思路。未来的研究可进一步探索和优化互联网招募的方法,建立更全面、准确的ASD专病队列。

孤独性障碍  /  队列研究  /  数据库, 文献型  /  儿童

The construction of autism spectrum disorders (ASD) specialty cohorts in China is still in its infancy, and the cost-effectiveness is insufficient when relying on diagnostic and treatment processes of child health care to collect ample and high-quality data. After 2000, the United States Simons Foundation's ASD Research Initiative, the Early ASD Risk Longitudinal Investigation (EARLI), and the British ASD Study of Infant Siblings (BASIS), which have been built based on Internet recruitment, have provided new insight for the construction of large-sample ASD specialty cohorts in China. Future research can further explore and optimize the methods of Internet recruitment, and establish a more comprehensive and accurate ASD specialty cohorts.

Autistic disorder  /  Cohort studies  /  Databases, bibliographic  /  Child
陈鑫, 高慧, 吴德, 陶芳标. 基于互联网招募的孤独症谱系障碍专病队列建设概况及启示. 中国学校卫生, 2025 , 46 (2) : 157 -161 . DOI: 10.16835/j.cnki.1000-9817.2025038
Xin CHEN, Hui GAO, De WU, Fangbiao TAO. Overview and implications of the cohort construction for autism spectrum disorders based on Internet recruitment[J]. Chinese Journal of School Health, 2025 , 46 (2) : 157 -161 . DOI: 10.16835/j.cnki.1000-9817.2025038
孤独症谱系障碍(autism spectrum disorder, ASD)是一组以社交沟通障碍、兴趣或活动范围狭窄以及重复刻板行为为主要特征的神经发育障碍,一般在3岁前发病,严重影响儿童青少年的身心健康,且给社会、医疗、家庭均带来重大经济和健康负担[1-3]。ASD病因和机制尚不清楚,目前没有批准的药物可以治疗其核心症状,而是主要开展康复训练和行为矫正,但相关疗效仍有待提升[4]。
全球大力开展相关研究以探索ASD病因及机制,多采用病例对照研究设计,因果推断能力有限[5]。最近,北京大学研究团队系统检索1 702项ASD队列研究并开展概括性评价,中国相关队列研究构成仅占3.53%[6]。全部研究中有163个队列有明确命名,大致分为出生队列、高危人群队列、ASD专病队列和自然人群队列,中国主要是依托国家出生队列建立的ASD亚队列及马鞍山出生队列[7-11]。这些出生队列通常建设伊始并不总是重点关注ASD,虽能够较为全面地捕获自孕前/孕期至儿童期的ASD潜在影响因素,但考虑ASD仅约1%的患病率且确诊程序复杂[12],往往队列纳入对象的样本量难以随访到足够数量的ASD确诊儿童。此外,中国ASD专病队列的建设尚在起步阶段,主要依托儿童保健等诊疗过程招募和随访,可以获得更精准诊断数据,甚至有磁共振、脑成像等采集难度非常大的相关信息,但通常纳入ASD儿童的样本量稍显不足[7];且ASD具有高度的病因和临床异质性,无法招募足够数量的研究对象使得研究结果的可重复性大大降低。
在欧洲、美洲等发达国家中,有研究者通过互联网发布招募信息,符合条件者可自行登录网页注册成为研究对象[13-15],因此队列样本量大且相对传统队列建设省时省力,对于后期随访数据的管理更加便捷高效,有其特定的优势。中国互联网现处于移动APP与消息流型社交网络并存阶段,未来超级APP以用户为基础,承载一切的内容和服务,最终完成互联网信息全面整合的时代也是可预见的。因此,积极学习如何通过互联网开展ASD队列研究及其成效,或许是开启ASD病因和机制研究的新机遇。
SPARK是全球最大样本量的ASD队列,其是一个不断增长的由ASD个体及其家庭和研究人员一起组成的社区,使命是促进对ASD的理解[13]。SPARK研究于2015年底试点后,2016年4月正式启动。截至目前,已有275 075人加入SPARK,其中有106 725名ASD患者(16 636名成人),26 415个有ASD患者的家庭参与,80 310名男性ASD患者(含儿童),超过30 000名ASD的妇女和女童,使SPARK成为美国最大的针对ASD妇女和女童的研究。SPARK临床站点网络包括全美31个顶级的研究中心和学术机构,291名科学家使用该数据进行科学研究。
SPARK的使命是通过确定ASD的原因并提供更有效的疗法、治疗、服务和支持来改善ASD患者的生活。SPARK网络中的所有研究中心和机构都接受了各自审查委员会的彻底审查,以确保研究以最高标准进行。此外,SPARK致力于研究的多样性、公平性和包容性,并努力倾听和包容ASD社区的所有声音。SPARK将为研究人员提供来自数以万计受ASD影响的个人和家庭的医学和遗传信息。这些数据将为新研究提供动力。
对Web ofScience核心集收录的共84项SPARK队列相关成果进行可视化分析。结果提示“spectrum disorder”“children”两个词中心度最高,其他词如“mutations”“Meta-analysis”“genome-wide association”等在整个网络的中心度也较高。在主题地图的第四象限的关键词为“children/risk”“autism/genes/mutation”等,第一象限的关键词为“girls/sex-differences”“questionnaire/young-children/development coordination disorder”“mutations/de-novo mutations/framework”等(图1A)。这些结果提示SPARK研究基础集中在儿童ASD的遗传方向,且当前仍然是其研究主题和热点领域;而性别差异和发育性协调障碍等问题也是SPARK最近研究比较重要且有良好发展的主流方向。
截至2024年3月12日,研究人员使用SPARK数据和SPARK Research Match项目调查从基因变异到学校服务的各种主题相关成果,推动ASD遗传病因、诊疗和管理等多个方面的研究进展[16-18]。SPARK联盟从队列建设背景、可扩展的表型分析和基因组分析方法、个体遗传结果和行为信息的反馈、招募策略和科学社区资源、研究对象保留和伙伴关系以及挑战和经验教训等6个方面详细介绍了SPARK研究[19]。社交媒体广告可有效覆盖大量潜在的ASD参与者,从而增加实现研究入组目标对象的可能性;应考虑将至少一部分招募资金分配给社交媒体平台,作为快速、廉价地接触目标人群的一种手段,包括通过面对面程序进行研究[20]。
采用全外显子测序检测457个ASD患者家庭成员的唾液样本并进行基因分型,在10.4%的家庭中验证出临床公认的ASD病因基因和位点变异;在另外的3.4%的家庭中发现了可能与ASD有关的遗传变异;荟萃分析仍然观察到26个与ASD有关基因,且BRSK2基因具有最强的统计学意义[21]。对SPARK队列中6 222个病例-伪对照对进行全基因组关联研究,鉴定出DDHD2是ASD风险相关的新基因[22]。
当ASD儿童缺少标准化的认知测试分数时,将机器学习与其他信息一起使用,正确“预测”何时有认知障碍的正确率约80%,利用这些信息或为ASD和认知障碍儿童开发更合适的诊疗方法[23]。
EARLI是一项出生队列研究,旨在检查ASD的遗传和环境风险因素;该队列于2008年开始启动,目前已经暂停招募[12, 14]。EARLI队列从母亲怀孕开始到幼儿3岁时密切关注参加该队列的家庭,其在美国有4个研究地点,超过200个有ASD患者的家庭参与。该项研究的目的是了解导致ASD的原因,研究人员收集患有ASD的母亲及其子女的环境和生物数据。EARLI网络的研究人员研究儿童产前、新生儿和产后早期ASD的可能危险因素和生物指标。研究人员的目标是患有ASD儿童的母亲,在新怀孕时开始跟踪新生儿兄弟姐妹的发育并持续到3岁。这项研究为了解不同发育窗口期间可能的ASD环境风险因素和生物标志物提供了独特的机会,并为研究遗传易感性和环境暴露之间的相互作用提供了机会。EARLI网络中的每所大学和机构都接受了各自审查委员会的彻底审查,以确保研究以最高标准进行。此外,所有美国国立卫生研究院指南和标准均在整个EARLI网络中得到维护。
Science核心集共收录EARLI队列相关成果28篇。结果提示“children”“exposure”“risk”“spectrum disorders”等关键词中心度最高,其他词如“DNA methylation”在整个网络的中心度也较高。在主题地图的第四象限的关键词为“children/DNA methylation/exposure”,第一象限的关键词为“autism spectrum disorder/bisphenol-a/traits”“congenital adrenal-hyperplasia/cord blood/general-population/autism”等(图1B)。提示EARLI研究基础集中在儿童ASD的暴露及表观遗传方面,也是当前研究主题和热点领域;而双酚A暴露、脐血样本及先天性肾上腺皮质增生等问题是EARLI最近研究比较重要且有良好发展的主流方向。
以101名来自EARLI队列的ASD儿童为研究对象,观察到脐带偏心率、胎盘最大厚度和脐带中心性与ASD儿童社会反应量表得分呈正相关,提示ASD儿童胎盘效率降低[24]。考虑诊断ASD病例数量较少,未来还需更大样本的前瞻性研究进一步验证胎盘结构和功能发育与ASD发病之间的关系。EARLI队列采用Illumina 450k人甲基化阵列检测140份孕早期血、75份孕后期血、133份脐血、106份胎盘母体面组织和107份胎盘胎儿面组织中DNA甲基化水平,分析其与儿童3岁确诊ASD的风险关联,并探究其在西蒙斯基金会ASD研究计划(Simons Foundation Autism Research Initiative, SFARI)数据库中收录的881个ASD风险基因上富集情况,发现所有5种组织中与ASD相关的DNA甲基化位点在144个(29.5%)SFARI基因处重叠,提示在ASD诊断之前检查相关组织DNA甲基化具有一定实用性[25]。研究者在父系精子中也确定了193个差异甲基化区域(differentially methylated megions, DMR)与12月龄婴儿ASD观察量表表现相关,DMR聚集在参与发育过程的基因附近,这些结果在Illumina 450k阵列上的75个探针结果一致,其中18个(24%)还显示ASD儿童与正常对照儿童小脑存在一致差异[26]。进一步研究还发现孕期镉、铅、汞、锰、硒等金属暴露与母血DNA甲基化的关联,其中铅与11个位点DNA高甲基化有关,主要富集在细胞粘附、神经系统发育和钙离子结合途径;锰与4个位点DNA高甲基化有关,主要富集在细胞代谢途径[27]。结果提示表现遗传改变或是孕期金属暴露损害儿童神经发育的潜在机制通路。
产前接触几类农药与儿童ASD之间存在关联,而饮食是如今使用的大多数农药的主要暴露来源。在EARLI队列的一项研究结果表明,怀孕期间饮食中的这些农药残留与3岁时儿童ASD相关测评结果之间关联无统计学意义,但较高的产前水果和蔬菜摄入量与儿童ASD样特征减少有关[28]。
BASIS于2008年5月正式启动,合作中心包括伯克贝克学院、伦敦大学等12所院校,已获得医学研究委员会的支持[15]。主要通过互联网发布招募信息,研究对象为有ASD同胞的0~9月龄婴儿的家庭,但也允许目标儿童有同父异母/同母异父的ASD同胞或不在上述年龄范围内的家庭提供相关信息。研究对象需提供联系方式、儿童姓名和年龄以及简短家族史。
BASIS是一个合作研究网络,通过建立一个负责招募、数据共享和科学交流的国家联络中心:(1)为英国ASD高危婴儿的研究提供国家战略重点和方向;(2)促进英国和国外研究婴儿同胞的临床科学家和基础科学家之间的合作;(3)向参与研究的家庭以及公众传播公共信息。BASIS科学家将利用新开发研究婴儿大脑和行为的技术,研究有无ASD同胞婴儿之间的发育是否存在差异。从长远来看,将有助于识别ASD早期迹象,能够更早、更有效地进行干预,以改善ASD儿童的生活质量。
BASIS自2010年开始每年9—10月在伦敦大学伯克贝克学院开展一次年度科学会议,2018—2020年科学会议由滑铁卢基金会赞助,重点讨论运动发育(2018年)、共生条件(2019年)以及睡眠和兴奋性(2020年)等相关议题。此后该网站没有再更新年度会议日程,尚不清楚该项目是否停止运营。目前在公共数据库中检索到发表论文成果较少。
通过上述ASD专病队列,不难发现这些队列特点之一是利用了互联网招募高效、便捷的优点。中国“互联网+”模式在医疗服务领域应用越来越广泛[29-30],通过互联网对患者进行观察和干预的模式在多种疾病中已发展较为成熟。例如,利用“互联网+”模式进行社区慢性病管理,建立微信群和微信公众号收集患者健康状况并实施干预[31],通过中国自闭症评估干预平台(https://www.alsolife.com/about/alsolife)干预ASD,利用大数据对大学生的心理健康进行调查分析[32]等。
当基于互联网招募建设ASD专病队列时,可从研究中得出一些重要的启示:(1)互联网招募为ASD研究提供了一种高效、便捷的方式,能够快速纳入大量患者并收集大规模的数据。(2)互联网招募能够打破地理限制,实现全球范围内的参与,增加样本的多样性和代表性。(3)互联网招募还能够降低研究成本,减少时间和人力资源的浪费。(4)互联网招募使研究者能够更好地与患者和家庭建立联系,促进信息共享和交流。通过在线问卷调查、远程访谈和社交媒体平台等工具,研究者可以获取更多的自述信息和日常行为数据,有助于深入了解ASD患者的特点和需求。(5)互联网招募还提供了更多的研究机会和合作可能性。研究者可以通过在线平台和社区与其他专家和机构进行合作,共享数据和研究资源,加速ASD研究的进展。
然而,互联网招募也面临一些挑战和限制。例如,数据的质量和可信度需要得到保证,隐私和伦理问题也需要妥善处理。基于互联网招募建设的ASD队列所获取的数据来源于医疗卫生服务的人群,可能会存在缺乏代表性和低估ASD患病率等偏倚[33]。此外,互联网招募还可能导致样本选择偏倚,需要采取适当的措施来纠正和控制。由于受制于研究对象的主观能动性并缺乏主动随访,可能导致较高的人群失访率[6]。
综上所述,基于互联网招募建设ASD专病队列具有广阔的应用前景,可为ASD研究提供高效、便捷的数据收集方式,促进研究者与患者之间的交流和合作,为推动ASD研究的发展做出重要贡献。然而,在实际应用中仍需克服一些挑战,以确保数据的质量和伦理合规性,如对缺乏主观能动性的研究对象适当采取主动随访的方式以减小人群失访率。未来的研究应进一步探索和优化互联网招募的方法和策略,以实现更全面、准确的ASD专病队列研究。
  • 国家自然科学基金面上项目(82473641);安徽省高校优秀青年项目(2023AH030118)
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2025年第46卷第2期
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doi: 10.16835/j.cnki.1000-9817.2025038
  • 接收时间:2024-09-09
  • 首发时间:2026-11-06
  • 出版时间:2025-02-25
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  • 收稿日期:2024-09-09
  • 修回日期:2024-11-14
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国家自然科学基金面上项目(82473641);安徽省高校优秀青年项目(2023AH030118)
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    1安徽医科大学第一附属医院儿科,合肥 230022
    2安徽医科大学公共卫生学院出生人口健康教育部重点实验室/环境与人口健康重点实验室

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