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通讯作者:

杜建(1986-),男,山东泰安人,副研究员,主要从事医学健康与数据科学(信息学、情报学)的交叉研究。E-mail:dujian@bjmu.edu.cn;

张路霞(1976-),女,甘肃兰州人,博士生导师,主要从事重大慢性疾病的变化趋势、疾病负担及防治的研究。E-mail:zhanglx@bjmu.edu.cn

中图分类号:R184R

文献标识码:A

文章编号:2096-8965(2021)01-0021-070

DOI:10.12287/j.issn.2096-8965.20210103

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目录contents

    摘要

    本文首先回顾了新型冠状病毒肺炎在全球蔓延后,由医疗不确定性造成的医疗决策困难,并剖析了这一突发公共卫生事件中医疗不确定性形成的原因和无效治疗带来的风险及医疗资源浪费。在此基础上,围绕如何在面临突发公共卫生事件时快速建立数据协作机制开展了现状回顾和讨论思考,即以数据为驱动,打破“数据孤岛”、提高“低价值数据”的数据质量和利用率,从而为应对相关事件提供有效证据。

    Abstract

    The problems of medical decision-making caused by medical uncertainty during the coronavirus disease 2019 (COVID-19) pandemic were reviewed, and the potential mechanisms were analyzed. Medical uncertainty could lead to increased risks of ineffective treatments and wastes of medical resources. Regarding coping the public health emergencies, rapidly building data consortium is crucial to break the boundaries of data silos, to improve the potentials of so-called “low-value data” and to provide evidence which could reduce medical uncertainty. Hence, the status of data consortium during public health emergencies was summarized, and the potential implications in China was also discussed.

  • 前言

  • 随着新型冠状病毒肺炎(Coronavirus Disease2019,COVID-19)的蔓延,全球医疗卫生体系正面临着前所未有的挑战。医疗资源短缺的问题随着跨地域捐赠、生产力增加等手段在较短的时间内得到一定程度缓解,然而,真正困扰一线临床工作人员及卫生政策决策者的是缺乏高质量的证据指导制定有效、规范的预防和治疗方案。

  • 在COVID-19流行期间,全球的一线临床人员和科研人员都在推进寻找有效药物和疗法的研究进程;过去一年中注册的相关临床试验、发表的相关论文数量激增 [1]。然而,随着瑞德西韦、羟氯喹相继被证明对治疗COVID-19无效,如何在不断涌现的证据中进行甄别、有效辅助临床决策是困扰医学界的关键问题。

  • 1 医疗不确定性导致临床医生面临决策困境

  • 1.1 信息爆炸易产生医疗逆转

  • 目前,学界对于COVID-19的病理生理特点、并发症以及发病机制有了一定的认知,但尚无突破性的特异性疗法广泛应用于临床。因此,《自然》 杂志发文称,过去一段时间研究者们提出的特异性疗法假说以及注册的相关临床试验,仅仅是建立在未经同行评审的预印本结果或是不完整数据之上的 [2];受试者不但无法从这些临床试验中获益,甚至面临“无效疗法”带来的额外风险。从疫情初期的信息缺乏到当前的信息爆炸,越来越多的数据及临床试验不但没有达到寻找“特异性”治疗方法及策略的作用,反而产生了大量“医疗不确定性”(Medical Uncertainty)、具有明显争议的研究结果以及临床主张。甚至《自然》杂志发文批评, COVID-19死亡率的下降,除医疗资源短缺情况改善、对于疾病认识更加充分、救治经验逐渐积累等原因之外,停止使用未经验证的“无效疗法”也是临床获益的原因之一 [3]

  • 停止使用未经验证的“无效疗法”来源于医疗逆转(Medical Reversal),即已用于临床实践的一项医疗措施,被随后的高质量临床研究证明无效,前后的知识主张构成矛盾 [4, 5]。现代医学中常见“医疗逆转”,曾有学者统计了发表于《新英格兰医学杂志》2001-2010年十年间的临床研究,其中医疗逆转发生率为40.2%[5]。在突发公共卫生事件中,由于早期对疾病的认识不足,临床上没有特异性治疗方法和药物,许多实验设计不完善的研究成果被发表出来。在提供了新结论、新疗法的同时,也产生了不完整、不严谨的知识。这些最早被报道的数据或者相关研究结果,即使在传统循证医学中的证据等级很低,在彼时也可被视作“高级别”证据,从而获得极高引用率并促进后续的临床研究广泛开展。随着人们对疾病发病机制认识的加深,以及全球范围内大规模的临床研究开展,对于COVID-19“特异性”疗法或药物,常常出现反对或颠覆前期研究结果的新证据,从而形成上述“医疗逆转”。医疗逆转不仅会使医疗决策层面遇到困惑,更重要的是带来了沉重的医疗负担。

  • 1.2 以羟氯喹为例看医疗逆转带来的负担

  • 氯喹/羟氯喹(Chloroquine/Hydroxychloroquine, CQ/HCQ) 结构相似,目前已被广泛应用于疟疾的预防、治疗以及系统性红斑狼疮和类风湿性关节炎等自身免疫性疾病当中 [6]。CQ/HCQ通过抑制唾液酸的生物合成、病毒蛋白翻译后修饰、增强可溶性抗原向树突状细胞的输出、CD8+T细胞应答等作用,抑制宿主受体的糖基化、蛋白水解过程和胞内体酸化,从而阻止病毒进入细胞;同时CQ/HCQ还能通过调节细胞信号转导,调节促炎性细胞因子的释放,以及抑制宿主细胞中的自噬体和溶酶体活性达到免疫调节作用 [7, 8]。CQ/HCQ在体外实验中均能抑制严重急性呼吸系统综合征冠状病毒2(SARS-CoV-2),但HCQ的抗病毒活性似乎更强 [9]

  • 关于CQ/HCQ用于治疗COVID-19,最先被报道的临床试验是一项针对法国36名COVID-19患者(HCQ组20例,对照组16例)的开放标签非随机试验;结果表明HCQ的使用与患者体内的病毒载量减少显著相关。虽然这项研究存在多种局限性,如样本量小、使用符合研究方案(Per-protocol, PP)分析高估疗效等,但该项研究结果仍获得同行的高度关注 [10]。随后,大量以CQ/HCQ为主要治疗手段治疗COVID-19的临床试验在国内外逐渐广泛开展。在中国,国家卫生健康委印发的《新型冠状病毒肺炎诊疗方案(试行第六版)》将“磷酸氯喹”纳入治疗适用药物名单当中 [11],随后在2020年3月4日更新的《新型冠状病毒肺炎诊疗方案(试行第七版)》中调整了磷酸氯喹的用法用量 [12],并出台《磷酸氯喹治疗新型冠状病毒肺炎的专家共识》[13]。2020年3月中旬,国外启动另一项临床试验,计划招募3 000例COVID-19患者 [14] 以研究SARS-CoV-2暴露后HCQ预防COVID-19疾病进展的有效性。同期,世界卫生组织(World Health Organization,WHO)及其卫生合作机构发起的国际临床试验“团结试验”(Solidarity Clinical Trial for COVID-19Treatments),旨在寻找针对COVID-19的有效治疗方法,CQ/HCQ也被纳入候选药物当中 [15],其作用也被媒体和政策制定者夸大渲染 [16]

  • 随着人们对HCQ的日益关注,药物不合理的应用也逐渐引起学界的关注、越来越多的临床专家开始对药物的规范使用及适当管理问题产生担忧 [17]。随后的观察性研究中,有研究报告HCQ与阿奇霉素联用,可能会对患者产生心律失常的潜在影响,并增加心血管死亡的风险 [18-21],一些大型临床试验也证实了HCQ的使用与插管或死亡复合终点的发生无关 [22, 23]。然而,真正把HCQ推上风口浪尖的,则是一项使用了Surgisphere公司(自称已经创建了世界上最大、最复杂的患者数据库之一的公司)数据的研究。该研究纳入近10万例COVID-19患者,结果显示使用CQ/HCQ与死亡和心律不齐的风险增加相关,与先前的导向形成显著的医疗逆转 [24]。该研究一经公布便引起学术界震动,随之带来的影响包括“团结试验”HCQ部门暂停临床注册,几天之内许多的药品安全机构都建议对HCQ治疗COVID-19撤销临床试验授权等 [25]。虽然该文章很快被发现数据来源涉嫌学术不端而被撤回,但后续的大型观察性研究也证明了HCQ缺乏预期的疗效,相关的临床试验也随之暂停 [26]

  • 最初,氯喹类药物的研究热潮大多起源于未经同行评议的预印本数据,数据的真实性、完整性和权威性并不能得到保证。氯喹类药物用于治疗COVID-19的医疗逆转显示,不受限制地访问未经同行评议的研究确实是一把双刃剑。此外,社交媒体的广泛传播、对研究结果的断章取义以及夸大渲染,使得大量且不必要的临床试验被重复注册及开展。执行未经确证的治疗或操作,只会使患者面临额外的医疗风险。同时,即使没有发生伤害,重复的医疗行为也会浪费有限的医疗资源 [5, 27]。无独有偶,抗病毒药物瑞德西韦治疗COVID-19也经历了类似的“医疗逆转 [28]。爱丁堡大学临床研究中心主任John Norrie教授评论瑞德西韦用于COVID-19的研究不足时认为:“研究者必须抵制降低证据标准的诱惑,因为采用无效且不安全的干预措施只会带来危害。对于大流行的疾病进行试验是特殊的挑战,需要强调数据共享的重要性,单个研究有失败的风险,但对多个把握度不足的高质量研究进行数据整合,是我们能够深入了解药物有效性、安全性、最佳获益人群的最有效方法”[29]。因此,构建数据协作机制,通过加强数据整合与利用、提升临床研究质量、减少低级别证据的发表与引用将有助于减少医疗逆转,从而减轻不确定性知识带来的决策困难与医疗负担。

  • 2 建立突发公共卫生事件数据协作机制

  • 2.1 建立数据协作机制的迫切性

  • 数据是公共卫生响应的基础,而快速响应的数据共享机制在突发公共卫生事件中至关重要 [30, 31]。在埃博拉病毒疫情期间就曾暴露了数据共享机制的缺陷 [30],进一步揭示突发公共卫生事件中迫切需要改进数据共享的规范和流程。由于医疗逆转频发,准确传播和获取科学信息,理解当前研究的局限性,减少低水平的重复研究,谨慎对待未经证实的数据和结论,将对认识疾病、控制疾病进程起到积极的促进作用。数据协作的要点不仅仅是将数据收集、整合、归一化,更重要的是如何加以利用。

  • 由于COVID-19人群普遍易感,除特异性疗法和药物的相关研究将会出现医疗逆转外,针对特殊人群的治疗与预后数据也常与早期研究相互矛盾,数据协作也可使特殊人群治疗、管理、预后分析获益。特殊人群治疗与预后数据的医疗逆转,可能是由如下几个原因造成:(1)对疾病认识不足。疫情早期,一线临床人员主要关注SARSCoV-2感染后的肺炎与急性呼吸窘迫综合征的情况,而随着对疾病认识的加深,病毒感染后的肺外表现如血液系统、心血管系统、肾脏、消化系统、神经系统等受累逐渐受到医学界的关注 [32];(2) 特殊患病人群预后改变。例如,肺外系统受累可能会改变特殊人群如孕妇、儿童、肿瘤患者、肾脏病患者等特定生理病理机制,从而影响其预后;(3)病理生理机制影响特殊用药人群预后。例如,由于病毒能与ACE2受体结合从而进入人体细胞,ACE2的表达可能受到服用血管紧张素转换酶抑制剂(Angiotensin Converting Enzyme Inhibitors,ACEI)或血管紧张素Ⅱ受体阻滞剂(Angiotensin Ⅱ Receptor Blockers,ARBs)的影响,因此对于服用此类药物的人群,疾病易感性、症状严重性及预后可能受到影响 [33]

  • 鉴于相关知识的严重缺乏,以及对特殊人群生理病理机制改变及预后的认识不足,有学者呼吁建立相关协作组,通过整合已患病人群数据,寻找影响特殊人群预后的危险因素,寻求最佳治疗方案;同时,对于未患病人群,临床上应该提升特殊护理质量及优化资源分配,如肿瘤患者择期手术、白血病患者血液制品分配、评估化疗及免疫疗法的临时指导等 [34]。事实上,由于医院感染控制部门、临床医生、药学专家、数据科学家等在医院层面上的分散,以及数据多源异构等问题,不可避免的形成“数据孤岛”,或单独应用价值有限的“低质量数据”,而疫情期间的“居家办公”政策也加剧了这一类问题的发生。建立数据协作机制,特别是对特殊人群建立相关协作组,从而实现大规模数据收集、组织、审查和分配工作,对于战略决策和共享最佳实践至关重要 [35]

  • 2.2 数据协作机制实施要点

  • 数据协作的合作基础是整合数据、利用共享,其目的则是采用标准化操作规程进行数据采集、数据清理、整合并加以利用。英国研究发展合作组织(UK Collaborative on Development Research)和全球传染病防范研究合作组织(Global Research Collaboration for Infectious Disease Preparedness)共同提出针对全球COVID-19的高质量研究原则:(1) 符合当前需要优先解决的研究问题;(2)具备快速研究的能力;(3)公平、包容的跨学科、跨部门的协作能力;(4)开放数据共享;(5)不伤害原则;(6)适当的伦理考量;(7)通过加强协调配合进行协作和学习 [36],并强调了协作机制在高质量研究中的重要作用。其中,数据协作机制的实施要点尤其应该包括以下几个方面:

  • 2.2.1 伦理考量

  • 联合国教科文组织国际生命伦理委员会和世界科学技术知识伦理委员会在巴黎发表联合声明指导决策并说明全球抗击COVID-19需要注意的伦理问题 [37]。其中提到,在数据整合、协作的同时,在伦理审查方面也需要达成共识。首先应符合2016年世界卫生组织(WHO)提出的《传染病暴发中伦理问题处理指南》原则,并根据特殊情况加以调整,其中也强调了由于传染病爆发期间不确定性的科学信息不断变化,快速数据共享至关重要,而各国应对数据共享的法律、政策和实践进行审查,确保患者个人信息得到充分保护。

  • 2.2.2 国际数据协作机制举例

  • 目前,尚无标准化操作规程来收集真实世界的诊疗数据,面临数据安全存放、多元异构、数据脱敏等方面的挑战。近期,美国国立卫生研究院国家转化科学促进中心(National Center for Advancing Translational Sciences,NCATS)、国家健康医疗大数据中心(Center for Data to Health,CD2H)及合作伙伴共同建立了国家层面的COVID-19队列合作平台(National COVID Cohort Collaborative Data Enclave,N3C),旨在全国范围内汇总、协调和提供临床数据,以加速了解疾病进程并确定有效治疗疾病的干预措施。该数据平台从电子病历记录中收集已接受COVID-19检测、或已报告相关症状的患者的信息。由NCATS与卫生保健机构签订数据共享协议,卫生保健提供者上传相关记录,再由NCATS、CD2H联合工作组成员通过分布计算网络(如Observational Health Data Sciences and Informatics)将诊疗数据、实验室检查数据进行标准化及归一化,形成通用数据模型,来提高数据质量和利用率,通过数据使用许可的研究者则可以申请相关数据进行分析 [38]

  • 2.2.3 特定人群协作组的建立

  • 由于COVID-19疾病进展的不确定性,整合、归一化数据的最终目的是如何更好地加以利用。通过建立特定人群协作组,可以使临床医疗大数据与临床研究紧密联系,如:糖尿病、妊娠、癌症、急性肾损伤、药物利用等,以促进临床医生、研究人员和数据科学家之间的广泛合作来提高研究价值。目前,美国癌症协会已建立了COVID-19肿瘤协作组,通过电子病历及与相关临床人员访谈进行分析,以改善肿瘤患者预后并改善疫情下特殊护理的需求;而针对未患COVID-19的肿瘤患者,该协作组也提出了相应的管理措施,如择期手术、白血病患者血液制品分配、评估化疗及免疫疗法的临时指导等 [39]

  • 2.3 国际实践对我国构建数据协作机制的启发

  • 在数据协作方面,我国于疫情爆发初始时第一时间(2020年1月)向WHO分享了新冠病毒序列信息 [40],同时,为加强科研成果交流,中华人民共和国科学技术部、国家卫生健康委员会、中国科学技术协会、中华医学会联合共建了“新型冠状病毒肺炎科研成果学术交流平台”,供科研人员发布成果、发表观点、参与讨论、开展述评 [41]。与此同时,中华医学会、中国中西医结合学会、中国医师协会等学术组织的下属专业委员会相继发表了专科患病人群的疫情防控、疾病管理、救治经验等相关专家共识。例如,针对血液透析患者,由于血液透析室属于人群集中、流动性大的COVID-19感染高风险区域,且透析患者通常合并如心脑血管疾病、糖尿病等多种慢性疾病,抵抗力较低,因此需要每周2~3次前往医院进行血液透析的患者感染COVID-19风险较高。在此情境下,相关联盟专家、学会委员迅速集结起来,发表了针对易感人群(工作人员、血液净化患者及家属)以及血液透析室的防控措施专家共识,并迅速推广至全国 [42, 43];同时,也为后期其他国家疫情爆发时血液净化患者的管理提供了宝贵经验 [44]

  • 目前我国针对突发公共卫生事件的数据协作机制尚不完善,主要是通过以专家为导向的经验共识来指导制定应急预案及临床实践。然而,建立突发公共卫生事件的数据协作机制应以数据为驱动,通过挖掘数据价值、构建疾病演化模型快速形成证据; 同时学术组织与相关领域专家则在数据共享机制中起咨询和监管等作用,这才能够及时有效避免频繁医疗逆转带来的决策困难及医疗资源浪费 [45]。因此,建立符合我国国情和数据安全需求的数据协作平台,应以数据为驱动,在保障安全隐私的前提下通过整合分散的真实世界数据“聚沙成塔”;并通过相关领域学术组织及专家进行监管并进行数据价值挖掘,从而为应对公共卫生应急事件提供有效证据。

  • 3 小结

  • 在包括COVID-19疫情在内的公共卫生应急事件下,医学不确定性及医疗逆转带来的问题与疑惑很难被完全消除;临床一线工作人员和卫生政策制定者应该充分认识到这种“不确定性”。当前,通过构建数据协作机制提高数据利用的效率和质量,能够减少COVID-19诊疗的临床决策困境,避免引发公众对于医疗体系的不信任感;对于特定人群(例如糖尿病和妊娠等)尤其重要。如何创建符合我国国情的突发公共卫生事件数据协作机制,充分发挥健康医疗大数据在疫情防控中的价值,减少不必要的资源浪费,仍是疫情防控工作中的重要一环。

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