Article(id=1241067202502250927, tenantId=1146029695717560320, journalId=1227665162245664772, issueId=1241067197318091153, articleNumber=null, orderNo=null, doi=10.20043/j.cnki.MPM.202411070, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1730908800000, receivedDateStr=2024-11-07, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1773823078989, onlineDateStr=2026-03-18, pubDate=1741536000000, pubDateStr=2025-03-10, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1773823078989, onlineIssueDateStr=2026-03-18, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1773823078989, creator=13701087609, updateTime=1773823078989, updator=13701087609, issue=Issue{id=1241067197318091153, tenantId=1146029695717560320, journalId=1227665162245664772, year='2025', volume='52', issue='5', pageStart='769', pageEnd='960', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1773823077754, creator=13701087609, updateTime=1773823268053, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1241067995544482681, tenantId=1146029695717560320, journalId=1227665162245664772, issueId=1241067197318091153, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1241067995544482682, tenantId=1146029695717560320, journalId=1227665162245664772, issueId=1241067197318091153, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=931, endPage=937, ext={EN=ArticleExt(id=1241067203227865556, articleId=1241067202502250927, tenantId=1146029695717560320, journalId=1227665162245664772, language=EN, title=Research design for evaluating long-term vaccine effectiveness based on extended test-negative design under fixed study duration model, columnId=1228016573156360233, journalTitle=Modern Preventive Medicine, columnName=Disease Control and Prevention, runingTitle=null, highlight=null, articleAbstract=
Objective

To explore a suitable research design for evaluating the long-term effects of vaccines, taking into account the heterogeneity caused by individual susceptibility, vaccination status, vaccination timing, and the confounding effects of healthcare-seeking behavior.

Methods

This study employed a Monte Carlo simulation method to extend the Test-Negative Design (TND),considering constant vaccine efficacy and two types of time-dependent vaccine efficacy under a fixed study duration model. A multivariable logistic regression model and a semi-parametric generalized additive model based on restricted cubic splines were constructed to evaluate the long-term effects of vaccines.

Results

When only considering changes in vaccine efficacy, the estimated vaccine effectiveness (VE) curves from both models accurately fit the actual decay trend of VE, being only slightly higher than the true VE (approximately 1%-3%). The VE curves were minimally affected by vaccination rates, the mean probability of influenza-like illness in the entire population, and the probability of influenza-like illness in the vaccinated population.

Conclusion

The extended TND under a fixed study duration model provides a feasible new approach for evaluating long-term vaccine effectiveness, with the potential for application to other types of vaccines. Both models demonstrated good fitting performance over time with no significant differences. However, further exploration is needed to comprehensively consider other heterogeneous influencing factors and to conduct simulation experiments with the extended TND after group assignment.

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目的

考虑个体易感性、接种状态、接种时间等因素导致的异质性以及就医行为混杂对疫苗长期效果评价的影响,探究适合评价疫苗长期效果的研究设计。

方法

本研究采用蒙特卡洛模拟法,对检测阴性设计(test-negative design, TND)进行扩展,在固定研究时长模式下考虑恒定疫苗效力和两种时依疫苗效力,构建基于时间限制性样条的多元logistic回归模型和半参数广义加性模型,评价疫苗长期效果。

结果

仅考虑疫苗效力变化时,两模型估计的疫苗有效性(vaccine effectiveness, VE)变化曲线均能较准确地拟合真实VE的衰减趋势,仅略高于真实VE(约1%~3%)。VE变化曲线受接种率、全人群流感样概率均值和已接种人群流感样概率的影响较小。

结论

固定研究时长模式下的扩展TND研究为评价疫苗长期效果提供了一个具有可行性的新思路,以期推广至其他种类的疫苗。两模型随时间变化的拟合效果较好且无明显差异。但未全面考虑其他异质性影响因素以及加入转组后的扩展TND的模拟实验,需进一步探索研究。

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王陵,E-mail:
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舒婷(2000—),女,硕士在读,研究方向:临床研究设计与方法学研究

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Generalized additive model and its application[J]. China Health Statistics, 2007, 24(3): 2.(In Chinese), articleTitle=Generalized additive model and its application, refAbstract=null), Reference(id=1241067224736256325, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241067202502250927, doi=null, pmid=null, pmcid=null, year=2021, volume=174, issue=8, pageStart=1118, pageEnd=1125, url=null, language=null, rfNumber=[21], rfOrder=22, authorNames=Follmann D, Fintzi J, Fay MP, journalName=Annals of Internal Medicine, refType=null, unstructuredReference=Follmann D, Fintzi J, Fay MP, et al. A Deferred-Vaccination design to assess durability of COVID-19 vaccine effect after the placebo group is vaccinated[J]. Annals of Internal Medicine, 2021,174(8): 1118-1125., articleTitle=A Deferred-Vaccination design to assess durability of COVID-19 vaccine effect after the placebo group is vaccinated, refAbstract=null)], funds=[Fund(id=1241067217383641237, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241067202502250927, awardId=82273729, language=CN, fundingSource=国家自然科学基金项目(82273729), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1241067207472501409, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241067202502250927, xref=1., ext=[AuthorCompanyExt(id=1241067207485084323, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241067202502250927, companyId=1241067207472501409, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Department of Health Statistics, Military Preventive Medicine, Air Force Medical University, Xi’an, Shaanxi 710032, China), AuthorCompanyExt(id=1241067207493472933, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241067202502250927, companyId=1241067207472501409, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1.空军军医大学军事预防医学系卫生统计学教研室,陕西 西安 710032)]), AuthorCompany(id=1241067207698993846, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241067202502250927, xref=2., ext=[AuthorCompanyExt(id=1241067207719965371, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241067202502250927, companyId=1241067207698993846, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2..桂林电子科技大学数学与计算科学学院,广西 桂林 541004)]), AuthorCompany(id=1241067207849988810, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241067202502250927, xref=3., ext=[AuthorCompanyExt(id=1241067207866766026, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241067202502250927, companyId=1241067207849988810, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=3.空军军医大学特殊作业环境危害评估与防治教育部重点实验室,陕西 西安 710032)])], figs=[ArticleFig(id=1241067212300145653, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241067202502250927, language=EN, label=Figure 1, caption=Schematic diagram of extended TND evaluation of vaccine effectiveness, figureFileSmall=1zbzFdErrGm4OuxVs6qAQw==, figureFileBig=UX1e1KD1VDrQ3AP1n9xBZg==, tableContent=null), ArticleFig(id=1241067215601062912, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241067202502250927, language=CN, label=图1, caption=扩展TND评价疫苗效果示意图

注:图A为TND和扩展TND示意图;图B为固定研究时长模式下的扩展TND时间-人数示意图。

, figureFileSmall=1zbzFdErrGm4OuxVs6qAQw==, figureFileBig=UX1e1KD1VDrQ3AP1n9xBZg==, tableContent=null), ArticleFig(id=1241067215869497374, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241067202502250927, language=EN, label=Figure 2, caption=Constant and time-dependent vaccine efficacy during 210 days, figureFileSmall=7FNer2NUgaJrLktSoKtkRA==, figureFileBig=RsgsMsGXi9HFFdXF+biDDA==, tableContent=null), ArticleFig(id=1241067216012103718, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241067202502250927, language=CN, label=图2, caption=210 d内恒定和两种时依性的疫苗效力, figureFileSmall=7FNer2NUgaJrLktSoKtkRA==, figureFileBig=RsgsMsGXi9HFFdXF+biDDA==, tableContent=null), ArticleFig(id=1241067216121155634, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241067202502250927, language=EN, label=Figure 3, caption=Simulation flow chart, figureFileSmall=oiyvX3eux5ekAIU2+HM1Gg==, figureFileBig=4Yo5UjfL/y2Qv0oJlTRvWg==, tableContent=null), ArticleFig(id=1241067216276344889, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241067202502250927, language=CN, label=图3, caption=模拟流程图, figureFileSmall=oiyvX3eux5ekAIU2+HM1Gg==, figureFileBig=4Yo5UjfL/y2Qv0oJlTRvWg==, tableContent=null), ArticleFig(id=1241067216410562625, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241067202502250927, language=EN, label=Figure 4, caption=Change curve of VE under constant 70% vaccine efficacy mode, figureFileSmall=eI/CQNEvh30gh0+MslaF5Q==, figureFileBig=PoTezMr6aYUxa14yqPAe0w==, tableContent=null), ArticleFig(id=1241067216553168972, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241067202502250927, language=CN, label=图4, caption=疫苗效力为恒定70%模式下VE变化曲线图

注:图A Vcover=30%, ILL1=30%, ILL2=30%;图B Vcover=50%, ILL1=30%, ILL2=70%;图C Vcover=50%, ILL1=50%, ILL2=50%;gam表示基于时间限制性样条的多元logistic回归模型绘制的VE衰减曲线;logit表示根据半参数广义加性模型绘制的VE衰减曲线;pVE表示接种完成后VE衰减曲线;rVE表示在全人群中的VE衰减曲线;rVE_OR表示根据TND算法绘制的VE衰减曲线。

, figureFileSmall=eI/CQNEvh30gh0+MslaF5Q==, figureFileBig=PoTezMr6aYUxa14yqPAe0w==, tableContent=null), ArticleFig(id=1241067216666415190, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241067202502250927, language=EN, label=Figure 5, caption=Change curve of VE in linear decline mode of vaccine efficacy, figureFileSmall=yEiTee5HJWli5NchDj+nHA==, figureFileBig=AIIo9WVEdOG/XEoH6o+gnQ==, tableContent=null), ArticleFig(id=1241067216758689886, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241067202502250927, language=CN, label=图5, caption=疫苗效力为线性衰减模式下VE变化曲线图

注:图A Vcover=30%, ILL1=30%, ILL2=58.6%;图B Vcover=50%, ILL1=30%, ILL2=70%;gam、logit、pVE、rVE、rVE_OR注释见图4

, figureFileSmall=yEiTee5HJWli5NchDj+nHA==, figureFileBig=AIIo9WVEdOG/XEoH6o+gnQ==, tableContent=null), ArticleFig(id=1241067216871936105, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241067202502250927, language=EN, label=Figure 6, caption=Change curve of VE in exponential decline mode of vaccine efficacy, figureFileSmall=PXYZ7Asv8CdZfWxqUFWolw==, figureFileBig=AAKjBkDPK09QRD31XbzIzw==, tableContent=null), ArticleFig(id=1241067217006153843, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241067202502250927, language=CN, label=图6, caption=疫苗效力为指数衰减模式下VE变化曲线图

注:图A Vcover=30%, ILL1=30%, ILL2=58.6%;图B Vcover=50%, ILL1=30%, ILL2=70%;gam、logit、pVE、rVE、rVE_OR注释见图4

, figureFileSmall=PXYZ7Asv8CdZfWxqUFWolw==, figureFileBig=AAKjBkDPK09QRD31XbzIzw==, tableContent=null), ArticleFig(id=1241067217106817149, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241067202502250927, language=EN, label=Table 1, caption=

Parameter settings and values

, figureFileSmall=null, figureFileBig=null, tableContent=
参数名称符号参数取值
总人群接种率vcover10%、30%、50%、60%
研究样本量n10 000
疫苗有效性(初始值)rVE随时间衰减(70%)
未接种人群感染率AR115%
脱落率Dp1%
已接种人群感染率AR2AR1*(1-rVE)
全人群流感样概率均值ILL30%、50%、70%
已接种人群流感样率ILL110%、30%、50%
未接种人群流感样率ILL2
), ArticleFig(id=1241067217241034891, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241067202502250927, language=CN, label=表1, caption=

参数设置及取值

, figureFileSmall=null, figureFileBig=null, tableContent=
参数名称符号参数取值
总人群接种率vcover10%、30%、50%、60%
研究样本量n10 000
疫苗有效性(初始值)rVE随时间衰减(70%)
未接种人群感染率AR115%
脱落率Dp1%
已接种人群感染率AR2AR1*(1-rVE)
全人群流感样概率均值ILL30%、50%、70%
已接种人群流感样率ILL110%、30%、50%
未接种人群流感样率ILL2
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基于固定研究时长模式下扩展检测阴性设计评价疫苗长期效果的研究设计
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舒婷 1, 2 , 曾祥艳 2 , 冯浚铃 1 , 王陵 1, 3
现代预防医学 | 疾病预防控制 2025,52(5): 931-937
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现代预防医学 | 疾病预防控制 2025, 52(5): 931-937
基于固定研究时长模式下扩展检测阴性设计评价疫苗长期效果的研究设计
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舒婷1, 2, 曾祥艳2, 冯浚铃1, 王陵1, 3
作者信息
  • 1.空军军医大学军事预防医学系卫生统计学教研室,陕西 西安 710032
  • 2..桂林电子科技大学数学与计算科学学院,广西 桂林 541004
  • 3.空军军医大学特殊作业环境危害评估与防治教育部重点实验室,陕西 西安 710032
  • 舒婷(2000—),女,硕士在读,研究方向:临床研究设计与方法学研究

通讯作者:

王陵,E-mail:
Research design for evaluating long-term vaccine effectiveness based on extended test-negative design under fixed study duration model
Ting SHU1, 2, Xiang-yan ZENG2, Jun-ling FENG1, Ling WANG1, 3
Affiliations
  • Department of Health Statistics, Military Preventive Medicine, Air Force Medical University, Xi’an, Shaanxi 710032, China
出版时间: 2025-03-10 doi: 10.20043/j.cnki.MPM.202411070
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目的

考虑个体易感性、接种状态、接种时间等因素导致的异质性以及就医行为混杂对疫苗长期效果评价的影响,探究适合评价疫苗长期效果的研究设计。

方法

本研究采用蒙特卡洛模拟法,对检测阴性设计(test-negative design, TND)进行扩展,在固定研究时长模式下考虑恒定疫苗效力和两种时依疫苗效力,构建基于时间限制性样条的多元logistic回归模型和半参数广义加性模型,评价疫苗长期效果。

结果

仅考虑疫苗效力变化时,两模型估计的疫苗有效性(vaccine effectiveness, VE)变化曲线均能较准确地拟合真实VE的衰减趋势,仅略高于真实VE(约1%~3%)。VE变化曲线受接种率、全人群流感样概率均值和已接种人群流感样概率的影响较小。

结论

固定研究时长模式下的扩展TND研究为评价疫苗长期效果提供了一个具有可行性的新思路,以期推广至其他种类的疫苗。两模型随时间变化的拟合效果较好且无明显差异。但未全面考虑其他异质性影响因素以及加入转组后的扩展TND的模拟实验,需进一步探索研究。

扩展TND  /  限制性立方样条  /  时依性  /  疫苗长期有效性
Objective

To explore a suitable research design for evaluating the long-term effects of vaccines, taking into account the heterogeneity caused by individual susceptibility, vaccination status, vaccination timing, and the confounding effects of healthcare-seeking behavior.

Methods

This study employed a Monte Carlo simulation method to extend the Test-Negative Design (TND),considering constant vaccine efficacy and two types of time-dependent vaccine efficacy under a fixed study duration model. A multivariable logistic regression model and a semi-parametric generalized additive model based on restricted cubic splines were constructed to evaluate the long-term effects of vaccines.

Results

When only considering changes in vaccine efficacy, the estimated vaccine effectiveness (VE) curves from both models accurately fit the actual decay trend of VE, being only slightly higher than the true VE (approximately 1%-3%). The VE curves were minimally affected by vaccination rates, the mean probability of influenza-like illness in the entire population, and the probability of influenza-like illness in the vaccinated population.

Conclusion

The extended TND under a fixed study duration model provides a feasible new approach for evaluating long-term vaccine effectiveness, with the potential for application to other types of vaccines. Both models demonstrated good fitting performance over time with no significant differences. However, further exploration is needed to comprehensively consider other heterogeneous influencing factors and to conduct simulation experiments with the extended TND after group assignment.

Extended TND  /  Restricted cubic splines  /  Time-dependency  /  Long-term vaccine effectiveness
舒婷, 曾祥艳, 冯浚铃, 王陵. 基于固定研究时长模式下扩展检测阴性设计评价疫苗长期效果的研究设计. 现代预防医学, 2025 , 52 (5) : 931 -937 . DOI: 10.20043/j.cnki.MPM.202411070
Ting SHU, Xiang-yan ZENG, Jun-ling FENG, Ling WANG. Research design for evaluating long-term vaccine effectiveness based on extended test-negative design under fixed study duration model[J]. Modern Preventive Medicine, 2025 , 52 (5) : 931 -937 . DOI: 10.20043/j.cnki.MPM.202411070
在当今全球化的时代,疫苗作为预防和控制传染病的传播和爆发的重要手段,在全球公共卫生领域发挥着举足轻重的作用。新疫苗通过Ⅲ期随机对照临床试验(randomized controlled trial, RCT)的安全性和保护效力的评价后获批上市或紧急授权(emergency use authorization, EUA)后投入现实世界使用。由于RCT研究在EUA前的随访时间较短且EUA后安慰剂组应获得有效的接种而不能作为疫苗长期效果评价的研究方法,需要进一步对真实世界人群中的疫苗效果和安全性进行长期综合评价以确认疫苗的公共卫生价值,同时对于新疫苗来说进行长期效果评价是获得社会认可的必要研究过程。
检测阴性设计(test-negative design, TND)因其在同一症候群的患者中展开研究,能够有效地减少选择偏倚和就医行为混杂而被广泛应用于真实世界研究中疫苗效果评价。但采用TND的大量研究[1-4]中局限于疫苗接种后某时点下不同接种剂次、不同毒株、疫苗种类、是否加强/序贯接种的相对效果评价。该方法通过比较接种疫苗后检测阳性人群比例与未接种疫苗但检测阴性人群比例,计算过程较为简单,仅考虑瞬时的感染状态和接种状态,未考虑年龄、距疫苗接种时间等混杂因素,只能初步估算出疫苗单个时间点的疫苗有效性(vaccine effectiveness, VE)。现有文献中采用以感染状态为因变量的logistic回归对TND评估VE的方法进行了改进[5],如Andrejko、Desai等[6-7]采用对年龄、性别、实验室检测时间等多个变量进行匹配的条件logistic回归模型,Butt等[8]利用倾向性分来匹配病例和对照的logistic回归模型,Sheikh等[9]采用以年龄、距疫苗接种时间为平滑项的广义加性logistic回归模型对不同年龄组、不同接种剂次人群的疫苗有效性进行评估等。
随着时间推移疫苗效力本身会发生衰减,多个研究表明COVID-19疫苗在完成两剂接种一个月后疫苗有效性达到最大值或对死亡、住院等严重临床后果有较高的保护作用(>90%)[10-11],但五个月后VE将衰减至40%左右[12]。类似地,不同亚型流感疫苗的VE基本保持5~6个月大于0且在流感季节期间衰减[13-14]。由此可见,疫苗诱导产生的相对保护效力以较快的速度减弱,个体获得短暂的保护失效后可能会再次感染,对不同年龄段和人群的风险程度进行序贯或加强接种以及最佳时机成为必要考虑的问题。在此背景下,本文计划基于TND加入随访过程以探究适合疫苗长期效果评价的研究设计,在固定研究时长模式下分析比较现有VE评价模型的适用性,开展模拟实验初步探索该设计的可行性。
无论是RCT研究[15]还是现有的TND研究,在评价疫苗长期效果方面均存在不同程度的问题,有待进一步完善和优化。本研究提出扩展TND设计,即在原TND基础上持续随访检测阴性人群,进一步评价长期预防效果。本文的扩展TND研究是基于固定研究时长模式展开,即研究开始前确定随访时间,TND研究与扩展的检测阴性人群随访同时开始于研究起点且同时结束于计划的研究截点,期间不断增加阴性队列的研究样本量。见图1
扩展TND最大的优势是可以通过前瞻性阴性人群的时依性影响、病原体变异、接种状态的改变等信息,弥补TND回顾性收集数据的缺陷,同时在随访过程中也可以动态更新TND研究数据,实时调整同时段基于TND的时依性VE估计,优化评价结果。
近年来,很多学者开始采用非线性的方法校正连续型混杂,如回归样条模型[16-17]、广义加性模型[9]等。本文以COVID-19疫苗效果评价为研究背景,参考Ferdinands、Nikas等[1618]的研究,在真实世界人群中模拟疫苗接种、病毒感染等数据,构建与回顾性数据整合的疫苗长期效果评价模型,包括基于时间限制性样条函数的多元logistic回归模型和半参数广义加性模型,并比较两者的优劣。模型构建考虑个体间存在感染风险异质性的时依混合效应,探索在固定研究时长模式下适合疫苗效力恒定和两种疫苗效力随时间变化的VE评价策略。
限制性立方样条/自然样条(restricted cubic aplines/natural aplines, RCS/NS)中节点的个数可由研究人员根据研究背景和数据量选择,且研究表明节点的重要性大于位置[19]。为了选择出拟合度最优的模型,在模拟实验中节点数的取值范围设为3~6,从中选择出赤池信息量准则(Akaike information criterion, AIC)最小的RCS函数。将RCS函数引入logistic回归中,即可得到基于时间限制性样条的多元logistic回归模型。模型如下:
其中,test=1为实验室检测为阳性,否则为0;Ptest=1为实验室检测为阳性的概率;(vacc)为完成疫苗接种指示变量,值为1表示接种,值为0表示未接种;vaccine为距疫苗完成接种天数(未接种疫苗的受试者为0),作为限制性样条函数纳入模型即rcs(vaccine, n),n为自定义的节点数;β为回归系数;xi为协变量包括性别、年龄等。
广义加性模型(generalized additive model, GAM)主要用于研究两个或多个连续型预测变量之间的交互作用。在实际应用中,若将所有可加项都作为非参数形式纳入模型时会导致模型计算量较大、拟合速率过慢、过度拟合等问题[20]。因此模拟实验中仅将关注的连续型混杂因素(如距完成疫苗接种天数)作为非参数形式纳入模型,其他的因素以与广义线性模型相似的参数形式纳入,即半参数广义加性模型(sem-parametric generalized additive model)表示为下式:
其中,μ=E(Y|X1,X2,…,Xp);g(·)为连接函数,响应变量的分布决定其连接函数的形式;Si(·)为平滑函数。
针对已提出的扩展TND及其评价模型,基于软件R 4.4.1,采用蒙特卡洛模拟法(Monte Carlo simulation, MC)进行模拟实验,在固定研究时长模式和不同疫苗效力衰减模式下初步探索扩展TND评价疫苗长期效果的可行性和模型的拟合度。
对TND研究中实验室检测结果阴性人群进行持续随访,扩展研究时长设定为一年,随访过程中按月记录实验室检测结果新发生感染状态、距完成疫苗接种天数等信息动态代入研究模型中估计时依性的VE,同时调整同一时段基于TND的时依性VE估计。并基于全人群进行定期监测VE衰减情况,作为TND随访研究的模拟参照。假设扩展研究开始前1个月内所有随机接种人群在均已完成接种并获得部分免疫保护,实验室检测结果具有高度敏感性和特异性(即不考虑假阳性和假阴性的检测结果)且非目标病原体感染不影响目标病原体的检测结果。
本模拟实验涉及的主要参数见表1。在不同参数组合和疫苗效力模式下模拟总体VE的衰减情况并绘制出VE衰减曲线。其中参数组合出现特殊情况时分别进行相应处理:当未接种人群流感样概率小于已接种人群流感样概率时,不符合实际情况,故不进行模拟;当未接种人群流感样概率大于100%,基于实际情况均改为100%带入模拟。
第一步,建立在210 d内初始疫苗有效性由70%衰减至10%的线性衰减函数和指数衰减函数,并创建长度为360 d的递减序列,见图2
文献[4]显示COVID-19疫苗在接种7~180 d后有效性从77%衰减至22%,由于本实验研究时间较长故设置VE衰减范围为210 d内由70%衰减至10%后维持稳定。
第二步,设置相关模拟参数取值。创建感染状态、接种状态、流感样状态、距完成疫苗接种天数、年龄、性别7个变量在内的200万人群总体框。
第三步,在患流感样且实验室检测结果为阴性的人群中随机抽取n=10 000的样本框作为纳入研究总人数。设定固定研究时长为12个月,采用均匀入组的方式纳入研究,以实现持续入组直至研究结束和扩大入组样本量。
第四步,基于总体框中已接种人群距完成疫苗接种天数的增长,观察不同距完成疫苗接种天数下群体疫苗有效性(1-RR)的衰减情况。
第五步,考虑每个月纳入研究人数的增长并剔除既往阳性病例,动态增加已接种人群中个体距完成疫苗接种天数(未接种人群保持不变)从而获得因距完成疫苗接种天数不同导致呈现出不同的感染率。
第六步,依据线性衰减函数或指数衰减函数得出不同时间点下VE的衰减程度,动态检测随访过程中转阳人群以及脱落人群。以此循环将生成的12个分析数据集并导入列表(除研究开始时的基础数据)。
第七步,基于TND算法(1-OR)计算不同研究时点下纳入不同距完成疫苗接种天数总人群的VE衰减情况。同时,构建以疫苗感染状态为因变量,距完成疫苗接种天数的RCS函数为自变量的多元logistic回归模型和以距完成疫苗接种天数和年龄拟合非参数形式的平滑样条的半参数广义加性模型。计算出个体接种疫苗和个体未接种疫苗发生感染的预测概率,取平均后得出估计VE。
第八步,对以上步骤循环200次产生的多个VE值,采用均值作为最终估计VE的点估计值以及bootstrap方法计算95%置信区间作为VE的区间估计值。见图3
当疫苗效力为恒定70%(即已接种人群的感染风险不随时间递增或递减)时,基于TND估计的VE与基于时间限制性样条的多元logistic回归模型、半参数广义加性模型估计的VE曲线近乎重合,三者之间的差异均小于0.01%可忽略不计。但与真实VE仍存在一定程度上的偏倚。通过不同参数组合的模拟实验发现,VE曲线受接种率、流感样概率均值以及已接种人群流感样概率影响较小,前期估计VE略有波动,随着研究样本量的增加最终会趋于平稳,约为73%。见图4
当疫苗效力为线性衰减模式(即已接种人群的感染风险随时间线性递增)或指数衰减模式(即已接种人群的感染风险随时间指数递增)时,仍可以得出三种估计VE方法的结果无明显差异。与基于全人群的真实VE相比两模型均能较准确地拟合出在群体中疫苗有效性的衰减情况,但衰减过程中两者都高估了VE,差异约为1%~3%。当接种率较低且研究所纳入的样本量较小时,VE衰减曲线会出现波动而后能够准确估计,见图56。由此可以看出研究样本量的设定会影响模型拟合的程度,扩展TND适合用于大样本量的疫苗研究。通过不同参数组合的模拟实验发现,VE衰减曲线基本不受接种率、流感样概率均值以及已接种人群流感样概率影响,最终估计VE维持在11%。
在既往真实世界研究中均监测到流感、COVID-19等疫苗的有效性随时间出现不同程度的减弱,本文考虑实际情况设置不同的疫苗效力进行模拟实验,以期更好地切合真实世界人群中疫苗长期效果。大多数流感疫苗研究都是直接基于实际收集的数据通过时依logistic模型估计VE,缺乏前瞻性的收集随访信息来完善后续研究结果,并且运用TND评价COVID-19疫苗有效性的文献中少有评估疫苗长期效果的研究。本研究对TND进行扩展,在检测阴性人群中进行固定研究时长为一年的长期随访以获得前瞻性的信息,期间不断滚动增加检测阴性队列人数,扩大研究样本量得到准确的结果。此设计能够简化长期数据的收集过程,利用现有数据转化为队列研究进行后续监测,减少了资源的浪费最大化地利用研究数据。实验分别模拟了疫苗效力在完成接种后210 d内呈恒定、线性衰减和指数衰减的情况,三种估计VE方法的结果均符合实际的衰减趋势且结果略高估于全人群的衰减结果,说明仅考虑疫苗效力时基于时间限制性样条的多元logistic模型和半参数广义加性模型的拟合能力并无明显差异,可能是因为个体的年龄、地区等异质性因素未完全纳入模型以及TND纳入方式导致存在一定程度上的选择偏倚。
本文提出的扩展TND与传统TND在实际应用中的不同点主要体现在两个方面:一是数据采集时传统TND只是回顾性地收集同一症候群患者的实验室检测结果,没有考虑后续患者的动态数据变化;而扩展TND在研究开始时采用与传统TND一致的回顾性收集数据方式,后续研究过程中前瞻性收集检测阴性人群的随访信息,同时不断增加检测阴性队列人数以扩大研究样本量。二是传统TND不涉及随访过程,仅研究感兴趣时间节点下的VE;而扩展TND可根据研究预先设置的固定研究时长来设计满足研究要求的病例报告表,按月(或周、天)对已纳入研究的人群进行监测随访,前瞻性收集实验室检测数据,动态监测VE的变化。由于真实世界研究中也存在伦理学的实际问题,后续应在扩展TND研究中引入RCT研究[21]提及的转组设计理念,即对纳入研究但未接种的人群进行疫苗接种,动态地改变接种状态和感染状态。在长期随访过程中结合转组设计更符合真实世界的接种疫苗情况。在模型中调整距完成疫苗接种天数在内的潜在混在因素,个体因完成疫苗接种时间不同而表现出感染风险的异质性。传统TND在实际应用中并没有类似的考量。
综上所述,固定研究时长模式下的扩展TND研究为评价疫苗长期效果提供了一个具有可行性的新思路,立足于COVID-19疫苗展开研究,模拟实验中也考虑不同的接种率、目标病原体感染率和患流感样率,以期推广至其他种类疫苗。但本文的模拟实验仅验证了两模型在疫苗效力的恒定和时依衰减情况下的适用性,并未引入转组设计后的扩展TND。后续仍需在此基础上进行模拟实验,同时纳入年龄、地区等影响疫苗有效性异质性的因素,进一步探索模型的适用性。
  • 国家自然科学基金项目(82273729)
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2025年第52卷第5期
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doi: 10.20043/j.cnki.MPM.202411070
  • 接收时间:2024-11-07
  • 首发时间:2026-03-18
  • 出版时间:2025-03-10
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  • 收稿日期:2024-11-07
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国家自然科学基金项目(82273729)
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    1.空军军医大学军事预防医学系卫生统计学教研室,陕西 西安 710032
    2..桂林电子科技大学数学与计算科学学院,广西 桂林 541004
    3.空军军医大学特殊作业环境危害评估与防治教育部重点实验室,陕西 西安 710032

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2种不同金属材料的力学参数

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Genus
种数
Number of
species
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Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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