临床干预措施效力-效果差距弥合的方法学研究进展（二）：增强临床试验结果的外推性

目的 随机对照试验（RCT）通常具有严格的实施标准,纳入的研究对象特征以及干预实施条件与真实临床环境具有较大差异,这会导致干预措施在实际临床应用中的风险-效益与RCT中表现出的风险-效益存在差异, 结果的外推性受到很大限制。因此需要一些方法增强RCT结果的外推性,以评估药物在真实人群和真实临床实践环境中的真实效果。方法 检索PubMed、Embase、Web of Science、万方数据知识服务平台、维普数据库、中国知网6个数据库从建库至2022年12月31日的中英文文献。采用概括性综述的方法,对纳入文献进行归纳整合和定性描述。结果 共纳入12篇文献。纳入文献中增强效力外推性的方法可以归纳为3类：①改善传统RCT设计,增强人群代表性;②将RCT数据与真实世界数据（RWD）结合分析;③根据真实世界患者特征,校准RCT结果。结论 改进RCT设计,增强人群代表性,可提高RCT结果的外推性;将RCT数据与RWD结合分析,可发挥不同来源数据的优势;根据真实世界人群特征校准RCT结果,可预估干预措施在真实世界患者群体中的效果。     

提高医院感染诊断相关病原学送检率的干预措施及效果评价

目的 探讨二级综合医院提高医院感染诊断相关病原学送检率的干预措施及效果。 方法 选取2021—2022年某二级综合医院的所有住院患者中上报的医院感染病例作为研究对象,2021年为干预前组,2022为干预后组,比较实施干预改进措施前后医院感染诊断相关病原学送检率指标。 结果 2021年全年医院感染诊断相关病原学送检率为66.07%,实施干预改进措施后,2022年全年送检率达91.55%,符合规范要求的≥90%,干预前后比较差异有统计学意义(χ²=12.85,P＜0.01)。实施干预改进措施后,医院住院患者抗菌药物使用率,限制级、特殊级抗菌药物使用构成比比较,差异均有统计学意义(均P < 0.05)。 结论 实施有效的干预改进措施可以提高医院感染诊断相关病原学送检率,但质控指标还有待改进和完善之处。     

应用广义估计方程评估儿童肥胖综合干预效果

目的 评估儿童肥胖综合干预项目在控制儿童超重/肥胖及改善儿童肥胖相关知识-态度-行为的效果, 为制定儿童肥胖干预措施提供依据。方法 通过整群随机对照实验设计并采用广义估计方程模型对儿童肥胖相关重复测量数据进行统计分析。结果 实验组965 人, 对照组895 人。实验组的学生从正常体重发展为超重/肥胖的风险是对照组学生的0.824 倍, 即干预措施降低了17.6%成为超重/肥胖的风险（P＝0.031）。此外, 实验组学生肥胖相关知识正确率的均值提高一个单位的可能性是对照组学生的1.044 倍（P＝0.001）;实验组学生肥胖相关正确态度率的均值提高一个单位的可能性是对照组学生的1.023 倍（P＝0.001）;实验组学生肥胖相关行为的均值提高一个单位的可能性是对照组学生的1.522 倍（P＝0.046）。结论 基于知识-态度-行为模式建立的针对儿童肥胖的干预措施可有效降低正常体重儿童发展为超重/肥胖的风险, 并在改善儿童肥胖相关知识-态度-行为方面呈现一定的效果。     

健康素养及运动干预控制糖尿病患者血糖水平的效果评估

目的 评估健康素养及运动干预降低2型糖尿病（T2DM）患者血糖水平的效果。方法 以上海市闵行区和长宁区799名最近一次糖化血红蛋白（HbA1c）≥ 7.5%（或FPG≥10 mmol/L）的T2DM患者为研究对象,采用整群随机分组方法分为健康素养干预组、运动干预组、综合干预组（健康素养＋运动干预）和对照组,每组各约200人。基线调查、身体测量及生化检测完成后,各干预组分别接受为期1年的干预。第3、6和12个月时,对所有患者进行问卷调查随访、身体测量和HbA1c检测。结果 3、6和12个月时患者的总应答率分别为99.4%、98.4%和95.2%。干预满3个月时,综合干预组HbA1c达标率（HbA1c<7.0%）最高,为25.3%,6和12个月时运动干预组达标率最高,分别为25.3%和34.6%。与基线时相比,各干预组HbA1c值在不同随访时段均有下降,以6个月时最明显,综合干预组平均下降0.48%（95% CI：-0.71%～-0.25%）,健康素养干预组下降0.33%（95% CI：-0.55%～-0.11%）,运动干预组下降0.70%（95% CI：-0.92%～-0.48%）,而对照组略升高0.03%（95% CI：-0.19%～0.25%）,差异有统计学意义（P<0.001）。以对照组为参比,调整可能的混杂因素后,3个月时综合干预组HbA1c效果最佳（β=-0.47,95% CI：-0.73～-0.20）;随后运动干预的效果逐渐凸现,6和12个月时HbA1c降幅分别达-0.73（95% CI：-0.98～-0.47）和-0.75（95% CI：-1.05～-0.45）。分层分析显示,在健康素养较低的患者中3种干预手段均有效,而在算术能力高者中运动干预更为有效。结论 健康素养及运动干预均可有效降低上海市社区T2DM患者的HbA1c水平,这将有助于降低患者并发症的发生和早死风险。     

杭州市社区医疗机构职工开展生活方式健康促进的效果评价

目的 了解杭州市社区医疗机构医务人员健康促进生活方式的干预现况,评估干预措施效果.方法 采用问卷方式调查杭州市3个代表性城区(下城区、拱墅区和西湖区)社区医务人员,内容包括职工日常饮食习惯、生活方式,工作场所开展吸烟、饮食和体力活动干预措施及同事间健康促进影响情况.采用x2检验及logistic回归法评估工作场所健康促进活动的干预效果.结果 工作场所吸烟干预措施中,讲座、戒烟规定及个体戒烟咨询均无显著效果；在饮食干预中参加平衡膳食、合理营养讲座课程与经常吃蔬菜、水果间存在关联,其经常吃蔬菜、水果的频率是未参与者的1.74倍(OR=1.74,95％CI:1.22～2.47)；体力活动干预措施中,同伴效应效果显著,和同事-起参与体力活动的职工进行有规律的高、中度体力活动频率是非干预措施组的1.62倍(OR=1.62,95％CI:1.15～2.29).干预措施的联合效应分析表明,无论是饮食干预还是体力活动干预,多干预措施联合作用可显著提高职工健康饮食和规律运动的行为习惯.结论 在工作场所开展饮食和体力活动干预,可显著改进职工的健康促进行为.     

老年人高温热浪健康教育干预效果混合效应模型分析

目的 评价对老年人开展预防高温热浪健康教育的效果。方法 采用类随机对照试验，从广州市番禺区市桥街28个社区随机抽取2个社区，然后将抽取的社区随机分为对照组和干预组，以≥60岁常住居民为研究对象。干预组采用8种健康教育方式在夏季进行3个月热浪干预，对照组不采取任何干预措施。干预前后两组均采用相同问卷收集信息进行效果评价。采用混合效应模型进行数据分析。结果 控制家庭人均月收入、安装空调、饮酒、基础疾病史和时间效应后，干预组热浪风险感知平均得分升高1.62分，对照组升高0.51分，两组差异有统计学意义（t=2.76，P=0.006）；干预措施的效果也体现在两组因慢性病入院的差异上，干预组最近3个月因慢性病加重去过医院住院或就诊由干预前32.39%（46/142）下降至干预后28.87%（41/142），对照组由干预前26.28%（41/156）上升至干预后的36.53%（57/156）；热浪知识得分、热浪适应性行为得分两组差异无统计学意义。结论 健康教育能增强老年人对热浪的健康风险感知，可有效降低老年人群在热浪期间因慢性病加重而引起的就诊住院。     

我国职业场所高血压综合干预效果评价

目的 评价在职业场所开展高血压综合干预的效果。方法 采用整群随机对照设计,在全国选取20个分中心,每个分中心选取条件相匹配的2~4家职业场所,随机分为管理组和常规组。管理组采取职业场所心血管病一级预防和高血压患者规范化管理的综合干预策略,每位患者至少管理2年;常规组沿用现行管理办法,收集基线及2年时的资料。本研究对职业场所中入选的30家国企单位（管理组20家,常规组10家）高血压患者资料进行分析。主要指标为高血压控制率,干预效果为管理组差值（率/均值）-常规组差值（率/均值）。结果 共有2 622名患者完成2年随访,其中,管理组2 055人,常规组567人。实施综合干预后,与常规组相比,管理组患者SBP和DBP的干预效果分别为-7.5 mmHg和-3.9 mmHg（P<0.05）,BMI为-0.4 kg/m²（P<0.05）,规律运动率和饮酒率分别为36.4%和-14.0%（P<0.05）,而吸烟率为-6.1%（P>0.05）,血压控制率的干预效果为25.0%（P<0.05）。亚组分析显示高中文化程度（27.6%）、白领（41.9%）、属于医疗机构已分离企业（41.9%）的患者控制率干预效果更好（P<0.05）。结论 在职业场所开展高血压综合干预可显著改善高血压控制状况。     

宁波市男男性行为人群艾滋病干预成本效果预测

目的 预测并比较宁波市MSM在不同艾滋病干预覆盖面下,投入成本与健康效果,为相关领域的资源配置和决策提供参考依据。方法 以MSM为目标人群,应用Optima HIV软件设计数据收集工具,测算不同干预覆盖水平下的艾滋病相关结局指标,并分析相应的经费预算。结果 2020年宁波市MSM规模估计数为19 584人,如果维持基线2020年干预服务水平,2021-2030年宁波市MSM中存活的HIV感染者数、HIV新发感染数和HIV相关死亡例数均呈上升趋势。如果在2020年基线的干预覆盖率水平上扩增至3.0倍,经费投入为基线的2.4倍,估计2021-2030年,累计可减少7.9%的HIV新发感染和1.7%的死亡;干预覆盖率继续扩增,HIV新发感染人数不再减少。结论 扩大基线2020年宁波MSM艾滋病干预覆盖和增加资金投入,能够降低HIV相关死亡人数和新发感染人数,但存在干预效果的饱和点。为获得较好的艾滋病相关结局指标,有关研究者和政策决策者需要探寻更加有效的干预措施和组合。     

简短戒烟干预研究的Meta分析

目的 采用Meta分析评价简短戒烟干预的有效性.方法 计算机检索2000年1月至2014年9月中外生物医学数据库(The Cochrane Library、Medline、EMbase、中文期刊全文数据库、万方电子期刊数据库、维普中文科技期刊数据库和中国生物医学文献数据库)中有关简短戒烟干预随机对照试验,采用Revman 5.1软件进行Meta分析.结果 最终纳入9篇文献,随机效应模型合并RR值(95%CI)=1.57(1.01～2.44) .与未进行干预的吸烟者相比,接受了简短戒烟干预的吸烟者,其戒烟的可能性提高了57%.研究对象为孕妇和就诊患者,干预时间≤10 min的亚组更易戒烟,但各亚组分析结果之间的差异均无统计学意义.结论 简短戒烟干预可提高戒烟率,但该结论尚需纳入更多高质量大样本的随机对照试验加以证实.     

健康管理方案对超重/肥胖人群的减肥效果分析

目的 探索健康管理方案对超重/肥胖人群的减肥效果,为制订安全有效的减肥方案提供依据。方法 通过志愿招募的方式于2013年9月1日至10月15日招募在北京居住满1年、年龄在22~55岁之间、BMI≥24 kg/m²且无器质性病变的志愿者738人,将其随机分为一般管理组和健康管理组,进行为期6个月的减肥干预;在基线和干预6个月时测量身高、体重、腰围和体成分指标,通过比较干预前、后各指标的差异评价健康管理方案的减肥效果。结果 共有618名研究对象完成了随访,其中健康管理组297人,一般管理组321人。与干预前相比,干预后健康管理组和一般管理组的体重和体脂率均有所下降,干预前后差异有统计学意义(P<0.001),健康管理组的体重下降量(2.19 kg)和体脂率下降量(2.19%)均高于一般管理组的0.97 kg和1.28%,差异有统计学意义(P<0.001)。健康管理组的减重有效率(24.2%)和减脂肪有效率(52.5%)高于一般管理组的11.8%和34.3%,差异有统计学意义(P<0.001)。结论 健康管理方案能够有效降低超重/肥胖者的体重和体脂率。     

Replication of Randomized,Controlled Trials Using Real-World Data: What Could Go Wrong?

With the growing interest in using real-world evidence (RWE) for regulatory purposes, researchers and policy makers are considering how best to assess the credibility of RWE. Because the randomized controlled trial (RCT) has long been regarded as the gold standard for high-quality research, one approach being pursued is to see to what extent findings from RCTs can be replicated based on analyses of nonrandomized real-world data (RWD). If findings are congruent, the reasoning goes, this would bolster confidence in the underlying RWD sources and validity of the RWE generated. But it is well known that medical interventions perform differently in experimental clinical trials versus real-world clinical practice, reflecting a phenomenon known as the “efficacy-effectiveness gap.” So even with the highest-quality RWD sources and strongest analytic methods, we can and should expect to observe discrepancies in findings between RCTs and RWE. This calls into question the objectives of RCT replication efforts and makes clear that impugning RWD sources and analytic methods for failing to align with RCT findings is inappropriate and, worse, potentially harmful to the growing acceptance of RWE in stakeholder decision making.     

真实世界证据与随机对照试验：RCT DUPLICATE项目启动、实施、进展解读与启示（一）

近些年,医疗产品监管机构开始重新审视真实世界证据（RWE）对监管决策的潜在价值。RWE能否代替金标准随机对照试验（RCT）产生的证据尚不确定。哈佛大学研究团队于2018年发起了RCT DUPLICATE项目,旨在利用医疗索赔数据库模拟30个RCT,以探索效力-效果差距的量化方法并解释其潜在来源,增强RWE的可信度。本文回顾了RCT DUPLICATE项目的产生背景,重点介绍RCT DUPLICATE项目的研究目的、研究设计和实施流程,以期帮助国内学者更好地理解RWE的适用范围和应用价值。     

Randomized cohort trial was shown to be feasible for evaluating treatments in low back pain

ObjectiveTo investigate the feasibility of conducting a cohort, factorial randomized controlled trial (RCT) in the treatment of patients with low back pain (LBP).Study Design and SettingPragmatic feasibility factorial RCT nested within an observational cohort study in two general practices in York, United Kingdom.ResultsEight hundred forty-five patients aged between 18 and 65 years who had consulted their general practitioner about LBP within the preceding 12 months were mailed an invitation to participate in a cohort trial, with the possibility of later joining a treatment RCT. One hundred twenty-four patients consented to participate in the cohort and treatment trial, and one consented only to the cohort only. Ultimately, 59 patients were randomized into the nested RCT. Outcomes included recruitment, acceptability, and attrition rates as measures of the feasibility of the design and Roland Morris Disability Questionnaire. No statistically significant differences in outcome between treatment groups and usual care were found.ConclusionsThe design was feasible for the evaluation of different back pain treatments. We found zero attrition after randomization and showed that for a remitting relapsing condition, the design allows us to recruit initially ineligible patients from the cohort. Additional statistical analysis using regression discontinuity can also be used with this design.     

临床真实世界研究中的实验性研究设计

真实世界研究作为解释性随机对照试验在医疗实践中评价干预措施效果的进一步验证和补充已成为医疗卫生领域关注的焦点。但是也存在错误将真实世界研究等同于观察性研究,认为真实世界研究不能实施人为干预,更不能采取随机化。实际上,真实世界研究的基本设计既可以是观察性的,也可以是实验性的。其中真实世界研究的实验性研究设计主要是指实用性随机对照试验和基于注册登记研究的随机对照试验,也可采用非随机对照、自适应设计等其他研究设计方案。     

Rotavirus vaccine effectiveness in low-income settings: An evaluation of the test-negative design

BackgroundThe test-negative design (TND), an epidemiologic method currently used to measure rotavirus vaccine (RV) effectiveness, compares the vaccination status of rotavirus-positive cases and rotavirus-negative controls meeting a pre-defined case definition for acute gastroenteritis. Despite the use of this study design in low-income settings, the TND has not been evaluated to measure rotavirus vaccine effectiveness.MethodsThis study builds upon prior methods to evaluate the use of the TND for influenza vaccine using a randomized controlled clinical trial database. Test-negative vaccine effectiveness (VE-TND) estimates were derived from three large randomized placebo-controlled trials (RCTs) of monovalent (RV1) and pentavalent (RV5) rotavirus vaccines in sub-Saharan Africa and Asia. Derived VE-TND estimates were compared to the original RCT vaccine efficacy estimates (VE-RCTs). The core assumption of the TND (i.e., rotavirus vaccine has no effect on rotavirus-negative diarrhea) was also assessed.ResultsTND vaccine effectiveness estimates were nearly equivalent to original RCT vaccine efficacy estimates. Neither RV had a substantial effect on rotavirus-negative diarrhea.ConclusionsThis study supports the TND as an appropriate epidemiologic study design to measure rotavirus vaccine effectiveness in low-income settings.     

真实世界研究在医疗器械临床评价中的应用

该文通过阐明真实世界研究(RWS)的相关概念,以及分析RWS与随机对照试验(RCT)的区别及联系、医疗器械临床评价的发展趋势,并结合RWS在医疗器械临床评价中的发展与应用,剖析将真实世界数据(RWD)应用于医疗器械临床评价中的各类情形,同时结合实际指出RWS在开展过程中存在的问题,探讨如何利用RWS在医疗器械临床评价中...     

Enclosing a pen reduced time to response to questionnaire mailings

ObjectivesTo assess the effectiveness of including a pen in postal questionnaires on response rate, necessity of reminders, time to response, and completeness of response to the primary outcome question (POQ).Study Design and SettingA two-arm randomized controlled trial (RCT) embedded within the screening of older women for prevention of fracture trial (SCOOP). Women, aged 70–75 years, were randomized to receive a pen with their questionnaire (n = 3,826) or to receive the questionnaire alone (n = 3,829). The results were combined with another embedded RCT in a meta-analysis.ResultsA response rate of 92.4% was observed in the pen group compared with 91.3% in the control group (odds ratio [OR] = 1.16; 95% confidence interval [CI]: 0.98, 1.37; P = 0.08). There was a difference in reminders required (OR = 0.88; 95% CI: 0.79, 0.98; P = 0.02), time to response (hazard ratio = 1.06; 95% CI: 1.01, 1.11; P = 0.01) and some difference in the completeness of response to the POQ (OR = 1.18; 95% CI: 1.00, 1.39; P = 0.05). The pooled OR from the meta-analysis for response rate was 1.21 (95% CI: 1.05, 1.39; P = 0.01).ConclusionInclusion of a pen with postal questionnaires potentially has a positive impact on response rates and the number of reminders required. There may be some reduction in time to response. Studies of different participant groups are needed to test the effectiveness over more diverse populations.     

Use of surveillance data to calculate the sample size and the statistical power of randomized clinical trials testing Staphylococcus aureus vaccine efficacy in orthopedic surgery

BackgroundPatients undergoing primary total hip arthroplasty (THA) would be a worthy population for anti-staphylococcal vaccines. The objective is to assess sample size for significant vaccine efficacy (VE) in a randomized clinical trial (RCT).MethodsData from a surveillance network of surgical site infection in France between 2008 and 2011 were used. The outcome was S. aureus SSI (SASSI) within 30 days after surgery. Statistical power was estimated by simulations repeated for theoretical VE ranging from 20% to 100% and for sample sizes from 250 to 8000 individuals per arm.Results18,688 patients undergoing THA were included; 66 (0.35%) SASSI occurred. For a 1% SASSI rate, the sample size would be at least 1316 patients per arm to detect significant VE of 80% with 80% power.ConclusionSimulations with real-life data from surveillance of hospital acquired infections allow estimation of power for RCT and sample size to reach the required power.     

Selective exclusion of treatment arms in multi-arm randomized clinical trials

In this paper we discuss a design for multi-arm randomized clinical trials (RCTs) in which clinicians and their patients can selectively exclude one of the randomized treatment arms. This approach has the advantage that it should expedite protocol development, and allow easier and faster recruitment of patients into the trial. However, to preserve the randomized nature of treatment comparisons, not all recruited patients can be included in all treatment comparisons. This dictates that treatment arms are compared in a pairwise fashion, and that the numbers of patients included in different treatment comparisons may not be equal. The total trial size of a multi-arm RCT that allowed selective exclusion of arms would be greater than the size of an equivalent standard multi-arm RCT. However, the duration of time taken to recruit the study would be reduced. The implications for the design, monitoring and analysis of such RCTs are discussed.     

Physical interventions for the treatment of trauma and stressor-related disorders: A comprehensive systematic review

BackgroundCognitive behavioral therapies for posttraumatic stress disorder (PTSD) are evidence-based and effective for many. However, the reach and impact of these interventions are limited. Physical interventions hold potential to bridge a gap in the unmet treatment of trauma and stressor-related disorders.MethodThis systematic review examined 84 studies from four decades of research on physical interventions for trauma and stressor-related disorders to: 1) describe the state of the field and 2) summarize the best available evidence. Reviewed studies were described in terms of measured sample characteristics and assessed outcomes. Treatment effect patterns were analyzed by intervention content and study design.ResultsThe majority of studies (65.9%) reported statistically significant reductions in posttraumatic stress symptoms; 40.9% used a randomized controlled trial (RCT) design. Among RCTs, one performed rigorous, statistically powered analyses in an intention-to-treat sample.LimitationsHigh variability in reporting strategies among reviewed studies precludes analysis of variables such as intervention length, frequency, and dropout.ConclusionPreliminary evidence for the efficacy of physical interventions for trauma and stressor-related disorders is promising. Larger scale RCTs powered and designed to identify mediators and moderators of these interventions are warranted.