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1、系统综述和Meta分析概述一、系统综述和META分析的基本概念系统评价与Meta分析1980s 综述本身就是一种科学研究Light RJ & Pillemer DB. Summing up：The Science of reviewing research. Cambridge, MA: Harvard Univ Press. 1984Oxman AD & Guyatt Gh. Guidelines for reading literature reviews. CMAJ, 1988;138:697-703综述的目的：综合研究的证据，得到一个准确的结论系统评价与Meta分析1976： Gene
2、 Glass提出meta分析概念Meta分析：合成结果，减少随机误差1993.7：BMJ：Systematic review=Systematic review=科学综述科学综述+meta+meta分析分析Meta分析其实质是一个统计学方法系统误差随机误差Meta分析A meta-analysis is a two-stage process.提取单个研究的数据，并估计其进行点估计和可信区间.决定是否合适将结果汇总，若是，计算其汇总值MetaMeta分析不仅是简单将单个研究的数据累加系统综述对某一具体的临床问题系统、全面地收集所有已发表或未发表的相关的临床研究文章用统一、科学的评价标准筛选出合
3、格的研究质量评价应用统计学方法定量综合/描述性方法进行定性综合得出可靠的结论随着新的临床研究结果的出现及时作出更新系统综述的特征：最佳证据规范的临床问题全面、完整的资料对原始研究的质量评价，纳入合格的研究统计学综合(meta-分析)/ 描述性综合(偏倚)进行敏感性分析和亚组分析规范的评价报告(明确的方法学可允许重复)随着新的研究结果出现进行及时更新综述综述MetaMeta分析分析SRFrom: Critical Appraisal Skills Programme (CASP), Oxford.A systematic review may have a statistical combina
4、tion of studies (a meta-analysis) but it does not have to系统综述传统综述和SR比较l研究问题：涉及范围泛 常集中于某一问题l文献来源：不全面 明确，常为多渠道l检索方法：常未说明 有明确检索策略 l文献选择：有潜在偏倚 有明确入选/排除标准l文献评价：方法不统一 有严格评价方法l结果合成：定性 定量/定性l结论推断：有时遵循研究依据 大多遵循研究依据l结果更新：不定期更新 依据新试验定期更新 传统综述 SR为什么进行系统评价/meta分析信息太多、医生太忙、时间太少减少偏倚和随机误差提高统计效度探索研究结果的不一致性临床决策依据为以后的
5、知识更新提供一个系统简易的方法为临床实践提供一个好的证据临床医生需要获得明确的信息系统综述的类型定量SR/定性SR累积性SRIPD/APDMethodology reviewOverview of reviews干预研究SR诊断试验准确性SRNetwork meta分析频率meta分析生存资料meta分析二、系统综述的基本步骤介绍系统综述的基本步骤介绍系统综述的基本步骤介绍SR步骤（2008CochraneSR手册）建立一个规范化的问题制定纳入研究的标准检索研究筛选研究和收集数据研究质量的严格评阅分析数据并在可能的情况下进行meta-分析解决报告的偏倚陈述结果并制作结果摘要表格解释结果，得出结
6、论只有当研究质量足够好Cochrane的系统综述联系相应的评价小组注册系统综述的题目准备研究计划书由编辑组对其进行审稿将研究计划书发表在Cochrane 图书馆完成系统综述全文并接受评审系统综述在Cochrane 图书馆发表定期更新注册申请北京EBM201217注册申请例子Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birthRoberts D, Dalziel S Cochrane Database of Systematic Reviews 200
7、6 Issue 3. Copyright 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 系统综述问题提出？Respiratory distress syndrome (RDS) is a serious complication of preterm birth and the primary cause of early neonatal mortality and disability. Effects of antenatal corticosteroids for preterm birthP
8、ICO_S始终贯穿SRSR1：建立一个规范化问题PICO的含义临床问题 vs 基础问题PICO的概念延伸PICO_S 始终始终贯穿贯穿SRlPopulationlInterventionlComparatorlOutcomeslStudy design提出研究问题提出临床问题PICO原则P population/patients 人群/病人群关心的是哪一类病人群或对象I intervention/exposure 干预/暴露 我们所感兴趣的治疗策略，诊断试验或暴露是什么？如一种药物、食物，外科手术方式，诊断试验或暴露于一种化学？提出临床问题PICO原则C comparison or contr
9、ol 比较物或对照 我们感兴趣的干预措施相比较的对照物、处理策略、试验或暴露是什么？O outcome 结果 病人经干预处理后得到的结果是什么？1) “1) “焦点焦点” ” 问题问题: :The review addresses whether corticosteroids are more effective than placebo or no corticosteroids in reducing the risk of respiratory distress syndrome, neonatal death, intraventricular haemorrhage, necro
10、tising enterocolitis, chronic lung disease in survivors of neonatal intensive care, the use of surfactant in the newborn, the cost of neonatal care, and the duration of neonatal hospital care. 定义了干预定义了对象定义了结果因素过程是“问题驱策”而不是“资料驱策”系统综述定义了对照SR2：纳入标准和排除标准研究对象（Participants）干预措施（Interventions）结果（Outcome）:
11、Primary Outcome研究类型（根据研究问题选择，干预研究：随机对照研究RCT）SR3：检索研究全面系统地检索检索的策略：PICOSR4：筛选研究和提取信息（一）评价研究合格性，两位以上的研究者独立提取数据。区分 study 与 report数据收集表的设计要符合研究目标，正式应用前需要试用报道的数据可能格式不同，需要转换成适合meta分析的格式.SR4：筛选研究和提取信息（一）SourceStudy ID (created by review author).Report ID (created by review author).Review author ID (created
12、by review author).Citation and contact details.EligibilityConfirm eligibility for review.Reason for exclusion.MethodsStudy design.Total study duration.Sequence generation*.Allocation sequence concealment*.Blinding*.Other concerns about bias*.ParticipantsTotal number.Setting.Diagnostic criteria.Age.S
13、ex.Country.Co-morbidity.Socio-demographics.Ethnicity.Date of study.InterventionsTotal number of intervention groups.For each intervention and comparison group of interest:Specific intervention.Intervention details (sufficient for replication, if feasible).Integrity of intervention.OutcomesOutcomes a
14、nd time points (i) collected; (ii) reported*.For each outcome of interest:Outcome definition (with diagnostic criteria if relevant).Unit of measurement (if relevant).For scales: upper and lower limits, and whether high or low score is good.ResultsNumber of participants allocated to each intervention
15、 group.For each outcome of interest:Sample size.Missing participants*.Summary data for each intervention group (e.g. 22 table for dichotomous data; means and SDs for continuous data).Estimate of effect with confidence interval; P value.Subgroup analyses.MiscellaneousFunding source.Key conclusions of
16、 the study authors.Miscellaneous comments from the study authors.References to other relevant studies.Correspondence required.Miscellaneous comments by the review authors.SR4：筛选研究和提取信息（一）SR5：文献评阅要用批评的眼光看结果A研究结果是否真实？（真实性，validity）B研究结果是什么？（可靠性，reliability） C研究结果是否对我的患者有帮助？（应用性，applicability）CochraneH
17、andbook标准随机分配方法隐蔽分组盲法结果数据的完整性选择性报告研究其他偏倚来源Riskofbias（区分实施与报告）sequence generation (selection bias)allocation sequence concealment (selection bias)blinding of participants and personnel (performance bias)blinding of outcome assessment (detection bias)incomplete outcome data (attrition bias)selective o
18、utcome reporting (reporting bias)other potential sources of bias.SR6：数据分析两分变量 (e.g.死/活)2X2 tablesRR (log), OR (log), RD (sensitive to baseline differences)连续变量 (e.g.胆固醇水平)Mean differencesStandardized mean differences (if different scales)Mean difference for each study divided by the within sudy vari
19、ance (SD) for that scaleResponse ratios相关系数RevMan5RevMan5STATASTATAM-HOR/RR/ARPeto倒方差法计量均数发表偏倚漏斗图BeggsXEggersX剪补法XLAbbe图X森林图异质性分析I2X2meta回归X累积metaX合并效应模型随机效应固定效应双效应X柏建岭，田金徽，2010SR6：数据分析数据分析二分类变量从各研究中提取出四格表将数据输入RevMan软件对OR、RR值进行Meta分析特殊情况下对RD进行Meta分析使用NNT时，需要同时提供对照组的风险范围（range of baseline risks）森林图的意
20、义数据分析连续性变量从各研究中提取出各组的研究例数、平均值和标准差。正态分布数据进行Meta分析是安全的，偏态分布数据需特殊处理。若各研究使用统一的单位或量表，则对平均值差进行Meta分析。若各研究的单位或量表不同，则对标准平均值差进行Meta分析。资料数据分析异质性分析（一）异质性：各研究结果之间的差异，包括：多样性（Diversity）: 各研究之间真实的差异，如因研究对象，干预措施、剂量等不同引起的差异偏倚（Bias）：如因研究设计、质量控制等引起的差异数据分析异质性分析（二）异质性检验统计检验: 2检验，Q值越大，异质性越大量化异质性：I2值，I值越大，异质性越大Q-d.f QI2 =
21、资料异质性较大数据分析异质性分析（三）异质性较大时检查提取的数据: 更换统计方法：异质性不明显时：考虑固定效应模型（fixed effect model）异质性明显时：考虑不做Meta分析，或随机效应模型（random-effect model）寻找异质性原因：亚组分析、meta回归 等数据分析异质性分析（四）固定效应模型假定所有研究的治疗效果均相同各研究间的不同结果仅由随机误差引起随机效应模型各研究之间的治疗效果均不同各研究之间的治疗效果服从一定的分布（一般为正态分布）不同假设模型的选择固定效应模型 Mantel-Haenszel法 比(OR、RR) Peto法 比数比(OR) Genera
22、l Variance-Based 比、差值、回归系数随机效应模型 DerSimonian-Laird 比和差值模型假设 统计方法 效果测量形式SR7：报告的偏倚EntryJudgementSupport for judgementRandom sequence generation (selection bias)Low risk.Quote: “patients were randomly allocated.”Comment: Probably done, since earlier reports from the same investigators clearly describe
23、use of random sequences (Cartwright 1980).Allocation concealment (selection bias)High risk.Quote: “.using a table of random numbers.”Comment: Probably not done.Blinding of participants and personnel (performance bias)Low risk.Quote: “double blind, double dummy”; “High and low dose tablets or capsule
24、s were indistinguishable in all aspects of their outward appearance. For each drug an identically matched placebo was available (the success of blinding was evaluated by examining the drugs before distribution).”Comment: Probably done.Blinding of outcome assessment (detection bias) (patient-reported
25、 outcomes) Low risk.Quote: “double blind”.Comment: Probably done.Blinding of outcome assessment (detection bias) (Mortality) Low risk.Obtained from medical records; review authors do not believe this will introduce bias.Incomplete outcome data addressed (attrition bias) (Short-term outcomes (2-6 wee
26、ks) High risk.4 weeks: 17/110 missing from intervention group (9 due to lack of efficacy); 7/113 missing from control group (2 due to lack of efficacy).Incomplete outcome data addressed (attrition bias) (Longer-term outcomes (6 weeks) High risk.12 weeks: 31/110 missing from intervention group; 18/11
27、3 missing from control group. Reasons differ across groups.Selective reporting (reporting bias)High risk.Three rating scales for cognition listed in Methods, but only one (with statistically significant results) is reported. SR7：报告的偏倚SR7：报告的偏倚Risk of biasInterpretationWithin a studyAcross studiesLow
28、 risk of bias.Plausible bias unlikely to seriously alter the results.Low risk of bias for all key domains.Most information is from studies at low risk of bias.Unclear risk of bias.Plausible bias that raises some doubt about the results.Unclear risk of bias for one or more key domains.Most informatio
29、n is from studies at low or unclear risk of bias.High risk of bias.Plausible bias that seriously weakens confidence in the results.High risk of bias for one or more key domains.The proportion of information from studies at high risk of bias is sufficient to affect the interpretation of results.Possi
30、bleapproachforsummaryassessmentsoftheriskofbiasforeachimportantoutcome(acrossdomains)withinandacrossstudiesSR7：报告的偏倚漏斗图Funnel plotSR8:陈述结果森林图结果总结表SR目的是为卫生决策服务，所以同时要用科普语言.结果总结表Compression stockings compared with no compression stockings for people taking long flights Patients or population: Anyone ta
31、king a long flight (lasting more than 6 hours) Settings: International air travelIntervention: Compression stockings1Comparison: Without stockingsOutcomes Illustrative comparative risks* (95% CI) Relative effect(95% CI) Number of participants(studies) Quality of theevidence(GRADE) Comments Assumed r
32、iskCorresponding riskWithout stockings With stockings Symptomatic deep vein thrombosis (DVT) See comment See comment Not estimable 2821(9 studies) See comment 0 participants developed symptomatic DVT in these studies. Symptom-less deep vein thrombosisLow risk population 2 RR 0.10(0.04 to 0.26) 2637(
33、9 studies) + High 10 per 1000 1 per 1000 (0 to 3) High risk population 2 30 per 1000 3 per 1000 (1 to 8) Superficial vein thrombosis 13 per 10006 per 1000 (2 to 15) RR 0.45(0.18 to 1.13) 1804(8 studies) +OModerate3 OedemaPost-flight values measured on a scale from 0, no oedema, to 10, maximum oedema
34、. The mean oedema score ranged across control groups from 6 to 9. The mean oedema score in the intervention groups was on average4.7 lower (95% CI 4.9 to 4.5). 1246(6 studies) +OO Low4 Pulmonary embolusSee comment See comment Not estimable 2821(9 studies) See comment 0 participants developed pulmona
35、ry embolus in these studies. 5DeathSee comment See comment Not estimable 2821(9 studies) See comment 0 participants died in these studies.Adverse effects See comment See comment Not estimable 1182(4 studies) See comment The tolerability of the stockings was described as very good with no complaints
36、of side effects in 4 studies. 6 *The basis for the assumed risk is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the intervention group and the relative effect of the intervention (and its 95% CI).CI: Confidence interval; RR: Risk rat
37、io GRADE: GRADE Working Group grades of evidence (see explanations) SR9：解释结果，得出结论1.考虑研究的局限性：如发表偏倚2.考虑证据强度效应大小，变异比较其它综述3.考虑可应用性外延性：结果还适合于哪些患者治疗描述：若应用这个治疗，需详细描述4.考虑benefit/harm5.考虑经济学评价可支付性相对于其它治疗6.考虑进一步研究是否需要进一步研究来明确答案得出结论综述的结果对临床实践的影响综述的结果对进一步研究的影响三、国内系统综述常见的问题国内发表的系统综述常见的问题临床问题的提出干预措施：定义不准确结果因素：main, primary, secondary国内发表的系统综述常见的问题操作层面：研究前期缺乏基线调查对综述方法学的描述不够检索不全面，有的系统评价仅检索中文的文献研究选择的方法不能避免选择性偏倚对纳入与排除的研究描述随意缺乏对原始研究的质量评价，大多研究质量低下资料提取和分析未按意向性治疗分析原理国内发表的系统综述常见的问题缺乏亚组分析和敏感性分析对异质性处理太过简单，缺乏分析不重视纳入研究的可能存在的偏倚结论轻率，没有结合临床
