循证医学与系统评价

四川大学华西口腔医院院史宗道

循证医学的概念

循证医学是指在疾病的诊治过程中，将个人的临床经验与现有的最好临床科学证据结合起来进行综合考虑，为病员作出最佳诊治决策。个人的临床经验是指临床医师通过临床实践获得的精湛学识和敏锐的判断能力；现有的最好证据是指从临床相关的研究、基础医学研究、特别是以病人为中心的临床研究中产生的科学结论。

有必要学习循证医学吗？ 层出不穷的临床科学证据，只要为临床医务工作者所熟知和应用，才能对疾病的诊治产生重大影响 临床实践的质量与熟知最新的知识和信息密切相关，随着随机对照试验的增多，我们面临的问题不再是缺乏新的科学证据，而是已有许多最好证据可能被应用于临床第一线。形势迫使临床医生必须不断学习并更新知识。

有必要学习 循证医学吗？

尽管临床实践每天都需要新的信息，却常常难以及时获得

据估计临床一线医师每半天会碰到大约 16 次因疾病诊治问题需要查寻相应信息 , 但常因三方面的原因而难以及时获得最新信息：没有时间查寻；教科书知识过时；手边杂志的种类数量有限，难以查到急需的必要信息。阅读杂志是获取最新信息的首要途径，但全世界每年约有 200 万篇有关生物医学的文章发表在 4万种医学杂志上，一个繁忙的临床医师有可能随时在信息的海洋中找寻自己所需要的最可靠的临床研究证据吗？

繁忙的医生读书时间非常有限据估计一个内科医师需要每天不间断地阅读 19篇本专业的杂志文章，才能基本上掌握本专业的新证据和新进展。过去在一周内英国内科临床医师阅读医学文献时间的调查，发现其阅读时间中位数不超过 90分钟，高年资住院医师以上的各级医师中，有15 ％～ 40 ％在过去一周内未阅读过任何医学文献。这说明繁忙的医生读书的时间非常有限。

现有的知识和临床技能将逐渐过时

传统的医学教育方式使人们掌握最新知识的水平与从医学院毕业的年限之间呈显著负相关关系。如果不注意获取临床医学研究的新证据，我们的临床技能将逐渐减退，从而影响医疗质量。

随时更新知识

自学以问题为基础的循证医学课程，掌握实践循证医学的技巧和方法；查寻和应用他人进行循证医学研究的结果，一是选择研究方法科学、结论准确且有临床实用价值的文章，以结构摘要形式的二次出版，并附有专家评述。这类文章只占所有临床医学文献的 2 ％，

系统评价systematic review and its appraisal

系统评价systematic review

它是针对同一临床问题查寻收集所有随机对照试验结果，进行评价和分析总结而成，为疾病防治提供高质量的证据。这使忙碌的临床医务工作者能在短时间内查到科学、可靠的证据信息

Why are systematic reviews important?

Systematic reviews of randomised controlled trials are considered the best level of evidence for answering questions about the effectiveness of healthcare interventions.In addition to the reduction in bias, one of the many advantages of systematic reviews is that they enable us to reduce the ever-increasing torrent of both published and unpublished research literature into manageable portions

Advantage of meta-analysis

Pooling of data from individual studies leads to an increase in sample size, and an increase in power

which is particularly important when the size of effect is small or there is a relatively low event rate.

The increase in sample size not only means an increase in power, but also an increase in the precision in the estimate of effect

Where to find systematic reviews?

The best solution is to search the Cochrane Library, which contains two databases dedicated to helping you locate the systematic review you need. The Cochrane Database of Systematic Reviews (CDSR) includes full text systematic reviews that have been completed to the exacting standards of the Cochrane Collaboration, and protocols of reviews that are underway. The Database of Abstracts of Reviews of Effectiveness (DARE) is a compilation of abstracts of systematic reviews that are published in paper journals, along with helpful commentary on their quality.

Critically appraising systematic reviews

1. What are the review’s objectives? To focus on well-defined questions, stating the

populations, intervention/control groups, and outcomes to be included.2. How comprehensive was the search strategy?

To search for all the literature relevant to the question. Published and unpublished literature should be sought, any restrictions regarding language of publication should be stated and justified, as should the time period covered by the search. Ideally a systematic review needs to be up to date, incorporating all the recent literature.

Appraisal of SW

3. What were the inclusion/exclusion criteria? The criteria for selecting or rejecting studies should be

clearly stated and appropriate. The process* by which articles are assessed for relevance should also be recorded. 4. How was the validity of the primary studies assessed?

The process* by which validity assessment was undertaken and the criteria used to assess the quality of the primary studies should be clear. It should also be apparent how the results of the validity assessment are used within the review’s data synthesis.

Appraisal of SW

5. How were data extracted from the primary studies?

The process* by which data was extracted from the primary studies should be transparent. 6. Are the characteristics of the included studies clearly displayed?

A table illustrating the study characteristics of each included primary study should be presented.

Appraisal of SW

7. Does the review examine differences/similarities between

the included studies and their results? Heterogeneity between studies should be explored and the

reasons for any variations discussed. Heterogeneity can be explored statistically, graphically or through a narrative.8. Was the synthesis of the data carried out appropriately?

Was data pooled qualitatively or statistically? If statistical pooling (meta-analysis) was used, was it used appropriately? 9. Were the results interpreted appropriately?

Any conclusions, implications for research or practice should follow on logically from the results.

How to produce a Systematic

Review?

How is a systematic review conducted?

First step: to specify a tight question. population (group to whom the intervention will apply), intervention (the therapy, treatment or preventive policy to be carried out),comparison (what will the intervention be compared against – it could be a common alternative intervention, a placebo or no intervention) and outcomes (what do we wish to measure at the end, what is important to us and to consumers?).

A clear protocol

Describing the background to the work, hypothesis to be tested and methodology to be used Allowing peer (and often consumer) review of the question to be asked, and methods to be used, so that these can be improved. It also limits vague inclusion criteria that may preferentially allow in studies with ‘good’ results, and data dredging where lots of analyses are tried out, but only those with significant results reported.

Clear inclusion and exclusion criteria

Besides the population, intervention, comparison and outcomes that should be represented in the inclusion and exclusion criteria, it is important to specify the type of studies that will offer the least biased evidence for the review-- RCTIdeally the process of deciding on inclusion of studies is performed independently by at least two people, on a form specifically designed for the review, sometimes blinded to authors and results.

Transparent inclusive search strategy

To include all the published and preferably also unpublished data that exist.Ideally several types of searching are adopted, so that if one strategy misses a relevant study it may be picked up through another searching method. Search strategies generally include several of the following: structured searches of several electronic databases (including the Cochrane Library) Checking through the reference lists of included studies and relevant reviewsLetters to relevant pharmaceutical companies and experts in the field asking about unpublished or ongoing work Handsearching of relevant journals or conference abstracts, Translation of foreign language articles.

Quality assessment of the included studies

Assessment of study validity (preferably independently duplicated) and some statement on how those biases may affect outcomes is essential in understanding the believability of the results of a systematic review Selection bias Attrition bias (where more participants drop out of one experimental arm for some reason),Performance bias (where those receiving the intervention and/or those caring for them are aware of the experimental allocation and may alter concurrent treatments accordingly)Detection bias (where those assessing outcomes are aware of the experimental allocation and may be open to biased outcome measurement).8

Extracting data

Ideally the process is independently duplicated, based on prior decisions (in the protocol), comprehensive (on a form designed for the review, and may involve contacting authors to fill in any gaps in published reports)

Clearly tabulated to allow transparency and possibly corrections at a later date.

Pooling of data

Narrative or statistical pooling or meta-analysis?

Narrative or meta-analytic comparisons and sub-groupings should be pre-specified in the protocol (to avoid multiple analyses being carried out with only the ‘statistically significant’ ones being published).

What is meta-analysis?

To pool extracted numerical data, weighted so that larger studies, or those with less variability, contribute more to the outcome.

This pooling provides an answer with greater precision that each included study on its own

The pictorial representation of a meta-analysis is called a forest plot (see example).

Forest plot of continuous data

Statistical analysis

Fixed effects (where it is assumed that the true outcomes of the various studies are the same)Random effects methodologies (where the true outcomes are assumed to vary a little with differing study inclusion, dose, duration etc). Where fixed effects meta-analysis produces a result that is statistically heterogeneous it is usual to switch to random effects meta-analysis. Statistical heterogeneity of studies (large differences in their results, suggesting differing true outcomes) is ideally explored through subgrouping or meta-regression.

How can I perform a meta-analysis?

A meta-analysis is a very good way of summarising data from a group of studies. However, this is only useful where the set of studies is representative of the whole body of literature, so should generally be restricted to use within systematic reviews. Meta-analyses can be performed by hand or with a calculator, but are usually completed with the help of specialised computer software (that may also create a forest plot). There are many very good types of software available, but for those embarking on a Cochrane review the free Review Manager software (downloadable from the main Cochrane website) is excellent, creating forest plots

Cochrane Collaboration ， Cochrane Library and Oral Health

Group

Background of the Cochrane Collaboration

In 1972, the British epidemiologist Archie Cochrane published an influential book Effectiveness and Efficiency. Random Reflections on Health Services. “It is surely a great criticism of our profession that we have not organised a critical summary, by speciality or subspecialty, updated periodically, of all relevant randomised controlled trials” (Archie Cochrane)

Structure of the Cochrane Collaboration

Cochrane Collaboration was formed in October 1993. The Cochrane Collaboration aims to help people make well-informed decisions about health care by preparing, maintaining, and promoting the accessibility of systematic reviews of the effects of health care interventions. Over the last ten years it has grown into an international organisation, currently over 6,000 people contributing from over 60 countries. What is remarkable about the Cochrane Collaboration is that the majority of these contributors undertake their Cochrane work in their own time.

The Cochrane Library

The main product of the Cochrane Collaboration is The Cochrane Database of Systematic Reviews that forms part of The Cochrane Library, a quarterly electronic publication. It contains the full text of more than 1350 regularly updated systematic reviews and more than 1,000 protocols for reviews in progress. Several hundred reviews and protocols are added annually.

CL policy

It is Cochrane policy that reviewers revisit their review and update it within two years of it being published on The Cochrane Library. There are several stages to the Cochrane peer review process, including the assessment of protocols, evaluation of the review’s methodology and content by editors, peer reviewers and potential end users / consumers.It has been suggested that the existence of such a thorough refereeing process ultimately leads to Cochrane reviews being less prone to bias than systematic reviews and meta-analysis published in paper-based journals.

Cochrane Oral Health Group

Responsible for preparing and maintaining systematic reviews within the scope of oral health. Oral health is broadly conceived to include the prevention, treatment and rehabilitation or oral, dental and craniofacial diseases and disorders. Alexia Antczak-Bouckoms initially set up the OHG in New England (USA) in 1994. The group moved to Manchester (UK) in 1996 and secured National Health Service (NHS) funding for the editorial base in 1997.The editorial base is situated in the Manchester Dental Education Centre, University Dental Hospital of Manchester under the Co-ordinating Editorship of Professor William Shaw and Dr Helen Worthington.

OHG’s Specialised Register of Trials

It currently holds over 13,400 reports of oral health related trials (RCTs, CCTs) and related references from a wide range of bibliographical sources including MEDLINE, EMBASE, CINAHL, CANCERLIT, PSYCLIT, and the Cochrane Controlled Trials Register in addition to conference proceedings. The register is continually growing as a result of on-going electronic searching and the OHG’s organised programme of handsearching the oral health literature. This handsearching programme also contributes to the Cochrane Collaboration’s worldwide handsearching programme co-ordinated by the New England Cochane Centre, USA. This collection of references from various sources makes the Specialised Register a unique and valuable resource and the best starting point for anyone considering a systematic review with the oral health field.

Ways to contribute

The Oral Health Group welcomes all those interested in contributing to the work of the group. There are several options for participation, either as a lead reviewer, assisting as a co-reviewer, handsearching a journal to identify RCTs, or by becoming a member of the panel of peer reviewers or consumers. For further details or an information pack please refer to the group’s website: www.cochrane-oral.man.ac.ukContact: Emma Tavender, Co-ordinator, Cochrane Oral Health Group, MANDEC, University Dental Hospital of Manchester, Higher Cambridge Street, Manchester M15 6FH. Tel: +44 161 275 7818, Fax: +44 161 275 7815, Email: emma.tavender@man.ac.uk

如何在临床应用循证医学？

提出可问答的临床问题 临床发现 如何全面正确地搜集病史和进行体格检查？如何合理地解释临床发现？病因 如何通过各项检查找到明确的病因？

疾病的病因及危险因素 具体患者的疾病病因及危险因素 治疗过程与不良事件的因果关系●鉴别诊断 根据病因存在的可能性、严重性和可处理性进行排序？如冠心病心肌梗死患者，伴有高血压、血脂升高及糖尿病，在抢救病人时，如何处理这些因素才能迅速取得疗效？

提出可问答的临床问题 (2)

. 诊断试验 如何根据诊断试验的精确性、准确性、病人的可接受性、费用和安全性等方面进行选择，如何解释诊断试验结果？预后 如何估计疾病的病程和并发症？治疗 如何为患者选择利大于弊、成本低效果好的最佳治疗方案？

提出可问答的临床问题 (3)

预防 如何通过识别和消除危险因素以减少疾病的发生？如何通过筛查以早期诊断疾病？知识的自我更新 如何更新知识、提高临床技能、进行更有效的临床实践？是花 1小时到图书馆查阅教科书和杂志，还是花 30 分钟在计算机上查阅最近 5－10 年的有关文献？

如何选择急需解决的问题？在临床实践中，每天都会要面临许多问

题，一下解决所有问题是不可能的在病人的诊治过程中，哪一个问题最重

要？在现在有限的时间内，最有可能回答哪一个

问题？最感兴趣的问题是什么？哪一个问题在临床实践中经常遇到？

    查寻最好的证据查寻临床医学证据的渠道

教科书、专著、专业杂志电子出版物

Cochrane library

MEDLINE(1966-)

EMBASE

Sciesearch(Science Citation Index)

中国生物医学文献数据库 CBMdisc (1981-)

累积期刊索引

查寻的策略

要系统、全面地查寻与某一临床问题相关的最新信息，检索前确定检索的渠道和资料库，具体检索方法、检索年限和语种等。采用多种渠道查寻，避免遗漏重要信息；图书管理员共同检索 提高检索的敏感性和特异性；正确应用检索词 先用多个检索词或意义相近的检索词进行检索，然后逐渐缩窄范围。检索词应包括：研究的疾病、采用的干预措施以及研究的设计方案等，检索词应明确、具体。

  评价临床证据

临床证据的评价应包括两方面的内容：◆证据的真实性 (validity)

◆临床重要性 (importance)

●应对病因、诊断、治疗、预后等方面证据评价

诊断试验 : 是否具有真实性、重要性

诊断性试验的可行性、准确性和精确性 是否具备实施该诊断试验的技术和设备条件？其准确性和精确性如何？成本－效果比如何？在不同的亚组病人中，应用同一诊断性试验，其价值是不同的。在晚期病例中，诊断试验的似然比较高，而在早期轻型病例中则较低。应使用多层次的似然比，减少诊断试验偏差。在应用诊断试验证据时，要考虑上述因素的影响，并估计由此产生的似然比或验后概率的变化是否足以改变诊断的结果和临床的决策。

诊断试验 : 是否具有真实性、重要性 (1)能否合理估计具体医疗环境中病人的验前概率 在临床实践中应根据病人的症状、体征等重要资料估计所在医疗机构某一疾病的验前概率（患病率）如缺乏此资料，诊治条件、病人特征类似于诊断试验报告中的情况时可应用文献的验前概率；诊断条件、病人特征与文献报道有差别，可以报告的验前概率为基点并根据实际情况在一定的范围内变动，观察验后概率的变化，确定该诊断试验的实用价值。

诊断试验 : 是否具有真实性、重要性 (2)验后概率能否影响对病人的诊断和治疗决策 “试验阈值”，诊断试验为阴性时患某病的验后概率很低，不必再作进一步的诊断试验。“治疗阈值”，即诊断试验为阳性时患病的验后概率很高，据此可肯定诊断以选择最佳治疗方案。上述两种情况下，可停止诊断试验。当验后概率介于试验阈值与治疗阈值之间时，则要做进一步的检查以肯定或否定待查的疾病。当单个诊断试验不能确定试验－治疗阈值时，可采用联合试验的方法，然后计算总的验后概率以帮助临床决策。

治疗性研究是否具有真实、重要性 ? 疗措施是否适合具体病人 具体患者同文献中的研究对象在性别、年龄、并存症、疾病严重程度、社会因素、生物学及临床特征等方面的差异如何 ?结合生物学知识和临床专业知识综合判断该治疗研究的外延性。样本大的试验或系统综述的结论对指导具体病人用药更有参考价值。

治疗性研究是否具有真实、重要性 ?(1)

治疗措施用于具体病人时效果如何？治疗性试验报告的结果是作用于病人的平均治疗效果，针对单个具体的病人如何考虑其效果？采用测量 治疗措施是否有效的 指标NNT ，即治疗多少例病人才能防止一例发生某种结局。

治疗性研究是否具有真实、重要性 ?(2)确定发生某种结局的绝对易感性即期望事件率 (patient expected event rate, PEER) ，乘以文献报告的 RRR值 ( 相对危险降低率 ) 得到 ARR ，然后转换为 NNT 。例如：某一病人的 PEER 为 40 ％，文献报告的 RRR＝ 50 ％，则 ARR ＝ 40 ％ 50 ％＝ 20 ％， NNT ＝1/ARR ＝ 1/20 ％＝ 5 ，即每治疗 5 个病人可避免一个事件发生。参照文献报告中病人对治疗方案的敏感性，确定具体病人的相对敏感性，二者的比值以 F 表示，假定敏感性不同时， RRR 不变，则文献报告的 NNT除以 F 得到你的病人的 NNT 。权衡治疗方案的效果、安全性与病人的喜好

治疗中不良反应证据的应用

具体病人是否确实不同于文献中的研究对象，是否存在本质的差别 ?确定具体病人发生不良反应的可能性与文献报告病人发生不良反应可能性的比值（ F ），用文献报告的 NNH即需要治疗多少例病人才会发生 1例不良反应的结果除以 F ，即得到具体病人发生不良反应的 NNH 。例如：使用非甾体类抗炎药，具体病人发生胃肠道出血的可能性是一队列研究中研究对象的 4倍，队列研究的 NNH 为 2000 ，则你的病人的 NNH ＝ 2000/4 ＝ 500 ，即每治疗 500例病人就有 1例发生胃肠道出血。

治疗中不良反应证据的应用 (1)

确定和考虑病人的喜好、关心和希望解决的问题 针对具体的病人进行治疗决策时可根据病人意见改变 F值，然后将 NNH 与 NNT 进行比较。一般来说，如果 NNH值 <NNT值，则要考虑改变治疗措施。.即使调整后的 NNH>NNT ，治疗措施的不良反应也不是很严重，但如果有不良反应更小的措施备选也应考虑更换为其它治疗措施，以尽可能减少或避免不良反应。例如高血压患者使用血管紧张素转换酶抑制剂发生咳嗽，可改用无此不良反应的降压药。

临床决策分析的评价和应用 在临床实践中，如何根据患者具体情况进行决策？决策分析 (clinical decision analysis) ，即改变不同方案的某些变量值，分析其对结论的影响程度，最后选择最佳方案。临床决策分析是一种定量分析方法，它将最好的外部证据与个人专业知识、病人的选择有机地结合起来综合考虑，在循证医学中已得到广泛应用。临 床 决 策 分析采用图形 表示，称为“决 策树” (decision tree) ，将不同的备选方案和可能发生的结果用图表示出来。

临床决策证据评价和应用 (1)

  是否包括了所有重要的临床策略及其结局？ 每种结局发生概率的可信性：是否采用明确、合理的方法查寻並选择最好的外部证据来确定每種结局的发生概率？ 效用值是否明确、合理？来源是否可靠？ 是否检验了结论的论证强度？即结局发生概率和效用值在合理范围内变动时对结论的影响如何？

临床决策分析证据的重要性

首先要确定某一决策是否使患者在寿命或其它效用指标方面获得具有临床重要意义的效益。此效益越大，则结论越可靠；其次要进行敏感性分析，即当重要结局的发生率和效用值在临床合理的范围内发生变化时，结论或决策将发生什么改变？如果决策的方向不变，未改变对决策的选择，则该临床决策分析是稳定、可靠的；如果决策方向改变，则该决策分析是不可靠的。

临床决策分析证据的应用

临床决策分析中的概率是否适合于具体的病人？如果不适合，能否进行合理的调整？具体病人能否以稳定的方式确定不同健康状态时的效用值？病人对疾病状态以及费用的期望。

在临床应用循证医学的意义

循证医学的意义循证医学是临床医学的新兴基础学科―临床流行病学发展的产物。它要求临床医务人员把病人的疾苦放在第一位，因时因地制宜，为病员提出个体化的最佳方案要求临床医务人员具有敏锐的头脑，善于从实践中发现和提出问题，善于利用现代科技手段迅速找出问题的答案，善于批判地吸收前人、他人的知识，以临床问题为中心，以科学证据为依据，更快、更好、更省地为病员解除痛苦。

每一个临床医务人员都应当学习循证医学

实践循证医学将使各专业临床医务人员在承担繁忙的医疗任务时保持与时代同步，始终站在时代前沿，吐故纳新，批判地吸收与继承人类知识宝库

成为本专业内学识丰富，医术清湛，善于解决临床疑难问题的临床医学专家。