Douglas G.Altman，David Moher

Douglas G.Altman，David Moher.關(guān)于研究文獻(xiàn)透明化的聲明——一種克服不充分研究報(bào)告的方法[J].中國全科醫(yī)學(xué)，2014，17(2)：119-122.[www.chinagp.net]

Douglas G.Altman(道格拉斯G.沃特曼)：英國牛津大學(xué)生物統(tǒng)計(jì)學(xué)教授、生物統(tǒng)計(jì)中心主任；國際著名方法學(xué)家，Cochrane協(xié)作網(wǎng)方法學(xué)組負(fù)責(zé)人，曾任內(nèi)科學(xué)年鑒主編，現(xiàn)任國際方法學(xué)專業(yè)雜志Trials主編；隨機(jī)對(duì)照試驗(yàn)報(bào)告指南(CONSORT)工作組負(fù)責(zé)人之一；國際促進(jìn)衛(wèi)生研究質(zhì)量與透明化協(xié)作網(wǎng)(EQUATOR)主要負(fù)責(zé)人;國際期刊編輯倫理委員會(huì)(COPE)成員。

David Moher(大衛(wèi).墨赫爾)：加拿大渥太華大學(xué)公共衛(wèi)生流行病學(xué)教授，臨床試驗(yàn)中心主任，世界衛(wèi)生組織國際臨床試驗(yàn)注冊(cè)平臺(tái)專家組成員。國際著名臨床研究方法學(xué)家，CONSORT工作組負(fù)責(zé)人之一，Cochrane協(xié)作網(wǎng)替代醫(yī)學(xué)組首席方法學(xué)家，EQUATOR特邀專家，COPE成員。

“確保所發(fā)表的報(bào)告無偏倚、準(zhǔn)確地重現(xiàn)研究是每一位參與者的責(zé)任”[1]。

研究記錄常常會(huì)做簡化處理，但卻存在對(duì)患者不利的風(fēng)險(xiǎn)。因此，醫(yī)學(xué)研究界需要變革來保證讀者獲得所有研究的真相，特別是隨機(jī)對(duì)照試驗(yàn)報(bào)告，具有解答什么是對(duì)患者最有利治療的作用。

如果不發(fā)表所有研究特別是隨機(jī)對(duì)照試驗(yàn)的結(jié)果，將嚴(yán)重地誤導(dǎo)循證臨床決策。最近一項(xiàng)關(guān)于瑞波西汀治療抑郁的系統(tǒng)評(píng)價(jià)發(fā)現(xiàn)約有四分之三參與研究的患者未在發(fā)表試驗(yàn)中[2]。904項(xiàng)治療缺血性卒中(1955—2008年)的已完成試驗(yàn)中，有五分之一沒有被適當(dāng)?shù)匕l(fā)表，“其中有的大到足以影響臨床實(shí)踐以及系統(tǒng)評(píng)價(jià)和Meta分析的結(jié)果”[3]。

與不發(fā)表一樣惡劣的是，不完整或誤導(dǎo)發(fā)表導(dǎo)致的問題更大。發(fā)表在同行評(píng)審刊物的臨床試驗(yàn)結(jié)果可能與之前呈報(bào)到管理機(jī)構(gòu)的不同[4-6]，陽性結(jié)果可能更多。主要測量指標(biāo)常與研究者在研究計(jì)劃[7-8]或注冊(cè)機(jī)構(gòu)[9-10]中所描述的不一樣。選擇性地不發(fā)表不利的有統(tǒng)計(jì)學(xué)意義的結(jié)果，使文獻(xiàn)產(chǎn)生偏倚[11-12]。更有甚者，作者常歪曲表述和解釋他們的研究結(jié)果。一項(xiàng)研究發(fā)現(xiàn)，72個(gè)主要測量指標(biāo)差異無統(tǒng)計(jì)學(xué)意義的隨機(jī)對(duì)照試驗(yàn)都存在同樣問題[13]。在診斷準(zhǔn)確性試驗(yàn)研究中也有相似的發(fā)現(xiàn)[14]。

同行專家評(píng)審不能保證雜志發(fā)表的文章包含有讀者需要的詳細(xì)的臨床和方法學(xué)的關(guān)鍵內(nèi)容。對(duì)已發(fā)表的隨機(jī)對(duì)照試驗(yàn)報(bào)告的評(píng)估發(fā)現(xiàn)，其常缺乏對(duì)干預(yù)措施的評(píng)估[15-16]、患者納入標(biāo)準(zhǔn)[17]和結(jié)果[18-19]的詳細(xì)信息；研究方法的詳細(xì)信息也不充分，特別是關(guān)于分組的信息。一項(xiàng)2006年的研究發(fā)現(xiàn)，僅三分之一的研究報(bào)告描述了隨機(jī)序列的產(chǎn)生方法、僅四分之一充分描述了隱蔽分組方法[20]。一項(xiàng)包含357個(gè)Ⅲ期腫瘤臨床試驗(yàn)的綜述總結(jié)道：“大量的內(nèi)容在許多試驗(yàn)中都沒有報(bào)告”[21]。不利事件也常常報(bào)告不充分[22-23]。

其他類型研究在結(jié)果和報(bào)告中的問題可能較隨機(jī)對(duì)照試驗(yàn)更嚴(yán)重。雖然集中研究較少，相似觀點(diǎn)已經(jīng)在有關(guān)的流行病學(xué)[24-25]、藥物流行病學(xué)[26]、診斷性研究[27]、預(yù)后研究[28]和臨床前研究[29-30]中表達(dá)過。當(dāng)然，高質(zhì)量報(bào)告并不等于有同樣高質(zhì)量的研究。但是，完整和清楚的報(bào)告可讓讀者判斷研究的可靠性，獲取所需的相關(guān)信息。有人認(rèn)為商業(yè)資助的研究可能更多地不被發(fā)表[2，31]，一旦發(fā)表這些試驗(yàn)報(bào)告則更加完整[32]。

那么，什么是必須的？報(bào)告應(yīng)該對(duì)研究者如何實(shí)施其研究及研究結(jié)果進(jìn)行清楚和透明地描述。忽略方法學(xué)或研究實(shí)施的重要細(xì)節(jié)應(yīng)被認(rèn)為是不可接受的，期刊不應(yīng)發(fā)表這樣的報(bào)告。雖然找到一些缺失信息需要額外的途徑(例如從試驗(yàn)注冊(cè)機(jī)構(gòu)或研究計(jì)劃獲得信息)，多數(shù)缺失信息在稿件中都很明顯并能檢測出來，盡管報(bào)告指南如CONSORT[33]容易獲得，但這種狀況的改善仍然緩慢[34]。

由于研究者對(duì)信息的刻意隱瞞使試驗(yàn)結(jié)果不易獲得，這與赫爾辛基宣言相違背，不僅不符合當(dāng)前研究的道義和科學(xué)性，而且浪費(fèi)了大量稀缺資源、降低了研究的社會(huì)價(jià)值[35]。由于誤導(dǎo)或不充分地發(fā)表研究結(jié)果使研究者和資助組織失去了公眾的信任。從科學(xué)的角度，這不利于系統(tǒng)評(píng)價(jià)研究者匯集所有的證據(jù)，與使用所有信息的評(píng)估比較，只評(píng)估部分內(nèi)容會(huì)對(duì)有效性和安全性的評(píng)估產(chǎn)生偏倚，降低準(zhǔn)確性，不利于找到最利于患者的措施。

有一個(gè)幾乎立刻就能實(shí)施的計(jì)劃：我們建議每本雜志在作者投稿時(shí)都增加一個(gè)所有作者簽署的發(fā)表透明化聲明，在為其他目的提交報(bào)告時(shí)，如對(duì)監(jiān)管機(jī)構(gòu)，也需做類似的聲明(見下文示例)。

透明化聲明：負(fù)責(zé)作者*證明，本文對(duì)研究所做的報(bào)告是誠實(shí)、準(zhǔn)確和透明的；沒有遺漏重要的內(nèi)容，對(duì)與研究計(jì)劃(如果有，與所注冊(cè)的信息)的任何不一致均做了解釋。

注：*指文稿的保證人

編輯和編輯團(tuán)隊(duì)可以通過更新其“作者須知”來支持本倡議，將完整的發(fā)表透明化保證作為投稿程序的一部分。我們認(rèn)為這與當(dāng)前廣泛實(shí)施的要求作者做“利益沖突聲明”相似，具有科學(xué)上的必要性。采用這樣的措施之后還有隱瞞或發(fā)表不正確信息的報(bào)告，將作為制裁學(xué)術(shù)不端行為的證據(jù)。我們希望此措施將鼓勵(lì)作者更加仔細(xì)地撰寫論文，并鼓勵(lì)他們按照相關(guān)報(bào)告指南審核自己的文稿。BMJ，我們中的一人(Douglas G.Altman)是其高級(jí)統(tǒng)計(jì)學(xué)編輯，和BMJ開放版(BMJOpen)正在帶頭實(shí)施這項(xiàng)政策。我們邀請(qǐng)其他雜志也實(shí)行這項(xiàng)政策，并支持EQUATOR網(wǎng)站(www.equator-network.org)的透明化聲明。

科學(xué)界和公眾對(duì)準(zhǔn)確和完整的研究報(bào)告寄予厚望，我們需要變革來給以保障。廣泛認(rèn)可和實(shí)行的發(fā)表透明化聲明是幫助實(shí)現(xiàn)醫(yī)學(xué)研究最大價(jià)值的一條途徑，然而其影響不了未發(fā)表的研究，這仍然是一件恥辱。

DeclarationofTransparencyforEachResearchSrticle

"Itistheresponsibilityofeveryoneinvolvedtoensurethatthepublishedrecordisanunbiased,accuraterepresentationofresearch."1

The research record is often manipulated for short term gain but at the risk of harm to patients.The medical research community needs to implement changes to ensure that readers obtain the truth about all research,especially reports of randomised trials,which hold a special place in answering what works best for patients.

Failure to publish the findings of all studies,especially randomised trials,seriously distorts the evidence base for clinical decision making.A recent systematic review of reboxetine for treating depression found that almost three quarters of included patients were in unpublished trials2.Of 904 completed trials of interventions for acute ischaemic stroke (1955—2008),a fifth were not properly published,"several of which may be large enough to influence clinical practice and the findings of systematic reviews and meta-analyses"3.

Bad as non-publication is,incomplete or misleading publications cause greater problems.Results of clinical trials published in peer reviewed publications may differ from what was previously submitted to regulatory agencies4-6,with the published data being more positive.The primary outcome often differs from what the researchers had stated in the trial protocol7-8or clinical trial registry9-10.Selective non-publication favours statistically significant findings,biasing the literature11-12.Furthermore,authors often distort the presentation and interpretation of their findings.One study found that such "spin" was common in 72 reports of randomised controlled trials with statistically non-significant primary outcomes13.Similar findings have been reported recently for studies of the accuracy of diagnostic tests14.Peer review is failing to ensure that journal articles contain the key clinical and methodological details that readers need.Reviews of published reports of randomised trials have found common deficiencies in the details of the interventions being evaluated15-16,participant eligibility criteria17,and outcomes18-19.Details of study methods are also often inadequate,especially in relation to allocation.A 2006 study found that only a third of trial reports described how the randomisation sequence was generated and only a quarter described an adequate method of allocation concealment20.A review of 357 phase Ⅲ oncology trials concluded that "numerous items remained unreported for many trials"21.Harms too are poorly reported22-23.

The problems associated with publishing and reporting other types of research may be worse than for randomised trials.Although less intensively studied,similar concerns have been expressed in relation to epidemiology24-25,pharmacoepidemiology26,diagnosis research27,prognosis research28,and preclinical research29-30.Of course,good reporting is not the same as high quality research.But a full and clear report allows readers to judge a study′s reliability and relevance.There are concerns that commercially sponsored research may be more likely to remain unpublished2,31,but when published these trials are reported more fully32.

So what is needed? Published research articles should provide a clear and transparent description of how researchers conducted their study and what they found.Omission of important details of methods or study conduct should be deemed unacceptable,and journals should not publish them.Although detection of some deficiencies requires external information (for example,from a trials register or protocol),most deficiencies are inherent in a submitted manuscript and should be detected.Despite the availability of reporting guidelines such as CONSORT33,improvements are slow to materialise34.

By not making results of their research easily accessible,researchers are withholding knowledge,in contravention of the Declaration of Helsinki.Not only are current practices questionable on moral and scientific grounds,failure to publish all research findings is a massive waste of scarce resources and diminishes the social value of the research35.Researchers and funding organisations also fail the public when research findings are published in a misleading or inadequate way.Scientifically,this harms systematic reviewers who want to aggregate all of the evidence.Reviewing a partial picture provides biased and less precise estimates of effectiveness and safety than when the full information is used,and it may compromise the identification of what works best for patients.

We have a proposal that can be acted on almost immediately.We suggest that authors should sign a publication transparency declaration (box) as part of every journal submission.The same declaration could be appropriate for submissions in other contexts-for example,to regulatory agencies.

Transparencydeclaration：Theleadauthor*affirmsthatthismanuscriptisanhonest,accurate,andtransparentaccountofthestudybeingreported;thatnoimportantaspectsofthestudyhavebeenomitted;andthatanydiscrepanciesfromthestudyasplanned(and,ifrelevant,registered)havebeenexplained.

*Themanuscript′sguarantor.

Editors and editorial groups can support this initiative by updating their instructions to authors so that a completed publication transparency pledge is required as part of the submission process.We see this action as a necessary scientific analogue of the current widespread practice of asking authors about conflicts of interest.Subsequent revelation of withheld or incorrect information would be evidence of scientific misconduct for which various actions could be taken.We hope that this step will encourage authors to reflect more carefully on how they write their article and encourage them to check that they have adhered to relevant reporting guidelines.TheBMJ,for which one of us (DGA) is the senior statistics editor,andBMJOpenare leading the way by implementing this policy immediately.We invite other journals to do likewise and support the transparency declaration on the EQUATOR website (www.equator-network.org).

The scientific community and the public at large deserve an accurate and complete record of research;we need to make changes to ensure that we will get one.Widespread endorsement and implementation of a publication transparency declaration is one way to help to get the maximum value from medical research.It will,however,have no influence on the non-publication of studies,which is a continuing disgrace.

1 PLoS Medicine Editors.An unbiased scientific record should be everyone′s agenda[J].PLoS Med,2009,24(6):e1000038.

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3 Gibson LM,Brazzelli M,Thomas BM,et al.A systematic review of clinical trials of pharmacological interventions for acute ischaemic stroke (1955—2008) that were completed,but not published in full[J].Trials,2010,11:43.

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22 Bagul NB,Kirkham JJ.The reporting of harms in randomized controlled trials of hypertension using the CONSORT criteria for harm reporting[J].ClinExp Hypertens,2012,34(8):548-554.

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