Hi. So, this chap here, he thinks he can tell you the future. His name is Nostradamus, although here the Sun have made him look a little bit like Sean Connery. (Laughter)
嗨!报纸上的这个家伙 认为他能预知未来。 他叫诺查丹玛斯,尽管太阳报 把他画得有点像肖恩·康纳利。(笑声)
And like most of you, I suspect, I don't really believe that people can see into the future. I don't believe in precognition, and every now and then, you hear that somebody has been able to predict something that happened in the future, and that's probably because it was a fluke, and we only hear about the flukes and about the freaks. We don't hear about all the times that people got stuff wrong. Now we expect that to happen with silly stories about precognition, but the problem is, we have exactly the same problem in academia and in medicine, and in this environment, it costs lives.
像你们一样,我很怀疑,我不太相信 人真能预知未来。 我不相信先知,你常常会 听说有人能够预知某事的发生, 但这可能仅仅是因为瞎猫撞着死耗子,而且我们也仅仅 听说了那些侥幸和怪异之事。 我们可不会听说那些被预测搞砸的事情。 我们认为这就是关于预知的 荒诞故事的原因,但问题在于, 同样问题也存在于学术领域, 和医学方面,这关乎人命。
So firstly, thinking just about precognition, as it turns out, just last year a researcher called Daryl Bem conducted a piece of research where he found evidence of precognitive powers in undergraduate students, and this was published in a peer-reviewed academic journal and most of the people who read this just said, "Okay, well, fair enough, but I think that's a fluke, that's a freak, because I know that if I did a study where I found no evidence that undergraduate students had precognitive powers, it probably wouldn't get published in a journal. And in fact, we know that that's true, because several different groups of research scientists tried to replicate the findings of this precognition study, and when they submitted it to the exact same journal, the journal said, "No, we're not interested in publishing replication. We're not interested in your negative data." So this is already evidence of how, in the academic literature, we will see a biased sample of the true picture of all of the scientific studies that have been conducted.
所以,首先想想“预知”这个问题,因为去年 有一个叫达里尔·贝姆的研究者进行了 一个研究,他发现了关于大学生的 预知能力的证据, 并且这篇论文被发表在了一本同行评议的学术期刊中。 很多读过这篇论文的人都说:“好吧,嗯, 有道理,但我认为这是巧合,因为我知道 如果我进行研究,并得出没有任何证据 表明大学生有预知能力, 这篇论文很可能不会被在期刊中发表。 其实,我们知道这个问题是存在的, 因为几组科学家尝试 重复关于预知能力的研究, 但当他们试图发表在这同一本期刊上时, 期刊编辑说:“不,我们对重复实验不感兴趣。 我们对你的负面数据不感兴趣。” 所以这就是证据,在学术文献中, 我们会看到真实情况的例证, 几乎所有科学研究都是存在偏见。
But it doesn't just happen in the dry academic field of psychology. It also happens in, for example, cancer research. So in March, 2012, just one month ago, some researchers reported in the journal Nature how they had tried to replicate 53 different basic science studies looking at potential treatment targets in cancer, and out of those 53 studies, they were only able to successfully replicate six. Forty-seven out of those 53 were unreplicable. And they say in their discussion that this is very likely because freaks get published. People will do lots and lots and lots of different studies, and the occasions when it works they will publish, and the ones where it doesn't work they won't. And their first recommendation of how to fix this problem, because it is a problem, because it sends us all down blind alleys, their first recommendation of how to fix this problem is to make it easier to publish negative results in science, and to change the incentives so that scientists are encouraged to post more of their negative results in public.
但这并不只发生在枯燥的心理学领域。 在癌症研究方面这个问题也存在。 所以,在2012年3月,也就是一个月前,一些研究人员 在自然杂志上发表文章,表示他们如何尝试 重复53个关于癌症潜在疗法的 基本科学研究, 结果在这53个研究中,他们只能成功 重复其中六个。 剩余47个实验则无法成功重复。 他们在分析中指出这很有可能是 因为怪异的结果容易被发表。 人们会做许多许多不同的实验, 实验成功就会被发表, 不成功则难见天日。 他们对解决这个问题的第一个建议, 因为这确实是个问题,它把我们都送进死胡同, 他们纠正这个问题的第一个建议就是 让在科学界发表负面结果变得更加容易, 并改变科学家们的奖励机制,鼓励他们 更多地公开发表负面的结果。
But it doesn't just happen in the very dry world of preclinical basic science cancer research. It also happens in the very real, flesh and blood of academic medicine. So in 1980, some researchers did a study on a drug called lorcainide, and this was an anti-arrhythmic drug, a drug that suppresses abnormal heart rhythms, and the idea was, after people have had a heart attack, they're quite likely to have abnormal heart rhythms, so if we give them a drug that suppresses abnormal heart rhythms, this will increase the chances of them surviving. Early on its development, they did a very small trial, just under a hundred patients. Fifty patients got lorcainide, and of those patients, 10 died. Another 50 patients got a dummy placebo sugar pill with no active ingredient, and only one of them died. So they rightly regarded this drug as a failure, and its commercial development was stopped, and because its commercial development was stopped, this trial was never published.
这不仅仅发生在枯燥的 临床基础癌症研究。 它还发生在活生生的 学术医学领域。在1980年, 一些研究人员研究了一种叫劳卡胺的药物, 这是一种抗心律失常药, 可以抑制不正常的心率。 研究者想法是,当病人心脏病发作, 他们很可能心率失常, 所以如果我们给他们抑制心率失常的药, 他们的存活率就会增加。 在研究早期,他们进行了一个非常小规模的实验, 只有100个病人参加。 50人服用劳卡胺,他们中有10人死了。 另外50人服用了假的(安慰剂糖片)药片, 没有摄入任何有效成分,他们中只有1人死了。 所以研究人员很诚实地将这种药列为失败产品, 有关的商业开发马上停止,而导致了 这次研究的结果一直没有发表。
Unfortunately, over the course of the next five, 10 years, other companies had the same idea about drugs that would prevent arrhythmias in people who have had heart attacks. These drugs were brought to market. They were prescribed very widely because heart attacks are a very common thing, and it took so long for us to find out that these drugs also caused an increased rate of death that before we detected that safety signal, over 100,000 people died unnecessarily in America from the prescription of anti-arrhythmic drugs.
不幸的是,在接下来的五到十年里, 其它公司也有制造同样药物的想法—— 对心脏病人使用抗心律不齐药物。 这些药物被投入市场,并被 广为使用,因为心脏病是种很常见的病。 我们花了很长时间才意识到这些药物 致使患者死亡率上升。 在我们发现到这一点之前, 美国十万多条本可挽留的生命就因 使用这种抗心律不齐药物而失去。
Now actually, in 1993, the researchers who did that 1980 study, that early study, published a mea culpa, an apology to the scientific community, in which they said, "When we carried out our study in 1980, we thought that the increased death rate that occurred in the lorcainide group was an effect of chance." The development of lorcainide was abandoned for commercial reasons, and this study was never published; it's now a good example of publication bias. That's the technical term for the phenomenon where unflattering data gets lost, gets unpublished, is left missing in action, and they say the results described here "might have provided an early warning of trouble ahead."
实际上,在1993年, 那些在1980年进行早期实验的研究人员 发表了公开道歉,以对科学界表达歉意。 他们写道:“当我们在1980年进行研究时, 我们以为劳卡胺实验组的 死亡率上升只是巧合罢了。” 劳卡胺的研发因商业原因被停止, 而这项研究也从未被发表。 这就是‘发表偏倚’(Publication bias)的极佳例子。 ‘发表偏倚’(Publication bias)是一个用来形容负面数据被忽视, 不被发表,的特有名词 之后,他们得出的结论是 “本可以在灾难之前提前敲响警钟。”
Now these are stories from basic science. These are stories from 20, 30 years ago. The academic publishing environment is very different now. There are academic journals like "Trials," the open access journal, which will publish any trial conducted in humans regardless of whether it has a positive or a negative result. But this problem of negative results that go missing in action is still very prevalent. In fact it's so prevalent that it cuts to the core of evidence-based medicine. So this is a drug called reboxetine, and this is a drug that I myself have prescribed. It's an antidepressant. And I'm a very nerdy doctor, so I read all of the studies that I could on this drug. I read the one study that was published that showed that reboxetine was better than placebo, and I read the other three studies that were published that showed that reboxetine was just as good as any other antidepressant, and because this patient hadn't done well on those other antidepressants, I thought, well, reboxetine is just as good. It's one to try. But it turned out that I was misled. In fact, seven trials were conducted comparing reboxetine against a dummy placebo sugar pill. One of them was positive and that was published, but six of them were negative and they were left unpublished. Three trials were published comparing reboxetine against other antidepressants in which reboxetine was just as good, and they were published, but three times as many patients' worth of data was collected which showed that reboxetine was worse than those other treatments, and those trials were not published. I felt misled.
这是些基础科学界的故事。 这些都是20,30年前的老故事了。 如今,学术出版业大环境已经今非昔比。 现在有类似《试验》的开源期刊(the open access journal), 这些期刊是不论结果好坏,只要关于人体试验的 悉数发表的学术期刊。 但负面结果被忽视的问题 还是很严重。实际上,这严重到了 威胁“循证医药学”的根本。 这是一种叫做瑞波西汀的药物,之前 我也开过这药的处方。这是一种抗抑郁的药物。 而我又比较死板书呆子,所以我浏览了 所有我能找到关于此药的文章。我读到的其中一篇声称 瑞波西汀比安慰剂要有效果, 我又读到另外三篇声称 瑞波西汀和其他抗抑药物的效果没什么差别, 就因为那个病人对其他抗抑郁的药物没什么反应, 所以我觉得,瑞波西汀效果也不错。试试也没什么坏处。 但最终证明我是被误导了。实际上, 有七项关于瑞波西汀和 安慰糖片的比较试验。其中一项 效果出众也得以发表,其他六项 无效果,导致无法发表结论。 三项发表的试验记载 在瑞波西汀和其他抗抑郁药物的对比中,瑞波西汀 效果同样显著,并得以发表, 而另外收集的多达三倍的病例数据 显示瑞波西汀的表现 远不如其它药物的疗效,而这些试验结果没有被发表。 我感觉被误导了。
Now you might say, well, that's an extremely unusual example, and I wouldn't want to be guilty of the same kind of cherry-picking and selective referencing that I'm accusing other people of. But it turns out that this phenomenon of publication bias has actually been very, very well studied. So here is one example of how you approach it. The classic model is, you get a bunch of studies where you know that they've been conducted and completed, and then you go and see if they've been published anywhere in the academic literature. So this took all of the trials that had ever been conducted on antidepressants that were approved over a 15-year period by the FDA. They took all of the trials which were submitted to the FDA as part of the approval package. So that's not all of the trials that were ever conducted on these drugs, because we can never know if we have those, but it is the ones that were conducted in order to get the marketing authorization. And then they went to see if these trials had been published in the peer-reviewed academic literature. And this is what they found. It was pretty much a 50-50 split. Half of these trials were positive, half of them were negative, in reality. But when they went to look for these trials in the peer-reviewed academic literature, what they found was a very different picture. Only three of the negative trials were published, but all but one of the positive trials were published. Now if we just flick back and forth between those two, you can see what a staggering difference there was between reality and what doctors, patients, commissioners of health services, and academics were able to see in the peer-reviewed academic literature. We were misled, and this is a systematic flaw in the core of medicine.
也许你会说,那可能是个案中的个案吧, 我也不必自己和自己较真, 不必为其他人这种只挑有利的选择性 发表而指责别人。 但结果证实这种“发表偏倚” 已经被很深入的研究过了。 举个例子,你如何看待它。 经典的例子就是,你有了一堆 已经临床使用过并有结论的试验 而你要找学术文献机构 询问是否曾经有发表。他们寻找了所有抗抑郁药物有关的 被食品药物管理局15年前审批的 相关临床案例。 他们根据所有曾经上交给食品医药管理局的试验案例作为基础。 所以那并不是所有此类药物的所有临床试验结果, 因为我们不知道那些没有被公布的, 只知道那些为了获得上市批准而进行试验研究的结果。 之后,他们去了解那些试验有没有被发表 在那些需同行审核的学术期刊中。这是他们的发现结果。 是大致上平分秋色。现实情况,一半试验显示 效果显著,另外一半显示效果不显著。 但他们从那些需审核的学术机构里搜索那些试验的时候, 他们发现结果是截然不同的。 只有三项效果负面的试验被发表了出来, 而除了一例几乎所有效果显著的试验案例都被发表了出去。 当我们前后跳转进行两者对比的话, 你能发现横在现实和 医生、病人、卫生服务专员、专业学者 所能读到的审核的学术期刊文献,之间消息的鸿沟了。 所能读到的审核的学术期刊文献,之间消息的鸿沟了。 我们被误导了,这是医药学核心中的体制漏洞。 我们被误导了,这是医药学核心中的体制漏洞。
In fact, there have been so many studies conducted on publication bias now, over a hundred, that they've been collected in a systematic review, published in 2010, that took every single study on publication bias that they could find. Publication bias affects every field of medicine. About half of all trials, on average, go missing in action, and we know that positive findings are around twice as likely to be published as negative findings.
实际上,如今已经有很多关于 “发表偏倚”的研究了, 在2010年发表的被收集并系统性的调查中, 他们能找到的所有的“发表偏倚”的研究 “发表偏倚”的试验案例有一百多项。 “发表偏倚”影响了医学的所有领域。 大约一半的试验,被遗忘忽视, 我们还发现,有效果的结果发表的几率 几乎是没效果发表几率的两倍。
This is a cancer at the core of evidence-based medicine. If I flipped a coin 100 times but then withheld the results from you from half of those tosses, I could make it look as if I had a coin that always came up heads. But that wouldn't mean that I had a two-headed coin. That would mean that I was a chancer and you were an idiot for letting me get away with it. (Laughter) But this is exactly what we blindly tolerate in the whole of evidence-based medicine. And to me, this is research misconduct. If I conducted one study and I withheld half of the data points from that one study, you would rightly accuse me, essentially, of research fraud. And yet, for some reason, if somebody conducts 10 studies but only publishes the five that give the result that they want, we don't consider that to be research misconduct. And when that responsibility is diffused between a whole network of researchers, academics, industry sponsors, journal editors, for some reason we find it more acceptable, but the effect on patients is damning.
这是循证医药学中的毒瘤。 如果我抛100次硬币,但是 隐瞒一半的投掷结果, 我就能让它看以来是一个永远头像朝上的硬币。 但这不代表我这硬币有两面都是头像。 这只能说我是个投机者 而你是相信我说法的白痴。(笑声) 但这就是我们在循证医药学中盲目纵容的现状。 但这就是我们在循证医药学中盲目纵容的现状。 对我来说,这是学术不端行为。 如果我做某项研究,而我隐瞒了 此研究中一半的数据, 你就有权利指控我,学术诈骗。 但出于某种原因,如果某人做了 10项研究但只发表其中他希望的5项的话, 我们却不会考虑这是学术不端。 但当学术不端的责任分散于学术网络,学术期刊,商业赞助商,期刊编辑的时候, 但当学术不端的责任分散于学术网络,学术期刊,商业赞助商,期刊编辑的时候, 但当学术不端的责任分散于学术网络,学术期刊,商业赞助商,期刊编辑的时候, 不知怎么的,我们觉得这样是可以接受的, 但这对病人的后果是惨痛的。
And this is happening right now, today. This is a drug called Tamiflu. Tamiflu is a drug which governments around the world have spent billions and billions of dollars on stockpiling, and we've stockpiled Tamiflu in panic, in the belief that it will reduce the rate of complications of influenza. Complications is a medical euphemism for pneumonia and death. (Laughter) Now when the Cochrane systematic reviewers were trying to collect together all of the data from all of the trials that had ever been conducted on whether Tamiflu actually did this or not, they found that several of those trials were unpublished. The results were unavailable to them. And when they started obtaining the writeups of those trials through various different means, through Freedom of Information Act requests, through harassing various different organizations, what they found was inconsistent. And when they tried to get a hold of the clinical study reports, the 10,000-page long documents that have the best possible rendition of the information, they were told they weren't allowed to have them. And if you want to read the full correspondence and the excuses and the explanations given by the drug company, you can see that written up in this week's edition of PLOS Medicine.
如今这样的情况还在发生。 这是种叫达菲的药物。达菲是 全球政府花费了数十亿美元的 资金作为应急储备的, 我们储备达菲,以备不时之需, 因为我们相信,它能减少流感所带来的并发症。 并发症则是医学上对肺炎和死亡的 婉转说法。(笑声) 如今,当科克伦(Cochrane临床对照试验资料库)系统审核员 想收集所有关于达菲临床应用的, 是否有效的试验案例时, 他们发现很多试验是未被发表的。 他们无法找到那些实验的结果。 当他们通过不同渠道,通过《信息自由法案》, 当他们通过不同渠道,通过《信息自由法案》, 向各种不同组织打探消息后,他们发现里面有很多矛盾的地方。 当他们想查看那一万多页 包括了所有试验结果信息的 临床学术报告的时候, 他们被告知,他们无权使用。 如果你想知道那些制药公司 对此给出的解释和借口全文的话, 你可以关注一下这周出版的 《公共科学图书馆•医学》的期刊。
And the most staggering thing of all of this, to me, is that not only is this a problem, not only do we recognize that this is a problem, but we've had to suffer fake fixes. We've had people pretend that this is a problem that's been fixed. First of all, we had trials registers, and everybody said, oh, it's okay. We'll get everyone to register their trials, they'll post the protocol, they'll say what they're going to do before they do it, and then afterwards we'll be able to check and see if all the trials which have been conducted and completed have been published. But people didn't bother to use those registers. And so then the International Committee of Medical Journal Editors came along, and they said, oh, well, we will hold the line. We won't publish any journals, we won't publish any trials, unless they've been registered before they began. But they didn't hold the line. In 2008, a study was conducted which showed that half of all of trials published by journals edited by members of the ICMJE weren't properly registered, and a quarter of them weren't registered at all. And then finally, the FDA Amendment Act was passed a couple of years ago saying that everybody who conducts a trial must post the results of that trial within one year. And in the BMJ, in the first edition of January, 2012, you can see a study which looks to see if people kept to that ruling, and it turns out that only one in five have done so.
但对我来说,最惊人的事情是, 不仅之前讨论的这个问题,和我们是否意识到了 这个问题,还包括我们要忍受装作问题已被解决。 我们让人们以为这个问题已经解决了。 首先,我们有试验注册,所有人都说, 这样就行了。我们让所有人都注册他们的试验案例,他们会发布行业规则的, 事先宣布他们要做什么了, 之后,我们就能查出是否所有的进行过的试验案例都被发表了。 之后,我们就能查出是否所有的进行过的试验案例都被发表了。 但人们并没有乖乖来注册。 之后国际医学杂志编辑委员会跳出来, 他们说,那好吧,我们会坚守底线的。 除非试验案例之前已经注册过了, 否则我们是不会让它发表在学术期刊上的。 但他们还是没守住底线。2008年,一篇对此的研究 表明,被国际医学杂志编辑委员会成员 审核的上述期刊中半数的试验 没有被完整注册在案,四分一的案例甚至就根本没有注册。 最后,食品药物修正法案在几年后通过施行 强调任何实施临床试验的人 都必须在之后一年内公布临床试验的结果。 在英国医学杂志,2012年1月第一版, 你能找到一项关于人们是否履行上述法案的研究 结果表明只有五分一的人照此办理。 结果表明只有五分一的人照此办理。
This is a disaster. We cannot know the true effects of the medicines that we prescribe if we do not have access to all of the information.
悲剧阿,悲剧。 如果我们不能了解所有的相关信息, 我们就无法了解我们所开的药物的 真实疗效。
And this is not a difficult problem to fix. We need to force people to publish all trials conducted in humans, including the older trials, because the FDA Amendment Act only asks that you publish the trials conducted after 2008, and I don't know what world it is in which we're only practicing medicine on the basis of trials that completed in the past two years. We need to publish all trials in humans, including the older trials, for all drugs in current use, and you need to tell everyone you know that this is a problem and that it has not been fixed. Thank you very much. (Applause) (Applause)
但这问题不是那么难去克服的。 我们需要强制人们发表所有临床 试验的结果,包括较早以前的案例, 因为食品药物修正法只要求公开2008年之后的临床试验, 我不知道循证医药学的世界会变成什么样, 如果我们用药只依靠这两年里的实验数据。 我们需要公布所有现用药物的所有临床试验的结果,包括较早以前的试验, 我们需要公布所有现用药物的所有临床试验的结果,包括较早以前的试验, 而且你们需要告诉你认识的所有人 这是个问题,这个问题还有待解决。 谢谢大家。(掌声) (掌声)