手機版
ANIL POTTI, Joseph Nevins and their colleagues at Duke University in Durham, North Carolina, garnered widespread attention in 2006. They reported in the New England Journal of Medicine that they could predict the course of a patient’s lung cancer using devices called expression arrays, which log the activity patterns of thousands of genes in a sample of tissue as a colourful picture (see above). A few months later, they wrote in Nature Medicine that they had developed a similar technique which used gene expression in laboratory cultures of cancer cells, known as cell lines, to predict which chemotherapy would be most effective for an individual patient suffering from lung, breast or ovarian cancer.
2006年，北卡羅來納州達勒姆市杜克大學的阿尼爾•波提、約瑟夫•奈文斯及其同事受到廣泛關注。他們在《新英格蘭醫學雜志》上發表文章，說是可以使用一種叫做表達序列的手段來預測肺癌病人的癌變過程，這種方法可以把組織樣本中成千種基因的活動形態記錄成一張彩色圖片（如上圖）。幾個月后，他們又在《自然醫學》上報告說，他們已經研發出一種同類的技術，可以使用實驗室培養的癌細胞（即細胞系）中的基因表達，來預測對于一個肺癌、乳腺癌或卵巢癌患者來說，哪一種化療方法會最有效。
At the time, this work looked like a tremendous advance for personalised medicine—the idea that understanding the molecular specifics of an individual’s illness will lead to a tailored treatment. The papers drew adulation from other workers in the field, and many newspapers, including this one (see article), wrote about them. The team then started to organise a set of clinical trials of personalised treatments for lung and breast cancer. Unbeknown to most people in the field, however, within a few weeks of the publication of the Nature Medicine paper a group of biostatisticians at the MD Anderson Cancer Centre in Houston, led by Keith Baggerly and Kevin Coombes, had begun to find serious flaws in the work.
當時，這一研究好象是個性化醫療的重大突破——想想看，只要我們了解一個人的病癥在分子層面有哪些特點，就可以對之進行針對性的治療，這是多么聰明的想法！因此，這些論文從同一領域的其他研究者那里獲得了大量贊譽，包括《經濟學人》在內的許多報紙雜志都載文予以報道。這個研究小組接著開始組織一系列的臨床試驗，為肺癌和乳腺癌病人提供個性化的治療。不過，這個領域里的多數人都不知道，在《自然醫學》上那篇論文發表后短短幾周內，休斯頓安德森癌癥中心的一群生物統計學家就在基思•拜格里和凱文•庫姆斯的領導下，開始在上述研究中發現嚴重的缺陷。
Dr Baggerly and Dr Coombes had been trying to reproduce Dr Potti’s results at the request of clinical researchers at the Anderson centre who wished to use the new technique. When they first encountered problems, they followed normal procedures by asking Dr Potti, who had been in charge of the day-to-day research, and Dr Nevins, who was Dr Potti’s supervisor, for the raw data on which the published analysis was based—and also for further details about the team’s methods, so that they could try to replicate the original findings.
拜格里博士和庫姆斯博士本來是因應安德森中心的臨床研究員想要使用這項新技術的需要，而準備再現波提博士的研究結果的。最初遇到困難時，他們按照常規，請負責日常研究工作的波提博士以及他的主管奈文斯博士提供他們所發表的論文原始數據，并進一步詳細詢問他們的研究方法，以便能夠復制他們原來的發現。
A can of worms問題多多
Dr Potti and Dr Nevins answered the queries and publicly corrected several errors, but Dr Baggerly and Dr Coombes still found the methods’ predictions were little better than chance. Furthermore, the list of problems they uncovered continued to grow. For example, they saw that in one of their papers Dr Potti and his colleagues had mislabelled the cell lines they used to derive their chemotherapy prediction model, describing those that were sensitive as resistant, and vice versa. This meant that even if the predictive method the team at Duke were describing did work, which Dr Baggerly and Dr Coombes now seriously doubted, patients whose doctors relied on this paper would end up being given a drug they were less likely to benefit from instead of more likely.
波提博士和奈文斯博士回答了他們的問題，還公開更正了幾個錯誤，但是拜格里博士和庫姆斯博士還是發現，他們的所謂預測方法其實跟碰運氣差不多。而且，新的問題還在接踵而至。比如，他們發現在一篇論文中，波提博士及其同事把他們用來推導化療預測模型的細胞系標錯了，把敏感性的標成了有抗性的，又把有抗性的標成了敏感性的。這也就是說，即使杜克大學研究小組所描述的這個預測方法是可行的——當然，拜格里博士和庫姆斯博士現在已經表示嚴重懷疑——假如醫生依賴這篇論文的話，就會給病人開錯藥，結果病人獲益的程度可能不但不會增加，反而會降低。
Another alleged error the researchers at the Anderson centre discovered was a mismatch in a table that compared genes to gene-expression data. The list of genes was shifted with respect to the expression data, so that the one did not correspond with the other. On top of that, the numbers and names of cell lines used to generate the data were not consistent. In one instance, the researchers at Duke even claimed that their work made biological sense based on the presence of a gene, called ERCC1, that is not represented on the expression array used in the team’s experiments.
安德森中心的研究員說他們還發現了一個錯誤，就是用來比較基因和基因表達數據的表格錯位了——基因列相對于表達數據出現了位移，結果彼此不相對應。此外，用來得出數據的細胞系的數量和名稱前后也不一致。有一個地方，杜克大學的研究員甚至聲稱由于一個叫做ERCC1的基因的存在，證明他們的研究完全合乎生物科學，可是這個基因在他們實驗所使用的表達系列里根本就沒有出現。
Even with all these alleged errors, the controversy might have been relegated to an arcane debate in the scientific literature if the team at Duke had not chosen, within a few months of the papers’ publication (and at the time questions were being raised about the data’s quality) to launch three clinical trials based on their work. Dr Potti and his colleagues also planned to use their gene-expression data to guide therapeutic choices in a lung-cancer trial paid for by America’s National Cancer Institute (NCI). That led Lisa McShane, a biostatistician at the NCI who was already concerned about Dr Potti’s results, to try to replicate the work. She had no better luck than Dr Baggerly and Dr Coombes. The more questions she asked, the less concrete the Duke methods appeared.
雖然存在這些有爭議的錯誤，如果杜克大學的研究小組沒有選擇在論文發表后幾個月內（而且當時關于數據質量存在的問題已經開始浮出水面），就以他們的研究為基礎開始三項臨床試驗，這場論戰本來可能會降級為科學文獻里晦澀難懂的爭辯。波提博士及其同事還計劃把他們的基因表達數據用來在一項由美國國家癌癥研究所（NCI）出資進行的肺癌試驗中指導治療方法的選擇，這就促使原本就對波提博士的研究結果持保留意見的NCI生物統計學家麗薩•麥克申也開始嘗試復制他們的工作。結果跟拜格里博士和庫姆斯博士一樣，她提出的問題越多，杜克大學的研究方法就顯得越不靠譜。
In light of all this, the NCI expressed its concern about what was going on to Duke University’s administrators. In October 2009, officials from the university arranged for an external review of the work of Dr Potti and Dr Nevins, and temporarily halted the three trials. The review committee, however, had access only to material supplied by the researchers themselves, and was not presented with either the NCI’s exact concerns or the problems discovered by the team at the Anderson centre. The committee found no problems, and the three trials began enrolling patients again in February 2010.
有鑒于此，NCI向杜克大學的管理層就該項研究的實際情形表示了擔憂。2009年10月，杜克大學的官員對波提博士和奈文斯博士的研究工作進行了外部審核，并暫時中止了三項臨床試驗�？墒菍彶槲瘑T會只收到了研究方自己所提供的材料，他們既不知道NCI的保留意見細節，也不清楚安德森中心研究人員所發現的問題。結果委員會沒發現任何問題，三項臨床試驗也于2010年2月重新開始招收病人。
Finally, in July 2010, matters unravelled when the Cancer Letter reported that Dr Potti had lied in numerous documents and grant applications. He falsely claimed to have been a Rhodes Scholar in Australia (a curious claim in any case, since Rhodes scholars only attend Oxford University). Dr Baggerly’s observation at the time was, “I find it ironic that we have been yelling for three years about the science, which has the potential to be very damaging to patients, but that was not what has started things rolling.”
一直到2010年7月，《癌癥通訊》報道說，波提博士在若干文件和撥款申請中造了假，謊稱自己是澳大利亞的羅茲獎學者（這一聲明非常稀奇，因為羅茲獎學者是只能上牛津大學的），事情才開始敗露。拜格里博士當時評論說：“我覺得特別具有諷刺意味的是，我們為了他們的研究大喊大叫了三年，因為可能會嚴重損害到病人，可那并沒能讓他們停下來。”
A bigger can?還有更多的問題？
By the end of 2010, Dr Potti had resigned from Duke, the university had stopped the three trials for good, scientists from elsewhere had claimed that Dr Potti had stolen their data for inclusion in his paper in the New England Journal, and officials at Duke had started the process of retracting three prominent papers, including the one in Nature Medicine. (The paper in the New England Journal, not one of these three, was also retracted, in March of this year.) At this point, the NCI and officials at Duke asked the Institute of Medicine, a board of experts that advises the American government, to investigate. Since then, a committee of the institute, appointed for the task, has been trying to find out what was happening at Duke that allowed the problems to continue undetected for so long, and to recommend minimum standards that must be met before this sort of work can be used to guide clinical trials in the future.
2010年底，波提博士離開了杜克大學，而杜克大學也徹底終止了那三項臨床試驗。有其它地方的科學家宣稱，波提博士在《新英格蘭醫學雜志》上的那篇論文中盜用了他們的數據，于是杜克大學的官員啟動程序，開始撤回連同《自然醫學》上那篇文章在內的三篇重要論文。（《新英格蘭醫學雜志》上的那篇論文不算在這三篇之內，不過也已于今年3月撤回。）與此同時，NCI和杜克大學的官員邀請為美國政府提供專家咨詢的醫學協會著手進行調查。從那時開始，該協會專門為此成立的委員會一直在研究，這些問題為什么會在杜克大學持續存在這么久而沒人發現，以便就將來把此類研究工作用于指導臨床試驗前必須滿足的最低標準提出建議。
At the committee’s first meeting, in December 2010, Dr McShane stunned observers by revealing her previously unpublished investigation of the Duke work. Subsequently, the committee’s members interviewed Dr Baggerly about the problems he had encountered trying to sort the data. He noted that in addition to a lack of unfettered access to the computer code and consistent raw data on which the work was based, journals that had readily published Dr Potti’s papers were reluctant to publish his letters critical of the work. Nature Medicine published one letter, with a rebuttal from the team at Duke, but rejected further comments when problems continued. Other journals that had carried subsequent high-profile papers from Dr Potti behaved in similar ways. (Dr Baggerly and Dr Coombes did not approach the New England Journal because, they say, they “never could sort that work enough to make critical comments to the journal”.) Eventually, the two researchers resorted to publishing their criticisms in a statistical journal, which would be unlikely to reach the same audience as a medical journal.
在該委員會于2010年12月召開的第一次會議上，麥克申博士公布了她之前就杜克大學的研究所做的未公開發表的調查，結果令觀察員大吃一驚。隨后，委員會的成員就拜格里博士梳理數據時所遇到的問題跟他進行了談話。拜格里博士說，除了無法自由取得作為該項研究基礎的計算機編碼和前后一致的原始數據外，那些發布了波提博士論文的雜志都不肯發表他批評該項研究的信函�！蹲匀会t學》發表了一封他的信，連同杜克大學研究小組的辯駁，但是在問題持續得不到解決時，卻拒絕發表更多的評論。其它后來發表了波提博士高調論文的刊物也一樣。（拜格里博士和庫姆斯博士沒有跟《新英格蘭醫學雜志》聯系過，因為他們“一直無法徹底理清那項研究，因而無法向該雜志提出批評意見”。）最終，這兩位研究員只得把他們的批評發表在一個統計刊物上，其讀者群自然跟醫學雜志的不一樣。
Two subsequent sessions of the committee have included Duke’s point of view. At one of these, in March 2011, Dr Nevins admitted that some of the data in the papers had been “corrupted”. He continued, though, to claim ignorance of the problems identified by Dr Baggerly and Dr Coombes until the Rhodes scandal broke, and to support the overall methods used in the papers—though he could not explain why he had not detected the problems even when alerted to anomalies.
該委員會接下來的兩次會議聽取了杜克大學的意見。在2011年3月的那次會議上，奈文斯博士承認這些論文中有些數據“存在缺陷”。不過，他聲稱在羅茲丑聞發生前，他對于拜格里博士和庫姆斯博士所發現的問題一無所知，而且他對于論文中所使用的總體方法表示支持，雖然他無法解釋為什么當有人指出一些反常情況時，他沒能及時發覺問題。
At its fourth, and most recent meeting, on August 22nd, the committee questioned eight scientists and administrators from Duke. Rob Califf, a vice-chancellor in charge of clinical research, asserted that what had happened was a case of the “Swiss-cheese effect” in which 15 different things had to go awry to let the problems slip through unheeded. Asked by The Economist to comment on what was happening, he said, “As we evaluated the issues, we had the chance to review our systems and we believe we have identified, and are implementing, an improved approach.”
8月22日，在第四次也是最近的一次會議上，委員會詢問了杜克大學的八位科學家及其管理人員。負責臨床研究的副校長羅勃•卡利夫說，這起事件是典型的“瑞士奶酪效應”，也就是說，有15件不同的事情都出了錯，才導致問題發生而無人察覺。當《經濟學人》就所發生的事請他評論時，他說：“我們在評估這些問題時，也借這個機會審查了我們的系統。我們相信已經找到了、并且正在實施改進的措施。”
The university’s lapses and errors included being slow to deal with potential financial conflicts of interest declared by Dr Potti, Dr Nevins and other investigators, including involvement in Expression Analysis Inc and CancerGuide DX, two firms to which the university also had ties. Moreover, Dr Califf and other senior administrators acknowledged that once questions arose about the work, they gave too much weight to Dr Nevins and his judgment. That led them, for example, to withhold Dr Baggerly’s criticisms from the external-review committee in 2009. They also noted that the internal committees responsible for protecting patients and overseeing clinical trials lacked the expertise to review the complex, statistics-heavy methods and data produced by experiments involving gene expression.
杜克大學的過失和錯誤包括：在處理波提博士、奈文斯博士及其他研究員所公開的潛在財務利益沖突時反應過慢，這其中包括當事人在表達分析公司（Expression Analysis Inc）和癌癥指導診斷公司（CancerGuide DX）中的介入，而這兩間公司跟杜克大學也有關聯。此外，卡利夫博士及其他高級管理人員也承認，研究工作出問題以后，他們過于倚賴奈文斯博士和他的判斷，以至于在2009年舉行那次外部審查時，沒有把拜格里博士的批評意見告訴審查委員會。他們也注意到，大學內部負責保護病人和監督臨床試驗的委員會缺乏專業知識，無法審查基因表達試驗中所使用的復雜統計方法及其所得出的數據。
That is a theme the investigating committee has heard repeatedly. The process of peer review relies (as it always has done) on the goodwill of workers in the field, who have jobs of their own and frequently cannot spend the time needed to check other people’s papers in a suitably thorough manner. (Dr McShane estimates she spent 300-400 hours reviewing the Duke work, while Drs Baggerly and Coombes estimate they have spent nearly 2,000 hours.) Moreover, the methods sections of papers are supposed to provide enough information for others to replicate an experiment, but often do not. Dodgy work will out eventually, as it is found not to fit in with other, more reliable discoveries. But that all takes time and money.
這是一個調查委員會反復聽到的主題。同行審查這一程序依靠的是同一領域其他同行的善意（一直以來都是如此），但是這些同行也都有他們自己的工作，通常沒有足夠的時間來徹底仔細地檢查別人的論文。（麥克申博士估計，她花了300-400小時檢查杜克大學的研究；拜格里博士和庫姆斯博士估計，他們花了將近2,000小時。）此外，論文的方法部分本來應該為其他人復制實驗提供足夠的信息，但通常情況都不是這樣。騙人的研究如果跟其它更可靠的發現相違，最終會被拆穿，但這一切都需要時間和費用。
The Institute of Medicine expects to complete its report, and its recommendations, in the middle of next year. In the meantime, more retractions are coming, according to Dr Califf. The results of a misconduct investigation are expected in the next few months and legal suits from patients who believe they were recruited into clinical trials under false pretences will probably follow.
醫學協會計劃明年年中完成報告及其建議。與此同時，按照卡利夫博士的說法，還會有更多的論文被撤回。在接下來的幾個月里，瀆職調查會見分曉，隨之而來的可能是因為虛假陳述而報名參加臨床試驗的病人提起法律訴訟。
The whole thing, then, is a mess. Who will carry the can remains to be seen. But the episode does serve as a timely reminder of one thing that is sometimes forgotten. Scientists are human, too.
整件事情一團糟。最后誰會成為炮灰還不知道，不過這些情節提醒我們記住一個常常被忽略的事實——科學家也是人。
Correction: This article originally stated that by the end of 2010 officials at Duke University began the process of retracting five papers. That should have been three papers. This was corrected on September 8th.
更正：本文原來說，截止到2010年底，杜克大學的官員啟動程序，開始撤回五篇論文，實際為三篇，故于9月8日更正。
原文鏈接：http://www.economist.com/node/21528593
相關閱讀：東北農業大學實驗室感染事故引發的安全思考
