给Nature投稿：一个失败的故事

信源：司华博客

60多年前（45，46年），浙江大学教师贝时璋，王淦昌，束星北，何增禄四位教授在Nature上共发表了6篇论文。自那以后浙江大学教师在就没有在nature上以第一作者（或通信作者），且第一单位发表过论文（第二单位还是有的，例如童利民教授）。值得一提的是，上个月18日刘树生教授的一篇论文，实现了第二个顶级期刊Science零的突破。

近20年来，浙大每年都有一些教授向Nature，Science投稿，主要集中在生科院，医学院，农学院等。据我所知，其中汪元美，罗琛，吴平等教授的工作已经很接近发表在Nature，Science上的标准。刘树生教授更是十年磨一箭，要不发都难。

2007年10月28日，我也斗胆敲了一下Nature的门。

07年初写国家自然基金标书时，有一篇重要的参考文献（发表在nature上），而且作者的实验数据是公开的。然后我开发了一个算法进行计算，发现其中的最重要的结论是有问题的。于是我想应该可以发一篇好的期刊文章，就斗胆投了nature的子刊：nature medicine （影响因子：28.8）。投的栏目是brief communication。结果5天后退稿，没有过编辑这一关，根本就没能进入peer review（同行评议）阶段。

他们说我是对nature的文章提出争议，所以建议我投nature杂志的Letter to the Editor栏目，当时我对nature的这个栏目发表的文章还不十分了解，以为在这个栏目发了，在SCI收录时，文章的类型可能是Editorial Material，那么这篇文章连一篇SCI都不算。这是因为中国科技信息研究所统计各单位的SCI论文时，只有文章类型为article，review，letter才算SCI论文。那样我不是亏大了？另一方面，投nature我还是有些怯场，和世界级牛人在国际顶级期刊PK, 怕怕的。其实主要还是自己底气不足，虽然我叫板他们的最主要结论，但不是全部结论，我甚至通过计算重复了他们的另一个结论 （后来我把他们这个结论也从另一个侧面否定了)。结果，我没有听从Nature medicine编辑的忠告，我投了New England Journal of Medicine。

“新英格兰医学”SCI影响因子51.3，是世界上影响因子排第二的期刊，医学期刊no.1，浙大在这个期刊也没有实现零的突破。新英格兰医学也发有letter to the Editor栏目，对于挑战其他刊物的文章它也发（一般期刊只刊登挑战本期刊上发表的论文的Letter）。投稿的结果还是：退你没商量！不过，14天后才退。这也算是一个进步，正好两周。国际著名期刊不像中国期刊，他们的编辑都是专家级的，能使自己的文章在新英格兰医学编辑部待上两周，虽然很失望，但心中还是有些快慰。

投到Nature去！这是因为，Nature偶尔还发一篇data reanalysis文章，就是对已经发表的一些数据进行再分析，但是投稿前要给编辑部发一个拟投论文的大纲。这样的文章如果发了，SCI检索时文章的类型是Article。因此，就斗胆发了一个大纲过去，3天后又退了。

事到如今，还是不甘心，就硬着头皮投nature的“Letter to the Editor”。其实现在的nature根本就没有“Letter to the Editor”这个栏目，这个栏目现在叫Brief Communications Arising，这个栏目把nature原来的brief communication也合并进去了，SCI收录时把这个栏目的文章归类为Letter类型。还没有把manuscript上传上去，再研究Author information 发现有这样的说法：

Brief Communications Arising are exceptionally interesting or important scientific comments and clarifications on original research papers or other peer-reviewed material published in Nature.

Submissions should challenge the main conclusions of the Nature paper and contain new, unpublished data to support the arguments.

Submissions that contradict only part of the Nature paper are not considered unless they concern a matter of exceptional interest.

而且：

* Comments should be sent to the authors of the paper under discussion before submission to Nature, so that disputes can be resolved directly whenever possible and points where both parties agree removed from the submitted contribution. Allow 2 weeks for the original authors to respond.

* When a contribution is submitted to Nature, copies of correspondence with the original authors should be enclosed for the editor's information, even if the original author has failed to respond. The correspondence should accompany the submission as an attachment clearly labelled as 'Correspondence with the Nature authors'.

很显然，我们只是挑战原作者的部分结论，而谈不上main conclusions，因此只好暂停投稿过程，结果nature发email要我们继续上传manuscript。由于信心不足，只好完全放弃投稿。

没有金刚钻，别揽瓷器活。不过心里还是希望投一个高影响因子的期刊，类型是一般研究文章。因此，我又回过头来看原文，再进行计算。原来有些结论由于医学知识没有明白，所以，这次和co-author们见面，面谈，后来又打了很多电话交流。终于彻底把文章研究明白了，结果又发现的nature原文作者的两个破绽，这时，我们的底气足了很多。完全可以谈得上挑战其main conclusions。所以，我们不打算投其他期刊，准备再杀它个回马枪。因为我们觉得有理由理直气壮地投nature了。我们的manuscript摘要如下：

Both mRNA and microRNA (miRNA) profiles can be used for the classification of human cancers. In the experiments done by Lu et al., the samples used to examine the miRNA and mRNA expression profiles were identical, making their two studies directly comparable. However, the main conclusions of their study are not correct, including (1) sufficient cancer diagnostic information is encoded in a relatively small number of miRNAs; (2) among the epithelial samples, gut-derived samples all clustered together when using miRNA expression profiles, whereas this phenomenon was not observed in mRNA expression profiles; and (3) by using miRNA expression profiles, poorly differentiated tumors (PDT) could be classified more accurately, whereas mRNA expression profiles were almost completely inaccurate when applied to the same samples. Here we show that information encoded in miRNAs is not sufficient to classify cancers; gut-derived samples cluster together more perfectively when using mRNA expression profiles compared with miRNA's; and PDT could be classified by mRNA expression profiles at the accuracy of 100% (versus 93.8% of miRNA's). Further more, we proved that mRNA expression profiles have higher ability of tissue classification than that of miRNA's.

编辑的初步决定（11月1日）：把我们的文章给nature原文章作者

Dear Dr Peng

Thank you for submitting your Communications Arising entitled "Cancer classification by expression profiles: microRNA versus mRNA" to Nature. This message is to tell you that we are sending your paper out to the Nature authors for their response according to our policy (see our guidelines to authors of Communications Arising www.nature.com/nature/authors/gta/commsarising.html). Once we have received their reply, we shall decide whether or not to send the exchange out for review.

This decision is reached after discussion with the appropriate specialist editors and depends on a number of factors, including the likely impact of the criticism, the topicality of the discussion, and its interest to the non-specialist readers of this section of the journal (many debates are referred to the specialist literature at this point or the issues are addressed in the form of a published clarification from the criticised authors).

If we have several comments under consideration on one of our published papers, this may introduce delays while we coordinate these steps in the editorial process, so please allow four weeks before sending us any status enquiries.

Please note that consideration of your comment by Nature is contigent on there being no discussion of its content with the media in advance of publication (see www.nature.com/nature/authors/policy).

Yours sincerely

Angela

Angela K Eggleston, PhD

Senior Editor

Nature

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Nature的guideline写道：

If the Nature authors do not respond within 10 days of receipt of the comment, the editor will proceed without the response. Late Replies may not be considered for publication.

也就是说，nature按理只给10天给原作者response。那么应该在11月11日前应该收到原作者的response。这一个Email同时提醒我们有可能要等4个星期，再问文章的结果。

等了六个星期后，我发了email询问：

我们的Email全文如下：

Dear editor,

After the submission of our manuscript entitled "Cancer classification by expression profiles: microRNA versus mRNA" (tracking number: 2007-10-11332) to Nature, six weeks have passed. So I would like to inquire the status of our manuscript.

We think that our comments on the original paper of Nature will cause widespread interest to both experts and non-experts. This is because microRNA is a hot spot in life science; the author of the original paper is a VIP in cancer research based on gene expression profiles, with a SCI H index of 45, total citations more than 15,000 times, and this paper citied 365 times; and the algorithm we proposed outperforms the recent state-of-the-art algorithm. Moreover, by using other state-of-the-art algorithms, we can also prove that the original author's main conclusions are wrong.

I am looking forward to your reply. Thanks a lot.

Sincerely yours,

Sihua Peng, PhD.

2007-12-10

最后的结局：经过44天的漫长等待，最后还是退稿！

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退稿信：

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11th December 2007

Dear Dr Peng

Thank you for your submission to Brief Communications Arising, which I am afraid we must decline to publish. As is our policy on these occasions, we showed your comment to the Nature authors, and their response is enclosed below.

In light of this reply and of the competition in this section of the journal, we have regretfully decided that publication of this debate is not justified: this is because in our view it would not add sufficiently to our understanding or otherwise clarify the issues for our readers.

Thank you again, however, for writing to us.

With kind regards

Angela

Angela K Eggleston, PhD

Senior Editor

Nature

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以下是原nature作者的response

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Nature Author:

Peng and colleagues describe their efforts to reanalyze the miRNA results reported by Lu et al.

One of the great triumphs of the genomic era is that datasets are now publicly available, and can be analyzed by the entire scientific community, often leading to new insights into old data, or refining methodologies.

The present manuscript is somewhat difficult to evaluate because of the paucity of methodological detail. However, it appears that the stunning classification accuracy described by Peng et al (that was lacking in the Lu et al paper), is a result of the two-step feature selection approach. Indeed, it is not at all surprising that such an approach would yield the appearance of improved classification. The problem, well-known to those experienced in genomic analyses, is that there is a serious danger of over-fitting the model to a given dataset -- particularly in this high dimensional space. Peng et al use a leave-one-out classification method to address, this, but it is applied AFTER feature selection, at which point the damage is already done. It is imperitive that the feature selection be done outside the cross-validation loop, and ideally, the model would be applied to an independent set of samples. Likewise, it is not surprising in the least that if features are first

selected (i.e. for gut vs. non-gut derived tumors), that the samples will appear to cluster together. But clustering in the space of features selected in a supervised manner is meaningless, and the result is without question a result of serious over-fitting.

While it certainly remains possible that, as the authors suggest, the mRNA profiles contain diagnostically useful signatures, the proposed approach is not convincing, and indeed is fundamentally flawed. If this interpretation is a misunderstanding, then this issue could be clarified in the form of a full-length report, rather than a correspondence, where such detail obviously cannot be included.

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总结:

1．Nature把我们拒了，还不给我们的申辩的机会。所以，心里很不服气，到这里也算发泄一下。他们在author guideline里写道：

The editors will not consider appeals against decisions not to publish Communications Arising from Nature Articles and Letters unless the grounds for appeal consist of a previously overlooked and important scientific point and are clearly explained in these terms.

2．我们在稿件状态询问信中写道：Moreover, by using other state-of-the-art algorithms, we can also prove that the original author's main conclusions are wrong. 因此希望搞生物信息学，数据挖掘，机器学习的高手继续挑战这篇文章的主要结论的正确性。原文是：Nature 435, 834-838, 2005.

3．这是我第一次以第一作者（兼通信作者）的身份投稿，我的文章写法，与编辑及nature原文作者的沟通Email的措辞有否不妥的地方，请有经验的老师指教一下，以便下次不犯同类错误。

4．这个失败的故事也许能给各位投nature的老师一些有益的启示。浙大在走向世界一流的过程中，需要更多像刘树生教授那样的在Science，Nature上发表文章的人。我觉得，浙江大学如果不在这两个期刊每年发表5篇以上的论文，不能称为世界一流大学（我们浙大建校110年总共只发了7篇）。像哈佛大学那样的世界顶尖一流高校，在这两个期刊每年共发表100篇以上（只算通信作者）。