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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.
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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.
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Angela K Eggleston, PhD
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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.
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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
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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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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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2£®ÎÒÃÇÔÚ¸å¼þ״̬ѯÎÊÐÅÖÐдµÀ£ºMoreover, by using other state-of-the-art algorithms, we can also prove that the original author's main conclusions are wrong. Òò´ËÏ£Íû¸ãÉúÎïÐÅϢѧ£¬Êý¾ÝÍÚ¾ò£¬»úÆ÷ѧϰµÄ¸ßÊÖ¼ÌÐøÌôÕ½ÕâƪÎÄÕµÄÖ÷Òª½áÂÛµÄÕýÈ·ÐÔ¡£ÔÎÄÊÇ£ºNature 435, 834-838, 2005.
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