In 2016, researchers published a paper showing that an RNA molecule may be overactive in breast tumor tissue. But after reading the paper, three biologists believed the data supported the opposite conclusion.
What happened after that is a tale of misunderstandings and unnecessarily bruised feelings. We’ve seen plenty of cases where researchers ignore criticism, which at first glance seemed to be the case here. But upon closer inspection, it wasn’t.
The concerned readers—Debomoy Lahiri, Kumar Sambamurti and Bryan Maloney—contacted the authors in June 2017 for clarification on the apparent contradiction between the results and data. When they didn’t hear back, the trio submitted a letter to the journal, Gene, a week later, highlighting potential “critical errors” in the article. According to the journal editor, in the interest of transparency, it published the letter—which contains highly pointed critiques of the paper—in September. But the letter appears without comment or clarification from the paper’s authors.
The first author says the journal didn’t reach out before publishing the letter; what’s more, the first and the corresponding authors argue the critics simply misinterpreted their findings, and the first author has asked them to withdraw the letter. The critics say they were confused by misleading legends on some figures. The journal editor says he wishes the entire dialogue had stayed private.
Here’s what sparked confusion over the paper, “MiR-346 promotes the biological function of breast cancer cells by targeting SRCIN1 and reduces chemosensitivity to docetaxel,” which has been cited three times, according to Clarivate Analytics’ Web of Science. First author Fan Yang and corresponding author Jin-hai Tang—who both work at Nanjing Medical University Affiliated Cancer Hospital in China—reported that MiR-346 may fuel the spread of breast cancer. But Lahiri, Sambamurti and Maloney believed two figures in the paper showed that MiR-346 decreases, not increases, in cancer tissue. As they write in the letter, “When figures and data contradict text: MiR346 is apparently reduced in breast cancer tissue, contrary to claims by a paper’s author:”
The problem with these statements is that they contradict the actual data presented in the paper!…In its current state, the text will certainly create confusion in the field and lead to incorrect assumptions…
Yang and Tang told us the critics simply misinterpreted the data. The explanation lies in the statistical tools they used: The authors say they had calculated the expression of miR-346 in tumor tissue and healthy tissue using the widely accepted method, 2−ΔΔCt, but had depicted this activity in the two figures in question using a different method, ΔCt. Tang and Yang explained they used the ΔCt method “for the beauty and saliency of the figure,” but that the 2−ΔΔCt method reveals that “the expression of miR-346 in tumor tissue is about two times higher than in normal tissue.”
Yang also explained why the critics didn’t get a response when they first emailed in June:
… for personal reasons, I haven’t been here and read the mail for some time, so I didn’t find out they had contacted me before.
Yang also said the journal “didn’t contact me directly.”
One misunderstanding after another
The editor-in-chief of Gene, Andre van Wijnen, told us he couldn’t remember if Tang and Yang reviewed the letter before it was published:
By procedure, our intent is that authors have a chance at a reply, and typically this is done by inviting the authors as ‘reviewers’ by routing the letter as if it is a full paper submission. The original authors may or may not have responded in time, or they may have responded and provided non-constructive comments.
Regardless, van Wijnen explained, “we proceeded with the Letter for the reason that it exposed major weaknesses:”
Personally, I think that the authors should have just kept this a private conversation between colleagues and then reach some kind of consensus followed by a corrigendum that clarifies uncertainties. At least that is how I think science should be conducted.
The idea behind the corresponding author is that this is the point person who will handle any inquiries to the work. Why anyone would want to escalate disagreements about data to the level of a public letter that is somewhat scathing is beyond me, but since the journal offers the format, it would be a form of censoring if letter writers did not have a forum in GENE to express their view.
After we reached out, Yang emailed Lahiri October 4 to address the concerns with the 2016 paper, and to ask why Lahiri hadn’t contacted the authors directly. Yang also asked that Lahiri and colleagues to withdraw their letter.
Lahiri responded to Yang on October 7:
We are grateful for providing us with an explanation for the apparent misinterpretation of your study. We did not contact the editors of Gene frivolously or as any sort of disrespect.
Lahiri told us:
We agree that we missed the fact that they presented ΔCt for one half of the figures while using 2-ΔΔCt, for the remainder. In our defense, all we have is one small representation (ΔCt) embedded within a large label on the Y axis, and no explanation in the figure legend. Figure legends do not indicate that authors were changing the presentation of these values for “saliency and beauty”. Without the clear notation of the exception in the figure legend, the readers are forced to depend on a tiny change in the Y axis of the figure and depend on minutia of the methodology. Moreover, “Materials and Methods” of their paper just lists one method of analysis: 2−ΔΔCt, and not ΔCt.
Lahiri also told us:
we are grateful for the opportunity to clarify events and bring to light a potentially severe shortcoming in the published article. We feel that it is an obligation for authors to provide clarification in the form of revised figures and legends for the benefit of future readers.
Regarding the fate of the paper and letter, van Wijnen told us:
This Letter is there on its own merit, and readers can make up their mind whether the accepted paper should stand. If the arguments in the Letter are true, you would expect the authors to volunteer and request a retraction. If they do not, then the Letter is there for all to see, and the work is critically debunked. It is not about necessarily about publishing, but whether a paper is useful and citable.
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