Retraction Watch

Tracking retractions as a window into the scientific process

Head of major diagnostic lab in Canada steps down amid investigation

with 23 comments

AJPA_v185_i7_COVER.inddA prominent endocrinologist pathologist has resigned from running the largest hospital diagnostic laboratory in Canada following an investigation that has uncovered evidence of falsified data in two papers, Retraction Watch has learned.

Sylvia Asa was the Program Medical Director of the Laboratory Medicine Program at the University Health Network, affiliated with the University of Toronto, until this past spring when she stepped down, according to UHN spokesperson Gillian Howard:

Our Laboratory Medicine Program has an interim Program Medical Director.  Dr. Sylvia Asa stepped down this past spring from her position as PMD.

Thank you for understanding that a legal process means that we cannot comment on any matter before the courts.

Asa, based at Princess Margaret Cancer Centre, has co-authored nearly 100 papers with Shereen Ezzat, who also works as a researcher at Princess Margaret. According to a 2007 article in a Pituitary Network Association newsletter, they are married and have worked together since 1992.

However, two of their papers are now being retracted by the American Journal of Pathology. The journal will be issuing the same note for both papers, about the genetics of breast cancer. It confirms the existence of a UHN investigation, and the presence of “falsified data” in the papers. It ends with a defense of the work by Ezzat, who asserts that the authors have “confirmed the validity and reproducibility of the findings”:

Following correspondence in September 2012 from a concerned reader regarding the May 2010 article entitled, “Genetic and Epigenetic Mechanisms Down-Regulate FGF Receptor 2 to Induce Melanoma-Associated Antigen A in Breast Cancer” by Xuegong Zhu, Sylvia L. Asa, and Shereen Ezzat (Volume 176, pages 2333e2343; http://dx.doi.org/10.2353/ajpath.2010.091049) and the December 2010 article entitled “Loss of Heterozygosity and DNA Methylation Affect Germline Fibroblast Growth Factor Receptor 4 Polymorphism to Direct Allelic Selection in Breast Cancer” by Xuegong Zhu, Lei Zheng, Sylvia L. Asa, Shereen Ezzat (Volume 177, pages 2860e2869; http://dx.doi.org/10.2353/ajpath. 2010.100509), the Editors of The American Journal of Pathology commenced an inquiry into the validity of results reported. Initial communication between the editorial office and corresponding author Dr. Ezzat failed to resolve the matter. Therefore, in March 2013 the Editors contacted University Health Network, University of Toronto (Toronto, ON, Canada), with which all authors were affiliated, and requested an investigation of the data.

The University Health Network, University of Toronto appointed an investigative committee. Dr. Christopher Paige, Vice-President of Research, University Health Network, and Dr. Charles Chan, Vice-President of Medical Affairs & Quality, University Health Network, informed the Editors in April 2015 that the articles in question contain falsified data. Specifically, in Zhu et al (Am J Pathol 176:2333e2343) Figures 1D, 2C, 4A, 4C, and 5B contain manipulated and/or fabricated data. Original source data for the published images in Figure 2C (top) were unavailable to the committee for review. In Zhu et al (Am J Pathol 177:2860e2869), Figures 1C, 4B, 5B, 5C, and 5D contain manipulated and/or fabricated data. Original source data for the published images in Figures 1C and 5C were unavailable to the committee for review. The articles are therefore being retracted from The American Journal of Pathology by the American Society for Investigative Pathology (the owner and publisher) with the concurrence of the co-authors. Dr. Ezzat states, “On behalf of all of the other authors, we wish to state that we have collectively confirmed the validity and reproducibility of the findings reported in these articles. Nevertheless, we request that these papers be retracted.”

(Due to a publisher production error, an earlier version of the notice is posted to the site, but should be fixed shortly, we understand.)

The first paper, “Genetic and Epigenetic Mechanisms Down-Regulate FGF Receptor 2 to Induce Melanoma-Associated Antigen A in Breast Cancer,” has been cited 14 times and the second, “Loss of Heterozygosity and DNA Methylation Affect Germline Fibroblast Growth Factor Receptor 4 Polymorphism to Direct Allelic Selection in Breast Cancer,” has been cited four times, according to Thomson Scientific’s Web of Knowledge.

In response to our questions about the UHN investigation, the editor in chief of the journal told us:

These concerns have been evaluated and addressed following the procedures described in the American Journal of Pathology scientific integrity policy.  The results from this process will be published in the August issue of the Journal.

Scientists have raised other questions about the couple’s research, including commenters on PubPeer who pointed out problems with several other papers authored by Asa and Ezzat.

One of those papers, in Molecular Endocrinology, issued a correction in May for a “typographical error”:

In the article “FGFR4 Polymorphic Variants Modulate Phenotypic Features of Cushing Disease” by Tae Nakano-Tateno, Toru Tateno, Maw Maw Hlaing, Lei Zheng, Katsuhiko Yoshimoto, Shozo Yamada, Sylvia L. Asa, and Shereen Ezzat (Mol Endocrinol 28:525–533, 2014; doi: 10.1210/me.2013-1412) the authors report the following typographical error in the published paper: The graphs in Figures 1B and 3, B and D, should have been labeled on the right vertical axes, as presented below. This allows a clearer appreciation that the statistical comparisons are within each group as indicated by the horizontal bars. The authors regret this error.

We’ve asked for updates on the other papers flagged by PubPeer commenters from each journal.

When contacted regarding potential issues with papers authored by Asa and Ezzat, a spokesperson for the Endocrine Society, the publisher of Molecular Endocrinology, said that they were waiting for the results of the investigation.

The Endocrine Society is cooperating with University of Toronto’s University Health Network and awaiting the results of its investigation.

We’ve called and emailed Asa and Ezzat for comment. We’re unable to find contact information for first author Xuegong Zhu. We’ll update with any response.

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Written by Ross Keith

July 24th, 2015 at 4:17 pm

Comments
  • fernando pessoa July 24, 2015 at 8:05 pm
    • fernado pessoa July 30, 2015 at 9:10 am

      A 2015 note of concern has been published for this 2003 paper.
      http://ajp.amjpathol.org/article/S0002-9440(15)00322-3/fulltext

      “It has been brought to our attention that Figure 2 A of “Ikaros Isoforms in Human Pituitary Tumors: Distinct Localization, Histone Acetylation, and Activation of the 5′ Fibroblast Growth Factor Receptor-4 Promoter,” by Shereen Ezzat, Shunjiang Yu, and Sylvia L. Asa (Volume 163, Issue 3, pages 1177–1184 of the September 2003 issue of The American Journal of Pathology; http://dx.doi.org/10.1016/S0002-9440(10)63477-3) contains data for PGK-1 that are identical to data published in Figure 1B of Ezzat et al J Clin Invest 2002, 109:69–78; http://dx.doi.org/10.1172/JCI14036).”

  • fernando pessoa July 24, 2015 at 8:09 pm

    Likely band duplication in a 2008 paper.
    https://pubpeer.com/publications/685311CEF5DAD92CC6E89165B3C1D8

  • fernando pessoa July 24, 2015 at 8:10 pm

    Cutting and pasting in a 2007 paper.
    https://pubpeer.com/publications/17545628

  • fernando pessoa July 24, 2015 at 8:11 pm
  • fernando pessoa July 24, 2015 at 8:12 pm
  • fernando pessoa July 24, 2015 at 8:14 pm
  • fernando pessoa July 24, 2015 at 8:50 pm

    Image re-imaging in 2002 paper.

    https://pubpeer.com/publications/11781352

  • fernando pessoa July 24, 2015 at 8:57 pm
  • fernando pessoa July 24, 2015 at 8:59 pm
  • fernando pessoa July 25, 2015 at 7:43 am

    2003 paper. Band inside darker than general background rectangle.

    https://pubpeer.com/publications/268128C00E116B33D71253423A44E6#fb34025

  • Steven McKinney August 1, 2015 at 1:53 am

    http://www.680news.com/2015/07/30/staff-working-for-scientists-accused-of-falsifying-data-altered-images-document/

    “Staff working for scientists accused of falsifying data altered images: Document”

    Looks like it’s time to throw the post-docs under the bus.

    The PIs have lawyered up.

    “The court document says a former employee of the lab, Xuogong Zhu, told the committee he had changed images in two of the papers under investigation. It goes on to say Zhu reported that use of Photoshop — a computer program that can alter images — was common in the lab in question.

    Zhu, who is now a post-doctoral fellow at the University of Cincinnati, declined to be interviewed.

    Another member of the lab staff, Wei Liu, told the investigating committee that a third member of the staff, Miao Guo, told him she had altered an image to enhance it, after seeing Zhu do something similar.

    Liu told the hospital he reported Guo’s action to Ezzat but the court document says Ezzat denied the conversation took place. Later, Liu said he believed it was Asa he had told.”

    So the PIs were informed of Photoshop activities. As the PubPeer entries show, this went on from 2002 right up to the present (see Paul Brookes’ PubPeer entry for a 2015 Oncogene paper https://pubpeer.com/publications/BBC278257761C0C12E5D38844873DF ).

    Over a decade of photoshopping – this is an example of the cartoonification of science. The PIs have to take responsibility.

    “With each new sanction, journal retraction and funding opportunity lost, the applicants’ work becomes less and less credible and the applicants’ opportunities to advance their work in cancer detection and treatment are lost,” the document says.

    Is this really the kind of work that should be advanced? How is it ethical to propose treatments for humans based on photoshopped evidence?

  • Herman Chui August 1, 2015 at 12:44 pm

    The immunohistochemical images from these two studies are quite convincing, and support Dr Ezzat’s defense of the validity of the work. The use of the manipulated gel images is unfortunate; it is likely the result of sloppiness and poor record-keeping of the data collector, rather than egregious fabrication of all the data presented in these studies.

    • Marco August 2, 2015 at 3:57 am

      Would this be a comment from Michael Herman Chui, who has published with Shereen Ezzat and Sylvia Asa?

      • Herman Chui August 2, 2015 at 7:26 pm

        Yes, that would be me. I have published a minor case report with them as co-authors (you will not find any manipulated images there, in case you are checking), but that is irrelevant. I could have posted a comment anonymously; however, I have nothing to hide. Prior to this being in the news, I had no knowledge of data manipulation taking place in their lab.
        I cannot deny the fact that there are manipulated images in the papers in question. However, in my limited personal interactions with Drs Ezzat and Asa, I get the sense that they are honest, well-meaning physicians, who would not condone this behaviour if they knew about it.

  • How interesting. August 1, 2015 at 5:20 pm

    Herman Chui
    The immunohistochemical images from these two studies are quite convincing, and support Dr Ezzat’s defense of the validity of the work. The use of the manipulated gel images is unfortunate; it is likely the result of sloppiness and poor record-keeping of the data collector, rather than egregious fabrication of all the data presented in these studies.

    No one is claiming that all the data is falsified, but one does not photoshop out of sloppiness, or out of poor record keeping. As the hospital investigation concluded, there is evidence of deliberate manipulation, and one of the authors has now admitted to it. In addition, there are multiple papers from this lab demonstrating egregious image manipulation, with many different co-authors. Clearly there was a problem with the internal culture of this lab.

    I’m sad that people are defending this. It is indefensible, and unfortunate that the directors of the lab, instead of doing everything possible to increase transparency and regain trust, are pursuing judicial review.

  • Not interesting August 1, 2015 at 6:47 pm

    The term “photoshop” doesn’t mean anything. You can simply crop or change exposure with photoshop. In the case of these papers, it is not so much photoshopping per se, but duplicate gel images. It is possible that gels were mislabeled or mixed up or misplaced and so a band showing a similar result was re-used, (perhaps out of laziness of re-doing the blot). Granted, this type of behaviour should not be condoned; however, it may be premature to invalidate the conclusions from the entire study, especially when it is likely that legitimate data is provided by co-authors without knowledge of this taking place.

    How do you propose that the directors “do everything possible to increase transparency and regain trust”?

    • hollace henry August 5, 2015 at 8:12 am

      i find it strange and worrying that a photoshopped image has any defenders ; not to mention the lack of responsibility felt by this pair.
      With the Kardashianization of Science ,I and the willingness to surround the wagons to protect careers leaves me less likely to support research. As a patient I’m aghast.

  • Highly interesting August 1, 2015 at 10:58 pm

    Not interesting
    The term “photoshop” doesn’t mean anything. You can simply crop or change exposure with photoshop. In the case of these papers, it is not so much photoshopping per se, but duplicate gel images. It is possible that gels were mislabeled or mixed up or misplaced and so a band showing a similar result was re-used, (perhaps out of laziness of re-doing the blot). Granted, this type of behaviour should not be condoned; however, it may be premature to invalidate the conclusions from the entire study, especially when it is likely that legitimate data is provided by co-authors without knowledge of this taking place.
    How do you propose that the directors “do everything possible to increase transparency and regain trust”?

    You can’t say that photoshopping doesn’t mean anything, and then in the same breath say that in these papers the issue isn’t photoshopping! I am using the term loosely, true enough, but examine the first Am J Path paper on FGFR4 , and consider figure 5. It looks like a collage: the point is made well on the pub peer illustration. Assembling a gel out of separate components qualifies as photoshopping, according to the common use of the term, and can’t be done by mere poor record keeping or laziness.

    I’m pointing out that there is obvious image manipulation going on, and this casts some doubt on the reliability of the data. Surely not ALL the data is falsified, but on the basis of what evidence should an objective observer decide what is good data and what is not?

    Finally, the way to increase trust and transparency is for the lead investigators to admit the obvious: there is a problem in that lab, that perhaps the lead investigators were not aware of. In this case, they could have called a moratorium on research in the lab themselves, pending review, instead of having one imposed. I admit, this would be professionally very difficult, but the way to increase trust when the problem is obvious is not to ask for a judicial review, but to admit there is an obvious problem. Who knows, it may be too late to do anything now.

  • fernando pessoa August 3, 2015 at 5:50 pm

    2015 retraction of J Clin Invest. 2002;109(1):69–78. doi:10.1172/JCI14036.

    http://www.jci.org/articles/view/83399

  • fernandopessoa July 30, 2017 at 9:43 am

    Anticancer Res. 2010 May;30(5):1681-8.
    Osteopontin (OPN) expression in thyroid carcinoma.
    Briese J1, Cheng S, Ezzat S, Liu W, Winer D, Wagener C, Bamberger AM, Asa SL.
    Author information

    1
    Department of Laboratory Medicine and Pathobiology, University of Toronto, Department of Pathology, University Health Network, and Ontario Cancer Institute, Toronto, Ontario, Canada.

    Figure 4. http://imgur.com/EEMlfTe

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