FRESH SCIENCE for Clinicians

News about basic science of interest and relevance for cancer clinicians

Friday, January 7, 2011

Duke Scientists Retract Another Paper – and the Damage Spreads

I wrote about the scandal surrounding Anil Potti – who falsified credentials on his CV and whose work has been called into question – in OT’s September 10 issue. Since then Dr. Potti resigned from Duke, he and his (former) colleagues retracted a key paper published in the Journal of Clinical Oncology, and the university repaid more than $437,000 to the American Cancer Society from a grant previously awarded to Dr. Potti and colleagues.


Yet, the saga continues to reverberate through the oncology community at many levels.


Just today, the Duke group published a formal retraction of their 2006 Nature Medicine paper. A brief statement in the January issue of Nature Medicine, published online today, says:


We wish to retract this article because we have been unable to reproduce certain crucial experiments showing validation of signatures for predicting response to chemotherapies, including docetaxel and topotecan. Although we believe that the underlying approach to developing predictive signatures is valid, a corruption of several validation data sets precludes conclusions regarding these signatures. As these results are fundamental to the conclusions of the paper, we formally retract the paper. We deeply regret the impact of this action on the work of other investigators.


I have to wonder if a retraction of the group’s 2006 New England Journal of Medicine study will follow. 


That paper, too, has been the subject of corrections and criticism.


I called the senior author on the paper, Joseph Nevins, PhD, the  Barbara Levine Professor of Breast Cancer Genomics and Director of Duke’s Institute for Genome Science and Policy’s Center for Applied Genomics & Technology, to ask but have not heard back. (I’ll certainly update my post if I do.)


In the meantime, a Nature blog, posted two days ago, suggests that Duke leadership and the Duke Institutional Review Board (IRB) mishandled an initial investigation into Dr. Potti’s work.


After Keith Baggerly, PhD, and Kevin Coombes, PhD, both from the Department of Bioinformatics and Computational Biology at the University of Texas MD Anderson Cancer Center, informed the university that they were unable to reproduce Dr. Potti’s analyses, the university suspended three clinical trials that were based on the work and asked an internal panel to review it.


While the panel was still deliberating, Drs. Baggerly and Coombes realized that the underlying data used in Dr. Potti’s analyses were mislabeled and that the mislabeling was a crucial part of the problem. They informed Duke leadership about their new insight into the problem, and according to the investigation by Nature, the leadership shared that information with the Duke IRB.


Then, however, the IRB and the leadership together declined to pass the new information to the panel reviewing Dr. Potti’s work, worrying that it would unfairly bias the group.


Shortly thereafter, the review panel said they were able to reproduce the data (relying on the mislabeled data supplied by Dr. Potti). And the three trials, involving more than 300 patients were allowed to restart.


“To the extent that there are any patients upset that these [trials] didn’t get closed sooner, this [revelation] won’t make them happy,” Dr. Baggerly told me today in a phone interview.


He said that he and Dr. Coombes have been trying to understand how the university could have allowed the trials to resume given the problems they had discovered, but had been unable previously to get those answers.


On another front, the Institute of Medicine’s Committee on the Review of Omics-Based Tests for Predicting Patient Outcomes in Clinical Trials held their first meeting on December 20 in Washington DC. Unlike many first meetings, which are mainly organizational in character, this one proved “unusually informative,” said Dr. Baggerly.


The National Cancer Institute decided to present everything they knew about the Duke situation, and supplied hundreds of pages of documentation. Additionally, one of the NCI’s biostatisticians, Lisa McShane, PhD, described her efforts to reproduce the data.


An article in the most recent Cancer Letter describes the committee’s meeting and includes portions of Dr. McShane’s statement. And anyone short on reading material, can find all 550 pages of NCI documents on the Cancer Letter website. 


Dr. Baggerly says that he and Dr. Coombes have been reviewing all of the NCI documents at the request of the Cancer Letter, and have put together extensive annotations of what’s included. Those insights will be available next week in The Cancer Letter.


As I said, the fallout continues. And depending on how deep the community wants to consider the issues and implications, it will continue to spread for a while more.


In the simplest sense, I won’t be surprised if we see more retractions. But it is the bigger questions that are the more disturbing ones.


For example, as Dr. Baggerly pointed out when I interviewed him for my original article, humans aren’t very good at seeing problems in large batches of data, such as what is produced regularly now with ‘omics experiments.


So even though fraud and error have surely been a part of science as long as science has been around, the new technology and the massive quantity and form of the data are going to make problems more difficult to detect.


Add to that the immense community pressure to move drugs and techniques into the clinic quickly – before too much patent life is consumed, for example – it is unlikely that this is the only time patients are going to get caught up in scientific missteps.


The idea, however, that the Duke IRB failed to protect patients, even when they had an understanding of what was going wrong with the experiments – or at the very least, charges of what was going wrong – is possibly the most disturbing to me. And yet, that’s perhaps not entirely surprising either when one remembers that the institutions responsible for monitoring research quality and integrity also derive financial benefits from the work.