Dutch Investigation Finds Serious Flaws In Influential New England Journal Of Medicine Study Reply

Erasmus Medical Center says it has wrapped up its investigation of Don Poldermans, the disgraced cardiology researcher who was fired for research misconduct. The full extent of the misconduct has never been known, and from an examination of the Erasmus report it appears likely that it never will be known.

One major finding– though downplayed in the medical center’s press release– is that the most prestigious and influential publication from the Poldermans’ group, the 1999 publication of the DECREASE 1 study in the New England Journal of Medicine– appears to be riddled with serious problems.

Click here to read the full post on Forbes.

 

 

Medicine faculty of the Erasmus MC, taken in t...

Medicine faculty of the Erasmus MC, taken in the afternoon (Photo credit: Wikipedia)

 

About these ads

Leading European Cardiologist Accused Of Plagiarism Reply

Thomas Lüscher, the editor of the European Heart Journal and one of the most prominent cardiologists in Europe, has been accused of plagiarism. An irony in the case is that  Lüscher has taken a strong public position against scientific misconduct of all sorts, including plagiarism.

Click here to read the full post on Forbes.

 

This Blog Is ‘Not Suitable For Dissemination Through The Internet’ 1

The editors of the prestigious European Heart Journal have decided that this blog, or at least one recent post, “is “not suitable for dissemination through the internet.”

I beg to differ.

In an EHJ editorial, Is the panic about beta-blockers in perioperative care justified?the authors, the editors of the journal, led by editor-in-chief Thomas Lüscher, repeatedly criticize a post I wrote a few weeks ago with an intentionally provocative headline, “Medicine Or Mass Murder? Guideline Based on Discredited Research May Have Caused 800,000 Deaths In Europe Over The Last 5 Years.”

Their editorial begins:

Controversial issues need proper discussion, both in science and clinical medicine. Sometimes the interpretation of the available data is complex and not suitable for dissemination through the internet.1

That reference at the end refers to my earlier article.

Click here to read the full post on Forbes.

 

Censorship
Censorship (Photo credit: IsaacMao)

Medicine Or Mass Murder? Guideline Based on Discredited Research May Have Caused 800,000 Deaths In Europe Over The Last 5 Years 2

Last summer British researchers provoked concern when they published a paper raising the possibility that by following an established guideline UK doctors may have caused as many as 10,000 deaths each year. Now they have gone a step further and published an estimate that the same guideline may have led to the deaths of as many as 800,00 people in Europe over the last five years. The finding, they write, “is so large that the only context in the last 50 years comes from the largest scale professional failures in the political sphere.” The 800,000 deaths are comparable in size to the worst cases of genocide and mass murder in recent history.

In their new article published in the European Heart Journal, Graham Cole and Darrel Francis continue to explore the extent and implications of the damage caused by the Don Poldermans research misconduct case….

Click here to read the full post on Forbes.

Hannibal Lecter

Hannibal Lecter (Photo credit: Wikipedia)

First Retraction In the Don Poldermans Case Reply

Retraction Watch reports the first formal retraction of a paper by Don Poldermans, the disgraced Dutch cardiovascular researcher.

  • Feringa HH, Elhendy A, Bax JJ, Boersma E, de Jonge R, Schouten O, Karagiannis SE, Schinkel AF, Lindemans J, Poldermans D. Coron Artery Dis. 2006 May;17(3):255-9. Baseline plasma N-terminal pro-B-type natriuretic peptide is associated with the extent of stress-induced myocardial ischemia during dobutamine stress echocardiography.

Here is the text of the retraction:

Feringa HH, Elhendy A, Bax JJ, Boersma E, de Jonge R, Schouten O, et al. Baseline plasma N-terminal pro-B-type natriuretic peptide is associated with the extent of stress-induced myocardial ischemia during dobutamine stress echocardiography. Coron Artery Dis 2006; 17:255–259.—A Committee established by the Board of Erasmus Medical Center, The Netherlands, that reported in September 2012, considers the reporting of the research by Feringa et al. to have been negligent and scientifically incorrect according to two criteria: the inclusion and exclusion criteria reported in the publication were not applied consistently, with the result that the patient population actually studied differs in material ways from the published description; and, there are material differences between the source documentation (the patients’ dossier), the case record form used in the study, the study database, and the publication. For this reason the article by Feringa et al. is retracted from publication.

In 2012 JACC issued a notice of concern about three papers co-authored by Poldermans, but those papers have not been retracted so far. I am not aware of any other retractions or similar notices of concern. However, the European Society of Cardiology has stated that it is performing an urgent review of the guidelines for perioperative beta-blockade following a report last summer that the guidelines– which relied heavily on discredited research by Poldermans– may be responsible for thousands of deaths each year.

Click here for my previous coverage of the Poldermans case.

 

The Italian Research Scandal Grows: New Questions And More Confusion Reply

New questions are being raised about yet another published study from an embattled Italian research group. It also appears that despite attempts by some of the participants to respond to some of the previous questions and accusationst there is little likelihood that the growing scandal will be resolved anytime soon.

The new allegations are the latest episode in an ongoing saga that began last year with the arrest of 9 Italian cardiologists as part of a broad investigation into serious medical misconduct at Modena Hospital (Policlinico di Modena). The most prominent figure arrested was Maria Grazia Modena, the former head of cardiology. Since the arrests last year I have reported about numerous errors and other problems related to 2 studies by many of the same cardiologists published in the journals Heart and the American Journal of Cardiology.

The new questions concern a paper published in Circulation Cardiovascular Inteventions. Specifically, the paper claims that the study enrolled all consecutive STEMI patients from 2002 to 2008, obtained informed consent from all patients, and achieved 100% followup at 1 year. In addition, I found 2 mathematical errors in Table 2, including the apparent paradox of a subgroup of low risk men (n = 548) being larger than the entire group of men (n = 522). (Click to enlarge the image of the Table.)

The question about the enrollment of all STEMI patients is further complicated by the fact that (at least) 2 previous papers (the Heart and  AJC papers mentioned abovehave claimed to enroll, obtain consent, and achieve complete followup of the same STEMI population from the same hospital at the same time. Do the authors claim that informed consent was obtained for each of these studies and from each of the patients?

A Weak Defense

In response to my story about the American Journal of Cardiology paper the first author of that study, Daniel Monopoli, sent a lengthy response. (I have reprinted the entire response at the bottom of this post.) Readers should of course judge for themselves, but I do not believe Monopoli has satisfactorily resolved any of the questions raised about the paper. In some instances I think he has, inadvertently, worsened his position.

Click here to read the full post on Forbes.

 

 

 

A Paper In The American Journal Of Cardiology About A Study That Was ‘Not Real’ Reply

New allegations about scientific misconduct have been raised about a cardiology group in a hospital in Italy. Some of the allegations come from a surprising source: Maria Grazia Modena, the former and highly prominent chief of cardiology at the hospital where the research was said to have been performed.

The new allegations are the latest episode in an ongoing saga that began last year involving many of the same researchers, including Maria Grazia Modena herself. As I first reported last November, nine Italian cardiologists were arrested as part of a broad investigation into serious medical misconduct at Modena Hospital (Policlinico di Modena). The charges included conspiracy, fraud, embezzlement, bribery, forgery and performing unauthorized clinical trials. The most prominent person arrested was Maria Grazia Modena, who is also a former president of the Italian Society of Cardiology. (The fact that she shares her last name with the city and the hospital where she works appears to be a coincidence.)

The suspicion that there might be problems with the paper  first emerged when Maria Grazia Modena, who was originally listed as a co-author, publicly distanced herself from the paper and said that she was not an author of the paper and had had nothing to do with the study. To date the only public acknowledgement that there might be problems with the paper is an erratum published in AJC stating that Modena “was not associated with this manuscript” and that “the authors apologize for this error.”

I personally asked the physicians and fellows who were working in the department (except the authors of the manuscript) if anyone have ever heard about the study. Nobody had ever seen informed consents or appointments for study-related peripheral echo in 8 years.

 In the methods section of their manuscript, the authors stated that echo examinations  were made with [a GE Healthcare transducer]… That echocardiography machine was bought around 2005-2006 (the authors  report they started the study  in 2002).

Click here to read the full post on Forbes.

 

Saying Sorry May Not Be Good Enough For Novartis Reply

Novartis has issued a formal apology over misconduct relating to valsartan (Diovan) research in Japan, but that apology does not appear likely to satisfy the Japanese Health, Labor and Welfare Ministry, which plans to fully investigate the company’s role in the scandal. If necessary, ministry officials are prepared to raid the company’s offices in Japan.

A Novartis official apologized to the Japanese public for the apparent manipulation of data. David Epstein, the head of the pharmaceutical division at Novartis, met with the Japanese health minister. “We express our deep regret for the concern that the issue has brought to patients, to the medical society as well as the ministry,” Epstein was quoted by Reuters after the meeting. He said the company was “willing to work with” Japanese investigators and will “take additional actions and potential sanctions in order to bring the issue to a good conclusion.”

Click here to read the full post on Forbes.

Diovan Data Was Fabricated, Say Japanese Health Minister And University Officials Reply

Following a long series of accusations, retractions, and the resignation of a prominent professor, it now is clear that data from a large Japanese study of valsartan (Diovan, Novartis) was fabricated. On Thursday officials at Kyoto Prefectural University of Medicine said that “had patient records been used in their entirety,” the Kyoto Heart Study “would have had a different conclusion,” reported AFB.

In 2009 the Kyoto Heart Study investigators, including the chief investigator, Hiroaki Matsubara, reported that treatment with valsartan resulted in significant cardiovascular benefits independent of the drug’s blood-pressure lowering effect. Now officials at the university say the drug had no such effect.

On Friday Norihisa Tamura, Japan’s health minister, said data had been “fabricated and falsified.” Tamura said he would set up a committee to prevent episodes like this from happening again.

Click here to read the full story on Forbes.

 

Norihisa Tamura

Recent €23 Million Biotech IPO Relied Heavily On Questionable Research 2

A successful €23 million initial public offering  (IPO) last week was based on highly questionable research, according to a group of UK physicians who have scrutinized the available data. In addition, one of the researchers, a prominent European cardiologist, failed to disclose in a key paper that he helped to start, and held a significant interest in, the company, Cardio3 BioSciences.

On July 4 Cardio3 BioSciences, a biotechnology company focusing on cardiac stem cell therapy, said that it had raised €23 million in an IPO on the NYSE Euronext Brussels and NYSE Euronext Paris. The company’s main product is called C-Cure, which it defines as “a unique cell therapy aimed at repairing damaged tissue and improving heart function, clinical outcomes and quality of life.” C-Cure uses uses pre-programmed cardiac progenitor cells to treat heart failure. As described by the company, “the supporting science is the result of Mayo Clinic innovation leading to advanced product development, manufacturing scale-up, and clinical trial execution by Cardio3 BioSciences catalyzed by ongoing collaboration facilitated through Mayo Clinic Ventures.”

The company plans to use the IPO money for a Phase III trial, following what the company describes as “positive Phase II results, recently published in the Journal of the American College of Cardiology.”

But the phase II results are a bit more complicated, according to Darrel Francis and colleagues (who last week published a paper highly critical of a different stem cell group). Francis et al have identified numerous errors in the paper which raise serious questions about the validity of the data and whether any useful conclusions can be drawn from the paper.

One striking finding– obvious once it has been pointed out– is that the authors report at different times different number of patients enrolled in the trial. The text of the paper says 48 patients were randomized, Figure 1 lists 47, and Table 1 lists 45 (42 men and 3 women).

Click here to read the full story on Forbes.

 

 

Paper Raises Hundreds Of Questions About The Integrity Of Stem Cell Research Group 2

Serious questions have been raised about the integrity and validity of research performed by a well-established German stem cell research group. A paper published in the International Journal of Cardiology exhaustively details a multitude of discrepancies and contradictions in papers from the researcher’s group. Further, the revelation of such widespread misconduct may lead to broader disturbing questions about the reliability of scientific publications and the ability of the clinical research system to police itself.

In “Autologous bone marrow-derived stem cell therapy in heart disease: Discrepancies and contradictions,” Darrel Francis and colleagues scrutinize 48 papers from the research group of Bodo-Eckehard Strauer. According to Francis et al, the 48 papers from Strauer’s group contained reports on only 5 actual clinical studies, or “families” of reports, and that duplicate or overlapping reports were common. The paper contains details about more than 200 errors in the papers, including contradictory descriptions of the design, protocol and results of the trials. Francis et al write:

“Readers cannot always tell whether a study is randomised versus not, open-controlled or blinded placebo-controlled, or lacking a control group. There were conflicts in recruitment dates, criteria, sample sizes, million-fold differences in cell counts, sex reclassification, fractional numbers of patients and conflation of competitors’ studies with authors’ own.

Contradictory results were also common. These included arithmetical miscalculations, statistical errors, suppression of significant changes, exaggerated description of own findings, possible silent patient deletions, fractional numbers of coronary arteries, identical results with contradictory sample sizes, contradictory results with identical sample sizes, misrepresented survival graphs and a patient with a negative NYHA class.”

Click here to read the full post on Forbes.

Bodo-Eckehard Strauer

Suspicions Raised About Another Japanese Cardiovascular Researcher Reply

Significant questions about research misconduct have been raised about a prominent Japanese cardiovascular researcher, Issei Komuro.

Last year a Nature paper on which Komuro served as a co-author was corrected because “several images were mistakenly switched or duplicated during preparation of the artwork.” The Nature correction states that the “corrections do not alter any of the conclusions” of the paper. Now, however, a Japanese blog, entitled Issei Komuro – image manipulation -, raises questions about 13 additional papers. The papers were all published in well-known journals, including a second Nature paper, Nature Medicine, and 4 separate papers in Circulation. On many of the papers Komuro served as the senior author.

Click here to read the full post on Forbes.

 

 

Scrutiny Of Sodium Meta-Analysis In Heart Uncovers Duplicated And Missing Data Reply

A meta-analysis published in the journal Heart has been retracted. As Adam Marcus writes in Retraction Watch, the retraction occurred when the journal editors learned “that two of the six studies included in the review contained duplicated data.  Those studies, it so happens, were conducted by one of the co-authors [of the meta-analysis].”

The article, “Low sodium versus normal sodium diets in systolic heart failure: systematic review and meta-analysis,” was published online in August 2012. In their attempt to investigate the duplicate data, the Heart editors reported “that the raw data are no longer available having been lost as a result of computer failure.”

The authors of the meta-analysis were James J DiNicolantonio (Wegmans Pharmacy, Ithaca, NY), Pietro Di Pasquale (Chief Division of Cardiology, “Paolo Borsellino”, G.F. Ingrassia Hospital, Palermo, Italy),  Rod S Taylor (Peninsula Medical School, University of Exeter, Exeter, UK), and Daniel G Hackam (University of Western Ontario and the London Health Sciences Centre, London, Ontario, Canada).

It was the second author, De Pasquale, who was the co-author of the duplicated papers that also contained the missing data.

You can read the entire story in Retraction Watch. Don’t miss the comments. Here’s one:

“computer failure” is the scientist’s version of “the dog ate my homework”

 

heart cover may13

Japanese Research Scandal Expands To A Second Trial And A Novartis Employee Reply

A Japanese research scandal, which has so far centered on actions taken by the once-prominent cardiologist Hiroaki Matsubara, has now expanded. As has been previously reported, several papers authored by Matsubara have been retracted, including, most notably, the main publication of the Kyoto Heart Study in the European Heart Journal.

Now, however, questions have been raised about  another clinical trial, the Jikei Heart Trial, which was published in the Lancet in 2007.  (Matsubara was not involved in this trial.) Novartis, which manufactures valsartan (Diovan), the drug studied in both trials, has announced that it is investigating both trials in response to new allegations that a Novartis employee worked on the trials without any disclosure of his company affiliation.

Click here to read the full story on Forbes.

A Closer Look At A Case Of Duplicate Publication In JACC 2

English: http://en.wikipedia.org/wiki/Linda_an...

The Journal of the American College of Cardiology has published a Notice of Duplication about a review article written by a respected European cardiology researcher who has played a central role in the development of fractional flow reserve (FFR). The brief statement from JACC provides few details and could lead to various interpretations, but a further investigation suggests that the story may be fairly simple.

The notice states that a 2012 review article by Nico H.J. Pijls and Jan-Willem E.M. Sels, Functional Measurement of Coronary Stenosis, “duplicates to a considerable extent both the text and figures of a prior article,” Fractional flow reserve: a review” published in 2008 in Heart, by two different authors, Bernard De Bruyne and J. Sarma. Here is the JACC editors explanation:

Dr. Piljs attributes this duplication to the close collaboration that he has had over many years with Dr. De Bruyne, and the fact that both authors drew text and figures for these reviews from the same repository of material used for a joint educational program. He acknowledges his lack of care in the preparation of the manuscript and apologizes for the duplication. While the Editors accept this apology, we lament the replication of information that prevented the pages devoted to Dr. Piljs’ article from being filled with new material.

De Buyne and Pijls are longtime colleagues who have played a central role in the development of fractional flow reserve, serving as principal investigators of the seminal FAME and FAME II clinical trials. I asked them for a response to this situation. Here is their statement:

The cryptical phrasing “repository of……..” is not ours, but made by JACC.

The “repository” they mean is a keynote lecture from the bi-annual Aalst-Eindhoven-Course on Coronary Physiology, which we organize once or twice a year in Brussels since 2001. The Course is endorsed by the European Society of Cardiology and has been organized by us already 17 times.

The opening lecture of that course (keynote lecture) is always entitled: “Practice and advanced applications of Coronary Pressure Measurement” and alternatively given by Dr de Bruyne and Dr Pijls.

That lecture has been built up by us and developed carefully over the years and has been streamlined for optimum educational content and benefit, including phrasing and slides.Not a single word is not ours.

The slides are always distributed among the participants and used by many of them for their own lectures or presentations or any educational purposes. In fact , they are public domain. Consequently, we have seen (parts of) our text and slides been used by others a myriad of times and are proud to have contributed to the dissemination of valuable medical knowledge.

When Dr De Bruyne wrote his review for HEART in 2008 , he used that keynote lecture as the basis of his paper.

When Dr Pijls wrote his State-of-the-Art paper ( i.e also a review) on the invitation of JACC in 2012, he also used text and slides of that keynote lecture (extended in the meantime) without realizing that Dr De Bruyne had done the same some years earlier. As a result, the first part of Dr Pijls paper is very close to Dr De Bruyne’s review, wheras the second part of Dr Pijls paper reflects the new data and insights obtained in those last 4 years.

So, there is nothing mysterious about that “repository” and we explained this to JACC in a similar way as we do now to you.

And by the way, when Dr Pijls submitted his paper to JACC, he mentioned explicitely in the submission letter that – as the nature of this paper was a State-of-the-Art paper – it was a concise reflection of the knowledge in the field and not original data.

Answering your last question: Neither Dr De Bruyne nor Dr Pijls ever received any financial or other compensation from whoever or in whatsoever way for writing any of these papers.

Writing these papers was on the strict invitation of the editors of Heart and JACC respectively and except the authors and staff of the Journals, nobody was even aware of it before they were published.

And as stated above: any single word or figure in any of these papers is completely our own work to which we equally contributed.

Comment: When I first read the notice it seemed to me like the case was an indication of a larger wrongdoing. I’m glad my initial suspicions were proven wrong. This is a great example of why editor’s notes should be much more detailed. The truth needs to come out no matter which way it falls.

Scientific Misconduct: From Darwin And Mendel To Poldermans And Matsubara Reply

Responding to recent episodes of scientific misconduct in cardiovascular research involving once prominent cardiovascular researchers, the editor of the European Heart Journal, Thomas Lüscherhas written an editorial discussing the significance of the new cases and placing them in a historical context that includes allegations of scientific misconduct by Mendel and Darwin, among many others.

Poldermans was the first or the senior author in 7 papers published in EHJ. Lüscher writes that the chairman of the Poldermans investigative committee “made it clear that the vast amount of publications led by Poldermans over the last decades made it impossible to assess their scientific validity in all cases.” As a result, Poldermans announces that “the editors of the European Heart Journal therefore would like to make an expression of concern related to the papers where Poldermans was the responsible author.”

Comment: Without more information there will continue to be a large cloud of uncertainty hanging over the cardiovascular literature. The statement of the chairman of the Poldermans committee bears repeating: “the vast amount of publications led by Poldermans over the last decades made it impossible to assess their scientific validity in all cases.”

 Click here to read the full story on Forbes.

 

Gregor Mendel
Gregor Mendel

 

Don Poldermans

 

 

 

 

Embers Of Poldermans Case Still Smoldering Reply

Poldermans

Don Poldermans

A prominent US cardiologist has rebuked Don Poldermans, the cardiovascular researcher at the center of a research scandal in the Netherlands. As reported here previously, Poldermans was fired for scientific misconduct by the Erasmus Medical Center in Rotterdam, where he had been a professor of medicine and the head of perioperative cardiac care. He was widely published and active in the field, serving as a member of the European Society of Cardiology committee for practice guidelines and as the chairperson of the ESC guidelines on pre-operative cardiac risk assessment and perioperative cardiac management in non-cardiac surgery. He was also the lead author of the influential (but controversial) 1999 New England Journal of Medicine DECREASE study on the use of bisoprolol during vascular surgery. An investigation at Erasmus found that Poldermans used patient data without written permission, used fictitious data, and submitted two reports to conferences which included knowingly unreliable data.

The new episode has its origins in a review article published last October by prominent cardiologist University of Michigan cardiologist Kim Eagle, and a colleague, Vineet Chopra, in the American Journal of Medicine. The article, “Perioperative Mischief: The Price of Academic Misconduct,” discusses the “caustic” effects of the Poldermans case, noting the dilemma facing clinicians “now that a considerable portion of the literature is enshrouded in uncertainty.” Now (as first reported by Retraction Watch) Poldermans and the Michigan cardiologists have exchanged letters in the April issue of the journal.

In his letter responding to Eagle and Chopra’s review article, Poldermans is critical of the Michigan authors for accusing him of “scientific fraud.” Poldermans acknowledges in his letter that he made various mistakes, including failure to obtain written informed consent and “negligent” data collection. He denies, however, that he fabricated data or published any results based on the compromised data. He writes that Eagle and Chopra assumed he was guilty despite the fact that the final report from the Erasmus Medical Center had not been released. He notes that in the final report Erasmus had concluded that “no evidence was found for any manipulation of the research results by the researchers in the sense of deliberate steering of results into a particular direction.”

In their response, Eagle and Chopra said that in their article they had stated that the accusations of fraud were still allegations. More importantly, Poldermans missed the larger point of their paper:

Click here to read the full story on Forbes.

Kim Eagle

Kim Eagle

 

 

 

European Heart Journal Retracts Main Paper Of The Kyoto Heart Study 1

The editors of the European Heart Journal have retracted the 2009 paper reporting the main results of the Kyoto Heart Study, a randomized, open-labeled study testing the add-on effect of valsartan to conventional therapy in high-risk hypertension. The retraction notice gave no details about the problems that led to the retraction. Here is the full text of the retraction notice:

“This article has been retracted by the journal. Critical problems existed with some of the data reported in the above paper. The editors of the European Heart Journal hereby retract this paper and discourage citations of it.”

Click here to read the full story on Forbes.

Screen Shot 2013-02-02 at 11.50.51 AM

JACC Issues Notice of Concern Over Three Poldermans Papers 2

The editors of the Journal of the American College of Cardiology have issued a “Notice of Concern” over three JACC articles in which Don Poldermans, the disgraced Dutch researcher, served as the first or the last author. The editors relied on the report of the investigation committee at Erasmus Medical Center published in October. In each case the editors have accepted the committee’s finding that although the studies contain numerous examples of scientific “irregularities,” the evidence does not warrant full retractions for the papers.
jaccFor the first paper, the committee cited numerous irregularities, including  inconsistencies between source documentation and the Case Report Forms and “an unreliable working procedure for collection of scientific data.” But the committee also found no “evidence for any manipulation of the research results by the researchers in the sense of deliberate steering of results into a particular direction” or that “the research conclusions as published in the above mentioned article are wrong.” “It is impossible,” the editors write, for them “to determine the effect of this breach of scientific integrity upon the overall conclusions of the manuscript.”
For the second study, the committee expressed “doubt about the validity of the causes of death recorded in the data base.” The lack of  source documentation is “unfortunate” but the editors, like the committee, “could not determine how these facts influenced the conclusions of the manuscript.”
For the third study, the committee found negligence relating to informed consent, preservation of case report forms, and data collection. Although the committee was “unable to vouch for  the reliability of the findings” the editors, once again, “could not determine with certainty that the findings of the study were erroneous.”
Here is the conclusion of the editors’ notice of concern:

Since it is not possible for the Editors of JACC to determine with certainty that the findings in the above articles were erroneous, we have elected not to retract these manuscripts. However, given the uncertainty regarding the accuracy of the data, and the inability to validate the collection of data, readers should be cautioned in the application of the findings of these manuscripts to clinical practice.

Hat tip: Marilyn Mann

Yet Another Look At The Transcendental Meditation Paper 85

Editor’s note: Below are two responses to Robert Schneider’s defense of his Transcendental Meditation paper, which Schneider wrote in response to my earlier article about the publication of his paper.  In the first part I respond to some of the general issues raised by Schneider. The second part, from Sanjay Kaul, addresses the statistical issues discussed by Schneider.

I’m grateful for Kaul’s highly technical analysis of the statistical issues raised by Schneider, but I don’t think this case really requires a terribly high level of technical expertise. Common sense actually works pretty well in this case. A trial with barely 200 patients can not be expected to provide broad answers about the health benefits of a novel intervention. As Kaul and others have stated on many other occasions, “extraordinary claims require extraordinary evidence,” and it is quite clear that the evidence in this trial is not extraordinary, at least in any positive sense.

Questions About Trial Reliability And Data– In his response Schneider tries to skate away from the inevitable questions raised about this paper when Archives of Internal Medicine chose to withdraw the paper only 12 minutes before its scheduled publication time. Schneider can pretend that this incident never occurred, but outsider readers can not help but wonder what sparked this extraordinary incident, and will not be satisfied  until the details are fully explained.

There are additional red flags about the trial. Schneider told WebMD that since the Archives incident “the data was re-analyzed. Also, new data was added and the study underwent an independent review.” Said Schneider:

“This is the new and improved version.”

This is an extraordinary claim, because a clinical trial can not be “new and improved” unless there were serious flaws with the earlier version. What exactly does it mean to say that a paper published in 2012 about a trial completed in 2007 is “new and improved”? (According to ClinicalTrials.Gov the study was completed in July 2007, while June 2007 was the “final data collection date” for the primary endpoint.)
Click to continue reading…

Investigator Defends Controversial Transcendental Meditation Paper 5

Editor’s Note: Here is a response by Dr. Robert Schneider to my story last week about his controversial paper on Transcendental Meditation that appeared in Circulation: Cardiovascular Quality & Outcomes. I will respond to Dr. Schneider’s post later this week.

Response from Dr. Robert Schneider

We appreciate the interest in our article published in Circulation: Cardiovascular Outcomes and Quality, November 2012.  However, there are several errors and inaccuracies in the blog. Many of these points were addressed in the Circulation Outcomes publication.  Below are highlights.

Robert Schneider, MD, director of the Institute for Natural Medicine and Prevention and dean of Maharishi College of Perfect Health in Fairfield, Iowa. Courtesy MAPI

1.     This was a prospective, randomized, controlled, single-blinded clinical trial.  This report is the first publication of data from the trial. It was revised in response to extensive peer-review over the past months.  Whatever unpublished version of the manuscript the bloggers had access to previously did not have the benefit of the most current peer review and revision.

2. There were a range of check and balances built into the study to ensure veracity.  For example:

  • data were collected blindly at the clinical site in Milwaukee
  • the trial was monitored by independent data safety and monitoring board
  • end point events were adjudicated by an independent reviewer using standardized criteria
  • results were confirmed by independent data analysis
  • limitations are enumerated and discussed in the publication

3. Regarding the hypothesis testing capacity of the study, according to the Consolidated Standards of Reporting Trials (CONSORT) guidelines,

“Randomised clinical trials (RCTs) are generally considered to produce the most solid evidence for the effectiveness of medical interventions”  (Keech 2007).  The CONSORT guidelines are recommended by the International Committee of Medical Journal Editors (ICMJE). The design, implementation, analysis and reporting of this trial followed CONSORT guidelines.  Thus this clinical trial was an experimental study that tested an hypothesis.  By contrast, observational studies, which this was not, generates hypotheses (http://en.wikipedia.org/wiki/Observational_study).

4.  The total number of primary end point events is within one of an earlier, unpublished version of the manuscript (noted in blog update November 18).  In preparation for the revised manuscript, one additional event was identified.  However, this had no meaningful effect on the results or statistical significance. That is, the main results are essentially unchanged.
Click to continue reading…

Mysterious Disappearing Paper Finally Reappears In Another Journal 34

Robert Schneider, MD, director of the Institute for Natural Medicine and Prevention and dean of Maharishi College of Perfect Health in Fairfield, Iowa. Courtesy MAPI

Updated– Last year, in what may have been an unprecedented action, a paper on the effects of Transcendental Mediation (TM) in African Americans was withdrawn by the editors only 12 minutes before the paper’s scheduled publication in Archives of Internal Medicine. No definitive explanation was ever provided, though the editors and authors said that the action was prompted by last minute questions from reviewers at the NIH, which helped fund the study. (The episode was covered in detail on CardioBrief  (here and here) and on RetractionWatch.)

Now a new version of the paper has been published in Circulation: Cardiovascular Quality & Outcomes. The first author is Robert Schneider, from the Institute for Natural Medicine and Prevention at Maharishi University of Management in Maharishi Vedic City, Iowa. The co-authors are from the same institution and from the department of medicine at the Medical College of Wisconsin in Wisconin. It is clearly the same study of 201 African American patients randomized to TM or health education (HE) and followed for 5.4 years, though some of the numbers have changed in important ways between the earlier and later publications. One change involves the primary endpoint: the new paper in Circ:CVQ&O reports  52 primary endpoint events (the composite of death, MI, or stroke). Of these, 20 events occurred in the TM group and 32 in the HE group. By contrast, in the previous Archives version there were 51 primary endpoint events: 20 in the TM group and 31 in the control group.

In both papers the difference in the primary endpoint did not achieve statistical significance until after the investigators adjusted for baseline differences. The unadjusted hazard ratio (HR) for the new study was 0.64, (confidence interval 0.3701.12, p = 0.12); after adjusting for age, gender, and lipid lowering medications the HR drops, presto-chango, to 0.52 (0.29-0.92, p=0.025) and achieves statistical significance..

Dome shaped building on MUM campus, for the group practice of the TM-Sidhi program and Yogic Flying (Photo credit: Wikipedia)

Here are some other key questions that I have asked AHA, Circulation editors, and other experts to address:

– Was the AHA or the Circulation staff aware at any time that an earlier version of this paper had been scheduled for publication in Archives of Internal Medicine and withdrawn only 12 minutes before the scheduled publication time? Should this information have been disclosed by the study authors when submitting the paper?

– As mentioned above, the original publication in Archives appeared to have been cancelled because of questions raised by NIH reviewers. Have the Circulation: Cardiovascular Quality & Outcomes editors received any assurance that these questions have been addressed in the new paper?

– This trial was started all the way back in 1998 but was not registered on ClinicalTrials.Gov until February 2011 (shortly before the intended Archives publication). Why was it not registered earlier than 2011?

– June 2007 is listed in ClinicalTrials.Gov as the final data collection date for primary outcome measure. Why are the primary endpoint numbers different between the Archives and new version of this paper?

Update, November 13-Harlan Krumholz, the editor of  Circulation: Cardiovascular Quality & Outcomes, sent the following statement:

“We had no prior knowledge of what transpired with the Archives of Internal Medicine.  The Schneider paper went through rigorous peer review, statistical review and editorial discussions and the authors of the article were responsive to the review process.  As a result, the paper was accepted for publication and we are going ahead as planned.  If you have any further questions, we suggest you contact the researchers directly.”

Update, November 18–  An earlier version of this article contained several mistakes. First, the difference in the number of primary endpoint events between the two papers is much smaller than I had stated. The original paper reported 51 primary endpoint events. The new paper reports 52 endpoint events. I am still unclear about why there should be any difference between the two, since, as mentioned above, June 2007 was the final data collection date for the primary endpoint. I also incorrectly claimed that some  data reported in the original Archives paper were not included in the new paper. In fact, as a reader pointed out in the comments section below, these data were reported in Figure 1. I apologize for this mistake and regret the error. –LH

I asked Sanjay Kaul for his perspective on the paper. Here are his points:
Click to continue reading…

Nine Italian Cardiologists Arrested In Broad Investigation Of Research Fraud And Misconduct 2

The Arrest of Maria Grazia Modena, from Il Resto Del Carlino

Nine Italian cardiologists have been arrested as part of a broad investigation into serious medical misconduct at Modena Hospital, according to multiple reports in the Italian media. The investigation encompasses at least 67 other individuals and a dozen medical equipment companies, including 6 foreign companies. The charges include conspiracy, fraud, embezzlement, bribery, forgery and performing unauthorized clinical trials. Several news reports mentioned that stents and angioplasty balloons were involved.

According to one Italian website, the investigation started in 2011 in response to allegations by a group, Amici del Cuore (Friends of the Heart), that patients at the Modena Hospital (Policlinico di Modena) received treatments and procedures as part of unauthorized experiments. In some cases the procedures may have resulted in fatal outcomes. The accused physicians “performed experimental tests without making it known to patients for the sole purpose of writing about these trials in specialized magazines collecting money through bogus non-profit organization,” the website reported. [All translations in this story taken from Google Translate.]

“We wanted to ask questions about certain procedures that went far beyond the standard ones, and that seemed unusual to us,” the president of Friends of the Heart, Professor Giovanni Spinella, told Il Salvagente. “We were aware that invasive procedures were performed, often on peripheral organs, and sometimes had little to do [with] the heart. And unfortunately had caused discomfort and damage to several patients.”

Another Italian site quoted a police official who called it “a major operation” and said the accused “committed human clinical trials without authorization and installed medical devices and equipment defective in patients unaware of being subjected to an experimental treatment.” The accused physicians then “created false medical records to cover medical errors.” The Italian media said the investigation included recordings of telephone conversations between the suspects. The Italian police named the operation camici sporchi (“dirty gowns”).

The most prominent person arrested was Maria Grazia Modena, the chief of cardiology at Modena Hospital and a former president of the Italian Society of Cardiology. (Grazia Modena was the subject of a profile in Circulation European Perspectives (PDF) in 2007.) Modena, 60 years old, was trained partly at New York University and the Mayo Clinic. The second main focus of the investigation appears to be the head of the catheterization laboratory at the hospital, Giuseppe Sangiorgi. According to news reports, he is the only arrested physician who is still in jail.

Here are the names of the nine physicians:

  • Maria Grazia Modena, chief of cardiology
  • Giuseppe Sangiorgi, head of the catheterization laboratory
  • Luigi Vincenzo Politi
  • April Alexander
  • Simona Lambertini
  • Giuseppe Biondi Zoccai
  • Fabrizio Clement
  • Alessandro Mauriello
  • Andrea Amato, 36

Don Poldermans And The Dutch Research Scandal 4

The publication last week of the final report from the Erasmus Medical Center on the Don Poldermans research scandal in the Netherlands ends the first and most explosive chapter of an ugly episode of scientific misconduct. But there are still many important questions regarding scientific integrity and the culture of medical research raised by the case. And one key detail about the case remains– and is likely to remain– unanswered. Did Don Poldermans commit scientific fraud by fabricating data or was he only guilty of the serious but lesser sin of poor or negligent supervision of a research factory?

The final report on the Poldermans affair from his former institution and employer, Erasmus MC, accuses him of serious scientific misconduct, including:

  • “failure to preserve essential source documentation,”  so that “further verification and analysis ” is now impossible;
  • “failure to record actual medication use, in a study focusing on an intervention using medicines”; and
  • failure to obtain informed consent, or to do so improperly.

The most serious accusation is that “fictitious data” was used in one study, “a serious breach of academic integrity.” However, this accusation does not appear to be rock solid, since it is based on disparities between the study data and a database examined by the committee. However, Poldermans claims that the database examined by the committee was provided to them by the whistleblower (a fellow in his laboratory) who did not have access to the original database (which Poldermans claims was destroyed) and was not the database used in the study. It’s unlikely that the full truth about this will ever be known. Poldermans says that the committee’s conclusions were “suggestive, speculative and often even demonstrably false.”

In an hour-long interview with me during the recent ESC meeting in Munich, Poldermans talked a great deal about the case, accepted responsibility for the less serious charges but adamantly  denied the more serious charges. Poldermans, who is now working as a vascular medicine physician at a non-teaching hospital, said he has no expectation of ever regaining his former position or resuming research: “that’s something I can accept, but I can’t accept that people would think I faked patients or that patients were hurt,” he told me.
Click to continue reading…

Erasmus Medical Center Releases Final Report On Cardiovascular Research Scandal 2

After an extensive investigation, a large medical center in the Netherlands has confirmed earlier charges of research misconduct against a prominent cardiovascular researcher. On Tuesday, Erasmus MC in Rotterdam released a final report on the scientific integrity of trials conducted by Don Poldermans, a well-known and highly prolific Dutch cardiovascular researcher. The final report contains numerous allegations of scientific misconduct related to the conduct of several clinical trials run by Poldermans at Erasmus MC.

Poldermans admits responsibility for some instances of misconduct but also vigorously denies the most serious charges involving scientific fraud. He provided CardioBrief with detailed written responses to the charges and also presented a spirited defense during an exclusive interview conducted in August during the ESC meeting in Munich.

In a statement to the press, Erasmus MC said that the new report confirms the earlier suspicions raised in the case, which ignited a firestorm of conroversy in the Netherlands last winter. The press statement mentions”serious shortcomings” in obtaining informed consent for patients enrolled in studies and the submissions of “unreliable data” based on “scientifically inaccurate data collection.” Poldermans and Erasmus MC are in full agreement, however, that the misconduct “did not lead to health damage to patients.”

In a statement prepared for CardioBrief in response to the report, Poldermans apologizes for his “administrative carelessness” and accepts full responsibility for the missing consent forms. He accepts the “extreme consequence”–  his dismissal from Erasmus MC–  over this issue, but emphasizes that no harm occurred to any of the patients and, further, that no additional or unnecessary treatments or diagnostic procedures took place. He vigorously denies any larger scientific misconduct or fraud.

The committee report — and Poldermans defense — are often highly technical, and the report is based on incomplete and inconsistent information obtained by the investigating committee at Erasmus MC. One problem is missing data. Investigators scrutinizing Polderman’s work have been unable to find the case files and other documentation for some patients in the trials. Consequently, the report raises concerns about possible data fabrication. Poldermans strongly denies this suggestion and states that he properly stored all the files at Erasmus MC. His defense is that some records were damaged by water and some records disappeared when the hospital itself threw out boxes of documents stored in the archives.

Poldermans had been a professor of medicine and the head of perioperative cardiac care at the Erasmus Medical Center. He was widely published and active in the field, serving as a member of the European Society of Cardiology committee for practice guidelines and as the chairperson of the ESC guidelines on pre-operative cardiac risk assessment and perioperative cardiac management in non-cardiac surgery. He was also the lead author of the influential 1999 New England Journal of Medicine DECREASE study on the use of bisoprolol during vascular surgery. Poldermans now works as a vascular medicine physician at a nonteaching hospital in the Netherlands.

CardioBrief will publish a followup story in the near future based on an interview with Poldermans conducted in Munich during the ESC.

Related Links: