The Revolving-Door Cohort at the Karolinska Institute

The Karolinska Institute (KI) in Stockholm is Sweden’s premier medical research institution, and among the most well known and respected in the world. For several years a group of researchers in the KI’s Department of Medical Epidemiology and Biostatistics has published numerous studies of the health risks related to snus use.

As I stated in a recent commentary published in Sweden (link here), “the health risks identified in the KI studies are the raison d’être for the ban on snus in the E.U. (except Sweden), but it has also had a profound impact on tobacco regulation in the U.S. and other countries,” making access to snus difficult or impossible.

The KI studies have profoundly influenced regulatory actions all over the world, but they are compromised by important, troubling and unresolved discrepancies that KI researchers have refused to address. This post describes the biggest problem in detail.

The KI studies are based on over 300,000 male Swedish construction workers who enrolled in a health program from 1971 to 1992, including roughly 135,000 workers who were enrolled in the program during the 1971-1974 period. This group is important, because there are potentially serious questions about the adequacy of tobacco use information for these workers. In fact, the information is so questionable that KI researchers have included and excluded them in a revolving door fashion in published analyses over the last several years.

The story goes back to 1994, when KI investigator Gunilla Bolinder and colleagues reported that snus use was a risk factor for cardiovascular diseases. (abstract here). In that study Dr. Bolinder studied only the construction workers from the 1971-74 group (hereafter, the “Bolinder” cohort). That report, one of only a few linking snus use with heart disease and stroke, had some obvious but inexplicable technical problems, which I raised in a 1995 letter to the editor of the journal (here). Dr. Bolinder did not resolve these problems.

Fast-forward 13 years to 2007, when KI investigators Luo et al. published a high profile study in The Lancet finding that snus use was a risk factor for pancreas cancer (here). In their analysis, Luo et al. excluded ALL of the workers in the Bolinder cohort “because of ambiguities in the coding of smoking status” of participants. In other words, Luo tossed out the 135,000 workers of the Bolinder cohort. The justification for these exclusions was an “unpublished” observation by Zendehdel, another KI investigator.

I published a letter to the editor of The Lancet (here) observing that, if the Bolinder cohort was deficient, then the validity of the Bolinder study was suspect. Luo et al. responded that perhaps the exclusions were not warranted (here), citing a KI study that was about to be published. That study, which found that snus use was associated with esophageal and stomach cancer, included the Bolinder cohort (here). The lead author on that study was Zendehdel.

Confusing? Absolutely. First, KI researchers cited Zendehdel as the justification for excluding the Bolinder cohort, but then Zendehdel included the Bolinder cohort in his published study.

To illustrate how many times KI researchers have subjected the Bolinder cohort to revolving door treatment, here is a list of publications.

The Bolinder Revolving Door Cohort At the Karolinska Institute
Year	First Author	Journal	Disease	Bolinder Cohort In/Out
1994	Bolinder	American Journal of Public Health	Cardiovascular	In
2005	Odenbro	British Journal of Cancer	Skin cancer	In
2007	Luo	Lancet	Pancreas cancer	Out
2007	Odenbro	British Journal of Dermatology	Melanoma	In
2007	Fernberg	Cancer Research	Leukemia	In
2007	Hergens	Journal of Internal Medicine	Heart attack	Out
2008	Zendehdel	International Journal of Cancer	Gastrointestinal cancer	In
2008	Hergens	Epidemiology	Stroke	Out
2008	Hergens	Journal of Internal Medicine	Hypertension	Out
2010	Carlens	American Journal of Respiratory and Critical Care Medicine	Inflammatory Diseases	Out
2011	Nordenvall	International Journal of Cancer	Colon-rectal cancer	In

This is unacceptable from a scientific perspective, but there are many other problems. For example, it appears that Dr. Bolinder’s definition of snus use was inconsistent with later definitions. I’ll have more to say about this in a future post.

Why Doesn't the Karolinska Institute Want To Disclose How They Conducted Their Research On Snus?

On February 7, Dagens Industri, Sweden’s prestigious business newspaper, published my commentary on snus misinformation emanating from the Karolinska Institute, Sweden’s premier research institution. The commentary is available in Swedish (here); the English version of my submission follows. I will post a detailed description of the Karolinska Institute misinformation in a few days.

Published in Dagens Industri, February 7, 2011

Many research studies from Sweden have not found any health risks from snus use, but researchers at the Karolinska Institute have produced a series of reports, based on a large cohort of Swedish construction workers, that emphasize very small risks for esophagus and pancreas cancer and fatal heart attack and stroke.

The KI reports do not change these indisputable scientific facts: the health risks from the use of Swedish snus are so low that they are difficult to measure with modern epidemiologic methods. Snus use by Swedish men has resulted in the lowest rates of smoking-related diseases and deaths in Europe for the past sixty years.

However, the KI studies have obvious technical problems and contradictions, and I have documented these concerns in medical journals. For example, in 1994 Dr. Gunilla Bolinder studied 135,000 Swedish construction workers who had enrolled in a health program from 1971 to 1974. She found that snus users had elevated risks for cardiovascular diseases.

But in 2007 another KI study excluded the 1971-74 workers because of “ambiguities” in tobacco use. Then another KI-study in 2008 included them.

These problems are unacceptable from a scientific perspective, and I gave the KI researchers several opportunities to resolve them. There was no response.

Over two years ago I asked KI researchers for access to the construction worker data so that their findings could be validated. In the past the KI has given data to American researchers while fully protecting the identity of the participants. But the KI refused my request.

I was at an impasse with the KI from a scientific perspective, so I pursued the matter in the administrative court as a last resort. The court ruled that the data is a matter of public record, and it encouraged KI to make a thorough and comprehensive assessment of which data can be disclosed. But the institute has twice failed to comply with the court’s instructions, and it has provided no reasonable explanation for its intransigence.

KI – which in this respect is a Swedish authority – recently decided that I should be granted partial access to the data. But not digitally – which is customary – but only via pieces of paper. In addition KI will remove information about health conditions, i.e. the very information that I want to validate! This means that I would get hundreds of thousands of pages of worthless paper, for which KI has the right to invoice me.

This cannot be seen as anything but pure obstruction, and KI’s position is that its research is exempt from validation.

Researchers at KI have more than implied that I am running the errands of the tobacco industry. That is of course not the case. For years my university has accepted unrestricted funding from tobacco manufacturers including Swedish Match. This is very common in the U.S., as well as in Europe. We would never – nor would KI – let our funding direct the focus or results of our research.

Personally I have conducted tobacco research for two decades, and I developed a deep understanding of Swedish snus as a visiting scientist at the University of Umeå in 2002.

At first glance this matter appears to be just a minor dispute between a sole American professor and a prestigious and powerful Swedish research institute. I would argue the issue is bigger than that.

The health risks identified in the KI studies are the raison d’être for the ban on snus in the E.U. (except Sweden), but it has also had a profound impact on tobacco regulation in the U.S. and other countries.

It would be a tragedy if snus restrictions and prohibitions were improperly based on exaggerated or fictitious health risks. As a result, millions of inveterate smokers outside Sweden might never know that snus is a much safer substitute for cigarettes.

KI’s position is counter to the scientific and ethical principles of data sharing among medical institutions. These principles require that scientific results are open to challenge by other scientists to determine their accuracy and integrity.

The best solutions for scientific debates are not found in the courts. I therefore hope that KI decides to follow the practices of the world of medical research. If the KI does not release the data, it risks damaging its outstanding international reputation.

Professor Brad Rodu
University of Louisville, U.S.A.