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Thinking about Life Sciences


http://blog.aesisgroup.com

Wednesday, January 10, 2007

Subtle But Powerful, Publication Bias Goes Beyond Financial Incentives

Many of you are aware of the phenomenon of “publication bias” in the scientific literature. This most
commonly refers to the fact that “negative” results find their way into publication much less commonly than
“positive” results.
Human Nature and Bias
Given human nature, rarely does one want to publicly show their own hypothesis being disproved. While
scientists are certainly a competitive sort, the profession finds it more dignified to go about constructively
proving one’s own hypotheses than necessarily trashing others. The lack of public disclosure about
negative results is a shame since one of the most important scientific experiments of all time – the
Michelson-Morley experiment of 1887 – utterly failed to prove the hypothesis of the stationary ether. This
would have experimentally implied that the speed of light would vary according to its orientation with
respect to the earth’s movement through space. The hypothesis of the stationary ether, which buttressed
the careers of nearly all professional physicists at the time, was trashed. Forward thinkers needed to
entertain the concept that the speed of light was a fixed constant. The negative Michelson-Morley result
made possible the more radical, positive steps that Einstein took with his theory of relativity. Human
nature was not enough to suppress publication of the Michelson-Morley experiment. In fact, this result
was so important (albeit negative) that Michelson and Morley gained worldwide renown (and Albert
Michelson a Nobel Prize in 1907) for their work. That’s not typically the case.
In our less-innocent modern age where money often rules science more than gentility, there are additional
forces influencing publication bias. Who knows what would have happened if International Ether, Inc. had
sponsored the experiment. Would the publication have been suppressed? Would the conclusions have been
made sufficiently obtuse that proper interpretation was not possible? For the price to maintain
International Ether’s stock, the world – with no nuclear power, no atom bomb and no advanced wireless
technology, which are all dependent on relativity – would have been strikingly different.
The EPO controversy
Especially under the influence of financial pressures, publication bias can be very subtle. I came across this
on Dec. 26, 2006 as I read a Wall Street Journal article headlined “Medical Journal Spikes Article on Industry
Ties of Kidney Group”. The article reported on the publication turmoil surrounding recent studies linking
the use of the drug erythropoietin (EPO) in kidney disease patients to an increased risk of heart failure and
an accelerated progression to dialysis. The article looked into a complex set of circumstances in which the
New England Journal of Medicine refused to publish - the more colorful term is “spiked” an editorial by
former deputy editor Robert Steinbrook. Instead, Steinbrook submitted the editorial for publication by a
rival publication: the British journal Lancet. Steinbrook’s editorial in question pointed out that another
article in the New England Journal of Medicine did not sufficiently reveal underlying financial conflicts of
interest. Except for the fact that very illustrious and accomplished physician scientists were involved, it
certainly sounded like something out of Jerry Springer.
Predicted in 1989

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The reason the article caught my eye was not necessarily because of the journalistic politics but because I
had also written about this very topic as a medical student back in 1989. At that time, I sent a letter to the
Annals of Internal Medicine commenting on what was then one of the very first studies evaluating the use of
EPO in pre-dialysis kidney disease patients.
In that letter – which is published for your perusal here – I acknowledged that EPO “clearly ameliorated
the anemia”. I also pointed out that “it is important to consider the possibility of two significant side
effects: systemic hypertension as well as an acceleration in the progression of chronic renal failure”. I
based my conclusion on the fact that while the original paper stated in both the abstract and its summary
that there were no changes in mean blood pressure, careful reading of the methods section revealed that
three of the 11 treated patients required an increase in their anti-hypertensive medications. I interpreted
this to mean that this dangerous, hypertensive side effect was in fact masked by the change in
anti-hypertensive regimen and that the conclusions of the paper could – to put it graciously – be
misinterpreted. To put it less graciously, the authors were covering up a “negative result” (e.g. a potential
adverse effect) by medicating it away and not forthrightly presenting that in the conclusions to their paper.
Though these 1989 studies were sponsored by Ortho Pharmaceuticals, I decided not to point that out
thinking this would be too inflammatory.
As a mere medical student, I certainly had no industry ties, no fancy consulting contracts and no stock
options (nor do I have at present any such industry ties related to EPO). Nevertheless, my 1989 letter was
never published. As the phrase goes, it was spiked. In retrospect, this is a shame since greater awareness as
early as 1989 of this problem (e.g. getting past the veil of publication bias) could have saved untold
millions of dollars and perhaps many patient lives. Ironically, 1989 was a very different time than 2007.
Back then, not having significant industry and financial support put into question the legitimacy of what
one had written. Now, the sensitivities and tables have turned. It is those who have significant financial
conflicts of interest whose legitimacy now begins to be questioned.
So what is to be done?
A problem as complex as publication bias – and all its attendant consequences – cannot be addressed in a
short article such as this column. The onus recently has been placed on authors to proactively document
all their financial conflicts of interest. That trend should continue to be encouraged. However, bias goes
beyond just financial incentives. All of this is human endeavor with human frailties and human powers. As
circumstances dictate, it is important for readers to understand some of the other, more subtle (yet still
powerful) forces that determine bias. The presence of bias – which is always there – is not automatically
bad nor does it necessarily invalidate information. It just needs to be recognized and taken into
consideration.
Even Einstein was biased. He was certainly biased against Nazi Germany when he brought the
possibilities of the atomic bomb to President Roosevelt. Though relatively agnostic, Einstein did invoke
his belief that “God does not play dice” in his disbelief of quantum mechanics. Biased as he was, Einstein
certainly did make enormous contributions to the world.
Perhaps you might be asking: “What is the bias of the author of this column?” Financial incentives? No.
As a columnist and in my own line of work, I try to anticipate future directions in biotech and medical
technology. Certainly my bias would be to exercise and demonstrate such a predictive capability.
Feel free to find some bias in this article with respect to taking the trouble to show how the developments
in EPO that are hitting the press now were predicted 15 years ago. I’ll leave it up to you whether that
invalidates the opinions expressed here.

Ogan Gurel, MD MPhil


gurel@aesisgroup.com

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