Hope: The Mother of Bias in Research

I realized the other day that underlying every slanted report or overly-optimistic interpretation of a trial's results, every contorted post hoc analysis, every Big Pharma obfuscation, is hope.  And while hope is generally a good, positive emotion, it engenders great bias in the interpretation of medical research.  Consider this NYT article from last month:  "Dashing Hopes, Study Shows Cholesterol Drug Had No Effect on Heart Health."  The title itself reinforces my point, as do several quotes in the article.

“All of us would have put money on it,” said Dr. Peter Libby, a Harvard cardiologist. The drug, he said, “was the great hope.”

 Again, hope is wonderful, but it blinds people to the truth in everyday life and I'm afraid researchers are no more immune to its effects than the laity.  In my estimation, three main categories of hope creep into the evaluation of research and foments bias:

1. Hope for a cure, prevention, or treatment for a disease (on the part of patients, investigators, or both)
2. Hope for career advancement, funding, notoriety, being right (on the part of investigators) and related sunk cost bias
3. Hope for financial gain (usually on the part of Big Pharma and related industrial interests)

Consider prone positioning for ARDS.  For over 20 years, investigators have hoped that prone positioning improves not only oxygenation but also outcomes (mostly mortality).  So is it any wonder that after the most recent trial, in spite of the 4 or 5 previous failed trials, the community enthusiastically declared "success!"  "Prone Positioning works!"  Of course it is no wonder - this has been the hope for decades.

But consider what the most recent trial represents through the lens of replicability:  a failure to replicate previous results showing that prone positioning does not improve mortality.  The recent trial is the outlier.  It is the "false positive" rather than the previous trials being the "false negatives."

This way of interpreting the trials of prone positioning in the aggregate should be an obvious one, and it astonishes me that it took me so long to see the results this way - as a single failure to replicate previously replicable negative results.  But it hearkens to the underlying bias - we view results through the magnifying glass of hope, and it distorts our appraisal of the evidence.

Indeed, I have been accused of being a nihilist because of my views on this blog, which some see as derogating the work of others or an attempt to dash their hopes.  But these critics engage, or wish me to engage in a form of outcome bias - the value of the research lies in the integrity of its design, conduct, analysis, and reporting, not in its results.  One can do superlative research and get negative results, or shoddy research and get positive results.  My goal here is and always has been to judge the research on its merits, regardless of the results or the hopes that impel it.

(Aside:  Cholesterol researchers have a faith or hope in the cholesterol hypothesis - that cholesterol is a causal factor in pathways to cardiovascular outcomes.  Statin data corroborate this, and preliminary PCSK9 inhibitor data do, too.  But how quickly we engage in hopeful confirmation bias!  If cholesterol is a causal factor, it should not matter how you manipulate it - lower the cholesterol, lower cardiovascular events.  The fact that it does appear to matter how you lower it suggests that either there are multiplicity of agent effects (untoward and unknown effects of some agents negate some their beneficial effects in the cholesterol causal pathway) or that cholesterol levels are epiphenomena - markers of the effects of statins and PCSK9 inhibitors on the real, but as yet undelineated causal pathways.  Maybe the fact that we can easily measure cholesterol and that it is associated with outcomes in untreated individuals is a convenient accident of history that led us to trial statins which work in ways that we do not yet understand.)