Saturday, April 27, 2013

Tell Them to Go Pound Salt: Ideology and the Campaign to Legislate Dietary Sodium Intake

In the March 28th, 2013 issue of the NEJM, a review of sorts entitled "Salt in Health and Disease - A Delicate Balance" by Kotchen et al can be found.  My interest in this topic stems from my interest in the question of association versus causation, my personal predilection for salt, my observation that I lose a good deal of sodium in outdoor activities in the American Southwest, and my concern for bias in the generation of and especially the implementation of evidence in medicine as public policy.

This is an important topic, especially because sweeping policy changes regarding the sodium content of food are proposed, but it is a nettlesome topic to study, rife with hobgoblins.  First we need a well-defined research question:  does reduction in dietary sodium intake:  a.) reduce blood pressure in hypertensive people?  in all people?  b.) does this reduction in hypertension lead to improved outcomes (hypertension is in some ways a surrogate marker)?  In a utopian world, we would randomize thousands of participants to diets low in sodium and "normal" in sodium, we would measure sodium intake carefully, and we would follow the participants for changes in blood pressure and clinical outcomes for a protracted period.  But alas, this has not been done, and it will not likely be done because of cost and logistics, among other obstacles (including ideology).

Friday, April 19, 2013

David versus Goliath on the Battlefield of Non-inferiority: Strangeness is in the Eye of the Beholder

In this week's JAMA is my letter to the editor about the CONSORT statement revision for the reporting of non-inferiority trials, and the authors' responses.  I'll leave it to interested readers to view for themselves the revised CONSORT statement, and the letter and response.

In sum, my main argument is that Figure 1 in the article is asymmetric, such that inferiority is stochastically less likely than superiority and an advantage is therefore conferred to the "new" [preferred; proprietary; profitable; promulgated] treatment in a non-inferiority trial.  Thus the standards for interpretation of non-inferiority trials are inherently biased.  There is no way around this, save for revising the standards.

The authors of CONSORT say that my proposed solution is "strange" because it would require revision of the standards of interpretation for superiority trials as well.  For me it is "strange" that we would endorse asymmetric and biased standards of interpretation in any trial.  The compromised solution, as I suggested in my letter, is that we force different standards for superiority only in the context of a non-inferiority trial.  Thus, superiority trial interpretation standards remain untouched.  It is only if you start with a non-inferiority trial that you have a higher hurdle to claiming superiority that is contingent on evidence of non-inferiority in the trial that you designed.  This would disincentivise the conduct of non-inferiority trials for a treatment that you hope/think/want to be superior.  In the current interpretation scheme, it's a no-brainer - conduct a non-inferiority trial and pass the low hurdle for non-inferiority, and then if you happen to be superior too, BONUS!

In my proposed scheme, there is no bonus superiority that comes with a lower hurdle than inferiority.  As I said in the last sentence, "investigators seeking to demonstrate superiority should design a superiority trial."  Then, there is no minimal clinically important difference (MCID) hurdle that must be cleared, and a statistical difference favoring new therapy by any margin lets you declare superiority.  But if you fail to clear that low(er) hurdle, you can't go back and declare non-inferiority.  

Which leads me to something that the word limit of the letter did not allow me to express:  we don't let unsuccessful superiority trials test for non-inferiority contingently, so why do we let successful non-inferiority trials test for superiority contingently?

Symmetry is beautiful;  Strangeness is in the eye of the beholder.

(See also:  Dabigatran and Gefitinib especially the figures, analogs of Figure 1 of Piaggio et al, on this blog.)

Wednesday, April 17, 2013

Out to Lunch: Nutrition and Supplementation in Critical Illness

A study in week's issue of the NEJM (Heyland et al, Glutamine in Critical Illness, April 18th, 2013) left me titillated in consideration of how new evidence demonstrates underlying misconceptions, shortcomings, and biases in our understanding of, and general approach to, disease and its pathophysiology.  Before you read on, try to predict:  Will supplemental glutamine and anti-oxidants influence the course of critical illness?

The Canadian Critical Care Trials group has continued the effort to determine the causal role of macro- and micronutrients and their deficiency and supplementation in critical (and other) illness.  The results are discouraging (glutamine and anti-oxidants don't work), but only if we consider RCTs to be a tool for the assessment of the therapeutic value of putative molecules and their manipulation in disease states.  RCTs are such a tool, but only if we happen to be fortunate enough to be pursuing a causal pathway.  In the absence of this good fortune, RCTs remain valuable but only to help us understand that the associations we have labored to delineate are not causal associations, and that we should direct our focus to other, potentially more fruitful, investigations.  As I articulated in the last post, this dual role of RCTs represents a paradox which can be the source of great cognitive dissonance (and misunderstanding).  The (properly conducted and adequately powered) RCT is a method for determining if observational associations are causal associations, but the promise of confirming causal associations in an RCT by manipulating dependent variables with a potential therapeutic agents carries with it the possibility of proving the efficacy of a disease treatment.   During this protracted scientific process, there is a tendency to get carried away, such that our hypothesis mutates into a premise that we are studying a causal factor and the RCT is the last hurdle to confirming that we have advanced not only the science of causation, but also clinical therapeutics.  Alas, the historical record shows that we are far better at advancing our understanding (if we are willing to accept the results for what they are) than we are at finding new treatments for disease, because most of the associations we are investigating turn out not to be causal.