White Noise: Trials of Pharmaceuticals for Alzheimer's Disease

"But we are not here concerned with hopes or fears, only with the truth as far as our reason allows us to discover it." - Charles Darwin

In yesterday's NEJM, the results of two trials of antiamyloid monoclonal antibodies (sonalezumab and bapeneuzumab)  for Alzheimer's Disease (AD) are published.  I became interested in the evidence for AD treatments after the recent trial of Vitamin E and Mematine for AD (the TEAM-AD VA Cooperative Trial) was published in JAMA earlier this month.  Regular readers know that I think that the prior probability that vitamins, minerals, and antioxidants are beneficial for any disease outside of deficiency states is very low.  The vitamin E trial was the impetus for some background investigation which I will summarize below.

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.