Sunday, May 16, 2010

What do erythropoetin, strict rate control, torcetrapib, and diagonal earfold creases have in common? The normalization heuristic

I was pleased to see the letters to the editor in the May 6th edition of the NEJM regarding the article on the use of synthetic erythropoetins (see ). The letter writers must have been reading our paper on the normalization heuristic (NH)! (Actually, I doubt it. It's in an obscure journal. But maybe they should.)

In our article (available here: ), we operationalized the definition of the NH and attributed it to 4 errors in reasoning that lead it to be fallible as a general clinical hypothesis. Here is the number one reasoning error:

Where the normalization hypothesis is based on the assumption that the abnormal value is causally related to downstream patient outcomes, but in reality the abnormal value is not part of the causal pathway and rather is an epiphenomenon of another underlying process.

The authors of some of the letters to the editor of the NEJM have the same concerns about normalizing hemoglobin values, and the assumptions that this practice involves about our understanding of causal pathways. Which is what I want to focus on. So please turn your attention to, yes, the picture of the billiards.

I wager that the pathophysiological processes that occur in the body are more complex than the 16 balls in the photo, but it serves as a great analogy for understanding the limitations of what we know about what's going on in the body. Suppose that every time (or a high percentage of the time - we can probability adjust and not lose the meaning of the analogy) the cue ball, launched from the same spot at the same speed and angle, hits the 1--2--4--7--11 balls. We know the 11 ball is, say, cholesterol. We have figured this out. And it falls in the corner pocket - it gets "lower". But we don't know what the other balls represent, or even how many of them there are, or where they fall. We needn't know all of this to make some inferences. We see that when the cue ball is launched at a certain speed and angle, the 11 ball, cholesterol, falls. So we think we understand cholesterol. But the playing field is way more complex than the initiating event and the one final thing that we happen to be watching or measuring - the corner pocket. In the whole body, we don't even know how many balls and how many pockets we're dealing with! We only can see what we know to look for!

Suppose also that as a consequence of this cascade, the 7 ball hits the 12 ball, which falls in another corner pocket. We happen to be watching that pocket also. We know what it does. For lack of a better term, let's call it the "reduced cardiovascular death pocket." Every time this sequence of balls is hit, cholesterol (number 11) falls in one corner pocket, and the 12 ball falls in another pocket, and we infer that cholesterol is part of the causal pathway to cardiovascular death. But look carefully at the diagram. We can remove the 11 ball altogether, the 7 ball will still hit the 12 and sink it thus reducing cardiovascular death. So it's not the cholesterol at all! We misunderstood the causal pathway! It's not cholesterol falling per se, but rather some epiphenomenon of the sequence.

By now, you've inferred who is breaking. His name is atorvastatin (which I fondly refer to as the Lipid-Torpedo). When a guy called torcetrapib breaks, all hell breaks loose. We learn that there's another pocket called "increased cardiovascular death pocket" and balls start falling into there.

(A necessary aside here - I am NOT challenging the cholesterol hypothesis here. It may or may not be correct, and I certainly am not the one to figure that out. I merely wish to emphasize how we COULD make incorrect inferences about causal pathways.)

So when I see an article like there was a couple of weeks ago in the NEJM (see ) about "strict rate control" for atrial fibrillation (AF), I am not surprised that it doesn't work. I am not surprised that there are processes going on in a patient with AF that we can't even begin to understand. And the coincidental fact that we can measure heart rate and control it does not mean that we're interrupting the causal pathway that we wish to.

A new colleague of mine told me the other day of a joke he likes to make that causes this to all resonate harmoniously - "We don't go around trying to iron out diagonal earfold creases to reduce cardiovascular mortality." But show us a sexy sequence of molecular cascades that we think we understand, and the sirens begin to sing their irresistible song.

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