PRECISE-ly Wrong (1/2): The Crystal Ball

When biomedical research abandons biological plausibility, using a statistical software or a crystal ball is the same.

Wow. JAMA made my day again.

It is fun, I admit. And it is somehow reinvigorating. The only problem is that whenever I see a study like the PRECISE study, I postpone publishing two deeper and more elegant posts I prepared using Hemingway and Goethe for a commentary on Kunhn's epistemology and another on disease models.

Hemingway and Goethe will have to wait a few more weeks. They passed away so long ago that I bet they won't care. Their magistral feats lie on a clean bare metal bed, while academics dissect all the beauty and the poetry from their bodies naked by the white light.

However, the PRECISE trial is alive now. It is recruiting now, and results are expected in two years.

“The idea of the future, pregnant with an infinity of possibilities, is thus more fruitful than the future itself, and this is why we find more charm in hope than in possession, in dreams than in reality.” Henri Bergson

Let's leave those great inspiring men in the past and return to our mundane reality, like the summer flies on your kitchen table.

The PRECISE study tests whether a balanced solution increases survival over normal saline in a specific subgroup of septic patients. It has the same mistakes I have been pointing out and naming here on my substack.

In short, they are prospectively classifying the patients into four phenotypes divinated in an earlier study. Patients with a Group D phenotype will receive a balanced solution instead of normal saline, probably around one or two liters.

The intervention they will test in PRECISE boils down to giving around 3 grams of additional chloride, the same amount in a teaspoon of table salt. Mortality will be measured 30 days after the fluid infusion. Yes, you read it. This is the current level of critical care research. I have written about The Chloride Case here if you want to go deeper.

PRECISE's preliminary study presenting the phenotypes is actually more interesting than PRECISE. It is a para-scientific divinatory trance where the four phenotypes were summoned over a collection of 12 thousand patients’ vital signs. I am not overstating it. Once you ignore biological plausibility, it is still not science if you obtain your presages using a statistical package instead of tarot cards, palm readings, or whatever.

The phenotypes are:

Group A patients were hyperthermic, tachycardic, and tachypneic and were relatively hypotensive.

Group B were also hyperthermic, tachycardic, and tachypneic, but not as pronounced as Group A, and were hypertensive.

Group C and Group had lower temperatures, heart rates, and respiratory rates, with Group C being normotensive and Group D being the most hypotensive sub-phenotype.

As you can see, patients were classified based on temperature, heart and respiratory rates, and blood pressure. The authors found that a specific arbitrary combination of these variables, Group D, predicts a survival benefit for those receiving a balanced solution. This is pure juice of post-hoc P-fishing. Having “discovered” Group D, the researchers advanced to prospectively testing the hypothesis in the PRECISE study.

The rationale above lacks any mechanistic reasoning. The study premises are entirely Backward Reasoning, a cognitive failure that drives the study toward a spurious association.

I defined this cognitive mistake as “When the researcher pushes an association in a clinical study that makes no sense in real human biology and tries a post-hoc explanation of the spurious association without noticing it's spurious.”

If they see a positive or negative association at the end of PRECISE, they will need backward reasoning again in the Discussion section. It will be backward reasoning on top of backward reasoning.

How can the authors mechanistically explain that Group D patients have different mortality after receiving 1-2 liters of normal saline or a balanced solution?

AI render of a clairvoyant preparing a manuscript for JAMA

Well, this premonitory study didn't even bother to attempt mechanistic reasoning.

They just saw the words GROUP D in their crystal ball, and suddenly had an epiphany accompanied by flashing lights GROUP D PATIENTS DIE MORE IF THEY RECEIVE THREE ADDITIONAL GRAMS OF CHLORIDE IN THE EMERGENCY DEPARTMENT. MEASURE MORTALITY A MONTH AFTER THE FLUID INFUSION AND YOU WILL SEE. DON'T ASK WHY.

This is the current state of critical care research published in JAMA. Now, let's come back to earthly matters. I need someone to explain what makes Group D uniquely sensitive to fluid choice, contrasting with the other three groups. Of course, no one knows the explanation because it is a spurious association obtained by inappropriate subgroup comparisons. You can not make a subgroup analysis where the subgroups are not causally related to the association you are studying. It is bad science, it is a poor understanding of Medicine, and it also reflects a field that gave up thinking as a physician.

If we give up biological reasoning and thus abandon what was once called Internal Medicine, we are no better than Integrative Medicine practitioners. I refuse to let my specialty sink. I stand for Internal Medicine and Critical Care, even if the JAMA editors don't.

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I predict the PRECISE study will at best find nothing, and at worst find a spurious association that will make unreasonable medical authorities call for the use of the phenotypes in emergency departments everywhere in the world. No crystal ball was needed for such a foresight. All one needs is to learn to think critically. Medical education has stolen it from us and most physicians must discover how to regain it.

In the next post, I will explain how studies like PRECISE are funded, performed, and published without anyone noticing its absurdity. The discussion is backgrounded in the book “The Physician's War: The Story of the Hidden Battle between Physicians and a Science Based on Pathological Consensus".

Here is the Amazon link to the book.

Thanks for reading The Thoughtful Intensivist!

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More on the book

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More on disease models