A biomarker is a stand-in for something you actually care about. Forgetting that it is a stand-in is how medicine has repeatedly harmed people while watching the numbers improve.
What a biomarker is standing in for, why moving a number is not the same as helping a person, and the two cases that made this lesson unavoidable.
You do not want a particular cholesterol value. You want to not have a heart attack. You do not want a specific blood sugar reading. You want to keep your eyesight and your kidneys.
The numbers are proxies. They are measurable now, whereas the thing you actually care about takes decades to happen and cannot be observed in a fifteen-minute appointment. That trade is reasonable and necessary. It is also the source of most bad health reasoning.
The structureShowing that something moves a number is comparatively easy: a modest study, a few weeks, a measurable change. Showing that it prevents disease requires thousands of people followed for years, at enormous expense.
So the first arrow gets demonstrated and the second gets assumed. Usually the assumption holds. Sometimes it does not — and when it fails, it can fail badly.
When the assumption brokeExtra heartbeats after a heart attack are associated with higher risk of dying. Drugs existed that reliably suppressed them — the biomarker improved, exactly as intended. When a large trial finally tested whether patients actually lived longer, the answer was the reverse: the treated group died at a higher rate than those on placebo. The trial was stopped early. The number had improved while the people did worse.
HDL is associated with lower cardiovascular risk, so a drug that raised it substantially looked extremely promising. In the trial, cardiovascular events and deaths increased. The program was abandoned. Being associated with good outcomes is not the same as causing them — and a drug can move a marker by a route that does not carry the benefit the association implied.
Neither of these was fraud or carelessness. They were reasonable inferences from real associations, and they were wrong. That is the point: the dashed arrow is not a formality.
The question to askWhen you meet a health claim, locate it on the chain. Almost all of them are claims about the first arrow, presented as though they were about the second.
None of this means biomarkers are useless. They are how medicine acts before damage is done, and some are extremely well validated — blood pressure and ApoB have been tested against real outcomes many times over. The skill is knowing which arrow a given claim has actually demonstrated, and treating the other one as an open question rather than a completed one.
Antiarrhythmic drugs that suppressed post-infarction ectopic beats increased mortality in a large randomized trial, despite improving the marker.
A drug that substantially raised HDL cholesterol increased cardiovascular events and deaths in trial, contradicting the observational association.
Some biomarkers — blood pressure and ApoB among them — have been validated against hard outcomes across many randomized trials.
Surrogate endpoints are used because outcome trials are slow and expensive; this is a practical necessity rather than a scientific preference.
That improving any given biomarker necessarily improves health, in the absence of outcome data for that specific intervention.
A biomarker stands in for an outcome you cannot measure yet — and because the link between the two is usually assumed rather than tested, moving a number is not the same as helping a person.
Health makes more sense when more than one person is looking at it. Everything here is free to read.
Want the rest? The foundation bundles collect these lessons into one file, free.
A visual guide to how metabolism, mitochondria, hormones, sleep, muscle, the heart, the gut and the brain influence one another — the whole system on one page, with the strongest connections written out. Use it as your roadmap while you work through the lessons.
Free. The map is yours to keep. Plus occasional new lessons and evidence-based updates. No spam. Unsubscribe any time.
Free to download right now — no email needed:
The Health Map — a visual guide to how metabolism, mitochondria, hormones, sleep, muscle, the heart, the gut and the brain influence one another. Every lesson on the site stays free to read either way.
Free. No spam, unsubscribe any time.
