No, Smoking Won't Save You From COVID-19

A critically important study is being misinterpreted.

This week – an absolutely HUGE study out of England gives us insight into who is at risk of dying with COVID-19.

But beware folks – this is a pre-print. No peer review has had it’s way with the study yet. Nevertheless that hasn’t stopped major news outlets from covering it, with some drawing potentially dangerous conclusions. Let’s set the record straight.

This is a paper out of Ben Goldacre’s lab.

If you don’t know Ben, he is an extremely well-regarded British physician and evidence-based-medicine evangelist. His TED talk on Bad Science has over 500,000 views on Youtube and is well worth a watch.  He knows what he’s doing.

In fact, some people consider me the American Ben Goldacre. Those people are my parents. And that’s it.

This is a study of more than 17,000,000 individuals in England who receive primary care from clinics using a standardized electronic health record system. The analysis was restricted to those with at least one year of data in the system to ensure relatively good capture of relevant comorbidities. The huge dataset was then linked to a registry of COVID-19 deaths (there were 5,683 of those at the time the data was analyzed).

The real advantage over other studies here is clear. You’re not looking at people who got tested, or people with symptoms, you are looking at basically everyone. It allows you to ask the question, who, in England at least, is most at risk of dying with COVID-19?

The results confirm a lot of what we have seen from other studies.

The risk of death, for example, was markedly higher as age increased.

The COVID death rate was 26 times higher among those over age 80 compared to those between ages 50-60, for example. They also showed that the COVID death rate in men was higher substantially higher than that in women.

The authors honestly could have stopped here. There are people at higher risk – here are some things that make people higher risk. But they went a step farther than most other groups have gone. They put these risk factors in a multivariable model to provide a deeper level of understanding.

This is awesome, but be careful. This is not causality.

We all want to know what causes COVID-19 deaths. Because it would imply that, if we change that thing, we can reduce COVID-19 deaths.  Not just predict them.  It’s actually a really important difference.

Let me give an example.

Does high blood pressure cause COVID-19 death? In other words, would lowering blood pressure reduce COVID-19 deaths.

Well, people with high blood pressure were about 20% more likely to die of COVID-19 than people without high blood pressure.

But that doesn’t mean it’s the blood pressure that did it, right?  Maybe people with high blood pressure tended to have other things that caused the death. Maybe they don’t get as much exercise, maybe they have more heart disease?  We can create little causal diagrams (also known as directed acyclic graphs) like this to sketch out those hypotheses.

After adjustment for comorbidities, notably including heart disease, the association between high blood pressure and COVID-19 death went away.

Does that mean that high blood pressure doesn’t cause COVID-19 death?

Again, not exactly.

It depends what you adjust for.  Hypertension does cause cardiovascular disease. Let’s assume that having cardiovascular disease is a causal part of why people die of COVID-19. If that’s the case, then if we reduced hypertension we could reduce heart disease and thus reduce COVID-19 death. That’s causality. High blood pressure is causally related to COVID-19 death VIA it’s effect on cardiovascular disease. It’s like how not wearing a seatbelt causes motor vehicle death via it’s effect on having you not fly through a window.

When you are trying to figure out what causes what, it’s really important that you NOT adjust for factors that may lie along the causal pathway.  It’s also really important that you DO adjust for confounders – those factors associated with both hypertension and COVID-death that don’t lie along the causal pathway.

How do you tell the difference? It’s really hard. A lot of it begins with simple clinical intuition.

Which leads us to this finding, which has garnered a LOT of attention.  Does smoking protect against COVID-19 death?!

This article from The Economist raises the possibility based on this very study. But actually, this result looks to be the result of adjusting for something on the causal pathway.

In the unadjusted analysis, current smoking was associated with a 25% increased risk of COVID-19 death. Makes sense to me – this is a lung virus. Smoking  hurts the lungs. I’m on board. But after adjustment, current smoking appears to have a 12% reduced risk of death.

A casual interpretation may be “all else being equal, smoking is protective”.  Or, in other words, start smoking.

This is obviously wrong, but let’s go through why.

A causal diagram (or directed acyclic graph) showing the relationship between smoking and COVID-19 death.

I’m going to hypothesize that smoking actually does cause an increase in COVID-19 death.

I’m further going to hypothesize that the mechanism is via respiratory disease.

The fully adjusted model adjusts for respiratory disease.  So when we look at the adjusted risk of smoking, what we are saying is basically “if all these smokers didn’t have respiratory disease, they’d actually be more likely to survive COVID-19” then non-smokers. Ok. But that’s just like saying “if all these people who don’t wear their seat belt didn’t fly through the window, they’d be more likely to survive car accidents”. Fine, I guess, but definitely not a reason to take off your seat belt.

The researchers actually looked at this, and found, sure enough, all you have to do is adjust for respiratory disease to make smoking look protective.

The key take-home here is that you need to be SUPER thoughtful when you are trying to assess causality in observational data. “Adjust for everything” is not a good strategy, because you run the risk of adjusting for things on the causal pathway which totally screws up your results.

Now, Ben Goldacre (the British Perry Wilson) knows this and makes NO claim to causality in the paper. But that doesn’t stop newspapers, twitter, blogs, and the rest of the world from making the mistake.

Hopefully now, you won’t.

Don’t smoke if you got em.

This commentary first appeared on medscape.com