Migraine and venous thrombosis: Another important piece of the puzzle

Asking the right question is arguably the hardest thing to do in science, or at least in epidemiology. The question that you want to answer dictates the study design, the data that you collect and the type of analyses you are going to use. Often, especially in causal research, this means scrutinizing how you should frame your exposure/outcome relationship. After all, there needs to be positivity and consistency which you can only ensure through “the right research question”. Of note, the third assumption for causal inference i.e. exchangeability, conditional or not, is something you can pursue through study design and analyses. But there is a third part of an epidemiological research question that makes all the difference: the domain of the study, as is so elegantly displayed by the cartoon of Todays Random Medical News or the twitter hash-tag “#inmice“.

The domain is the type of individuals to which the answer has relevance. Often, the domain has a one-to-one relationship with the study population. This is not always the case, as sometimes the domain is broader than the study population at hand. A strong example is that you could use young male infants to have a good estimation of the genetic distribution of genotypes in a case-control study for venous thrombosis in middle-aged women. I am not saying that that case-control study has the best design, but there is a case to be made, especially if we can safely assume that the genotype distribution is not sex chromosome dependent or has shifted through the different generations.

The domain of the study is not only important if you want to know to whom the results of your study actually are relevant, but also if you want to compare the results of different studies. (as a side note, keep in mind the absolute risks of the outcome that come with the different domains: they highly affect how you should interpret the relative risks)

Sometimes, studies look like they fully contradict with each other. One study says yes, the other says no. What to conclude? Who knows! But are you sure both studies actually they answer the same question? Comparing the way the exposure and the outcome are measured in the two studies is one thing – an important thing at that – but it is not the only thing. You should also make sure that you take potential differences and similarities between the domains of the studies into account.

This brings us to the paper by KA and myself that just got published in the latest volume of RPTH. In fact, it is a commentary written after we have reviewed a paper by Folsom et al. that did a very thorough job at analyzing the role between migraine and venous thrombosis in the elderly. They convincingly show that there is no relationship, completely in apparent contrast to previous papers. So we asked ourselves: “Why did the study by Folsom et al report findings in apparent contrast to previous studies?  “

There is, of course, the possibility f just chance. But next to this, we should consider that the analyses by Folsom look at the long term risk in an older population. The other papers looked at at a shorter term, and in a younger population in which migraine is most relevant as migraine often goes away with increasing age. KA and I argue that both studies might just be right, even though they are in apparent contradiction. Why should it not be possible to have a transient increase in thrombosis risk when migraines are most frequent and severe, and that there is no long term increase in risk in the elderly, an age when most migraineurs report less frequent and severe attacks?

The lesson of today: do not look only at the exposure of the outcome when you want to bring the evidence of two or more studies into one coherent theory. Look at the domain as well, as you might just dismiss an important piece of the puzzle.

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Go beyond the binary outcome!

You were just diagnosed with a debilitating disease. You try to make sense of what the next steps are going to be. You ask your doctor, what do I need to do in order to get back to fully functioning adult as good as humanly possible. The doctor starts to tell what to tell you in order to reduce the risk of future events.

That sounds logical at first sight, but in reality, it is not. The question and the answer are disconnected on various levels: what is good for lowering your risk is not necessarily the same thing as the thing that will bring functionality back into your live. Also, they are about different time scales: getting back to a normal life is about weeks, perhaps months, and trying to keep recurrence risk as low as possible is a long term game – lifelong in fact.
A lot of research in various fields have bungled these two things up. The effects of acute treatment are evaluated in studies with 3-5 years of follow up. Or reducing recurrence risk is studied in large cohorts with only 6-12 months of follow up. I am not arguing that this is always a bad idea, but i do think that a better distinction between these concepts could help some fields make some progress. 

We do that in stroke. Since a while now we have adopted the so called modified Rankin scale as the primary outcome in acute stroke trials. It is a 7 category ordinal scale often measured at 90 days after the stroke that actually tells us whether the patients completely recovered (mRS 0) or actually dies (mRS 6) and anything in between. This made so much sense for stroke that I started to wonder whether this would also make sense for other diseases.

I think it does. In a recent paper published a couple of months ago in the RPTH by JLR and me, we call upon the greater thrombosis community to consider to look beyond a binary outcome. I stand by this idea, and for that reason I brought it up again at the Maastricht Consensus Conference on Thrombosis. During that conference another speaker, EK, said that the field needed a new way to capture functionality after VTE. You guessed it, we got together over coffee, shared ideas, recruited SB as a third critical thinker, and we came up with this: a call to action to improve measuring functional limitations after venous thromboembolism.

This is not just a call from us to others to get some action, this is a start of some new upcoming research activity together with EK, SB and myself. First we need the input from other experts on the scale itself. Second, we need to standardize the way we actually score patients, then test this and get the patients perspective on the logistics and questions behind the scale. third we need to know the reliability of scale and how the logistics work in a true RCT setting. Only when we complete all these steps, we will be certain whether looking the binary outcome indeed brings more actionable information when you have talk to your doctor and you ask yourself “how do i increase my chances of getting back to a fully functioning adult as good as humanly possible”.