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.

Results dissemination from clinical trials conducted at German university medical centers was delayed and incomplete.

My interests are broader than stroke, as you can see my tweets as well as my publications. I am interested in how the medical scientific enterprise works – and more importantly how it can be improved. The latest paper looks at both.

The paper, with the relatively boring title “Results dissemination from clinical trials conducted at German university medical centres was delayed and incomplete.” is a collaboration with QUEST, and carried by DS and his team. The short form of the title might just as well have been “RCT don’t get published, and even if they do it is often too late.”

Now, this is not a new finding, in the sense that older publications also showed high rates of non-publishing. Newer activities in this field, such as the trial trackers for the FDAA and the EU, confirm this idea. The cool thing about these newer trackers is that they rely on continuous data collection through bots that crawl all over the interwebs to look for new trials. This upside thas a couple of downsides though: with constant being updated, these trackers do not work that well as a benchmarking tool. Second, they might miss some obscure type of publication which might lead to underreporting of reporting. Third, to keep the trackers simple they tend to only use one definition as what counts as “timely publication” even though the field, nor the guidelines, are conclusive.

So our project is something different. To get a good benchmark, we looked at whether trials executed by/at German University medical centers were published in a timely fashion. We collected the data automatically as far as we could, but also did a complete double check by hand to ensure we didn’t skip publications (hint, we did, hand search is important, potentially because of the language thing). Then we put all the data in a database, made a shiny app so that readers themselves can decide what definitions and subsets they are interested in. The bottomline, on average only ~50% of trials get published within two years after their formal end. That is too little and too slow.

shiny app

This is a cool publication because it provides a solid benchmark that truly captures the current state. Now, it is up to us, and the community to improve our reporting. We should track progress in the upcoming years by automated trackers, and in 5 years or so do the whole manual tracking once more. But that is not the only reason why it was so inspiring to work on the projects; it was the diverse team of researchers from many different groups that made the work fun to do. The discussions we had on the right methodology were complex and even led to an ancillary paper by DS and his group. But the way this publication was published in the most open way possible (open data, preprint, etc) was also a good experience.

The paper is here on Pubmed, the project page on OSF can be found here and the preprint is on bioRxiv, and let us not forget the shiny app where you can check out the results yourself. Kudos go out to DS and SW who really took the lead in this project.

Joining the PLOS Biology editorial board

I am happy and honored that I can share that I am going to be part of the PLOS Biology editorial board. PLOS Biology has a special model for their editorial duties, with the core of the work being done by in-house staff editors – all scientist turned professional science communicators/publishers. They are supported by the academic editors – scientists who are active in their field and can help the in-house editors with insight/insider knowledge. I will join the team of academic editors.

When the staff editors asked me to join the editorial board, it quickly became clear that they invited because I might be able to contribute to the Meta-research section in the journal. After all, next to some of my peer review reports I wrote for the journal, I published a paper on missing mice, the idea behind sequential designs in preclinical research, and more recently about the role of exact replication.

Next to the meta-research manuscripts that need evaluation, I am also looking forward to just working with the professional and smart editorial office. The staff editors already teased a bit that a couple of new innovations are coming up. So, next to helping meta-research forward, I am looking forward to help shape and evaluate these experiments in scholarly publishing.

Kuopio Stroke Symposium

Kuopio in summer

Every year there is a Neurology symposium organized in the quiet and beautiful town of Kuopio in Finland. Every three years, just like this year, the topic is stroke and for that reason, I was invited to be part of the faculty. A true honor, especially if you consider the other speakers on the program who all delivered excellent talks!

But these symposia are much more than just the hard cold science and prestige. It is also about making new friends and reconnecting with old ones. Leave that up to the Fins, whose decision to get us all on a boat and later in a sauna after a long day in the lecture hall proved to be a stroke of genius.

So, it was not for nothing that many of the talks boiled down to the idea that the best science is done with friends – in a team. This is true for when you are running a complex international stroke rehabilitation RCT, or you are investigating whether the lower risk in CVD morbidity and mortality amongst frequent sauna visitors. Or, in my case, about the role of hypercoagulability in young stroke – pdf of my slides can be found here –

My talk in Augsburg – beyond the binary

@BobSiegerink & Jakob Linseisen discussing the p-values. Thank you for your visit and great talk pic.twitter.com/iBt5ZQxaMi— Sebastian Baumeister (@baumeister_se) 3 May 2019

I am writing this as I am sitting in the train on my way back to Berlin. I was in Augsburg today (2x 5.5 hours in the train!), a small University city next to Munich in the south of Berlin. SB, fellow epidemiologist and BEMC alumnus, invited me to give a talk in their Vortragsreihe.

I had a blast – in part because this talk posed a challenge for me as they have a very mixed audience. I really had to think long and hard how I could provide something a stimulating talk with a solid attention arc for everybody on the audience. Take a look at my slides to see if I succeeded: http://tiny.cc/beyondbinary

My talk at Kuopio stroke symposium

In 6 weeks or so I will be traveling to Finland to speak at the Kuopio stroke symposium. They asked me to talk about my favorite subject, hypercoagulability and ischemic stroke. although I still working on the last details of the slides, I can already provide you with the abstract.

The categories “vessel wall damage” and “disturbance of blood flow” from Virchow’s Triad can easily be used to categorize some well known risk factors for ischemic stroke. This is different for the category “increased clotting propensity”, also known as hypercoagulability. A meta-analysis shows that markers of hypercoagulability are stronger associated with the risk of first ischemic stroke compared to myocardial infarction. This effect seems to be most pronounced in women and in the young, as the RATIO case-control study provides a large portion of the data in this meta-analysis. Although interesting from a causal point of view, understanding the role of hypercoagulability in the etiology of first ischemic stroke in the young does not directly lead to major actionable clinical insights. For this, we need to shift our focus to stroke recurrence. However, literature on the role of hypercoagulability on stroke recurrence is limited. Some emerging treatment targets can however can be identified. These include coagulation Factor XI and XII for which now small molecule and antisense oligonucleotide treatments are being developed and tested. Their relative small role in hemostasis, but critical role in pathophysiological thrombus formation suggest that targeting these factors could reduce stroke risk without increasing the risk of bleeds. The role of Neutrophilic Extracellular Traps, negatively charged long DNA molecules that could act as a scaffold for the coagulation proteins, is also not completely understood although there are some indications that they could be targeted as co-treatment for thrombolysis.

I am looking forward to this conference, not in the least to talk to some friends, get inspired by great speakers and science and enjoy the beautiful surroundings of Kuopio.

postscript: here are my slides that I used in Kuopio

Should you drink one glass of alcohol to reduce your stroke risk?

The answer: no. For a long time there has been doubt whether or not we should believe the observational data whether or not limited alcohol use is in fact good for. You know, the old “U-curve” association. Now, with some smart thinking from the KADORIE guys from China/ Oxford as well as some other methods experts, the ultimate analyses has been done: A Mendelian Randomization study published recently in the Lancet.

If you wanna know what that actually does, you can read a paper I co-wrote a couple of years ago for NDT or the version in Dutch for the NTVG. In short, the technique uses genetic variation as a proxy for the actual phenotype you are interested in. This can be a biomarker, or in this case, alcohol consumption. A large proportion of the Chinese population has some genetic variations in the genes that code for the enzymes that break down alcohol in your blood. These genetic markers are therefore a good indicators how much you can actually can drink – at least on a group level. And as in most regions in China alcohol drinking is the standard, at least for men- how much you can drink is actually a good proxy of how much you actually do drink. Analyse the risk of stroke according the unbiased genetic determined alcohol consumption instead of the traditional questionnaire based alcohol consumption and voila: No U curve in sight –> No protective effect of drinking a little bit of alcohol.

Why I am writing about that study on my own blog? I didn’t work on the research, that is for sure! No, it is because the Dutch newspaper NRC actually contacted me to get some background information which I was happy to do. The science section in the NRC has always been one of the best in the NL, which made it quite an honor as well as an adventure to get involved like that. The journalist, SV, did an excellent job or wrapping all what we discussed in that 30-40 video call into just under 600 words, which you can read here (Dutch).  I really learned a lot helping out and I am looking forward doing this type of work sometime in the future.