Intrinsic Coagulation Pathway, History of Headache, and Risk of Ischemic Stroke: a story about interacting risk factors

Yup, another paper from the long-standing collaboration with Leiden. this time, it was PhD candidate HvO who came up with the idea to take a look at the risk of stroke in relation to two risk factors that independently increase the risk. So what then is the new part of this paper? It is about the interaction between the two.

Migraine is a known risk factor for ischemic for stroke in young women. Previous work also indicated that increased levels of the intrinsic coagulation proteins are associated with an increase in ischemic stroke risk. Both roughly double the risk. so what does the combination do?

Let us take a look at the results of analyses in the RATIO study. High levels if antigen levels of coagulation factor FXI are associated with a relative risk of 1.7. A history of severe headache doubles the risk of ischemic stroke. so what can we then expect is both risks just added up? Well, we need to take the standard risk that everybody has into account, which is RR of 1. Then we add the added risk in terms of RR based on the two risk factors. For FXI this is (1.7-1=) 0.7. For headache that is 2.0-1=) 1.0. So we would expect a RR of (1+0.7+1.0=) 2.7. However, we found that the women who had both risk factors had a 5-fold increase in risk, more than what can b expected.

For those who are keeping track, I am of course talking about additive interaction or sometimes referred to biological interaction. this concept is quite different from statistical interaction which – for me – is a useless thing to look at when your underlying research is of a causal nature.

What does this mean? you could interpret this that some women only develop the disease because they are exposed to both risk factors. IN some way, that combination becomes a third ‘risk entity’ that increases the risk in the population. How that works on a biochemical level cannot be answered with this epidemiological study, but some hints from the literature do exist as we discuss in our paper

Of course, some notes have to be taken into account. In addition to the standard limitations of case-control studies, two things stand out: because we study the combination of two risk factors, the precision of our study is relatively low. But then again, what other study is going to answer this question? The absolute risk of ischemic stroke is too low in the general population to perform prospective studies, even when enriched with loads of migraineurs. Another thing that is suboptimal is that the questionnaires used do not allow to conclude that the women who report severe headache actually have a migraine. Our assumption is that many -if not most- do. even though mixing ‘normal’ headaches with migraines in one group would only lead to an underestimation of the true effect of migraine on stroke risk, but still, we have to be careful and therefore stick to the term ‘headache’.

HvO took the lead in this project, which included two short visits to Berlin supported by our Virchow scholarship. The paper has been published in Stroke and can be seen ahead of print on their website.

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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.

medRxiv: the pre-print server for medicine

Pre-print servers are a place to place share your academic work before actual peer review and subsequent publication. They are not so new completely new to academia, as many different disciplines have adopted pre-print servers to quickly share ideas and keep the academic discussion going. Many have praised the informal peer-review that you get when you post on pre-print servers, but I primarily like the speed.

But medicine is not one of those disciplines. Up until recently, the medical community had to use bioRxiv, a pre-print server for biology. Very unsatisfactory; as the fields are just too far apart, and the idiosyncrasies of the medical sciences bring some extra requirements. (e.g. ethical approval, trial registration, etc.). So here comes medRxiv, from the makers of bioRxiv with support of the BMJ. Let’s take a moment to listen to the people behind medRxiv to explain the concept themselves.

source: https://www.medrxiv.org/content/about-medrxiv

I love it. I am not sure whether it will be adopted by the community at the same space as some other disciplines have, but doing nothing will never be part of the way forward. Critical participation is the only way.

So, that’s what I did. I wanted to be part of this new thing and convinced with co-authors for using the pre-print concept. I focussed my efforts on the paper in which we describe the BeLOVe study. This is a big cohort we are currently setting up, and in a way, is therefore well-suited for pre-print servers. The pre-print servers allow us to describe without restrictions in word count, appendices or tables and graphs to describe what we want to the level of detail of our choice. The speediness is also welcome, as we want to inform the world on our effects while we are still in the pilot phase and are still able to tweak the design here or there. And that is actually what happened: after being online for a couple of days, our pre-print already sparked some ideas by others.

Now we have to see how much effort it took us, and how much benefit w drew from this extra effort. It would be great if all journals would permit pre-prints (not all do…) and if submitting to a journal would just be a “one click’ kind of effort after jumping through the hoops for the medRxiv.

This is not my first pre-print. For example, the paper that I co-authored on the timely publication of trials from Germany was posted on biorXiv. But being the guy who actually uploads the manuscript is a whole different feeling.

REWARD | EQUATOR Conference 2020 in Berlin

https://www.reward-equator-conference-2020.com

Almost 5 years ago something interesting happened in Edinburgh. REWARD and EQUATOR teamed up and organized a joint conference on “Increasing value and reducing waste in biomedical research “. Over the last five years, that topic has dominated Meta-research and research improvement activities all over the world. Now 5 years later, it is again time for another REWARD and EQUATOR conference, this time in Berlin. And I have the honor to serve on the local organizing committee.

My role is so small, that the LOC is currently not even mentioned on the website. But the website does show some other names, promising a great event! it starts with the theme. which is “Challenges and opportunities for Improvement for Ethics Committees and Regulators, Publishers, Institutions and Researchers, Funders – and Methods for measuring and testing Interventions”. That is not a sexy title like 5 years ago, but it shows that the field has outgrown the alarmistic phase and is now looking for real and lasting changes for the better – a move I can only encourage. See you in Berlin?

https://www.reward-equator-conference-2020.com

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 –