Messy epidemiology: the tale of transient global amnesia and three control groups

Clinical epidemiology is sometimes messy. The methods and data that you might want to use might not be available or just too damn expensive. Does that mean that you should throw in the towel? I do not think so.

I am currently working in a more clinical oriented setting, as the only researcher trained as a clinical epidemiologist. I could tell about being misunderstood and feeling lonely as the only who one who has seen the light, but that would just be lying. The fact is that my position is one privilege and opportunity, as I work with many different groups together on a wide variety of research questions that have the potential to influence clinical reality directly and bring small, but meaningful progress to the field.

Sometimes that work is messy: not the right methods, a difference in interpretation, a p value in table 1… you get the idea. But sometimes something pretty comes out of that mess. That is what happened with this paper, that just got published online (e-pub) in the European Journal of Neurology.  The general topic is the heart brain interaction, and more specifically to what extent damage to the heart actually has a role in transient global amnesia. Now, the idea that there might be a link is due to some previous case series, as well as the clinical experience of some of my colleagues. Next step would of course to do a formal case control-study, and if you want to estimate true measure of rate ratios, a lot effort has to go into the collection of data from a population based control group. We had neither time nor money to do so, and upon closer inspection, we also did not really need that clean control group to answer some of our questions that would progress to the field.

So instead, we chose three different control groups, perhaps better referred as reference groups, all three with some neurological disease. Yes, there are selections at play for each of these groups, but we could argue that those selections might be true for all groups. If these selection processes are similar for all groups, strong differences in patient characteristics of biomarkers suggest that other biological systems are at play. The trick is not to hide these limitations, but as a practiced judoka, leverage these weaknesses and turn them into a strengths. Be open about what you did, show the results, so that others can build on that experience.

So that is what we did. Compared patients with migraine with aura, vestibular neuritis and transient ischemic attack, patients with transient global amnesia are more likely to exhibitsigns of myocardial stress. This study was not designed – nor will if even be able to – understand the cause of this link, not do we pretend that our odds ratios are in fact estimates of rate ratios or something fancy like that. Still, even though many aspects of this study are not “by the book”, it did provide some new insights that help further thinking about and investigations of this debilitating and impactful disease.

The effort was lead by EH, and the final paper can be found here on pubmed.

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Impact of your results: Beyond the relative risk

I wrote about this in an earlier topic: JLR and I published a paper in which we explain that a single relative risk, irrespective of its form, is jus5t not enough. Some crucial elements go missing in this dimensionless ratio. The RR could allow us to forget about the size of the denominator, the clinical context, the crude binary nature of the outcome. So we have provided some methods and ways of thinking to go beyond the RR in an tutorial published in RPTH (now in early view). The content and message are nothing new for those trained in clinical research (one would hope). Even for those without a formal training most concepts will have heard the concepts discussed in a talk or poster . But with all these concepts in one place, with an explanation why they provide a tad more insight than the RR alone, we hope that we will trigger young (and older) researchers to think whether one of these measures would be useful. Not for them, but for the readers of their papers. The paper is open access CC BY-NC-ND 4.0, and can be downloaded from the website of RPTH, or from my mendeley profile.  

Advancing prehospital care of stroke patients in Berlin: a new study to see the impact of STEMO on functional outcome

There are strange ambulances driving around in Berlin. They are the so-called STEMO cars, or Stroke Einsatz Mobile, basically driving stroke units. They have the possibility to make a CT scan to rule out bleeds and subsequently start thrombolysis before getting to the hospital. A previous study showed that this descreases time to treatment by ~25 minutes. The question now is whether the patients are indeed better of in terms of functional outcome. For that we are currently running the B_PROUD study of which we recently published the design here.

Virchow’s triad and lessons on the causes of ischemic stroke

I wrote a blog post for BMC, the publisher of Thrombosis Journal in order to celebrate blood clot awareness month. I took my two favorite subjects, i.e. stroke and coagulation, and I added some history and voila!  The BMC version can be found here.

When I look out of my window from my office at the Charité hospital in the middle of Berlin, I see the old pathology building in which Rudolph Virchow used to work. The building is just as monumental as the legacy of this famous pathologist who gave us what is now known as Virchow’s triad for thrombotic diseases.

In ‘Thrombose und Embolie’, published in 1865, he postulated that the consequences of thrombotic disease can be attributed one of three categories: phenomena of interrupted blood flow, phenomena associated with irritation of the vessel wall and its vicinity and phenomena of blood coagulation. This concept has now been modified to describe the causes of thrombosis and has since been a guiding principle for many thrombosis researchers.

The traditional split in interest between arterial thrombosis researchers, who focus primarily on the vessel wall, and venous thrombosis researchers, who focus more on hypercoagulation, might not be justified. Take ischemic stroke for example. Lesions of the vascular wall are definitely a cause of stroke, but perhaps only in the subset of patient who experience a so called large vessel ischemic stroke. It is also well established that a disturbance of blood flow in atrial fibrillation can cause cardioembolic stroke.

Less well studied, but perhaps not less relevant, is the role of hypercoagulation as a cause of ischemic stroke. It seems that an increased clotting propensity is associated with an increased risk of ischemic stroke, especially in the young in which a third of main causes of the stroke goes undetermined. Perhaps hypercoagulability plays a much more prominent role then we traditionally assume?

But this ‘one case, one cause’ approach takes Virchow’s efforts to classify thrombosis a bit too strictly. Many diseases can be called multi-causal, which means that no single risk factor in itself is sufficient and only a combination of risk factors working in concert cause the disease. This is certainly true for stroke, and translates to the idea that each different stroke subtype might be the result of a different combination of risk factors.

If we combine Virchow’s work with the idea of multi-causality, and the heterogeneity of stroke subtypes, we can reimagine a new version of Virchow’s Triad (figure 1). In this version, the patient groups or even individuals are scored according to the relative contribution of the three classical categories.

From this figure, one can see that some subtypes of ischemic stroke might be more like some forms of venous thrombosis than other forms of stroke, a concept that could bring new ideas for research and perhaps has consequences for stroke treatment and care.

Figure 1. An example of a gradual classification of ischemic stroke and venous thrombosis according to the three elements of Virchow’s triad.

However, recent developments in the field of stroke treatment and care have been focused on the acute treatment of ischemic stroke. Stroke ambulances that can discriminate between hemorrhagic and ischemic stroke -information needed to start thrombolysis in the ambulance-drive the streets of Cleveland, Gothenburg, Edmonton and Berlin. Other major developments are in the field of mechanical thrombectomy, with wonderful results from many studies such as the Dutch MR CLEAN study. Even though these two new approaches save lives and prevent disability in many, they are ‘too late’ in the sense that they are reactive and do not prevent clot formation.

Therefore, in this blood clot awareness month, I hope that stroke and thrombosis researchers join forces and further develop our understanding of the causes of ischemic stroke so that we can Stop The Clot!

Increasing efficiency of preclinical research by group sequential designs: a new paper in PLOS biology

We have another paper published in PLOS Biology. The theme is in the same area as the first paper I published in that journal, which had the wonderful title “where have all the rodents gone”, but this time we did not focus on threats to internal validity, but we explored whether sequential study designs can be useful in preclinical research.

Sequential designs, what are those? It is a family of study designs (perhaps you could call it the “adaptive study size design” family) where one takes a quick peek at the results before the total number of subject is enrolled. But, this peek comes at a cost: it should be taken into account in the statistical analyses, as it has direct consequence for the interpretation of the final result of the experiment. But the bottom line is this: with the information you get half way through can decide to continue with the experiment or to stop because of efficacy or futility reasons. If this sounds familiar to those familiar with interim analyses in clinical trials, it is because it is the sam concept. however, we explored its impact when applied to animal experiments.

Figure from our publication in PLOS Biology describing sequential study designs in or computer simulations

Old wine in new bottles” one might say, and some of the reviewers for this paper published rightfully pointed out that our paper was not novel in terms of showing how sequential designs are more efficient compared to non sequential designs. But there is not where the novelty lies. Up untill now, we have not seen people applying this approach to preclinical research in a formal way. However, our experience is that a lot of preclinical studies are done with some kind of informal sequential aspect. No p<0.05? Just add another mouse/cell culture/synapse/MRI scan to the mix! The problem here is that there is no formal framework in which this is done, leading to cherry picking, p-hacking and other nasty stuff that you can’t grasp from the methods and results section.

Should all preclinical studies from now on half sequential designs? My guess would be NO, and there are two major reasons why. First of all, sequential data analyses have their ideosyncrasies and might not be for everyone. Second, the logistics of sequential study designs are complex, especially if you are affraid to introduce batch effects. We only wanted to show preclinical researchers that the sequential approach has their benefits: the same information with on average less costs. If you translate “costs” into animals the obvious conclusion is: apply sequential designs where you can, and the decrease in animals can “re-invested” in more animals per study to obtain higher power in preclinical research. But I hope that the side effect of this paper (or perhaps its main effect!) will be that the readers just think about their current practices and whether thise involve those ‘informal sequential designs’ that really hurt science.

The paper, this time with aless exotic title, “Increasing efficiency of preclinical research by group sequential designs” can be found on the website of PLOS biology.

Associate editor at BMC Thrombosis Journal

source: https://goo.gl/CS2XtJ
source: https://goo.gl/CS2XtJ

In the week just before Christmas, HtC approached me by asking whether or not I would like to join the editorial board of BMC Thrombosis Journal as an Associate Editor. the aims and scope of the journal, taken from their website:

“Thrombosis Journal  is an open-access journal that publishes original articles on aspects of clinical and basic research, new methodology, case reports and reviews in the areas of thrombosis.Topics of particular interest include the diagnosis of arterial and venous thrombosis, new antithrombotic treatments, new developments in the understanding, diagnosis and treatments of atherosclerotic vessel disease, relations between haemostasis and vascular disease, hypertension, diabetes, immunology and obesity.”

I talked to HtC, someone at BMC, as well as some of my friends and colleagues whether or not this would be a wise thing to do. Here is an overview of the points that came up:

Experience: Thrombosis is the field where I grew up in as a researcher. I know the basics, and have some extensive knowledge on specific parts of the field. But with my move to Germany, I started to focus on stroke, so one might wonder why not use your time to work with a stroke related journal. My answer is that the field of thrombosis is a stroke related field and that my position in both worlds is a good opportunity to learn from both fields. Sure, there will be topics that I have less knowledge off, but here is where an associate editor should rely on expert reviewers and fellow editors.

This new position will also provide me with a bunch of new experiences in itself: for example, sitting on the other side of the table in a peer review process might help me to better understand a rejection of one of my own papers. Bottom line is that I think that I both bring and gain relevant experiences in this new position.

Time: These things cost time. A lot. Especially when you need to learn the skills needed for the job, like me. But learning these skills as an associate editor is an integral part of the science apparatus, and I am sure that the time that I invest will help me develop as a scientist. Also, the time that I need to spend is not necessary the type of time that I currently lack, i.e. writing time. For writing and doing research myself I need decent blocks of time to dive in and focus  — 4+ hours if possible. The time I need to perform my associate editor tasks is more fragmented: find peer reviewers, read their comments and make a final judgement are relative fragmented activities and I am sure that as soon as I get the hang of it I can squeeze those activities within shorter slots of time. Perhaps a nice way to fill those otherwise lost 30 minutes between two meetings?

Open science: Thrombosis journal is part of the Biomed central family. As such, it is an 100% OA journal. It is not that I am an open science fanboy or sceptic, but I am very curious how OA is developing and working with an OA journal will help me to understand what OA can and cannot deliver.

Going over these points, I am convinced that I can contribute to the journal with my experience in the fields of coagulation, stroke and research methodology. Also, I think that the time that it will take to learn the skills needed are an investment that in the end will help me to grow as a researcher. So, I replied HtC with a positive answer. Expect email requesting for a peer review report soon!

The paradox of the BMI paradox

2016-10-19-17_52_02-physbe-talk-bs-pdf-adobe-reader

I had the honor to be invited to the PHYSBE research group in Gothenburg, Sweden. I got to talk about the paradox of the BMI paradox. In the announcement abstract I wrote:

“The paradox of the BMI paradox”
Many fields have their own so-called “paradox”, where a risk factor in certain
instances suddenly seems to be protective. A good example is the BMI paradox,
where high BMI in some studies seems to be protective of mortality. I will
argue that these paradoxes can be explained by a form of selection bias. But I
will also discuss that these paradoxes have provided researchers with much
more than just an erroneous conclusion on the causal link between BMI and
mortality.

I first address the problem of BMI as an exposure. Easy stuff. But then we come to index even bias, or collider stratification bias. and how selections do matter in a recurrence research paradox -like PFO & stroke- or a health status research like BMI- and can introduce confounding into the equation.

I see that the confounding might not be enough to explain all that is observed in observational research, so I continued looking for other reasons there are these strong feelings on these paradoxes. Do they exist, or don’t they?I found that the two sides tend to “talk in two worlds”. One side talks about causal research and asks what we can learn from the biological systems that might play a role, whereas others think with their clinical  POV and start to talk about RCTs and the need for weight control programs in patients. But there is huge difference in study design, RQ and interpretation of results between the studies that they cite and interpret. Perhaps part of the paradox can be explained by this misunderstanding.

But the cool thing about the paradox is that through complicated topics, new hypothesis , interesting findings and strong feelings about the existence of paradoxes, I think that the we can all agree: the field of obesity research has won in the end. and with winning i mean that the methods are now better described, better discussed and better applied. New hypothesis are being generated and confirmed or refuted. All in all, the field makes progress not despite, but because the paradox. A paradox that doesn’t even exist. How is that for a paradox?

All in all an interesting day, and i think i made some friends in Gothenburg. Perhaps we can do some cool science together!

Slides can be found here.