Helping patients to navigate the fragmented healthcare landscape in Berlin: the NAVICARE stroke-atlas

the cover the Berlin Stroke Atlas

Research on healthcare delivery can only do so much to improve the lives of patients. Identifying the weak spots is important to start off with, but is not going to help patients one bit if they don’t get information that is actually useful let alone in time.

It is for that reason that the NAVICARE project not only focusses on doing research but also to provide information for patients, as well as bringing healthcare providers together in the NAVICARE network. The premise of NAVICARE is that somehow we need to help patients to navigate the fragmented healthcare landscape. We do so by using the diseases stroke and lung cancer as model diseases, prototypical diseases that help us focus our attention.

One deliverable is the stroke atlas: a document that provides different healthcare providers – and people and organizations who can help you in the broadest sense possible once you or your loved one is affected by a stroke. This stroke atlas, in conjunction with our personal approach at the stroke service point of the CSB/BSA, will help our patients. You can find the stroke atlas here (in German of course).

But this is only a first step. the navigator model is currently being further developed, for which NAVICARe has received additional funding this summer. I will not be part of those steps (see my post on my reshuffled research focus), but others at the CSB will.

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.

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 –

new paper: pulmonary dysfunction and CVD outcome in the ELSA study

 This is a special paper to me, as this is a paper that is 100% the product of my team at the CSB.Well, 100%? Not really. This is the first paper from a series of projects where we work with open data, i.e. data collected by others who subsequently shared it. A lot of people talk about open data, and how all the data created should be made available to other researchers, but not a lot of people talk about using that kind of data. For that reason we have picked a couple of data resources to see how easy it is to work with data that is initially not collected by ourselves.

It is hard, as we now have learned. Even though the studies we have focussed on (ELSA study and UK understanding society) have a good description of their data and methods, understanding this takes time and effort. And even after putting in all the time and effort you might still not know all the little details and idiosyncrasies in this data.

A nice example lies in the exposure that we used in this analyses, pulmonary dysfunction. The data for this exposure was captured in several different datasets, in different variables. Reverse engineering a logical and interpretable concept out of these data points was not easy. This is perhaps also true in data that you do collect yourself, but then at least these thoughts are being more or less done before data collection starts and no reverse engineering is needed. new paper: pulmonary dysfunction and CVD outcome in the ELSA study

So we learned a lot. Not only about the role of pulmonary dysfunction as a cause of CVD (hint, it is limited), or about the different sensitivity analyses that we used to check the influence of missing data on the conclusions of our main analyses (hint, limited again) or the need of updating an exposure that progresses over time (hint, relevant), but also about how it is to use data collected by others (hint, useful but not easy).

The paper, with the title “Pulmonary dysfunction and development of different cardiovascular outcomes in the general population.” with IP as the first author can be found here on pubmed or via my mendeley profile.

New paper: Contribution of Established Stroke Risk Factors to the Burden of Stroke in Young Adults

2017-06-16 09_26_46-Contribution of Established Stroke Risk Factors to the Burden of Stroke in Young2017-06-16 09_25_58-Contribution of Established Stroke Risk Factors to the Burden of Stroke in Young

Just a relative risk is not enough to fully understand the implications of your findings. Sure, if you are an expert in a field, the context of that field will help you to assess the RR. But if ou are not, the context of the numerator and denominator is often lost. There are several ways to work towards that. If you have a question that revolves around group discrimination (i.e. questions of diagnosis or prediction) the RR needs to be understood in relation to other predictors or diagnostic variables. That combination is best assessed through the added discriminatory value such as the AUC improvement or even more fancy methods like reclassification tables and net benefit indices. But if you are interested in are interested in a single factor (e.g. in questions of causality or treatment) a number needed to treat (NNT) or the Population Attributable Fraction can be used.

The PAF has been subject of my publications before, for example in these papers where we use the PAF to provide the context for the different OR of markers of hypercoagulability in the RATIO study / in a systematic review. This paper is a more general text, as it is meant to provide in insight for non epidemiologist what epidemiology can bring to the field of law. Here, the PAF is an interesting measure, as it has relation to the etiological fraction – a number that can be very interesting in tort law. Some of my slides from a law symposium that I attended addresses these questions and that particular Dutch case of tort law.

But the PAF is and remains an epidemiological measure and tells us what fraction of the cases in the population can be attributed to the exposure of interest. You can combine the PAF to a single number (given some assumptions which basically boil down to the idea that the combined factors work on an exact multiplicative scale, both statistically as well as biologically). A 2016 Lancet paper, which made huge impact and increased interest in the concept of the PAF, was the INTERSTROKE paper. It showed that up to 90% of all stroke cases can be attributed to only 10 factors, and all of them modifiable.

We had the question whether this was the same for young stroke patients. After all, the longstanding idea is that young stroke is a different disease from old stroke, where traditional CVD risk factors play a less prominent role. The idea is that more exotic causal mechanisms (e.g. hypercoagulability) play a more prominent role in this age group. Boy, where we wrong. In a dataset which combines data from the SIFAP and GEDA studies, we noticed that the bulk of the cases can be attributed to modifiable risk factors (80% to 4 risk factors). There are some elements with the paper (age effect even within the young study population, subtype effects, definition effects) that i wont go into here. For that you need the read the paper -published in stroke- here, or via my mendeley account. The main work of the work was done by AA and UG. Great job!

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!

Cardiovascular events after ischemic stroke in young adults (results from the HYSR study)

2016-05-01 21_39_40-Cardiovascular events after ischemic stroke in young adults

The collaboration with the group in finland has turned into a nice new publication, with the title

“Cardiovascular events after ischemic stroke in young adults”

this work, with data from Finland was primarily done by KA and JP. KA came to Berlin to learn some epidemiology with the aid of the Virchow scholarship, so that is where we came in. It was great to have KA to be part of the team, and even better to have been working on their great data.

Now onto the results of the paper: like in the results of the RATIO follow-up study, the risk of recurrent young stroke remained present for a long-term time after the stroke in this analysis of the Helsinki Young Stroke Registry. But unlike the RATIO paper, this data had more information on their patients, for example the TOAST criteria. this means that we were able to identify that the group with a LAA had a very high risk of recurrence.

The paper can be found on the website of Neurology, or via my mendeley profile.

Pregnancy loss and risk of ischaemic stroke and myocardial infarction

2016-04-08 13_36_29-Posteingang - - Outlook

Together with colleagues I worked on a paper on relationship between pregnancy, its complications and stroke and myocardial infarction in young women, which just appeared online on the BJH website.

The article, which analyses data from the RATIO study, concludes that only if you have multiple pregnancy losses, your risk of stroke is increased (OR 2.4) compared to those who never experienced a pregnancy loss. The work was mainly done by AM, and is a good example of international collaborations where we benefitted from the expertise of all team members.

The article, with the full title “Pregnancy loss and risk of ischaemic stroke and myocardial infarction” can be found via PubMed, or via my personal Mendeley page.

Statins and risk of poststroke hemorrhagic complications

2016-03-28 13_00_38-Statins and risk of poststroke hemorrhagic complicationsEaster brought another publication, this time with the title

“Statins and risk of poststroke hemorrhagic complications”

I am very pleased with this paper as it demonstrates two important aspects of my job. First, I was able to share my thought on comparing current users vs never users. As has been argued before (e.g. by the group of Hérnan) and also articulated in a letter to the editor I wrote with colleagues from Leiden, such a comparison brings forth an inherent survival bias: you are comparing never users (i.e. those without indication) vs current users (those who have the indication, can handle the side-effects of the medication, and stay alive long enough to be enrolled into the study as users). This matter is of course only relevant if you want to test the effect of statins, not if you are interested in the mere predictive value of being a statin user.

The second thing about this paper is the way we were able to use data from the VISTA collaboration, which is a large amount of data pooled from previous stroke studies (RCT and observational). I believe such ways of sharing data brings forward science. Should all data be shared online for all to use? I do am not sure of that, but the easy access model of the VISTA collaboration (which includes data maintenance and harmonization etc) is certainly appealing.

The paper can be found here, and on my mendeley profile.


– update 1.5.2016: this paper was topic of a comment in the @greenjournal. See also their website

update 19.5.2016: this project also led to first author JS to be awarded with the young researcher award of the ESOC2016.



New article published – Ankle-Brachial Index and Recurrent Stroke Risk: Meta-Analysis

Another publication, this time on the role of the ABI as a predictor for stroke recurrence. This is a meta analysis, which combines data from 11 studies allowing us to see that ABI was moderately associated with recurrent stroke (RR1.7) and vascular events (RR 2.2). Not that much, but it might be just enough to increase some of the risk prediction models available for stroke patients when ABI is incorperated.

This work, the product of the great work of some of the bright students that work at the CSB (JBH and COL), is a good start in our search for a good stroke recurrence risk prediction model. Thiswill be a major topic in our future research in the PROSCIS study which is led by TGL. I am looking forward to the results of that study, as better prediction models are needed in the clinic especially true as more precise data and diagnosis might lead to better subgroup specific risk prediction and treatment.

The article can be found on pubmed and my mendeley profile and should be cited as

Hong J Bin, Leonards CO, Endres M, Siegerink B, Liman TG. Ankle-Brachial Index and Recurrent Stroke Risk. Stroke 2015; : STROKEAHA.115.011321.

First results from the RATIO follow up study

Another article got published today in the JAMA Int Med, this time the results from the first analyses of the RATIO follow-up data. For these data, we linked the RATIO study to the dutch national bureau of statistics (CBS), to obtain 20 years of follow-up on cardiovascular morbidity and mortality. We first submitted a full paper, but later we downsized to a research letter with only 600 words. This means that only the main message (i.e. cardiovascular recurrence is high, persistent over time and disease specific) is left.

It is a “Leiden publication”, where I worked together with AM and FP from Milano. Most of the credit of course goes to AM, who is the first author of this piece. The cool thing about this publication is that the team worked very hard on it for a long time (data linking and analyses where not an easy thing to do, as well as changing from 3000 words to 600 in just a week or so), and that in the end all the hard work paid off. But next to the hard work, it is also nice to see results being picked up by the media. The JAMA Int Med put out an international press release, whereas the LUMC is going to publish its own Dutch version. In the days before the ‘online first’ publication I already answered some emails from writers for medical news sites, some with up to 5.000K views per month. I do not know if you think that’s a lot, but for me it is. The websites that cover this story can be found here (, / / / / and perhaps more to come. Why not just take a look at the Altmetric of this article).

– edit 26.11.2015: a dutch press release from the LUMC can be found here) – edit: oops, has a published great report/interview, but used a wrong title…”Repeat MI and Stroke Risks Defined in ‘Younger’ Women on Oral Contraceptives”. not all women were on OC of course.

Of course, @JAMAInternalMed tweeted about it


The article, with the full title Recurrence and Mortality in Young Women With Myocardial Infarction or Ischemic Stroke: Long-term Follow-up of the Risk of Arterial Thrombosis in Relation to Oral Contraceptives (RATIO) Study can be found via JAMA Internal Medicine or via my personal Mendeley page.

As I reported earlier, this project is supported by a grant from the LUF den Dulk-Moermans foundation, for which we are grateful.

New article: Lipoprotein (a) as a risk factor for ischemic stroke: a meta-analysis


Together with several co-authors, with first author AN in the lead, we did a meta analyses on the role of Lp(a) as a risk factor of stroke. Bottomline, Lp(a) seems to be a risk factor for stroke, which was most prominently seen in the young.

The results are not the only reason why I am so enthusiastic by this article. It is also about the epidemiological problem that AN encountered and we ended up discussing over coffee. The problem: the different studies use different categorisations (tertiles, quartiles, quintiles). How to use these data and pool them in a way to get a valid and precise answer to the research question? In the end we ended up using the technique proposed used by D Danesh et al. JAMA. 1998;279(18):1477-1482 that uses the normal distribution and the distances in SD. A neat technique, even though it assumes a couple of things about the uniformity of the effect over the range of the exposure. An IPD would be better, as we would be free to investigate the dose relationship and we would be able to keep adjustment for confounding uniform, but hey… this is cool in itself!

The article can be found on pubmed and on my mendeley profile.

Moving to Berlin!

After about 8 years learning and working in Leiden at the LUMC, it is time for something new. I’ve got a new job as the head of the ‘Clinical Epidemiology and Health Services Research in Stroke’ unit at the Center for Stroke research in Berlin (CSB, This a very exciting opportunity for me: working with new colleagues on new projects, learning more about stroke research and strengthen the epidemiological studies that are executed at the CSB. I am looking forward to work with these brilliant and creative minds especially the guys from the CEHRIS team.

With moving to Berlin I will have to leave Leiden, which do regret. Not only because of the great research, but also because of the students and co-workers. Fortunately, I think that this new chapter in my academic life will provide ample opportunity to start new collaborations between Berlin and Leiden.

New article: the intrinsic coagulation proteins and the risk of arterial thrombosis

I got good news today! A manuscript on the role of the intrinsic coagulation factors in the causal mechanisms leading to myocardial infarction and ischaemic stroke has been accepted for publication by the JTH. It took sometime, but in the end I’m very glad that this paper was published in the JTH because its readership is both clinical as well as biomedical: just the place where I feel most at home.

The basic message? These factors do contribute to ischaemic risk, but not to the risk of myocardial infarction. This is mostly the case for coagulation factor XI, which is a nice finding, because it could be a new target for anti-thrombotic therapies.

The article is now in print and will be made available soon. In the mean time, you can refer to my thesis, in which this research was also described.