Papers get rejected all the time. Desk rejections are a different breed. “Out of the scope”, “no interest”, “we just had a similar paper like this”, “not interested”… I heard it all. In fact, I like desk rejections – it allows you to move on and find a better, or at least a different platform, platform for your work. But the desk rejection I got today is different:

The easy availability and promotion of the preprint mean that our practice of blinded peer review is not possible for your manuscript.

Quote from a desk rejection email

The email had comments, further explaining the desk rejection, but that is not relevant for this blog-post. It also doesn’t matter which journal rejected which preprint, and it doesn’t matter who was the editor. The evidence / merits / consequences of double-blind peer review also do not matter to be honest, because, in essence, it is just a fact – a preprint excludes double-blind peer review.

I have two observations on this:

First, if a journal wants to have double-blind peer review as part of its procedures, then one might conclude that it is their prerogative. “You do you”, and what not. The problem is that the scientific enterprise doesn’t work if all individuals just started to do things their own way. There has to be some commonality, a common way of approaching the idea when we think about what it means “to do science”. All the variations in the publishing and peer review system (preprints, registered reports, post-publication peer review, blinded, optionally open, mandatory open). I know that innovation require (temporal) variation and failures, but one thing is sure, .it doesn’t get simpler.

Second, is blind peer review even possible anymore? Preprints are an obvious problem, but more and more snippets of our research can be found online. For example: post-COVID conferences are now more and more online, preregistration of projects exist and should be findable, and might be linked to FAIR databases.

These observations are not new, and definitely not just mine, as they were in part inspired by this nice little exchange on Twitter. Nonetheless, they do make me wonder – when do we all know enough to shift from one older way to do science to a newer way to do science?

Got a paper desk rejected: "The easy availability and promotion of the preprint mean that our practice of blinded peer review is not possible for your manuscript. pic.twitter.com/Vs8HNKTvqZ

— bob siegerink (@BobSiegerink) June 30, 2022

PS, after the desk rejection, I exchanged some emails with the editor where we both were looking if and how the issue even could be solved if we wanted to. The jury is still out if we are going to resubmit, also because there were more relevant points and comments. But the desk rejection gave me the lesson that good intentions sometimes collide – a very relevant lesson in an ever-changing research enterprise.

I have a love/hate relationship with Twitter – it feeds me with scientific knowledge, I learn about new developments in science and I stay in touch with friends and their interesting projects. But it also gives me anxiety and low-key FOMO: I see research papers and op-eds being published that I have had in my head for months, people celebrating grants and prizes that I didn’t get, and meetings and conferences described in a way that I am sure I missed the most important meeting of the year. And, being an epidemiologist, there is the usual COVID-19 vitriol from trolls and #doyourownresearch “researchers”.

So, in that sense, #AcademicTwitter is in no way different from normal Twitter. Why then am I going to advocate that Ph.D. candidates should all become (semi-)active Twitter users on an upcoming course of the Dutch Society for Thrombosis and Hemostasis? The answer starts with Latour’s “Laboratory Life”.

In this book, the authors partake for quite some time in academic research at the Salk Institute. This approach makes up a useful sociology insight into a single lab – What goes in? What does it produce? How do the people in the lab work towards shared or individual goals? What are those goals anyway? But with “The Construction of Scientific Facts” as its subtitle, I think we should think a bit bigger. After all, can a single lab from 1986 paint the full picture of how we do and organize our research in 2022?

From this book, I take that science takes place in a much broader context than a single experiment, lab, or even institute. It is this broader context and the interplay between all players that I want to help improve, slowly but surely, with the QI program that wants to “improve the way we do and organize our research”. Let us take a look at how social media plays a role in this goal: since a large part of how we do research is online, individual scientists need an online presence. Various online platforms have popped up in the last decade, ranging from author disambiguation services to scientific profiles, and open science platforms. These platforms are tools for science, and therefore should be in the toolbox of every scientist. It is also very useful for meta-research if I might add. However, they often lack the connectivity with peers and members of the public that is needed to debate that other question – how do we organize our research?

The Scientific Enterprise is subject to change. Especially with recent technological, methodological, moral, organizational, and societal developments driving the rate of change, how we will organize our research ten years from now will be different from today. To understand the rate of change, we only have to look at this 10-year-old report from the royal society that calls for a more open scientific enterprise and compare it to the current implementation of open science practices, later reports, as well as the “recognition and rewards” movement in Dutch Academia.

That debate, that helps shape the future of the Scientific Enterprise, is of course part of symposia, meetings, conferences, and small talk at the water cooler. But it is also held online – on social media, especially on Twitter. So, for that reason alone, I think that all researchers should become “active” on Twitter. Please note that it depends on your goals whether active here means actually means actively engaging – sometimes just knowing what the debate is all about is more than enough. Actually, take your time, and actively ask yourself some questions to help identify your goals before you actually start with social media. Make sure that how you are going to use social media is in line with those goals. Make it is a nice place to spend your time usefully, that you consume content that is in line with your goals, and that you only post what you want to share. After all, despite that it is part of the online scientific enterprise, academic social media is still social media.

My slide-deck for this talk can be found on OSF: osf.io/xzwq9/

Irrespective of what specific field they are working in, epidemiologists have had an interesting two years. On the one side, we might get the flack for the countermeasures taken to battle the corona pandemic, on the other side we do not need to explain anymore what an epidemiologist actually does. You win some, you lose some.

But we are not all working on COVID-19 24/7. Still, even when you are not an infectious disease epidemiologist, chances are you that your work has been affected. Take my case, for example. My expertise lies in clinical epidemiology, especially from non-communicable diseases – I know a lot about how to study the causes and consequences of diseases that are not transferable between people. Even though I leave the hardcore infectious disease epidemiology to the experts, my skill set can bring useful insights and contributions. I have listed my CVOID-19 contributions below.

• The PCFS: mentioned on this blog before, we have come up with an ordinal outcome in May 2020 of which we think is useful in measuring and thereby understanding the long term consequences of COVID-19 (aka long-covid). The scale is adopted in various ways (clinically, in guidelines, observational studies and trials). We published a couple of papers, and are now looking into the use and misuse of the PCFS in the current literature, with student JL in the lead. More on the OSF can be found on this OSF page, and in this earlier post.
• COVID-19 hospital admissions in NL – the Dutch hospital admission numbers are given daily. That in and of itself is useful, but their context is important. We sketch out this contact, especially in light of a so-called code black, an ominous yet valid way of saying that we need to take into account non-medical factors into account to triage patients as we only have limited resources on the ICU and wards. More on this can be found on this OSF page. The apper is submitted to a Dutch Journal and expected to be published in the next couple of days.
• The WHO definition of long covid – I have contributed in various meetings/Delphi rounds etc to the WHO definition of long COVID, published in October 2021. This definition reads: Post COVID-19 condition occurs in individuals with a history of probable or confirmed SARS CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms and that last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms include fatigue, shortness of breath, cognitive dysfunction but also others and generally have an impact on everyday functioning. Symptoms may be new onset following initial recovery from an acute COVID-19 episode or persist from the initial illness. Symptoms may also fluctuate or relapse over time.
• Post corona core outcome set – I am a participant in the PC-COS effort to come to a core outcome set that helps to study all that happens after COVID-19. Standardization of outcomes is critical, otherwise we are comparing apples to oranges (or even mushrooms for that matter!). If you want to learn more, take a look at the COMET website with some information on the study, or the PC-COS project page. Or just take a look at the video below:

We are prepping for a new PhD candidate position for the team. Since we are more in the planning phase of things, this is not a formal job opening (yet). We are currently looking more into what type of individuals would like to join the team, in order to have the final job description be a bit more clear. Since this is not grant money, there is no fixed project, and thereby no fixed job description. The candidate could jump onto one of the following projects, but own ideas and interests are very welcome, especially at this planning stage.

• Jurisprudence for research integrity platform
  The candidate will initially work on setting up-up and subsequently analyzing an open and searchable jurisprudence database for research integrity. This database will include all ~500 outcomes of investigations into scientific misconduct in the Netherlands and will grow with ~50 cases per year. The candidate will work with various disciplines (lawyers, data scientists) to qualitatively and quantitatively analyze clusters and patterns over time with varied methodologies ranging from expert interviews, surveys to natural language processing both in isolation as well as mixed-methods. These analyses, together with a description of landmark cases will form the jurisprudence platform that will be used during future investigations of scientific fraud.
• Differences in data handling and analysis
  Many meta-research projects that look to whether methodologies and statistics are used correctly focus on analyses of publications or existing databases of research output. The individual researcher is often hard to reach, and those that do participate in this type of research are not likely to be representative. The candidate will execute several smaller subprojects that combine principles of “many analyst” and “multi-verse analysis” approach to study the use and misuse of methods and statistics in some selected medical specializations. The lessons learned hopefully lead to the development of a platform that is designed to lower the threshold of participation and thus increase representativeness.
• Authors behind retractions
  There are various papers describing the frequency and some characteristics of scientific articles that were retracted from literature. The focus is less often on the people behind those retractions. Can we distinguish the culprits from the innocent bystanders? What are the causes and consequences of retractions for the individual researcher? Are there differences between various scientific fields? The candidate will approach these questions with the various epidemiological tools and study designs that we have at our disposal.

Some provisional requirements and other details

Open from:	Jan 1st   2022 at the earliest. Please get in touch.
Open to:	People who hold (or almost hold) a MSc degree in relevant disciplines, which include -but are not limited- to biomedical sciences, medicine, biology or even law. Although no formal requirement, some experience with quantitative research and knowledge of open science practices are welcomed
Language:	For some subprojects it is pivotal to be fluent in both Dutch (mother tongue or at least C1) and English (mother tongue or at least C1).

What we offer – The QI activities are driven by a small interdisciplinary team of researchers and policy makers from the medical sciences. Evidence driven, we aim to improve the way we do science through research and policy changes through collaboration with numerous researchers from within and outside the LUMC. For this project, we team up with prof dr. Frits Rosendaal (LUMC, co-chair CWI Leiden) and dr. Yvonne Erkens (Leiden Law School, co-chair CWI Leiden). The research of the team is formally embedded within the department of clinical epidemiology (dr Bob Siegerink / Frits Rosendaal). Take a look at our relative new OSF page of our activities – https://osf.io/2syfm/ and https://osf.io/ku9rh/ for more information.

Interested? Please get in touch with primary supervisor Bob Siegerink (b.siegerink@lumc.nl / bobsiegerink.com / @bobsiegerink). If interested, please send a short motivational statement, and perhaps a short resume that outlines your educational background, research experience as well as relevant software skills. Your responses will help us to further define the roles/activities and corresponding requirements of the new candidate in the team.

Some days ago I was a member of the opposition committee, this time for candidate BO. She did a fantastic job of combining qualitative and quantitative research on the effect of the academic and scientific training we give our medical students, both within and outside the regular curriculum. She showed, in various studies, how the approach chosen in the LUMC seems to stimulate young MD to do research. I won’t do in too much detail, because I am afraid I won’t do the work justice to be honest -BO was not only diligent in her methodology, but also strong in showing the strong and weak sports in her methods and reasoning. So, if you want to know, you can find her thesis, with the inspiring title ‘Future physician-scientists: let’s catch them young! Unraveling the role of motivation for research’ in the repository of the Leiden University

The Dutch PhD defense seems sometimes more of a ritual, than an actual exam. This is because the outcome is clear to all involved – if the candidate is allowed to defend (sometimes referred to as the viva), the candidate will get her doctorate. I think the only way you will not be awarded your doctorate is if you actually pass out or something else massive, which renders answering any question impossible. The questions are thought to be an exchange of thoughts, and function thus as a way to showcase your work and not so much to challenge or test it. Or is it?

I was not the only thinking this was excellent work. BO got Cum Laude, which is the highest evaluation that is only given to about the top 5% of candidates. Cum Laude not only requires more external evaluators (all asked their opinions in secrecy), but is also dependent on the defense. Indeed, it is possible for a candidate to not perform well enough, and the candidates just passes the defense like everybody else. So it is always a surprise for the candidate to hear those words at the end of what sometimes really is an exam: You have passed the exam with the highest honors.

Sometimes, open science seems to be the thing that is going to solve all the nasty bits that are part of the current scientific enterprise. No added value from peer review? Registered report! Duplicate work? Preprints and preregistration! People working on the same problem as you are? Share data!

But recently I came across a stark reminder that that is not the whole story. I was asked to review a short research letter from people who were looking to gather all evidence to answer a particular clinical question. While doing so, they actually stumbled upon a deluge of meta-analyses: 20 meta-analyses were published in 17 different journals. What a body of evidence is then perhaps the first reaction, but the problem was that is actually all these analyses were based on only 4 trials.

The authors pointed towards the enormous waste of energy and even talked about an epidemic of meta-analyses. I see in this a great example how the root cause lies in that science is being done for publications and not publications are made for the betterment of science. This is the root cause of many problems in the scientific enterprise. And as long as that is not addressed, open science practices are just a stopgap – something which might work for a bit, but it does not address the root cause and therefore does not solve the problem. If you want to read the whole argument, with some details on what open science practices were actually in place with these 20 meta-analyses, the paper is only a minute 5-minute read.

This commentary is a joint production with FRR. This paper was a preprint first on our OSF page and is now published in the journal of thrombosis and hemostasis and can be accessed here (open access).

There is a change in the Dutch academic air. There is a broad movement, fuelled by those who pay for most of the grants, to change how we reward and recognizes individual contributions to academia. The bottom line is simple: journal impact factors and the number of publications might be used to assess these contributions, but they are just not the right metrics. They incentivize behavior that is not desirable, but most of all – a focus on scientific excellence makes that we are not valuing important work in academia. To strive for scientific excellence might be a good thing, but teaching, patient care and outreach should also be valued.

On that background, a group of 170 (mostly senior) researchers published an open letter arguing against this new approach. Their main argument – impact factor and Indices are, despite its flaws, the current international standard, and leaving them behind us will jeopardize the international standing of our researchers. A lot can be said of that point of view – it is old-fashioned, it is short-sighted, and it is the story of only the winners of the old system. But then again, they are right, aren’t they?

Yes and no. Yes – impact factors are indeed a hallmark of various hiring and promotion procedures in a large part of international academia. No – more and more organizations come around and see that the way we evaluate contributions to science should go beyond a counting how many “impact points” one has collected. DORA has been signed by many Dutch organizations like VSNU, NLU, NFU, KNAW, NWO en ZonMw but most importantly, the European Research Council just joined as well. And also, the various new formats for recognition and rewards in the Netherlands just add the possibilities to explain your success story, which might or might not include a publication in Nature.

This makes this movement not fringe, weird or leaving out those people who were successful in the old system. It adds possibilities. The premise of their main point – the Netherlands is one of the first countries to make this change – is true and this has consequences. It is up to Dutch Academia to move from idea to policy in a healthy way. That means that some ideas of these researchers need to be taken into account in order not to create a split civitas academia.

These ideas are the backbone of a response that a bunch of young members of the scientific enterprise wrote – me included. The little kerfuffle even reached the regular news media, with a short piece in the Volkskrant.

A lot has happened in the last six months. It all started with moving from Berlin back to my Alma Mater in Leiden, but also shifting from a group leader in neurovascular epidemiology to a position as leader of the program Quality and Integrity of Biomedical Research. This program is a combined effort of the department of clinical epidemiology as well as the directorate of research policy, both at the LUMC. The goal of the program is both to understand and improve the quality of research. The tools of the trade will be research-on-research on one side and policymaking on the other – with the combination being our secret weapon.

The projects

Over the last six months a lot of ideas have already taken shape. Here are some examples:

• Retractors and retractees– in this project, in collaboration with the people at retraction watch and the CWTS, we will look not only at just the retracted articles but also at the people behind the retractions, the “retractors and the retractees”.
• Research on researchers – a lot of meta-research is based on publications and other “made to look good” output. This approach leaves the actual process during the research relatively untouched. I am looking to change that – meta-research should go from research on published research to research on researchers. This idea is also similar to the retractees project which focuses on the individual behind the retraction.
• Understanding misconduct – in this project I will collect the decisions of all committees for scientific misconduct active in the Netherlands. By collecting these and subsequently making them available, we can not only measure the variability of the decisions, understand patterns over time, but also help to standardize future decisions and rulings.
• Cohort of PhD students – All LUMC Ph.D. candidates enroll in this graduate school, and with ~150-200 Ph.D. candidates per year. I think this is the biggest graduate school in the university. I want to build a cohort of Ph.D. students, to follow their successes over time, and improve the way we train and prepare these young scientists for a future in science. I am also looking forward to building some much-needed training modules on the topic of quality and integrity.
• Redesigning IRBs @ LUMC – When you do research in the Netherlands, there are various laws and guidelines that have to adhere to. An independent committee that looks at your research plans before you actually start is needed. The current system at the LUMC is outdated, and I have the task to help redesign the system.

The people

The last six months have also given me the opportunity to slowly build a team again. I have written about building a team before, with some lessons I drew from my experiences from starting my new job in Berlin six years ago. That time, I took over a team. This time, I am starting from scratch.

I will run the team together with FRR from the clinical epi, and JT from the directorate of research. I am quite happy with ALL, who is a young and bright Ph.D. student on the team. She will be working with me on most of the projects mentioned above, specifically the retractors project. Other Ph.D. students from the department are also likely to join the QI for a project, as an addition to their own research. The same will go for various colleagues of the department, outside the department outside the LUMC, or even outside the university (some old colleagues at QUEST come to mind).

I am now supervising two students (AdK and LP), both on the retractees projects. I am keen to have two to four students on at any given time working on either the research side or the policy side of things.  If you are a student looking for an interesting project, don’t be afraid to get in touch!

The dreams for the future

One big dream of mine is to organize some summer labs: bring a group of roughly 10 young minds together into one room to tackle a problem within 4-6 weeks, pressure cooker style. I hope that this summer will be my first edition, but I am unsure if this is a realistic idea given the direction of the COVID-19 pandemic in the Netherlands.

Another ultimate dream is to build up a network, both within the LUMC and within the university, not unlike what we did with BEMC. Not just a social network for drinks, or a network of peers to learn from best practices, but a network that can help change policy for the better and both broaden and deepen research projects.

The other stuff

I will continue to work with some collaborators in the neurovascular field (both in Leiden and at the CSB). Some general epidemiological projects might also just find their way on my desk, but to make the best out of QI, I will need to focus. The only thing I now need to learn is to say “no” more often.

Onward!

Another paper focussed on coagulation. After our paper on FVIII and cognitive function, a paper on the genetic determinants of FXI and FXII, and various papers on intrinsic coagulation protein in the etiology of first stroke and myocardial infarction (for example here, here and here), it was time to make the next step: risk of secondary events.

But studying causal effects in patient groups comes with its own difficulties such as the critical timing of the blood draw to avoid acute phase reactants showing up as causal factors, as well as a phenomenon of index event bias. JLR, who took lead in this project, made it all work, and the team indeed found out that increased FXI and FVIII was related to higher cardiovascular risk in the patients included in the PROSCIS-B study. Even though the figure only shows unadjusted results, they kinda get the whole idea of just looking at this Kaplan-Meier.

Does this mean that we should be measuring or even targeting FXI and FVIII immediately in all stroke patients? No, not really, at least not yet. The HRs are modest (HR of ~2) and therefore not likely to lead to enormous improvement of stroke prediction models – perhaps we can expect a modest contribution in the future, but only in combinations with some other biomarkers which are measured in a simple and reliable way. Targeting FXI and FVIII for treatment is an interesting option, but we are nowhere near a final stage. These proteins (esp. FVIII) is critical in proper hemostasis, and therefore messing with FVIII could lead to some serious side-effects. This is less of a problem for FXI, but still, some more works needs to be done, including the identification of the groups of patients that that will have the highest benefit.

The paper, again with the wonderful JLR in the lead, used to be a preprint at medRxiv, was published in the JTH, is open access, and can be found on my Publons profile and Mendeley profile.

In 2013, one of my then very new colleagues in Berlin published a very interesting paper with the title “Smoking-thrombolysis paradox: recanalization and reperfusion rates after intravenous tissue plasminogen activator in smokers with ischemic stroke”. When you translate this to something less technical, you will conclude that it appears that stroke patients who smoke seem to react better to acute treatment. The drug that they get administered seems to perform better with opening up the blood vessels in the brain so that the oxygen rich blood for can flow again. It sounds weird, even to us at the time, but there is -albeit unlikely – biological scenario that could actually explain this finding.

Irrespective of biology , this first finding was too preliminary to draw strong conclusions as it is based on imaging outcomes only. It didn’t say anything on whether the patients who were active smokers ended up having fewer symptoms. So that’s where this project came is. Using data from the Dutch PSI study, we were able to study the effect of the treatment and whether that effect was actually different in patients who smoked.

The short answer is no – we didn’t find evidence that patients who were active smokers would actually have more benefit from thrombolysis. If we had found this effect, the RR should have been much extremer in the +/+ category than the effect in the +/- category. In fact, all that we saw showed that there was no real difference. But there are some serious limitations to our study, with the main one being that the patients included in this dataset might not have been the best subset of stroke patient to study this phenomenon. So, even though we didn’t see evidence of the phenomenon, we can’t rule it out and conclude, as so often, “that future research is needed”. Before you ask, yes, we indeed did that future research ourselves. The paper is currently under review, but I can already tell you that the conclusion is not going to change a lot. But that paper is still under review (hint: nothing changes)

Our paper, with AK in the lead, was published in Frontiers of Neurology last september (sorry for the delay), and can be found on my Publons profile and Mendeley profile.

Micro vesicles have for some years now been a topic in cardiovascular research, mainly in cardiology. The source of these vesicles are various cell types, and their function remains in large unclear -are they active parts of the bodies’ system, or are they mere bystanders.

Irrespective of that, if these MV are related to cardiovascular risk in cardiology patients, it is interesting to know to what extent they are related to cardiovascular risk in stroke patients. If so, that will be an indication that they are actually part of the causal mechanism or perhaps a good biomarker that might help stratify patients in meaningful subgroups.

So what did we do? We teamed up with cardiologist specialized in MV to measures various subtypes in 600+ patients with a first-ever ischemic stroke. We then looked at the risk of recurrent events and all cause mortality over a span of three years. Our findings tell a clear story – the higher the levels of MW, the higher the risk. The interpretation however, remains as unsure as when we started. We still do not know whether these MV are a cause, a bystander. More research, also just some hardcore basic research will be needed to further elucidate this distinction. In any case, the HR are not too impressive in this mild to moderate stroke cohort, so don’t expect MV to be added to any risk screening panel anytime soon, especially as the measurement is quite laborious.

Our paper, with SH in the lead, is published in Neurology, and can be found here as well as on my Publons profile and Mendeley profile.

When I teach undergraduates what kind of different research questions one might want to answer, I sometimes use the mental image of a patient in the doctor’s office. The questions that are asked can be roughly categorized in “What is wrong with me?”, “How did I get it?”, “What will happen from now on?”, and “What can we do about it?”. Students with a quick mind can recognize the concepts of diagnosis, etiology, prognosis, and treatment hidden in these questions. I usually treat these as quite separate questions, and that for each category different study designs and statistical techniques are preferable.

But that changed after I prepared for the PhD defense of SB. As a member of the “opposite”, I was tasked to examine the PhD candidate on her knowledge and her work presented in her thesis. Titled “The early identification of patients with an unfavorable prognosis”, this thesis focussed on the theme of whether treatment response could be incorporated in prediction models in order to improve the prediction of outcome. I think this is an interesting concept and potentially heavily underutilized and at least heavily understudied.

SB started out by showing that in psychiatry the majority of care is consumed by a minority of patients, thereby conceptually proving the need of identifying patients with an unfavorable outcome. The next chapters test whether adding information on treatment response for three different diseases: depression, asthma and high blood pressure.

Being the last of the opposition committee to examine the candidate, I was able to ask more about the methodological details (presence of co-linearity, the calibration/validation of the final models, the use of complete case analyses, etc). These introductory questions led us to the broader question that focused on her approach to include information about treatment response. SB consistently used the delta of two absolute measurements as an indicator of treatment response, and I asked whether that could be replaced or even complimented by using the delta in the variation of certain measurements. The bottom line is of course is that we don’t know, but that is also not the objective of a Dutch PhD ceremony. The objective is to start a conversation during which the candidate can show that he or she masters the material and is ready to become an independent researcher. And that is what SB did, congratulations!

So what did I learn from all this? Perhaps using the four categories of research questions is too restrictive and that sometimes, by combining the ideas and concepts from questions on treatment and prediction we can actually improve the care we can better distribute the care we can provide for all our patients.

The newest addition to our publications is this paper on the role of high levels of coagulation factor VIII and cognitive function, as well as white matter intensities in the brain. The theory behind is that since hypercoagulability is related to young, overt, stroke, would hypercoagulability perhaps also be linked to non-overt cerebrovascular mishap? Hypercoagulability here is measured as high levels of FVIII, one of the most potent risk factors for thrombosis, and the cerebrovascular mishap is the presence and intensity of white matter lesions. This paper has a long history in three very different, but meaningful ways.

The first “long”aspect is that you need to have a very long, and complex, follow-up to study this. Where clinical stroke is a sudden onset type disease, what were are studying in this project has a for more gradual character. So not months, but years. Decades even! And not a lot of studies have the prerequisites to study this question: first there must be the possibility to measure FVIII, which means citrate. But most long term follow-up studies do not have citrate. Second, there must be MRI data available throughout the study. However, most large longitudinal studies only have MRI at baseline as an exposure measure. Third, The studies must go on for a very long time, which comes with the complication that often the participation in these type of studies can dwindle over the years. So, all in all, there was really only one cohort who had all the data already collected and ready to analyze: the Cardiovascular Health Study. So we requested access to the data with a focus on FVIII, cognitive functioning and multiple measures of white matter lesions in order to assess worsening of lesions and were ready to analyze!

Interestingly, this brings us to the second “long” aspect of this paper – getting acces to and using the CHS data. The idea for this paper came roughly in 2013, when I got in touch with some CHS researchers for the first time. That is a long time ago from today, end of 2020. So what took us so long? Well first there was the move to Berlin. I decided to take this project me, but immigrating to a different country and starting a new job at the same tends to put some delays on ongoing projects. A second reason is that the CHS data is open for non CHS researchers to use, under one very strict condition – CHS researchers don’t just hand our data but they help you set up and execute your plan. This approach is not completely “open science” but it might be better. After all, it does ensure that the knowledge and experience that comes from actually collecting the data is taken into account when you prepare for and actually analyze the data. But that process takes time, especially when working with collaborators several time zones away.

A third and final “long” aspect was the time between first time submission and final publication. Our paper got rejected by 4 different journals before we got accepted at PLOS one. This is definitely not a record, but the delay isn’t pretty. The reasons for rejection were different at these journals, but the fact that this was a “null” finding in a general population cohort did certainly not help.

The paper, with the title “Coagulation factor VIII, white matter hyperintensities and cognitive function: Results from the Cardiovascular Health Study” is published in PLOS One. You can also find it at the usual places. JLR took the lead of the project after I moved to Berlin, masterfully navigating and combining all the comments and input from this group of co-authors. Well done to all.

As you might have read in my previous post, I start sept 1^st at the LUMC, Leiden in the Netherlands, where I will be working to improve the quality and integrity of (biomedical) science. Locally and hopefully beyond the walls of the LUMC as well.  

There will also be a 4 year PhD-position available, starting as early Sept 1. The PhD candidate will be supervised by me and prof dr Frits Rosendaal. Even though the theme is fixed (i.e. Q&I of science), we are still working on the exact topic and projects. For now, all is quite open. Please note that we are open to applications from various fields, such as medicine, anyone of the biomedical sciences, medical humanities, meta-research, law, ethics, psychology etc.

If you know somebody who might be interested, please share this email with that person directly. If not, please share with people that might. Those who are interested/want to get more information can get in touch by sending an email with a short(!) bio-sketch to b.siegerink@gmail.com with “PhD position Q&I” in the subject line.

Science is not quick. In fact, it is slow most of the time. Therefore, most researchers work on multiple papers at the same time. This is not necessarily bad, as parallel activities can be leveraged to increase the quality of the different projects. But sometimes this approach leads to significant delays. Imagine a paper that is basically done, and then during the peer review process, all the lead figures in the author team get different positions. Perhaps a Ph.D. student moves institutes for a post-doc, or junior doctors finish their training and set up their own practices, or start their demanding clinical duties in an academic medical center. All these steps are understandable and good for science in general but can hurt the speediness of individual papers.

This happened for example with a recently published paper in the Dutch PSI study. I say recently published because the work started > 5 years ago and has been finished more or less for the majority of that time. In this paper, we show that cancer prevalence is higher for stroke patients. But not all cancers are affected: it is primarily bladder cancer and head and neck type of effect. This might be explained by the shared risk factor smoking (bladder cancer, repository tract) and perhaps cancer treatment (central nervous system/ head and neck cancer). Not world shocking results with direct clinical implications, but relevant if you want to have a clear understanding of the consequences of cancer.

Now don’t get me wrong, I am very glad we, in the end, got all their ducks in a row and find a good place for the paper to be published. But the story is also a good warning: It was the willpower of some in the team to make this happen. Next time such a situation comes around, we might not have the right people with will right amount of power to keep on going with a paper like this. 

How to avoid this? Is “pre-print” the solution? I am not sure. On the surface, it indeed seems the answer, as it will give others at least the chance to see the work we did. But I am a firm believer that some form of peer review is necessary – just ‘dumping’ papers on a pre-print server is really a non-solution and I am afraid that a culture like that will only diminish the drive to get things formally published is even lower when manuscripts are already in the public domain. Post-publication peer review then? I am also skeptical here, as I the idea of pre-publication peer review is so deeply embedded within the current scientific enterprise that  I do not see post-publication peer review playing a big role anytime soon. The lack of incentive for peer review – let alone post-publication peer review – is really not helping us to make the needed changes anytime sooner. 

Luckily, there is a thing called intrinsic motivation, and I am glad that JW and LS had enough to get this paper published. The paper, with the title “Cancer prevalence higher in stroke patients than in the general population: the Dutch String-of-Pearls Institute (PSI) Stroke study. is published in European Journal of Neurology and can be found on Pubmed, as well as on my Mendeley and Publons profile.

I started to work in the CSB about 5 years ago. I took over an existing research group, CEHRIS, which provided services to other research groups in our center. Data management, project management and biostatisticians who worked on both clinical and preclinical research where all included in this team. My own research was a bit on the side, including old collaborations with Leiden and a new Ph.D. project with JR.

But then, early summer 2018 things started to change. The generous funding under the IFB scheme ran out, and CSB 3.0 had to switch to a skeleton crew. Now, for most research activities this had no direct impact, as funding for many key projects did not come from the CSB 2.0 grant. However, a lot of services to make our researchers perform at peak capability were hit. this included my team. CEHRIS, the service group ready to help other researchers was no longer.

But I stayed on, and I used the opportunity to focus my efforts on my own interest. I detached myself from projects I inherited but were not so engaged with, and I engaged myself with projects that interested me. This was, of course, a process over many months, starting end 2017. I feel now that it is time to share with you that I have a clear idea of what my new direction is. It boils downs to this:

My stroke research focuses on three projects in which we collect(ed) data ourselves: PROSCIS, BSPATIAL, BELOVE. The data collection in each of these projects is in different phases, and more papers will be coming out of these projects sooner later than later. Next to this, I will also help to analyze and publish data from others – that is after all what epidemiologists do. My methods research remains a bit of a hodgepodge where I still need to find focus and momentum. The problem here is that funding for this type of research has been lacking so far and will always be difficult to find – especially in Germany. But many ideas that come to from stroke projects have ripened into methodology working papers and abstracts, hopefully resulting in fully published papers quite soon. The third pillar is formed by the meta-research activities that I undertake with QUEST. Until now, these activities were a bit of a hobby, and always on the side. That has changed with the funding of SPOKES.

SPOKES is a new project that wants to improve the way we do biomedical research, especially translational research. Just pointing towards the problem (meta-research) or new top-down policy (ivory tower alert) is not enough. There has to be time and money for early and mid-career researchers to chip in as well in the process. SPOKES is going to facilitate that by making both time and money available. This starts with dedicated time and money for myself: I now work one day a week with the QUEST team. I will provide more details on SPOKES in a later post, but for now, I will just acknowledge that looking forward to this project within the framework of the Wellcome Trust Translational Partnership.

So there you have it, the three new pillars of my research activities in a single blog post. I have decided to lose the name CEHRIS to show that the old service focussed research group is no more. I have been struggling with choosing a new name, but in the end, I have settled for the German standard “AG-Siegerink”. Part lack of imagination, part laziness, and part underlining that there are three related but distinct research lines within that research group.

Up to the next 5 years!?

Pfew, there has been quite some excitement when it comes to the STEMO, the stroke ambulance in Berlin. The details are too specific -and way too German- for this blog, but the bottomline is this: during our evaluation of the STEMO, we noticed that STEMO was not always used as it should be. And if you do not use a tool like you should, it is hot half as effective. So we keep on trying to improve how STEMO is used in Berlin, even though the evaluation is going on.

We need to take these changes into account, so we wrote a new plan to evaluate STEMO, which was published open access the new BMC journal Neurological Research and Practice. The money to continue the evaluation was secured and we thought we were ready to go. But then reality set in: during budget negotiations a lower committee from the Berlin Senate said simply “NO” to STEMO. A day later however, the Major of Berlin used a “Machtword”, an informal veto to say that STEMO will be kept in the budget in order to finish the formal evaluation.

A true rollercoaster, which will show how directly our research has an impact on the society. The numerous calls, tweets and emails we have received in support of our now 3 STEMO ambulances over last couple of weeks underlines this even more (just the fact that a complete stranger started a petition with all nuances of the case taken into account is just mind boggeling !). But the science has to speak, and we still need to definitively evaluate the effectiveness of STEMO when used like it should be – something we will do over the next months with renewed energy in the whole team.

The text below is the English version of the official and very formal German text.

The QUEST center is looking for a project manager for the SPOKES project. SPOKES is part of the Wellcome Trust translational partnership program and aims to “Create Traction and Stimulate Grass-Root Activities to Promote a Culture of Translation Focused on Value”. SPOKES will be looking for grassroots activities from early and mid-career scientist who want to sustainably increase the value of the research in their own field.

The position will be located within the QUEST Center for Transforming Biomedical Research at the Berlin Institute of Health (BIH). The goal of QUEST is to optimize biomedical research in terms of sound scientific methodology, bio-ethics and access to research.

SPOKES is a new program organized by the QUEST Team at the Berlin Institute of Health. SPOKES enables our own researchers at the Charité / BIH to improve the way we do science. Your task is to identify and support these scientists. More specifically, we expect you to:

• Promote the program within the BIH research community (interviews, newsletters, social media, events, etc)
• Find the right candidates for this program (recruiting and selection)
• Organize the logistics and help prepare the content of all our meetings (workshops, progress meetings, symposia, etc)
• Support the selected researchers in their projects where possible (design, schedule and execute)

Next to this, there is an opportunity to perform some meta-research yourself.

We are looking for somebody with

• A degree in biomedical research (MD, MSc, PhD or equivalent)
• Proficiency in both English and German (both minimally C1)
• Enthusiasm for improving science – if possible demonstrated by previous courses or other activities

Although no formal training as a project manager is required, we are looking for people who have some experience in setting up and running projects of any kind that involve people with different (scientific) backgrounds.

@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

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