Why most of “clinical” imaging research is methodological – and why that’s OK

When people ask me what kind of research I did during my PhD (and indeed what kind I do now), I tell them I did MRI methods research. But what I do is very different to the image that comes up in people’s minds when I tell them this. I don’t build radiofrequency coils for MRI scanners, nor do I write MR sequences or even develop new analysis methods. I spent the majority of my PhD making small, incremental changes to the way MRI data is acquired and analyzed, and then testing how these changes affect how we measure certain things in the brain.

This type of research exists within what I consider a spectrum of phases of clinical research (NB: this has nothing to do with the phases of clinical trials of interventions – it’s only “clinical” in the sense that the research is being done on humans):

1. New methods are developed

2. They are validated by testing how well they perform in certain settings and improvements are made accordingly (followed by more validation).

3. Then, when they’re good and ready (this can take years), they’re used to answer clinical or biological questions.

People often neglect the second phase – the validation, improvement, and re-validation. It’s sometimes completely overlooked, but arguably the bigger problem is that it’s often conflated with the latter stage – the testing of clinical or biological hypotheses. The line between these phases is often blurred and when, as a researcher, you try to emphasize the separation of the two, it’s considered pedantic and dull.

Several types of scenarios exist – for example, you can have a method that measures a phenomenon X in a different way to an established method or you can have an operationalized measurement of phenomenon X (i.e. an indirect measurement, almost like a surrogate marker). The key question has to be: am I measuring what I think I’m measuring? This can be done by directly comparing the performance of the new method  to a more established method, or by testing to see if that method gives you the results you would expect in a biological or clinical situation that has been previously well studied and described.

For the record, I think the second option, although indirect, is completely valid – taking a method that’s under development and testing if it reflects a well-established biological phenomenon (if that’s what it’s meant to reflect) – that still counts as validation (I’ve done this myself on several occasions – e.g. here, here, and here). But the key thing is that it has to be well-established. Expecting a method you’re still trying to comprehensively understand to tell you something completely – or even mostly – new makes no sense.

Unfortunately, that’s often what’s expected of this kind of research. It’s expected from the researchers doing the work themselves, from their colleagues and/or supervisors, from manuscript reviewers, as well as from funding agencies. The reason is simple (albeit deeply misguided), and it confronts researchers working on improving and validating methods in clinical research very often: people want you tell them something new about biology or pathophysiology. They very often don’t want to hear that you’re trying to reproduce something established, even if it is with a new method that might be better for very practical reasons (applicability, interpretability, etc). This has presented itself to me over the years in many ways – reviewers bemoaning that my studies “provide no new biological insights” or well-meaning colleagues discouraging me from writing my PhD dissertation in a way that makes it sound “purely methodological” (“you need to tell the reader something new, something previously unknown”).

The irony is that, in the years I’ve spent doing (and reading) imaging research, I’ve become fairly convinced that the majority of clinical imaging studies  should fall into the second category mentioned above. However, it’s often mixed up with, and presented as though it belongs to, the third category. Researchers use new method Y to test a “novel” hypothesis, and interpret the results assuming (without proper evidence) that method Y is indeed measuring what it’s supposed to be. I notice this when I read papers – the introduction talks about the study as if its aim is to test and validate method Y, and the discussion ends up focusing on all the wonderful new insights we’ve learned from the study.

To be clear, I’m in no way saying that the ultimate goal of a new method shouldn’t be to be taken to studies of the third category. Validate, improve, validate, then apply with the hope of learning something new – that’s should clearly be the goal of any new method meant for clinical use. But we shouldn’t expect both to be done simultaneously. Instead, we need to acknowledge the clear separation between the types of clinical research and their respective goals, and to recognize that not all research is new and exciting in terms of what it tells us about biology or pathophysiology.

Per Tolosa totjorn mai

Writing about a French city while in magnificent Portugal is very unusual. However, I got some great news today – an abstract which I submitted a few months ago for the 2013 European Society for Magnetic Resonance in Medicine and Biology (ESMRMB) Congress has been accepted as a poster presentation. I will be attending the congress during my four-month mobility stay at the Université Bordeaux Segalen and will present a small project which I worked on during my first lab rotation in Berlin.

Posts about Coimbra, Portugal soon! (There’s much to say!)

Who needs an MRI? Welcome to the Third World

This post was inspired by a comment made by one of my professors during a lecture last week. She was explaining to the class how older, experienced physicians (from ‘way back when’) can pinpoint lesions with great accuracy based on symptoms and signs alone, without the need for fancy modern equipment such as MRI scanners. This is of course true, but it got me thinking of my own medical education.

One of the advantages of having studied medicine in a Third World country is that I was taught from early on to rely on clinical features to come up with accurate and precise diagnoses. While I am certainly no expert in doing so, I think people who practice in underdeveloped countries have a distinct advantage over their more technologically-oriented counterparts in developed countries. This is particularly true for emergency situations – MRI machines (and even CT scanners) are few in poor countries – laboratory tests are often outdated and transiently available and immunologic or genetic testing are especially cumbersome to locate. Thus, a junior doctor quickly develops the prowess of analyzing a patient’s presentation to come up with a single faulty aspect to be blamed.

In no other discipline is pinpointing precise lesion locations more important than in neurology. In fact, that is what neurology is all about. If we were to remove this aspect of the discipline then the specialty as we know it would cease to exist. In the preface to the first edition of one of my favorite books: ‘Introduction to Clinical Neurology’, neurologist Dr. Douglas J Gelb asks that very question – Is neurology obsolete? At least it lives on in developing countries, for now.

Holiday penumbras

In anticipation of my upcoming lab rotation at the Centre for Stroke Research in Berlin, I have been reading up on the focus of my project.
The ischemic penumbra is an area of a stroke patient’s brain which is dying as a result of the blockage of one of the arteries supplying the tissue. The keyword here is dying, not quite dead yet unlike the core of the tissue affected – which makes it a prime target for salvation in terms of stroke treatment. Left untreated, this penumbra transforms into dead brain tissue, and thus contributes to the patient’s permanent symptoms or neurological deficit. The region, which cannot be readily seen on more conventional imaging techniques like CT or standard MRI, was first noticed in PET scans, which basically measure the amount of energy the brain uses and maps it onto an image. Now, with the availability of more sophisticated MRI techniques such as diffusion and perfusion weighted imaging, this area can be mapped and its natural history identified, but most important is the fact that its response to treatment can be established. Simply, can this area be saved and to what degree, is the question on our minds.
The group which I am going to be working with has made much progress in this field, and what drew me to their projects most was their unique and innovative approach to the subject of stroke, which is a major killer and prominent cause of disability worldwide. For example, every doctor knows that stroke has a relatively short time window in which treatment can be given, and more importantly it is within this time window, typically around three hours from the onset of the stroke, that benefits of the treatment outweigh the risks. This time window was derived years ago from large studies which showed that only patients who received treatment within this time benefited from it. But now people are thinking of a new approach. Researchers are now trying to replace this seemingly arbitrary number of three hours with more objective and reliable criteria such as various signs on MRI, so that everyone who might benefit from treatment but falls outside of this window can have the opportunity to end up with less permanent disability than if doctors only relied on the time from stroke onset.
Needless to say I am very excited at the prospect of participating in something which has the potential to be so groundbreaking! Which is why I feel the need to be prepared, and that’s what I’m spending my holiday attempting to do. I will be posting more about this soon! 🙂