By: Thomas Meinel, Diana Aguiar De Sousa
ESO European Stroke Science Workshop 2023
Session 3: Methods Matter
Dr. Sarah McCann
In her excellent keynote lecture on meta-research, Dr. McCann challenged the preclinical stroke research community with an alarming in-depth analysis of published laboratory stroke studies analyzing key quality metrics. A large proportion of preclinical research is not reproducible in humans, mostly due to significant weaknesses of design and reporting.
Weaknesses include selective outcome reporting and publication bias. Frequently, animal models are also not reflective of the human disease population, e.g. an antihypertensive drug tested in young healthy male mice as opposed to an older, more often female human population that this drug would then be used in.
The same tools that we take for granted in clinical research, namely large-sized registries, multicenter studies, randomization and blinding of performing the treatment and outcome assessment are useful tools to overcome those methodological flaws in preclinical studies. Successful examples of such large collaborations are the Stroke Preclinical Assessment Network (SPAN) and INFORM-Stroke.
The recently launched CoReS hub aims to bring together primary researchers and evidence synthesists to provide infrastructure and support systems to empower the community in the performance of systematic reviews on preclinical evidence. Journal policies have also modestly helped to improve design and reporting of animal experiments such as adopted by Nature publishing group and Stroke. Open data policies are another piece of the puzzle to enhance the transparency and external validity. The suggestions have been incorporated into design guidelines (EDA), and publication guidelines (ARRIVE).
The discussion acknowledged the urgent need for improvement and great potential of the proposed improvements.
Overall, the analysis and proposed solutions are a highly relevant contribution to improve validity, transparency, and reproducibility of laboratory stroke research. Following those recommendations ultimately means less waste in preclinical research, less potential harm for patients and more robust and fruitful translational research.
Professor Maren Ranhoff Hov
In her outstanding lecture on innovative trial designs with the example of cluster randomized trials in the prehospital setting, Professor Ranhoff Hov pointed out the particularities and challenges of prehospital research. Learning from the trauma community, that put into place a very standardized approach to ensure fast and high-quality care, she mentioned the potential of such an approach to address the heterogeneity of stroke presentations, especially for those presenting with less severe or less specific symptoms and other hurdles for a rapid activation of the stroke chain of survival. One such approach was the ParaNASPP trial, that used prehospital NIHSS assessment by an app. Since randomization and blinding is not possible on a patient-level, the design was a stepped-wedged cluster randomized trial. This also allowed to provide training of the cluster sequentially. The downside of this approach include a potential secular effect during the trial, especially given the fact that the COVID pandemic happened during recruitment. As an example, the delay of on-scene time of about 5 minutes is not necessarily only due to the use of the prehospital app, but might (partially) be a pandemic effect. She encouraged the stroke research community to engage in prehospital research making use of novel technical solutions such as videocalls and mobile apps with live communication to the stroke center.
Professor Joanna Wardlaw
Professor Joanna Wardlaw presented the tremendous effort to update and expand the STRIVE recommendations for imaging features of small vessel disease in the STRIVE-2 update. This included an analysis of adoption of the recommendations, which was mostly good, but there is ongoing debate mostly about the best term for “recent small subcortical infarcts”. The update includes novel and emerging features such as cortical superficial siderosis as well as small cortical infarcts as well as recommendations on image acquisition and analysis. For sure, those recommendations will continue to influence guidelines and improve research and patient care.
Professor Will Whiteley
How to do research under the time pressure of a pandemic was the topic of the last talk of the session. There was a massive inflation of research, but weaknesses included lack of collaboration with duplicative, small studies instead of larger, well conducted studies. The peer review system failed to filter dogmatic and flawed research. Positive developments to provide timely and truthful information include the use of master protocols, rapid governance, and easy data flow. Since the information should be available freely, researchers should use preprints, as well as open data and open code. In the next pandemic, policy makers should quickly set up few, but well designed and large projects providing sufficient funding combining several perspectives. One such positive example is the RECOVERY trial.