Planning preclinical confirmatory multicenter trials to strengthen translation from basic to clinical research – a multi-stakeholder workshop report

Clinical translation from bench to bedside often remains challenging even despite promising preclinical evidence. Among many drivers like biological complexity or poorly understood disease pathology, preclinical evidence often lacks desired robustness. Reasons include low sample sizes, selective reporting, publication bias, and consequently inflated effect sizes. In this context, there is growing consensus that confirmatory multicenter studies -by weeding out false positives- represent an important step in strengthening and generating preclinical evidence before moving on to clinical research. However, there is little guidance on what such a preclinical confirmatory study entails and when it should be conducted in the research trajectory. To close this gap, we organized a workshop to bring together statisticians, clinicians, preclinical scientists, and meta-researcher to discuss and develop recommendations that are solutionoriented and feasible for practitioners. Herein, we summarize and review current approaches and outline strategies that provide decision-critical guidance on when to start and subsequently how to plan a confirmatory study. We define a set of minimum criteria and strategies to strengthen validity before engaging in a confirmatory preclinical trial, including sample size considerations that take the inherent uncertainty of initial (exploratory) studies into account. Beyond this specific guidance, we highlight knowledge gaps that require further research and discuss the role of confirmatory studies in translational biomedical research. In conclusion, this workshop report highlights the need for close interaction and open and honest debate between statisticians, preclinical scientists, meta-researchers (that conduct research on research), and clinicians already at an early stage of a given preclinical research trajectory

Planning preclinical confirmatory multicenter trials to strengthen translation from basic to clinical research – a multi-stakeholder workshop report

Clinical translation from bench to bedside often remains challenging even despite promising preclinical evidence. Among many drivers like biological complexity or poorly understood disease pathology, preclinical evidence often lacks desired robustness. Reasons include low sample sizes, selective reporting, publication bias, and consequently inflated effect sizes. In this context, there is growing consensus that confirmatory multicenter studies -by weeding out false positives- represent an important step in strengthening and generating preclinical evidence before moving on to clinical research. However, there is little guidance on what such a preclinical confirmatory study entails and when it should be conducted in the research trajectory. To close this gap, we organized a workshop to bring together statisticians, clinicians, preclinical scientists, and meta-researcher to discuss and develop recommendations that are solution-oriented and feasible for practitioners. Herein, we summarize and review current approaches and outline strategies that provide decision-critical guidance on when to start and subsequently how to plan a confirmatory study. We define a set of minimum criteria and strategies to strengthen validity before engaging in a confirmatory preclinical trial, including sample size considerations that take the inherent uncertainty of initial (exploratory) studies into account. Beyond this specific guidance, we highlight knowledge gaps that require further research and discuss the role of confirmatory studies in translational biomedical research. In conclusion, this workshop report highlights the need for close interaction and open and honest debate between statisticians, preclinical scientists, meta-researchers (that conduct research on research), and clinicians already at an early stage of a given preclinical research trajectory

Frontoparietal activity and its structural connectivity in binocular rivalry

To understand the brain areas associated with visual awareness and their anatomical interconnections, we studied binocular rivalry with functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI). Binocular rivalry occurs when one image is viewed by one eye and a different image by the other; it is experienced as perceptual alternations between the two images. Our first experiment addressed problems with a popular comparison condition, namely permanent suppression, by comparing rivalry with binocular fusion instead. We found an increased fMRI signal in right frontal, parietal, and occipital regions during rivalry viewing. The pattern of neural activity differed from findings of permanent suppression comparisons, except for adjacent activity in the right superior parietal lobule. This location was near fMRI signal changes related to reported rivalry alternations in our second experiment, indicating that neighbouring areas in the right parietal cortex may be involved in different components of rivalry. In our second experiment, we used probabilistic tractography to detect white matter fibres between right-hemispheric areas that showed event-related fMRI signal changes time-locked to reported perceptual alternations during rivalry viewing. Most of these functionally defined areas were linked by probabilistic fibre tracts, some of which followed long-distance connections such as the inferior occipitofrontal fasciculus. Corresponding anatomical pathways might mediate communication within the functional network associated with changes in conscious perception during binocular rivalry

The fiber tracts affected by the patient's lesion.

<p>The patient's acute lesion (a, yellow) and affected fibre tracts (purple) in the chronic brain, superimposed on the patient's fractional anisotropy image. The tracts include at the posterolateral edge of the pulvinar the inferior fronto-occipital fasciculus (b), which projects to the external capsule and the insula.</p

T.R.'s neuropsychological test scores.

<p>Language: Boston naming test <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0079938#pone.0079938-ThuillardColombo1" target="_blank">[45]</a>, Fluency test <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0079938#pone.0079938-Cardebat1" target="_blank">[46]</a>; Apraxia: sub-test CAMCOG <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0079938#pone.0079938-Huppert1" target="_blank">[47]</a>; Agnosia: Protocole Montréal-Toulouse d'Evaluation des Gnosies Visuelles <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0079938#pone.0079938-Agniel1" target="_blank">[48]</a>; Memory: Span (sub-test CAMCOG), 16 words (Grober and Buschke test, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0079938#pone.0079938-VanderLinden1" target="_blank">[49]</a>); Executive function: Luria test <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0079938#pone.0079938-Luria1" target="_blank">[50]</a>, Stroop <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0079938#pone.0079938-Moroni1" target="_blank">[51]</a>, Trail Making Test <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0079938#pone.0079938-Tombaugh1" target="_blank">[52]</a>; Neglect <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0079938#pone.0079938-Azouvi1" target="_blank">[53]</a>. Percentil: per.</p

Egocentric reachable task.

<p>(a) schematic setup and illustration of the mean distance estimates of reachable stimuli; (b) estimates of T.R. (diamond) and control group (triangles) of the border of their peripersonal egocentric space.</p

The patient's acute ischemic lesion.

<p>The figure shown on axial slices of the diffusion weighted image, involves the right ventrolateral posterior thalamus, the lateral edge of the pulvinar and the adjacent white matter down to the right hippocampus.</p

Egocentric distance task.

<p>(a) schematic setup and illustration of the mean distance estimates between participants and experimenter; (b) mean estimates of T.R. and control group of a distance in their extrapersonal egocentric space.</p

Spatial Hyperschematia without Spatial Neglect after Insulo-Thalamic Disconnection.

Different spatial representations are not stored as a single multipurpose map in the brain. Right brain-damaged patients can show a distortion, a compression of peripersonal and extrapersonal space. Here we report the case of a patient with a right insulo-thalamic disconnection without spatial neglect. The patient, compared with 10 healthy control subjects, showed a constant and reliable increase of her peripersonal and extrapersonal egocentric space representations - that we named spatial hyperschematia - yet left her allocentric space representations intact. This striking dissociation shows that our interactions with the surrounding world are represented and processed modularly in the human brain, depending on their frame of reference