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Collaborative European NeuroTrauma Effectiveness Research in TBI

Periodic Report Summary 4 - CENTER-TBI (Collaborative European NeuroTrauma Effectiveness Research in TBI)

Project Context and Objectives:
Traumatic Brain Injury (TBI) is a major cause of death and disability, causing great personal suffering to victims and relatives as well as huge direct and indirect costs to society. Recent data show that approximately 2.5 million people in the European Union (EU-28) suffer a TBI, of whom 1.5 million are admitted to hospital and 57,000 die. Worldwide it affects 50 million people and costs the global economy US$400 billion annually. Given an estimated gross world product of about $74 trillion, this means that about $1 in every $200 of annual global output is spent on the costs or consequences of TBI. TBI is a complex disease, but strong evidence in support of treatment recommendations is lacking and approaches seldom adequately targeted. Conventionally, clinical TBI research has involved reductionist attempts to isolate out single factors for treatment. This approach does not account for the complexity of TBI and lacks generalisability. Modern computational techniques and the availability of robust risk adjustment models facilitate more holistic approaches, such as Comparative Effectiveness Research (CER). CER makes use of differences in treatment and outcome, rather than attempting to exclude these. A specific feature of TBI that favours CER is the large between-centre and between-country differences in management and outcome. CENTER-TBI is a large scale CER project, aiming to (1) improve characterization and classification of TBI and (2) identify the most effective clinical care, providing high quality evidence in support of treatment recommendations and guidelines. It brings together leading experts from 47 scientific institutes worldwide. CENTER-TBI is part of the International Initiative on TBI Research (InTBIR - a collaboration of funding agencies. CENTER-TBI is an integrative project that will optimize existing knowledge and merge this with new evidence generated from a prospective observational Core Study and a Registry, collecting data on patients with TBI from 20 countries in Europe and Israel (Figure 1). As the study progressed, we have included substantial contributions to the study from Australia, China and India. The wider range of clinical practice provided by these new contributions will allow us to examine greater variations in practice and use such variations to underpin CER analyses. Extensive profiling of participating centres has been performed to inform CER analysis. In the Core Study, the consortium aims to collect detailed data on approximatively 5400 patients across all severities of TBI. Enrolment will be in three strata, differentiated by care path: (1) patients seen in the emergency room and discharged (ER stratum); (2) patients admitted to hospital, but not to the intensive care unit (admission stratum); (3) patients admitted to the Intensive Care Unit (ICU stratum). Participating centres will also maintain a Registry of basic data on all patients presenting with TBI (CENTER-TBI Registry), aiming to assess representativeness of the Core Study and to analyse effects of structural parameters (e.g. organisational) in greater numbers (15,000 – 25,000 patients). The Core Study will combine emerging techniques (e.g. biomarkers, advanced Magnetic Resonance (MR) imaging, genomics), with innovative approaches to analysis, including state-of-the-art biostatistics and neuroinformatics. Repositories will be created to allow legacy research with future technologies, benefitting from the extensive and systematic data collection in CENTER-TBI, including long term outcome. To identify (cost) effective medical care (both acute and post-acute), the CENTER-TBI consortium will analyse the effects of structure and processes of care at both the organisational (country, region) and at the individual patient level. Research results will be integrated with systematic reviews in a process of knowledge transfer and disseminated to patients, health care professionals and policy makers, thus contributing to improved and harmonised recommendations for the treatment of TBI. CENTER-TBI wishes to break with past dogmas and restrictive traditions. As such the consortium will seek global collaborations, include emergent technologies, involve non-medical scientists, in particular bio-informatics specialists, and seek collaborative data sharing initiatives. The project duration is 6.5 years, including up to 3 years for recruitment – revised upwards compared to the original plan to recruit subjects over an 18 month period.
Project Results:
The CENTER-TBI project consists of three main components: 1) Evidence generation, 2) Evidence synthesis, 3) Evidence dissemination and knowledge transfer. During the fourth year of the project lifetime, the main focus was on evidence generation (recruitment into Core Study and Registry), but substantial accomplishment also resulted from the two latter domains, as detailed hereafter.
Evidence generation
Recruitment into the Core Data Study and Registry continued over reporting year 4. A total of 65 sites had enrolled 4,655 patients into the Core Data Study and 21,724 into the CENTER-TBI Registry in Europe and Israel. On a global level, a total of 5041 patients have been enrolled in the Core study, and 37,916 into the Registry (Table 1). The target recruitment for the ICU stratum was reached. However, recruitment into the ER stratum lagged behind expectations and for this reason, the recruitment duration for this stratum was extended until December the 1st 2017. Large efforts have been dedicated towards data curation. The Data Curation Task Force (18 members) was established together with a SWAT team located in Antwerp to coordinate and execute communications with sites with regard to data completeness and quality. Preliminary analysis in larger numbers confirmed the previously observed trend to higher ages across all strata and the Registry compared to previous observational studies. This reflects a clear change in epidemiologic pattern. The percentage of patients with mild TBI admitted to the ICU remained constant at approximately 30%. The increasing age of patients with TBI has important consequences for healthcare planning and prevention programmes, whilst the relatively high incidence of patients with mild TBI admitted to the ICU raises issues of efficient use of resources.
Evidence synthesis
We have refrained from detailed analysis of Core Data or Registry Data until recruitment has been completed and a clean dataset provided. The provider profiling has been completed and documented substantial differences in structure and process of care between centres and countries. Linguistic validation of translated outcome instruments was performed (WP10) and health utility indices developed (WP11). A total of two Living Systematic Reviews (optimizing existing evidence) have now been published in open access format.
Methods development in Imaging WPs in CENTER-TBI
CENTER-TBI has three WPs which are involved in imaging research: WP4 (Neuroimaging), WP8 (Phenotyping by CT and MR), and WP18 (Prediction of recovery from coma and outcome). Each of these has a different focus in CENTER-TBI, but each is developing image processing tools that represent significant resources for the TBI imaging community, since conventional imaging pipelines work unreliably in TBI (especially in severe TBI, where distortions compromise normalisation). Indeed, the intention at the outset was to let several different imaging science groups work on this difficult problem, in a “competition amicale”, in order to let the best methods emerge. The efforts from WP8 in this regard were reported in detail in the last year, and continuing work is summarised in this Periodic Report. The outputs from WP4 and WP15 are described in some detail in the current Periodic Report. We believe that this diversity in methods development is a substantial asset, and plan to organise a symposium on this topic, to which we will also invite external groups to the extent that funding permits, in order to provide a summary of the State of the Art in processing TBI images for research.
Evidence dissemination and knowledge transfer
A total of 42 publications have already resulted from the CENTER-TBI project, of which two relate to Living Systematic Reviews, three to traditional systematic reviews and five to the provider profiling. The Commissioned Issue on TBI for The Lancet Neurology has been accepted for publication and will be published on November the 7th 2017 during an event at The European Parliament. In addition, four review manuscripts addressing various aspects of TBI have been published in regular issues of The Lancet Neurology. Taken together, this represents a major accomplishment.
Potential Impact:
CENTER-TBI is a project that will last 6.5 years. Improvement of treatment and outcome for TBI is expected to result from 3 main pathways:
• A better characterisation of TBI, facilitating Precision Medicine approaches
• The identification of best practices by Comparative Effectiveness Research
• Improved prognostic models which may be used for benchmarking quality of care
These pathways are summarized in Figure 2.

In addition, the extensive network developed within and beyond the CENTER-TBI participants and investigators are expected to yield great benefits far outside of the European CENTER-TBI context. Collaboration within the InTBIR framework will permit transatlantic comparative analysis, and meta-analysis of individual patient data in larger numbers. The inclusion of data from Australia, China and India will permit global comparisons. This is particularly relevant, as Pharma is increasingly shifting the conduct of trials to the Far east.
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