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Collaborative European NeuroTrauma Effectiveness Research in TBI

Periodic Report Summary 6 - 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. 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. In addition, meta-analysis across studies participating in the IntBIR initiative will increase the power of numbers. Extensive profiling of participating centres has been performed to inform CER analysis. In the Core Study, the consortium has collected detailed data in over 4500 patients across all severities of TBI in the EU and Israel and an additional 1,000 in Australia and India. Enrolment was 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 also maintained 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 (recruitment: 22,772 patients). The Core Study combines 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 have been 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 actively seeks global collaborations, includes emergent technologies, involves non-medical scientists, in particular bio-informatics specialists, and seeks collaborative data sharing initiatives. The project duration is 7 1/4 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 sixth year of the project lifetime, the main focus was on data curation and analysis and synthesis of evidence, whilst substantial accomplishments were also obtained in relation to dissemination and knowledge transfer.

The recruitment into the Core data study and the Registry was completed on December 17th, 2017. A total of 4,559 subjects were recruited in Europe and Israel to the Core data study and 22,849 in the Registry (Figure 1). Internationally, recruitment from Australia and India increased numbers of the Core study to over 5,000 and to over 40,000 in the Registry, respectively approaching and exceeding targets (5400 for Core and 20-25000 for Registry). Details are provided in Figure 1. Repositories were established for imaging data (Icometrix, Leuven) and a biobank for storage of blood samples (Pecs, Hungary). The neuroimaging repositories contains raw de-identified data of 4247 scans obtained on presentation to study hospitals. An additional 1181 follow-up and post-op scans are included. MR scans were obtained from 612 patients. To our knowledge this neuro-imaging repository is the largest in the world on TBI. The admission CT scans have all been centrally reviewed and reported according to the recommendations of the common data elements. The CENTER-TBI biobank is established in Pècs (Hungary); the current contents are 56,873 cryovials from 3,573 subjects, serum samples from 3331 subjects. Whole blood samples have been banked for genetic analysis from 3,646 patients. A total of 6,069 citrate plasma and 1,421 EDTA plasma samples from 573 patients were obtained for extended analysis of coagulation cascades. This is particularly relevant as TBI may induce coagulopathic disturbances and because pre-existing bleeding disorders or anticoagulant medication may increase the risk of cerebral bleeding. All admission samples have been analyzed for a panel of 6 biomarkers (S100B, NSE, GFAP, UCHL1, NFL and total tau). We found that all biomarkers scaled with injury severity (classified according to the Glasgow Coma Scale) and care path (stratum). Analysis on the added value of biomarkers compared to clinical characteristics for predicting the likelihood of CT abnormalities in patients with mild TBI is ongoing.
The CENTER-TBI database is hugely complex with over 2,600 unique variables, many of which are recorded at multiple time points and include longitudinal data and extensive outcome assessments. The complexity of the datasets in combination with the vast volume of data necessitated a substantial effort in data curation. Although the initial curation has been completed, we have come to recognize that data curation is an ongoing task as new issues may arise as analyses are progressing. A custom data access portal Neurobot was developed, in combination with an extensive data dictionary, and version 1 released in November 2018. Version 2 including multiple updates was released in May 2019. The analyses of CENTER-TBI were underpinned by the implementation of a study proposal platform, summarizing all research plans submitted by internal as well as external researchers. To date, 155 proposals have been accepted. A total of 18 proposals were submitted by external researchers.

Evidence dissemination and knowledge transfer:
A major deliverable of CENTER-TBI was the acceptance of the publication of the main descriptive analysis of CENTER-TBI in the Lancet Neurology (Steyerberg EW, Wiegers E, Sewalt C, et al. Case-mix, care pathways, and outcomes in patients with traumatic brain injury in CENTER-TBI: a European prospective, multicentre, longitudinal, cohort study. Lancet Neurology 2019; 18(10): 923-34). A further 44 publications from CENTER-TBI resulted from reporting year 6 and included a landmark paper on the evolution of guidelines in TBI. The living systematic reviews were completed with the publication of an LSR on Apolipoprotein E4 polymorphism and outcome after TBI.
Potential Impact:
CENTER-TBI is a project that will last 7 ¼ years. Improvement of treatment and outcome for TBI is expected to result from 3 main pathways:
• A better characterization 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

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. Collaboration has been established with the MIP platform of The Human Brain Project to explore development of a European platform for data sharing and analysis. The inclusion of data from Australia, China and India will permit global comparisons. Finally, the CENTER-TBI Registry format helped inform the development of a Global TBI registry developed by the NIHR Global Health research Group on Neurotrauma (
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