Standardisation of data collection in traumatic brain injury: key to the future?

Great variability exists in data collection and coding of variables in studies on traumatic brain injury (TBI). This confounds comparison of results and analysis of data across studies. The difficulties in performing a meta-analysis of individual patient data were recently illustrated in the IMPACT project (International Mission on Prognosis and Clinical Trial Design in TBI): merging data from 11 studies involved over 10 person years of work. However, these studies did confirm the great potential for advancing the field by this approach. Although randomized controlled trials remain the prime approach for investigating treatment effects, these can never address the many uncertainties concerning multiple treatment modalities in TBI. Pooling data from different studies may provide the best possible source of evidence we can get in a cost efficient way. Standardisation of data collection and coding is essential to this purpose. Recommendations hereto have been proposed by an interagency initiative in the US. These proposals deserve to be taken forward at an international level. This initiative may well constitute one of the most important steps forwards, paving the road for harvesting successful results in the near future

Imputation of Ordinal Outcomes: A Comparison of Approaches in Traumatic Brain Injury.

Loss to follow-up and missing outcomes data are important issues for longitudinal observational studies and clinical trials in traumatic brain injury. One popular solution to missing 6-month outcomes has been to use the last observation carried forward (LOCF). The purpose of the current study was to compare the performance of model-based single-imputation methods with that of the LOCF approach. We hypothesized that model-based methods would perform better as they potentially make better use of available outcome data. The Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study (n = 4509) included longitudinal outcome collection at 2 weeks, 3 months, 6 months, and 12 months post-injury; a total of 8185 Glasgow Outcome Scale extended (GOSe) observations were included in the database. We compared single imputation of 6-month outcomes using LOCF, a multiple imputation (MI) panel imputation, a mixed-effect model, a Gaussian process regression, and a multi-state model. Model performance was assessed via cross-validation on the subset of individuals with a valid GOSe value within 180 ± 14 days post-injury (n = 1083). All models were fit on the entire available data after removing the 180 ± 14 days post-injury observations from the respective test fold. The LOCF method showed lower accuracy (i.e., poorer agreement between imputed and observed values) than model-based methods of imputation, and showed a strong negative bias (i.e., it imputed lower than observed outcomes). Accuracy and bias for the model-based approaches were similar to one another, with the multi-state model having the best overall performance. All methods of imputation showed variation across different outcome categories, with better performance for more frequent outcomes. We conclude that model-based methods of single imputation have substantial performance advantages over LOCF, in addition to providing more complete outcome data

Between-centre differences and treatment effects in randomized controlled trials: A case study in traumatic brain injury

BACKGROUND: In Traumatic Brain Injury (TBI), large between-centre differences in outcome exist and many clinicians believe that such differences influence estimation of the treatment effect in randomized controlled trial (RCTs). The aim of this study was to assess the influence of between-centre differences in outcome on the estimated treatment effect in a large RCT in TBI. METHODS: We used data from the MRC CRASH trial on the efficacy of corticosteroid infusion in patients with TBI. We analyzed the effect of the treatment on 14 day mortality with fixed effect logistic regression. Next we used random effects logistic regression with a random intercept to estimate the treatment effect taking into account between-centre differences in outcome. Between-centre differences in outcome were expressed with a 95% range of odds ratios (OR) for centres compared to the average, based on the variance of the random effects (tau2). A random effects logistic regression model with random slopes was used to allow the treatment effect to vary by centre. The variation in treatment effect between the centres was expressed in a 95% range of the estimated treatment ORs. RESULTS: In 9978 patients from 237 centres, 14-day mortality was 19.5%. Mortality was higher in the treatment group (OR = 1.22, p = 0.00010). Using a random effects model showed large between-centre differences in outcome (95% range of centre effects: 0.27- 3.71), but did not substantially change the estimated treatment effect (OR = 1.24, p = 0.00003). There was limited, although statistically significant, between-centre variation in the treatment effect (OR = 1.22, 95% treatment OR range: 1.17-1.26). CONCLUSION: Large between-centre differences in outcome do not necessarily affect the estimated treatment effect in RCTs, in contrast to current beliefs in the clinical area of TBI

Handling of Missing Outcome Data in Traumatic Brain Injury Research: A Systematic Review.

Traumatic brain injury (TBI) research commonly measures long-term functional outcome, but studies often suffer from missing data as patients are lost to follow-up. This review assesses the extent and handling of missing outcome data in the TBI literature and provides a practical guide for future research. Relevant electronic databases were searched from January 1, 2012 to October 27, 2017 for TBI studies that used the Glasgow Outcome Scale or Glasgow Outcome Scale-Extended (GOS/GOSE) as an outcome measure. Studies were screened and data extracted in line with Cochrane guidance. A total of 195 studies, 21 interventional, 174 observational, with 104,688 patients were included. Using the reported follow-up rates in a mixed model, on average 91% of patients were predicted to return to follow-up at 6 months post-injury, 84% at 1 year, and 69% at 2 years. However, 36% of studies provided insufficient information to determine the number of subjects at each time-point. Of 139 studies that did report missing outcome data, only 50% attempted to identify why data were missing, with just 4 reporting their assumption on the "missingness mechanism." The handling of missing data was heterogeneous, with the most common method being its exclusion from analysis. These results confirm substantial variability in the standard of reporting and handling of missing outcome data in TBI research. We conclude that practical guidance is needed to facilitate meaningful and accurate study interpretation, and therefore propose a framework for the handling of missing outcome data in future TBI research.The work of HFL, AIRM, DN, EWS, DKM and LW was supported in the context of CENTERTBI (www.center-tbi.eu) by the Fp7 program of the EU (602150). VFJN was supported by an Academy of Medical Sciences / The Health Foundation Clinician Scientist Fellowship. SR was supported by a National Institute of Health Research (NIHR) Academic Clinical Fellowship. The research was supported by the NIHR Biomedical Research Centre based as the Cambridge University Hospitals NHS Foundation Trust and University of Cambridge

Ventricular drainage catheters versus intracranial parenchymal catheters for intracranial pressure monitoring-based management of traumatic brain injury: a systematic review and meta-analysis

traumatic brain injury (TBI), but different approaches to monitoring exist. The aim of this Abstract: Journal of Neurotrauma Page 4 of 41 Intracranial pressure (ICP) monitoring is one of the mainstays in the treatment of severe systematic review and meta-analysis is to compare the effectiveness and complication rate of ventricular drainage (VD) versus intracranial parenchymal (IP) catheters to monitor and treat raised ICP in patients with TBI

Rehabilitation after traumatic brain injury: A survey in 70 European neurotrauma centres participating in the CENTER-TBI study.

OBJECTIVE: To describe variation in structural and process characteristics of acute in-hospital rehabilitation and referral to post-acute care for patients with traumatic brain injury across Europe. DESIGN: Survey study, of neurotrauma centres. METHODS: A 14-item survey about in-hospital rehabilitation and referral to post-acute care was sent to 71 neurotrauma centres participating in a European multicentre study (CENTER-TBI). The questionnaire was developed based on literature and expert opinion and was pilot-tested before sending out to the centres. RESULTS: Seventy (99%) centres in 20 countries completed the survey. The included centres were predominately academic level I trauma centres. Among the 70 centres, a multidisciplinary rehabilitation team can be consulted at 41% (n = 29) of the intensive care units and 49% (n = 34) of the wards. Only 13 (19%) centres used rehabilitation guidelines in patients with traumatic brain injury. Age was reported as a major determinant of referral decisions in 32 (46%) centres, with younger patients usually referred to specialized rehabilitation centres, and patients ≥ 65 years also referred to nursing homes or local hospitals. CONCLUSION: Substantial variation exists in structural and process characteristics of in-hospital acute rehabilitation and referral to post-acute rehabilitation facilities among neurotrauma centres across Europe

Prehospital Management of Traumatic Brain Injury across Europe: A CENTER-TBI Study.

BACKGROUND: Prehospital care for traumatic brain injury (TBI) is important to prevent secondary brain injury. We aim to compare prehospital care systems within Europe and investigate the association of system characteristics with the stability of patients at hospital arrival. METHODS: We studied TBI patients who were transported to CENTER-TBI centers, a pan-European, prospective TBI cohort study, by emergency medical services between 2014 and 2017. The association of demographic factors, injury severity, situational factors, and interventions associated with on-scene time was assessed using linear regression. We used mixed effects models to investigate the case mix adjusted variation between countries in prehospital times and interventions. The case mix adjusted impact of on-scene time and interventions on hypoxia (oxygen saturation <90%) and hypotension (systolic blood pressure <100mmHg) at hospital arrival was analyzed with logistic regression. RESULTS: Among 3878 patients, the greatest driver of longer on-scene time was intubation (+8.3 min, 95% CI: 5.6-11.1). Secondary referral was associated with shorter on-scene time (-5.0 min 95% CI: -6.2- -3.8). Between countries, there was a large variation in response (range: 12-25 min), on-scene (range: 16-36 min) and travel time (range: 15-32 min) and in prehospital interventions. These variations were not explained by patient factors such as conscious level or severity of injury (expected OR between countries: 1.8 for intubation, 1.8 for IV fluids, 2.0 for helicopter). On-scene time was not associated with the regional EMS policy (p= 0.58). Hypotension and/or hypoxia were seen in 180 (6%) and 97 (3%) patients in the overall cohort and in 13% and 7% of patients with severe TBI (GCS <8). The largest association with secondary insults at hospital arrival was with major extracranial injury: the OR was 3.6 (95% CI: 2.6-5.0) for hypotension and 4.4 (95% CI: 2.9-6.7) for hypoxia. DISCUSSION: Hypoxia and hypotension continue to occur in patients who suffer a TBI, and remain relatively common in severe TBI. Substantial variation in prehospital care exists for patients after TBI in Europe, which is only partially explained by patient factors

The added value of ordinal analysis in clinical trials: an example in traumatic brain injury

INTRODUCTION: In clinical trials, ordinal outcome measures are often dichotomized into two categories. In traumatic brain injury (TBI) the 5-point Glasgow outcome scale (GOS) is collapsed into unfavourable versus favourable outcome. Simulation studies have shown that exploiting the ordinal nature of the GOS increases chances of detecting treatment effects. The objective of this study is to quantify the benefits of ordinal analysis in the real-life situation of a large TBI trial. METHODS: We used data from the CRASH trial that investigated the efficacy of corticosteroids in TBI patients (n = 9,554). We applied two techniques for ordinal analysis: proportional odds analysis and the sliding dichotomy approach, where the GOS is dichotomized at different cut-offs according to baseline prognostic risk. These approaches were compared to dichotomous analysis. The information density in each analysis was indicated by a Wald statistic. All analyses were adjusted for baseline characteristics. RESULTS: Dichotomous analysis of the six-month GOS showed a non-significant treatment effect (OR = 1.09, 95% CI 0.98 to 1.21, P = 0.096). Ordinal analysis with proportional odds regression or sliding dichotomy showed highly statistically significant treatment effects (OR 1.15, 95% CI 1.06 to 1.25, P = 0.0007 and 1.19, 95% CI 1.08 to 1.30, P = 0.0002), with 2.05-fold and 2.56-fold higher information density compared to the dichotomous approach respectively. CONCLUSIONS: Analysis of the CRASH trial data confirmed that ordinal analysis of outcome substantially increases statistical power. We expect these results to hold for other fields of critical care medicine that use ordinal outcome measures and recommend that future trials adopt ordinal analyses. This will permit detection of smaller treatment effects

Psychometric Characteristics of the Patient-Reported Outcome Measures Applied in the CENTER-TBI Study.

Traumatic brain injury (TBI) may lead to impairments in various outcome domains. Since most instruments assessing these are only available in a limited number of languages, psychometrically validated translations are important for research and clinical practice. Thus, our aim was to investigate the psychometric properties of the patient-reported outcome measures (PROM) applied in the CENTER-TBI study. The study sample comprised individuals who filled in the six-months assessments (GAD-7, PHQ-9, PCL-5, RPQ, QOLIBRI/-OS, SF-36v2/-12v2). Classical psychometric characteristics were investigated and compared with those of the original English versions. The reliability was satisfactory to excellent; the instruments were comparable to each other and to the original versions. Validity analyses demonstrated medium to high correlations with well-established measures. The original factor structure was replicated by all the translations, except for the RPQ, SF-36v2/-12v2 and some language samples for the PCL-5, most probably due to the factor structure of the original instruments. The translation of one to two items of the PHQ-9, RPQ, PCL-5, and QOLIBRI in three languages could be improved in the future to enhance scoring and application at the individual level. Researchers and clinicians now have access to reliable and valid instruments to improve outcome assessment after TBI in national and international health care