Article Text

Original research
Discrepancy between disability and reported well-being after traumatic brain injury
  1. Isabel Rosalie Arianne Retel Helmrich1,
  2. David van Klaveren1,2,
  3. Nada Andelic3,4,
  4. Hester Lingsma1,
  5. Andrew Maas5,
  6. David Menon6,
  7. Suzanne Polinder7,
  8. Cecilie Røe3,4,
  9. Ewout W Steyerberg1,8,
  10. Ernest Van Veen1,9,
  11. Lindsay Wilson10
  12. The CENTER-TBI participants and investigators
    1. 1Department of Public Health, Center for Medical Decision Making, Erasmus Medical Center, Rotterdam, Zuid-Holland, The Netherlands
    2. 2Predictive Analytics and Comparative Effectiveness Center, Institute for Clinical Research and Health Policy Studies/Tufts Medical Center, Boston, Massachusetts, USA
    3. 3Research Centre for Habilitation and Rehabilitation Models and Services (CHARM), Department of Health and Society, University of Oslo, Oslo, Norway
    4. 4Department of Physical Medicine and Rehabilitation, Oslo University Hospital, Oslo, Norway
    5. 5Department of Neurosurgery, University Hospital Antwerp, Edegem, Antwerp, Belgium
    6. 6Division of Anaesthesia, Cambridge University, Cambridge, Cambridgeshire, UK
    7. 7Department of Public Health, Erasmus Medical Center, Rotterdam, Zuid-Holland, The Netherlands
    8. 8Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands
    9. 9Department of Intensive Care, Erasmus Medical Center, Rotterdam, Zuid-Holland, The Netherlands
    10. 10Division of Psychology, University of Stirling, Stirling, UK
    1. Correspondence to Isabel Rosalie Arianne Retel Helmrich, Department of Public Health, Center for Medical Decision Making, Erasmus Medical Center, 3000 CA Rotterdam, Zuid-Holland, The Netherlands; i.retelhelmrich{at}erasmusmc.nl

    Abstract

    Background Following traumatic brain injury (TBI), the clinical focus is often on disability. However, patients’ perceptions of well-being can be discordant with their disability level, referred to as the ‘disability paradox’. We aimed to examine the relationship between disability and health-related quality of life (HRQoL) following TBI, while taking variation in personal, injury-related and environment factors into account.

    Methods We used data from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury study. Disability was assessed 6 months post-injury by the Glasgow Outcome Scale-Extended (GOSE). HRQoL was assessed by the SF-12v2 physical and mental component summary scores and the Quality of Life after Traumatic Brain Injury overall scale. We examined mean total and domain HRQoL scores by GOSE. We quantified variance in HRQoL explained by GOSE, personal, injury-related and environment factors with multivariable regression.

    Results Six-month outcome assessments were completed in 2075 patients, of whom 78% had mild TBI (Glasgow Coma Scale 13–15). Patients with severe disability had higher HRQoL than expected on the basis of GOSE alone, particularly after mild TBI. Up to 50% of patients with severe disability reported HRQoL scores within the normative range. GOSE, personal, injury-related and environment factors explained a limited amount of variance in HRQoL (up to 29%).

    Conclusion Contrary to the idea that discrepancies are unusual, many patients with poor functional outcomes reported well-being that was at or above the boundary considered satisfactory for the normative sample. These findings challenge the idea that satisfactory HRQoL in patients with disability should be described as ‘paradoxical’ and question common views of what constitutes ‘unfavourable’ outcome.

    • TRAUMATIC BRAIN INJURY
    • QUALITY OF LIFE
    • NEUROPSYCHOLOGY

    Data availability statement

    Data are available on reasonable request. Individual participant data will be available immediately following publication, conditional to approved study proposal, with no end date. Data will be available to researchers who provide a methodologically sound study proposal that is approved by the management committee to achieve the aims in the approved proposal. Proposals can be submitted online at https://www.center-tbi.eu/data. A data access agreement is required and all access must comply with regulatory restrictions imposed on the original study.

    http://creativecommons.org/licenses/by-nc/4.0/

    This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

    Statistics from Altmetric.com

    Introduction

    Disability relates to a set of difficulties a person may experience when interacting with their social and physical environments.1 2 Disability is common following moderate and severe traumatic brain injury (TBI), and increasingly recognised as a consequence of mild TBI.3 Following TBI, individuals often experience impairments in different aspects of their life, including physical, social and cognitive limitations, which may impact their well-being.4–8

    Clinical decisions about the management of TBI are often based on the likelihood of the person remaining dependent on others in daily life and therefore having impaired quality of life.9 However, healthy people can overestimate the emotional impact that chronic illness and disability will have on a persons’ well-being.10 Furthermore, patients’ perceptions of quality of life can be discordant with their objective health status.11 This phenomenon has been described as the ‘disability paradox’: a discrepancy between severe disability that is observable by others and good quality of life reported by the patient.11 However, critics argue that the ‘paradox’ depends on the assumption that disability determines well-being.12

    Previous reports consistent with the idea of a ‘disability paradox’ indicates that patients with severe disability several months following TBI can experience good or excellent well-being.13 A common explanation for this phenomenon is anosognosia: lack of awareness of disability, as a result of neurological impairment.14 In the classic descriptions of anosognosia, the individual may, for example, deny having hemiparesis after stroke.15 Anosognosia following TBI might be related to behavioural disorders, frontal lobe syndromes and/or problems with social cognition. Other explanations for the ‘disability paradox’ include psychological processes such as coping,11 and personal and environment factors:16 for instance, how patients experience disabilities might be affected by employment, preinjury mental health and satisfaction with social support.12 This is in agreement with the way in which the relationship between health and disability is described by the WHO: disability is a complex construct involving an interaction between the person and their environment.1

    To date, the discordance between disability level and well-being and the ‘disability paradox’ have mainly been described as a theoretical construct,11–13 16 or observed in practice without receiving much attention in empirical studies.

    We aimed to examine the relationship between functional outcome, and health-related quality of life (HRQoL) in individuals 6 months following TBI, while taking variation in personal, injury-related and environment factors into account. We hypothesised that the relationship between disability and HRQoL differs by injury severity. Predictors of functional outcome for mild injuries differ from those for more severe injuries,17 suggesting that these subgroups have distinctive characteristics. Further, we hypothesised that contextual factors, including personal, injury-related and environment factors contribute to explaining variation in HRQoL.

    Methods

    Study population

    We analysed data from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. This is a prospective, multicentre, longitudinal, observational study.18 19 Data were collected for patients with a clinical diagnosis of TBI and an indication for CT, presenting within 24 hours of injury in one of the 59 participating centres.

    Participants were recruited from December 2014 to December 2017 in 18 countries across Europe and Israel. In our study, patients were included if they were aged ≥16 years and had available GOSE, and SF-12v2 or Quality of Life after Traumatic Brain Injury overall scale (QOLIBRI-OS) scores at 6-months post-injury.

    Data for the CENTER-TBI study were entered by participating sites on the Quesgen e-CRF (Quesgen Systems, USA), hosted on the International Neuroinformatics Coordinating Facility (INCF) platform, and extracted via the INCF Neurobot tool (INCF, Sweden) (database Core 2.1). Informed consent was obtained from all participants according to local and national requirements.

    In our study, we included 2075 patients aged 16 years or over who had completed the outcome assessments at 6 months post-injury (online supplemental file 1). Patients with missing questionnaires or with proxy responses on HRQoL assessments were excluded.

    Supplemental material

    Outcome assessment

    Disability

    The Glasgow Outcome Scale-Extended (GOSE) is widely used as a global measure of functional outcome and disability. The scale has eight categories: (1) death, (2) vegetative state, (3) lower severe disability, (4) upper severe disability, (5) lower moderate disability, (6) upper moderate disability, (7) lower good recovery and (8) upper good recovery20 (online supplemental table 1). In CENTER-TBI, the GOSE was assessed as a structured interview or a questionnaire completed by the patient or a carer. At 6 months follow-up, the format of the assessment was an interview in 79% cases and a questionnaire in 20% (online supplemental table 2). The respondent for the GOSE was almost always the patient, either alone or with a relative or carer (98%). The GOSE was scored centrally combining the ratings of the interviews and the questionnaires. Missing GOSE values were imputed based on GOSE measurements at other time points if available.21

    Health-related quality of life

    We used the Short Form-12 V.2 (SF-12v2) and the QOLIBRI-OS to assess health-related quality of life (HRQoL). The SF-12v2 is a 12-item patient-reported HRQoL outcome which assesses multiple aspects of health-related functioning and well-being.22 The SF-12v2 comprises eight subscales and two summary scores: physical functioning, role limitations due to physical health, bodily pain and general health perceptions, are included in the physical component summary (PCS) score, and vitality, social functioning, role limitations due to emotional health and general mental health, are included in the mental component summary (MCS) score. The PCS emphasises aspects of functional status, while the MCS incorporates well-being including mental health.23 The norm-based T-scores (standardised to mean 50 and SD of 10) were calculated for the MCS and PCS. MCS and PCS scores range between 2 (poorest possible HRQoL) and 74 (best possible HRQoL). For the SF-12v2, scores of 45 and above are considered within the normative range for the general population, scores of 40–45 are borderline, and scores below 40 are considered impaired.22

    The QOLIBRI-OS is a six-item patient-reported HRQoL outcome specifically developed for patients following TBI.24 The QOLIBRI-OS assesses satisfaction with aspects of life (cognition, self, daily life and autonomy, social relationships, current situation and future prospects) and ranges from 0 (poorest possible HRQoL) to 100 (best possible HRQoL). Scores of 61 and above are considered within the normative range, scores of 52–60 are considered borderline and scores below 52 are considered low or impaired.25

    Contextual factors related to HRQoL following TBI

    We studied the following personal and injury-related factors that are relevant to HRQoL: age,26 sex,26 marital status, level of education,27 type of employment preinjury,27 preinjury mental health problems,28 preinjury substance abuse,29 preinjury health status (The American Society of Anesthesiologists—physical status classification system (ASA-PS)), cause of injury, injury severity,29 30 the presence of intracranial abnormality and major extracranial injury (MEI).31 Initial injury severity was assessed with the GCS. TBI was considered mild in patients with GCS 13–15, moderate in patients with GCS 9–12 and severe in patients with GCS of 3–8.19 The definition of ‘mild’ injury allows that patients may have an abnormality on CT.3 Preinjury health status was assessed with the ASA-PS; patients are categorised as ‘normal healthy patient’, ‘mild systemic disease’, ‘severe systemic disease’ or ‘severe systemic disease that is a constant threat to life’. The categories ‘severe systemic disease’ and ‘severe systemic disease that is constant threat to life’ were combined. MEI was defined as an Abbreviated Injury Scale≥3 regarding the following body regions; face, thoracic/ lumbar spine, thorax/chest, abdomen/pelvic contents, extremities and pelvic girdle, or external (skin), thus excluding head and neck. Environment factors involve satisfaction with social support, satisfaction with support from the hospital and health services and satisfaction with support from rehabilitation services 6 months post-injury.26 27 32

    Statistical analyses

    Descriptive statistics are presented as medians (IQR) or frequencies (percentage).

    We examined the relationships between disability and HRQoL in three ways: (I) we calculated the percentage of patients by GOSE category that have scores in the normative range on the QOLIBRI-OS and MCS; (II) we examined differences between the PCS and the MCS as a measure of dissociation between physical and mental HRQoL and (III) we studied the association of the GOSE and HRQoL using linear regression analysis, including personal, injury-related and environment factors.

    All analyses were performed separately for individuals with mild (Glasgow Coma Scale (GCS) 13–15) and moderate/severe (GCS 3–12) TBI. The decision to combine patients with moderate and severe TBI was motivated by the sample size (Moderate/severe TBI N=466), and the limited number of patients classified as moderate TBI (N=149). To account for differences in the relationship between GOSE and HRQoL following mild, moderate and severe TBI, we performed two-way analysis of variance (ANOVA) for SF-12 PCS, MCS and QOLIBRI-OS. The relationship between HRQoL following TBI and the GOSE, personal, injury-related and environment factors were analysed with linear regression analyses. The contribution of predictors to the explained variance (R2) for each outcome was shown graphically by the partial R2. Furthermore, the associations between the GOSE and the MCS and QOLIBRI-OS total score, adjusted for personal, injury-related and environment factors were shown graphically.

    Analyses are performed with R statistical software (R V.3.6.0). We used the rms package to fit the regression models.33

    Results

    Study sample

    We included 2075 adult patients who completed the GOSE and SF-12v2 or the QOLIBRI-OS 6 months post-injury (online supplemental figure 1). SF-12v2 and QOLIBRI-OS completion rates at follow-up differed by GOSE category (online supplemental table 3): patients with GOSE three had the lowest completion rates (QOLIBRI-OS: 60%, SF-12v2: 65%), while completion rates for patients with higher levels of functioning were higher and generally above 75%.

    The median age was 51 years (IQR=32–64) (table 1). Most patients (78%) were classified as having a mild TBI. A third (35%) had MEI. Fifty-three per cent was employed, 23% was retired, and 18% unemployed. About 10% had preinjury mental health problems. Moreover, 40% reported preinjury comorbid health issues.

    Table 1

    Patients’ demographic and injury characteristics

    Patients following moderate/severe TBI were younger, more often male and more often involved in traffic accidents than patients after mild TBI (table 1). Rehabilitation was less often received by patients after mild TBI (24%) compared with those after moderate/severe TBI (79%) (table 2).

    Table 2

    Patients’ satisfaction with social support, use of rehabilitation services and outcomes 6-month post-injury

    Six months after TBI, 186 patients experienced severe disability (9%) (GOSE 3–4), 528 patients experienced moderate disability (25%) (GOSE 5–6) and 1361 (66%) could be classified as having a good recovery (GOSE 7–8) (table 2).

    Health-related quality of life stratified by injury severity and disability

    Overall, SF-12 PCS, MCS and QOLIBRI-OS scores 6 months following TBI increased with the GOSE (figure 1). In both severity groups, the PCS showed an almost linear relationship with the GOSE. This contrasts with the relationship with the MCS, particularly at lower levels of outcome. Specifically, following mild TBI, patients with a GOSE of 3–4, reported higher MCS scores than patients with a GOSE of 5 (mean 42 (95% CI 38 to 47) and 48 (41 to 47) for GOSE 3 and 4 vs 38 (36 to 40) for GOSE 5) (online supplemental table 4). The results for the QOLIBRI-OS in the mild group mirror those of the MCS (QOLIBRI-OS mean 45 (95% CI 37 to 54) and 54 (48 to 60) for GOSE 3 and 4 vs 48 (44 to 52) for GOSE 5).

    Figure 1

    Plots of the SF-12v2 physical and mental health component summary scores (top) and the QOLIBRI-OS (bottom) by time point for mild (left) and moderate and severe TBI (right). The points are means and error bars are 95% CI. QOLIBRI-OS, Quality of Life after Traumatic Brain Injury overall scale; TBI, traumatic brain injury.

    Based on the ANOVA, there were significant differences on all HRQoL outcomes by GCS and GOSE. The interaction between GCS and GOSE was significant for MCS (F=4.137, df 1, p<0.01) but not for QOLIBRI-OS (F=0.55, df 1, p=0.46) and PCS (F=0.098, df 1, p=0.75).

    For patients following mild TBI, the lowest mean score on the MCS was reported for those with lower moderate disability (GOSE 5) (online supplemental table 4) (mean 38 (95% CI 36 to 40) compared with >42 (95% CI 38 to 47)). Following moderate and severe TBI, patients with lower severe disabilities (GOSE 3) reported the lowest mean MCS scores (mean 41 (95% CI 39 to 45) compared with >42 (39 to 45)). For four SF-12 subscales, namely ‘bodily pain’, ‘general health’, ‘role emotional’ and ‘mental health’, and the QOLIBRI-OS items ‘how your brain is working’, ‘feelings and emotions’, ‘social life’ and ‘current situation and future prospects’ individuals following mild TBI with lower moderate disability (GOSE 5) scored lower than patients with upper severe disability (GOSE 4) (online supplemental table 4). The median score on the PCS increased with recovery level on the GOSE. Similarly, the MCS and QOLIBRI-OS scores generally increased with recovery level on the GOSE, but in patients following mild TBI, HRQoL scores did not increase from GOSE 3 to 5.

    Discordance between disability and health-related quality of life: the ‘disability paradox’

    Similar to the trends depicted in figure 1, a higher percentage of patients following mild TBI with upper severe disability (GOSE 4) reported HRQoL scores within the normative range than patients with lower moderate disability (GOSE 5) (MCS 50% vs 30%; QOLIBRI-OS 42% vs 35%) (table 3).

    Table 3

    Number and percentage of patients with HRQoL scores within the normative range 6-month post-injury, and mean differences between the MCS and PCS

    Following mild TBI, up to half of the individuals with severe disability (N=93) had normative QOLIBRI-OS and MCS scores 6 months following TBI (QOLIBRI-OS 29% and 42%, MCS 40% and 50%) (table 3). In contrast, a smaller proportion of individuals with severe disabilities had normative PCS scores (11% and 24%). Following moderate and severe TBI, more than a third of individuals with severe disability (N=88) had normative QOLIBRI-OS and MCS scores 6 months following TBI (QOLIBRI-OS 40% and 37%; MCS 26% and 13%) (table 3).

    Second, we calculated the difference between the PCS and the MCS by recovery level on the GOSE. Patients with severe disability had larger mean differences between the MCS and PCS compared with patients with moderate disability and good recovery (table 3). The difference for patients with severe disability was nearly 10 points, which is equivalent to one SD at the population level. This implies that severely disabled individuals have a substantial discordance between the PCS and MCS.

    The relation between disability, contextual factors and HRQoL

    The GOSE had the largest contribution to explaining the variance of HRQoL compared with personal, injury-related and environment factors (figure 2).

    Figure 2

    Contribution of predictors to explained variance (partial R2) of the models for SF-12 PCS (left), SF-12 MCS (middle) and QOLIBRI-OS (right). The partial R2 is calculated as follows: total R2 of multivariable model – R2 multivariable model without individual predictor: total R2 of multivariable model without individual predictor=partial R2. MCS, mental component summary; PCS, physical component summary; QOLIBRI-OS, Quality of Life after Traumatic Brain Injury overall scale.

    While adjusting for personal, injury-related and environment factors in patients with mild TBI, estimates of the MCS and QOLIBRI-OS for patients with GOSE 5 were lower than estimates for patients with GOSE 3–4 (figure 3). Thus, personal and injury-related factors (including MEI) and satisfaction with social support did not explain the discrepancies between GOSE and HRQoL in patients following mild TBI.

    Figure 3

    Adjusted association between the GOSE and the SF-12 MCS (upper) and QOLIBRI-OS (lower) for the ‘average’ patient (sex=male; age=51; marital status=married; highest level of education=second/high school, type of employment=working, preinjury mental health problems=no, preinjury substance abuse=no; preinjury health status (ASA-PS)=healthy; injury severity (GCS)=15; cause of injury=incidental fall; major extracranial injury=no; presence of intracranial traumatic abnormalities=present; satisfaction with social support=high; satisfaction with support from the hospital and health services=high; satisfaction with support from rehabilitation services=high). ASA-PS, The American Society of Anesthesiologists-physical status classification system; GOSE, Glasgow Outcome Scale-Extended; MCS, mental component summary; PCS, physical component summary; QOLIBRI-OS, Quality of Life after Traumatic Brain Injury overall scale; TBI, traumatic brain injury.

    Besides the GOSE, satisfaction with social support 6 months following TBI contributed to explaining the variance in HRQoL (figure 2). Independent of initial injury severity based on GCS, patients with lower moderate disabilities (GOSE 5) were least satisfied with the support they received from rehabilitation (67% vs ≥70% for mild and 75% vs ≥79% for moderate and severe TBI) (online supplemental table 5). As expected, patients with moderate disability (GOSE 5–6) were less likely than patients with severe disability (GOSE 3–4) to receive rehabilitation 6 months post-injury (54%–62% vs <51% for mild TBI, respectively; 9%–19% vs <5% for moderate/severe TBI respectively) (online supplemental table 6).

    Up to 29% (mild) and 28% (moderate and severe) of the variance in QOLIBRI-OS and 21% (mild) and 11% (moderate and severe) of the variance in MCS were explained by the combination of GOSE, personal and injury related characteristics and satisfaction with social support at 6 months post-injury.

    Discussion

    We examined the relationship between disability assessed with the GOSE and HRQoL measured with the SF12v2 MCS and QOLIBRI-OS 6 months following TBI in the CENTER-TBI study. Following mild TBI, patients can have poor functional outcomes, which is consistent with growing awareness that patients classified as mild by GCS criteria can suffer a range of problems.3 In patients following mild TBI, HRQoL did not decrease linearly with greater disability. Specifically, patients with severe disability on the GOSE reported higher MCS and QOLIBRI-OS scores than patients with moderate disabilities. Furthermore, between a third and half of patients with severe disabilities reported HRQoL within the normative range. Our study therefore confirms that individuals’ perceptions of aspects of well-being and mental health are often discordant with their objective functioning following TBI.

    Our findings are consistent with prior studies describing good or excellent well-being and quality of life following TBI.13 34 Furthermore, our findings imply that satisfactory HRQoL in patients with disabilities is not a ‘paradox’, since individuals frequently report HRQoL within the normative range following TBI. Discordance between disability and HRQoL should therefore be regarded as a characteristic of TBI outcomes. Characterising HRQoL within the normative range despite severe disability as a ‘paradox’ has serious shortcomings, as it implies that patients with severe disability cannot normally experience satisfactory HRQoL.13 Discrepancies between disability and HRQoL have been observed in prior studies in TBI.35–37 To provide quantification of the discordance between physical and mental health, we therefore examined the difference between the SF-12v2 MCS and PCS. Similarly, patients with severe disabilities had the largest discordance between the MCS and PCS.

    It is often suggested that patients with severe disability after TBI have lower self-awareness or anosognosia and a bias towards responding positively on outcome assessments.14 38 This might explain, for example, positive ratings on the QOLIBRI-OS among more disabled individuals. Although impairments of self-awareness can be present after TBI, Sasse et al38 found that the influence on reported HRQoL was weak. Furthermore, in our study, patients showed awareness of functional limitations on the PCS and nonetheless gave positive ratings of HRQoL on the MCS. The dissociation observed for two summary components of the same self-reported outcome appears to rule out an account in terms of global lack of awareness. That is, the discrepancy means that patients were not simply responding with positive ratings across all items, in a way that one might expect if the person had profound loss of awareness, and would imply that the responses were meaningless. Nonetheless, more selective limitations of awareness may play a role, for example, lack of awareness of cognitive impairment or mental health problems.39 Alterations in awareness may thus contribute to discrepancies, and this deserves further study.

    Besides deficits in general functional outcome cognitive impairments are likely to play a role in perception of well-being after TBI. A prior CENTER-TBI study found that MCS scores generally decreased with increasing cognitive impairment and apparently reached a plateau in the severely disabled group.37 Cognition may play a number of different roles, and it is possible that cognitive impairment has some protective role in the most severely disabled patients.38 Data on cognitive impairments from severely disabled patients (GOSE 3–4) were too limited to allow us to examine this issue, and it remains an important topic for future research. Furthermore, prevalence of cognitive impairment is likely to be a key difference between the two severity groups that we studied.40 Notably, discrepancies were observed in both groups and were not more pronounced in more severely injured patients than the group with mild injuries.

    Following TBI, disability is often assessed using functional outcome scales such as the GOSE. The SF-12v2 and QOLIBRI-OS also try to capture the patient’s subjective experience of their well-being in daily life.7 Decisions about the management of TBI are sometimes founded on the likelihood of the person remaining dependent, under the assumption this will lead to impaired HRQoL, and therefore classified as an ‘unfavourable’ outcome. In contrast, our findings showed that HRQoL does not simply follow functioning. Our results thus represent a strong caution against adopting a negative view of potential HRQoL and well-being in patients who are severely disabled based on the GOSE.

    We found the lowest levels of HRQoL in patients with moderate disability. Similarly, in a study of patients after severe TBI, Mailhan and colleagues35 found the lowest level of life satisfaction in patients with moderate disability, which they attribute to lower satisfaction in the domains social and family life. Our results also indicated that patients with moderate disability might be less satisfied with their social support and were less likely to receive rehabilitation. As expected, access to rehabilitation services is more likely among patients following moderate and severe TBI and patients with severe disability compared with their respectively less severely injured and disabled counterparts.41 A previous study showed that patients after less severe TBI report more unmet rehabilitation needs than those following severe TBI.42 Patients with moderate disability are independent, but are unable to return to work, and experience activity limitations.20 43 Although these patients experience activity limitations, the injury and its consequences might be less visible to their environment compared with patients with severe disability, which could result in less (social) support. To be unable to work and be isolated in the community, may well be worse for well-being than being dependent in daily life but well-supported by others. Our results thus suggest that patients with lower moderate disability living in the community should be a particular target for additional support, rehabilitation and interventions. Furthermore, as perceptions of well-being are often discordant with disability level following TBI, recovery should be based on a multidimensional outcome measure including disability on multiple domains including physical, cognitive and social disabilities and HRQoL.

    The disability ‘paradox’ has more than once been described as good well-being ‘against all odds’, implying that physical disabilities are the main driver of well-being.11 However, we found that personal, injury-related and environment factors explain a proportion of HRQoL outcomes beyond functional outcome. Nevertheless, only up to 29% of the variance in QOLIBRI-OS and 21% of the variance in MCS was explained by GOSE, personal and injury-related characteristics and satisfaction with social support. Furthermore, personal, injury-related and environment factors did not explain the discrepancies between the GOSE and HRQoL in patients following mild TBI. Injury-related factors included MEI, which is known to have a dominant effect on outcome after mild TBI.31 As the majority of variance remained unexplained, future research should consider the effect of coping, resilience, adaptation and cognitive impairments on HRQoL following TBI. To further explain HRQoL in patients following TBI, it is crucial to involve patients and their relatives. The focus on mixed methods research, combining quantitative and qualitative methods, might help to elucidate patients’ perceptions of satisfactory quality of life following TBI.

    Strengths

    The strengths of this study include the use of data from a large international, multicentre observational study. Consequently, we made use of a standardised collection of data and a well described and contemporary cohort of patients. Furthermore, the CENTER-TBI study enrolled patients following mild, moderate and severe TBI, which enabled us to compare HRQoL outcomes by injury severity. Moreover, to describe HRQoL following TBI, we used generic (SF-12v2) and disease-specific (QOLIBRI-OS) instruments. The combination of generic and disease-specific instruments has been recommended to more fully capture patients’ HRQoL following TBI.7 Furthermore, we demonstrated the dissociation between physical and mental HRQoL using two scales from the same instrument, arguing against the idea that the discordance results from compromised self-awareness following TBI.12 13

    Limitations

    Several limitations of our study have to be considered. Patients with lower functional outcome on the GOSE and lower HRQoL were less likely to complete the questionnaires, potentially resulting in a response bias. Furthermore, the SF-12v2 is not suitable for patients with major cognitive impairment or language difficulties. Thus, the most severely disabled patients, who are likely to be among the most distressed, are not represented in the data. Taken together, the results of our study can only be generalised to patients who are able to respond to follow-up questionnaires, implying that our findings will not apply to a subgroup of patients with profound disability, severe neurological problems, or language difficulties.

    Conclusion

    Our study confirms that patients’ perceptions of HRQoL are often discordant with level of disability following TBI. Contrary to the idea that discrepancies are unusual, many patients with poor functional outcomes report satisfactory well-being, particularly in patients after mild injury. These results indicate that the effects of ‘mild’ TBI can be extensive and warrant further investigation. Furthermore, the findings challenge the idea that good quality of life in patients with disability should be described as ‘paradoxical’ and question common views of what constitutes ‘unfavourable’ outcome.

    Data availability statement

    Data are available on reasonable request. Individual participant data will be available immediately following publication, conditional to approved study proposal, with no end date. Data will be available to researchers who provide a methodologically sound study proposal that is approved by the management committee to achieve the aims in the approved proposal. Proposals can be submitted online at https://www.center-tbi.eu/data. A data access agreement is required and all access must comply with regulatory restrictions imposed on the original study.

    Ethics statements

    Patient consent for publication

    Ethics approval

    The CENTER-TBI study (EC grant 602150) has been conducted in accordance with all relevant laws of the EU if directly applicable or of direct effect and all relevant laws of the country where the Recruiting sites were located, including but not limited to, the relevant privacy and data protection laws and regulations (the 'Privacy Law'), the relevant laws and regulations on the use of human materials, and all relevant guidance relating to clinical studies from time to time in force including, but not limited to, the ICH Harmonised Tripartite Guideline for Good Clinical Practice (CPMP/ICH/135/95) (“ICH GCP”) and the World Medical Association Declaration of Helsinki entitled 'Ethical Principles for Medical Research Involving Human Subjects'. Informed Consent by the patients and/or the legal representative/next of kin was obtained, accordingly to the local legislations, for all patients recruited in the Core Dataset of CENTER-TBI and documented in the e-CRF. Ethical approval was obtained for each recruiting site. The list of sites, Ethical Committees, approval numbers and approval dates can be found on the website: https://www.center-tbi.eu/project/ethical-approval. Name of the Ethics Committees and Number of approval: Ethikkommission der Medizinischen Universität Wien (1646/2014); Ethikkommission der Medizinischen Universität Innsbruck (AN2014-0336 343/4.22); Centraal Ethisch Comité—Ethisch Comité Universitair Ziekenhuis Antwerpen en de Universiteit Antwerpen (B300201422714); Centraal Ethisch Comité—Ethisch Comité Universitair Ziekenhuis Antwerpen en de Universiteit Antwerpen (B300201422714 17-NOV-2014); Comité d’Ethique (412 1427); Centraal Ethisch Comité—Ethisch Comité Universitair Ziekenhuis Antwerpen en de Universiteit Antwerpen (B300201422714); Comité d’Ethique hospitalo-facultaire niversitaire de Liège (707) (B707201422102/2014-244); Centraal Ethisch Comité—Ethisch Comité Universitair Ziekenhuis Antwerpen en de Universiteit Antwerpen (B300201422714); Comissie Medische Ethiek UZ KU Leuven/Onderzoek (B322201523981/S57019 (ML11365)); De Videnskabsetiske Komitéer for Region Syddanmark (S-20140215); De Videnskabsetiske Komitéer for Region Syddanmark (S-20140215); Varsinais suomen sairaanhoitopiirin kuntayhtyma—Eettinen Toimikunta (95/1801/2014); Varsinais suomen sairaanhoitopiirin kuntayhtyma—Eettinen Toimikunta (95/1801/2014); Agence Nationale de Sécurité du Médicament et des Produits de Santé ANSM (141421B-31); Agence Nationale de Sécurité du Médicament et des Produits de Santé ANSM (141421B-31); Agence Nationale de Sécurité du Médicament et des Produits de Santé ANSM (141421B-31); Agence Nationale de Sécurité du Médicament et des Produits de Santé ANSM (141421B-31); Agence Nationale de Sécurité du Médicament et des Produits de Santé ANSM (141421B-31); Agence Nationale de Sécurité du Médicament et des Produits de Santé ANSM (141421B-3); Ethikkommission Medizinsche Fakultät Heidelberg (S-435/2014); Ethikkommission an der Medizinsche FakultätDer rheinsch-Westfälischen Technischen Hocgschule Aachen (1098/15); Ethikkommission an der Medizinsche Fakultät Der rheinsch-Westfälischen Technischen Hocgschule Aachen (EK 174/15); Ethikkommission Medizinsche Fakultät Heidelberg (S-435/2014); ETT TUKEB Egészségügyi Tudományos Tanács (42558-3/2014/EKU); Pécsi Tudományegyetem (5421); ETT TUKEB Egészségügyi Tudományos Tanács (42558-3/2014/EKU); Szegedi Tudományegyetem (3803); Helsinki Committee, Rambam Health Care Campus (RMB 373-14); Hadassah Medical Organization IRB (0590-16 HMO); Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico - Direzione Scientifica Comitato Etico (542/2014); Comitato Etico—Ospedale San Raffaele (217/2014); Comitato Etico Interaziendale A.O.U. Città della Salute e della Scienza di Torino—A.O. Ordine Mauriziano—A.S.L. (0015269); Comitato Etico IRST IRCCS AVR (1675/2015 I.5/207); Comitato Etico—Ospedale San Raffaele (217/2014); Comitato Etico Della Provincia Monza Brianza (1978/2014); Comitato Etico Interaziendale A.O.U. ‘Maggiore della Carità’ (CE 46/15); Comitato Etico—Ospedale Niguarda Ca’ Granda (636-122015); Ethics Committee for Clinical Research at Pauls Stradins Clinical University Hospital Development Society (171215-1E); Ethics Committee for Clinical Research at Pauls Stradins Clinical University Hospital Development Society (171215-1E); Ethics Committee for Clinical Research at Pauls Stradins Clinical University Hospital Development Society (171215-1E); VILNIAUS REGIONINIS BIOMEDICININIŲ TYRIMŲ ETIKOS KOMITETAS (158200-15-801-323); KAUNO REGIONINIS BIOMEDICININIŲ TYRIMŲ ETIKOS KOMITETAS (BE-2-6); Leids Universitair Centrum—Commissie Medische Ethiek (P14.222/NV/nv); Leids Universitair Centrum—Commissie Medische Ethiek (P14.222/NV/nv); Regional komité for medisinsk og helsefaglig forskningsetikk REK midt-Norge (REK midt) (2014/1454); Comitetului de Etica a Spitalului Clinic Judeteam de Urgenta Timisoara (N/A); Etidkog odbora Klinidkog centra Vojvodine (00-08/332); Comité Etico de Investigacion Clinica del Hospital Universitario 12 de Octubre (14/262); Comité ético de investigación clínica y comisión de proyectos de investigación del hospital universitari Vall d’Hebron (ID-RTF080); Comité Etico de Investigacion Clinica de Euskadi (PI2014158); Comité Etico de Investigacion Clinica del Clínico Universitario de Valencia (F-CE-GEva-15); EPN (Regionala Etikprövningsnämnden i Stockholm) (2014/1473-31/4); La Commission cantonale (VD) d’éthique de la recherche sur l’être humain (CER-VD) (473/11); NHS HRA (14/SC/1370); UHB Research Governance Office—Queen Elizabeth Hospital (RRK5224); NHS HRA (14/SC/1370); Research and Development Department - Cambridge University Hospital NHS Foundation Trust (AO9318); NHS HRA (14/SC/1370); Research Governance Office—University Hospitals Southampton NHS Trust (RHM CRI0294); Research and Development Department—Sheffield Teaching Hospitals NHS Foundation Trust (STH18187); Research and Development Department—Salford Royal Hospital NHS Foundation Trust (2015/025ET); Research NHS Scotland (14/SS/1086); Research and Development Department—University Hospitals Division NHS Lothian (2015/0171). Participants gave informed consent to participate in the study before taking part.

    Acknowledgments

    We are grateful to all patients and investigators who participated in the CENTER-TBI study.

    References

    Supplementary materials

    • Supplementary Data

      This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

    Footnotes

    • Collaborators The CENTER-TBI participants and investigators: Cecilia Åkerlund (Department of Physiology and Pharmacology, Section of Perioperative Medicine and Intensive Care, Karolinska Institutet, Stockholm, Sweden), Krisztina Amrein (János Szentágothai Research Centre, University of Pécs, Pécs, Hungary), Nada Andelic (Division of Surgery and Clinical Neuroscience, Department of Physical Medicine and Rehabilitation, Oslo University Hospital and University of Oslo, Oslo, Norway), Lasse Andreassen (Department of Neurosurgery, University Hospital Northern Norway, Tromso, Norway), Audny Anke (Department of Physical Medicine and Rehabilitation, University Hospital Northern Norway, Tromso, Norway), Anna Antoni (Trauma Surgery, Medical University Vienna, Vienna, Austria), Gérard Audibert (Department of Anesthesiology & Intensive Care, University Hospital Nancy, Nancy, France), Philippe Azouvi (Raymond Poincare hospital, Assistance Publique—Hopitaux de Paris, Paris, France), Maria Luisa Azzolini (Department of Anesthesiology & Intensive Care, S Raffaele University Hospital, Milan, Italy), Ronald Bartels (Department of Neurosurgery, Radboud University Medical Center, Nijmegen, The Netherlands), Pál Barzó (Department of Neurosurgery, University of Szeged, Szeged, Hungary), Romuald Beauvais (International Projects Management, ARTTIC, Munchen, Germany), Ronny Beer (Department of Neurology, Neurological Intensive Care Unit, Medical University of Innsbruck, Innsbruck, Austria), Bo-Michael Bellander (Department of Neurosurgery & Anesthesia & Intensive Care Medicine, Karolinska University Hospital, Stockholm, Sweden), Antonio Belli (NIHR Surgical Reconstruction and Microbiology Research Centre, Birmingham, UK), Habib Benali (Anesthesie-Réanimation, Assistance Publique—Hopitaux de Paris, Paris, France), Maurizio Berardino (Department of Anesthesia & ICU, AOU Città della Salute e della Scienza di Torino—Orthopedic and Trauma Center, Torino, Italy), Luigi Beretta (Department of Anesthesiology & Intensive Care, S Raffaele University Hospital, Milan, Italy), Morten Blaabjerg (Department of Neurology, Odense University Hospital, Odense, Denmark), Peter Bragge (BehaviourWorks Australia, Monash Sustainability Institute, Monash University, Victoria, Australia), Alexandra Brazinova (Department of Public Health, Faculty of Health Sciences and Social Work, Trnava University, Trnava, Slovakia), Vibeke Brinck (Quesgen Systems Inc., Burlingame, California, USA), Joanne Brooker (Australian & New Zealand Intensive Care Research Centre, Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia), Camilla Brorsson (Department of Surgery and Perioperative Science, Umeå University, Umeå, Sweden), Andras Buki (Department of Neurosurgery, Medical School, University of Pécs, Hungary and Neurotrauma Research Group, János Szentágothai Research Centre, University of Pécs, Hungary), Monika Bullinger (Department of Medical Psychology, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany), Manuel Cabeleira (Brain Physics Lab, Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK), Alessio Caccioppola (Neuro ICU, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy), Emiliana Calappi (Neuro ICU, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy), Maria Rosa Calvi (Department of Anesthesiology & Intensive Care, S Raffaele University Hospital, Milan, Italy), Peter Cameron (ANZIC Research Centre, Monash University, Department of Epidemiology and Preventive Medicine, Melbourne, Victoria, Australia), Guillermo Carbayo Lozano (Department of Neurosurgery, Hospital of Cruces, Bilbao, Spain), Marco Carbonara (Neuro ICU, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy), Simona Cavallo (Department of Anesthesia & ICU, AOU Città della Salute e della Scienza di Torino—Orthopedic and Trauma Center, Torino, Italy), Giorgio Chevallard (NeuroIntensive Care, Niguarda Hospital, Milan, Italy), Arturo Chieregato (NeuroIntensive Care, Niguarda Hospital, Milan, Italy), Giuseppe Citerio (School of Medicine and Surgery, Università Milano Bicocca, Milano, Italy; NeuroIntensive Care, ASST di Monza, Monza, Italy), Hans Clusmann (Department of Neurosurgery, Medical Faculty RWTH Aachen University, Aachen, Germany), Mark Coburn (Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn, Bonn, Germany), Jonathan Coles (Department of Anesthesia & Neurointensive Care, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK), Jamie D Cooper (School of Public Health & PM, Monash University and The Alfred Hospital, Melbourne, Victoria, Australia), Marta Correia (Radiology/MRI Department, MRC Cognition and Brain Sciences Unit, Cambridge, UK), Amra Čović (Institute of Medical Psychology and Medical Sociology, Universitätsmedizin Göttingen, Göttingen, Germany), Nicola Curry (Oxford University Hospitals NHS Trust, Oxford, UK), Endre Czeiter (Department of Neurosurgery, Medical School, University of Pécs, Hungary and Neurotrauma Research Group, János Szentágothai Research Centre, University of Pécs, Hungary), Marek Czosnyka (Brain Physics Lab, Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK), Claire Dahyot‑Fizelier (Intensive Care Unit, CHU Poitiers, Potiers, France), Paul Dark (University of Manchester NIHR Biomedical Research Centre, Critical Care Directorate, Salford Royal Hospital NHS Foundation Trust, Salford, UK), Helen Dawes (Movement Science Group, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, UK), Véronique De Keyser (Department of Neurosurgery, Antwerp University Hospital and University of Antwerp, Edegem, Belgium), Vincent Degos (Anesthesie-Réanimation, Assistance Publique – Hopitaux de Paris, Paris, France), Francesco Della Corte (Department of Anesthesia & Intensive Care, Maggiore Della Carità Hospital, Novara, Italy), Hugo den Boogert (Department of Neurosurgery, Radboud University Medical Center, Nijmegen, The Netherlands), Bart Depreitere (Department of Neurosurgery, University Hospitals Leuven, Leuven, Belgium), Đula Đilvesi (Department of Neurosurgery, Clinical centre of Vojvodina, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia), Abhishek Dixit (Division of Anaesthesia, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK), Emma Donoghue (Australian & New Zealand Intensive Care Research Centre, Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia), Jens Dreier (Center for Stroke Research Berlin, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany), Guy‑Loup Dulière (Intensive Care Unit, CHR Citadelle, Liège, Belgium), Ari Ercole (Division of Anaesthesia, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK), Patrick Esser (Movement Science Group, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, UK), Erzsébet Ezer (Department of Anaesthesiology and Intensive Therapy, University of Pécs, Pécs, Hungary), Martin Fabricius (Departments of Neurology, Clinical Neurophysiology and Neuroanesthesiology, Region Hovedstaden Rigshospitalet, Copenhagen, Denmark), Valery L Feigin (National Institute for Stroke and Applied Neurosciences, Faculty of Health and Environmental Studies, Auckland University of Technology, Auckland, New Zealand), Kelly Foks (Department of Neurology, Erasmus MC, Rotterdam, the Netherlands), Shirin Frisvold (Department of Anesthesiology and Intensive care, University Hospital Northern Norway, Tromso, Norway), Alex Furmanov (Department of Neurosurgery, Hadassah-Hebrew University Medical Center, Jerusalem, Israel), Pablo Gagliardo (Fundación Instituto Valenciano de Neurorrehabilitación (FIVAN), Valencia, Spain), Damien Galanaud (Anesthesie-Réanimation, Assistance Publique—Hopitaux de Paris, Paris, France), Dashiell Gantner (ANZIC Research Centre, Monash University, Department of Epidemiology and Preventive Medicine, Melbourne, Victoria, Australia), Guoyi Gao (Department of Neurosurgery, Shanghai Renji hospital, Shanghai Jiaotong University/School of Medicine, Shanghai, China), Pradeep George (Karolinska Institutet, INCF International Neuroinformatics Coordinating Facility, Stockholm, Sweden), Alexandre Ghuysen (Emergency Department, CHU, Liège, Belgium), Lelde Giga (Neurosurgery Clinic, Pauls Stradins Clinical University Hospital, Riga, Latvia), Ben Glocker (Department of Computing, Imperial College London, London, UK), Jagoš Golubovic (Department of Neurosurgery, Clinical Centre of Vojvodina, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia), Pedro A Gomez (Department of Neurosurgery, Hospital Universitario 12 de Octubre, Madrid, Spain), Johannes Gratz (Department of Anesthesia, Critical Care and Pain Medicine, Medical University of Vienna, Austria), Benjamin Gravesteijn (Department of Public Health, Erasmus Medical Center-University Medical Center, Rotterdam, The Netherlands), Francesca Grossi (Department of Anesthesia & Intensive Care, Maggiore Della Carità Hospital, Novara, Italy), Russell L Gruen (College of Health and Medicine, Australian National University, Canberra, Australia), Deepak Gupta (Department of Neurosurgery, Neurosciences Centre & JPN Apex trauma centre, All India Institute of Medical Sciences, New Delhi-110029, India), Juanita A Haagsma (Department of Public Health, Erasmus Medical Center-University Medical Center, Rotterdam, The Netherlands), Iain Haitsma (Department of Neurosurgery, Erasmus MC, Rotterdam, the Netherlands), Raimund Helbok (Department of Neurology, Neurological Intensive Care Unit, Medical University of Innsbruck, Innsbruck, Austria), Eirik Helseth (Department of Neurosurgery, Oslo University Hospital, Oslo, Norway), Lindsay Horton (Division of Psychology, University of Stirling, Stirling, UK), Jilske Huijben (Department of Public Health, Erasmus Medical Center-University Medical Center, Rotterdam, The Netherlands), Peter J Hutchinson (Division of Neurosurgery, Department of Clinical Neurosciences, Addenbrooke’s Hospital & University of Cambridge, Cambridge, UK), Bram Jacobs (Department of Neurology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands), Stefan Jankowski (Neurointensive Care, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK), Mike Jarrett (Quesgen Systems Inc., Burlingame, California, USA), Ji‑yao Jiang (Karolinska Institutet, INCF International Neuroinformatics Coordinating Facility, Stockholm, Sweden), Faye Johnson (Salford Royal Hospital NHS Foundation Trust Acute Research Delivery Team, Salford, UK), Kelly Jones (National Institute for Stroke and Applied Neurosciences, Faculty of Health and Environmental Studies, Auckland University of Technology, Auckland, New Zealand), Mladen Karan (Department of Neurosurgery, Clinical centre of Vojvodina, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia), Angelos G Kolias (Division of Neurosurgery, Department of Clinical Neurosciences, Addenbrooke’s Hospital & University of Cambridge, Cambridge, UK), Erwin Kompanje (Department of Intensive Care and Department of Ethics and Philosophy of Medicine, Erasmus Medical Center, Rotterdam, The Netherlands), Daniel Kondziella (Departments of Neurology, Clinical Neurophysiology and Neuroanesthesiology, Region Hovedstaden Rigshospitalet, Copenhagen, Denmark), Evgenios Kornaropoulos (Division of Anaesthesia, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK), Lars‑Owe Koskinen (Department of Clinical Neuroscience, Neurosurgery, Umeå University, Umeå, Sweden), Noémi Kovács (Hungarian Brain Research Program—Grant No. KTIA_13_NAP-A-II/8, University of Pécs, Pécs, Hungary), Ana Kowark (Department of Anaesthesiology, University Hospital of Aachen, Aachen, Germany), Alfonso Lagares (Department of Neurosurgery, Hospital Universitario 12 de Octubre, Madrid, Spain), Linda Lanyon (Karolinska Institutet, INCF International Neuroinformatics Coordinating Facility, Stockholm, Sweden), Steven Laureys (Cyclotron Research Center, University of Liège, Liège, Belgium), Fiona Lecky(Centre for Urgent and Emergency Care Research (CURE), Health Services Research Section, School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK; Emergency Department, Salford Royal Hospital, Salford UK), Didier Ledoux (Cyclotron Research Center, University of Liège, Liège, Belgium), Rolf Lefering (Institute of Research in Operative Medicine (IFOM), Witten/Herdecke University, Cologne, Germany), Valerie Legrand (VP Global Project Management CNS, ICON, Paris, France), Aurelie Lejeune (Department of Anesthesiology-Intensive Care, Lille University Hospital, Lille, France), Leon Levi (Department of Neurosurgery, Rambam Medical Center, Haifa, Israel), Roger Lightfoot (Department of Anesthesiology & Intensive Care, University Hospitals Southampton NHS Trust, Southampton, UK), Hester Lingsma (Department of Public Health, Erasmus Medical Center-University Medical Center, Rotterdam, The Netherlands), Andrew I R Maas (Department of Neurosurgery, Antwerp University Hospital and University of Antwerp, Edegem, Belgium), Ana M Castaño‑León (Department of Neurosurgery, Hospital Universitario 12 de Octubre, Madrid, Spain), Marc Maegele (Cologne-Merheim Medical Center (CMMC), Department of Traumatology, Orthopedic Surgery and Sportmedicine, Witten/Herdecke University, Cologne, Germany), Marek Majdan (Department of Public Health, Faculty of Health Sciences and Social Work, Trnava University, Trnava, Slovakia), Alex Manara (Intensive Care Unit, Southmead Hospital, Bristol, Bristol, UK), Geoffrey Manley (Department of Neurological Surgery, University of California, San Francisco, California, USA), Costanza Martino (Department of Anesthesia & Intensive Care, M. Bufalini Hospital, Cesena, Italy), Hugues Maréchal (Intensive Care Unit, CHR Citadelle, Liège, Belgium), Julia Mattern (Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany), Catherine McMahon (Department of Neurosurgery, The Walton centre NHS Foundation Trust, Liverpool, UK), Béla Melegh (Department of Medical Genetics, University of Pécs, Pécs, Hungary), David Menon (Division of Anaesthesia, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK), Tomas Menovsky (Department of Neurosurgery, Antwerp University Hospital and University of Antwerp, Edegem, Belgium), Ana Mikolic (Department of Public Health, Erasmus Medical Center-University Medical Center, Rotterdam, The Netherlands), Benoit Misset (Cyclotron Research Center, University of Liège, Liège, Belgium), Visakh Muraleedharan (Karolinska Institutet, INCF International Neuroinformatics Coordinating Facility, Stockholm, Sweden), Lynnette Murray (ANZIC Research Centre, Monash University, Department of Epidemiology and Preventive Medicine, Melbourne, Victoria, Australia), Ancuta Negru (Department of Neurosurgery, Emergency County Hospital Timisoara, Timisoara, Romania), David Nelson (Department of Physiology and Pharmacology, Section of Perioperative Medicine and Intensive Care, Karolinska Institutet, Stockholm, Sweden), Virginia Newcombe (Division of Anaesthesia, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK), Daan Nieboer (Department of Public Health, Erasmus Medical Center-University Medical Center, Rotterdam, The Netherlands), József Nyirádi (János Szentágothai Research Centre, University of Pécs, Pécs, Hungary), Otesile Olubukola (Centre for Urgent and Emergency Care Research (CURE), Health Services Research Section, School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK), Matej Oresic (School of Medical Sciences, Örebro University, Örebro, Sweden), Fabrizio Ortolano (Neuro ICU, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy), Aarno Palotie (Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Analytic and Translational Genetics Unit, Department of Medicine; Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics; The Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA), Paul M Parizel (Department of Radiology, University of Antwerp, Edegem, Belgium), Jean‑François Payen (Department of Anesthesiology & Intensive Care, University Hospital of Grenoble, Grenoble, France), Natascha Perera (International Projects Management, ARTTIC, Munchen, Germany), Vincent Perlbarg (Anesthesie-Réanimation, Assistance Publique—Hopitaux de Paris, Paris, France), Paolo Persona (Department of Anesthesia & Intensive Care, Azienda Ospedaliera Università di Padova, Padova, Italy), Wilco Peul (Department of Neurosurgery, Leiden University Medical Center, Leiden, The Netherlands and Department of Neurosurgery, Medical Center Haaglanden, The Hague, The Netherlands), Anna Piippo-Karjalainen (Department of Neurosurgery, Helsinki University Central Hospital), Matti Pirinen (Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland), Horia Ples (Department of Neurosurgery, Emergency County Hospital Timisoara, Timisoara, Romania), Suzanne Polinder (Department of Public Health, Erasmus Medical Center-University Medical Center, Rotterdam, The Netherlands), Inigo Pomposo (Department of Neurosurgery, Hospital of Cruces, Bilbao, Spain), Jussi P Posti (Division of Clinical Neurosciences, Department of Neurosurgery and Turku Brain Injury Centre, Turku University Hospital and University of Turku, Turku, Finland), Louis Puybasset (Department of Anesthesiology and Critical Care, Pitié -Salpêtrière Teaching Hospital, Assistance Publique, Hôpitaux de Paris and University Pierre et Marie Curie, Paris, France), Andreea Radoi (Neurotraumatology and Neurosurgery Research Unit (UNINN), Vall d'Hebron Research Institute, Barcelona, Spain), Arminas Ragauskas (Department of Neurosurgery, Kaunas University of technology and Vilnius University, Vilnius, Lithuania), Rahul Raj (Department of Neurosurgery, Helsinki University Central Hospital), Malinka Rambadagalla (Department of Neurosurgery, Rezekne Hospital, Latvia), Jonathan Rhodes (Department of Anaesthesia, Critical Care & Pain Medicine NHS Lothian & University of Edinburg, Edinburgh, UK), Sylvia Richardson (Director, MRC Biostatistics Unit, Cambridge Institute of Public Health, Cambridge, UK), Sophie Richter (Division of Anaesthesia, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK), Samuli Ripatti (Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland), Saulius Rocka (Department of Neurosurgery, Kaunas University of Technology and Vilnius University, Vilnius, Lithuania), Cecilie Roe (Department of Physical Medicine and Rehabilitation, Oslo University Hospital/University of Oslo, Oslo, Norway), Olav Roise (Division of Orthopedics, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway), Jonathan Rosand (Broad Institute, Cambridge MA Harvard Medical School, Boston, MA, Massachusetts General Hospital, Boston, MA, USA), Jeffrey V Rosenfeld (National Trauma Research Institute, The Alfred Hospital, Monash University, Melbourne, Victoria, Australia), Christina Rosenlund (Department of Neurosurgery, Odense University Hospital, Odense, Denmark), Guy Rosenthal (Department of Neurosurgery, Hadassah-hebrew University Medical Center, Jerusalem, Israel), Rolf Rossaint (Department of Anaesthesiology, University Hospital of Aachen, Aachen, Germany), Sandra Rossi (Department of Anesthesia & Intensive Care, Azienda Ospedaliera Università di Padova, Padova, Italy), Daniel Rueckert (Department of Computing, Imperial College London, London, UK) Martin Rusnák (International Neurotrauma Research Organisation, Vienna, Austria), Juan Sahuquillo (Neurotraumatology and Neurosurgery Research Unit (UNINN), Vall d'Hebron Research Institute, Barcelona, Spain), Oliver Sakowitz (Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany; Klinik für Neurochirurgie, Klinikum Ludwigsburg, Ludwigsburg, Germany), Renan Sanchez‑Porras (Klinik für Neurochirurgie, Klinikum Ludwigsburg, Ludwigsburg, Germany), Janos Sandor (Division of Biostatistics and Epidemiology, Department of Preventive Medicine, University of Debrecen, Debrecen, Hungary), Nadine Schäfer (Institute of Research in Operative Medicine (IFOM), Witten/Herdecke University, Cologne, Germany), Silke Schmidt (Department Health and Prevention, University Greifswald, Greifswald, Germany), Herbert Schoechl (Department of Anaesthesiology and Intensive Care, AUVA Trauma Hospital, Salzburg, Austria), Guus Schoonman (Department of Neurology, Elisabeth-TweeSteden Ziekenhuis, Tilburg, the Netherlands), Rico Frederik Schou (Department of Neuroanesthesia and Neurointensive Care, Odense University Hospital, Odense, Denmark), Elisabeth Schwendenwein (Trauma Surgery, Medical University Vienna, Vienna, Austria), Charlie Sewalt (Department of Public Health, Erasmus Medical Center-University Medical Center, Rotterdam, The Netherlands), Toril Skandsen (Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, NTNU, Trondheim, Norway; Department of Physical Medicine and Rehabilitation, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway), Peter Smielewski (Brain Physics Lab, Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK), Abayomi Sorinola (Department of Neurosurgery, University of Pécs, Pécs, Hungary), Emmanuel Stamatakis (Division of Anaesthesia, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK), Simon Stanworth (Oxford University Hospitals NHS Trust, Oxford, UK), Robert Stevens (Division of Neuroscience Critical Care, John Hopkins University School of Medicine, Baltimore, USA), William Stewart (Department of Neuropathology, Queen Elizabeth University Hospital and University of Glasgow, Glasgow, UK), Ewout W Steyerberg (Department of Public Health, Erasmus Medical Center-University Medical Center, Rotterdam, The Netherlands; Department of Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands), Nino Stocchetti (Department of Pathophysiology and Transplantation, Milan University, and Neuroscience ICU, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Italy), Nina Sundström (Department of Radiation Sciences, Biomedical Engineering, Umeå University, Umeå, Sweden), Riikka Takala (Perioperative Services, Intensive Care Medicine and Pain Management, Turku University Hospital and University of Turku, Turku, Finland), Viktória Tamás (Department of Neurosurgery, University of Pécs, Pécs, Hungary), Tomas Tamosuitis (Department of Neurosurgery, Kaunas University of Health Sciences, Kaunas, Lithuania), Mark Steven Taylor (Department of Public Health, Faculty of Health Sciences and Social Work, Trnava University, Trnava, Slovakia), Braden Te Ao (National Institute for Stroke and Applied Neurosciences, Faculty of Health and Environmental Studies, Auckland University of Technology, Auckland, New Zealand), Olli Tenovuo (Division of Clinical Neurosciences, Department of Neurosurgery and Turku Brain Injury Centre, Turku University Hospital and University of Turku, Turku, Finland), Alice Theadom (National Institute for Stroke and Applied Neurosciences, Faculty of Health and Environmental Studies, Auckland University of Technology, Auckland, New Zealand), Matt Thomas (Intensive Care Unit, Southmead Hospital, Bristol, Bristol, UK), Dick Tibboel (Intensive Care and Department of Pediatric Surgery, Erasmus Medical Center, Sophia Children’s Hospital, Rotterdam, The Netherlands), Marjolein Timmers (Department of Intensive Care and Department of Ethics and Philosophy of Medicine, Erasmus Medical Center, Rotterdam, The Netherlands), Christos Tolias (Department of Neurosurgery, Kings college London, London, UK), Tony Trapani (ANZIC Research Centre, Monash University, Department of Epidemiology and Preventive Medicine, Melbourne, Victoria, Australia), Cristina Maria Tudora (Department of Neurosurgery, Emergency County Hospital Timisoara, Timisoara, Romania), Andreas Unterberg (Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany), Peter Vajkoczy (Neurologie, Neurochirurgie und Psychiatrie, Charité—Universitätsmedizin Berlin, Berlin, Germany), Shirley Vallance (ANZIC Research Centre, Monash University, Department of Epidemiology and Preventive Medicine, Melbourne, Victoria, Australia), Egils Valeinis (Neurosurgery clinic, Pauls Stradins Clinical University Hospital, Riga, Latvia), Zoltán Vámos (Department of Anaesthesiology and Intensive Therapy, University of Pécs, Pécs, Hungary), Mathieu van der Jagt (Department of Intensive Care Adults, Erasmus MC– University Medical Center Rotterdam, Rotterdam, the Netherlands), Gregory Van der Steen (Department of Neurosurgery, Antwerp University Hospital and University of Antwerp, Edegem, Belgium), Joukje van der Naalt (Department of Neurology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands), Jeroen T J M van Dijck (Department of Neurosurgery, Leiden University Medical Center, Leiden, The Netherlands and Department of Neurosurgery, Medical Center Haaglanden, The Hague, The Netherlands), Thomas A van Essen (Department of Neurosurgery, Leiden University Medical Center, Leiden, The Netherlands and Department of Neurosurgery, Medical Center Haaglanden, The Hague, The Netherlands), Wim Van Hecke (icoMetrix NV, Leuven, Belgium), Caroline van Heugten (Movement Science Group, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, UK), Dominique Van Praag (Psychology Department, Antwerp University Hospital, Edegem, Belgium), Thijs Vande Vyvere (icoMetrix NV, Leuven, Belgium), Roel P J van Wijk (Department of Neurosurgery, Leiden University Medical Center, Leiden, The Netherlands and Department of Neurosurgery, Medical Center Haaglanden, The Hague, The Netherlands), Alessia Vargiolu (NeuroIntensive Care, ASST di Monza, Monza, Italy), Emmanuel Vega (Department of Anesthesiology-Intensive Care, Lille University Hospital, Lille, France), Kimberley Velt (Department of Public Health, Erasmus Medical Center-University Medical Center, Rotterdam, The Netherlands), Jan Verheyden (icoMetrix NV, Leuven, Belgium), Paul M Vespa (Director of Neurocritical Care, University of California, Los Angeles, USA), Anne Vik (Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, NTNU, Trondheim, Norway; Department of Neurosurgery, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway), Rimantas Vilcinis (Department of Neurosurgery, Kaunas University of Health Sciences, Kaunas, Lithuania), Victor Volovici (Department of Neurosurgery, Erasmus MC, Rotterdam, the Netherlands), Nicole von Steinbüchel (Institute of Medical Psychology and Medical Sociology, Universitätsmedizin Göttingen, Göttingen, Germany), Daphne Voormolen (Department of Public Health, Erasmus Medical Center-University Medical Center, Rotterdam, The Netherlands), Petar Vulekovic (Department of Neurosurgery, Clinical centre of Vojvodina, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia), Kevin K W Wang (Department of Emergency Medicine, University of Florida, Gainesville, Florida, USA), Eveline Wiegers (Department of Public Health, Erasmus Medical Center-University Medical Center, Rotterdam, The Netherlands), Guy Williams (Division of Anaesthesia, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK), Lindsay Wilson (Division of Psychology, University of Stirling, Stirling, UK), Stefan Winzeck (Division of Anaesthesia, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK), Stefan Wolf (Department of Neurosurgery, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany), Zhihui Yang (Broad Institute, Cambridge MA Harvard Medical School, Boston MA, Massachusetts General Hospital, Boston MA, USA), Peter Ylén (VTT Technical Research Centre, Tampere, Finland), Alexander Younsi (Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany), Frederick A Zeiler (Division of Anaesthesia, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK; Section of Neurosurgery, Department of Surgery, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada), Veronika Zelinkova (Department of Public Health, Faculty of Health Sciences and Social Work, Trnava University, Trnava, Slovakia), Agate Ziverte (Neurosurgery clinic, Pauls Stradins Clinical University Hospital, Riga, Latvia), Tommaso Zoerle (Neuro ICU, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy).

    • Contributors IRARH and LW conceived the original idea for the manuscript. LW supervised the project. DvK advised on statistical analysis. IRARH took the lead in writing the manuscript with major contributions from LW. All authors contributed to interpretation of the data, provided feedback on earlier drafts and approved the final manuscript. IRARH was responsible for the overall content of the manuscript. IRARH and LW had final responsibility for the decision to publish.

    • Funding The research leading to these results was supported by the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 602 150 (CENTER-TBI). Additional funding was obtained from the Hannelore Kohl Stiftung (Germany), from OneMind (USA) and from Integra LifeSciences Corporation (USA).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.