Health status and psychological outcomes after trauma: A prospective multicenter cohort study.

Introduction Survival after trauma has considerably improved. This warrants research on non-fatal outcome. We aimed to identify characteristics associated with both short and long-term health status (HS) after trauma and to describe the recovery patterns of HS and psychological outcomes during 24 months of follow-up. Methods Hospitalized patients with all types of injuries were included. Data were collected at 1 week 1, 3, 6, 12, and 24 months post-trauma. HS was assessed with the EuroQol-5D-3L (EQ-5D-3L) and the Health Utilities Index Mark 2 and 3 (HUI2/3). For the screening of symptoms of post-traumatic stress, anxiety and depression, the Impact of Event Scale (IES) and the Hospital Anxiety and Depression Scale (HADS) subscale anxiety (HADSA) and subscale depression (HADSD) were used. Recovery patterns of HS and psychological outcomes were examined with linear mixed model analyses. Results A total of 4,883 patients participated (median age 68 (Interquartile range 53–80); 50% response rate). The mean (Standard Deviation (SD)) pre-injury EQ-5D-3L score was 0.85 (0.23). One week post-trauma, mean (SD) EQ-5D-3L, HUI2 and HUI3 scores were 0.49 (0.32), 0.61 (0.22) and 0.38 (0.31), respectively. These scores significantly improved to 0.77 (0.26), 0.77 (0.21) and 0.62 (0.35), respectively, at 24 months. Most recovery occurred up until 3 months. At long-term follow-up, patients of higher age, with comorbidities, longer hospital stay, lower extremity fracture and spine injury showed lower HS. The mean (SD) scores of the IES, HADSA and HADSD were respectively 14.80 (15.80), 4.92 (3.98) and 5.00 (4.28), respectively, at 1 week post-trauma and slightly improved over 24 months post-trauma to 10.35 (14.72), 4.31 (3.76) and 3.62 (3.87), respectively. Discussion HS and psychological symptoms improved over time and most improvements occurred within 3 months post-trauma. The effects of severity and type of injury faded out over time. Patients frequently reported symptoms of post-traumatic stress. Trial registration ClinicalTrials.gov identifier: NCT02508675.


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The data underlying the results presented in the study are available from (include the name of the third party • Data of the BIOS are unsuitable for public deposition due to the privacy of participant data. Data are anonymized, but due to relatively few severe cases, patients could be identified. Therefore, BIOS data are available for any interested researcher who meets the criteria for access to confidential data. The Brabant Trauma Registry (e-mail: secretariaat@nazb.nl) may be contacted to request data. and contact information or URL). This text is appropriate if the data are owned by a third party and authors do not have permission to share the data. The text of the original manuscript has been modified entirely in line with the valuable comments and recommendations of you and the three reviewers. The changes will be addressed one by one in the addendum. We trust that the changes and improvements made this completely revised manuscript suitable for publication in PlosOne.
On behalf of all authors, I am looking forward to hearing from you.

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The fact that trauma has an impact on diverse aspects of patient health, illustrates that a 68 multidimensional approach is necessary for a comprehensive understanding of non-fatal outcomes 69 after trauma. This also allows studying the mutual relations between non-fatal outcomes. Using a 70 multidimensional approach to measure outcomes including HS and symptoms of depression, anxiety 71 and post-traumatic stress will result in a comprehensive understanding of non-fatal outcomes after 72 trauma. In addition, to assess prognostic factors for a poor outcome it is important to cover the entire 73 spectrum of the trauma population without exclusion of particular patient groups (e.g. elderly

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To increase the response rate, patients who did not complete a questionnaire up until 3 or 6 121 months post-trauma were asked to complete a short version of the BIOS-questionnaire. Patients who 122 completed the shortened questionnaire included those who could not be reached by phone and did 123 not return a BIOS questionnaire. In this short questionnaire, educational level, comorbidities, the EQ-124 5D-3L and the IES were included.This short questionnaire did not include proxy assessments. In the 125 shortened questionnaire, pre-injury HS was not collected.

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If participants did not complete the questionnaire, they were not excluded from the study but 127 they were still invited at the subsequent time points.
tariffs [42]. The EQ-VAS is a vertical visual analogue scale with 0 indicating the worst imaginable 142 health state and 100 indicating the best imaginable health state. The EQ-5D and EQ-VAS were also 143 measured pre-injury, by asking participants 1 week or 1 month and proxy informants 1 month after the 144 trauma for the patients' HS before sustaining the injury. The EQ-VAS was not included in the short 145 questionnaire.

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The HUI is a self-administered HS questionnaire that covers the main health domains that are 147 affected by injury, with a particular focus on functional capacities.

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For both the EQ-5D and the HUI, a scoring algorithm is used in which a score of 1 represents

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The IES was used to assess self-reported symptoms of post-traumatic stress [

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To determine socio-economic status (SES), educational level was used. Educational level was 179 categorized into three levels; low (primary education, preparatory secondary vocational education or

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Four linear mixed models [46] with a random intercepts were performed to assess longitudinal 205 association between prognostic factors and HS over the 24 months after trauma, which were divided 206 into short-term (1 week and 1 month), mid-term (3 and 6 months) and long-term (12 and 24 months) 207 associations. HS was measured with the EQ-5D-3L summary score.

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The results were considered statistically significant at a level of p<0.05. All analyses were  were included (50% response rate). Of these 4,883 participants, 1,099 filled out the shortened 221 questionnaires (see Fig 1).

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At 1 week and 1, 3, 6, 12 and 24 months following the trauma, we collected data from of 223 1,776, 2,971, 3,109, 3,418, 3,105 and 2,734 participants (36.4%, 60.8%, 63.7%, 69.9%, 63.6% and 224 56.0%, respectively, of the study population) (see Fig 1). A total of 1,105 participants (22.6% of the 225 study population) completed all BIOS questionnaires at each time point. In addition, data on pre-injury 226 HS were obtained from 3,366 participants (69% of the study population). After the first week 227 assessment, missing questionnaires were the result of non-response (i.e., patients who had provided 228 no data at any of the previous time points) and loss to follow-up (i.e., patients who had provided data 229 for at least one of the previous time points). The main reason for participants to be lost to follow-up 230 during the study period was that completing the questionnaires was too time consuming. Elderly, 231 participants with low educational levels, longer hospital LOS, moderate injury (ISS 9-15), a hip 232 fracture, severe traumatic brain injury (TBI) and those with severe abdominal trauma showed lower 233 response rates to the 1 week questionnaire but provided data thereafter. In the BIOS, patients aged 234 18-24 and those who recovered completely were most likely to be lost to follow-up.

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Compared to the non-responders, participants were more severely injured and had a higher 244 probability of being admitted to the ICU. In addition, responders had a higher median status score 245 (based on the mean income, % of people with a low income, % of people with low educational level 246 and % of unemployed people in the neighborhood) compared to the general Dutch population (mean 247 0.28) and compared to the median status score of the non-responders (median 0.33, min. score -3.03, 248 max. score 2,58). Patients aged 18-44 and ≥85 years showed relatively low response rates (35%-40% 249 and 39%, respectively). Patients with minor injuries (ISS 1-3) revealed a low response rate (46%), as 250 well as patients with a hospital LOS of ≤2 or ≥15 days (46% and 45%, respectively).     Table 2). With 262 regard to the individual domains of the EQ-5D, trauma patients reported various problems on the 263 'mobility, 'usual activities' and 'pain/discomfort' dimensions during the 24 months of follow-up (see Fig   264   2). In addition, during the 24 months, the prevalence of problems on all dimensions of the EQ-5D 265 decreased, but remained higher at 24 months compared to pre-injury (46% and 32%, respectively for 266 mobility, 23% and 16%, respectively for self-care, 44% and 26%, respectively for usual activities, 52% 267 and 32%, respectively for pain/discomfort and 22% and 16%, respectively for anxiety/depression).         Table 2).

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The results revealed that patients with symptoms of post-traumatic stress (IES≥35) showed 293 worse outcomes on the EQ-5D-3L than patients with no symptoms of post-traumatic stress (Fig. 3). Overall, HS measured as with the EQ-5D-3L increased over at least up until 6 months for all 299 groups of patients and stabilized between 6 and 12 months post-trauma for most groups (see Table   300 3). Female patients had a lower HS compared to males at every time point.

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At all time points, patients aged 85 and older had the lowest HS compared to the other age 302 categories. At 3 and 6 months, all patient groups between 25 and 74 years reported the same HS 303 whereas patients aged between 18 and 24 reported a higher EQ-5D summary score. HS stabilized at 304 6 or 12 months for every age group, except for patients between 25 and 44 years for whom HS 305 increased further.

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Except for 1 week, patients with a high educational level had the highest HS.

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After adjustment for confounding 320 factors, short-term (1 week and 1 month) prognostic factors for a significant lower EQ-5D summary 321 score were female gender, a higher number of comorbidities, a longer LOS, a higher ISS, pelvic injury, 322 tibia/complex foot or femur fracture, radius/ulna/hand fracture, shoulder/upper arm injury, rib fracture, 323 spinal cord injury and stable vertebral fracture/disc injury (see Table 4). Mid-term (3 and 6 months) 324 prognostic factors were a higher number of comorbidities, an ISS between 4 and 15, a longer LOS, 325 radius/ulna/hand fracture, tibia/complex foot or femur fracture, severe TBI, spinal cord injury and 326 stable vertebral fracture/disc injury. Long-term (12 and 24 months) prognostic factors for a lower HS 327 were: age 75 and above, 2 or more comorbidities, a longer LOS, tibia/complex foot or femur fracture, 328 spinal cord injury and stable vertebral fracture/disc injury were prognostic factors. A high educational 329 level was associated with higher HS in the long-term analysis.

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Therefore, it provides a more valid assessment of the magnitude of recovery thereafter.

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In this study, the prevalence of symptoms of anxiety and depression was slightly higher

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Most improvements in HS and psychological symptoms occurred within the first 3 months post-trauma.

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After two years post trauma, the vast majority of trauma patients did not achieve their pre-injury HS.

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Recovery trajectories varied widely in which female gender, age ≥75 years, spinal cord injury, having

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The fact that trauma has an impact on diverse aspects of patient health, illustrates that a

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For both the EQ-5D and the HUI, a scoring algorithm is used in which a score of 1 represents injuries (see S1 Table). Patients who suffer multiple injuries could be classified into one or more injury

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Score options from each dimension of the EQ-5D were dichotomized into 0='no problems' and

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Four linear mixed models [46] with a random intercepts were performed to assess longitudinal 209 association between prognostic factors and HS over the 24 months after trauma, which were divided 210 into short-term (1 week and 1 month), mid-term (3 and 6 months) and long-term (12 and 24 months) 211 associations. HS was measured with the EQ-5D-3L summary score.

212
The results were considered statistically significant at a level of p<0.05. All analyses were were included (50% response rate). Of these 4,883 participants, 1,099 filled out the shortened 225 questionnaires (see Fig 1).
At 1 week and 1, 3, 6, 12 and 24 months following the trauma, we collected data from of 227  1). A total of 1,105 participants (22.6% of the study population) completed all BIOS questionnaires at each time point. In addition, data on pre-injury

Study population 242
The median age of the study population was 68 years (IQR 53-80) ( Table 1)

247
Compared to the non-responders, participants were more severely injured and had a higher    Table 2). With 266 regard to the individual domains of the EQ-5D, trauma patients reported various problems on the 267 'mobility, 'usual activities' and 'pain/discomfort' dimensions during the 24 months of follow-up (see Fig   268   2). In addition, during the 24 months, the prevalence of problems on all dimensions of the EQ-5D 269 decreased, but remained higher at 24 months compared to pre-injury (46% and 32%, respectively for 270 mobility, 23% and 16%, respectively for self-care, 44% and 26%, respectively for usual activities, 52% 271 and 32%, respectively for pain/discomfort and 22% and 16%, respectively for anxiety/depression).      Table 2).

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The results revealed that patients with symptoms of post-traumatic stress (IES≥35) showed 297 worse outcomes on the EQ-5D-3L than patients with no symptoms of post-traumatic stress (Fig. 3).  Table  12 At all time points, patients aged 85 and older had the lowest HS compared to the other age 306 categories. At 3 and 6 months, all patient groups between 25 and 74 years reported the same HS Except for 1 week, at all time points patients with a high educational level had the highest HS.  After adjustment for confounding 13 prognostic factors were a higher number of comorbidities, an ISS between 4 and 15, a longer LOS, stable vertebral fracture/disc injury. Long-term (12 and 24 months) prognostic factors for a lower HS were: an age 75 and above, 2 or more comorbidities, a longer LOS, tibia/complex foot or femur

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In this study, the prevalence of symptoms of anxiety and depression was slightly higher

Response to comments
Additional Editor Comments -The additional explanation of SES needs to describe whether higher or lower scores indicate greater disadvantage to avoid potential mis-interpretation. A: In the 'statistical analyses' paragraph, we described the following sentence: a lower status score indicates a lower SES whereas a higher status score indicates a higher SES. Furthermore, we described in the discussion and conclusion paragraphs that a lower status scores is an indicator of a lower SES-level (lines 425 and 473).
-The axes on Figure 5 are not clear. Which data do the titles on the left and right-hand x axes correspond to? Moreover, are these truly demonstrating "differences" or mean values? Ideally it is a good idea to depict variability (e.g., sd, se or 95%CI around the mean). A: We changed Figure 3 as supposed by the editor. Furthermore, we made the description of the yaxis more clear.
-Supplementary Figure 5 does not appear to have been uploaded. A: In this manuscript, there is no supplementary Figure 5. In the text, we did not refer to Supplementary Figure 5.
-The explanation of how to interpret a beta score is not sufficient. I suggest you follow the recommendation of Reviewer 2 in providing a clearer explanation of the beta value.
A: See the comment of reviewer 2: we have changed the sentence as supposed by the reviewer.
Comments reviewer 1 -There is still some language editing required which can be done at the proofing stage if the manuscript is accepted by the journal. A: We did made several improvements in language editing throughout the manuscript.
-One sentence that is important to address in the abstract is: 'We aimed to describe the recovery patterns of health status (HS) and psychological outcomes during 24 months of follow-up and to identify subgroups at risk of both short and long-term HS after trauma'. The authors should make it clear that the focus is on identification of sub-groups at risk of poor health status. A: In the abstract and manuscript, we now described: ' -Line 108. Please explain 'randomly controlled the data' in the data verification process more detail. All patient files or a sample? Did you check completeness, consistency, coherence and/or chronology? A: We now described the following sentence: 'Quality of the data of the BTR and BIOS was checked on outliers and completeness by a trauma coordinator and researcher respectively. Furthermore, data from a sample of the trauma registry was checked manually by a trauma surgeon.' -Line 240. Spell out FU. Again, using too many acronyms that are not widely recognized makes reading very arduous A: We have spelled out the FU as 'follow-up' as suggested by the reviewer.
- Table 4 'Beta: measures how strong each predictor variable influences the dependent variable' could be replaced by 'mean increase in EQ-5D-3L score (improvement in quality of life) compared to the reference category. A: We thank the reviewer for this suggestion. We changed the sentence as supposed by the reviewer.
Comments reviewer 3 -I am still a little confused by the status-scores. A: In the 'statistical analyses' paragraph, we described the following sentence: a lower status score indicates a lower SES whereas a higher status score indicates a higher SES. Hopefully, this will lead to a better interpretation of the status score. Furthermore, we described in the discussion and conclusion paragraphs that a lower status scores is an indicator of a lower SES-level (lines 425 and 473). To interpret the results, we added the minimum and maximum scores.
-Some of the confidence intervals contains negative figures. What are the extremes of the scale? As this seems to be a Dutch scale, you could explain this better to international readers. A: We added the minimum and maximum score of the EQ-5D-3L under Table 4.
-In the study design and participants section it is stated: "The Brabant Trauma Registry (BTR) complies pre-hospital and hospital data of all trauma patients admitted after presentation to the ED in the Noord-Brabant region." You probably intended to say compiles? A: Indeed, we intented to say 'compile' instead of 'complies'. We changed the word 'complies' into 'compiles'.
Same paragraph: "Before the data of the BTR and data of the BIOS-study were merged, the researchers randomly controlled the data of the trauma registry." This is commendable, but what was "randomly"? 1 of 100, 1 of 1000, 20%? Please elaborate, otherwise this statement is not very descriptive. A: We deleted the following text: 'Before the data of the BTR and data of the BIOS-study were merged, the researchers randomly controlled the data of the trauma registry'. We replaced this text with the following sentence: 'Quality of the data of the BTR and BIOS was checked on outliers and completeness by a trauma coordinator and researcher respectively. Furthermore, data from a sample of the trauma registry was checked manually by a trauma surgeon.'