Group-based trajectory analysis applications for prognostic biomarker model development in severe TBI: a practical example.

Over the last decade, biomarker research has identified potential biomarkers for the diagnosis, prognosis, and management of traumatic brain injury (TBI). Several cerebrospinal fluid (CSF) and serum biomarkers have shown promise in predicting long-term outcome after severe TBI. Despite this increased focus on identifying biomarkers for outcome prognostication after a severe TBI, several challenges still exist in effectively modeling the significant heterogeneity observed in TBI-related pathology, as well as the biomarker-outcome relationships. Biomarker data collected over time are usually summarized into single-point estimates (e.g., average or peak biomarker levels), which are, in turn, used to examine the relationships between biomarker levels and outcomes. Further, many biomarker studies to date have focused on the prediction power of biomarkers without controlling for potential clinical and demographic confounders that have been previously shown to affect long-term outcome. In this article, we demonstrate the application of a practical approach to delineate and describe distinct subpopulations having similar longitudinal biomarker profiles and to model the relationships between these biomarker profiles and outcomes while taking into account potential confounding factors. As an example, we demonstrate a group-based modeling technique to identify temporal S100 calcium-binding protein B (S100b) profiles, measured from CSF over the first week post-injury, in a sample of adult subjects with TBI, and we use multivariate logistic regression to show that the prediction power of S100b biomarker profiles can be superior to the prediction power of single-point estimates.

Acute serum hormone levels: characterization and prognosis after severe traumatic brain injury.

Experimental traumatic brain injury (TBI) studies report the neuroprotective effects of female sex steroids on multiple mechanisms of injury, with the clinical assumption that women have hormonally mediated neuroprotection because of the endogenous presence of these hormones. Other literature indicates that testosterone may exacerbate injury. Further, stress hormone abnormalities that accompany critical illness may both amplify or blunt sex steroid levels. To better understand the role of sex steroid exposure in mediating TBI, we 1) characterized temporal profiles of serum gonadal and stress hormones in a population with severe TBI during the acute phases of their injury; and 2) used a biological systems approach to evaluate these hormones as biomarkers predicting global outcome. The study population was 117 adults (28 women; 89 men) with severe TBI. Serum samples (n=536) were collected for 7 days post-TBI for cortisol, progesterone, testosterone, estradiol, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). Hormone data were linked with clinical data, including acute care mortality and Glasgow Outcome Scale (GOS) scores at 6 months. Hormone levels after TBI were compared to those in healthy controls (n=14). Group based trajectory analysis (TRAJ) was used to develop temporal hormone profiles that delineate distinct subpopulations in the cohort. Structural equations models were used to determine inter-relationships between hormones and outcomes within a multivariate model. Compared to controls, acute serum hormone levels were significantly altered after severe TBI. Changes in the post-TBI adrenal response and peripheral aromatization influenced hormone TRAJ profiles and contributed to the abnormalities, including increased estradiol in men and increased testosterone in women. In addition to older age and greater injury severity, increased estradiol and testosterone levels over time were associated with increased mortality and worse global outcome for both men and women. These findings represent a paradigm shift when thinking about the role of sex steroids in neuroprotection clinically after TBI.

The association of race, cultural factors, and health-related quality of life in persons with spinal cord injury.

OBJECTIVE: To examine the association of race and cultural factors with quality-of-life factors (participation, life satisfaction, perceived health status) in people with spinal cord injury (SCI). DESIGN: Cross-sectional multisite study using structured questionnaires. SETTING: Six National SCI Model Systems centers. PARTICIPANTS: People with SCI (N=275; age ≥16y; SCI with discernable neurologic impairments; used power or manual wheelchair for >1y as primary means of mobility; nonambulatory except for exercise purposes). INTERVENTIONS: None. MAIN OUTCOME MEASURES: Participation (Craig Handicap Assessment and Reporting Technique Short Form); satisfaction (Satisfaction With Life Scale); and perceived health status (2 items from 36-Item Short Form Health Survey). RESULTS: African American (n=96) with SCI reported more experiences of discrimination in health care, greater perceived racism, more health care system distrust, and lower health literacy than whites (n=156; P range, <.001-<.05). Participants who reported experiencing more discrimination in health care reported better occupational functioning (odds ratio [OR], 1.5; 95% confidence interval [CI], 1.07-2.09; P<.05). Those who perceived more racism in health care settings reported better occupational functioning (OR, 1.65; 95% CI, 1.12-2.43; P<.05) and greater perceived health (ß=.36; 95% CI, .05-.68; P<.05). Those who reported more distrust in the health care system reported better current health compared with 1 year ago (ß=.38; 95% CI, .06-.69; P<.05). Those who reported better communication with their health care provider reported higher levels of mobility (OR, 1.5; 95% CI, 1.05-2.13; P<.05) and better general health (ß=.27; 95% CI, .01-.53; P<.05). CONCLUSIONS: In this cross-sectional study of people with SCI, higher levels of perceived discrimination and racism and better communication with health care providers were associated with an increase in participation and functioning and improvements in perceptions of well-being. These associations are different from those reported in other study populations and warrant confirmation in future prospective studies.

CSF Bcl-2 and cytochrome C temporal profiles in outcome prediction for adults with severe TBI.

The biochemical cascades associated with cell death after traumatic brain injury (TBI) involve both pro-survival and pro-apoptotic proteins. We hypothesized that elevated cerebrospinal fluid (CSF) Bcl-2 and cytochrome C (CytoC) levels over time would reflect cellular injury response and predict long-term outcomes after TBI. Cerebrospinal fluid Bcl-2 and CytoC levels were measured for 6 days after injury for adults with severe TBI (N=76 subjects; N=277 samples). Group-based trajectory analysis was used to generate distinct temporal biomarker profiles that were compared with Glasgow Outcome Scale (GOS) and Disability Rating Scale (DRS) scores at 6 and 12 months after TBI. Subjects with persistently elevated temporal Bcl-2 and CytoC profiles compared with healthy controls had the worst outcomes at 6 and 12 months (P≤0.027). Those with CytoC profiles near controls had better long-term outcomes, and those with declining CytoC levels over time had intermediate outcomes. Subjects with Bcl-2 profiles that remained near controls had better outcomes than those with consistently elevated Bcl-2 profiles. However, subjects with Bcl-2 values that started near controls and steadily rose over time had 100% good outcomes by 12 months after TBI. These results show the prognostic value of Bcl-2 and CytoC profiles and suggest a dynamic apoptotic and pro-survival response to TBI.

Reliability and validity analysis of the transfer assessment instrument.

OBJECTIVES: To describe the development and evaluate the reliability and validity of a newly created outcome measure, the Transfer Assessment Instrument (TAI), to assess the quality of transfers performed by full-time wheelchair users. DESIGN: Repeated measures. SETTING: 2009 National Veterans Wheelchair Games in Spokane, WA. PARTICIPANTS: A convenience sample of full-time wheelchair users (N=40) who perform sitting pivot or standing pivot transfers. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Intraclass correlation coefficients (ICCs) for reliability and Spearman correlation coefficients for concurrent validity between the TAI and a global assessment scale (0-100 visual analog scale [VAS]). RESULTS: No adverse events occurred during testing. Intrarater ICCs for 3 raters ranged between .35 and .89, and the interrater ICC was .642. Correlations between the TAI and a global assessment VAS ranged between .19 (P=.285) and .69 (P>.000). Item analyses of the tool found a wide range of results, from weak to good reliability. Evaluators found the TAI to be safe and able to be completed in a short time. CONCLUSIONS: The TAI is a safe, quick outcome measure that uses equipment typically found in a clinical setting and does not ask participants to perform new skills. Reliability and validity testing found the TAI to have acceptable interrater and a wide range of intrarater reliability. Future work indicates the need for continued refinement including removal or modification of items found to have low reliability, improved education for clinicians, and further reliability and validity analysis with a more diverse subject population. The TAI has the potential to fill a void in assessment of transfers.

Effect of an intense wheelchair propulsion task on quantitative ultrasound of shoulder tendons.

OBJECTIVE: To investigate acute ultrasound changes of biceps and supraspinatus tendon appearance after an intense wheelchair propulsion task, and how these changes relate to demographic and biomechanical risk factors. DESIGN: A survey. SETTING: Research laboratory and research space at the National Veterans Wheelchair Games. PARTICIPANTS: A convenience sample of 60 manual wheelchair users were recruited through research registries and rehabilitation clinics as well as from participants at the 2007 and 2008 National Veterans Wheelchair Games. The subjects were between 18 and 65 years of age at least 1 year after injury and did not have progressive disabilities. MAIN OUTCOME MEASURES: Quantitative ultrasound (QUS) measures of biceps and supraspinatus tendon appearance, stroke frequency, resultant force, tendinopathy score, and duration of wheelchair use. RESULTS: Biceps tendon appearance after an intense propulsion task was significantly related to chronic biceps tendinopathy, duration of wheelchair use, stroke frequency, and resultant force. The subjects with a higher stroke frequency or resultant force tended to have a brighter, more organized tendon appearance compared with the prepropulsion imaging session (baseline). The subjects with tendinopathy or a longer duration of wheelchair use were more likely to have a darker, diffuse tendon appearance immediately after the propulsion task. Supraspinatus tendon appearance after propulsion was only significantly predicted by baseline QUS measures. CONCLUSIONS: QUS has proven to be sensitive to risk factors for tendon pathology. Future studies can apply grayscale-based QUS to study the development and prevention of repetitive strain injuries, particularly on an individual basis.

Endothelin-1 is increased in cerebrospinal fluid and associated with unfavorable outcomes in children after severe traumatic brain injury.

Severe pediatric traumatic brain injury (TBI) is associated with unfavorable outcomes secondary to injury from activation of the inflammatory cascade, the release of excitotoxic neurotransmitters, and changes in the reactivity of cerebral vessels, causing ischemia. Hypoperfusion of injured brain tissues after TBI is also associated with unfavorable outcomes. Therapeutic hypothermia is an investigational treatment strategy for use in patients with severe TBI that has shown differential effects on various cerebrospinal fluid (CSF) mediators in pediatric patients. Endothelin-1 (ET-1) is a powerful vasoconstrictor that exerts its effects on the cerebrovascular endothelium for sustained periods after TBI. The purpose of this study was to determine if CSF concentrations of ET-1 are increased after severe TBI in children, and if they are associated with demographics and outcomes that are affected by therapeutic hypothermia. This was an ancillary study to a prospective, randomized-controlled trial of early hypothermia in a tertiary care pediatric intensive care unit. Children (n = 34, age 3 months-15 years) suffering from severe TBI were randomized to hypothermia (n = 19) and normothermia (n = 15) as part of the efficacy study. Children undergoing diagnostic lumbar puncture (n = 11) to rule out infection were used as controls. Patients received either mild to moderate hypothermia (32-33°C) or normothermia as part of their treatment protocol. CSF was serially collected during the first 5 days after TBI. ET-1 concentrations were quantitated in patient and control CSF samples by a validated ELISA in duplicate with a limit of quantification of 0.195 pg/mL. CSF ET-1 concentrations were increased by two- to threefold in children after TBI compared to controls, and the increase was sustained for up to 5 days post-TBI. This relationship was not affected by hypothermia, and there were no differences in ET-1 response between children with inflicted and accidental TBI. Group-based trajectory analysis revealed two distinct groups with similar ET-1 levels over time. Univariate analysis showed a significant association between ET-1 levels and Glasgow Outcome Scale (GOS) scores, for which higher ET-1 levels over time were associated with unfavorable outcomes. ET-1 is increased in children with severe TBI and is associated with unfavorable outcomes. This increase in ET-1 may mediate the hypoperfusion or cerebrovascular dysfunction accompanying severe TBI in children. Importantly, hypothermia does not affect the brain's ET-1 response as measured in the CSF.