The impact of different imputation methods on estimates and model performance: an example using a risk prediction model for premature mortality.

OBJECTIVE: To compare how different imputation methods affect the estimates and performance of a prediction model for premature mortality. STUDY DESIGN AND SETTING: Sex-specific Weibull accelerated failure time survival models were run on four separate datasets using complete case, mode, single and multiple imputation to impute missing values. Six performance measures were compared to access predictive accuracy (Nagelkerke R2, integrated brier score), discrimination (Harrell's c-index, discrimination slope) and calibration (calibration in the large, calibration slope). RESULTS: The highest proportion of missingness for a single variable was 10.86% for the female model and 8.24% for the male model. Comparing the performance measures for complete case, mode, single and multiple imputation: the Nagelkerke R2 values for the female model was 0.1084, 0.1116, 0.1120 and 0.111-0.1120 with the male model exhibited similar variation of 0.1050, 0.1078, 0.1078 and 0.1078-0.1081. Harrell's c-index also demonstrated small variation with values of 0.8666, 0.8719, 0.8719 and 0.8711-0.8719 for the female model and 0.8549, 0.8548, 0.8550 and 0.8550-0.8553 for the male model. CONCLUSION: In the scenarios examined in this study, mode imputation performed well when using a population health survey compared to single and multiple imputation when predictive performance measures is the main model goal. To generate unbiased hazard ratios, multiple imputation methods were superior. This study shows the need to consider the best imputation approach for a predictive model development given the conditions of missing data and the goals of the analysis.

Rho GTPases: Non-canonical regulation by cysteine oxidation.

Rho GTPases are critically important and are centrally positioned regulators of the actomyosin cytoskeleton. By influencing the organization and architecture of the cytoskeleton, Rho proteins play prominent roles in many cellular processes including adhesion, migration, intra-cellular transportation, and proliferation. The most important method of Rho GTPase regulation is via the GTPase cycle; however, post-translational modifications (PTMs) also play critical roles in Rho protein regulation. Relative to other PTMs such as lipidation or phosphorylation that have been extensively characterized, protein oxidation is a regulatory PTM that has been poorly studied. Protein oxidation primarily occurs from the reaction of reactive oxygen species (ROS), such as hydrogen peroxide (H2 O2 ), with amino acid side chain thiols on cysteine (Cys) and methionine (Met) residues. The versatile redox modifications of cysteine residues exemplify their integral role in cell signalling processes. Here we review prominent members of the Rho GTPase family and discuss how lipidation, phosphorylation, and oxidation on conserved cysteine residues affects their regulation and function.

Utility of Person-Environment-Occupation model in exploring sex-specific causes of work-related traumatic brain injury: a retrospective chart review.

BACKGROUND: Work-related traumatic brain injury (wr-TBI) is on the rise. The pre-injury period, a significant consideration for preventive initiatives, is largely unexplored. OBJECTIVES: To identify Person-Environment-Occupation (PEO) variables associated with wr-TBI to inform sex-specific primary prevention. METHODS: Retrospective chart review data were analyses. Two-tailed t-test and chi-squared tests were used to study sex differences. Multivariate logistic regression models of wr-TBI were fit with a priori defined PEO variables. RESULTS: The sample comprised 330 consecutive workers with wr-TBI (40.8 ± 11.1 years old, 71% male). Sex differences were observed across PEO variables. In multivariable logistic regression analyses the odds of sustaining a wr-TBI from a fall increased with the presence of a mood disorder and participation in non-labourer occupations (odds ratio (OR) 2.89 (95% CI 1.06-7.89) and OR 2.89 (95% CI 1.06-7.89), respectively) and decreased being a male (OR 0.31 (95% CI 0.17-0.54)). The odds of sustaining a wr-TBI from being striken by an object was greater in workers with prior head injury (OR 2.8 (95% CI 1.24-6.45)). None of the variables studied were associated with wr-TBI sustained from being striken against an object. CONCLUSIONS: Workers' health status pre-injury is associated with external causes of wr-TBI. Sex differences across PEO categories warrant further study.

Pre-injury health status and excess mortality in persons with traumatic brain injury: A decade-long historical cohort study.

An increasing number of patients are able to survive traumatic brain injuries (TBIs) with advanced resuscitation. However, the role of their pre-injury health status in mortality in the following years is not known. Here, we followed 77,088 consecutive patients (59% male) who survived the TBI event in Ontario, Canada for more than a decade, and examined the relationships between their pre-injury health status and mortality rates in excess to the expected mortality calculated using sex- and age-specific life tables. There were 5792 deaths over the studied period, 3163 (6.95%) deaths in male and 2629 (8.33%) in female patients. The average excess mortality rate over the follow-up period of 14 years was 1.81 (95% confidence interval = 1.76-1.86). Analyses of follow-up time windows showed different patterns for the average excess rate of mortality following TBI, with the greatest rates observed in year one after injury. Among identified pre-injury comorbidity factors, 33 were associated with excess mortality rates. These rates were comparable between sexes. Additional analyses in the validation dataset confirmed that these findings were unlikely a result of TBI misclassification or unmeasured confounding. Thus, detection and subsequent management of pre-injury health status should be an integral component of any strategy to reduce excess mortality in TBI patients. The complexity of pre-injury comorbidity calls for integration of multidisciplinary health services to meet TBI patients' needs and prevent adverse outcomes.

Data Mining to Understand How Health Status Preceding Traumatic Brain Injury Affects Functional Outcome: A Population-Based Sex-Stratified Study.

OBJECTIVES: To understand how health status preceding traumatic brain injury (TBI) affects relative functional gain after inpatient rehabilitation using a data mining approach. DESIGN: Population-based, sex-stratified, retrospective cohort study using health administrative data from Ontario, Canada (39% of the Canadian population). SETTING: Inpatient rehabilitation. PARTICIPANTS: Patients 14 years or older (N=5802; 63.4% male) admitted to inpatient rehabilitation within 1 year of a TBI-related acute care discharge between April 1, 2008, and March 31, 2015. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Relative functional gain (RFG) in percentage, calculated as ([discharge FIM-admission FIM]/[126-admission FIM]×100). Health status prior to TBI was identified and internally validated using a data mining approach that categorized all International Classification of Diseases, 10th revision, codes for each patient. RESULTS: The average RFG was 52.8%±27.6% among male patients and 51.6%±27.1% among female patients. Sex-specific Bonferroni adjusted multivariable linear regressions identified 10 factors of preinjury health status related to neurology, emergency medicine, cardiology, psychiatry, geriatrics, and gastroenterology that were significantly associated with reduced RFG in FIM for male patients. Only 1 preinjury health status category, geriatrics, was significantly associated with RFG in female patients. CONCLUSIONS: Comorbid health conditions present up to 5 years preceding the TBI event were significantly associated with RFG. These findings should be considered when planning and executing interventions to maximize functional gain and to support an interdisciplinary approach. Best practices guidelines and clinical interventions for older male and female patients with TBI should be developed given the increasingly aging population with TBI.

A study protocol for a predictive model to assess population-based avoidable hospitalization risk: Avoidable Hospitalization Population Risk Prediction Tool (AvHPoRT).

INTRODUCTION: Avoidable hospitalizations are considered preventable given effective and timely primary care management and are an important indicator of health system performance. The ability to predict avoidable hospitalizations at the population level represents a significant advantage for health system decision-makers that could facilitate proactive intervention for ambulatory care-sensitive conditions (ACSCs). The aim of this study is to develop and validate the Avoidable Hospitalization Population Risk Tool (AvHPoRT) that will predict the 5-year risk of first avoidable hospitalization for seven ACSCs using self-reported, routinely collected population health survey data. METHODS AND ANALYSIS: The derivation cohort will consist of respondents to the first 3 cycles (2000/01, 2003/04, 2005/06) of the Canadian Community Health Survey (CCHS) who are 18-74 years of age at survey administration and a hold-out data set will be used for external validation. Outcome information on avoidable hospitalizations for 5 years following the CCHS interview will be assessed through data linkage to the Discharge Abstract Database (1999/2000-2017/2018) for an estimated sample size of 394,600. Candidate predictor variables will include demographic characteristics, socioeconomic status, self-perceived health measures, health behaviors, chronic conditions, and area-based measures. Sex-specific algorithms will be developed using Weibull accelerated failure time survival models. The model will be validated both using split set cross-validation and external temporal validation split using cycles 2000-2006 compared to 2007-2012. We will assess measures of overall predictive performance (Nagelkerke R2), calibration (calibration plots), and discrimination (Harrell's concordance statistic). Development of the model will be informed by the Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis (TRIPOD) statement. ETHICS AND DISSEMINATION: This study was approved by the University of Toronto Research Ethics Board. The predictive algorithm and findings from this work will be disseminated at scientific meetings and in peer-reviewed publications.

The effect of sleep disorders on dementia risk in patients with traumatic brain injury: A large-scale cohort study.

Introduction: We investigated the association between sleep disorders (SDs) and incident dementia in adults with traumatic brain injury (TBI). Methods: Adults with a TBI between 2003 and 2013 were followed until incident dementia. Sleep disorders at TBI were predictors in Cox regression models, controlling for other dementia risks. Results: Over 52 months, 4.6% of the 712,708 adults (59% male, median age 44, <1% with SD) developed dementia. An SD was associated with a 26% and a 23% of increased risk of dementia in male and female participants (hazard ratio [HR] 1.26, 95% confidence interval [CI] 1.11-1.42 and HR 1.23, 95% CI 1.09-1.40, respectively). In male participants, SD was associated with a 93% increased risk of early-onset dementia (HR 1.93, 95% CI 1.29-2.87); this did not hold in female participants (HR 1.38, 95% CI 0.78-2.44). Discussion: In a province-wide cohort, SDs at TBI were independently associated with incident dementia. Clinical trials testing sex-specific SD care after TBI for dementia prevention are timely. Highlights: TBI and sleep disorders are linked to each other, and to dementia.It is unclear if sleep disorders pose a sex-specific dementia risk in brain injury.In this study, presence of a sleep disorder increased dementia risk in both sexes.The risk differed by type of sleep disorder, which differed between the sexes.Sleep disorder awareness and care in persons with brain injury is vital for dementia prevention.

Synthesis and Use of the Bifunctional Sulfenic Acid Probe BCN-E-BCN for In Vitro and Cell-Based Assays of Protein Oxidation.

The reversible oxidation of cysteine thiol groups to sulfenic acid by reactive oxygen species (ROS) such as hydrogen peroxide can impact protein function, activity, and localization. As a consequence, ROS have profound effects on cell functions including proliferation, differentiation, and survival. Furthermore, there are clear associations between the effects of ROS on cells and the etiology of several diseases including cancer and neurodegeneration. In spite of the importance of cysteine sulfenylation as a validated post-translational modification, its labile nature impedes efficient and reproducible detection of proteins with cysteine sulfenic acid residues. To overcome this challenge, we developed a novel cell-permeable bifunctional reagent, consisting of two linked bicyclo[6.1.0]nonyne (BCN) moieties coupled with a short ethylenediamine-derived linker (BCN-E-BCN) that enables the detection of sulfenylated proteins in vitro and in intact cells. The two symmetrical BCN groups allow protein sulfenic acids to be selectively tagged with a BCN at one end while allowing for copper-free click chemistry with azide-tagged reagents of the opposite BCN. In this protocol, the synthesis of BCN-E-BCN and its use to detect cysteine sulfenic acids will be detailed. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Copper-mediated cyclopropanation of 1,5-cyclooctadiene Basic Protocol 2: Synthesis of endo- and exo-bicyclononyne Basic Protocol 3: Synthesis of endo-BCN-E-BCN Basic Protocol 4: BCN-E-BCN treatment of wild-type and cysteine-deficient mutant recombinant cofilin protein Basic Protocol 5: BCN-E-BCN labeling in live cells Basic Protocol 6: Western blotting and visualization of BCN-E-BCN-labeled samples.

The Impact of a Comorbid Spinal Cord Injury on Cognitive Outcomes of Male and Female Patients with Traumatic Brain Injury.

INTRODUCTION: Evidence of the effect of comorbid spinal cord injury (SCI) on cognitive outcomes in persons undergoing rehabilitation following newly diagnosed traumatic brain injury (TBI) is limited. We conducted a population-based study to investigate this effect. OBJECTIVE: To compare cognitive outcomes in patients with TBI with and without a comorbid SCI. SETTING/PARTICIPANTS: Adult patients diagnosed with TBI were identified and followed for 1 year through provincial health administrative data; those who entered inpatient rehabilitation were studied. DESIGN: A retrospective matched cohort study using the National Rehabilitation Reporting System data of all acute care and freestanding rehabilitation hospitals in Ontario, Canada. MAIN MEASURES: The exposure was a comorbid SCI in patients with diagnosed TBI. Exposed patients were matched to unexposed (TBI-only) on sex, age, injury severity, and income, in a ratio of one to two. Gain differences in the cognitive subscale of the Functional Independence Measure were compared between exposed and unexposed patients using multivariable mixed linear model, controlling for comorbidity propensity score, gains in motor function, and rehabilitation care indicators. RESULTS: Over the first year post injury, 12 750 (0.84%) of all TBI patients entered inpatient rehabilitation, of whom 1359 (10.66%) had a comorbid SCI. A total of 1195 exposed patients (65.4% male, mean age 50.9 ± 20.6 for male and 61.8 ± 21.8 for female patients) were matched to 2390 unexposed patients. Controlling for confounding, exposed patients had lower cognitive gain (beta -0.43; 95% CI -0.72, -0.15), for both male (beta -0.39; 95% CI -0.75, -0.03) and female (beta -0.51; 95% CI -0.97, -0.05) patients. The adverse effects of comorbid SCI were driven largely by lower gains in problem solving and comprehension. CONCLUSIONS: Adult patients with TBI and comorbid SCI showed a lower cognitive domain response to inpatient rehabilitation than patients with TBI alone. Identifying patients at risk for worse cognitive outcomes may facilitate the development of targeted strategies that improve cognitive outcomes.

A study protocol for a predictive algorithm to assess population-based premature mortality risk: Premature Mortality Population Risk Tool (PreMPoRT).

BACKGROUND: Premature mortality is an important population health indicator used to assess health system functioning and to identify areas in need of health system intervention. Predicting the future incidence of premature mortality in the population can facilitate initiatives that promote equitable health policies and effective delivery of public health services. This study protocol proposes the development and validation of the Premature Mortality Risk Prediction Tool (PreMPoRT) that will predict the incidence of premature mortality using large population-based community health surveys and multivariable modeling approaches. METHODS: PreMPoRT will be developed and validated using various training, validation, and test data sets generated from the six cycles of the Canadian Community Health Survey (CCHS) linked to the Canadian Vital Statistics Database from 2000 to 2017. Population-level risk factor information on demographic characteristics, health behaviors, area level measures, and other health-related factors will be used to develop PreMPoRT and to predict the incidence of premature mortality, defined as death prior to age 75, over a 5-year period. Sex-specific Weibull accelerated failure time models will be developed using a Canadian provincial derivation cohort consisting of approximately 500,000 individuals, with approximately equal proportion of males and females, and about 12,000 events of premature mortality. External validation will be performed using separate linked files (CCHS cycles 2007-2008, 2009-2010, and 2011-2012) from the development cohort (CCHS cycles 2000-2001, 2003-2004, and 2005-2006) to check the robustness of the prediction model. Measures of overall predictive performance (e.g., Nagelkerke's R2), calibration (e.g., calibration plots), and discrimination (e.g., Harrell's concordance statistic) will be assessed, including calibration within defined subgroups of importance to knowledge users and policymakers. DISCUSSION: Using routinely collected risk factor information, we anticipate that PreMPoRT will produce population-based estimates of premature mortality and will be used to inform population strategies for prevention.

A population-based sex-stratified study to understand how health status preceding traumatic brain injury affects direct medical cost.

OBJECTIVE: To understand how pre-injury health status present five-years preceding traumatic brain injury (TBI) affects direct medical cost two years post-injury. METHODS: Patients age ≥19 years in the emergency department (ED) or acute care for a TBI between April 1, 2007 and March 31, 2014 in Ontario, Canada (N = 55,669) were identified from population-based health administrative data. Forty-three factors of pre-injury health status (i.e., comorbidities and personal, social, and environmental factors) that were internally validated for the TBI population were assessed in this study. The outcome of interest was direct medical cost within two years of discharge. Sex-specific multivariable linear regressions were conducted to understand the associations between direct medical cost within two years of discharge and pre-injury health status. RESULTS: Patients who received care in the ED (81.9% of total sample) incurred a median cost of $2,492/male patient (average $12,342/patient) and $3,508/female patient (average $65,285/patient) within two years of injury; 37 pre-injury factors were significantly associated with increased direct medical costs. Patients who first received care for their TBI in acute care (18.1%) incurred a median cost of $25,081/male patient (average $63,060/patient) and $30,277/female patient (average $65,285/patient) within two years of injury; 21 factors were significantly associated with increased direct medical costs. Among more prevalent factors, those associated with increased medical cost by at least 50% included mental health disorders, substance abuse, disorders or medical conditions frequently observed among the elderly, cardiovascular disorders, stroke and emergencies involving the brain, metabolic disorders and abdominal symptoms, conditions and symptoms of abdomen and pelvis, genitourinary disorders and disorders of prostate, and pulmonary abdominal and other emergencies. CONCLUSIONS: Direct medical costs two years post-TBI differed significantly between patients with and without adverse pre-existing health status. Interdisciplinary teams to promote early identification of pre-existing health conditions and appropriate management and integration of these conditions in TBI care across the continuum of healthcare may be opportunities to reduce direct medical costs post-injury.

Sex-specific incident dementia in patients with central nervous system trauma.

INTRODUCTION: Despite evidence that central nervous system (CNS) trauma, including traumatic brain injury and spinal cord injury, can cause sustained neurocognitive impairment, it remains unclear whether trauma-related variables are associated with incident dementia independently of other known risk factors. METHODS: All adults without dementia entering the health-care system with diagnoses of CNS trauma were examined for occurrence of dementia. All trauma-related variables were examined as predictors in sex-specific Cox regression models, controlling for other known risk factors. RESULTS: Over a median follow-up of 52 months, 32,834 of 712,708 patients (4.6%) developed dementia. Traumatic brain injury severity and spinal cord injury interacted with age to influence dementia onset; women were at a greater risk of developing dementia earlier than men, all other factors being equal. DISCUSSION: Risk stratification of patients with CNS trauma by sex is vital in identifying those most likely to develop dementia and in understanding the course and modifying factors.