Hua He

Sex differences in outcome after mild traumatic brain injury.

The objective of this study was to estimate the independent association of sex with outcome after mild traumatic brain injury (mTBI). We performed an analysis of a subset of an established cohort involving 1425 mTBI patients presenting to an academic emergency department (ED). The associations between sex and three outcomes determined 3 months after the initial ED visit were examined: post-concussive symptom (PCS) score (0, 1-5, 6-16, and >16), the number of days to return of normal activities (0, 1-7, and >7), and the number of days of work missed (0, 1-7,and >7). Logistic regression analyses were used to determine the relationship between sex and each outcome after controlling for 12 relevant subject-level variables. Of the 1425 subjects, 643 (45.1%) were female and 782 (54.9%) were male. Three months after mTBI, males had significantly lower odds of being in a higher PCS score category (odds ratio [OR] 0.62, 95% confidence interval [CI]: 0.50, 0.78); this association appeared to be more prominent during child-bearing years for females. Males and females did not significantly differ with respect to the odds of poorer outcome as defined by the number of days to return of normal activities or the number of days of work missed. Female sex is associated with significantly higher odds of poor outcome after mTBI, as measured by PCS score, after control for appropriate confounders. The observed pattern of peak disability for females during the child-bearing years suggests disruption of endogenous estrogen or progesterone production. Attempts to better understand how mTBI affects production of these hormones acutely after injury and during the recovery period may shed light on the mechanism behind poorer outcome among females and putative therapeutic interventions.

Elevated Serum Ubiquitin Carboxy-Terminal Hydrolase L1 Is Associated with Abnormal Blood–Brain Barrier Function after Traumatic Brain Injury

Serum S100B elevations accurately reflect blood-brain barrier (BBB) damage. Because S100B is also present in peripheral tissues, release of this protein may not be specific to central nervous system (CNS) injury. Ubiquitin C-terminal hydrolase 1 (UCHL1), and phosphorylated neurofilament heavy chain (pNF-H) are found exclusively in neurons, but their relationship to BBB dysfunction has not been determined. The objective of this study was to determine the accuracy of serum UCHL1 and pNF-H as measures of BBB integrity after traumatic brain injury (TBI), to and compare them to S100B. We performed a prospective study of 16 patients with moderate to severe TBI (Glasgow Coma Scale [GCS] score ≤12) and 6 patients with non-traumatic headache who had cerebrospinal fluid (CSF) collected by ventriculostomy or lumbar puncture (LP). Serum and CSF were collected at the time of LP for headache patients and at 12, 24, and 48u2009h after injury for TBI patients. BBB function was determined by calculating albumin quotients (Q(A)), where Q(A)=[albumin(CSF)]/[albumin(serum)]. S100B, UCHL1, and pNF-H were measured by enzyme-linked immunosorbent assay (ELISA). Pearsons correlation coefficient and area under the receiver operator characteristic (ROC) curve were used to determine relationships between serum markers and Q(A). At 12 hours after TBI, a significant relationship was found between Q(A) and serum UCHL1 concentrations (AUC=0.76; 95% CI 0.55,1.00), and between Q(A) and serum S100B concentrations (AUC=0.794; 95% CI 0.57,1.02). There was no significant relationship found between these markers and Q(A) at other time points, or between pNF-H and Q(A) at any time point. We conclude that serum concentrations of UCHL1 are associated with abnormal BBB status 12u2009h after moderate to severe TBI. This relationship is similar to that observed between serum S100B and Q(A,) despite the fact that S100B may be released from peripheral tissues after multi-trauma. We conclude that peripheral release of S100B after multi-trauma is probably negligible and that UCHL1 may have some utility to monitor BBB disruption following TBI.

Direct estimation of the area under the receiver operating characteristic curve in the presence of verification bias

The area under a receiver operating characteristic (ROC) curve (AUC) is a commonly used index for summarizing the ability of a continuous diagnostic test to discriminate between healthy and diseased subjects. If all subjects have their true disease status verified, one can directly estimate the AUC nonparametrically using the Wilcoxon statistic. In some studies, verification of the true disease status is performed only for a subset of subjects, possibly depending on the result of the diagnostic test and other characteristics of the subjects. Because estimators of the AUC based only on verified subjects are typically biased, it is common to estimate the AUC from a bias-corrected ROC curve. The variance of the estimator, however, does not have a closed-form expression and thus resampling techniques are used to obtain an estimate. In this paper, we develop a new method for directly estimating the AUC in the setting of verification bias based on U-statistics and inverse probability weighting (IPW). Closed-form expressions for the estimator and its variance are derived. We also show that the new estimator is equivalent to the empirical AUC derived from the bias-corrected ROC curve arising from the IPW approach.

Classification accuracy of serum Apo A-I and S100B for the diagnosis of mild traumatic brain injury and prediction of abnormal initial head computed tomography scan.

The objective of the current study was to determine the classification accuracy of serum S100B and apolipoprotein (apoA-I) for mild traumatic brain injury (mTBI) and abnormal initial head computed tomography (CT) scan, and to identify ethnic, racial, age, and sex variation in classification accuracy. We performed a prospective, multi-centered study of 787 patients with mTBI who presented to the emergency department within 6 h of injury and 467 controls who presented to the outpatient laboratory for routine blood work. Serum was analyzed for S100B and apoA-I. The outcomes were disease status (mTBI or control) and initial head CT scan. At cutoff values defined by 90% of controls, the specificity for mTBI using S100B (0.899 [95% confidence interval (CI): 0.78-0.92]) was similar to that using apoA-I (0.902 [0.87-0.93]), and the sensitivity using S100B (0.252 [0.22-0.28]) was similar to that using apoA-I (0.249 [0.22-0.28]). The area under the receiver operating characteristic curve (AUC) for the combination of S100B and apoA-I (0.738, 95% CI: 0.71, 0.77), however, was significantly higher than the AUC for S100B alone (0.709, 95% CI: 0.68, 0.74, p=0.001) and higher than the AUC for apoA-I alone (0.645, 95% CI: 0.61, 0.68, p<0.0001). The AUC for prediction of abnormal initial head CT scan using S100B was 0.694 (95%CI: 0.62, 0.77) and not significant for apoA-I. At a S100B cutoff of <0.060 μg/L, the sensitivity for abnormal head CT was 98%, and 22.9% of CT scans could have been avoided. There was significant age and race-related variation in the accuracy of S100B for the diagnosis of mTBI. The combined use of serum S100B and apoA-I maximizes classification accuracy for mTBI, but only S100B is needed to classify abnormal head CT scan. Because of significant subgroup variation in classification accuracy, age and race need to be considered when using S100B to classify subjects for mTBI.

Assay sensitivity and study features in neuropathic pain trials An ACTTION meta-analysis

Objective: Our objective was to identify patient, study, and site factors associated with assay sensitivity in placebo-controlled neuropathic pain trials. Methods: We examined the associations between study characteristics and standardized effect size (SES) in a database of 200 publicly available randomized clinical trials of pharmacologic treatments for neuropathic pain. Results: There was considerable heterogeneity in the SESs among the examined trials. Univariate meta-regression analyses indicated that larger SESs were significantly associated with trials that had 1) greater minimum baseline pain inclusion criteria, 2) greater mean subject age, 3) a larger percentage of Caucasian subjects, and 4) a smaller total number of subjects. In a multiple meta-regression analysis, the associations between SES and minimum baseline pain inclusion criterion and age remained significant. Conclusions: Our analyses have examined potentially modifiable correlates of study SES and shown that a minimum pain inclusion criterion of 40 or above on a 0 to 100 scale is associated with a larger SES. These data provide a foundation for investigating strategies to improve assay sensitivity and thereby decrease the likelihood of falsely negative outcomes in clinical trials of efficacious treatments for neuropathic pain.

Risk factors for poor visual outcome in patients with idiopathic intracranial hypertension

Objectives: Determine potential risk factors for progressive visual field loss in the Idiopathic Intracranial Hypertension Treatment Trial, a randomized placebo-controlled trial of acetazolamide in patients with idiopathic intracranial hypertension and mild visual loss concurrently receiving a low sodium, weight reduction diet. Methods: Logistic regression and classification tree analyses were used to evaluate potential risk factors for protocol-defined treatment failure (>2 dB perimetric mean deviation [PMD] change in patients with baseline PMD −2 to −3.5 dB or >3 dB PMD change with baseline PMD −3.5 to −7 dB). Results: Seven participants (6 on diet plus placebo) met criteria for treatment failure. The odds ratio for patients with grades III to V papilledema vs those with grades I and II was 8.66 (95% confidence interval [CI] 1.65–∞, p = 0.025). A 1-unit decrease in the number of letters correct on the ETDRS (Early Treatment Diabetic Retinopathy Study) chart at baseline was associated with an increase in the odds of treatment failure by a factor of 1.16 (95% CI 1.04–1.30, p = 0.005). Compared with female participants, the odds ratio for male participants was 26.21 (95% CI 1.61–433.00, p = 0.02). The odds of treatment failure were 10.59 times higher (95% CI 1.63–116.83, p = 0.010) for patients with >30 transient visual obscurations per month vs those with ≤30 per month. Conclusions: Male patients, those with high-grade papilledema, and those with decreased visual acuity at baseline were more likely to experience treatment failure. All but one of these patients were treated with diet alone. These patients should be monitored closely and be considered for aggressive treatment of their idiopathic intracranial hypertension.

A robust method using propensity score stratification for correcting verification bias for binary tests.

Sensitivity and specificity are common measures of the accuracy of a diagnostic test. The usual estimators of these quantities are unbiased if data on the diagnostic test result and the true disease status are obtained from all subjects in an appropriately selected sample. In some studies, verification of the true disease status is performed only for a subset of subjects, possibly depending on the result of the diagnostic test and other characteristics of the subjects. Estimators of sensitivity and specificity based on this subset of subjects are typically biased; this is known as verification bias. Methods have been proposed to correct verification bias under the assumption that the missing data on disease status are missing at random (MAR), that is, the probability of missingness depends on the true (missing) disease status only through the test result and observed covariate information. When some of the covariates are continuous, or the number of covariates is relatively large, the existing methods require parametric models for the probability of disease or the probability of verification (given the test result and covariates), and hence are subject to model misspecification. We propose a new method for correcting verification bias based on the propensity score, defined as the predicted probability of verification given the test result and observed covariates. This is estimated separately for those with positive and negative test results. The new method classifies the verified sample into several subsamples that have homogeneous propensity scores and allows correction for verification bias. Simulation studies demonstrate that the new estimators are more robust to model misspecification than existing methods, but still perform well when the models for the probability of disease and probability of verification are correctly specified.

Meta-analysis of assay sensitivity and study features in clinical trials of pharmacologic treatments for osteoarthritis pain

To identify patient, study, and site factors associated with assay sensitivity in clinical trials of pharmacologic treatments for osteoarthritis (OA) pain.

A Comparison of the Assay Sensitivity of Average and Worst Pain Intensity in Pharmacologic Trials: An ACTTION Systematic Review and Meta-Analysis

Identifying methods to improve assay sensitivity in randomized clinical trials (RCTs) may facilitate the discovery of efficacious pain treatments. RCTs evaluating pain treatments typically use average pain intensity (API) or worst pain intensity (WPI) as the primary efficacy outcome. However, little evidence is available comparing the assay sensitivity of these 2 measures. In this systematic review and meta-analysis, we comprehensively reviewed all low back pain, osteoarthritis pain, fibromyalgia, diabetic peripheral neuropathy pain, and postherpetic neuralgia RCTs that used a parallel group design. Eligibility required: 1) primary RCT report published between 1980 and 2016, 2) comparing 1 or more active, efficacious pharmacologic pain treatment(s) with placebo, and 3) providing data on the standardized effect size (SES) for API as well as WPI for all treatment arms. Twenty-seven active versus placebo comparisons were identified in 23 eligible articles. Using a random-effects meta-analysis, API SES and WPI SES did not differ significantly (differenceu2009=u2009-.021, 95% confidence interval = -.047 to .004, Pu2009=u2009.12). The findings indicate that, depending on the objectives of the study, either API or WPI could be used as a primary outcome measure in clinical trials for the chronic pain conditions included in this analysis.nnnPERSPECTIVEnUnderstanding the comparative assay sensitivity of API and WPI may advance pain treatment research. A meta-analysis of trials of efficacious pharmacologic treatments in 5 pain conditions did not show a statistically significant difference between the assay sensitivity of API and WPI.