A Population-Based Approach to Reporting System-Level Performance Measures for Rheumatoid Arthritis Care.

OBJECTIVE: To operationalize and report on nationally endorsed rheumatoid arthritis (RA) performance measures (PMs) using health administrative data for British Columbia (BC), Canada. METHODS: All patients with RA in BC ages ≥18 years were identified between January 1, 1997 and December 31, 2009 using health administrative data and followed until December 2014. PMs tested include: the percentage of incident patients with ≥1 rheumatologist visit within 365 days; the percentage of prevalent patients with ≥1 rheumatologist visit per year; the percentage of prevalent patients dispensed disease-modifying antirheumatic drug (DMARD) therapy; and time from RA diagnosis to DMARD therapy. Measures were reported on patients seen by rheumatologists, and in the total population. RESULTS: The cohort included 38,673 incident and 57,922 prevalent RA cases. The percentage of patients seen by a rheumatologist within 365 days increased over time (35% in 2000 to 65% in 2009), while the percentage of RA patients under the care of a rheumatologist seen yearly declined (79% in 2001 to 39% in 2014). The decline was due to decreasing visit rates with increasing follow-up time rather than calendar effect. The percentage of RA patients dispensed a DMARD was suboptimal over follow-up (37% in 2014) in the total population but higher (87%) in those under current rheumatologist care. The median time to DMARD in those seen by a rheumatologist improved from 49 days in 2000 to 23 days in 2009, with 34% receiving treatment within the 14-day benchmark. CONCLUSION: This study describes the operationalization and reporting of national PMs using administrative data and identifies gaps in care to further examine and address.

Automated estimation of echocardiogram image quality in hospitalized patients.

We developed a machine learning model for efficient analysis of echocardiographic image quality in hospitalized patients. This study applied a machine learning model for automated transthoracic echo (TTE) image quality scoring in three inpatient groups. Our objectives were: (1) Assess the feasibility of a machine learning model for echo image quality analysis, (2) Establish the comprehensiveness of real-world TTE reporting by clinical group, and (3) Determine the relationship between machine learning image quality and comprehensiveness of TTE reporting. A machine learning model was developed and applied to TTEs from three matched cohorts for image quality of nine standard views. Case TTEs were comprehensive studies in mechanically ventilated patients between 01/01/2010 and 12/31/2015. For each case TTE, there were two matched spontaneously breathing controls (Control 1: Inpatients scanned in the lab and Control 2: Portable studies). We report the overall mean maximum and view specific quality scores for each TTE. The comprehensiveness of an echo report was calculated as the documented proportion of 12 standard parameters. An inverse probability weighted regression model was fit to determine the relationship between machine learning quality score and the completeness of a TTE report. 175 mechanically ventilated TTEs were included with 350 non-intubated samples (175 Control 1: Lab and 175 Control 2: Portable). In total, the machine learning model analyzed 14,086 echo video clips for quality. The overall accuracy of the model with regard to the expert ground truth for the view classification was 87.0%. The overall mean maximum quality score was lower for mechanically ventilated TTEs (0.55 [95% CI 0.54, 0.56]) versus 0.61 (95% CI 0.59, 0.62) for Control 1: Lab and 0.64 (95% CI 0.63, 0.66) for Control 2: Portable; p = 0.002. Furthermore, mechanically ventilated TTE reports were the least comprehensive, with fewer reported parameters. The regression model demonstrated the correlation of echo image quality and completeness of TTE reporting regardless of the clinical group. Mechanically ventilated TTEs were of inferior quality and clinical utility compared to spontaneously breathing controls and machine learning derived image quality correlates with completeness of TTE reporting regardless of the clinical group.

A Meta-Analysis of Case Fatality Rates of Recurrent Venous Thromboembolism and Major Bleeding in Patients with Cancer.

BACKGROUND: Knowing the case fatality rates of recurrent venous thromboembolism (VTE) and major bleeding is important for weighing the relative risks and benefits of anticoagulation and deciding on the duration of anticoagulant therapy, but these rates are uncertain in patients with cancer-associated thrombosis. METHODS: We performed a systematic review and a meta-analysis to determine the incidence of recurrent VTE and major bleeding and their respective case fatality rates in patients with cancer-associated VTE. RESULTS: Our analysis included 29 studies (15 prospective cohort studies and 14 randomized controlled trials) from 1980 to January 2019. Data from 8,000 cancer patients with 4,786 patient-years of follow-up were summarized. Rates of recurrent VTE and fatal recurrent VTE were 23.7 (95% confidence interval [CI]: 20.1-27.8) and 1.9 (95% CI: 0.8-4.0) per 100 patient-years of follow-up, respectively, with a case fatality rate of 14.8% (95% CI: 6.6-30.1%). The rates of major bleeding and fatal major bleeding events were 13.1 (95% CI: 10.3-16.7) and 0.8 (95% CI: 0.3-2.1) per 100 patient-years of follow-up, respectively, with a case fatality rate of 8.9% (95% CI: 3.5-21.1%). While the estimates of case fatality vary by anticoagulation regimen and study design, the differences between them were not statistically significant. CONCLUSION: In cancer patients receiving anticoagulation, the case fatality rate of recurrent VTE is higher than the case fatality rate of major bleeding. These findings may help to inform decisions regarding the management of anticoagulation in patients with active cancer and VTE.

Health Utility Weighting of the Modified Rankin Scale: A Systematic Review and Meta-analysis.

Importance: The utility-weighted modified Rankin Scale (UW-mRS) has been proposed as a patient-centered alternative primary outcome for stroke clinical trials. However, to date, there is no clear consensus on an approach to weighting the mRS. Objective: To characterize the between-study variability in utility weighting of the mRS in a population of patients who experienced stroke and its implications when applied to the results of a clinical trial. Data Sources: In this systematic review and meta-analysis, MEDLINE, Embase, and PsycINFO were searched from January 1987 through May 2019 using major search terms for stroke, health utility, and mRS. Study Selection: Original research articles published in English were reviewed. Included were studies with participants 18 years or older with ischemic or hemorrhagic stroke, transient ischemic attack, or subarachnoid hemorrhage, with mRS scores and utility weights evaluated concurrently. A total of 5725 unique articles were identified. Of these, 283 met criteria for full-text review, and 24 were included in the meta-analysis. Data Extraction and Synthesis: PRISMA guidelines for systematic review were followed. Data extraction was performed independently by multiple researchers. Data were pooled using mixed models. Main Outcomes and Measures: The mean utility weights and 95% CIs were calculated for each mRS score and health utility scale. Geographic differences in weighting for the EuroQoL 5-dimension (EQ-5D) and Stroke Impact Scale-based UW-mRS were explored using inverse variance-weighted linear models. The results of 18 major acute stroke trials cited in current guidelines were then reanalyzed using the UW-mRS weighting scales identified in the systematic review. Results: The meta-analysis included 22 389 individuals; the mean (SD) age of participants was 65.9 (4.0) years, and the mean (SD) proportion of male participants was 58.2% (7.5%). For all health utility scales evaluated, statistically significant differences were observed between the mean utility weights by mRS score. For studies using an EQ-5D-weighted mRS, between-study variance was higher for worse (mRS 2-5) compared with better (mRS 0-1) scores. Of the 18 major acute stroke trials with reanalyzed results, 3 had an unstable outcome when using different UW-mRSs. Conclusions and Relevance: Multiple factors, including cohort-specific characteristics and health utility scale selection, can influence mRS utility weighting. If the UW-mRS is selected as a primary outcome, the approach to weighting may alter the results of a clinical trial. Researchers using the UW-mRS should prospectively and concurrently obtain mRS scores and utility weights to characterize study-specific outcomes.

Patient characteristics and long-term outcomes beyond the first 6 months after a diagnosis of cancer-associated venous thromboembolism.

INTRODUCTION: Little is known about the clinical course and treatment decisions in patients with cancer-associated venous thromboembolism (VTE) beyond the initial treatment period of 3 to 6 months. This information is important for clinicians and patients to inform their decisions regarding duration of anticoagulation. MATERIALS AND METHODS: We reviewed health records from consecutive patients referred to our institution for cancer-associated VTE management between 2013 and 2015 to describe their clinical course and outcomes from 6 to 24 months following their index VTE. Details on patient and cancer characteristics, objectively documented recurrent venous thromboembolism (rVTE), clinically relevant bleeding (CRB) and overall mortality were captured. RESULTS: 524 patients met eligibility criteria and 322 were alive at 6 months after the index VTE. At 6 months, anticoagulation was continued in 222 patients (68.9%). During follow-up, there were 33 rVTE events in 30 patients (1-year cumulative incidence of 8.2%; 95% CI: 5.5%-11.6%), and 16 CRB events in 15 patients (1-year cumulative incidence of 4.1%; 95% CI: 2.3%-6.7%); 20 (60.6%) rVTE events and 13 (81.3%) CRB events occurred while on anticoagulation. One-year survival beyond 6 months was 73.7% (95% CI: 68.5%-78.2%). A higher proportion of patients with advanced cancer and receiving cancer treatment was found among those who continued anticoagulation beyond 6 months compared to those who stopped anticoagulation. CONCLUSIONS: Patients with cancer-associated VTE who are alive at 6 months after VTE diagnosis remain at high risk of rVTE, CRB and death.

Pregnancy Outcomes among Women Receiving rVSVΔ-ZEBOV-GP Ebola Vaccine during the Sierra Leone Trial to Introduce a Vaccine against Ebola.

Little information exists regarding Ebola vaccine rVSVΔG-ZEBOV-GP and pregnancy. The Sierra Leone Trial to Introduce a Vaccine against Ebola (STRIVE) randomized participants without blinding to immediate or deferred (18-24 weeks postenrollment) vaccination. Pregnancy was an exclusion criterion, but 84 women were inadvertently vaccinated in early pregnancy or became pregnant <60 days after vaccination or enrollment. Among immediate vaccinated women, 45% (14/31) reported pregnancy loss, compared with 33% (11/33) of unvaccinated women with contemporaneous pregnancies (relative risk 1.35, 95% CI 0.73-2.52). Pregnancy loss was similar among women with higher risk for vaccine viremia (conception before or <14 days after vaccination) (44% [4/9]) and women with lower risk (conception >15 days after vaccination) (45% [10/22]). No congenital anomalies were detected among 44 live-born infants examined. These data highlight the need for Ebola vaccination decisions to balance the possible risk for an adverse pregnancy outcome with the risk for Ebola exposure.

Early predictors of developing problematic spasticity following traumatic spinal cord injury: A prospective cohort study.

Objective: To identify early predictors and develop reliable, validated prediction models for development of problematic spasticity after traumatic spinal cord injury (SCI).Design: Prospective cohort study of the Rick Hansen Spinal Cord Injury Registry (RHSCIR), retrospective review of inpatient medical charts.Setting: Quaternary trauma center, rehabilitation center, community settings.Participants: Individuals with traumatic SCI between March 1, 2005, and March 31, 2014, prospectively enrolled in the Vancouver site RHSCIR.Interventions: None.Main Outcome Measure: Spasticity limiting function or requiring treatment (problematic spasticity) on the Spinal Cord Injury Health Questionnaire.Results: In 350 patients, variables documented during hospitalization that predicted the development of problematic spasticity up to 5 years post-injury included: initial Glasgow Coma Scale; age at time of injury; admission to rehabilitation center; community discharge anti-spasticity medication prescription, neurological status, Penn Spasm Frequency Scale, and pain interference with quality of life, sleep, activities; greater change in AIS motor scores between admission and discharge. The predictive models had area under the receiver operating characteristic curve of 0.80 (95% CI 0.75, 0.85) in the development set (N = 244) and 0.84 (95% CI 0.74, 0.92) in the validation set (N = 106) for spasticity limiting function and 0.81 (95% CI 0.76, 0.85) in the development set and 0.85 (95% CI 0.77, 0.92) in the validation set for spasticity requiring treatment.Conclusions: Our prediction models provide an early prognosis of risk of developing problematic spasticity after traumatic SCI, which can be used to improve clinical spasticity management and assist research (e.g. risk stratification in interventional trials).

Randomized trial comparing the safety and antibody responses to live attenuated versus inactivated influenza vaccine when administered to breastfeeding women.

BACKGROUND: Live attenuated influenza vaccine (LAIV) and inactivated influenza vaccine (IIV) are both licensed for administration to nursing mothers. Little is known about the potential for transmission of LAIV viruses from the mother to the infant and the comparative breast milk antibody responses to LAIV and IIV. METHODS: We performed a randomized, double-blind study comparing the immunogenicity of LAIV to IIV when administered to nursing mothers. The safety of LAIV to IIV in women and their infants was also compared. Women received LAIV + intramuscular placebo, or IIV + intranasal placebo on Day 0. Breast milk and nasal swabs (from women and infants) were collected on Days 0, 2, and 8 for detection of LAIV. Breast milk and serum antibody responses were measured at Days 0 and 28. The primary hypothesis was that LAIV would provide superior induction of breast milk IgA responses to influenza as compared to IIV when administered to nursing mothers. RESULTS: Breast milk IgG, breast milk IgA (H1N1 only), serum hemagglutination inhibition (HAI), and serum IgG responses were significantly higher following administration of IIV compared to LAIV. Receipt of either LAIV or IIV was safe in women and their infants. One (1%) LAIV recipient transmitted vaccine virus to her infant who remained well. No influenza virus was detected in breast milk. CONCLUSIONS: Breast milk and serum antibody responses were higher for IIV compared to LAIV. LAIV and IIV were safe for nursing women but there was one (1%) possible transmission of LAIV to an infant. This study suggests that IIV may be the preferred vaccine for nursing mothers.

Treatment patterns of in-patient spasticity medication use after traumatic spinal cord injury: a prospective cohort study.

STUDY DESIGN: Prospective cohort study using the Rick Hansen SCI Registry (RHSCIR) and retrospective medical chart review. OBJECTIVE: To describe treatment patterns of in-patient anti-spasticity medication use following traumatic spinal cord injury (SCI) in acute and rehabilitation hospital settings in British Columbia, Canada. SETTING: Quaternary trauma center, rehabilitation center. METHODS: Individuals with traumatic SCI between 2005 and 2014 enrolled in the Vancouver RHSCIR site (N = 917) were eligible for inclusion. Oral and injectable anti-spasticity medication use were the main outcome measures. RESULTS: In 769 participants, higher neurological level and injury severity were associated with in-patient anti-spasticity medication use (p < 0.001 for both). Of individuals with cervical and thoracic injuries (n = 589), 37% were prescribed anti-spasticity medication during hospital admission. Baclofen was the most commonly used first line oral therapy. Mean (SD) and median time from injury to Baclofen initiation was 70 (69) and 50 days, respectively. The probability of having initiated an in-patient anti-spasticity medication was 55% (95% CI (49, 60)) for individuals 6 months post-injury, and 71% (95% CI (62, 79)) for individuals 12 months post-injury. At community discharge, the prevalence of oral and injectable anti-spasticity medication use was 26 and 5%. Practice patterns of anti-spasticity medication use (2005-2009 vs. 2010-2014) have not changed significantly over time. CONCLUSIONS: This is the first large prospective cohort study of in-patient anti-spasticity medication use following traumatic SCI. Results from our study inform clinicians and individuals of "real world" anti-spasticity medication use among individuals with traumatic SCI and may help guide care for this population in the community.

Multivariate association between single-nucleotide polymorphisms in Alzgene linkage regions and structural changes in the brain: discovery, refinement and validation.

Using publicly-available data from the Alzheimer's Disease Neuroimaging Initiative, we investigate the joint association between single-nucleotide polymorphisms (SNPs) in previously established linkage regions for Alzheimer's disease (AD) and rates of decline in brain structure. In an initial, discovery stage of analysis, we applied a weighted RV test to assess the association between 75,845 SNPs in the Alzgene linkage regions and rates of change in structural MRI measurements for 56 brain regions affected by AD, in 632 subjects. After confirming association, we selected refined lists of 1694 and 22 SNPs via a bootstrap-enhanced sparse canonical correlation analysis. In a final, validation stage, we confirmed association between the refined list of 1694 SNPs and the imaging phenotypes in an independent data set. Genes corresponding to priority SNPs having the highest contribution in the validation data have previously been implicated or hypothesized to be implicated in AD, including GCLC, IDE, and STAMBP1andFAS. Though the effect sizes of the 1694 SNPs in the priority set are likely small, further investigation within this set may advance understanding of the missing heritability in AD. Our analysis addresses challenges in current imaging-genetics studies such as biased sampling designs and high-dimensional data with low association signal.

A Bayesian group sparse multi-task regression model for imaging genetics.

MOTIVATION: Recent advances in technology for brain imaging and high-throughput genotyping have motivated studies examining the influence of genetic variation on brain structure. Wang et al. have developed an approach for the analysis of imaging genomic studies using penalized multi-task regression with regularization based on a novel group l2,1-norm penalty which encourages structured sparsity at both the gene level and SNP level. While incorporating a number of useful features, the proposed method only furnishes a point estimate of the regression coefficients; techniques for conducting statistical inference are not provided. A new Bayesian method is proposed here to overcome this limitation. RESULTS: We develop a Bayesian hierarchical modeling formulation where the posterior mode corresponds to the estimator proposed by Wang et al. and an approach that allows for full posterior inference including the construction of interval estimates for the regression parameters. We show that the proposed hierarchical model can be expressed as a three-level Gaussian scale mixture and this representation facilitates the use of a Gibbs sampling algorithm for posterior simulation. Simulation studies demonstrate that the interval estimates obtained using our approach achieve adequate coverage probabilities that outperform those obtained from the nonparametric bootstrap. Our proposed methodology is applied to the analysis of neuroimaging and genetic data collected as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI), and this analysis of the ADNI cohort demonstrates clearly the value added of incorporating interval estimation beyond only point estimation when relating SNPs to brain imaging endophenotypes. AVAILABILITY AND IMPLEMENTATION: Software and sample data is available as an R package 'bgsmtr' that can be downloaded from The Comprehensive R Archive Network (CRAN). CONTACT: nathoo@uvic.ca. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

A New QT Interval Correction Formulae to Adjust for Increases in Heart Rate.

OBJECTIVES: This study sought to develop a formula from a large population-based study that best fit the QT-heart rate (HR) relationship independent of the standard mathematical relationships. BACKGROUND: Attempts to adjust or correct for the impact of HR on the QT interval (QTc) have applied various mathematical equations to electrocardiographic (ECG) data rather than allowing the data to determine the form of the relationship. METHODS: A spline correction function was developed using the ECG data from NHANES (National Health and Nutrition Examination Surveys) II and III. The magnitude of linear, quadratic, and cubic trends in the relationship between HR and each QTc was quantified using an F-statistic with differences between QTcs compared using a permutation procedure. RESULTS: The effect of HR on QT was obliterated by the spline QT for both men and women. The cross-validated spline QTc was superior (i.e., flatter) to 6 other formulae, including ones proposed previously. In ECGs from the clinic with HRs faster than 70 beats/min, the QTcs from different formulae were significantly (p < 0.0001) different from one another. Individual values suggest the use of the longest and shortest QTc intervals as developed originally. The new QTc and its population percentile ranking can be provided for clinical ECGs. CONCLUSIONS: A new QTc formula was developed which eliminates the relationship between QT and HR. At faster HRs, the 2 most commonly used QTcs provide numerical values at the extremes of QTc. Compared to existing formulae, the new formula had the best performance.