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The Electronic Health Record (EHR) contains information about social determinants of health (SDoH) such as homelessness. Much of this information is contained in clinical notes and can be extracted using natural language processing (NLP). This data can provide valuable information for researchers and policymakers studying long-term housing outcomes for individuals with a history of homelessness. However, studying homelessness longitudinally in the EHR is challenging due to irregular observation times. In this work, we applied an NLP system to extract housing status for a cohort of patients in the US Department of Veterans Affairs (VA) over a three-year period. We then applied inverse intensity weighting to adjust for the irregularity of observations, which was used generalized estimating equations to estimate the probability of unstable housing each day after entering a VA housing assistance program. Our methods generate unique insights into the long-term outcomes of individuals with a history of homelessness and demonstrate the potential for using EHR data for research and policymaking.

Comparisons between randomized trial analyses and observational analyses that attempt to address similar research questions have generated many controversies in epidemiology and the social sciences. There has been little consensus on when such comparisons are reasonable, what their implications are for the validity of observational analyses, or whether trial and observational analyses can be integrated to address effectiveness questions. Here, we consider methods for using observational analyses to complement trial analyses when assessing treatment effectiveness. First, we review the framework for designing observational analyses that emulate target trials and present an evidence map of its recent applications. We then review approaches for estimating the average treatment effect in the target population underlying the emulation: using observational analyses of the emulation data alone; and using transportability analyses to extend inferences from a trial to the target population. We explain how comparing treatment effect estimates from the emulation against those from the trial can provide evidence on whether observational analyses can be trusted to deliver valid estimates of effectiveness – a process we refer to as benchmarking – and, in some cases, allow the joint analysis of the trial and observational data. We illustrate different approaches using a simplified example of a pragmatic trial and its emulation in registry data. We conclude that synthesizing trial and observational data – in transportability, benchmarking, or joint analyses – can leverage their complementary strengths to enhance learning about comparative effectiveness, through a process combining quantitative methods and epidemiological judgements.

Huang proposes a method for assessing the impact of a point treatment on mortality either directly or mediated by occurrence of a nonterminal health event, based on data from a prospective cohort study in which the occurrence of the nonterminal health event may be preemptied by death but not vice versa. The author uses a causal mediation framework to formally define causal quantities known as natural (in)direct effects. The novelty consists of adapting these concepts to a continuous-time modeling framework based on counting processes. In an effort to posit "scientifically interpretable estimands," statistical and causal assumptions are introduced for identification. In this commentary, we argue that these assumptions are not only difficult to interpret and justify, but are also likely violated in the hepatitis B motivating example and other survival/time to event settings as well.

Open reduction internal fixation of tibial plateau and pilon fractures may be complicated by deep surgical site infection requiring operative debridement and antibiotic therapy. The management of superficial surgical site infection is controversial. We sought to determine whether superficial infection is associated with an increased risk of deep infection requiring surgical debridement after fixation of tibial plateau and pilon fractures.This is a secondary analysis of data from the VANCO trial, which included 980 adult patients with a tibial plateau or pilon fracture at elevated risk of infection who underwent open reduction internal fixation with plates and screws with or without intrawound vancomycin powder. An association of superficial surgical site infection with deep surgical site infection requiring debridement surgery and antibiotics was explored after matching on risk factors for deep surgical site infection.Of the 980 patients, we observed 30 superficial infections (3.1%) and 76 deep infections (7.8%). Among patients who developed a superficial infection, the unadjusted incidence of developing a deep infection within 90 days was 12.8% (95% confidence interval [CI] 1.3-24.2%). However, after a 3:1 match on infection risk factors, the 90-day marginal probability of a deep surgical site infection after sustaining a superficial infection was 6.0% (95% CI - 6.5-18.5%, p = 0.35).Deep infection after superficial infection is uncommon following operative fixation of tibial plateau and pilon fractures. Increased risk of subsequent deep infection attributable to superficial infection was inconclusive in these data.Prognostic Level II.

OBJECTIVE To evaluate the diagnostic performance of perfusion pressure (PP) thresholds for fasciotomy. DESIGN Prospective observational study. SETTING Seven Level-1 trauma centers. PATIENTS/PARTICIPANTS One hundred fifty adults with severe leg injuries and ≥2 hours of continuous PP data who had been enrolled in a multicenter observational trial designed to develop a clinical prediction rule for acute compartment syndrome (ACS). MAIN OUTCOME MEASUREMENTS For each patient, a given PP criterion was positive if it was below the specified threshold for at least 2 consecutive hours. The diagnostic performance of PP thresholds between 10 and 30 mm Hg was determined using 2 reference standards for comparison: (1) the likelihood of ACS as determined by an expert panel who reviewed each patient's data portfolio or (2) whether the patient underwent fasciotomy. RESULTS Using the likelihood of ACS as the diagnostic standard (ACS considered present if median likelihood ≥70%, absent if

Summary Whereas generic drugs offer a cost-effective alternative to brand name drugs, regulators need a method to assess therapeutic equivalence in a post-market setting. We develop such a method in the context of assessing the therapeutic equivalence of immediate release venlafaxine, based on a large insurance claims data set provided by OptumLabs\circledR. To address this question properly, our methodology must deal with issues of non-adherence, secular trends in health outcomes and lack of treatment overlap due to sharp uptake of the generic drug once it becomes available. We define, identify (under assumptions) and estimate (using G-computation) a causal effect for a time-to-event outcome by extending regression discontinuity to survival curves. We do not find evidence for a lack of therapeutic equivalence of brand and generic immediate release venlafaxine.

In randomized controlled trials of seriously ill patients, death is common and often defined as the primary endpoint. Increasingly, non-mortality outcomes such as functional outcomes are co-primary or secondary endpoints. Functional outcomes are not defined for patients who die, referred to as "truncation due to death", and among survivors, functional outcomes are often unobserved due to missed clinic visits or loss to follow-up. It is well known that if the functional outcomes "truncated due to death" or missing are handled inappropriately, treatment effect estimation can be biased. In this paper, we describe the package idem that implements a procedure for comparing treatments that is based on a composite endpoint of mortality and the functional outcome among survivors. Among survivors, the procedure incorporates a missing data imputation procedure with a sensitivity analysis strategy. A web-based graphical user interface is provided in the idem package to facilitate users conducting the proposed analysis in an interactive and user-friendly manner. We demonstrate idem using data from a recent trial of sedation interruption among mechanically ventilated patients.

OBJECTIVE To evaluate the association between patient- and center-level characteristics and discharge to an inpatient facility versus home after treatment for lower extremity trauma, as well as examine the variability in discharge disposition across clinical centers after controlling for these factors. DESIGN This is an analysis of data collected prospectively across 5 multicenter studies of extremity trauma. SETTING US Trauma Centers. PARTICIPANTS Patients 18-80 years with lower extremity trauma treated at 1 of 55 participating centers. MAIN OUTCOME MEASURE Discharge disposition. RESULTS Among 2365 patients treated at 1 of 55 centers across 13 states, 673 (28.5%) were discharged to an inpatient facility, and 1692 (71.5%) were discharged home. Individuals who were older, female, unmarried, insured, higher body mass index, history of severe alcohol abuse, Gustilo type IIIB or IIIC open injuries, bilateral, spine and upper extremity injuries, higher injury severity score scores, or intensive care unit stay were more likely to be discharged to an inpatient facility. Even after accounting for patient- and center-level characteristics, there was substantial variation in discharge disposition across centers (likelihood ratio test: P < 0.001). CONCLUSION Variation in discharge disposition may represent a potential for improvement in resource utilization and cost savings. Further studies are needed to examine the relationship between utilization of postdischarge inpatient facility after trauma and outcomes. LEVEL OF EVIDENCE Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Severe lower extremity trauma among working-age adults is highly consequential for returning to work; however, the economic impact attributed to injury has not been fully quantified. The purpose of this study was to examine work and productivity loss during the year following lower extremity trauma and to calculate the economic losses associated with lost employment, lost work time (absenteeism), and productivity loss while at work (presenteeism).This is an analysis of data collected prospectively across 3 multicenter studies of lower extremity trauma outcomes in the United States. Data were used to construct a Markov model that accumulated hours lost over time due to lost employment, absenteeism, and presenteeism among patients from 18 to 64 years old who were working prior to their injury. Average U.S. wages were used to calculate economic loss overall and by sociodemographic and injury subgroups.Of 857 patients working prior to injury, 47.2% had returned to work at 1 year. The average number of productive hours of work lost was 1,758.8/person, representing 84.6% of expected annual productive hours. Of the hours lost, 1,542.3 (87.7%) were due to working no hours or lost employment, 71.1 (4.0%) were due to missed hours after having returned, and 145.4 (8.3%) were due to decreased productivity while working. The 1-year economic loss due to injury totaled $64,427/patient (95% confidence interval [CI], $63,183 to $65,680). Of the 1,758.8 lost hours, approximately 88% were due to not being employed (working zero hours), 4% were due to absenteeism, and 8% were due to presenteeism. Total productivity loss was higher among older adults (≥40 years), men, those with a physically demanding job, and the most severe injuries (i.e., those leading to amputation as well as Gustilo type-IIIB tibial fractures and type-III pilon/ankle fractures).Patients with severe lower extremity trauma carry a substantial economic burden. The costs of lost productivity should be considered when evaluating outcomes.

To compare outcomes in patients with open tibia shaft fractures based on defect size.Retrospective review.Eighteen trauma centers.The study included 132 patients with diaphyseal tibia bone defects1 cm and ≥50% cortical loss treated with intramedullary nail.The primary outcome was number of secondary surgeries to promote healing (bone graft, revision fixation, or bone transport). Additional outcomes included occurrence of secondary surgeries (bone graft, infection, amputation, and flap failure) and proportion healed at one year. Results are compared by "radiographic apparent bone gap" of2.5 or ≥2.5 cm.The estimated conditional probability of bone grafting within one year given graft-free at 90 days was 44% and 47% in the2.5 cm and ≥2.5 cm groups, respectively. An estimated infection risk of 14% was observed in both groups [adjusted hazard ratio (HR) 0.98, 95% confidence interval (CI): 0.33-2.92], estimated amputation risk was 9% (2.5 cm) and 4% (≥2.5 cm) (unadjusted HR 0.66, 95% CI: 0.13-3.29), and estimated flap failure risk (among those with flaps) was 10% and 13%, respectively (unadjusted HR 1.71, 95% CI: 0.24-12.25). There was no appreciable difference in the proportion healed at one year between defect sizes [adjusted HR: 1.07 (95% CI, 0.63-1.82)].Larger size bone defects were not associated with higher number of secondary procedures to promote healing or a lower overall one-year healing rate.Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Randomized trials are often designed to collect outcomes at fixed points in time after randomization. In practice, the number and timing of outcome assessments can vary among participants (i.e., irregular assessment). In fact, the timing of assessments may be associated with the outcome of interest (i.e., informative assessment). For example, in a trial evaluating the effectiveness of treatments for major depressive disorder, not only did the timings of outcome assessments vary among participants but symptom scores were associated with assessment frequency. This type of informative observation requires appropriate statistical analysis. Although analytic methods have been developed, they are rarely used. In this article, we review the literature on irregular assessments with a view toward developing recommendations for analyzing trials with irregular and potentially informative assessment times. We show how the choice of analytic approach hinges on assumptions about the relationship between the assessment and outcome processes. We argue that irregular assessment should be treated with the same care as missing data, and we propose that trialists adopt strategies to minimize the extent of irregularity; describe the extent of irregularity in assessment times; make their assumptions about the relationships between assessment times and outcomes explicit; adopt analytic techniques that are appropriate to their assumptions; and assess the sensitivity of trial results to their assumptions.

In this article, I review the key elements of the proposed International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use E9 Addendum, present a constructive critique, and provide recommendations of how it can be improved. To highlight ideas, I present a case study involving a confirmatory trial for a chronic pain medication.

OBJECTIVES: To evaluate inter-rater reliability of the modified Radiographic Union Score for Tibial (mRUST) fractures among patients with open, diaphyseal tibia fractures with a bone defect treated with intramedullary nails (IMNs), plates, or definitive external fixation (ex-fix). DESIGN: Retrospective cohort study. SETTING: 15 level one civilian trauma centers; 2 military treatment facilities. PATIENTS/PARTICIPANTS: Patients ≥18-years-old with open, diaphyseal tibia fractures with a bone defect ≥1 centimeter surgically treated between 2007 and 2012. INTERVENTION: Three of six orthopaedic traumatologists reviewed and applied mRUST scoring criteria to radiographs from the last clinical visit within 13 months of injury. MAIN OUTCOME MEASUREMENTS: Inter-rater reliability was assessed using Krippendorff’s Alpha (KA) statistic; Intraclass correlation coefficient (ICC) is presented for comparison to previous publications. RESULTS: 213 patients met inclusion criteria including 115 IMNs, 24 plates, 29 ex-fixes, and 45 cases that no longer had instrumentation at evaluation. All reviewers agreed on the pattern of scoreable cortices for 90.4% of IMNs, 88.9% of those without instrumentation, 44.8% of rings, and 20.8% of plates. Thirty-one (15%) cases, primarily plates and ex-fixes, did not contribute to KA and ICC estimates because

Importance Despite the widespread use of systemic antibiotics to prevent infections in surgically treated patients with fracture, high rates of surgical site infection persist. Objective To examine the effect of intrawound vancomycin powder in reducing deep surgical site infections. Design, Setting, and Participants This open-label randomized clinical trial enrolled adult patients with an operatively treated tibial plateau or pilon fracture who met the criteria for a high risk of infection from January 1, 2015, through June 30, 2017, with 12 months of follow-up (final follow-up assessments completed in April 2018) at 36 US trauma centers. Interventions A standard infection prevention protocol with (n = 481) or without (n = 499) 1000 mg of intrawound vancomycin powder. Main Outcomes and Measures The primary outcome was a deep surgical site infection within 182 days of definitive fracture fixation. A post hoc comparison assessed the treatment effect on gram-positive and gram-negative-only infections. Other secondary outcomes included superficial surgical site infection, nonunion, and wound dehiscence. Results The analysis included 980 patients (mean [SD] age, 45.7 [13.7] years; 617 [63.0%] male) with 91% of the expected person-time of follow-up for the primary outcome. Within 182 days, deep surgical site infection was observed in 29 of 481 patients in the treatment group and 46 of 499 patients in the control group. The time-to-event estimated probability of deep infection by 182 days was 6.4% in the treatment group and 9.8% in the control group (risk difference, –3.4%; 95% CI, –6.9% to 0.1%;P = .06). A post hoc analysis of the effect of treatment on gram-positive (risk difference, –3.7%; 95% CI, –6.7% to –0.8%;P = .02) and gram-negative-only (risk difference, 0.3%; 95% CI, –1.6% to 2.1%;P = .78) infections found that the effect of vancomycin powder was a result of its reduction in gram-positive infections. Conclusions and Relevance Among patients with operatively treated tibial articular fractures at a high risk of infection, intrawound vancomycin powder at the time of definitive fracture fixation reduced the risk of a gram-positive deep surgical site infection, consistent with the activity of vancomycin. Trial Registration ClinicalTrials.gov Identifier:NCT02227446

We aim to help inform the choice of estimand (i.e., target of inference) and analysis method to be used in future COVID-19 treatment trials. To this end, we describe estimands for outcome types of particular interest in these trials (ordinal and time-to-event). When the outcome is ordinal, the estimands that we consider are the difference between study arms in the mean outcome, the Mann-Whitney (rank--based) estimand, and the average of the cumulative log odds ratios over the levels of the outcome. For time-to-event outcomes, we consider the difference between arms in the restricted mean survival time, the difference between arms in the cumulative incidence, and the relative risk. Advantageously, the interpretability of these estimands does not rely on a proportional odds or proportional hazards assumptions. For each estimand, we evaluate the potential value added by using estimators that leverage information in baseline variables to improve precision and reduce the required sample size to achieve a desired power. These are called covariate adjusted estimators. To evaluate the performance of the covariate adjusted and unadjusted estimators that we present, we simulate two-arm, randomized trials comparing a hypothetical COVID-19 treatment versus standard of care, where the primary outcome is ordinal or time-to-event. Our simulated distributions are derived from two sources: longitudinal data on over 500 patients hospitalized at Weill Cornell Medicine New York Presbyterian Hospital prior to March 28, 2020, and a CDC preliminary description of 2449 cases reported to the CDC from February 12 to March 16, 2020. We focus on hospitalized, COVID-19 positive patients and consider the following outcomes: intubation, ventilator use, and death. We conduct simulations using all three estimands when the outcome is ordinal, but only evaluate the restricted mean survival time when the outcome is time to event. Our simulations showed that, in trials with at least 200 participants, the precision gains due to covariate adjustment are equivalent to requiring 10-20% fewer participants to achieve the same power as a trial that uses the unadjusted estimator; this was the case for each outcome and estimand that we considered.

Objective This structured methodology review evaluated statistical approaches used in randomized controlled trials (RCTs) enrolling patients at high risk of death and makes recommendations for reporting future RCTs. Study design and setting Using PubMed, we searched for RCTs published in five general medicine journals from January 2014 to August 2019 wherein mortality was ≥10% in at least one randomized group. We abstracted primary and secondary outcomes, statistical analysis methods, and patient samples evaluated (all randomized patients vs. “survivors only”). Results Of 1947 RCTs identified, 434 met eligibility criteria. Of the eligible RCTs, 91 (21%) and 351 (81%) had a primary or secondary functional outcome, respectively, of which 36 (40%) and 263 (75%) evaluated treatment effects among “survivors only”. In RCTs that analyzed all randomized patients, the most common methods included use of ordinal outcomes (e.g., modified Rankin Scale) or creating composite outcomes (primary: 41 of 91 [45%]; secondary: 57 of 351 [16%]). Conclusion In RCTs enrolling patients at high risk of death, statistical analyses of functional outcomes are frequently conducted among “survivors only,” for which conclusions might be misleading. Given the growing number of RCTs conducted among patients hospitalized with COVID-19 and other critical illnesses, standards for reporting should be created.

In this paper, we present a method for conducting global sensitivity analysis of randomized trials in which binary outcomes are scheduled to be collected on participants at pre-specified points in time after randomization and these outcomes may be missing in a non-monotone fashion. We introduce a class of missing data assumptions, indexed by sensitivity parameters, that are anchored around the missing not at random assumption introduced by Robins (Statistics in Medicine, 1997). For each assumption in the class, we establish that the joint distribution of the outcomes are identifiable from the distribution of the observed data. Our estimation procedure uses the plug-in principle, where the distribution of the observed data is estimated using random forests. We establish √n asymptotic properties for our estimation procedure. We illustrate our methodology in the context of a randomized trial designed to evaluate a new approach to reducing substance use, assessed by testing urine samples twice weekly, among patients entering outpatient addiction treatment. We evaluate the finite sample properties of our method in a realistic simulation study. Our methods have been implemented in an R package entitled slabm. This article is protected by copyright. All rights reserved.

Background The Intrepid Dynamic Exoskeletal Orthosis (IDEO) is a custom energy-storing carbon fiber ankle-foot orthosis developed for lower-extremity trauma patients. Studies conducted at the military treatment facility where the IDEO was developed demonstrated benefits of the IDEO when used with the Return to Run Physical Therapy (RTR PT) program. The current study was designed to determine if results could be replicated at other military treatment facilities and to examine whether early performance gains in patient-reported functional outcomes remained at 12 months. Methods Study participants included service members who had functional deficits that interfered with daily activities at least 1 year after a traumatic unilateral lower-extremity injury at or below the knee. Participants were evaluated before receiving the IDEO, immediately following completion of RTR PT, and at 6 and 12 months. Agility, strength/power, and speed were assessed using well-established performance tests. Self-reported function was measured using the Short Musculoskeletal Function Assessment (SMFA). The Orthotics and Prosthetics Users' Survey was administered to assess satisfaction with the IDEO. Of 87 participants with complete baseline data, 6 did not complete any physical therapy and were excluded from the analysis. Follow-up rates immediately following completion of the RTR PT and at 6 and 12 months were 88%, 75%, and 79%, respectively. Results Compared with baseline, improvement at completion of RTR PT was observed in all but 1 performance test. SMFA scores for all domains except hand and arm function were lower (improved function) at 6 and 12 months. Satisfaction with the IDEO was high following completion of RTR PT, with some attenuation at the time of follow-up. Conclusions This study adds to the evidence supporting the efficacy of the IDEO coupled with RTR PT. However, despite improvement in both performance and self-reported functioning, deficits persist compared with population norms. Level of evidence Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

The impact of the Trauma Collaborative Care (TCC) program on surgeon confidence in managing the psychosocial sequelae of orthopaedic trauma was evaluated as part of a larger prospective, multisite, cluster clinical trial. We compared confidence and perceived resource availability among surgeons practicing in trauma centers that implemented the TCC program with orthopaedic trauma surgeons in similar trauma centers that did not implement the TCC.Prospective cohort design.Level-I trauma centers.Attending surgeons and fellows (N = 95 Pre and N = 82 Post).Self-report 10-item measure of surgeon confidence in managing psychosocial issues associated with trauma and perceived availability of support resources.Analyses, performed on the entire sample and repeated on the subset of 52 surgeons who responded to the survey at both times points, found surgeons at intervention sites experienced a significantly greater positive improvement (P0.05) in their (1) belief that they have strategies to help orthopaedic trauma patients change their psychosocial situation; (2) confidence in making appropriate referrals for orthopaedic trauma patients with psychosocial problems; and (3) belief that they have access to information to guide the management of psychosocial issues related to recovery.Initial data suggest that the establishment of the TCC program can improve surgeons' perceived availability of resources and their confidence in managing the psychosocial sequelae after injury. Further studies will be required to determine if this translates into beneficial patient effects.Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

In practice, both testable and untestable assumptions are generally required to draw inference about the mean outcome measured at the final scheduled visit in a repeated measures study with drop-out. Scharfstein et al. (2014) proposed a sensitivity analysis methodology to determine the robustness of conclusions within a class of untestable assumptions. In their approach, the untestable and testable assumptions were guaranteed to be compatible; their testable assumptions were based on a fully parametric model for the distribution of the observable data. While convenient, these parametric assumptions have proven especially restrictive in empirical research. Here, we relax their distributional assumptions and provide a more flexible, semi-parametric approach. We illustrate our proposal in the context of a randomized trial for evaluating a treatment of schizoaffective disorder.

The optimal technique for a transtibial amputation in a young, active, and healthy patient is controversial. Proponents of the Ertl procedure (in which the cut ends of the tibia and fibula are joined with a bone bridge synostosis) argue that the residual limb is more stable which confers better prosthetic fit and improved function especially among high-performing individuals. At the same time, the Ertl procedure is associated with longer operative and healing time and may be associated with a higher complication rate compared with the standard Burgess procedure. The TAOS is a prospective, multicenter randomized trial comparing 18-month outcomes after transtibial amputation using the Ertl versus Burgess approach among adults aged 18 to 60. The primary outcomes include surgical treatment for a complication and patient-reported function. Secondary outcomes include physical impairment, pain, and treatment cost.

Patients surgically treated for infection after extremity fractures are typically discharged with a 6- to 12-week antibiotic regimen. Intravenous (IV) antibiotics are associated with significant cost and potential complications of deep vein thrombosis, line clotting, and sepsis. Many of the pathogens that cause musculoskeletal infection have both oral (PO) and IV antibiotic options with adequate bioavailability and antibacterial effect, yet IV antibiotics remain the standard of care absent evidence that PO options are clinically as efficacious. The POvIV study is a prospective, multicenter, randomized trial to compare PO with IV antibiotic therapy in patients with postoperative wound infections after extremity fractures. Patients between the ages of 18 and 84 who have a culture-positive surgical site infection after internal fixation for fracture repair or arthrodesis are approached for this study, and if they provide consent, are randomly assigned to receive either PO or IV antibiotics. Antibiotic selection is based on culture and sensitivity results. Randomization determines the route of administration. Patients are followed for 1 year after study enrollment. This study will be the largest prospective randomized trial to evaluate the safety and effectiveness of PO antibiotic use for treatment of postoperative wound infections. Results will inform clinician decisions on antibiotic delivery in patients with postoperative wound infections.

Although limb salvage is now possible for many high-energy open fractures and crush injuries to the distal tibia, ankle, hindfoot, and midfoot, orthotic options are limited. The Intrepid Dynamic Exoskeletal Orthosis (IDEO) is a custom, energy-storing carbon fiber orthosis developed for trauma patients undergoing limb salvage. The IDEO differs from other orthoses in that it allows patients with ankle weakness to have more normal ankle biomechanics and increased ankle power. This article describes the design of a study to evaluate the effectiveness of the IDEO when delivered together with a high-intensity, sports medicine-based approach to rehabilitation. It builds on earlier studies by testing the program at military treatment facilities beyond the Brooke Army Medical Center and the Center for the Intrepid where the device was developed. The PRIORITI-MTF study is a multicenter before-after program evaluation where participants at least 1 year out from a traumatic lower extremity injury serve as their own controls. Participants are evaluated before receiving the IDEO, immediately after 4 weeks of physical therapy with the IDEO and at 6 and 12 months after the completion of physical therapy. Primary outcomes include functional performance, measured using well-validated assessments of speed, agility, power, and postural stability and self-reported functioning using the Short Musculoskeletal Function Assessment (SMFA) and the Veterans Health Survey (VR-12). Secondary outcomes include pain, depression, posttraumatic stress, and satisfaction with the IDEO.

The purpose of this study was to compare the number and types of extremity injuries treated at civilian trauma centers (CIV CENs) versus military treatment facilities (MTFs) participating in the Major Extremity Trauma Research Consortium (METRC) and to investigate the potential benefits of a clinical research network that includes both civilian trauma centers and MTFs. Two analyses were performed. First, registry data collected on all surgically treated fractures at four core MTFs and 21 CIV CENs over one year were compared. Second, actual numbers and distribution of patients by type of injury enrolled in three METRC studies were compared. While MTFs demonstrated higher percentages of severe injuries including open fractures, traumatic amputations, vascular injuries, contamination, and injuries with bone, muscle, and skin loss when compared to CIV CENS, the CIV CENs treated a substantially higher number and, more importantly, enrolled patients in almost all categories. Comparison of service members to civilians was challenged by several differences between the two patient populations including mechanism of injury, the medical care environment, and confounding factors such as age, social setting and co-morbidities. Despite these limitations, in times without active military conflict, clinical trials will likely rely on civilian trauma centers for patient enrollment; only when numbers are pooled across a large number of centers can requisite sample sizes be met. These data demonstrate the benefits of maintaining a military-civilian partnership to address the major gaps in research defined by the Military.

Background Step count monitors are frequently used in clinical research to measure walking activity. Systematically determining valid days and extracting informative measures of walking beyond total daily step count are among major analytical challenges. Research Question We introduce a novel data-driven anomaly detection algorithm to determine days representing typical walking activity (valid days) and examine the value of measures of walking fragmentation beyond total daily step count. Methods StepWatch data were collected on 230 adults with severe foot or ankle fractures. Average steps per minute (SC), average steps per active minute (SCA), active to sedentary transition probability (ASTP) and sedentary to active transition probability (SATP) were computed for each participant. The joint distribution of these measures was used to identify and eliminate invalid days through a multi-step process based on the support vector machine. The value of SCA, ASTP and SATP beyond SC were assessed by regressing Short Musculoskeletal Functional Assessment (SMFA), a measure of self-reported function, on these measures and quantifying the increase in the adjusted R-squared. In an unsupervised comparison, the total joint variability of SCA, ASTP and SATP was decomposed into the variability explained by SC and the unique variability of these three measures. Results Of the 4,448 days in the original data set, 39% were determined invalid. Individuals with higher average SC had higher SCA, lower ASTP and higher SATP. Measures of fragmentation (SCA, ASTP and SATP) explained 25% more of the variability in SMFA compared with SC alone. Approximately 41% of the variability in SCA, ASTP and SATP could not be explained by SC suggesting that these three measures provide unique information about walking patterns. Significance Applying SVM and quantifying fragmentation in walking bouts for step count data can help to more precisely assess activity in clinical studies employing this modality.

Summary We develop a Bayesian nonparametric (BNP) approach to evaluate the causal effect of treatment in a randomized trial where a nonterminal event may be censored by a terminal event, but not vice versa (i.e., semi-competing risks). Based on the idea of principal stratification, we define a novel estimand for the causal effect of treatment on the nonterminal event. We introduce identification assumptions, indexed by a sensitivity parameter, and show how to draw inference using our BNP approach. We conduct simulation studies and illustrate our methodology using data from a brain cancer trial. The R code implementing our model and algorithm is available for download at https://github.com/YanxunXu/BaySemiCompeting.

Importance Numerous studies have demonstrated that long-term outcomes after orthopedic trauma are associated with psychosocial and behavioral health factors evident early in the patient’s recovery. Little is known about how to identify clinically actionable subgroups within this population. Objectives To examine whether risk and protective factors measured at 6 weeks after injury could classify individuals into risk clusters and evaluate whether these clusters explain variations in 12-month outcomes. Design, Setting, and Participants A prospective observational study was conducted between July 16, 2013, and January 15, 2016, among 352 patients with severe orthopedic injuries at 6 US level I trauma centers. Statistical analysis was conducted from October 9, 2017, to July 13, 2018. Main Outcomes and Measures At 6 weeks after discharge, patients completed standardized measures for 5 risk factors (pain intensity, depression, posttraumatic stress disorder, alcohol abuse, and tobacco use) and 4 protective factors (resilience, social support, self-efficacy for return to usual activity, and self-efficacy for managing the financial demands of recovery). Latent class analysis was used to classify participants into clusters, which were evaluated against measures of function, depression, posttraumatic stress disorder, and self-rated health collected at 12 months. Results Among the 352 patients (121 women and 231 men; mean [SD] age, 37.6 [12.5] years), latent class analysis identified 6 distinct patient clusters as the optimal solution. For clinical use, these clusters can be collapsed into 4 groups, sorted from low risk and high protection (best) to high risk and low protection (worst). All outcomes worsened across the 4 clinical groupings. Bayesian analysis shows that the mean Short Musculoskeletal Function Assessment dysfunction scores at 12 months differed by 7.8 points (95% CI, 3.0-12.6) between the best and second groups, by 10.3 points (95% CI, 1.6-20.2) between the second and third groups, and by 18.4 points (95% CI, 7.7-28.0) between the third and worst groups. Conclusions and Relevance This study demonstrates that during early recovery, patients with orthopedic trauma can be classified into risk and protective clusters that account for a substantial amount of the variance in 12-month functional and health outcomes. Early screening and classification may allow a personalized approach to postsurgical care that conserves resources and targets appropriate levels of care to more patients.

To document the initial treatment of displaced acetabular fractures among older adults across multiple trauma centers and to investigate the factors that influence the decision to operate and the choice of operative procedure [open reduction internal fixation (ORIF) vs. total hip arthroplasty (THA)].Retrospective observational study.Fifteen US level-I trauma centers participating in the Major Extremity Trauma Research Consortium.Overall, 269 patients aged 60 years or older admitted for the treatment of a displaced acetabular fracture.None.Treatment.Sixty percent of fractures (n = 162) were treated operatively. Younger age (80 years), injury from high-energy mechanism, fractures with femoral head impaction, and fractures without hip congruency were significantly associated with receiving operative treatment (P0.05). Significant site variation in operative versus nonoperative treatment occurred even after accounting for these factors (P = 0.0044). Among operatively treated patients, 88% (n = 142) received ORIF and 12% (n = 20) received THA as the initial treatment. Women were more likely to be treated with initial THA compared with men; of the known risk factors for poor outcomes with ORIF (ie, dome or roof impaction, femoral head impaction, or posterior wall involvement), only dome impaction was significantly associated with receiving initial THA (P0.05).Currently, no treatment guidelines exist for acetabular fractures in older adults, which likely explains the significant site variation in operative versus nonoperative treatment. This study identifies patient and injury factors that drive treatment decisions, which will be important in planning and designing future trials needed to determine the best treatment for these fractures.

The treatment effect in subgroups of patients is often of interest in randomized controlled clinical trials, as this may provide useful information on how to treat which patients best. When a specific subgroup is characterized by the absence of certain events that happen postrandomization, a naive analysis on the subset of patients without these events may be misleading. The principal stratification framework allows one to define an appropriate causal estimand in such settings. Statistical inference for the principal stratum estimand hinges on scientifically justified assumptions, which can be included with Bayesian methods through prior distributions. Our motivating example is a large randomized placebo-controlled trial of siponimod in patients with secondary progressive multiple sclerosis. The primary objective of this trial was to demonstrate the efficacy of siponimod relative to placebo in delaying disability progression for the whole study population. However, the treatment effect in the subgroup of patients who would not relapse during the trial is relevant from both a scientific and patient perspective. Assessing this subgroup treatment effect is challenging as there is strong evidence that siponimod reduces relapses. We describe in detail the scientific question of interest, the principal stratum estimand, the corresponding analysis method for binary endpoints, and sensitivity analyses. Although our work is motivated by a randomized clinical trial, the approach has broader appeal and could be adapted for observational studies.

Randomized trials with patient-reported outcomes are commonly plagued by missing data. The analysis of such trials relies on untestable assumptions about the missing data mechanism. To address this issue, it has been recommended that the sensitivity of the trial results to assumptions should be a mandatory reporting requirement. In this paper, we discuss a recently developed methodology (Scharfstein et al., Biometrics, 2018) for conducting sensitivity analysis of randomized trials in which outcomes are scheduled to be measured at fixed points in time after randomization and some subjects prematurely withdraw from study participation. The methodology is explicated in the context of a placebo-controlled randomized trial designed to evaluate a treatment for bipolar disorder. We present a comprehensive data analysis and a simulation study to evaluate the performance of the method. A software package entitled SAMON (R and SAS versions) that implements our methods is available at www.missingdatamatters.org .

Intention-to-treat (ITT) analyses of randomized trials have been favored because they alleviate concerns about baseline confounding, but ITT analyses estimate the effect of being assigned to an int...

Mortality is a common primary endpoint in randomized controlled trials of patients with a high severity of illness, such as critically ill patients. However, researchers are increasingly evaluating functional outcomes, such as quality of life. Importantly, in such trials some patients may die before the assessment of a functional outcome, resulting in the functional outcome being “truncated due to death.” As described in this paper, defining and testing treatment effects on functional outcomes in this setting requires careful consideration. Data from a completed trial of critically ill patients are used to highlight key differences among three statistical approaches used when analyzing such trials.

Infection remains the most common and significant complication after high-energy fractures. The Bioburden Study is a multicenter, prospective, observational cohort study of wound bacterial bioburden and antibiotic care in severe open lower extremity fractures. The aims of this study are to (1) characterize the contemporary extremity wound "bioburden" at the time of definitive wound closure; (2) determine the concordance between polymerase chain reaction results and hospital microbiology; (3) determine, among those who develop deep infections, the concordance between the pathogens at wound closure and at deep infection; and (4) compare the probability of deep infection between those who did and did not receive an appropriate course of antibiotics based on bioburden at the time of wound closure. To address these aims, sites collected tissue samples from severe lower extremity injuries at the time of wound closure and at first surgery for treatment of a deep infection, nonunion, flap failure, amputation, or other complications (because these surgeries may be due to undetected infection). Otherwise, if no further surgical treatment occurred, participants were followed for 12 months. The study was conducted at 38 US trauma centers and has enrolled 655 participants aged 18-64 years. This is the first large multi-institutional study evaluating the wound bioburden of severe open tibia fractures and correlating this bioburden with the risk of wound complications after definitive soft tissue closure.

Poor pain control after orthopaedic trauma is a predictor of physical disability and numerous negative long-term outcomes. Despite increased awareness of the negative consequences of poorly controlled pain, analgesic therapy among hospitalized patients after orthopaedic trauma remains inconsistent and often inadequate. The Pain study is a 3 armed, prospective, double-blind, multicenter randomized trial designed to evaluate the effect of standard pain management versus standard pain management plus perioperative nonsteroidal anti-inflammatory drugs or pregabalin in patients of ages 18-85 with extremity fractures. The primary outcomes are chronic pain, opioid utilization during the 48 hours after definitive fixation and surgery for nonunion in the year after fixation. Secondary outcomes include preoperative and postoperative pain intensity, adverse events and complications, physical function, depression, and post-traumatic stress disorder. One year treatment costs are also compared between the groups.

Severe foot and ankle injuries are complex and challenging to treat, often requiring multiple operations to salvage the limb contributing to a prolonged healing period. There is some evidence to suggest that early amputation for some patients may result in better long-term outcomes than limb salvage. The challenge is to identify the regional injury burden for an individual that would suggest a better outcome with an amputation. The OUTLET study is a prospective, multicenter observational study comparing 18-month outcomes after limb salvage versus early amputation among patients aged 18-60 years with severe distal tibia, ankle, and foot injuries. This study aims to build upon the previous work of the Lower Extremity Assessment Project by identifying the injury and patient characteristics that help define a subgroup of salvage patients who will have better outcomes had they undergone a transtibial amputation.

A number of clinical studies in the spine literature suggest that the use of local vancomycin powder may substantially reduce surgical site infections (SSIs). These studies are primarily retrospective and observational and few focus on orthopaedic trauma patients. This study is a phase III, prospective, randomized, clinical trial to assess the efficacy of locally administered vancomycin powder in the prevention of SSI after fracture surgery. The primary goal of the VANCO Study is to compare the proportion of deep SSI 6 months after fracture fixation surgery. A secondary objective is to compare species and antibacterial susceptibilities among study patients who develop SSI. An additional objective is to build and validate a risk prediction model for the development of SSI. The study population consists of patients aged 18-80 years with tibial plateau or pilon (tibial plafond) fractures, at higher risk of infection, and definitively treated with plate and screw fixation. Participants are block randomized (within center) in a 1:1 ratio to either treatment group (local vancomycin powder up to a maximum dose of 1000 mg, placed immediately before wound closure) or control group (standard of care) for each study injury location, and return to the clinic for evaluations at 2 weeks, 3 months, and 6 months after fixation. The targeted sample size for the study is 500 fractures per study arm. This study should provide important information regarding the use of local vancomycin powder during the definitive treatment of lower extremity fractures and has the potential to significantly reduce the incidence of infection after orthopaedic trauma.

Previous research suggests that the care provided to trauma patients could be improved by including early screening and management of emotional distress and psychological comorbidity. The Trauma Collaborative Care (TCC) program, which is based on the principles of well-established models of collaborative care, was designed to address this gap in trauma center care. This article describes the TCC program and the design of a multicenter study to evaluate its effectiveness for improving patient outcomes after major, high-energy orthopaedic trauma at level 1 trauma centers. The TCC program was evaluated by comparing outcomes of patients treated at 6 intervention sites (n = 481) with 6 trauma centers where care was delivered as usual (control sites, n = 419). Compared with standard treatment alone, it is hypothesized that access to the TCC program plus standard treatment will result in lower rates of poor patient-reported function, depression, and posttraumatic stress disorder.

The diagnosis of acute compartment syndrome (ACS) is a common clinical challenge among patients who sustain high-energy orthopaedic trauma, largely because no validated criteria exist to reliably define the presence of the condition. In the absence of validated diagnostic standards, concern for the potential clinical and medicolegal impact of a missed compartment syndrome may result in the potential overuse of fasciotomy in "at-risk" patients. The goal of the Predicting Acute Compartment Syndrome Study was to develop a decision rule for predicting the likelihood of ACS that would reduce unnecessary fasciotomies while guarding against potentially missed ACS. Of particular interest was the utility of early and continuous monitoring of intramuscular pressure and muscle oxygenation using near-infrared spectroscopy in the timely diagnosis of ACS. In this observational study, 191 participants aged 18-60 with high-energy tibia fractures were prospectively enrolled and monitored for up to 72 hours after admission, then followed for 6 months. Treating physicians were blinded to continuous pressure and oxygenation data. An expert panel of 9 orthopaedic surgeons retrospectively assessed the likelihood that each patient developed ACS based on data collected on initial presentation, clinical course, and known functional outcome at 6 months. This retrospectively assigned likelihood is modeled as a function of clinical data typically available within 72 hours of admission together with continuous pressure and oxygenation data. This study will improve our understanding of the natural history of compartment syndrome and examine the utility of early and continuous monitoring of the physiologic status of the injured extremity in the timely diagnosis of ACS.

The treatment of high-energy open tibia fractures is challenging in both the military and civilian environments. Treatment with modern ring external fixation may reduce complications common in these patients. However, no study has rigorously compared outcomes of modern ring external fixation with commonly used internal fixation approaches. The FIXIT study is a prospective, multicenter randomized trial comparing 1-year outcomes after treatment of severe open tibial shaft fractures with modern external ring fixation versus internal fixation among men and women of ages 18-64. The primary outcome is rehospitalization for major limb complications. Secondary outcomes include infection, fracture healing, limb function, and patient-reported outcomes including physical function and pain. One-year treatment costs and patient satisfaction will be compared between the 2 groups, and the percentage of Gustilo IIIB fractures that can be salvaged without soft tissue flap among patients receiving external fixation will be estimated.

Supplemental perioperative oxygen (SPO) therapy has been proposed as one approach for reducing the risk of surgical site infection (SSI). Current data are mixed regarding efficacy in decreasing SSI rates and hospital inpatient stays in general and few data exist for orthopaedic trauma patients. This study is a phase III, double-blind, prospective randomized clinical trial with a primary goal of assessing the efficacy of 2 different concentrations of perioperative oxygen in the prevention of SSIs in adults with tibial plateau, pilon (tibial plafond), or calcaneus fractures at higher risk of infection and definitively treated with plate and screw fixation. Patients are block randomized (within center) in a 1:1 ratio to either treatment group (FiO2 80%) or control group (FiO2 30%) and stratified by each study injury location. Secondary objectives of the study are to compare species and antibacterial sensitivities of the bacteria in patients who develop SSIs, to validate a previously developed risk prediction model for the development of SSI after fracture surgery, and to measure and compare resource utilization and cost associated with SSI in the 2 study groups. SPO is a low cost and readily available resource that could be easily disseminated to trauma centers across the country and the world if proved to be effective.

We present a global sensitivity analysis methodology for drawing inference about the mean at the final scheduled visit in a repeated measures study with informative dropout. We review and critique the sensitivity frameworks developed by Rotnitzky et al. and Daniels and Hogan. We identify strengths and weaknesses of these approaches and propose an alternative. We illustrate our approach via a comprehensive analysis of the RIS-INT-3 trial.

We address estimation of intervention effects in experimental designs in which (a) interventions are assigned at the cluster level; (b) clusters are selected to form pairs, matched on observed characteristics; and (c) intervention is assigned to one cluster at random within each pair. One goal of policy interest is to estimate the average outcome if all clusters in all pairs are assigned control versus if all clusters in all pairs are assigned to intervention. In such designs, inference that ignores individual level covariates can be imprecise because cluster-level assignment can leave substantial imbalance in the covariate distribution between experimental arms within each pair. However, most existing methods that adjust for covariates have estimands that are not of policy interest. We propose a methodology that explicitly balances the observed covariates among clusters in a pair, and retains the original estimand of interest. We demonstrate our approach through the evaluation of the Guided Care program.

Zusammenfassung Zielsetzung Die Biopsie-Sensitivitat unter Dermatologen in Deutschland gegenuber Melanomen zu bestimmen und zu ermitteln, welchen Einfluss MelaFind® auf ihre Entscheidung hat, Melanome zu biopsieren. Studiendesign Randomisierte, zweiarmige Online-Leserstudie mit Prasentation von Fallinformationen, klinischen/dermatoskopischen Abbildungen pigmentierter Hautlasionen und MelaFind-Ergebnissen (Studienarm 2). Methoden Jeder Teilnehmer wurde aufgefordert, 130 pigmentierte Hautlasionen zu uberprufen. Die Biopsie-Entscheidungen von Dermatologen ohne MelaFind versus MelaFind und von Dermatologen ohne MelaFind versus Dermatologen mit MelaFind wurden miteinander verglichen. Ergebnisse Dermatologen ohne MelaFind zeigten eine durchschnittliche Sensitivitat gegenuber Melanomen von 69,5 % und eine durchschnittliche Spezifitat von 55,9 %. MelaFind hatte eine hohere Sensitivitat als Dermatologen ohne dieses Hilfsmittel (96,9 % vs. 69,5 %, einseitiger Test, p < 0,00001) bei niedrigerer Spezifitat (9,2 % vs. 55,9 %, einseitiger Test, p < 0,00001). Dermatologen mit MelaFind zeigten eine hohere Sensitivitat als Dermatologen ohne MelaFind (78 % vs. 69,5 %, einseitiger Test, p < 0,00001) und eine geringere Spezifitat (45,8 % vs. 55,9 %, einseitiger p < 0,00001). Die Zahl der Dermatologen, die uber 90 % der malignen Melanome entdeckten, stieg von 3 von 101 ohne MelaFind auf 22 von 101 mit MelaFind (p = 0,00006) bei weitestgehend unveranderter Spezifitat (23 % vs. 21 %, p = 0,99). Schlussfolgerungen Die durch MelaFind gewonnenen Informationen konnen, wenn sie in die Biopsie-Entscheidung mit einbezogen werden, die Sensitivitat verbessern bei nur geringer Beeinflussung der Spezifitat.

Summary Objectives To determine the biopsy sensitivity to melanoma of dermatologists in Germany and the impact of MelaFind® on their decisions to biopsy melanomas. Design Randomized two-armed online reader study presenting case information, clinical/dermatoscopic images of pigmented skin lesions and MelaFind results (Arm 2). Methods Each participant was asked to review 130 pigmented skin lesions. Biopsy decisions of dermatologists without MelaFind versus MelaFind and dermatologists without MelaFind versus dermatologists with MelaFind were compared. Results Dermatologists without MelaFind had average sensitivity to melanoma of 69.5 % and average specificity of 55.9 %. MelaFind had greater sensitivity than dermatologists alone (96.9 % vs. 69.5 %, one-sided p < 0.00001) and lower specificity (9.2 % vs. 55.9 %, one-sided p < 0.00001). Dermatologists with MelaFind had higher sensitivity than those without MelaFind (78 % vs. 69.5 %, one-sided p < 0.00001) and a lower specificity (45.8 % vs. 55.9 %, one-sided p < 0.00001). The number of dermatologists detecting over 90 % of melanomas increased from 3 of 101 without MelaFind to 22 of 101 with MelaFind (p = 0.00006) while specificity remained relatively equivalent (23 % vs. 21 %, p = 0.99). Conclusions The MelaFind information, when incorporated into the final biopsy decision, can improve biopsy sensitivity with modest effect on biopsy specificity.