TIGIT expression in renal cell carcinoma infiltrating T cells is variable and inversely correlated with PD-1 and LAG3.

PURPOSE: Immune checkpoint inhibitors have revolutionized the treatment of renal cell carcinoma (RCC), but many patients do not respond to therapy and the majority develop resistant disease over time. Thus, there is increasing need for alternative immunomodulating agents. The co-inhibitory molecule T-cell immunoglobulin and ITIM domain (TIGIT) may play a role in resistance to approved immune checkpoint inhibitors and is being investigated as a potential therapeutic target. The purpose of this study was to quantify TIGIT positivity in tumor-infiltrating T cells in RCC. METHODS: We employed tissue microarrays containing specimens from primary RCC tumors, adjacent normal renal tissue, and RCC metastases to quantify TIGIT within tumor-infiltrating CD3+ T cells using quantitative immunofluorescent analysis. We also compared these results to TIGIT+ CD3+ levels in four other tumor types (melanoma, non-small cell lung, cervical, and head and neck cancers). RESULTS: We did not observe significant differences in TIGIT positivity between primary RCC tumors and patient-matched metastatic samples. We found that the degree of TIGIT positivity in RCC is comparable to that in lung cancer but lower than that in melanoma, cervical, and head and neck cancers. Correlation analysis comparing TIGIT positivity to previously published, patient-matched spatial proteomic data by our group revealed a negative association between TIGIT and the checkpoint proteins PD-1 and LAG3. CONCLUSION: Our findings support careful evaluation of TIGIT expression on T cells in primary or metastatic RCC specimens for patients who may be treated with TIGIT-targeting antibodies, as increased TIGIT positivity might be associated with a greater likelihood of response to therapy.

GP100 expression is variable in intensity in melanoma.

Drugs or cellular products that bind to gp100 are being investigated for treatment of cutaneous melanoma. The relative specificity of gp100 expression in melanocytes makes it an attractive target to harness for therapeutic intent. For example, Tebentafusp, a bispecific gp100 peptide-HLA-directed CD3 T cell engager, has generated significant enthusiasm in recent years due to its success in improving outcomes for uveal melanoma and is being studied in cutaneous melanoma. However, the extent and intensity of gp100 expression in advanced cutaneous melanoma has not been well studied. Here, we interrogated a large cohort of primary and metastatic melanomas for gp100 expression by immunohistochemistry. Expression in metastatic samples was globally higher and almost uniformly positive, however the degree of intensity was variable. Using a quantitative immunofluorescence method, we confirmed the variability in expression. As gp100-binding drugs are assessed in clinical trials, the association between activity of the drugs and the level of gp100 expression should be studied in order to potentially improve patient selection.

First-Pass Success of Intubations Using Video Versus Direct Laryngoscopy in Children With Limited Neck Mobility.

OBJECTIVE: It is not clear whether video laryngoscopy (VL) is associated with a higher first-pass success rate in pediatric patients with limited neck mobility when compared with direct laryngoscopy (DL). We sought to determine the association between the laryngoscopy method and first-pass success. METHODS: In this retrospective cohort study, we examined intubation data extracted from 2 prospectively collected, multicenter, airway management safety databases (National Emergency Airway Registry and the National Emergency Airway Registry for children), obtained during the years 2013-2018 in the emergency department. Intubations were included if patients were aged younger than 18 and had limited neck mobility. We compared first-pass success rates for ED intubations that were performed using VL versus DL. We built a structural causal model to account for potential confounders such as age, disease category (medical or trauma condition), other difficult airway characteristics, use of sedatives/paralytics, and laryngoscopist training level. We also analyzed adverse events as a secondary outcome. RESULTS: Of 34,239 intubations (19,071 in the National Emergency Airway Registry and 15,168 in the National Emergency Airway Registry for children), a total of 341 intubations (1.0%) met inclusion criteria; 168 were performed via VL and 173 were performed via DL. The median age of patients was 124 months (interquartile range, 48-204). There was no difference in first-pass success between VL and DL (79.8% vs 75.7%, P = 0.44). Video laryngoscopy was not associated with higher first-pass success (odds ratio, 1.11; 95% confidence interval 0.84-1.47, with DL as a comparator) when a structural causal model was used to account for confounders. There was no difference in the adverse events between VL and DL groups (13.7% vs 8.7%, P = 0.19). CONCLUSION: In children with limited neck mobility receiving tracheal intubation in the ED, neither VL nor DL was associated with a higher first-pass success rate.

The Use of IV Vasoactive Intestinal Peptide (Aviptadil) in Patients With Critical COVID-19 Respiratory Failure: Results of a 60-Day Randomized Controlled Trial.

OBJECTIVES: Respiratory failure is a lethal complication of COVID-19 that has remained resistant to drug therapy. Vasoactive intestinal peptide (VIP) is shown in nonclinical studies to upregulate surfactant production, inhibit cytokine synthesis, prevent cytopathy, and block replication of the severe acute respiratory syndrome coronavirus 2 virus in pulmonary cells. The study aims to determine whether Aviptadil (synthetic VIP) can improve survival and recovery in patients with COVID-19 respiratory failure compared with placebo and demonstrate biological effects in such patients. DESIGN: A multicenter, placebo-controlled trial. SETTING: Ten U.S. hospitals: six tertiary-care hospitals and four community hospitals. PATIENTS: A total of 196 patients with COVID-19 respiratory failure. INTERVENTIONS: Participants were randomized 2:1 to receive 3 days of IV Aviptadil or placebo. MEASUREMENTS AND MAIN RESULTS: The primary end point (alive and free from respiratory failure at day 60) did not reach statistical significance (odds ratio [OR], 1.6; 95% CI, 0.86-3.11) for patients treated with Aviptadil when controlling for baseline ventilation status as prespecified in the protocol. There was, however, a statistically significant two-fold odds of improved survival (OR, 2.0; 95% CI, 1.1-3.9) at 60 days ( p = 0.035). There was significant improvement in respiratory distress ratio and reduced interleukin 6 cytokine release ( p = 0.02) by day 3.Subgroup analysis identified a statistically significant likelihood of achieving primary end point among those treated with high-flow nasal oxygen at baseline ( p = 0.039). Subjects on mechanical ventilation also experienced a 10-fold increased odds of survival with drug versus placebo ( p = 0.031). CONCLUSIONS: The primary end point did not reach statistical significance, indicating that there was no difference between Aviptadil versus placebo. However, Aviptadil improves the likelihood of survival from respiratory failure at day 60 in critical COVID-19 across all sites of care. Given the absence of drug-related serious adverse events and acceptable safety profile, we believe the benefit versus risk for the use of Aviptadil is favorable for patient treatment.

Designing a longitudinal clinical trial based on a composite endpoint: Sample size, monitoring, and adaptation.

Longitudinal clinical trials are often designed to compare treatments on the basis of multiple outcomes. For example in the case of cardiac trials, the outcomes of interest include mortality as well as cardiac events and hospitalization. For a COVID-19 trial, the outcomes of interest include mortality, time on ventilator, and time in hospital. Earlier work by these authors proposed a non-parametric test based on a composite of multiple endpoints referred to as the Finkelstein-Schoenfeld (FS) test (Finkelstein and Schoenfeld. Stat Med. 1999;18(11):1341-1354.). More recently, an estimate of the treatment comparison based on multiple endpoints (related to the FS test) was proposed (Pocock et al. Eur Heart J. 2011;33(2):176-182.). This estimate, which summarized the ratio of the number of patients who fared better vs worse on the experimental arm was coined the win ratio. The aim of this article is to provide guidance in the design of a trial that will use the FS test or the win ratio. The issues that will be considered are the sample size, sequential monitoring, and adaptive designs.

Alive and Ventilator Free: A Hierarchical, Composite Outcome for Clinical Trials in the Acute Respiratory Distress Syndrome.

OBJECTIVES: Survival from acute respiratory distress syndrome is improving, and outcomes beyond mortality may be important for testing new treatments. The "ventilator-free days" score, is an established composite that equates ventilation on day 28 to death. A hierarchical outcome treating death as a worse than prolonged ventilation would enhance face validity, but performance characteristics and reporting of such an outcome are unknown. We therefore evaluated the performance of a novel hierarchical composite endpoint, the Alive and Ventilator Free score. DESIGN: Using data from four Acute Respiratory Distress Syndrome Network clinical trials, we compared Alive and Ventilator Free to the ventilator-free days score. Alive and Ventilator Free compares each patient with every other patient in a win-lose-tie for each comparison. Duration of mechanical ventilation is only compared if both patients survived. We evaluated power of Alive and Ventilator Free versus ventilator-free days score under various circumstances. SETTING: ICUs within the Acute Respiratory Distress Syndrome Network. PATIENTS: Individuals enrolled in four Acute Respiratory Distress Syndrome Network trials. INTERVENTIONS: None for this analysis. MEASUREMENTS AND MAIN RESULTS: Within the four trials (n = 2,410 patients), Alive and Ventilator Free and ventilator-free days score had similar power, with Alive and Ventilator Free slightly more powerful when a mortality difference was present, and ventilator-free days score slightly more powerful with a difference in duration of mechanical ventilation. Alive and Ventilator Free less often found in favor of treatments that increased mortality and increased days free of ventilation among survivors. CONCLUSIONS: A hierarchical composite endpoint, Alive and Ventilator Free, preserves statistical power while improving face validity. Alive and Ventilator Free is less prone to favor a treatment with discordant effects on survival and days free of ventilation. This general approach can support complex outcome hierarchies with multiple constituent outcomes. Approaches to interpretation of differences in Alive and Ventilator Free are also presented.

Reappraisal of Ventilator-Free Days in Critical Care Research.

Ventilator-free days (VFDs) are a commonly reported composite outcome measure in acute respiratory distress syndrome trials. VFDs combine survival and duration of ventilation in a manner that summarizes the "net effect" of an intervention on these two outcomes. However, this combining of outcome measures makes VFDs difficult to understand and analyze, which contributes to imprecise interpretations. We discuss the strengths and limitations of VFDs and other "failure-free day" composites, and we provide a framework for when and how to use these outcome measures. We also provide a comprehensive discussion of the different analytic methods for analyzing and interpreting VFDs, including Student's t tests and rank-sum tests, as well as competing risk regressions treating extubation as the primary outcome and death as the competing risk. Using simulations, we illustrate how the statistical test with optimal power depends on the relative contributions of mortality and ventilator duration on the composite effect size. Finally, we recommend a simple analysis and reporting framework using the competing risk approach, which provides clear information on the effect size of an intervention, a statistical test and measure of confidence with the ability to adjust for baseline factors and allow interim monitoring for trials. We emphasize that any approach to analyzing a composite outcome, including other "failure-free day" constructs, should also be accompanied by an examination of the components.

Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19: A Randomized Clinical Trial.

Importance: Data on the efficacy of hydroxychloroquine for the treatment of coronavirus disease 2019 (COVID-19) are needed. Objective: To determine whether hydroxychloroquine is an efficacious treatment for adults hospitalized with COVID-19. Design, Setting, and Participants: This was a multicenter, blinded, placebo-controlled randomized trial conducted at 34 hospitals in the US. Adults hospitalized with respiratory symptoms from severe acute respiratory syndrome coronavirus 2 infection were enrolled between April 2 and June 19, 2020, with the last outcome assessment on July 17, 2020. The planned sample size was 510 patients, with interim analyses planned after every 102 patients were enrolled. The trial was stopped at the fourth interim analysis for futility with a sample size of 479 patients. Interventions: Patients were randomly assigned to hydroxychloroquine (400 mg twice daily for 2 doses, then 200 mg twice daily for 8 doses) (n = 242) or placebo (n = 237). Main Outcomes and Measures: The primary outcome was clinical status 14 days after randomization as assessed with a 7-category ordinal scale ranging from 1 (death) to 7 (discharged from the hospital and able to perform normal activities). The primary outcome was analyzed with a multivariable proportional odds model, with an adjusted odds ratio (aOR) greater than 1.0 indicating more favorable outcomes with hydroxychloroquine than placebo. The trial included 12 secondary outcomes, including 28-day mortality. Results: Among 479 patients who were randomized (median age, 57 years; 44.3% female; 37.2% Hispanic/Latinx; 23.4% Black; 20.1% in the intensive care unit; 46.8% receiving supplemental oxygen without positive pressure; 11.5% receiving noninvasive ventilation or nasal high-flow oxygen; and 6.7% receiving invasive mechanical ventilation or extracorporeal membrane oxygenation), 433 (90.4%) completed the primary outcome assessment at 14 days and the remainder had clinical status imputed. The median duration of symptoms prior to randomization was 5 days (interquartile range [IQR], 3 to 7 days). Clinical status on the ordinal outcome scale at 14 days did not significantly differ between the hydroxychloroquine and placebo groups (median [IQR] score, 6 [4-7] vs 6 [4-7]; aOR, 1.02 [95% CI, 0.73 to 1.42]). None of the 12 secondary outcomes were significantly different between groups. At 28 days after randomization, 25 of 241 patients (10.4%) in the hydroxychloroquine group and 25 of 236 (10.6%) in the placebo group had died (absolute difference, -0.2% [95% CI, -5.7% to 5.3%]; aOR, 1.07 [95% CI, 0.54 to 2.09]). Conclusions and Relevance: Among adults hospitalized with respiratory illness from COVID-19, treatment with hydroxychloroquine, compared with placebo, did not significantly improve clinical status at day 14. These findings do not support the use of hydroxychloroquine for treatment of COVID-19 among hospitalized adults. Trial Registration: ClinicalTrials.gov: NCT04332991.

Estimation for an accelerated failure time model with intermediate states as auxiliary information.

The accelerated failure time (AFT) model is a common method for estimating the effect of a covariate directly on a patient's survival time. In some cases, death is the final (absorbing) state of a progressive multi-state process, however when the survival time for a subject is censored, traditional AFT models ignore the intermediate information from the subject's most recent disease state despite its relevance to the mortality process. We propose a method to estimate an AFT model for survival time to the absorbing state that uses the additional data on intermediate state transition times as auxiliary information when a patient is right censored. The method extends the Gehan AFT estimating equation by conditioning on each patient's censoring time and their disease state at their censoring time. With simulation studies, we demonstrate that the estimator is empirically unbiased, and can improve efficiency over commonly used estimators that ignore the intermediate states.

Graphing the Win Ratio and its components over time.

Clinical trials are often designed to compare treatments on the basis of multiple outcomes. For the analysis of the treatment comparison from such a trial, in 1999, the Finkelstein-Schoenfeld test was proposed, which was a generalization of the Gehan-Wilcoxon test based on pairwise comparison of patients on a primary outcome when possible but otherwise on a secondary outcome. In 2012, Pocock and colleagues suggested an estimate based on this concept, the Win Ratio, which summarized the ratio of the number of patients who fared better versus worse on the experimental arm. However, in 2016, Oakes noted that the Win Ratio could be a function of the distribution of follow-up times of the trial. The aim of this paper is to propose an approach to representing the Win Ratio graphically in such a way that the effect of time on the estimate would be apparent. In addition, the methods are used to display the contribution of each endpoint to the composite. We apply the methods to clinical trials in cancer, cardiology, and neurology. Software is available named winRatioAnalysis in CRAN.

The Effect of Shared Decisionmaking on Patients' Likelihood of Filing a Complaint or Lawsuit: A Simulation Study.

STUDY OBJECTIVE: Shared decisionmaking has been promoted as a method to increase the patient-centeredness of medical decisionmaking and decrease low-yield testing, but little is known about its medicolegal ramifications in the setting of an adverse outcome. We seek to determine whether the use of shared decisionmaking changes perceptions of fault and liability in the case of an adverse outcome. METHODS: This was a randomized controlled simulation experiment conducted by survey, using clinical vignettes featuring no shared decisionmaking, brief shared decisionmaking, or thorough shared decisionmaking. Participants were adult US citizens recruited through an online crowd-sourcing platform. Participants were randomized to vignettes portraying 1 of 3 levels of shared decisionmaking. All other information given was identical, including the final clinical decision and the adverse outcome. The primary outcome was reported likelihood of pursuing legal action. Secondary outcomes included perceptions of fault, quality of care, and trust in physician. RESULTS: We recruited 804 participants. Participants exposed to shared decisionmaking (brief and thorough) were 80% less likely to report a plan to contact a lawyer than those not exposed to shared decisionmaking (12% and 11% versus 41%; odds ratio 0.2; 95% confidence interval 0.12 to 0.31). Participants exposed to either level of shared decisionmaking reported higher trust, rated their physicians more highly, and were less likely to fault their physicians for the adverse outcome compared with those exposed to the no shared decisionmaking vignette. CONCLUSION: In the setting of an adverse outcome from a missed diagnosis, use of shared decisionmaking may affect patients' perceptions of fault and liability.

Driving pressure and survival in the acute respiratory distress syndrome.

BACKGROUND: Mechanical-ventilation strategies that use lower end-inspiratory (plateau) airway pressures, lower tidal volumes (VT), and higher positive end-expiratory pressures (PEEPs) can improve survival in patients with the acute respiratory distress syndrome (ARDS), but the relative importance of each of these components is uncertain. Because respiratory-system compliance (CRS) is strongly related to the volume of aerated remaining functional lung during disease (termed functional lung size), we hypothesized that driving pressure (ΔP=VT/CRS), in which VT is intrinsically normalized to functional lung size (instead of predicted lung size in healthy persons), would be an index more strongly associated with survival than VT or PEEP in patients who are not actively breathing. METHODS: Using a statistical tool known as multilevel mediation analysis to analyze individual data from 3562 patients with ARDS enrolled in nine previously reported randomized trials, we examined ΔP as an independent variable associated with survival. In the mediation analysis, we estimated the isolated effects of changes in ΔP resulting from randomized ventilator settings while minimizing confounding due to the baseline severity of lung disease. RESULTS: Among ventilation variables, ΔP was most strongly associated with survival. A 1-SD increment in ΔP (approximately 7 cm of water) was associated with increased mortality (relative risk, 1.41; 95% confidence interval [CI], 1.31 to 1.51; P<0.001), even in patients receiving "protective" plateau pressures and VT (relative risk, 1.36; 95% CI, 1.17 to 1.58; P<0.001). Individual changes in VT or PEEP after randomization were not independently associated with survival; they were associated only if they were among the changes that led to reductions in ΔP (mediation effects of ΔP, P=0.004 and P=0.001, respectively). CONCLUSIONS: We found that ΔP was the ventilation variable that best stratified risk. Decreases in ΔP owing to changes in ventilator settings were strongly associated with increased survival. (Funded by Fundação de Amparo e Pesquisa do Estado de São Paulo and others.).

Phase IIb Trial of an α7 Nicotinic Receptor Partial Agonist With and Without Nicotine Patch for Withdrawal-Associated Cognitive Deficits and Tobacco Abstinence.

PURPOSE/BACKGROUND: The objective of this study was to determine whether a novel α7 nicotinic acetylcholine receptor partial agonist improves cognition during nicotine withdrawal and improves abstinence rates. To do so, the effect of the α7 nicotinic acetylcholine receptor partial agonist, encenicline, on cognition and abstinence was evaluated when given as monotherapy and when combined with transdermal nicotine patch (nicotine replacement therapy [NRT]). METHODS: Adult daily smokers, n = 160, who were motivated to quit smoking completed cognitive testing at satiated baseline and after overnight abstinence and then were randomized to receive a 12-week trial of encenicline 1 mg twice daily or identical placebo the day of the overnight abstinent cognitive testing. In the first 6 weeks of the 12-week encenicline administration, participants were also randomized to 6 weeks of NRT patch or placebo patch. Primary outcomes were cognition during abstinence and 7-day point-prevalence abstinence at week 12. RESULTS: No beneficial effects of encenicline were observed on cognition or abstinence when compared with placebo or when combined with NRT compared with placebo capsule + NRT. Of the 4 conditions, abstinence rates were lowest among those assigned to encenicline alone. CONCLUSIONS: Beneficial effects of NRT were observed on cognitive and abstinence outcomes when combined with encenicline compared with encenicline plus placebo patch. Addition of NRT to encenicline improved odds of abstinence approximately 3-fold compared with encenicline plus placebo patch. We conclude that encenicline, 1 mg/d, did not improve abstinence-associated cognitive impairment or abstinence rates as monotherapy or adjunctive therapy to NRT patch.

Nonlinear Imputation of PaO2/FIO2 From SpO2/FIO2 Among Mechanically Ventilated Patients in the ICU: A Prospective, Observational Study.

OBJECTIVES: In the contemporary ICU, mechanically ventilated patients may not have arterial blood gas measurements available at relevant timepoints. Severity criteria often depend on arterial blood gas results. Retrospective studies suggest that nonlinear imputation of PaO2/FIO2 from SpO2/FIO2 is accurate, but this has not been established prospectively among mechanically ventilated ICU patients. The objective was to validate the superiority of nonlinear imputation of PaO2/FIO2 among mechanically ventilated patients and understand what factors influence the accuracy of imputation. DESIGN: Simultaneous SpO2, oximeter characteristics, receipt of vasopressors, and skin pigmentation were recorded at the time of a clinical arterial blood gas. Acute respiratory distress syndrome criteria were recorded. For each imputation method, we calculated both imputation error and the area under the curve for patients meeting criteria for acute respiratory distress syndrome (PaO2/FIO2 ≤ 300) and moderate-severe acute respiratory distress syndrome (PaO2/FIO2 ≤ 150). SETTING: Nine hospitals within the Prevention and Early Treatment of Acute Lung Injury network. PATIENTS: We prospectively enrolled 703 mechanically ventilated patients admitted to the emergency departments or ICUs of participating study hospitals. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We studied 1,034 arterial blood gases from 703 patients; 650 arterial blood gases were associated with SpO2 less than or equal to 96%. Nonlinear imputation had consistently lower error than other techniques. Among all patients, nonlinear had a lower error (p < 0.001) and higher (p < 0.001) area under the curve (0.87; 95% CI, 0.85-0.90) for PaO2/FIO2 less than or equal to 300 than linear/log-linear (0.80; 95% CI, 0.76-0.83) imputation. All imputation methods better identified moderate-severe acute respiratory distress syndrome (PaO2/FIO2 ≤ 150); nonlinear imputation remained superior (p < 0.001). For PaO2/FIO2 less than or equal to 150, the sensitivity and specificity for nonlinear imputation were 0.87 (95% CI, 0.83-0.90) and 0.91 (95% CI, 0.88-0.93), respectively. Skin pigmentation and receipt of vasopressors were not associated with imputation accuracy. CONCLUSIONS: In mechanically ventilated patients, nonlinear imputation of PaO2/FIO2 from SpO2/FIO2 seems accurate, especially for moderate-severe hypoxemia. Linear and log-linear imputations cannot be recommended.

Global rank tests for multiple, possibly censored, outcomes.

Clinical trials often collect multiple outcomes on each patient, as the treatment may be expected to affect the patient on many dimensions. For example, a treatment for a neurological disease such as ALS is intended to impact several dimensions of neurological function as well as survival. The assessment of treatment on the basis of multiple outcomes is challenging, both in terms of selecting a test and interpreting the results. Several global tests have been proposed, and we provide a general approach to selecting and executing a global test. The tests require minimal parametric assumptions, are flexible about weighting of the various outcomes, and are appropriate even when some or all of the outcomes are censored. The test we propose is based on a simple scoring mechanism applied to each pair of subjects for each endpoint. The pairwise scores are then reduced to a summary score, and a rank-sum test is applied to the summary scores. This can be seen as a generalization of previously proposed nonparametric global tests (e.g., O'Brien, 1984). We discuss the choice of optimal weighting schemes based on power and relative importance of the outcomes. As the optimal weights are generally unknown in practice, we also propose an adaptive weighting scheme and evaluate its performance in simulations. We apply the methods to analyze the impact of a treatment on neurological function and death in an ALS trial.

Assessing survival benefit when treatment delays disease progression.

BACKGROUND: For a potentially lethal chronic disease like cancer, it is often infeasible to compare treatments on the basis of overall survival, so a combined outcome such as progression-free survival (which is the time from randomization to progression or death) has become an acceptable primary endpoint. The rationale of using an efficacy measure that is dominated by the time to progression is that an effective treatment will delay progression and when treatment is stopped at progression, the effect of treatment after this time is small. However, often trials that show a significant benefit for delaying progression but not on overall survival are not universally viewed as providing convincing evidence that the drug should become the standard of care. METHODS: We propose that when there is a significant treatment effect of delaying progression, a Bayesian analysis of overall survival should be undertaken. We suggest using a joint piecewise exponential model, where the treatment effect on the hazard for progression and for death after progression is captured through two distinct parameters. We develop a plot of the overall survival advantage of the new therapy versus the prior distribution of the relative hazard for death after progression. This plot can augment the discussion about whether the new treatment is beneficial on survival. RESULTS: In the example of an early breast cancer trial for which a new treatment significantly delayed disease recurrence, our Bayesian analysis showed that with very reasonable assumptions on the effects of treatment after recurrence, there is a high probability that the new treatment improves overall survival. CONCLUSION: For a clinical trial for which treatment delays progression, the proposed method can improve the interpretability of the survival comparison using data from the study.

Coronary CT angiography versus standard evaluation in acute chest pain.

BACKGROUND: It is unclear whether an evaluation incorporating coronary computed tomographic angiography (CCTA) is more effective than standard evaluation in the emergency department in patients with symptoms suggestive of acute coronary syndromes. METHODS: In this multicenter trial, we randomly assigned patients 40 to 74 years of age with symptoms suggestive of acute coronary syndromes but without ischemic electrocardiographic changes or an initial positive troponin test to early CCTA or to standard evaluation in the emergency department on weekdays during daylight hours between April 2010 and January 2012. The primary end point was length of stay in the hospital. Secondary end points included rates of discharge from the emergency department, major adverse cardiovascular events at 28 days, and cumulative costs. Safety end points were undetected acute coronary syndromes. RESULTS: The rate of acute coronary syndromes among 1000 patients with a mean (±SD) age of 54±8 years (47% women) was 8%. After early CCTA, as compared with standard evaluation, the mean length of stay in the hospital was reduced by 7.6 hours (P<0.001) and more patients were discharged directly from the emergency department (47% vs. 12%, P<0.001). There were no undetected acute coronary syndromes and no significant differences in major adverse cardiovascular events at 28 days. After CCTA, there was more downstream testing and higher radiation exposure. The cumulative mean cost of care was similar in the CCTA group and the standard-evaluation group ($4,289 and $4,060, respectively; P=0.65). CONCLUSIONS: In patients in the emergency department with symptoms suggestive of acute coronary syndromes, incorporating CCTA into a triage strategy improved the efficiency of clinical decision making, as compared with a standard evaluation in the emergency department, but it resulted in an increase in downstream testing and radiation exposure with no decrease in the overall costs of care. (Funded by the National Heart, Lung, and Blood Institute; ROMICAT-II ClinicalTrials.gov number, NCT01084239.).

Complexity of illness and adjunctive benzodiazepine use in outpatients with bipolar I or II disorder: results from the Bipolar CHOICE study.

Benzodiazepines are widely prescribed for patients with bipolar disorders in clinical practice, but very little is known about the subtypes of patients with bipolar disorder or aspects of bipolar illness that contribute most to benzodiazepine use. We examined the prevalence of and factors associated with benzodiazepine use among 482 patients with bipolar I or II disorder enrolled in the Bipolar CHOICE study. Eighty-one subjects were prescribed benzodiazepines at study entry and were considered benzodiazepine users. Stepwise logistic regression was used to model baseline benzodiazepine use versus nonuse, using entry and exit criteria of P < 0.1. In bivariate analyses, benzodiazepine users were prescribed a significantly higher number of other psychotropic medications and were more likely to be prescribed lamotrigine or antidepressants as compared with benzodiazepine nonusers. Benzodiazepine users were more likely to have a diagnosis of bipolar I disorder and comorbid anxiety disorder, but not comorbid alcohol or substance use disorders. Benzodiazepine users also had experienced more anxiety and depressive symptoms and suicidality, but not irritability or manic symptoms, than did benzodiazepine nonusers. In the multivariate model, anxiety symptom level (regardless of diagnosis), lamotrigine use, number of concomitant psychotropic medications, college education, and high household income predicted benzodiazepine use. Benzodiazepine use in patients with bipolar disorders is associated with greater illness complexity as indicated by a higher number of concomitant psychotropic medications and higher anxiety symptom burden, regardless of a comorbid anxiety disorder diagnosis. Demographic factors were also important determinants of benzodiazepine use, which may be related to access to care and insurance coverage for benzodiazepines.

A model-informed rank test for right-censored data with intermediate states.

The generalized Wilcoxon and log-rank tests are commonly used for testing differences between two survival distributions. We modify the Wilcoxon test to account for auxiliary information on intermediate disease states that subjects may pass through before failure. For a disease with multiple states where patients are monitored periodically but exact transition times are unknown (e.g. staging in cancer), we first fit a multi-state Markov model to the full data set; when censoring precludes the comparison of survival times between two subjects, we use the model to estimate the probability that one subject will have survived longer than the other given their censoring times and last observed status, and use these probabilities to compute an expected rank for each subject. These expected ranks form the basis of our test statistic. Simulations demonstrate that the proposed test can improve power over the log-rank and generalized Wilcoxon tests in some settings while maintaining the nominal type 1 error rate. The method is illustrated on an amyotrophic lateral sclerosis data set.

Detecting treatment-covariate interactions using permutation methods.

The primary objective of a Randomized Clinical Trial usually is to investigate whether one treatment is better than its alternatives on average. However, treatment effects may vary across different patient subpopulations. In contrast to demonstrating one treatment is superior to another on the average sense, one is often more concerned with the question that, for a particular patient, or a group of patients with similar characteristics, which treatment strategy is most appropriate to achieve a desired outcome. Various interaction tests have been proposed to detect treatment effect heterogeneity; however, they typically examine covariates one at a time, do not offer an integrated approach that incorporates all available information, and can greatly increase the chance of a false positive finding when the number of covariates is large. We propose a new permutation test for the null hypothesis of no interaction effects for any covariate. The proposed test allows us to consider the interaction effects of many covariates simultaneously without having to group subjects into subsets based on pre-specified criteria and applies generally to randomized clinical trials of multiple treatments. The test provides an attractive alternative to the standard likelihood ratio test, especially when the number of covariates is large. We illustrate the proposed methods using a dataset from the Treatment of Adolescents with Depression Study.