Multiple Testing With an Empirical Alternative Hypothesis

An optimal multiple testing procedure is identified for linear hypotheses under the general linear model, maximizing the expected number of false null hypotheses rejected at any significance level. The optimal procedure depends on the unknown data-generating distribution, but can be consistently estimated. Drawing information together across many hypotheses, the estimated optimal procedure provides an empirical alternative hypothesis by adapting to underlying patterns of departure from the null. Proposed multiple testing procedures based on the empirical alternative are evaluated through simulations and an application to gene expression microarray data. Compared to a standard multiple testing procedure, it is not unusual for use of an empirical alternative hypothesis to increase by 50% or more the number of true positives identified at a given significance level

Comparative efficacy of long-acting β2-agonists as monotherapy for chronic obstructive pulmonary disease: a network meta-analysis

Long-acting β2-agonists (LABAs) have demonstrated efficacy in patients with COPD in clinical trials. The purpose of this study was to assess the comparative efficacy of all available dosages of all LABA monotherapies using a network meta-analysis

Categorizing natural history trajectories of ambulatory function measured by the 6-minute walk distance in patients with Duchenne muscular dystrophy

High variability in patients' changes in 6 minute walk distance (6MWD) over time has complicated clinical trials of treatment efficacy in Duchenne muscular dystrophy (DMD). We assessed whether boys with DMD could be grouped into classes that shared similar ambulatory function trajectories as measured by 6MWD. Ambulatory boys aged 5 years or older with genetically confirmed DMD who were enrolled in a natural history study at 11 care centers throughout Italy were included. For each boy, standardized assessments of 6MWD were available at annual intervals spanning 3 years. Trajectories of 6MWD vs. age and trajectories of 6MWD vs. time from enrollment were examined using latent class analysis. A total of 96 boys were included. At enrollment, the mean age was 8.3 years (mean 6MWD: 374 meters). After accounting for age, baseline 6MWD, and steroid use, four latent trajectory classes were identified as explaining 3-year 6MWD outcomes significantly better than a single average trajectory. Patient trajectories of 6MWD change from enrollment were categorized as having fast decline (n\ue2\u80\u89=\ue2\u80\u8925), moderate decline (n\ue2\u80\u89=\ue2\u80\u8919), stable function (n\ue2\u80\u89=\ue2\u80\u8937), and improving function (n\ue2\u80\u89=\ue2\u80\u8915) during the 3-year follow-up. After accounting for trajectory classes, the standard deviation of variation in 6MWD was reduced by approximately 40%. The natural history of ambulatory function in DMD may be composed of distinct trajectory classes. The extent to which trajectories are associated with novel and established prognostic factors warrants further study. Reducing unexplained variation in patient outcomes could help to further improve DMD clinical trial design and analysis

Health-Related Quality of Life Following Allogeneic Hematopoietic Cell Transplantation with Omidubicel versus Umbilical Cord Blood

Omidubicel is an advanced cell therapy derived from umbilical cord blood (UCB) for use in allogeneic hematopoietic cell transplantation (HCT). A recent randomized phase 3 clinical trial demonstrated faster engraftment, shorter length of hospital stays, and lower rates of infection with omidubicel compared with standard UCB transplantation in patients with high-risk hematologic malignancies. Despite the proven clinical benefits of omidubicel, its impact on health-related quality of life (HRQL) from the patient's perspective has not been described. This study analyzed patient-reported HRQL measures collected prospectively in the randomized phase 3 trial comparing omidubicel to standard UCB transplantation. A total of 108 patients at 33 international stem cell transplantation centers underwent myeloablative allogeneic HCT with either omidubicel or standard UCB. Patients completed serial HRQL questionnaires at screening and on days 42, 100, 180, and 365 post-transplantation. The HRQL surveys included the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT), a 50-item cancer-specific questionnaire assessing physical, functional, emotional, social/family, and HCT-specific well-being, and the EuroQol 5-Dimension 3-Level, a 5-item generic HRQL survey. A mixed model with repeated measures was used to compare changes in HRQL from baseline in the 2 treatment arms. The average change in HRQL scores over time was compared by estimating the difference in the area under the curve (AUC) in each treatment group. Seventy-five patients (omidubicel arm, n = 37; standard UCB arm, n = 38) who completed the FACT-BMT at baseline and on 1 or more follow-up visits were included in this study. Baseline characteristics were similar in the 2 treatment arms. Over the first year post-transplantation, the AUCs of mean changes in physical, functional, and total FACT-BMT scores indicated significantly better HRQL with omidubicel (P < .05), with mean differences across time points ranging from 1.4 to 3.1 points, 1.6 to 3.2 points, and 7.2 to 11.0 points, respectively. The minimal clinically important difference was exceeded at 1 or more time points for each of these measures. The HRQL improvements with omidubicel were observed as early as 42 days post-transplantation and persisted at 1 year, indicating the potential long-term benefits of omidubicel on HRQL. Across all patients, adverse clinical outcomes, such as grade 3 viral infections and lower rates of neutrophil engraftment, were associated with worse HRQL scores. The observed improvements in HRQL measures may reflect the known clinical benefits of omidubicel. Compared with standard UCB, allogeneic HCT with omidubicel resulted in significant and clinically meaningful improvements in patient-reported HRQL measures

Clinical Outcomes with First-line Endocrine Therapy or Chemotherapy in Postmenopausal HR+/HER2-Metastatic Breast Cancer

Objective To describe patient profiles and clinical outcomes associated with first-line endocrine monotherapy (ET) and chemotherapy (CT) for postmenopausal HR+/HER2– metastatic breast cancer (mBC) patients. Methods This is a retrospective chart review of 139 postmenopausal HR+/HER2– mBC patients initiating first-line ET monotherapy or CT. Overall survival (OS) was described using Kaplan–Meier curves. Exploratory comparative proportional hazards regression was conducted. Results Patients on first-line CT had significantly more frequent liver metastases than patients on first-line ET monotherapy at baseline. The median OS was 35.5 months [95% confidence interval (CI), 22.7–41.2 months] for patients on first-line ET monotherapy and 22.2 months (95% CI, 13.6–25.9 months) for those on first-line CT ( P = 0.021). Adjusting for baseline characteristics, the OS between first-line ET monotherapy and CT was not significantly different. Conclusions Patients who were prescribed CT as first-line treatment had evidence of more advanced disease at baseline and shorter OS than those who received ET monotherapy as first-line treatment, suggesting a need for additional safe and effective treatment options for these patients

Comparative efficacy of long-acting &beta;2-agonists as monotherapy for chronic obstructive pulmonary disease: a network meta-analysis

Long-acting β2-agonists (LABAs) have demonstrated efficacy in patients with COPD in clinical trials. The purpose of this study was to assess the comparative efficacy of all available dosages of all LABA monotherapies using a network meta-analysis