Using preliminary data and prospective power analyses for mid-stream revision of projected group and subgroup sizes in pragmatic patient-centered outcomes research

Pragmatic clinical trials are commonly used in patient-centered outcomes research to assess heterogeneity of treatment effects. Patient-Centered Outcomes Research Institute (PCORI) methodology standards for assessing heterogeneity of treatment effects are extremely rigorous, but their implementation in real-world settings can be difficult. Predicting recruitment effectiveness and subgroup characteristics is often challenging and may require mid-stream revision of projected group and subgroup sizes. Yet, little real-world data are available to demonstrate methodologically valid approaches to address situations where such revisions are necessary. These data were used for mid-stream revision of group and subgroup sizes in the Management of Diabetes in Everyday Life (MODEL) clinical trial. The planned number of randomized participants retained over the one-year study period was reduced from 800 to 581 due to recruitment difficulties among potential participants residing in rural areas. Prospective power analyses are based on the revised target of 581 participants retained and the proportions of 167 participants with various key baseline characteristics, who had been randomized in MODEL by January 2018, as reported to the Patient Center Outcomes Research Institute (PCORI) and the MODEL Data Safety and Monitoring Committee. Power calculations are based on two-sided t-tests with type-I error rates of 0.05 and the assumption that effect sizes will range from small (standardized difference = 0.36) to medium (= 0.50). The primary outcome variables are how many days in the previous week participants 1) ate healthy meals, 2) participated in at least 30 minutes of physical activity, and 3) took medications as prescribed. The POWER procedure of SAS 9.4 was used for all analyses. These data, along with the approach, can assist statisticians as they plan future pragmatic clinical trials evaluating heterogeneity of treatment effects. These data can help inform investigators, conducting patient-centered outcomes research, as they define subgroups for either confirmatory analyses for testing heterogeneity of treatment effects or for exploratory analyses where estimation of confidence bounds may be useful for generating future hypotheses. (This work was supported through a Patient-Centered Outcomes Research Institute (PCORI) Project Program Award (SC15-1503-28336), www.ClinicalTrials.gov and Identifier: NCT02957513 [1].

Search for eccentric black hole coalescences during the third observing run of LIGO and Virgo

Despite the growing number of confident binary black hole coalescences observed through gravitational waves so far, the astrophysical origin of these binaries remains uncertain. Orbital eccentricity is one of the clearest tracers of binary formation channels. Identifying binary eccentricity, however, remains challenging due to the limited availability of gravitational waveforms that include effects of eccentricity. Here, we present observational results for a waveform-independent search sensitive to eccentric black hole coalescences, covering the third observing run (O3) of the LIGO and Virgo detectors. We identified no new high-significance candidates beyond those that were already identified with searches focusing on quasi-circular binaries. We determine the sensitivity of our search to high-mass (total mass M>70 M⊙) binaries covering eccentricities up to 0.3 at 15 Hz orbital frequency, and use this to compare model predictions to search results. Assuming all detections are indeed quasi-circular, for our fiducial population model, we place an upper limit for the merger rate density of high-mass binaries with eccentricities 0<e≤0.3 at 0.33 Gpc−3 yr−1 at 90\% confidence level

Search for gravitational-lensing signatures in the full third observing run of the LIGO-Virgo network

Gravitational lensing by massive objects along the line of sight to the source causes distortions of gravitational wave-signals; such distortions may reveal information about fundamental physics, cosmology and astrophysics. In this work, we have extended the search for lensing signatures to all binary black hole events from the third observing run of the LIGO--Virgo network. We search for repeated signals from strong lensing by 1) performing targeted searches for subthreshold signals, 2) calculating the degree of overlap amongst the intrinsic parameters and sky location of pairs of signals, 3) comparing the similarities of the spectrograms amongst pairs of signals, and 4) performing dual-signal Bayesian analysis that takes into account selection effects and astrophysical knowledge. We also search for distortions to the gravitational waveform caused by 1) frequency-independent phase shifts in strongly lensed images, and 2) frequency-dependent modulation of the amplitude and phase due to point masses. None of these searches yields significant evidence for lensing. Finally, we use the non-detection of gravitational-wave lensing to constrain the lensing rate based on the latest merger-rate estimates and the fraction of dark matter composed of compact objects

Ultralight vector dark matter search using data from the KAGRA O3GK run

Among the various candidates for dark matter (DM), ultralight vector DM can be probed by laser interferometric gravitational wave detectors through the measurement of oscillating length changes in the arm cavities. In this context, KAGRA has a unique feature due to differing compositions of its mirrors, enhancing the signal of vector DM in the length change in the auxiliary channels. Here we present the result of a search for U(1)B−L gauge boson DM using the KAGRA data from auxiliary length channels during the first joint observation run together with GEO600. By applying our search pipeline, which takes into account the stochastic nature of ultralight DM, upper bounds on the coupling strength between the U(1)B−L gauge boson and ordinary matter are obtained for a range of DM masses. While our constraints are less stringent than those derived from previous experiments, this study demonstrates the applicability of our method to the lower-mass vector DM search, which is made difficult in this measurement by the short observation time compared to the auto-correlation time scale of DM

National Trauma Institute Prospective Evaluation of the Ventilator Bundle in Trauma Patients: Does It Really Work?

BACKGROUND: Since its introduction by the Institute for Healthcare Improvement, the ventilator bundle (VB) has been credited with a reduction in ventilator-associated pneumonia (VAP). The VB consists of stress ulcer prophylaxis, deep venous thrombosis prophylaxis, head-of-bed elevation, and daily sedation vacation with weaning assessment. While there is little compelling evidence that the VB is effective, it has been widely accepted. The Centers for Medical and Medicaid Services has suggested that VAP should be a never event and may reduce payment to providers. To provide evidence of its efficacy, the National Trauma Institute organized a prospective multi-institutional trial to evaluate the utility of the VB. METHODS: This prospective observational multi-institutional study included six Level I trauma centers. Entry criteria required at least 2 days of mechanical ventilation of trauma patients in an intensive care unit (ICU). Patients were followed up daily in the ICU until the development of VAP, ICU discharge, or death. Compliance for each VB component was recorded daily, along with patient risk factors and injury specifics. Primary outcomes were VAP and death. VB compliance was analyzed as a time-dependent covariate using Cox regression as it relates to outcomes. RESULTS: A total 630 patients were enrolled; 72% were male, predominately with blunt injury; and mean age, Injury Severity Score (ISS), and 24-hour Glasgow Coma Scale (GCS) score were 47, 24, and 8.7, respectively. VAP occurred in 36%; mortality was 15%. Logistic regression identified male sex and pulmonary contusion as independent predictors of VAP and age, ISS, and 24-hour Acute Physiology and Chronic Health Evaluation as independent predictors of death. Cox regression analysis demonstrated that the VB, as a time-dependent covariate, was not associated with VAP prevention. CONCLUSION: In trauma patients, VAP is independently associated with male sex and chest injury severity and not the VB. While quality improvement activities should continue efforts toward VAP prevention, the Institute for Healthcare Improvement VB is not the answer. Financial penalties for VAP and VB noncompliance are not warranted. LEVEL OF EVIDENCE: Therapeutic study, level III