Managing clustering effects and learning effects in the design and analysis of multicentre randomised trials: a survey to establish current practice.

BACKGROUND:Patient outcomes can depend on the treating centre, or health professional, delivering the intervention. A health professional's skill in delivery improves with experience, meaning that outcomes may be associated with learning. Considering differences in intervention delivery at trial design will ensure that any appropriate adjustments can be made during analysis. This work aimed to establish practice for the allowance of clustering and learning effects in the design and analysis of randomised multicentre trials. METHODS:A survey that drew upon quotes from existing guidelines, references to relevant publications and example trial scenarios was delivered. Registered UK Clinical Research Collaboration Registered Clinical Trials Units were invited to participate. RESULTS:Forty-four Units participated (N = 50). Clustering was managed through design by stratification, more commonly by centre than by treatment provider. Managing learning by design through defining a minimum expertise level for treatment provider was common (89%). One-third reported experience in expertise-based designs. The majority of Units had adjusted for clustering during analysis, although approaches varied. Analysis of learning was rarely performed for the main analysis (n = 1), although it was explored by other means. The insight behind the approaches used within and reasons for, or against, alternative approaches were provided. CONCLUSIONS:Widespread awareness of challenges in designing and analysing multicentre trials is identified. Approaches used, and opinions on these, vary both across and within Units, indicating that approaches are dependent on the type of trial. Agreeing principles to guide trial design and analysis across a range of realistic clinical scenarios should be considered

Sleep Characteristics and Behavioral Problems Among Children of Alcoholics and Controls

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142546/1/acer13585_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142546/2/acer13585.pd

Visual Function Questionnaire as an outcome measure for homonymous hemianopia: subscales and supplementary questions, analysis from the VISION trial

Background: We conduct supplementary analyses of the NEI VFQ-25 data to evaluate where changes occurred within subscales of the NEI VFQ-25 leading to change in the composite scores between the three treatment arms, and evaluate the NEI VFQ-25 with and without the Neuro 10 supplement. Methods: A prospective, multicentre, parallel, single-blind, three-arm RCT of fourteen UK acute stroke units was conducted. Stroke survivors with homonymous hemianopia were recruited. Interventions included: Fresnel prisms for minimum 2 h, 5 days/week over 6-weeks (Arm a), Visual search training for minimum 30 min, 5 days/week over 6-weeks (Arm b) and standard care-information only (Arm c). Primary and secondary outcomes (including NEI VFQ-25 data) were measured at baseline, 6, 12 and 26 weeks after randomisation. Results: Eighty seven patients were recruited (69% male; mean age (SD) equal to 69 (12) years). At 26 weeks, outcomes for 24, 24 and 22 patients, respectively, were compared to baseline. NEI VFQ-25 (with and without Neuro 10) responses improved from baseline to 26 weeks with visual search training compared to Fresnel prisms and standard care. In subscale analysis, the most impacted across all treatment arms was ‘driving’ whilst the least impacted were ‘colour vision’ and ‘ocular pain’. Conclusions: Composite scores differed systematically for the NEI VFQ-25 (Neuro 10) versus NEI VFQ-25 at all time points. For subscale scores, descriptive statistics suggest clinically relevant improvement in distance activities and vision-specific dependency subscales for NEI VFQ-25 scores in the visual search treatment arm. Trial Registration: Current Controlled Trials ISRCTN05956042

A Candidate Brightest Proto-Cluster Galaxy at z = 3.03

We report the discovery of a very bright (m_R = 22.2) Lyman break galaxy at z = 3.03 that appears to be a massive system in a late stage of merging. Deep imaging reveals multiple peaks in the brightness profile with angular separations of ~0.''8 (~25 h^-1 kpc comoving). In addition, high signal-to-noise ratio rest-frame UV spectroscopy shows evidence for ~5 components based on stellar photospheric and ISM absorption lines with a velocity dispersion of sigma ~460 km s^-1 for the three strongest components. Both the dynamics and high luminosity, as well as our analysis of a LCDM numerical simulation, suggest a very massive system with halo mass M ~ 10^13 M_solar. The simulation finds that all halos at z = 3 of this mass contain sub-halos in agreement with the properties of these observed components and that such systems typically evolve into M ~ 10^14 M_solar halos in groups and clusters by z = 0. This discovery provides a rare opportunity to study the properties and individual components of z ~ 3 systems that are likely to be the progenitors to brightest cluster galaxies.Comment: 14 pages, 3 figures, submitted to ApJ Letter

Using A3 thinking to improve the STAT medication process

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/107994/1/jhm2222.pd

Counts-in-Cylinders in the Sloan Digital Sky Survey with Comparisons to N-body Simulations

Environmental statistics provide a necessary means of comparing the properties of galaxies in different environments and a vital test of models of galaxy formation within the prevailing, hierarchical cosmological model. We explore counts-in-cylinders, a common statistic defined as the number of companions of a particular galaxy found within a given projected radius and redshift interval. Galaxy distributions with the same two-point correlation functions do not necessarily have the same companion count distributions. We use this statistic to examine the environments of galaxies in the Sloan Digital Sky Survey, Data Release 4. We also make preliminary comparisons to four models for the spatial distributions of galaxies, based on N-body simulations, and data from SDSS DR4 to study the utility of the counts-in-cylinders statistic. There is a very large scatter between the number of companions a galaxy has and the mass of its parent dark matter halo and the halo occupation, limiting the utility of this statistic for certain kinds of environmental studies. We also show that prevalent, empirical models of galaxy clustering that match observed two- and three-point clustering statistics well fail to reproduce some aspects of the observed distribution of counts-in-cylinders on 1, 3 and 6-Mpc/h scales. All models that we explore underpredict the fraction of galaxies with few or no companions in 3 and 6-Mpc/h cylinders. Roughly 7% of galaxies in the real universe are significantly more isolated within a 6 Mpc/h cylinder than the galaxies in any of the models we use. Simple, phenomenological models that map galaxies to dark matter halos fail to reproduce high-order clustering statistics in low-density environments.Comment: 17 pages, 10 figures. Accepted, Ap

Small-Scale Structure in the SDSS and LCDM: Isolated L* Galaxies with Bright Satellites

We use a volume-limited spectroscopic sample of isolated galaxies in the Sloan Digital Sky Survey (SDSS) to investigate the frequency and radial distribution of luminous (M_r <~ -18.3) satellites like the Large Magellanic Cloud (LMC) around ~L* Milky Way analogs and compare our results object-by-object to LCDM predictions based on abundance matching in simulations. We show that 12% of Milky Way-like galaxies host an LMC-like satellite within 75 kpc (projected), and 42 % within 250 kpc (projected). This implies ~10% have a satellite within the distance of the LMC, and ~40% of L* galaxies host a bright satellite within the virialized extent of their dark matter halos. Remarkably, the simulation reproduces the observed frequency, radial dependence, velocity distribution, and luminosity function of observed secondaries exceptionally well, suggesting that LCDM provides an accurate reproduction of the observed Universe to galaxies as faint as L~10^9 Lsun on ~50 kpc scales. When stacked, the observed projected pairwise velocity dispersion of these satellites is sigma~160 km/s, in agreement with abundance-matching expectations for their host halo masses. Finally, bright satellites around L* primaries are significantly redder than typical galaxies in their luminosity range, indicating that environmental quenching is operating within galaxy-size dark matter halos that typically contain only a single bright satellite. This redness trend is in stark contrast to the Milky Way's LMC, which is unusually blue even for a field galaxy. We suggest that the LMC's discrepant color might be further evidence that it is undergoing a triggered star-formation event upon first infall.Comment: 14 pages, 11 figures; accepted to Ap

Antibiotic or silver versus standard ventriculoperitoneal shunts (BASICS): a multi-centre, single-blinded, randomised trial and economic evaluation

Background Insertion of a ventriculoperitoneal shunt for hydrocephalus is one of the commonest neurosurgical procedures worldwide. Infection of the implanted shunt affects up to 15% of these patients, resulting in prolonged hospital treatment, multiple surgeries, and reduced cognition and quality of life. Our aim was to determine the clinical and cost-effectiveness of antibiotic (rifampicin and clindamycin) or silver shunts compared with standard shunts at reducing infection. Methods In this parallel, multicentre, single-blind, randomised controlled trial, we included patients with hydrocephalus of any aetiology undergoing insertion of their first ventriculoperitoneal shunt irrespective of age at 21 regional adult and paediatric neurosurgery centres in the UK and Ireland. Patients were randomly assigned (1:1:1 in random permuted blocks of three or six) to receive standard shunts (standard shunt group), antibiotic-impregnated (0·15% clindamycin and 0·054% rifampicin; antibiotic shunt group), or silver-impregnated shunts (silver shunt group) through a randomisation sequence generated by an independent statistician. All patients and investigators who recorded and analysed the data were masked for group assignment, which was only disclosed to the neurosurgical staff at the time of operation. Participants receiving a shunt without evidence of infection at the time of insertion were followed up for at least 6 months and a maximum of 2 years. The primary outcome was time to shunt failure due the infection and was analysed with Fine and Gray survival regression models for competing risk by intention to treat. This trial is registered with ISRCTN 49474281. Findings Between June 26, 2013, and Oct 9, 2017, we assessed 3505 patients, of whom 1605 aged up to 91 years were randomly assigned to receive either a standard shunt (n=536), an antibiotic-impregnated shunt (n=538), or a silver shunt (n=531). 1594 had a shunt inserted without evidence of infection at the time of insertion (533 in the standard shunt group, 535 in the antibiotic shunt group, and 526 in the silver shunt group) and were followed up for a median of 22 months (IQR 10–24; 53 withdrew from follow-up). 32 (6%) of 533 evaluable patients in the standard shunt group had a shunt revision for infection, compared with 12 (2%) of 535 evaluable patients in the antibiotic shunt group (cause-specific hazard ratio [csHR] 0·38, 97·5% CI 0·18–0·80, p=0·0038) and 31 (6%) of 526 patients in the silver shunt group (0·99, 0·56–1·74, p=0·96). 135 (25%) patients in the standard shunt group, 127 (23%) in the antibiotic shunt group, and 134 (36%) in the silver shunt group had adverse events, which were not life-threatening and were mostly related to valve or catheter function. Interpretation The BASICS trial provides evidence to support the adoption of antibiotic shunts in UK patients who are having their first ventriculoperitoneal shunt insertion. This practice will benefit patients of all ages by reducing the risk and harm of shunt infection. Funding UK National Institute for Health Research Health Technology Assessment programme