Coping with Persistent Pain, Effectiveness Research into Self-management (COPERS): statistical analysis plan for a randomised controlled trial

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Ideologies and their points of view

© Springer International Publishing Switzerland 2016. It is well known that different arguments appeal to different people. We all process information in ways that are adapted to be consistent with our underlying ideologies. These ideologies can sometimes be framed in terms of particular axes or dimensions, which makes it possible to represent some aspects of an ideology as a region in the kind of vector space that is typical of many generalised quantum models. Such models can then be used to explain and predict, in broad strokes, whether a particular argument or proposal is likely to appeal to an individual with a particular ideology. The choice of suitable arguments to bring about desired actions is traditionally part of the art or science of rhetoric, and today’s highly polarised society means that this skill is becoming more important than ever. This paper presents a basic model for understanding how different goals will appeal to people with different ideologies, and thus how different rhetorical positions can be adopted to promote the same desired outcome. As an example, we consider different narratives and hence actions with respect to the environment and climate change, an important but currently highly controversial topic

Access to unpublished protocols and statistical analysis plans of randomised trials

Background: Access to protocols and statistical analysis plans (SAPs) increases the transparency of randomised trial by allowing readers to identify and interpret unplanned changes to study methods, however they are often not made publicly available. We sought to determine how often study investigators would share unavailable documents upon request. Methods: We used trials from two previously identified cohorts (cohort 1: 101 trials published in high impact factor journals between January and April of 2018; cohort 2: 100 trials published in June 2018 in journals indexed in PubMed) to determine whether study investigators would share unavailable protocols/SAPs upon request. We emailed corresponding authors of trials with no publicly available protocol or SAP up to four times. Results: Overall, 96 of 201 trials (48%) across the two cohorts had no publicly available protocol or SAP (11/101 high-impact cohort, 85/100 PubMed cohort). In total, 8/96 authors (8%) shared some trial documentation (protocol only [n = 5]; protocol and SAP [n = 1]; excerpt from protocol [n = 1]; research ethics application form [n = 1]). We received protocols for 6/96 trials (6%), and a SAP for 1/96 trial (1%). Seventy-three authors (76%) did not respond, 7 authors responded (7%) but declined to share a protocol or SAP, and eight email addresses were invalid (8%). A total of 329 emails were sent (an average of 41 emails for every trial which sent documentation). After emailing authors, the total number of trials with an available protocol increased by only 3%, from 52% in to 55%. Conclusions: Most study investigators did not share their unpublished protocols or SAPs upon direct request. Alternative strategies are needed to increase transparency of randomised trials and ensure access to protocols and SAPs

Accounting for centre-effects in multicentre trials with a binary outcome - when, why, and how?

BACKGROUND: It is often desirable to account for centre-effects in the analysis of multicentre randomised trials, however it is unclear which analysis methods are best in trials with a binary outcome. METHODS: We compared the performance of four methods of analysis (fixed-effects models, random-effects models, generalised estimating equations (GEE), and Mantel-Haenszel) using a re-analysis of a previously reported randomised trial (MIST2) and a large simulation study. RESULTS: The re-analysis of MIST2 found that fixed-effects and Mantel-Haenszel led to many patients being dropped from the analysis due to over-stratification (up to 69% dropped for Mantel-Haenszel, and up to 33% dropped for fixed-effects). Conversely, random-effects and GEE included all patients in the analysis, however GEE did not reach convergence. Estimated treatment effects and p-values were highly variable across different analysis methods. The simulation study found that most methods of analysis performed well with a small number of centres. With a large number of centres, fixed-effects led to biased estimates and inflated type I error rates in many situations, and Mantel-Haenszel lost power compared to other analysis methods in some situations. Conversely, both random-effects and GEE gave nominal type I error rates and good power across all scenarios, and were usually as good as or better than either fixed-effects or Mantel-Haenszel. However, this was only true for GEEs with non-robust standard errors (SEs); using a robust ‘sandwich’ estimator led to inflated type I error rates across most scenarios. CONCLUSIONS: With a small number of centres, we recommend the use of fixed-effects, random-effects, or GEE with non-robust SEs. Random-effects and GEE with non-robust SEs should be used with a moderate or large number of centres

Risk of selection bias in randomised trials

Background: Selection bias occurs when recruiters selectively enrol patients into the trial based on what the next treatment allocation is likely to be. This can occur even if appropriate allocation concealment is used if recruiters can guess the next treatment assignment with some degree of accuracy. This typically occurs in unblinded trials when restricted randomisation is implemented to force the number of patients in each arm or within each centre to be the same. Several methods to reduce the risk of selection bias have been suggested; however, it is unclear how often these techniques are used in practice. Methods: We performed a review of published trials which were not blinded to assess whether they utilised methods for reducing the risk of selection bias. We assessed the following techniques: (a) blinding of recruiters; (b) use of simple randomisation; (c) avoidance of stratification by site when restricted randomisation is used; (d) avoidance of permuted blocks if stratification by site is used; and (e) incorporation of prognostic covariates into the randomisation procedure when restricted randomisation is used. We included parallel group, individually randomised phase III trials published in four general medical journals (BMJ, Journal of the American Medical Association, The Lancet, and New England Journal of Medicine) in 2010. Results: We identified 152 eligible trials. Most trials (98%) provided no information on whether recruiters were blind to previous treatment allocations. Only 3% of trials used simple randomisation; 63% used some form of restricted randomisation, and 35% did not state the method of randomisation. Overall, 44% of trials were stratified by site of recruitment; 27% were not, and 29% did not report this information. Most trials that did stratify by site of recruitment used permuted blocks (58%), and only 15% reported using random block sizes. Many trials that used restricted randomisation also included prognostic covariates in the randomisation procedure (56%). Conclusions: The risk of selection bias could not be ascertained for most trials due to poor reporting. Many trials which did provide details on the randomisation procedure were at risk of selection bias due to a poorly chosen randomisation methods. Techniques to reduce the risk of selection bias should be more widely implemented

Core pinning by intragranular nanoprecipitates in polycrystalline MgCNi_3

The nanostructure and magnetic properties of polycrystalline MgCNi_3 were studied by x-ray diffraction, electron microscopy, and vibrating sample magnetometry. While the bulk flux-pinning force curve F_p(H) indicates the expected grain-boundary pinning mechanism just below T_c = 7.2 K, a systematic change to pinning by a nanometer-scale distribution of core pinning sites is indicated by a shift of F_p(H) with decreasing temperature. The lack of scaling of F_p(H) suggests the presence of 10 to 20% of nonsuperconducting regions inside the grains, which are smaller than the diameter of fluxon cores 2xi at high temperature and become effective with decreasing temperature when xi(T) approaches the nanostructural scale. Transmission electron microscopy revealed cubic and graphite nanoprecipitates with 2 to 5 nm size, consistent with the above hypothesis since xi(0) = 6 nm. High critical current densities, more than 10^6 A/cm^2 at 1 T and 4.2 K, were obtained for grain colonies separated by carbon. Dirty-limit behavior seen in previous studies may be tied to electron scattering by the precipitates, indicating the possibility that strong core pinning might be combined with a technologically useful upper critical field if versions of MgCNi_3 with higher T_c can be found.Comment: 5 pages, 6 figures, submitted to PR

Blinded Outcome Assessment Was Infrequently Used and Poorly Reported in Open Trials

Objective Unblinded outcome assessment can lead to biased estimates of treatment effect in randomised trials. We reviewed published trials to assess how often blinded assessment is used, and whether its use varies according to the type of outcome or assessor. Design and setting A review of parallel group, individually randomised phase III trials published in four general medical journals (BMJ, Journal of the American Medical Association, The Lancet, and New England Journal of Medicine) in 2010. Main outcome measures Whether assessment of the primary outcome was blinded, and whether this differed according to outcome or assessor type. Results We identified 258 eligible trials. Of these, 106 (41%) were reported as double-blind, and 152 (59%) as partially or fully open-label (that is, they included some groups who were unblinded, such as patients, those delivering the intervention, or those in charge of medical care). Of the 152 open trials, 125 required outcome assessment. Of these 125 trials, only 26% stated that outcome assessment was blinded; 51% gave no information on whether assessment was blinded or not. Furthermore, 18% of trials did not state who performed the assessment. The choice of outcome type (e.g. instrument measured, rated, or naturally occurring event) did not appear to influence whether blinded assessment was performed (range 24-32% for the most common outcome types). However, the choice of outcome assessor did influence blinding; independent assessors were blinded much more frequently (71%) than participant (5%) or physician (24%) assessors. Despite this, open trials did not use independent assessors any more frequently than double-blind trials (17% vs. 18% respectively). Conclusions Blinding of outcome assessors is infrequently used and poorly reported. Increased use of independent assessors could increase the frequency of blinded assessment

Brief of Corporate Law Professors as Amici Curie in Support of Respondents

The Supreme Court has looked to the rights of corporate shareholders in determining the rights of union members and non-members to control political spending, and vice versa. The Court sometimes assumes that if shareholders disapprove of corporate political expression, they can easily sell their shares or exercise control over corporate spending. This assumption is mistaken. Because of how capital is saved and invested, most individual shareholders cannot obtain full information about corporate political activities, even after the fact, nor can they prevent their savings from being used to speak in ways with which they disagree. Individual shareholders have no “opt out” rights or practical ability to avoid subsidizing corporate political expression with which they disagree. Nor do individuals have the practical option to refrain from putting their savings into equity investments, as doing so would impose damaging economic penalties and ignore conventional financial guidance for individual investors

A Novel Approach for Ellipsoidal Outer-Approximation of the Intersection Region of Ellipses in the Plane

In this paper, a novel technique for tight outer-approximation of the intersection region of a finite number of ellipses in 2-dimensional (2D) space is proposed. First, the vertices of a tight polygon that contains the convex intersection of the ellipses are found in an efficient manner. To do so, the intersection points of the ellipses that fall on the boundary of the intersection region are determined, and a set of points is generated on the elliptic arcs connecting every two neighbouring intersection points. By finding the tangent lines to the ellipses at the extended set of points, a set of half-planes is obtained, whose intersection forms a polygon. To find the polygon more efficiently, the points are given an order and the intersection of the half-planes corresponding to every two neighbouring points is calculated. If the polygon is convex and bounded, these calculated points together with the initially obtained intersection points will form its vertices. If the polygon is non-convex or unbounded, we can detect this situation and then generate additional discrete points only on the elliptical arc segment causing the issue, and restart the algorithm to obtain a bounded and convex polygon. Finally, the smallest area ellipse that contains the vertices of the polygon is obtained by solving a convex optimization problem. Through numerical experiments, it is illustrated that the proposed technique returns a tighter outer-approximation of the intersection of multiple ellipses, compared to conventional techniques, with only slightly higher computational cost