Network meta-analysis of diagnostic test accuracy studies identifies and ranks the optimal diagnostic tests and thresholds for healthcare policy and decision making

Objective: Network meta-analyses have extensively been used to compare the effectiveness of multiple interventions for healthcare policy and decision-making. However, methods for evaluating the performance of multiple diagnostic tests are less established. In a decision-making context, we are often interested in comparing and ranking the performance of multiple diagnostic tests, at varying levels of test thresholds, in one simultaneous analysis. Study design and setting: Motivated by an example of cognitive impairment diagnosis following stroke, we synthesized data from 13 studies assessing the efficiency of two diagnostic tests: Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA), at two test thresholds: MMSE <25/30 and <27/30, and MoCA <22/30 and <26/30. Using Markov Chain Monte Carlo (MCMC) methods, we fitted a bivariate network meta-analysis model incorporating constraints on increasing test threshold, and accounting for the correlations between multiple test accuracy measures from the same study. Results: We developed and successfully fitted a model comparing multiple tests/threshold combinations while imposing threshold constraints. Using this model, we found that MoCA at threshold <26/30 appeared to have the best true positive rate, whilst MMSE at threshold <25/30 appeared to have the best true negative rate. Conclusion: The combined analysis of multiple tests at multiple thresholds allowed for more rigorous comparisons between competing diagnostics tests for decision making

Direct health costs of inflammatory polyarthritis 10 years after disease onset:Results from the Norfolk Arthritis Register

Objectives: To explore the change in direct medical costs associated with inflammatory polyarthritis (IP) 10 to 15 years after its onset. Methods: Patients from the Norfolk Arthritis Register who had previously participated in a health economic study in 1999 were traced 10 years later and invited to participate in a further prospective questionnaire-based study. The study was designed to identify direct medical costs and changes in health status over a 6-month period using previously validated questionnaires as the primary source of data. Results: A representative sample of 101 patients with IP from the 1999 cohort provided complete data over the 6-month period. The mean disease duration was 14 years (SD 2.1, median 13.6, interquartile range 12.6–15.4). The mean direct medical cost per patient over the 6-month period was £1496 for IP (inflated for 2013 prices). This compared with £582 (95% CI £355–£964) inflated to 2013 prices per patient with IP 10 years earlier in their disease. The increased cost was largely associated with the use of biologics in the rheumatoid arthritis subgroup of patients (51% of total costs incurred). Other direct cost components included primary care costs (11%), hospital outpatient (19%), day care (12%), and inpatient stay (4%). Conclusion: The direct healthcare costs associated with IP have more than doubled with increasing disease duration, largely as a result of the use of biologics. The results showed a shift in the direct health costs from inpatient to outpatient service use

Understanding how appraisal of doctors produces its effects: a realist review protocol

INTRODUCTION: UK doctors are now required to participate in revalidation to maintain their licence to practise. Appraisal is a fundamental component of revalidation. However, objective evidence of appraisal changing doctors' behaviour and directly resulting in improved patient care is limited. In particular, it is not clear how the process of appraisal is supposed to change doctors' behaviour and improve clinical performance. The aim of this research is to understand how and why appraisal of doctors is supposed to produce its effect. METHODS AND ANALYSIS: Realist review is a theory-driven interpretive approach to evidence synthesis. It applies realist logic of inquiry to produce an explanatory analysis of an intervention that is, what works, for whom, in what circumstances, in what respects. Using a realist review approach, an initial programme theory of appraisal will be developed by consulting with key stakeholders in doctors' appraisal in expert panels (ethical approval is not required), and by searching the literature to identify relevant existing theories. The search strategy will have a number of phases including a combination of: (1) electronic database searching, for example, EMBASE, MEDLINE, the Cochrane Library, ASSIA, (2) 'cited by' articles search, (3) citation searching, (4) contacting authors and (5) grey literature searching. The search for evidence will be iteratively extended and refocused as the review progresses. Studies will be included based on their ability to provide data that enable testing of the programme theory. Data extraction will be conducted, for example, by note taking and annotation at different review stages as is consistent with the realist approach. The evidence will be synthesised using realist logic to interrogate the final programme theory of the impact of appraisal on doctors' performance. The synthesis results will be written up according to RAMESES guidelines and disseminated through peer-reviewed publication and presentations. TRIAL REGISTRATION NUMBER: The protocol is registered with PROSPERO 2014:CRD42014007092.UK Department of HealthNational Institute for Health Research (NIHR

Hydrogen bonding and coordination in normal and supercritical water from X-ray inelastic scattering

A direct measure of hydrogen bonding in water under conditions ranging from the normal state to the supercritical regime is derived from the Compton scattering of inelastically-scattered X-rays. First, we show that a measure of the number of electrons $n_e$ involved in hydrogen bonding at varying thermodynamic conditions can be directly obtained from Compton profile differences. Then, we use first-principles simulations to provide a connection between $n_e$ and the number of hydrogen bonds $n_{HB}$. Our study shows that over the broad range studied the relationship between $n_e$ and $n_{HB}$ is linear, allowing for a direct experimental measure of bonding and coordination in water. In particular, the transition to supercritical state is characterized by a sharp increase in the number of water monomers, but also displays a significant number of residual dimers and trimers.Comment: 14 pages, 5 figures, 1 tabl

Network meta-analysis of multiple outcome measures accounting for borrowing of information across outcomes

Background: Network meta-analysis (NMA) enables simultaneous comparison of multiple treatments while preserving randomisation. When summarising evidence to inform an economic evaluation, it is important that the analysis accurately reflects the dependency structure within the data, as correlations between outcomes may have implication for estimating the net benefit associated with treatment. A multivariate NMA offers a framework for evaluating multiple treatments across multiple outcome measures while accounting for the correlation structure between outcomes. Methods: The standard NMA model is extended to multiple outcome settings in two stages. In the first stage, information is borrowed across outcomes as well across studies through modelling the within-study and between-study correlation structure. In the second stage, we make use of the additional assumption that intervention effects are exchangeable between outcomes to predict effect estimates for all outcomes, including effect estimates on outcomes where evidence is either sparse or the treatment had not been considered by any one of the studies included in the analysis. We apply the methods to binary outcome data from a systematic review evaluating the effectiveness of nine home safety interventions on uptake of three poisoning prevention practices (safe storage of medicines, safe storage of other household products, and possession of poison centre control telephone number) in households with children. Analyses are conducted in WinBUGS using Markov Chain Monte Carlo (MCMC) simulations. Results: Univariate and the first stage multivariate models produced broadly similar point estimates of intervention effects but the uncertainty around the multivariate estimates varied depending on the prior distribution specified for the between-study covariance structure. The second stage multivariate analyses produced more precise effect estimates while enabling intervention effects to be predicted for all outcomes, including intervention effects on outcomes not directly considered by the studies included in the analysis. Conclusions: Accounting for the dependency between outcomes in a multivariate meta-analysis may or may not improve the precision of effect estimates from a network meta-analysis compared to analysing each outcome separately

The multiple sclerosis risk sharing scheme monitoring study - early results and lessons for the future

Background: Risk sharing schemes represent an innovative and important approach to the problems of rationing and achieving cost-effectiveness in high cost or controversial health interventions. This study aimed to assess the feasibility of risk sharing schemes, looking at long term clinical outcomes, to determine the price at which high cost treatments would be acceptable to the NHS. Methods: This case study of the first NHS risk sharing scheme, a long term prospective cohort study of beta interferon and glatiramer acetate in multiple sclerosis ( MS) patients in 71 specialist MS centres in UK NHS hospitals, recruited adults with relapsing forms of MS, meeting Association of British Neurologists (ABN) criteria for disease modifying therapy. Outcome measures were: success of recruitment and follow up over the first three years, analysis of baseline and initial follow up data and the prospect of estimating the long term cost-effectiveness of these treatments. Results: Centres consented 5560 patients. Of the 4240 patients who had been in the study for a least one year, annual review data were available for 3730 (88.0%). Of the patients who had been in the study for at least two years and three years, subsequent annual review data were available for 2055 (78.5%) and 265 (71.8%) patients respectively. Baseline characteristics and a small but statistically significant progression of disease were similar to those reported in previous pivotal studies. Conclusion: Successful recruitment, follow up and early data analysis suggest that risk sharing schemes should be able to deliver their objectives. However, important issues of analysis, and political and commercial conflicts of interest still need to be addressed

Novel methods to deal with publication biases: secondary analysis of antidepressant trials in the FDA trial registry database and related journal publications

Objective To assess the performance of novel contour enhanced funnel plots and a regression based adjustment method to detect and adjust for publication biases

Nonequilibrium evolution in scalar O(N) models with spontaneous symmetry breaking

We consider the out-of-equilibrium evolution of a classical condensate field and its quantum fluctuations for a scalar O(N) model with spontaneously broken symmetry. In contrast to previous studies we do not consider the large N limit, but the case of finite N, including N=1, i.e., plain $\lambda \phi^ 4$ theory. The instabilities encountered in the one-loop approximation are prevented, as in the large-N limit, by back reaction of the fluctuations on themselves, or, equivalently, by including a resummation of bubble diagrams. For this resummation and its renormalization we use formulations developed recently based on the effective action formalism of Cornwall, Jackiw and Tomboulis. The formulation of renormalized equations for finite N derived here represents a useful tool for simulations with realistic models. Here we concentrate on the phase structure of such models. We observe the transition between the spontaneously broken and the symmetric phase at low and high energy densities, respectively. This shows that the typical structures expected in thermal equilibrium are encountered in nonequilibrium dynamics even at early times, i.e., before an efficient rescattering can lead to thermalization.Comment: 31 pages, 19 Figures, LaTeX; extended discussion on the basis of: fluctuations, eff. potential, correlations, analytic calculation of parametric resonance for "pion"_and_ "sigma" field

Data visualisation approaches for component network meta-analysis:visualising the data structure

Abstract Background Health and social care interventions are often complex and can be decomposed into multiple components. Multicomponent interventions are often evaluated in randomised controlled trials. Across trials, interventions often have components in common which are given alongside other components which differ across trials. Multicomponent interventions can be synthesised using component NMA (CNMA). CNMA is limited by the structure of the available evidence, but it is not always straightforward to visualise such complex evidence networks. The aim of this paper is to develop tools to visualise the structure of complex evidence networks to support CNMA. Methods We performed a citation review of two key CNMA methods papers to identify existing published CNMA analyses and reviewed how they graphically represent intervention complexity and comparisons across trials. Building on identified shortcomings of existing visualisation approaches, we propose three approaches to standardise visualising the data structure and/or availability of data: CNMA-UpSet plot, CNMA heat map, CNMA-circle plot. We use a motivating example to illustrate these plots. Results We identified 34 articles reporting CNMAs. A network diagram was the most common plot type used to visualise the data structure for CNMA (26/34 papers), but was unable to express the complex data structures and large number of components and potential combinations of components associated with CNMA. Therefore, we focused visualisation development around representing the data structure of a CNMA more completely. The CNMA-UpSet plot presents arm-level data and is suitable for networks with large numbers of components or combinations of components. Heat maps can be utilised to inform decisions about which pairwise interactions to consider for inclusion in a CNMA model. The CNMA-circle plot visualises the combinations of components which differ between trial arms and offers flexibility in presenting additional information such as the number of patients experiencing the outcome of interest in each arm. Conclusions As CNMA becomes more widely used for the evaluation of multicomponent interventions, the novel CNMA-specific visualisations presented in this paper, which improve on the limitations of existing visualisations, will be important to aid understanding of the complex data structure and facilitate interpretation of the CNMA results

Anomalous Pseudoscalar-Photon Vertex In and Out of Equilibrium

The anomalous pseudoscalar-photon vertex is studied in real time in and out of equilibrium in a constituent quark model. The goal is to understand the in-medium modifications of this vertex, exploring the possibility of enhanced isospin breaking by electromagnetic effects as well as the formation of neutral pion condensates in a rapid chiral phase transition in peripheral, ultrarelativistic heavy-ion collisions. In equilibrium the effective vertex is afflicted by infrared and collinear singularities that require hard thermal loop (HTL) and width corrections of the quark propagator. The resummed effective equilibrium vertex vanishes near the chiral transition in the chiral limit. In a strongly out of equilibrium chiral phase transition we find that the chiral condensate drastically modifies the quark propagators and the effective vertex. The ensuing dynamics for the neutral pion results in a potential enhancement of isospin breaking and the formation of $\pi^0$ condensates. While the anomaly equation and the axial Ward identity are not modified by the medium in or out of equilibrium, the effective real-time pseudoscalar-photon vertex is sensitive to low energy physics.Comment: Revised version to appear in Phys. Rev. D. 42 pages, 4 figures, uses Revte