Publications by authors named "Rebecca Turner"

67 Publications

Worldwide border interceptions provide a window into human-mediated global insect movement.

Ecol Appl 2021 Jul 13:e02412. Epub 2021 Jul 13.

U.S. Department of Agriculture Forest Service Northern Research Station, Morgantown, West Virginia, 26505, USA.

As part of national biosecurity programs, cargo imports, passenger baggage, and international mail are inspected at ports of entry to verify compliance with phytosanitary regulations and to intercept potentially damaging nonnative species to prevent their introduction. Detection of organisms during inspections may also provide crucial information about the species composition and relative arrival rates in invasion pathways that can inform the implementation of other biosecurity practices such as quarantines and surveillance. In most regions, insects are the main taxonomic group encountered during inspections. We gathered insect interception data from nine world regions collected from 1995 to 2019 to compare the composition of species arriving at ports in these regions. Collectively, 8,716 insect species were intercepted in these regions over the last 25 yr, with the combined international data set comprising 1,899,573 interception events, of which 863,972 were identified to species level. Rarefaction analysis indicated that interceptions comprise only a small fraction of species present in invasion pathways. Despite differences in inspection methodologies, as well as differences in the composition of import source regions and imported commodities, we found strong positive correlations in species interception frequencies between regions, particularly within the Hemiptera and Thysanoptera. There were also significant differences in species frequencies among insects intercepted in different regions. Nevertheless, integrating interception data among multiple regions would be valuable for estimating invasion risks for insect species with high likelihoods of introduction as well as for identifying rare but potentially damaging species.
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http://dx.doi.org/10.1002/eap.2412DOI Listing
July 2021

Development of a B-cell maturation antigen-specific T-cell antigen coupler receptor for multiple myeloma.

Cytotherapy 2021 Sep 1;23(9):820-832. Epub 2021 Jul 1.

Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Canada. Electronic address:

Background Aims: T cells engineered with synthetic receptors have delivered powerful therapeutic results for patients with relapsed/refractory hematologic malignancies. The authors have recently described the T-cell antigen coupler (TAC) receptor, which co-opts the endogenous T-cell receptor (TCR) and activates engineered T cells in an HLA-independent manner. Here the authors describe the evolution of a next-generation TAC receptor with a focus on developing a TAC-engineered T cell for multiple myeloma.

Methods: To optimize the TAC scaffold, the authors employed a bona fide antigen-binding domain derived from the B-cell maturation antigen-specific monoclonal antibody C11D5.3, which has been used successfully in the clinic. The authors first tested humanized versions of the UCHT1 domain, which is used by the TAC to co-opt the TCR. The authors further discovered that the signal peptide affected surface expression of the TAC receptor. Higher density of the TAC receptor enhanced target binding in vitro, which translated into higher levels of Lck at the immunological synapse and stronger proliferation when only receptor-ligand interactions were present.

Results: The authors observed that the humanized UCHT1 improved surface expression and in vivo efficacy. Using TAC T cells derived from both healthy donors and multiple myeloma patients, the authors determined that despite the influence of receptor density on early activation events and effector function, receptor density did not impact late effector functions in vitro, nor did the receptor density affect in vivo efficacy.

Conclusions: The modifications to the TAC scaffold described herein represent an important step in the evolution of this technology, which tolerates a range of expression levels without impacting therapeutic efficacy.
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http://dx.doi.org/10.1016/j.jcyt.2021.05.007DOI Listing
September 2021

Embedding supervised exercise training for men on androgen deprivation therapy into standard prostate cancer care: a feasibility and acceptability study (the STAMINA trial).

Sci Rep 2021 06 14;11(1):12470. Epub 2021 Jun 14.

Allied Health Professionals, Radiotherapy and Oncology, Sheffield Hallam University, Sheffield, UK.

Lifestyle interventions involving exercise training offset the adverse effects of androgen deprivation therapy in men with prostate cancer. Yet provision of integrated exercise pathways in cancer care is sparse. This study assessed the feasibility and acceptability of an embedded supervised exercise training intervention into standard prostate cancer care in a single-arm, multicentre prospective cohort study. Feasibility included recruitment, retention, adherence, fidelity and safety. Acceptability of behaviourally informed healthcare and exercise professional training was assessed qualitatively. Despite the imposition of lockdown for the COVID-19 pandemic, referral rates into and adherence to, the intervention was high. Of the 45 men eligible for participation, 79% (n = 36) received the intervention and 47% (n = 21) completed the intervention before a government mandated national lockdown was enforced in the United Kingdom. Patients completed a mean of 27 min of aerobic exercise per session (SD = 3.48), at 77% heart rate maximum (92% of target dose), and 3 sets of 10 reps of 3 resistance exercises twice weekly for 12 weeks, without serious adverse event. The intervention was delivered by 26 healthcare professionals and 16 exercise trainers with moderate to high fidelity, and the intervention was deemed highly acceptable to patients. The impact of societal changes due to the pandemic on the delivery of this face-to-face intervention remain uncertain but positive impacts of embedding exercise provision into prostate cancer care warrant long-term investigation.
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http://dx.doi.org/10.1038/s41598-021-91876-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203669PMC
June 2021

Personalised randomised controlled trial designs-a new paradigm to define optimal treatments for carbapenem-resistant infections.

Lancet Infect Dis 2021 06 21;21(6):e175-e181. Epub 2021 Apr 21.

Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK; and Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam. Electronic address:

Antimicrobial resistance is impacting treatment decisions for, and patient outcomes from, bacterial infections worldwide, with particular threats from infections with carbapenem-resistant Enterobacteriaceae, Acinetobacter baumanii, or Pseudomonas aeruginosa. Numerous areas of clinical uncertainty surround the treatment of these highly resistant infections, yet substantial obstacles exist to the design and conduct of treatment trials for carbapenem-resistant bacterial infections. These include the lack of a widely acceptable optimised standard of care and control regimens, varying antimicrobial susceptibilities and clinical contraindications making specific intervention regimens infeasible, and diagnostic and recruitment challenges. The current single comparator trials are not designed to answer the urgent public health question, identified as a high priority by WHO, of what are the best regimens out of the available options that will significantly reduce morbidity, costs, and mortality. This scenario has an analogy in network meta-analysis, which compares multiple treatments in an evidence synthesis to rank the best of a set of available treatments. To address these obstacles, we propose extending the network meta-analysis approach to individual randomisation of patients. We refer to this approach as a Personalised RAndomised Controlled Trial (PRACTical) design that compares multiple treatments in an evidence synthesis, to identify, overall, which is the best treatment out of a set of available treatments to recommend, or how these different treatments rank against each other. In this Personal View, we summarise the design principles of personalised randomised controlled trial designs. Specifically, of a network of different potential regimens for life-threatening carbapenem-resistant infections, each patient would be randomly assigned only to regimens considered clinically reasonable for that patient at that time, incorporating antimicrobial susceptibility, toxicity profile, pharmacometric properties, availability, and physician assessment. Analysis can use both direct and indirect comparisons across the network, analogous to network meta-analysis. This new trial design will maximise the relevance of the findings to each individual patient, and enable the top-ranked regimens from any personalised randomisation list to be identified, in terms of both efficacy and safety.
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http://dx.doi.org/10.1016/S1473-3099(20)30791-XDOI Listing
June 2021

Cell-specific drug targeting in the lung.

Biochem Pharmacol 2021 Aug 19;190:114577. Epub 2021 Apr 19.

Department of Medicine, Firestone Institute for Respiratory Health, McMaster University, Hamilton, ON, Canada; Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada; Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON, Canada. Electronic address:

Non-targeted drug delivery systems have several limitations including the decreased bioavailability of the drug, poor stability and rapid clearance in addition to off-target distribution. Cell-specific targeted delivery approaches promise to overcome some of these limitations and enhance therapeutic selectivity. In this review, we aim to discuss cell-specific targeted approachesin the lung at the biochemical and molecular levels. These approaches include;a) directly administered small molecule drugs with intracellular action; b) targeted biologics and synthetic hybrids with extracellular action; c) site activateddrugs; and d) delivery systems.We discuss the pharmaceutical and biochemical parameters that govern the fate of drug molecules at delivery sites while presenting an overview of relevant literature surrounding this area of research and current advancements.
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http://dx.doi.org/10.1016/j.bcp.2021.114577DOI Listing
August 2021

The development of a theory and evidence-based intervention to aid implementation of exercise into the prostate cancer care pathway with a focus on healthcare professional behaviour, the STAMINA trial.

BMC Health Serv Res 2021 Mar 25;21(1):273. Epub 2021 Mar 25.

Institute for Population Health Sciences, Queen Mary, University of London, London, UK.

Background: Twice-weekly supervised aerobic and resistance exercise for 12 weeks reduces fatigue and improves quality of life in men on Androgen Deprivation Therapy for prostate cancer. Despite the National Institute for Health and Care Excellence (NICE) proposing this as standard of care, it does not routinely take place in practice. Healthcare professionals are in a prime position to deliver and integrate these recommendations. A change in the behaviour of clinical teams is therefore required. In this paper, we describe the development of a training package for healthcare professionals using theory and evidence to promote delivery of such recommendations as standard care.

Methods: The intervention development process was guided by the Medical Research Council guidance for complex interventions and the Behaviour Change Wheel. Target behaviours were identified from the literature and thirty-five prostate cancer care healthcare professionals (including oncologists, consultant urologists, clinical nurse specialists, physiotherapists, general practitioners and commissioners) were interviewed to understand influences on these behaviours. The Theoretical Domains Framework was used to identify theoretical constructs for change. Behaviour change techniques were selected based on theory and evidence and were translated into intervention content. The intervention was refined with the input of stakeholders including healthcare professionals, patients, and exercise professionals in the form of rehearsal deliveries, focus groups and a workshop.

Results: Seven modifiable healthcare professional target behaviours were identified to support the delivery of the NICE recommendations including identifying eligible patients suitable for exercise, recommending exercise, providing information, exercise referral, providing support and interpret and feedback on progress. Ten domains from the Theoretical Domain's Framework were identified as necessary for change, including improving knowledge and skills, addressing beliefs about consequences, and targeting social influences. These were targeted through twenty-two behaviour change techniques delivered in a half-day, interactive training package. Based on initial feedback from stakeholders, the intervention was refined in preparation for evaluation.

Conclusions: We designed an intervention based on theory, evidence, and stakeholder feedback to promote and support the delivery of NICE recommendations. Future work will aim to test this training package in a multi-centre randomised trial. If proven effective, the development and training package will provide a template for replication in other clinical populations, where exercise has proven efficacy but is insufficiently implemented.
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http://dx.doi.org/10.1186/s12913-021-06266-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992804PMC
March 2021

Remote interventions to improve exercise behaviour in sedentary people living with and beyond cancer: a systematic review and meta-analysis.

BMC Cancer 2021 Mar 24;21(1):308. Epub 2021 Mar 24.

College of Health, Wellbeing and Life Sciences, Sheffield Hallam University, Sheffield, UK.

Background: The COVID-19 pandemic has forced many cancer services to consider a transition to a remote format of delivery that is largely untested. Accordingly, we sought to perform a systematic review of the effects of remotely delivered interventions to improve exercise behaviour in sedentary adults living with and beyond cancer.

Methods: Eligible studies were randomised controlled trials comparing a remotely delivered exercise intervention to a usual care comparison in sedentary people over 18 years old with a primary cancer diagnosis. Nine electronic databases were searched from inception to November 2020.

Results: The review included three trials, totalling 186 participants. Two of the included trials incorporated prescriptions that meet current aerobic exercise recommendations, one of which also meets the guidelines for resistance exercise. No trials reported an intervention adherence of 75% or more for a set prescription that meets current exercise guidelines.

Conclusion: There is little evidence suggesting that remote exercise interventions promote exercise behaviours or improve physical function in sedentary adults living with and beyond cancer. The development and evaluation of novel remote exercise interventions is needed to establish their usefulness for clinical practice. Given the social response to the COVID-19 pandemic, further research in this area is urgently needed.
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http://dx.doi.org/10.1186/s12885-021-07989-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987748PMC
March 2021

Towards implementing exercise into the prostate cancer care pathway: development of a theory and evidence-based intervention to train community-based exercise professionals to support change in patient exercise behaviour (The STAMINA trial).

BMC Health Serv Res 2021 Mar 22;21(1):264. Epub 2021 Mar 22.

Institute for Population Health Sciences, Queen Mary University of London, London, UK.

Background: The National Institute for Health and Care Excellence (NICE) recommend that men on androgen deprivation therapy (ADT) for prostate cancer should receive supervised exercise to manage the side-effects of treatment. However, these recommendations are rarely implemented into practice. Community-based exercise professionals (CBEPs) represent an important target group to deliver the recommendations nationally, yet their standard training does not address the core competencies required to work with clinical populations, highlighting a need for further professional training. This paper describes the development of a training package to support CBEPs to deliver NICE recommendations.

Methods: Development of the intervention was guided by the Medical Research Council guidance for complex interventions and the Behaviour Change Wheel. In step one, target behaviours, together with their barriers and facilitators were identified from a literature review and focus groups with CBEPs (n = 22) and men on androgen deprivation therapy (n = 26). Focus group outputs were mapped onto the Theoretical Domains Framework (TDF) to identify theoretical constructs for change. In step two, behaviour change techniques and their mode of delivery were selected based on psychological theories and evidence to inform intervention content. In step three, the intervention was refined following delivery and subsequent feedback from intervention recipients and stakeholders.

Results: Six modifiable CBEPs target behaviours were identified to support the delivery of the NICE recommendations. Nine domains of the TDF were identified as key determinants of change, including: improving knowledge and skills and changing beliefs about consequences. To target the domains, we included 20 BCTs across 8 training modules and took a blended learning approach to accommodate different learning styles and preferences. Following test delivery to 11 CBEPs and feedback from 28 stakeholders, the training package was refined.

Conclusion: Established intervention development approaches provided a structured and transparent guide to intervention development. A training package for CBEPs was developed and should increase trust amongst patients and health care professionals when implementing exercise into prostate cancer care. Furthermore, if proven effective, the development and approach taken may provide a blueprint for replication in other clinical populations where exercise has proven efficacy but is insufficiently implemented.
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http://dx.doi.org/10.1186/s12913-021-06275-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982309PMC
March 2021

MultiBUGS: A Parallel Implementation of the BUGS Modelling Framework for Faster Bayesian Inference.

J Stat Softw 2020 Oct;95

MRC Biostatistics Unit University of Cambridge.

MultiBUGS is a new version of the general-purpose Bayesian modelling software BUGS that implements a generic algorithm for parallelising Markov chain Monte Carlo (MCMC) algorithms to speed up posterior inference of Bayesian models. The algorithm parallelises evaluation of the product-form likelihoods formed when a parameter has many children in the directed acyclic graph (DAG) representation; and parallelises sampling of conditionally-independent sets of parameters. A heuristic algorithm is used to decide which approach to use for each parameter and to apportion computation across computational cores. This enables MultiBUGS to automatically parallelise the broad range of statistical models that can be fitted using BUGS-language software, making the dramatic speed-ups of modern multi-core computing accessible to applied statisticians, without requiring any experience of parallel programming. We demonstrate the use of MultiBUGS on simulated data designed to mimic a hierarchical e-health linked-data study of methadone prescriptions including 425,112 observations and 20,426 random effects. Posterior inference for the e-health model takes several hours in existing software, but MultiBUGS can perform inference in only 28 minutes using 48 computational cores.
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http://dx.doi.org/10.18637/jss.v095.i07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116196PMC
October 2020

Considering unseen arrivals in predictions of establishment risk based on border biosecurity interceptions.

Ecol Appl 2020 12 24;30(8):e02194. Epub 2020 Sep 24.

Te Pūnaha Matatini, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.

Assessing species establishment risk is an important task used for informing biosecurity activities aimed at preventing biological invasions. Propagule pressure is a major contributor to the probability of invading species establishment; however, direct assessment of numbers of individuals arriving is virtually never possible. Inspections conducted at borders by biosecurity officials record counts of species (or higher-level taxa) intercepted during inspections, which can be used as proxies for arrival rates. Such data may therefore be useful for predicting species establishments, though some species may establish despite never being intercepted. We present a stochastic process-based model of the arrival-interception-establishment process to predict species establishment risk from interception count data. The model can be used to estimate the probability of establishment, both for species that were intercepted and species that had no interceptions during a given observation period. We fit the stochastic model to data on two insect families, Cerambycidae and Aphididae, that were intercepted and/or established in the United States or New Zealand. We also explore the effects of variation in model parameters and the inclusion of an Allee effect in the establishment probability. Although interception data sets contain much noise due to variation in inspection policy, interception effort and among-species differences in detectability, our study shows that it is possible to use such data for predicting establishments and distinguishing differences in establishment risk profile between taxonomic groups. Our model provides a method for predicting the number of species that have breached border biosecurity, including both species detected during inspections but also "unseen arrivals" that have never been intercepted, but have not yet established a viable population. These estimates could inform prioritization of different taxonomic groups, pathways or identification effort in biosecurity programs.
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http://dx.doi.org/10.1002/eap.2194DOI Listing
December 2020

Agreement was moderate between data-based and opinion-based assessments of biases affecting randomized trials within meta-analyses.

J Clin Epidemiol 2020 09 13;125:16-25. Epub 2020 May 13.

Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK; NIHR Applied Research Collaboration (ARC) West, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.

Background And Objective: Randomized trials included in meta-analyses are often affected by bias caused by methodological flaws or limitations, but the degree of bias is unknown. Two proposed methods adjust the trial results for bias using empirical evidence from published meta-epidemiological studies or expert opinion.

Methods: We investigated agreement between data-based and opinion-based approaches to assessing bias in each of four domains: sequence generation, allocation concealment, blinding, and incomplete outcome data. From each sampled meta-analysis, a pair of trials with the highest and lowest empirical model-based bias estimates was selected. Independent assessors were asked which trial within each pair was judged more biased on the basis of detailed trial design summaries.

Results: Assessors judged trials to be equally biased in 68% of pairs evaluated. When assessors judged one trial as more biased, the proportion of judgments agreeing with the model-based ranking was highest for allocation concealment (79%) and blinding (79%) and lower for sequence generation (59%) and incomplete outcome data (56%).

Conclusion: Most trial pairs found to be discrepant empirically were judged to be equally biased by assessors. We found moderate agreement between opinion and data-based evidence in pairs where assessors ranked one trial as more biased.
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http://dx.doi.org/10.1016/j.jclinepi.2020.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482431PMC
September 2020

Handling an uncertain control group event risk in non-inferiority trials: non-inferiority frontiers and the power-stabilising transformation.

Trials 2020 Feb 6;21(1):145. Epub 2020 Feb 6.

MRC Clinical Trials Unit, Institute of Clinical Trials and Methodology, University College London, 90 High Holborn, Second Floor, London, WC1V 6LJ, UK.

Background: Non-inferiority trials are increasingly used to evaluate new treatments that are expected to have secondary advantages over standard of care, but similar efficacy on the primary outcome. When designing a non-inferiority trial with a binary primary outcome, the choice of effect measure for the non-inferiority margin (e.g. risk ratio or risk difference) has an important effect on sample size calculations; furthermore, if the control event risk observed is markedly different from that assumed, the trial can quickly lose power or the results become difficult to interpret.

Methods: We propose a new way of designing non-inferiority trials to overcome the issues raised by unexpected control event risks. Our proposal involves using clinical judgement to specify a 'non-inferiority frontier', i.e. a curve defining the most appropriate non-inferiority margin for each possible value of control event risk. Existing trials implicitly use frontiers defined by a fixed risk ratio or a fixed risk difference. We discuss their limitations and propose a fixed arcsine difference frontier, using the power-stabilising transformation for binary outcomes, which may better represent clinical judgement. We propose and compare three ways of designing a trial using this frontier: testing and reporting on the arcsine scale; testing on the arcsine scale but reporting on the risk difference or risk ratio scale; and modifying the margin on the risk difference or risk ratio scale after observing the control event risk according to the power-stabilising frontier.

Results: Testing and reporting on the arcsine scale leads to results which are challenging to interpret clinically. For small values of control event risk, testing on the arcsine scale and reporting results on the risk difference scale produces confidence intervals at a higher level than the nominal one or non-inferiority margins that are slightly smaller than those back-calculated from the power-stabilising frontier alone. However, working on the arcsine scale generally requires a larger sample size compared to the risk difference scale. Therefore, working on the risk difference scale, modifying the margin after observing the control event risk, might be preferable, as it requires a smaller sample size. However, this approach tends to slightly inflate type I error rate; a solution is to use a slightly lower significance level for testing, although this modestly reduces power. When working on the risk ratio scale instead, the same approach based on the modification of the margin leads to power levels above the nominal one, maintaining type I error under control.

Conclusions: Our proposed methods of designing non-inferiority trials using power-stabilising non-inferiority frontiers make trial design more resilient to unexpected values of the control event risk, at the only cost of requiring somewhat larger sample sizes when the goal is to report results on the risk difference scale.
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http://dx.doi.org/10.1186/s13063-020-4070-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006194PMC
February 2020

A comparison of arm-based and contrast-based models for network meta-analysis.

Stat Med 2019 11 3;38(27):5197-5213. Epub 2019 Oct 3.

Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.

Differences between arm-based (AB) and contrast-based (CB) models for network meta-analysis (NMA) are controversial. We compare the CB model of Lu and Ades (2006), the AB model of Hong et al(2016), and two intermediate models, using hypothetical data and a selected real data set. Differences between models arise primarily from study intercepts being fixed effects in the Lu-Ades model but random effects in the Hong model, and we identify four key difference. (1) If study intercepts are fixed effects then only within-study information is used, but if they are random effects then between-study information is also used and can cause important bias. (2) Models with random study intercepts are suitable for deriving a wider range of estimands, eg, the marginal risk difference, when underlying risk is derived from the NMA data; but underlying risk is usually best derived from external data, and then models with fixed intercepts are equally good. (3) The Hong model allows treatment effects to be related to study intercepts, but the Lu-Ades model does not. (4) The Hong model is valid under a more relaxed missing data assumption, that arms (rather than contrasts) are missing at random, but this does not appear to reduce bias. We also describe an AB model with fixed study intercepts and a CB model with random study intercepts. We conclude that both AB and CB models are suitable for the analysis of NMA data, but using random study intercepts requires a strong rationale such as relating treatment effects to study intercepts.
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http://dx.doi.org/10.1002/sim.8360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899819PMC
November 2019

Bivariate network meta-analysis for surrogate endpoint evaluation.

Stat Med 2019 08 26;38(18):3322-3341. Epub 2019 May 26.

MRC Clinical Trials Unit, University College London, London, UK.

Surrogate endpoints are very important in regulatory decision making in healthcare, in particular if they can be measured early compared to the long-term final clinical outcome and act as good predictors of clinical benefit. Bivariate meta-analysis methods can be used to evaluate surrogate endpoints and to predict the treatment effect on the final outcome from the treatment effect measured on a surrogate endpoint. However, candidate surrogate endpoints are often imperfect, and the level of association between the treatment effects on the surrogate and final outcomes may vary between treatments. This imposes a limitation on methods which do not differentiate between the treatments. We develop bivariate network meta-analysis (bvNMA) methods, which combine data on treatment effects on the surrogate and final outcomes, from trials investigating multiple treatment contrasts. The bvNMA methods estimate the effects on both outcomes for all treatment contrasts individually in a single analysis. At the same time, they allow us to model the trial-level surrogacy patterns within each treatment contrast and treatment-level surrogacy, thus enabling predictions of the treatment effect on the final outcome either for a new study in a new population or for a new treatment. Modelling assumptions about the between-studies heterogeneity and the network consistency, and their impact on predictions, are investigated using an illustrative example in advanced colorectal cancer and in a simulation study. When the strength of the surrogate relationships varies across treatment contrasts, bvNMA has the advantage of identifying treatment comparisons for which surrogacy holds, thus leading to better predictions.
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http://dx.doi.org/10.1002/sim.8187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6618064PMC
August 2019

Incorporating external evidence on between-trial heterogeneity in network meta-analysis.

Stat Med 2019 04 28;38(8):1321-1335. Epub 2018 Nov 28.

MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, London, UK.

In a network meta-analysis, between-study heterogeneity variances are often very imprecisely estimated because data are sparse, so standard errors of treatment differences can be highly unstable. External evidence can provide informative prior distributions for heterogeneity and, hence, improve inferences. We explore approaches for specifying informative priors for multiple heterogeneity variances in a network meta-analysis. First, we assume equal heterogeneity variances across all pairwise intervention comparisons (approach 1); incorporating an informative prior for the common variance is then straightforward. Models allowing unequal heterogeneity variances are more realistic; however, care must be taken to ensure implied variance-covariance matrices remain valid. We consider three strategies for specifying informative priors for multiple unequal heterogeneity variances. Initially, we choose different informative priors according to intervention comparison type and assume heterogeneity to be proportional across comparison types and equal within comparison type (approach 2). Next, we allow all heterogeneity variances in the network to differ, while specifying a common informative prior for each. We explore two different approaches to this: placing priors on variances and correlations separately (approach 3) or using an informative inverse Wishart distribution (approach 4). Our methods are exemplified through application to two network metaanalyses. Appropriate informative priors are obtained from previously published evidence-based distributions for heterogeneity. Relevant prior information on between-study heterogeneity can be incorporated into network meta-analyses, without needing to assume equal heterogeneity across treatment comparisons. The approaches proposed will be beneficial in sparse data sets and provide more appropriate intervals for treatment differences than those based on imprecise heterogeneity estimates.
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http://dx.doi.org/10.1002/sim.8044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492109PMC
April 2019

FLOWERING LOCUS T2 regulates spike development and fertility in temperate cereals.

J Exp Bot 2019 01;70(1):193-204

Department of Plant Sciences, University of California Davis, Davis, CA, USA.

FLOWERING LOCUS T2 (FT2) is the closest paralog of the FT1 flowering gene in the temperate grasses. Here we show that overexpression of FT2 in Brachypodium distachyon and barley results in precocious flowering and reduced spikelet number, while down-regulation by RNA interference results in delayed flowering and a reduced percentage of filled florets. Similarly, truncation mutations of FT2 homeologs in tetraploid wheat delayed flowering (2-4 d) and reduced fertility. The wheat ft2 mutants also showed a significant increase in the number of spikelets per spike, with a longer spike development period potentially contributing to the delayed heading time. In the wheat leaves, FT2 was expressed later than FT1, suggesting a relatively smaller role for FT2 in the initiation of the reproductive phase. FT2 transcripts were detected in the shoot apical meristem and increased during early spike development. Transversal sections of the developing spike showed the highest FT2 transcript levels in the distal part, where new spikelets are formed. Our results suggest that, in wheat, FT2 plays an important role in spike development and fertility and a limited role in the timing of the transition between the vegetative and reproductive shoot apical meristem.
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http://dx.doi.org/10.1093/jxb/ery350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305198PMC
January 2019

Interventions for promoting habitual exercise in people living with and beyond cancer.

Cochrane Database Syst Rev 2018 09 19;9:CD010192. Epub 2018 Sep 19.

Centre for Sport and Exercise Science, Sheffield Hallam University, A124 Collegiate Hall, Collegiate Crescent, Sheffield, South Yorkshire, UK, S10 2BP.

Background: This is an updated version of the original Cochrane Review published in the Cochrane Library 2013, Issue 9. Despite good evidence for the health benefits of regular exercise for people living with or beyond cancer, understanding how to promote sustainable exercise behaviour change in sedentary cancer survivors, particularly over the long term, is not as well understood. A large majority of people living with or recovering from cancer do not meet current exercise recommendations. Hence, reviewing the evidence on how to promote and sustain exercise behaviour is important for understanding the most effective strategies to ensure benefit in the patient population and identify research gaps.

Objectives: To assess the effects of interventions designed to promote exercise behaviour in sedentary people living with and beyond cancer and to address the following secondary questions: Which interventions are most effective in improving aerobic fitness and skeletal muscle strength and endurance? Which interventions are most effective in improving exercise behaviour amongst patients with different cancers? Which interventions are most likely to promote long-term (12 months or longer) exercise behaviour? What frequency of contact with exercise professionals and/or healthcare professionals is associated with increased exercise behaviour? What theoretical basis is most often associated with better behavioural outcomes? What behaviour change techniques (BCTs) are most often associated with increased exercise behaviour? What adverse effects are attributed to different exercise interventions?

Search Methods: We used standard methodological procedures expected by Cochrane. We updated our 2013 Cochrane systematic review by updating the searches of the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, Embase, AMED, CINAHL, PsycLIT/PsycINFO, SportDiscus and PEDro up to May 2018. We also searched the grey literature, trial registries, wrote to leading experts in the field and searched reference lists of included studies and other related recent systematic reviews.

Selection Criteria: We included only randomised controlled trials (RCTs) that compared an exercise intervention with usual care or 'waiting list' control in sedentary people over the age of 18 with a homogenous primary cancer diagnosis.

Data Collection And Analysis: In the update, review authors independently screened all titles and abstracts to identify studies that might meet the inclusion criteria, or that could not be safely excluded without assessment of the full text (e.g. when no abstract is available). We extracted data from all eligible papers with at least two members of the author team working independently (RT, LS and RG). We coded BCTs according to the CALO-RE taxonomy. Risk of bias was assessed using the Cochrane's tool for assessing risk of bias. When possible, and if appropriate, we performed a fixed-effect meta-analysis of study outcomes. If statistical heterogeneity was noted, a meta-analysis was performed using a random-effects model. For continuous outcomes (e.g. cardiorespiratory fitness), we extracted the final value, the standard deviation (SD) of the outcome of interest and the number of participants assessed at follow-up in each treatment arm, to estimate the standardised mean difference (SMD) between treatment arms. SMD was used, as investigators used heterogeneous methods to assess individual outcomes. If a meta-analysis was not possible or was not appropriate, we narratively synthesised studies. The quality of the evidence was assessed using the GRADE approach with the GRADE profiler.

Main Results: We included 23 studies in this review, involving a total of 1372 participants (an addition of 10 studies, 724 participants from the original review); 227 full texts were screened in the update and 377 full texts were screened in the original review leaving 35 publications from a total of 23 unique studies included in the review. We planned to include all cancers, but only studies involving breast, prostate, colorectal and lung cancer met the inclusion criteria. Thirteen studies incorporated a target level of exercise that could meet current recommendations for moderate-intensity aerobic exercise (i.e.150 minutes per week); or resistance exercise (i.e. strength training exercises at least two days per week).Adherence to exercise interventions, which is crucial for understanding treatment dose, is still reported inconsistently. Eight studies reported intervention adherence of 75% or greater to an exercise prescription that met current guidelines. These studies all included a component of supervision: in our analysis of BCTs we designated these studies as 'Tier 1 trials'. Six studies reported intervention adherence of 75% or greater to an aerobic exercise goal that was less than the current guideline recommendations: in our analysis of BCTs we designated these studies as 'Tier 2 trials.' A hierarchy of BCTs was developed for Tier 1 and Tier 2 trials, with programme goal setting, setting of graded tasks and instruction of how to perform behaviour being amongst the most frequent BCTs. Despite the uncertainty surrounding adherence in some of the included studies, interventions resulted in improvements in aerobic exercise tolerance at eight to 12 weeks (SMD 0.54, 95% CI 0.37 to 0.70; 604 participants, 10 studies; low-quality evidence) versus usual care. At six months, aerobic exercise tolerance was also improved (SMD 0.56, 95% CI 0.39 to 0.72; 591 participants; 7 studies; low-quality evidence).

Authors' Conclusions: Since the last version of this review, none of the new relevant studies have provided additional information to change the conclusions. We have found some improved understanding of how to encourage previously inactive cancer survivors to achieve international physical activity guidelines. Goal setting, setting of graded tasks and instruction of how to perform behaviour, feature in interventions that meet recommendations targets and report adherence of 75% or more. However, long-term follow-up data are still limited, and the majority of studies are in white women with breast cancer. There are still a considerable number of published studies with numerous and varied issues related to high risk of bias and poor reporting standards. Additionally, the meta-analyses were often graded as consisting of low- to very low-certainty evidence. A very small number of serious adverse effects were reported amongst the studies, providing reassurance exercise is safe for this population.
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http://dx.doi.org/10.1002/14651858.CD010192.pub3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513653PMC
September 2018

Optimizing Clinical Trial Design to Maximize Evidence Generation in Pediatric HIV.

J Acquir Immune Defic Syndr 2018 08;78 Suppl 1:S40-S48

MRC Clinical Trials Unit at UCL, University College London, London, United Kingdom.

For HIV-infected children, formulation development, pharmacokinetic (PK) data, and evaluation of early toxicity are critical for licensing new antiretroviral drugs; direct evidence of efficacy in children may not be needed if acceptable safety and PK parameters are demonstrated in children. However, it is important to address questions where adult trial data cannot be extrapolated to children. In this fast-moving area, interventions need to be tailored to resource-limited settings where most HIV-infected children live and take account of decreasing numbers of younger HIV-infected children after successful prevention of mother-to-child HIV transmission. Innovative randomized controlled trial (RCT) designs enable several questions relevant to children's treatment and care to be answered within the same study. We reflect on key considerations, and, with examples, discuss the relative merits of different RCT designs for addressing multiple scientific questions including parallel multi-arm RCTs, factorial RCTs, and cross-over RCTs. We discuss inclusion of several populations (eg, untreated and pretreated children; children and adults) in "basket" trials; incorporation of secondary randomizations after enrollment and use of nested substudies (particularly PK and formulation acceptability) within large RCTs. We review the literature on trial designs across other disease areas in pediatrics and rare diseases and discuss their relevance for addressing questions relevant to HIV-infected children; we provide an example of a Bayesian trial design in prevention of mother-to-child HIV transmission and consider this approach for future pediatric trials. Finally, we discuss the relevance of these approaches to other areas, in particular, childhood tuberculosis and hepatitis.
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http://dx.doi.org/10.1097/QAI.0000000000001748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071856PMC
August 2018

A multi-centre investigation of delivering national guidelines on exercise training for men with advanced prostate cancer undergoing androgen deprivation therapy in the UK NHS.

PLoS One 2018 5;13(7):e0197606. Epub 2018 Jul 5.

Department of Oncology and Metabolism, University of Sheffield, Sheffield United Kingdom.

Background: National guidelines (NICE-CG175) recommended 12 weeks of supervised exercise training for men treated with androgen deprivation therapy (ADT) for prostate cancer to counter debilitating adverse effects of castration. As with other chronic conditions where exercise is indicated, it is uncertain if these services are being delivered in the health services. The aim of this multi-centre investigation was to examine what exercise referral is currently available for men on ADT as provided by the NHS and if a supervised, individually-tailored exercise training package (as per the national NICE guidelines CG175) is embedded within prostate cancer care.

Methods: A multi-centre investigation of current National Health Service (NHS) care involving a web-based survey of NHS prostate cancer care, five focus groups involving 26 men on ADT and 37 semi-structured interviews with healthcare professionals (HCPs) involved in the management of prostate cancer. Descriptive statistics and thematic analysis evaluated quantitative and qualitative data, respectively. Qualitative methods followed COREQ standards.

Results: HCPs and men on ADT asserted that medical castration has a serious and debilitating impact on many features of men's quality of life. There is support for exercise training programmes as part of cancer care and patients would support their initiation soon after diagnosis. Involving the Multidisciplinary Team (MDT) is proposed as key to this. Critically, traditional values in oncology would need to be overcome for widespread acceptance. Specialist further training for HCPs around behaviour change support could encourage this. Given that these schemes are seen as a fundamental part of cancer care, it is felt the NHS should commission and support provision. 79 representatives of 154 NHS trusts (51%) provided survey data on current delivery: only 17% could provide supervised exercise as per CG175.

Conclusions: Evidence-based national exercise guidelines are not being delivered to men on ADT as intended. Traditional values in oncology and the need for NHS financial support are seen as major barriers to provision of current best practice guidelines. Despite this both HCPs and men on ADT are in favour of such programmes being a fundamental part of their cancer care.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0197606PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033384PMC
December 2018

How do care home staff understand, manage and respond to agitation in people with dementia? A qualitative study.

BMJ Open 2018 06 30;8(6):e022260. Epub 2018 Jun 30.

UCL Department of Old Age Psychiatry, Division of Psychiatry, University College London, London, UK.

Objectives: Little is known about how care home staff understand and respond to distress in residents living with dementia labelled as agitation. The aim of this study was to describe how care home staff understand and respond to agitation and the factors that determine how it is managed.

Design: We conducted a qualitative thematic analysis.

Setting: We recruited staff from six care homes in South East England including residential and nursing homes of differing sizes run by both the private and charity sector and located in urban and rural areas.

Participants: We interviewed 25 care home staff using purposive sampling to include staff of either sex, differing age, ethnicity, nationality and with different roles and experience.

Results: We identified four overarching themes: (1) behaviours expressing unmet need; (2) staff emotional responses to agitation; (3) understanding the individual helps and (4) constraints on staff responses. Staff struggled with the paradox of trying to connect with the personhood of residents while seeing the person as separate to and, therefore, not responsible for their behaviours. Staff often felt powerless, frightened and overwhelmed, and their responses were constrained by care home structures, processes and a culture of fear and scrutiny.

Conclusions: Responding to agitation expressed by residents was not a linear process and staff faced tensions and dilemmas in deciding how to respond, especially when initial strategies were unsuccessful or when attempts to respond to residents' needs were inhibited by structural and procedural constraints in the care home. Future trials of psychosocial interventions should support staff to identify and respond to residents' unmet needs and include how staff can look after themselves.
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http://dx.doi.org/10.1136/bmjopen-2018-022260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6042579PMC
June 2018

Treatment in the STAMPEDE era for castrate resistant prostate cancer in the UK: ongoing challenges and underappreciated clinical problems.

BMC Cancer 2018 Jun 19;18(1):667. Epub 2018 Jun 19.

The Department of Oncology and Metabolism, University of Sheffield Medical School, Sheffield, UK.

Background: This study aimed to explore the opinions of healthcare professionals regarding the management of men with advanced prostate cancer with particular emphasis on treatment timing and sequencing; treatment adverse-effects and exercise a supportive therapy.

Methods: Semi-structured interviews with a purposively selected group of healthcare professionals involved in prostate cancer care within the NHS, conducted over the phone or face to face. A total of 37 healthcare professionals participated in the interviews including urologists, clinical oncologists, medical oncologists, clinical nurse specialists, general practitioners, physiotherapists, exercise specialists, service managers, clinical commissioners and primary care physicians.

Results: The availability of newer treatments for advanced prostate cancer as well as results from the STAMPEDE and CHAARTED trials has resulted in new challenges for patients and HCPs. This includes the impact of an increased workload on oncologists, a potential lack of clinical continuity between urology and oncology and uncertainties regarding optimal selection, timing and sequencing of chemotherapy and second-line treatment. Fitness for treatment in advanced prostate cancer populations remains a significant barrier to accessing therapies for patients with a poor performance status. Among this, muscle wastage can significantly affect performance status and consequentially compromise cancer therapy. Exercise was regarded as a potential therapy to mitigate the adverse-effects of treatment including the prevention or reduction in muscle wastage.

Conclusions: There is a lack of data guiding clinicians in this post STAMPEDE and CHAARTED era, work is needed to reassess and optimize the prostate cancer care pathway as it evolves. Exercise should be explored as a therapeutic option to mitigate the effects of long term ADT. Further study from a wider cohort of both prostate cancer care specialists and patients will aid in establishing a highly functioning pathway with optimal individualised care.

Trial Registration: Sustained exercise TrAining for Men wIth prostate caNcer on Androgen deprivation: the STAMINA programme (RP-DG-1213-10,010). REC Reference: 15/SW/0260 IRAS Project ID: 178340 Hospital ID: STH 18391 approved on 24/08/2015.
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http://dx.doi.org/10.1186/s12885-018-4527-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006691PMC
June 2018

Demonstration of the Use of Remote Temperature Monitoring Devices in Vaccine Refrigerators in Haiti.

Public Health Rep 2018 Jan/Feb;133(1):39-44. Epub 2017 Dec 20.

1 Global Immunization Division, Centers for Disease Control and Prevention, Atlanta, GA, USA.

After the 2010 earthquake, Haiti committed to introducing 4 new antigens into its routine immunization schedule, which required improving its cold chain (ie, temperature-controlled supply chain) and increasing vaccine storage capacity by installing new refrigerators. We tested the feasibility of using remote temperature monitoring devices (RTMDs) in Haiti in a sample of vaccine refrigerators fueled by solar panels, propane gas, or electricity. We analyzed data from 16 RTMDs monitoring 24 refrigerators in 15 sites from March through August 2014. Although 5 of the 16 RTMDs exhibited intermittent data gaps, we identified typical temperature patterns consistent with refrigerator door opening and closing, propane depletion, thermostat insufficiency, and overstocking. Actual start-up, annual maintenance, and annual electricity costs for using RTMDs were $686, $179, and $9 per refrigerator, respectively. In Haiti, RTMD use was feasible. RTMDs could be prioritized for use with existing refrigerators with high volumes of vaccines and new refrigerators to certify their functionality before use. Vaccine vial monitors could provide additional useful information about cumulative heat exposure and possible vaccine denaturation.
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http://dx.doi.org/10.1177/0033354917742119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805098PMC
December 2018

Between-trial heterogeneity in meta-analyses may be partially explained by reported design characteristics.

J Clin Epidemiol 2018 03 5;95:45-54. Epub 2017 Dec 5.

Population Health Sciences, Bristol Medical School, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol BS8 2PS, UK.

Objective: We investigated the associations between risk of bias judgments from Cochrane reviews for sequence generation, allocation concealment and blinding, and between-trial heterogeneity.

Study Design And Setting: Bayesian hierarchical models were fitted to binary data from 117 meta-analyses, to estimate the ratio λ by which heterogeneity changes for trials at high/unclear risk of bias compared with trials at low risk of bias. We estimated the proportion of between-trial heterogeneity in each meta-analysis that could be explained by the bias associated with specific design characteristics.

Results: Univariable analyses showed that heterogeneity variances were, on average, increased among trials at high/unclear risk of bias for sequence generation (λˆ 1.14, 95% interval: 0.57-2.30) and blinding (λˆ 1.74, 95% interval: 0.85-3.47). Trials at high/unclear risk of bias for allocation concealment were on average less heterogeneous (λˆ 0.75, 95% interval: 0.35-1.61). Multivariable analyses showed that a median of 37% (95% interval: 0-71%) heterogeneity variance could be explained by trials at high/unclear risk of bias for sequence generation, allocation concealment, and/or blinding. All 95% intervals for changes in heterogeneity were wide and included the null of no difference.

Conclusion: Our interpretation of the results is limited by imprecise estimates. There is some indication that between-trial heterogeneity could be partially explained by reported design characteristics, and hence adjustment for bias could potentially improve accuracy of meta-analysis results.
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http://dx.doi.org/10.1016/j.jclinepi.2017.11.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828111PMC
March 2018

Association Between Risk-of-Bias Assessments and Results of Randomized Trials in Cochrane Reviews: The ROBES Meta-Epidemiologic Study.

Am J Epidemiol 2018 05;187(5):1113-1122

Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.

Flaws in the design of randomized trials may bias intervention effect estimates and increase between-trial heterogeneity. Empirical evidence suggests that these problems are greatest for subjectively assessed outcomes. For the Risk of Bias in Evidence Synthesis (ROBES) Study, we extracted risk-of-bias judgements (for sequence generation, allocation concealment, blinding, and incomplete data) from a large collection of meta-analyses published in the Cochrane Library (issue 4; April 2011). We categorized outcome measures as mortality, other objective outcome, or subjective outcome, and we estimated associations of bias judgements with intervention effect estimates using Bayesian hierarchical models. Among 2,443 randomized trials in 228 meta-analyses, intervention effect estimates were, on average, exaggerated in trials with high or unclear (versus low) risk-of-bias judgements for sequence generation (ratio of odds ratios (ROR) = 0.91, 95% credible interval (CrI): 0.86, 0.98), allocation concealment (ROR = 0.92, 95% CrI: 0.86, 0.98), and blinding (ROR = 0.87, 95% CrI: 0.80, 0.93). In contrast to previous work, we did not observe consistently different bias for subjective outcomes compared with mortality. However, we found an increase in between-trial heterogeneity associated with lack of blinding in meta-analyses with subjective outcomes. Inconsistency in criteria for risk-of-bias judgements applied by individual reviewers is a likely limitation of routinely collected bias assessments. Inadequate randomization and lack of blinding may lead to exaggeration of intervention effect estimates in randomized trials.
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http://dx.doi.org/10.1093/aje/kwx344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5928453PMC
May 2018

Power analysis for random-effects meta-analysis.

Res Synth Methods 2017 Sep 4;8(3):290-302. Epub 2017 Apr 4.

MRC Biostatistics Unit, Cambridge, UK.

One of the reasons for the popularity of meta-analysis is the notion that these analyses will possess more power to detect effects than individual studies. This is inevitably the case under a fixed-effect model. However, the inclusion of the between-study variance in the random-effects model, and the need to estimate this parameter, can have unfortunate implications for this power. We develop methods for assessing the power of random-effects meta-analyses, and the average power of the individual studies that contribute to meta-analyses, so that these powers can be compared. In addition to deriving new analytical results and methods, we apply our methods to 1991 meta-analyses taken from the Cochrane Database of Systematic Reviews to retrospectively calculate their powers. We find that, in practice, 5 or more studies are needed to reasonably consistently achieve powers from random-effects meta-analyses that are greater than the studies that contribute to them. Not only is statistical inference under the random-effects model challenging when there are very few studies but also less worthwhile in such cases. The assumption that meta-analysis will result in an increase in power is challenged by our findings.
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http://dx.doi.org/10.1002/jrsm.1240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5590730PMC
September 2017

Caring for relatives with agitation at home: a qualitative study of positive coping strategies.

BJPsych Open 2017 Jan 9;3(1):34-40. Epub 2017 Feb 9.

, MD, Division of Psychiatry, University College London, London, UK; Camden and Islington NHS Foundation Trust, London, UK.

Background: Trials of psychological interventions for reducing agitation in people with dementia living at home have been unsuccessful.

Aims: To inform future interventions by identifying successful strategies of family carers with relatives with dementia and agitation living at home.

Method: Qualitative in-depth individual interviews were performed with 18 family carers. We used thematic analysis to identify emerging themes.

Results: Carers described initial surprise and then acceptance that agitation is a dementia symptom and learned to respond flexibly. Their strategies encompassed: prevention of agitation by familiar routine; reduction of agitation by addressing underlying causes and using distraction; prevention of escalation by risk enablement, not arguing; and control of their emotional responses by ensuring their relative's safety then walking away, carving out some time for themselves and using family and services for emotional and practical help.

Conclusions: These strategies can be manualised and tested in future randomised controlled trials for clinical effectiveness in reducing agitation in people with dementia living at home.

Declaration Of Interest: None.

Copyright And Usage: © The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license.
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http://dx.doi.org/10.1192/bjpo.bp.116.004069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5299384PMC
January 2017

Implementing informative priors for heterogeneity in meta-analysis using meta-regression and pseudo data.

Stat Med 2016 12 30;35(29):5495-5511. Epub 2016 Aug 30.

School of Social and Community Medicine, University of Bristol, U.K.

Many meta-analyses combine results from only a small number of studies, a situation in which the between-study variance is imprecisely estimated when standard methods are applied. Bayesian meta-analysis allows incorporation of external evidence on heterogeneity, providing the potential for more robust inference on the effect size of interest. We present a method for performing Bayesian meta-analysis using data augmentation, in which we represent an informative conjugate prior for between-study variance by pseudo data and use meta-regression for estimation. To assist in this, we derive predictive inverse-gamma distributions for the between-study variance expected in future meta-analyses. These may serve as priors for heterogeneity in new meta-analyses. In a simulation study, we compare approximate Bayesian methods using meta-regression and pseudo data against fully Bayesian approaches based on importance sampling techniques and Markov chain Monte Carlo (MCMC). We compare the frequentist properties of these Bayesian methods with those of the commonly used frequentist DerSimonian and Laird procedure. The method is implemented in standard statistical software and provides a less complex alternative to standard MCMC approaches. An importance sampling approach produces almost identical results to standard MCMC approaches, and results obtained through meta-regression and pseudo data are very similar. On average, data augmentation provides closer results to MCMC, if implemented using restricted maximum likelihood estimation rather than DerSimonian and Laird or maximum likelihood estimation. The methods are applied to real datasets, and an extension to network meta-analysis is described. The proposed method facilitates Bayesian meta-analysis in a way that is accessible to applied researchers. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.
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http://dx.doi.org/10.1002/sim.7090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5111594PMC
December 2016

Two new methods to fit models for network meta-analysis with random inconsistency effects.

BMC Med Res Methodol 2016 07 28;16:87. Epub 2016 Jul 28.

MRC Biostatistics Unit, Cambridge, UK.

Background: Meta-analysis is a valuable tool for combining evidence from multiple studies. Network meta-analysis is becoming more widely used as a means to compare multiple treatments in the same analysis. However, a network meta-analysis may exhibit inconsistency, whereby the treatment effect estimates do not agree across all trial designs, even after taking between-study heterogeneity into account. We propose two new estimation methods for network meta-analysis models with random inconsistency effects.

Methods: The model we consider is an extension of the conventional random-effects model for meta-analysis to the network meta-analysis setting and allows for potential inconsistency using random inconsistency effects. Our first new estimation method uses a Bayesian framework with empirically-based prior distributions for both the heterogeneity and the inconsistency variances. We fit the model using importance sampling and thereby avoid some of the difficulties that might be associated with using Markov Chain Monte Carlo (MCMC). However, we confirm the accuracy of our importance sampling method by comparing the results to those obtained using MCMC as the gold standard. The second new estimation method we describe uses a likelihood-based approach, implemented in the metafor package, which can be used to obtain (restricted) maximum-likelihood estimates of the model parameters and profile likelihood confidence intervals of the variance components.

Results: We illustrate the application of the methods using two contrasting examples. The first uses all-cause mortality as an outcome, and shows little evidence of between-study heterogeneity or inconsistency. The second uses "ear discharge" as an outcome, and exhibits substantial between-study heterogeneity and inconsistency. Both new estimation methods give results similar to those obtained using MCMC.

Conclusions: The extent of heterogeneity and inconsistency should be assessed and reported in any network meta-analysis. Our two new methods can be used to fit models for network meta-analysis with random inconsistency effects. They are easily implemented using the accompanying R code in the Additional file 1. Using these estimation methods, the extent of inconsistency can be assessed and reported.
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http://dx.doi.org/10.1186/s12874-016-0184-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4964019PMC
July 2016

Alpha-Fetoprotein Detection of Hepatocellular Carcinoma Leads to a Standardized Analysis of Dynamic AFP to Improve Screening Based Detection.

PLoS One 2016 16;11(6):e0156801. Epub 2016 Jun 16.

MRC Biostatistics Unit, Cambridge, CB2 0SR, United Kingdom.

Detection of hepatocellular carcinoma (HCC) through screening can improve outcomes. However, HCC surveillance remains costly, cumbersome and suboptimal. We tested whether and how serum Alpha-Fetoprotein (AFP) should be used in HCC surveillance. Record linkage, dedicated pathways for management and AFP data-storage identified i) consecutive highly characterised cases of HCC diagnosed in 2009-14 and ii) a cohort of ongoing HCC-free patients undergoing regular HCC surveillance from 2009. These two well-defined Scottish patient cohorts enabled us to test the utility of AFP surveillance. Of 304 cases of HCC diagnosed over 6 years, 42% (129) were identified by a dedicated HCC surveillance programme. Of these 129, 47% (61) had a detectable lesion first identified by screening ultrasound (US) but 38% (49) were prompted by elevated AFP. Despite pre-HCC diagnosis AFP >20kU/L being associated with poor outcome, 'AFP-detected' tumours were offered potentially curative management as frequently as 'US-detected' HCCs; and had comparable survival. Linearity of serial log10-transformed AFPs in HCC cases and in the screening 'HCC-free' cohort (n = 1509) provided indicators of high-risk AFP behaviour in HCC cases. An algorithm was devised in static mode, then tested dynamically. A case/control series in hepatitis C related disease demonstrated highly significant detection (p<1.72*10-5) of patients at high risk of developing HCC. These data support the use of AFP in HCC surveillance. We show proof-of-principle that an automated and further refine-able algorithmic interpretation of AFP can identify patients at higher risk of HCC. This approach could provide a cost-effective, user-friendly and much needed addition to US surveillance.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0156801PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4911090PMC
July 2017

Literal grid map models for animal navigation: Assumptions and predictions.

J Theor Biol 2016 09 3;404:169-181. Epub 2016 Jun 3.

Department of Mathematics, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Electronic address:

Many animals can navigate from unfamiliar locations to a familiar target location with no outward route information or direct sensory contact with the target or any familiar landmarks. Several models have been proposed to explain this phenomenon, one possibility being a literal interpretation of a grid map. In this paper we systematically compare four such models, which we label: Correct Bicoordinate navigation, both Target and Release site based, Approximate Bicoordinate navigation, and Directional navigation. Predictions of spatial patterns of initial orientation errors and efficiencies depend on a combination of assumptions about the navigation mechanism and the geometry of the environmental coordinate fields used as model inputs. When coordinates axes are orthogonal at the target the predictions from the Correct Bicoordinate (Target based) model and Approximate Bicoordinate model are identical. However, if the coordinate axes are non-orthogonal different regional patterns of initial orientation errors and efficiencies can be expected from these two models. Field anomalies produce high magnitudes of orientation errors close to the target, while region-wide nonlinearity leads to orientation errors increasing with distance from the target. In general, initial orientation error patterns are more useful for distinguishing between different assumption combinations than efficiencies. We discuss how consideration of model predictions may be helpful in the design of experiments.
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http://dx.doi.org/10.1016/j.jtbi.2016.05.038DOI Listing
September 2016
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