Bayesian adaptive designs for multi-arm trials: an orthopaedic case study

This is the final version. Available on open access from BMC via the DOI in this recordAvailability of data and materials: The data used in this study were generated as part of the CAST study. Requests to share individual, de-identified participant data, aggregated data, data dictionaries, and other study documents from this study should be sent to the CAST Chief Investigator (SEL). Data sharing requests will be assessed on their individual merits. The FACTS files used to simulate the Bayesian adaptive designs are publicly available at https://github.com/egryan90/Bayesian-adaptive-designs-for-CAST-study-Ryan-et-al.-2019Background: Bayesian adaptive designs can be more efficient than traditional methods for multi‐arm randomised controlled trials. The aim of this work was to demonstrate how Bayesian adaptive designs can be constructed for multi‐arm phase III clinical trials and assess potential benefits that these designs offer. Methods: We constructed several alternative Bayesian adaptive designs for the Collaborative Ankle Support Trial (CAST), which was a randomised controlled trial that compared four treatments for severe ankle sprain. These incorporated response adaptive randomisation, arm dropping, and early stopping for efficacy or futility. We studied the Bayesian designs’ operating characteristics via simulation. We then virtually re‐executed the trial by implementing the Bayesian adaptive designs using patient data sampled from the CAST study to demonstrate the practical applicability of the designs. Results: We constructed five Bayesian adaptive designs, each of which had high power and recruited fewer patients on average than the original design’s target sample size. The virtual executions 2 showed that most of the Bayesian designs would have led to trials that declared superiority of one of the interventions over the control. Bayesian adaptive designs with RAR or arm dropping were more likely to allocate patients to better performing arms at each interim analysis. Similar estimates and conclusions were obtained from the Bayesian adaptive designs as from the original trial. Conclusions: Using CAST as an example, this case study showed how Bayesian adaptive designs can be constructed for phase III multi‐arm trials using clinically relevant decision criteria. These designs demonstrated that they can potentially generate earlier results and allocate more patients to betterperforming arms. We recommend the wider use of Bayesian adaptive approaches in phase III clinical trials.Medical Research Council (MRC)National Co‐ordinating Centre for Health Technology AssessmentNational Institute of Health Researc

Bayesian adaptive designs for multi-arm trials: an orthopaedic case study

This is the final version. Available on open access from BMC via the DOI in this recordAvailability of data and materials: The data used in this study were generated as part of the CAST study. Requests to share individual, de-identified participant data, aggregated data, data dictionaries, and other study documents from this study should be sent to the CAST Chief Investigator (SEL). Data sharing requests will be assessed on their individual merits. The FACTS files used to simulate the Bayesian adaptive designs are publicly available at https://github.com/egryan90/Bayesian-adaptive-designs-for-CAST-study-Ryan-et-al.-2019Background: Bayesian adaptive designs can be more efficient than traditional methods for multi‐arm randomised controlled trials. The aim of this work was to demonstrate how Bayesian adaptive designs can be constructed for multi‐arm phase III clinical trials and assess potential benefits that these designs offer. Methods: We constructed several alternative Bayesian adaptive designs for the Collaborative Ankle Support Trial (CAST), which was a randomised controlled trial that compared four treatments for severe ankle sprain. These incorporated response adaptive randomisation, arm dropping, and early stopping for efficacy or futility. We studied the Bayesian designs’ operating characteristics via simulation. We then virtually re‐executed the trial by implementing the Bayesian adaptive designs using patient data sampled from the CAST study to demonstrate the practical applicability of the designs. Results: We constructed five Bayesian adaptive designs, each of which had high power and recruited fewer patients on average than the original design’s target sample size. The virtual executions 2 showed that most of the Bayesian designs would have led to trials that declared superiority of one of the interventions over the control. Bayesian adaptive designs with RAR or arm dropping were more likely to allocate patients to better performing arms at each interim analysis. Similar estimates and conclusions were obtained from the Bayesian adaptive designs as from the original trial. Conclusions: Using CAST as an example, this case study showed how Bayesian adaptive designs can be constructed for phase III multi‐arm trials using clinically relevant decision criteria. These designs demonstrated that they can potentially generate earlier results and allocate more patients to betterperforming arms. We recommend the wider use of Bayesian adaptive approaches in phase III clinical trials.Medical Research Council (MRC)National Co‐ordinating Centre for Health Technology AssessmentNational Institute of Health Researc

Cohort profile : Oxford Pain, Activity and Lifestyle (OPAL) Study, a prospective cohort study of older adults in England

Purpose: The ‘Oxford Pain, Activity and Lifestyle’ (OPAL) Cohort is a longitudinal, prospective cohort study of adults, aged 65 years and older, living in the community which is investigating the determinants of health in later life. Our focus was on musculoskeletal pain and mobility, but the cohort is designed with flexibility to include new elements over time. This paper describes the study design, data collection and baseline characteristics of participants. We also compared the OPAL baseline characteristics with nationally representative data sources. Participants: We randomly selected eligible participants from two stratified age bands (65–74 and 75 and over years). In total, 5409 individuals (42.1% of eligible participants) from 35 general practices in England agreed to participate between 2016 and 2018. The majority of participants (n=5367) also consented for research team to access their UK National Health Service (NHS) Digital and primary healthcare records. Findings: to date Mean participant age was 74.9 years (range 65–100); 51.5% (n=2784/5409) were women. 94.9% of participants were white, and 28.8% lived alone. Over 83.0% reported pain in at least one body area in the previous 6 weeks. Musculoskeletal symptoms were more prevalent in women (86.4%). One-third of participants reported having one or more falls in the last year. Most participants were confident in their ability to walk outside. The characteristics of OPAL Cohort participants were broadly similar to the general population of the same age. Future plans: Postal follow-up of the cohort is being undertaken at annual intervals, with data collection ongoing. Linkage to NHS hospital admission data is planned. This English prospective cohort offers a large and rich resource for research on the longitudinal associations between demographic, clinical, and social factors and health trajectories and outcomes in community-dwelling older people

Predictive modelling of Ross River virus notifications in southeastern Australia.

Ross River virus (RRV) is a mosquito-borne virus endemic to Australia. The disease, marked by arthritis, myalgia and rash, has a complex epidemiology involving several mosquito species and wildlife reservoirs. Outbreak years coincide with climatic conditions conducive to mosquito population growth. We developed regression models for human RRV notifications in the Mildura Local Government Area, Victoria, Australia with the objective of increasing understanding of the relationships in this complex system, providing trigger points for intervention and developing a forecast model. Surveillance, climatic, environmental and entomological data for the period July 2000-June 2011 were used for model training then forecasts were validated for July 2011-June 2015. Rainfall and vapour pressure were the key factors for forecasting RRV notifications. Validation of models showed they predicted RRV counts with an accuracy of 81%. Two major RRV mosquito vectors (Culex annulirostris and Aedes camptorhynchus) were important in the final estimation model at proximal lags. The findings of this analysis advance understanding of the drivers of RRV in temperate climatic zones and the models will inform public health agencies of periods of increased risk

The online version of an evidence-based hand exercise program for people with rheumatoid arthritis: A mixed-method, proof-of-concept study

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordIntroduction The Strengthening And stretching for Rheumatoid Arthritis of the Hand (SARAH) program is a tailored, 12-week hand and arm exercise program recommended in the National Institute for Health and Care Excellence (NICE) guidelines. It includes seven mobility exercises and four strength exercises against resistance. An online version of the SARAH program (mySARAH) has been developed to allow direct access for people with rheumatoid arthritis. Purpose To assess the feasibility, acceptability, and clinical impact of mySARAH in people with rheumatoid arthritis. Study design Mixed-method, proof-of-concept study. Methods mySARAH is a self-guided, online version of the SARAH program with six exercise training and review sessions. Participants were observed as they worked through four of the six online sessions. They were also asked to demonstrate the SARAH exercises. Participants undertook two sessions independently at home. At baseline and 12 weeks, hand pain, hand function, and grip strength were measured. At 12 weeks, feedback on mySARAH, and perceived recovery were also collected. Approximately one month later, a telephone follow-up was conducted to explore participants’ experiences with mySARAH. Pain, hand function, and perceived recovery were also assessed. Results Eleven participants (Males/Females: 3/8) with a median (Inter-quartile range) age of 63 (17) years took part. Six participants completed all mySARAH sessions. 512 exercise and load-setting demonstrations were observed and 491 (96%) were performed correctly. Improvements in grip strength and hand function were observed with no increase in pain. Most of the participants reported improvement and provided positive feedback. All participants perceived mySARAH as a useful resource. Features to improve the online exercise diary such as recording and tracking exercise dose and face-to-face or remote support by phone or Skype from health professionals were suggested to optimize user engagement. Conclusions Initial evaluation of mySARAH indicates that mySARAH was feasible, acceptable, and beneficial to participants. Further iteration and evaluation are needed before large-scale implementation.National Institute for Health Research (NIHR

Hand exercises for patients with rheumatoid arthritis: an extended follow-up of the SARAH randomised controlled trial

Objectives The Stretching And strengthening for Rheumatoid Arthritis of the Hand (SARAH) randomised controlled trial evaluated the effectiveness of a hand exercise programme and demonstrated it was clinically effective and cost-effective at 12 months. The aim of this extended follow-up was to evaluate the effects of the SARAH programme beyond 12 months. Methods Using postal questionnaires, we collected the Michigan Hand Questionnaire hand function (primary outcome), activities of daily living and work subscales, pain troublesomeness, self-efficacy and health-related quality of life. All participants were asked how often they performed hand exercises for their rheumatoid arthritis. Mean difference in hand function scores were analysed by a linear model, adjusted for baseline score. Results Two-thirds (n=328/490, 67%) of the original cohort provided data for the extended follow-up. The mean follow-up time was 26 months (range 19–40 months). There was no difference in change in hand function scores between the two groups at extended follow-up (mean difference (95% CI) 1.52 (−1.71 to 4.76)). However, exercise group participants were still significantly improved compared with baseline (p=0.0014) unlike the best practice usual care group (p=0.1122). Self-reported performance of hand exercises had reduced substantially. Conclusions Participants undertaking the SARAH exercise programme had improved hand function compared with baseline >2 years after randomisation. This was not the case for the control group. However, scores were no longer statistically different between the groups indicating the effect of the programme had diminished over time. This reduction in hand function compared with earlier follow-up points coincided with a reduction in self-reported performance of hand exercises. Further intervention to promote long-term adherence may be warranted

Effect of freshwater discharge from Namgang Dam on ichthyoplankton assemblage structure in Jinju Bay, Korea

The movement of fish eggs and larvae in bay and estuarine systems is affected by freshwater discharge. In this study, the assemblage structures of ichthyoplankton eggs and larvae were assessed for the first time in Jinju Bay, South Korea, to identify the spawning and nursery functions of the bay. Fish eggs and larvae and several environmental parameters were sampled monthly from April 2015 to March 2016 inside and outside of the bay. Within the bay we collected eggs and larvae from 25 and 35 species, respectively, indicating greater diversity than outside the bay, where we collected eggs and larvae of 20 and 28 species, respectively. Fluctuations in water temperature and salinity were larger inside than outside of the bay, and chlorophyll-a concentration was higher within the bay, likely due to discharge from the Namgang Dam, which causes water to flow from the inside to the outside of the bay. This process influences fish larva abundance, such that more larvae are found outside than inside the bay. We also found that 28 fish species use Jinju Bay as a spawning ground. For some species, the timing of egg and larva appearance differed inside and outside of the bay, suggesting that the timing of spawning may differ between the two environments

Development of an exercise intervention for the prevention of musculoskeletal shoulder problems after breast cancer treatment : the prevention of shoulder problems trial (UK PROSPER)

Background Musculoskeletal shoulder problems are common after breast cancer treatment. There is some evidence to suggest that early postoperative exercise is safe and may improve shoulder function. We describe the development and delivery of a complex intervention for evaluation within a randomised controlled trial (RCT), designed to target prevention of musculoskeletal shoulder problems after breast cancer surgery (The Prevention of Shoulder Problems Trial; PROSPER). Methods A pragmatic, multicentre RCT to compare the clinical and cost-effectiveness of best practice usual care versus a physiotherapy-led exercise and behavioural support intervention in women at high risk of shoulder problems after breast cancer treatment. PROSPER will recruit 350 women from approximately 15 UK centres, with follow-up at 6 and 12 months. The primary outcome is shoulder function at 12 months; secondary outcomes include postoperative pain, health related quality of life, adverse events and healthcare resource use. A multi-phased approach was used to develop the PROSPER intervention which was underpinned by existing evidence and modified for implementation after input from clinical experts and women with breast cancer. The intervention was tested and refined further after qualitative interviews with patients newly diagnosed with breast cancer; a pilot RCT was then conducted at three UK clinical centres. Discussion The PROSPER intervention incorporates three main components: shoulder-specific exercises targeting range of movement and strength; general physical activity; and behavioural strategies to encourage adherence and support exercise behaviour. The final PROSPER intervention is fully manualised with clear, documented pathways for clinical assessment, exercise prescription, use of behavioural strategies, and with guidance for treatment of postoperative complications. This paper adheres to TIDieR and CERT recommendations for the transparent, comprehensive and explicit reporting of complex interventions. Trial registration: International Standard Randomised Controlled Trial Number: ISRCTN 35358984

Continuous, Semi-discrete, and Fully Discretized Navier-Stokes Equations

The Navier--Stokes equations are commonly used to model and to simulate flow phenomena. We introduce the basic equations and discuss the standard methods for the spatial and temporal discretization. We analyse the semi-discrete equations -- a semi-explicit nonlinear DAE -- in terms of the strangeness index and quantify the numerical difficulties in the fully discrete schemes, that are induced by the strangeness of the system. By analyzing the Kronecker index of the difference-algebraic equations, that represent commonly and successfully used time stepping schemes for the Navier--Stokes equations, we show that those time-integration schemes factually remove the strangeness. The theoretical considerations are backed and illustrated by numerical examples.Comment: 28 pages, 2 figure, code available under DOI: 10.5281/zenodo.998909, https://doi.org/10.5281/zenodo.99890