scholarly journals Managing clustering effects and learning effects in the design and analysis of multicentre randomised trials: A survey to establish current practice

2019 ◽  
Author(s):  
Elizabeth J. Conroy ◽  
Jane M. Blazeby ◽  
Girvan Burnside ◽  
Jonathan A Cook ◽  
Carrol Gamble
Keyword(s):  
Current Practice ◽  
Face Validity ◽  
Sensitivity Analyses ◽  
Learning Effects ◽  
Treatment Provider ◽  
Intervention Delivery ◽  
Multicentre Trials ◽  
Different Types ◽  
Alternative Approaches ◽  
Question Survey

Abstract Background Patient outcomes can depend on the treating centre, or health professional, delivering the intervention. Skills of health professionals improve with experience in delivery, meaning that outcomes may also be associated with changes in skill, or learning. Considering any potential difference in intervention delivery at trial design will ensure that any adjustments can be made, as appropriate, at the analysis. The objective of this work was to establish current practice for the allowance of clustering and learning effects in the design and analysis of randomised multicentre trials. Methods A ten-question survey was developed comprising open and closed questions that drew upon quotes from existing guidelines, references to relevant publications, and example trial scenarios. It was piloted and checked for face validity within the research team. All registered UK Clinical Research Collaborative registered Clinical Trials Units were invited to participate. Results Completed surveys were obtained from 44 of 50 Units. Clustering was managed through design by stratification, commonly by centre and less commonly by treatment provider. Most Units had allowed for learning by design through defining a minimum level of expertise for treatment provider (89%). One third of Units reported experience of expertise-based designs. The majority of Units indicated experience in adjusting for clustering during analysis, by centre or treatment provider, although approaches to doing so varied. Analysis of learning was rarely performed for the main analysis (n=1), although many Units reported approaches to consider such effects, such as sensitivity analyses. Responders provided insight behind the approaches used within their Unit and reasons for, or against, alternative approaches. Conclusion This survey identifies widespread awareness of the potential methodological challenges associated with the design and analysis of multicentre trials, although approaches used and opinions on these vary. These results suggest that variation in approaches used exists both across Units and within, suggesting that this decision can depend on the type of trial being conducted. Reasons for approaches were provided and approaches justified by responders. These results highlight the need for more agreement between triallists about how to best design and analyse trials of different types and/or further research to establish optimal methods.

scholarly journals How to measure uncertainty in uncertainty sampling for active learning

2021 ◽  
Author(s):  
Vu-Linh Nguyen ◽  
Mohammad Hossein Shaker ◽  
Eyke Hüllermeier
Keyword(s):  
Machine Learning ◽  
Active Learning ◽  
Sampling Strategies ◽  
Total Uncertainty ◽  
Uncertainty Sampling ◽  
Different Types ◽  
Alternative Approaches ◽  
Active Learner ◽  
Probabilistic Nature ◽  
Different Sources

AbstractVarious strategies for active learning have been proposed in the machine learning literature. In uncertainty sampling, which is among the most popular approaches, the active learner sequentially queries the label of those instances for which its current prediction is maximally uncertain. The predictions as well as the measures used to quantify the degree of uncertainty, such as entropy, are traditionally of a probabilistic nature. Yet, alternative approaches to capturing uncertainty in machine learning, alongside with corresponding uncertainty measures, have been proposed in recent years. In particular, some of these measures seek to distinguish different sources and to separate different types of uncertainty, such as the reducible (epistemic) and the irreducible (aleatoric) part of the total uncertainty in a prediction. The goal of this paper is to elaborate on the usefulness of such measures for uncertainty sampling, and to compare their performance in active learning. To this end, we instantiate uncertainty sampling with different measures, analyze the properties of the sampling strategies thus obtained, and compare them in an experimental study.

scholarly journals A systematic review and economic evaluation of adalimumab and dexamethasone for treating non-infectious intermediate uveitis, posterior uveitis or panuveitis in adults

2017 ◽  
Vol 21 (68) ◽  
pp. 1-170 ◽  
Author(s):  
Hazel Squires ◽  
Edith Poku ◽  
Inigo Bermejo ◽  
Katy Cooper ◽  
John Stevens ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Cost Effectiveness ◽  
Current Practice ◽  
Clinical Effectiveness ◽  
Posterior Uveitis ◽  
Sensitivity Analyses ◽  
Dexamethasone Implant ◽  
Intermediate Uveitis ◽  
Sham Procedure ◽  
The Cost

BackgroundNon-infectious intermediate uveitis, posterior uveitis and panuveitis are a heterogeneous group of inflammatory eye disorders. Management includes local and systemic corticosteroids, immunosuppressants and biological drugs.ObjectivesTo evaluate the clinical effectiveness and cost-effectiveness of subcutaneous adalimumab (Humira®; AbbVie Ltd, Maidenhead, UK) and a dexamethasone intravitreal implant (Ozurdex®; Allergan Ltd, Marlow, UK) in adults with non-infectious intermediate uveitis, posterior uveitis or panuveitis.Data sourcesElectronic databases and clinical trials registries including MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and the World Health Organization’s International Clinical Trials Registry Platform were searched to June 2016, with an update search carried out in October 2016.Review methodsReview methods followed published guidelines. A Markov model was developed to assess the cost-effectiveness of dexamethasone and adalimumab, each compared with current practice, from a NHS and Personal Social Services (PSS) perspective over a lifetime horizon, parameterised with published evidence. Costs and benefits were discounted at 3.5%. Substantial sensitivity analyses were undertaken.ResultsOf the 134 full-text articles screened, three studies (four articles) were included in the clinical effectiveness review. Two randomised controlled trials (RCTs) [VISUAL I (active uveitis) and VISUAL II (inactive uveitis)] compared adalimumab with placebo, with limited standard care also provided in both arms. Time to treatment failure (reduced visual acuity, intraocular inflammation, new vascular lesions) was longer in the adalimumab group than in the placebo group, with a hazard ratio of 0.50 [95% confidence interval (CI) 0.36 to 0.70;p < 0.001] in the VISUAL I trial and 0.57 (95% CI 0.39 to 0.84;p = 0.004) in the VISUAL II trial. The adalimumab group showed a significantly greater improvement than the placebo group in the 25-item Visual Function Questionnaire (VFQ-25) composite score in the VISUAL I trial (mean difference 4.20;p = 0.010) but not the VISUAL II trial (mean difference 2.12;p = 0.16). Some systemic adverse effects occurred more frequently with adalimumab than with placebo. One RCT [HURON (active uveitis)] compared a single 0.7-mg dexamethasone implant against a sham procedure, with limited standard care also provided in both arms. Dexamethasone provided significant benefits over the sham procedure at 8 and 26 weeks in the percentage of patients with a vitreous haze score of zero (p < 0.014), the mean best corrected visual acuity improvement (p ≤ 0.002) and the percentage of patients with a ≥ 5-point improvement in VFQ-25 score (p < 0.05). Raised intraocular pressure and cataracts occurred more frequently with dexamethasone than with the sham procedure. The incremental cost-effectiveness ratio (ICER) for one dexamethasone implant in one eye for a combination of patients with unilateral and bilateral uveitis compared with limited current practice, as per the HURON trial, was estimated to be £19,509 per quality-adjusted life-year (QALY) gained. The ICER of adalimumab for patients with mainly bilateral uveitis compared with limited current practice, as per the VISUAL trials, was estimated to be £94,523 and £317,547 per QALY gained in active and inactive uveitis respectively. Sensitivity analyses suggested that the rate of blindness has the biggest impact on the model results. The interventions may be more cost-effective in populations in which there is a greater risk of blindness.LimitationsThe clinical trials did not fully reflect clinical practice. Thirteen additional studies of clinically relevant comparator treatments were identified; however, network meta-analysis was not feasible. The model results are highly uncertain because of the limited evidence base.ConclusionsTwo RCTs of systemic adalimumab and one RCT of a unilateral, single dexamethasone implant showed significant benefits over placebo or a sham procedure. The ICERs for adalimumab were estimated to be above generally accepted thresholds for cost-effectiveness. The cost-effectiveness of dexamethasone was estimated to fall below standard thresholds. However, there is substantial uncertainty around the model assumptions. In future work, primary research should compare dexamethasone and adalimumab with current treatments over the long term and in important subgroups and consider how short-term improvements relate to long-term effects on vision.Study registrationThis study is registered as PROSPERO CRD42016041799.FundingThe National Institute for Health Research Health Technology Assessment programme.

scholarly journals Locating Multiple Size and Multiple Type of Charging Station for Battery Electricity Vehicles

2018 ◽  
Vol 10 (9) ◽  
pp. 3267 ◽  
Author(s):  
Shaohua Cui ◽  
Hui Zhao ◽  
Huijie Wen ◽  
Cuiping Zhang
Keyword(s):  
Travel Time ◽  
Electric Vehicles ◽  
Sensitivity Analyses ◽  
Mixed Integer ◽  
Range Limit ◽  
Mixed Integer Linear Program ◽  
Charging Station ◽  
Different Types ◽  
Initial Charge ◽  
Charging Stations

As environmental and energy issues have attracted more and more attention from the public, research on electric vehicles has become extensive and in-depth. As driving range limit is one of the key factors restricting the development of electric vehicles, the energy supply of electric vehicles mainly relies on the building of charging stations, battery swapping stations, and wireless charging lanes. Actually, the latter two kinds of infrastructure are seldom employed due to their immature technology, relatively large construction costs, and difficulty in standardization. Currently, charging stations are widely used since, in the real world, there are different types of charging station with various levels which could be suitable for the needs of network users. In the past, the study of the location charging stations for battery electric vehicles did not take the different sizes and different types into consideration. In fact, it is of great significance to set charging stations with multiple sizes and multiple types to meet the needs of network users. In the paper, we define the model as a location problem in a capacitated network with an agent technique using multiple sizes and multiple types and formulate the model as a 0–1 mixed integer linear program (MILP) to minimize the total trip travel time of all agents. Finally, we demonstrate the model through numerical examples on two networks and make sensitivity analyses on total budget, initial quantity, and the anxious range of agents accordingly. The results show that as the initial charge increases or the budget increases, travel time for all agents can be reduced; a reduction in range anxiety can increase travel time for all agents.

scholarly journals Causal Mediation Analysis

2011 ◽  
Vol 11 (4) ◽  
pp. 605-619 ◽  
Author(s):  
Raymond Hicks ◽  
Dustin Tingley
Keyword(s):  
Mediation Analysis ◽  
Parametric Models ◽  
Sensitivity Analyses ◽  
Statistical Methodology ◽  
Mediation Effects ◽  
Explanatory Variables ◽  
Causal Mediation ◽  
Different Types ◽  
Recent Developments ◽  
Causal Mediation Analysis

Estimating the mechanisms that connect explanatory variables with the explained variable, also known as “mediation analysis,” is central to a variety of social-science fields, especially psychology, and increasingly to fields like epidemiology. Recent work on the statistical methodology behind mediation analysis points to limitations in earlier methods. We implement in Stata computational approaches based on recent developments in the statistical methodology of mediation analysis. In particular, we provide functions for the correct calculation of causal mediation effects using several different types of parametric models, as well as the calculation of sensitivity analyses for violations to the key identifying assumption required for interpreting mediation results causally.

scholarly journals Return to work recommendations after carpal tunnel release: a survey of UK hand surgeons and hand therapists

2018 ◽  
Vol 43 (8) ◽  
pp. 875-878 ◽  
Author(s):  
Lisa Newington ◽  
Kristin Francis ◽  
Georgia Ntani ◽  
David Warwick ◽  
Jo Adams ◽  
...  
Keyword(s):  
Return To Work ◽  
Carpal Tunnel ◽  
Current Practice ◽  
Carpal Tunnel Release ◽  
Evidence Base ◽  
British Society ◽  
Level Of Evidence ◽  
Functional Activities ◽  
Different Types ◽  
Carpal Tunnel Release Surgery

There is a limited evidence base from which to derive recommendations for safe and effective return to different types of occupation after carpal tunnel release surgery. The current practice of members of the British Society for Surgery of the Hand and the British Association of Hand Therapists was investigated with a questionnaire. In total, 173 surgeons and 137 therapists responded from an estimated sample of 1959. Median recommended return-to-work times were 7 days for desk-based duties, 15 days for repetitive light manual duties and 30 days for heavy manual duties. However, the responses were wide-ranging: 0–30 days for desk-based; 1–56 days for repetitive light manual; and 1–90 days for heavy manual. Variation in the recommended timescales for return to work and other functional activities after carpal tunnel release suggests that patients are receiving different and possibly even conflicting advice. Level of evidence: V

Comparative effects of different types of tree nut consumption on blood lipids: a network meta-analysis of clinical trials

2019 ◽  
Vol 111 (1) ◽  
pp. 219-227
Author(s):  
Kai Liu ◽  
Suocheng Hui ◽  
Bin Wang ◽  
Kanakaraju Kaliannan ◽  
Xiaozhong Guo ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Blood Lipids ◽  
Randomized Clinical Trials ◽  
Ldl Cholesterol ◽  
Meta Analysis ◽  
Control Diet ◽  
Sensitivity Analyses ◽  
Second Best ◽  
Different Types

ABSTRACT Background Recent evidence has confirmed that nuts are one of the best food groups at reducing LDL cholesterol and total cholesterol (TC). However, the comparative effects of different types of nuts on blood lipids are unclear. Objectives This network meta-analysis of randomized clinical trials aimed to assess the comparative effects of walnuts, pistachios, hazelnuts, cashews, and almonds on typical lipid profiles. Methods We conducted literature searches to identify studies comparing ≥2 of the following diets—walnut-enriched, pistachio-enriched, hazelnut-enriched, cashew-enriched, almond-enriched, and control diets—for the management of triglycerides (TGs), LDL cholesterol, TC, and HDL cholesterol. Random-effects network meta-analyses, ranking analyses based on the surface under the cumulative ranking (SUCRA) curves, and sensitivity analyses according to the potential sources of heterogeneity across the included studies were performed for each outcome. Results Thirty-four trials enrolling 1677 participants were included in this study. The pistachio-enriched diet was ranked best for TG (SUCRA: 85%), LDL cholesterol (SUCRA: 87%), and TC (SUCRA: 96%) reductions. For TG and TC reductions, the walnut-enriched diet was ranked as the second-best diet. Regarding LDL cholesterol reduction, the almond-enriched diet was ranked second best. The pistachio-enriched and walnut-enriched diets were more effective at lowering TG, LDL cholesterol, and TC compared with the control diet. Regarding TG and TC reductions, the pistachio-enriched diet was also more effective than the hazelnut-enriched diet. For TG reduction, the walnut-enriched diet was better than the hazelnut-enriched diet. However, these findings are limited by the low quality of evidence ratings. In addition, the quality of this network meta-analysis was limited by the small number and generally poor reporting of available studies. Conclusions The pistachio-enriched and walnut-enriched diet could be better alternatives for lowering TGs, LDL cholesterol, and TC compared with other nut-enriched diets included in this study. The findings warrant further evaluation by more high-quality studies. This network meta-analysis was registered at www.crd.york.ac.uk/PROSPERO as CRD42019131128.

Economic evaluation of screening for open-angle glaucoma

2008 ◽  
Vol 24 (02) ◽  
pp. 203-211 ◽  
Author(s):  
Rodolfo A. Hernández ◽  
Jennifer M. Burr ◽  
Luke D. Vale
Keyword(s):  
United Kingdom ◽  
Cost Effectiveness ◽  
Current Practice ◽  
Open Angle Glaucoma ◽  
Cost Effective ◽  
Screening Strategy ◽  
Sensitivity Analyses ◽  
Open Angle ◽  
The United Kingdom ◽  
Age Cohort

Objectives:The aim of this study was to assess the cost-effectiveness of screening for open-angle glaucoma (OAG) in the United Kingdom, given that OAG is an important cause of blindness worldwide.Methods:A Markov model was developed to estimate lifetime costs and benefits of a cohort of patients facing, alternatively, screening or current opportunistic case finding strategies. Strategies, varying in how screening would be organized (e.g., invitation for assessment by a glaucoma-trained optometrist [GO] or for simple test assessment by a technician) were developed, and allowed for the progression of OAG and treatment effects. Data inputs were obtained from systematic reviews. Deterministic and probabilistic sensitivity analyses were performed.Results:Screening was more likely to be cost-effective as prevalence increased, for 40 year olds compared with 60 or 75 year olds, when the re-screening interval was greater (10 years), and for the technician strategy compared with the GO strategy. For each age cohort and at prevalence levels of ≤1 percent, the likelihood that either screening strategy would be more cost-effective than current practice was small. For those 40 years of age, “technician screening” compared with current practice has an incremental cost-effectiveness ratio (ICER) that society might be willing to pay when prevalence is 6 percent to 10 percent and at over 10 percent for 60 year olds. In the United Kingdom, the age specific prevalence of OAG is much lower. Screening by GO, at any age or prevalence level, was not associated with an ICER &lt; £30,000.Conclusions:Population screening for OAG is unlikely to be cost-effective but could be for specific subgroups at higher risk.

Leukoreduction to Prevent Alloimmune Platelet (Plt) Refractoriness in a Dog Transfusion Model: Types of Residual White Blood Cells (WBCs) Directly Affect Transfusion Outcomes.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 835-835
Author(s):  
Sherrill J. Slichter ◽  
Kraig Abrams ◽  
Lakshmi Gaur ◽  
Karen Nelson ◽  
Esther Pellham ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
B Lymphocytes ◽  
Current Practice ◽  
Shared Epitope ◽  
Limit Of Detection ◽  
Relative Proportion ◽  
White Blood Cells ◽  
Different Types ◽  
Average Residual ◽  
Design And Methods

Abstract Introduction: Current practice assumes that just a quantitative reduction in the number of transfused wbcs to <1 to 5 x 106/transfusion is sufficient to prevent plt alloimmunization. However, our studies indicate that different leukoreduction strategies vary in their ability to remove immunizing wbcs, and this correlates with rates of alloimmune plt refractoriness in immunocompetent recipients. Experimental Design And Methods: Pairs of donor-recipient dogs were selected either at random, as having a shared DLA DR-B epitope, or as being specifically mismatched for this DLA locus. Non-leukoreduced or leukoreduced radiochromium-labeled donor plts were transfused weekly for up to 8 weeks or until the onset of plt refractoriness defined as <5% of the donor dog’s plts circulating in the recipient at 24 hours post-transfusion. Three methods of leukoreduction were evaluated: centrifugation leukoreduction (C-LR); filtration leukoreduction (F-LR) with different types of filters; or combined F-LR/C-LR. Flow cytometry was used to identify the types of residual wbcs following leukoreduction. Table 1 gives the number of residual wbcs and the transfusion outcomes based on the leukoreduction strategy used, while Table 2 gives the relative proportion of the types of residual wbcs after leukoreduction compared to the overall results for the leukoreduction method used. Results: Table 1 Method Of Leukoreduction Filter (Manufacturer) Average Residual WBCs Donor-Recipient DR-B Relationship Non-Refractory Recipients / Recipients Transfused ND-Not done. *Platelets were filtered sequentially using two PLF-1 filters. **Lower limit of detection of the assay. None --- 6.7 x 106 Random 1/3 (33%) Shared Epitope 0/4 (0%) C-LR --- 4.7 x 104 Random 3/21 (14%) F-LR: PL1-B (Pall) 5.0 x 104 ND ND PLF-1 (Pall) 7.9 x 104 Random 3/8 (38%) PLF-1 x2* (Pall) <3 x 103** Random 1/5 (20%) PLS-5A (Fenwal) 3.2 x 104 Mismatched 4/6 (66%) F-LR/C-LR: PL1-B (Pall) <3 x 103** Mismatched 1/9 (11%) <3 x 103** Shared Epitope 5/7 (71%) PLF-1 (Pall) <3 x 103** Random 15/16 (94%) <3 x 103** Mismatched 3/3 (100%) PLS-5A (Fenwal) <3 x 103** Mismatched 9/9 (100%) Table 2 RESIDUAL WBCs Lymphocytes Method of Leukoreduction T CD4 dim T CD4 bright B Monocytes Total Non-Refractory Recipients (%) ND-Not done. *Non-shared DR-B donor-recipient pairs/shared DR-B donor-recipient pairs (p=0.03). None ++ ++ +++ 14% C-LR + ++ + ++ 14% F-LR: PL1-B ++ ++ +++ +++ ND PLF-1 + +++ + 38% PLS-5A ++ + ++ 66% F-LR/C-LR: PL1-B ++ +++ + 11%/71%* PLF-1 ++ +++ 95% PLS-5A ++ + 100% Conclusions: 1) a quantitative reduction in wbcs does not prevent plt refractoriness; 2) the types of residual wbcs correlate directly with transfusion outcomes; 3) even after residual monocytes are removed by F-LR using PLF-1 and PLS-5A filters, residual CD4 bright T lymphocytes are associated with a high percentage of refractory recipients; 4) following F-LR/C-LR with PLF-1 and PLS-5A filters leaving B lymphocytes and CD4 dim T lymphocytes (NKT cells?), refractoriness is prevented even to DR-B mismatched donors; and 5) DLA DR-B matching significantly improves transfusion outcomes when residual monocytes remain following F-LR/C-LR using a PL1-B filter.

scholarly journals Evolution of the lateral extracavitary approach to the spine

2004 ◽  
Vol 16 (1) ◽  
pp. 1-3 ◽  
Author(s):  
Jason Lifshutz ◽  
Zvi Lidar ◽  
Dennis Maiman
Keyword(s):  
Minimally Invasive Surgery ◽  
Minimally Invasive ◽  
Vertebral Body ◽  
Invasive Surgery ◽  
Spinal Surgery ◽  
Current Practice ◽  
Evolutionary Change ◽  
Spinal Disorders ◽  
Alternative Approaches ◽  
Spine Disorders

The development of alternative approaches to spine disorders marked an evolutionary change in the methods by which surgeons address diseases that affect the ventral portion of the spine. From the advent of spinal surgery until quite recently, physicians used posterior approaches almost exclusively for the treatment of all pathological processes. Surgeons subsequently became frustrated and disenchanted with outcomes of patients with anterior vertebral body disease when these procedures were applied. This sentiment is best reflected in the surgical thought related to Pott disease. In this paper, the authors chart the development of an influential approach to the spine that is designed to address these issues: the lateral extracavitary approach. They trace its origins to early precursor procedures and follow its use in current practice for the treatment of a variety of spinal disorders. They also examine its applications, role, and continued importance in the age of minimally invasive surgery.

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