Partial factorial trials : comparing methods for statistical analysis and economic evaluation

The KAT trial was funded by the National Institute Health for Research (NIHR) Health Technology Assessment Programme (project number 95/10/01) and has been published in full in Health Technology Assessment. The NIHR provided partial funding of the Health Economics Research Centre during the time this research was undertaken. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health.Peer reviewedPublisher PD

A randomised controlled trial of the clinical effectiveness and cost-effectiveness of different knee prostheses : the Knee Arthroplasty Trial (KAT)

Peer reviewedPublisher PD

Pharmacotherapy for uveitis: current management and emerging therapy.

Uveitis, a group of conditions characterized by intraocular inflammation, is a major cause of sight loss in the working population. Most uveitis seen in Western countries is noninfectious and appears to be autoimmune or autoinflammatory in nature, requiring treatment with immunosuppressive and/or anti-inflammatory drugs. In this educational review, we outline the ideal characteristics of drugs for uveitis and review the data to support the use of current and emerging therapies in this context. It is crucial that we continue to develop new therapies for use in uveitis that aim to suppress disease activity, prevent accumulation of damage, and preserve visual function for patients with the minimum possible side effects

An update on the use of biologic therapies in the management of uveitis in Behçet's disease::a comprehensive review

Abstract ᅟ Behçet’s disease (BD) is a systemic vasculitis characterised by a relapsing remitting course, affecting multiple organ systems. In the eye, it is a cause of potentially blinding inflammation in the form of uveitis. Management of uveitis in BD often requires the use of systemic immunosuppression, in order to reduce disease activity and prevent accumulation of irreversible damage. Whilst corticosteroids remain the mainstay of treatment, long-term use is limited by the development of adrenocorticotrophic side effects. There has therefore been significant interest in the use of corticosteroid-sparing immunosuppressive agents, and more recently, biologic therapies. Recent publications have demonstrated biologic therapy to have beneficial effects both on overall disease control, and quality of life for patients with BD. Widespread use of such agents is however limited, partly by the lack of high quality research evidence, and partly by the prohibitive cost of biologic treatments. In this review, we discuss the most recent research investigating the use of biologic therapy in uveitis due to BD, with consideration of health economics and quality of life outcomes

Multiple imputation for patient reported outcome measures in randomised controlled trials : advantages and disadvantages of imputing at the item, subscale or composite score level

Background Missing data can introduce bias in the results of randomised controlled trials (RCTs), but are typically unavoidable in pragmatic clinical research, especially when patient reported outcome measures (PROMs) are used. Traditionally applied to the composite PROMs score of multi-item instruments, some recent research suggests that multiple imputation (MI) at the item level may be preferable under certain scenarios. This paper presents practical guidance on the choice of MI models for handling missing PROMs data based on the characteristics of the trial dataset. The comparative performance of complete cases analysis, which is commonly used in the analysis of RCTs, is also considered. Methods Realistic missing at random data were simulated using follow-up data from an RCT considering three different PROMs (Oxford Knee Score (OKS), EuroQoL 5 Dimensions 3 Levels (EQ-5D-3L), 12-item Short Form Survey (SF-12)). Data were multiply imputed at the item (using ordinal logit and predicted mean matching models), sub-scale and score level; unadjusted mean outcomes, as well as treatment effects from linear regression models were obtained for 1000 simulations. Performance was assessed by root mean square errors (RMSE) and mean absolute errors (MAE). Results Convergence problems were observed for MI at the item level. Performance generally improved with increasing sample sizes and lower percentages of missing data. Imputation at the score and subscale level outperformed imputation at the item level in small sample sizes (n ≤ 200). Imputation at the item level is more accurate for high proportions of item-nonresponse. All methods provided similar results for large sample sizes (≥500) in this particular case study. Conclusions Many factors, including the prevalence of missing data in the study, sample size, the number of items within the PROM and numbers of levels within the individual items, and planned analyses need consideration when choosing an imputation model for missing PROMs data

Modelling Future Coronary Heart Disease Mortality to 2030 in the British Isles.

OBJECTIVE: Despite rapid declines over the last two decades, coronary heart disease (CHD) mortality rates in the British Isles are still amongst the highest in Europe. This study uses a modelling approach to compare the potential impact of future risk factor scenarios relating to smoking and physical activity levels, dietary salt and saturated fat intakes on future CHD mortality in three countries: Northern Ireland (NI), Republic of Ireland (RoI) and Scotland. METHODS: CHD mortality models previously developed and validated in each country were extended to predict potential reductions in CHD mortality from 2010 (baseline year) to 2030. Risk factor trends data from recent surveys at baseline were used to model alternative future risk factor scenarios: Absolute decreases in (i) smoking prevalence and (ii) physical inactivity rates of up to 15% by 2030; relative decreases in (iii) dietary salt intake of up to 30% by 2030 and (iv) dietary saturated fat of up to 6% by 2030. Probabilistic sensitivity analyses were then conducted. RESULTS: Projected populations in 2030 were 1.3, 3.4 and 3.9 million in NI, RoI and Scotland respectively (adults aged 25-84). In 2030: assuming recent declining mortality trends continue: 15% absolute reductions in smoking could decrease CHD deaths by 5.8-7.2%. 15% absolute reductions in physical inactivity levels could decrease CHD deaths by 3.1-3.6%. Relative reductions in salt intake of 30% could decrease CHD deaths by 5.2-5.6% and a 6% reduction in saturated fat intake might decrease CHD deaths by some 7.8-9.0%. These projections remained stable under a wide range of sensitivity analyses. CONCLUSIONS: Feasible reductions in four cardiovascular risk factors (already achieved elsewhere) could substantially reduce future coronary deaths. More aggressive polices are therefore needed in the British Isles to control tobacco, promote healthy food and increase physical activity

Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription

AbstractBackground: Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase, the activity of which is inhibited by a variety of extracellular stimuli including insulin, growth factors, cell specification factors and cell adhesion. Consequently, inhibition of GSK-3 activity has been proposed to play a role in the regulation of numerous signalling pathways that elicit pleiotropic cellular responses. This report describes the identification and characterisation of potent and selective small molecule inhibitors of GSK-3.Results: SB-216763 and SB-415286 are structurally distinct maleimides that inhibit GSK-3α in vitro, with Kis of 9 nM and 31 nM respectively, in an ATP competitive manner. These compounds inhibited GSK-3β with similar potency. However, neither compound significantly inhibited any member of a panel of 24 other protein kinases. Furthermore, treatment of cells with either compound stimulated responses characteristic of extracellular stimuli that are known to inhibit GSK-3 activity. Thus, SB-216763 and SB-415286 stimulated glycogen synthesis in human liver cells and induced expression of a β-catenin-LEF/TCF regulated reporter gene in HEK293 cells. In both cases, compound treatment was demonstrated to inhibit cellular GSK-3 activity as assessed by activation of glycogen synthase, which is a direct target of this kinase.Conclusions: SB-216763 and SB-415286 are novel, potent and selective cell permeable inhibitors of GSK-3. Therefore, these compounds represent valuable pharmacological tools with which the role of GSK-3 in cellular signalling can be further elucidated. Furthermore, development of similar compounds may be of use therapeutically in disease states associated with elevated GSK-3 activity such as non-insulin dependent diabetes mellitus and neurodegenerative disease

An informatics consult approach for generating clinical evidence for treatment decisions.

BACKGROUND: An Informatics Consult has been proposed in which clinicians request novel evidence from large scale health data resources, tailored to the treatment of a specific patient. However, the availability of such consultations is lacking. We seek to provide an Informatics Consult for a situation where a treatment indication and contraindication coexist in the same patient, i.e., anti-coagulation use for stroke prevention in a patient with both atrial fibrillation (AF) and liver cirrhosis. METHODS: We examined four sources of evidence for the effect of warfarin on stroke risk or all-cause mortality from: (1) randomised controlled trials (RCTs), (2) meta-analysis of prior observational studies, (3) trial emulation (using population electronic health records (N = 3,854,710) and (4) genetic evidence (Mendelian randomisation). We developed prototype forms to request an Informatics Consult and return of results in electronic health record systems. RESULTS: We found 0 RCT reports and 0 trials recruiting for patients with AF and cirrhosis. We found broad concordance across the three new sources of evidence we generated. Meta-analysis of prior observational studies showed that warfarin use was associated with lower stroke risk (hazard ratio [HR] = 0.71, CI 0.39-1.29). In a target trial emulation, warfarin was associated with lower all-cause mortality (HR = 0.61, CI 0.49-0.76) and ischaemic stroke (HR = 0.27, CI 0.08-0.91). Mendelian randomisation served as a drug target validation where we found that lower levels of vitamin K1 (warfarin is a vitamin K1 antagonist) are associated with lower stroke risk. A pilot survey with an independent sample of 34 clinicians revealed that 85% of clinicians found information on prognosis useful and that 79% thought that they should have access to the Informatics Consult as a service within their healthcare systems. We identified candidate steps for automation to scale evidence generation and to accelerate the return of results. CONCLUSION: We performed a proof-of-concept Informatics Consult for evidence generation, which may inform treatment decisions in situations where there is dearth of randomised trials. Patients are surprised to know that their clinicians are currently not able to learn in clinic from data on 'patients like me'. We identify the key challenges in offering such an Informatics Consult as a service

Cost-Effectiveness of Pre-Referral Antimalarial, Antibacterial, and Combined Rectal Formulations for Severe Febrile Illness

BACKGROUND: Malaria and bacterial infections account for most infectious disease deaths in developing countries. Prompt treatment saves lives, but rapid deterioration often prevents the use of oral therapies; delays in reaching health facilities providing parenteral interventions are common. Rapidly and reliably absorbed antimalarial/antibacterial rectal formulations used in the community could prevent deaths and disabilities. Rectal antimalarial treatments are currently available; rectal antibacterial treatments are yet to be developed. Assessment of the likely cost-effectiveness of these interventions will inform research priorities and implementation. METHODS AND FINDINGS: The burden of malaria and bacterial infections worldwide and in Sub-Saharan and Southern Africa (SSA) and South and South-East Asia (SEA) was summarised using published data. The additional healthcare costs (USD) per death and per Disability Adjusted Life Year (DALY) avoided following pre-referral treatment of severe febrile illness with rectal antimalarials, antibacterials or combined antimalarial/antibacterials in populations at malaria risk in SSA/SEA were assessed. 46 million severe malaria and bacterial infections and 5 million deaths occur worldwide each year, mostly in SSA/SEA. At annual delivery costs of 0.02 dollars/capita and 100% coverage, rectal antimalarials (2 dollars per dose) would avert 240,000 deaths in SSA and 7,000 deaths in SEA at 5 and 177 dollars per DALY avoided, respectively; rectal antibacterials (2 dollars per dose) would avert 130,000 deaths in SSA and 27,000 deaths in SEA at 19 and 97 dollars per DALY avoided, respectively. Combined rectal formulations (2.50 dollars per dose) would avert 370,000 deaths in SSA and 33,000 deaths in SEA at 8 and 79 dollars per DALY avoided, respectively, and are a cost-effective alternative to rectal antimalarials or antibacterials alone. CONCLUSIONS: Antimalarial, antibacterial and combined rectal formulations are likely to be cost-effective interventions for severe febrile illness in the community. Attention should focus on developing effective rectal antibacterials and ensuring that these lifesaving treatments are used in a cost-effective manner