Randomised controlled trial of population screening for atrial fibrillation in people aged 70 years and over to reduce stroke: protocol for the SAFER trial.

INTRODUCTION: There is a lack of evidence that the benefits of screening for atrial fibrillation (AF) outweigh the harms. Following the completion of the Screening for Atrial Fibrillation with ECG to Reduce stroke (SAFER) pilot trial, the aim of the main SAFER trial is to establish whether population screening for AF reduces incidence of stroke risk. METHODS AND ANALYSIS: Approximately 82 000 people aged 70 years and over and not on oral anticoagulation are being recruited from general practices in England. Patients on the palliative care register or residents in a nursing home are excluded. Eligible people are identified using electronic patient records from general practices and sent an invitation and consent form to participate by post. Consenting participants are randomised at a ratio of 2:1 (control:intervention) with clustering by household. Those randomised to the intervention arm are sent an information leaflet inviting them to participate in screening, which involves use of a handheld single-lead ECG four times a day for 3 weeks. ECG traces identified by an algorithm as possible AF are reviewed by cardiologists. Participants with AF are seen by a general practitioner for consideration of anticoagulation. The primary outcome is stroke. Major secondary outcomes are: death, major bleeding and cardiovascular events. Follow-up will be via electronic health records for an average of 4 years. The primary analysis will be by intention-to-treat using time-to-event modelling. Results from this trial will be combined with follow-up data from the cluster-randomised pilot trial by fixed-effects meta-analysis. ETHICS AND DISSEMINATION: The London-Central National Health Service Research Ethics Committee (19/LO/1597) provided ethical approval. Dissemination will include public-friendly summaries, reports and engagement with the UK National Screening Committee. TRIAL REGISTRATION NUMBER: ISRCTN72104369.

The cost-effectiveness of a bimekizumab versus IL-17A inhibitors treatment-pathway in patients with active axial spondyloarthritis in Scotland.

OBJECTIVE: To estimate the cost-effectiveness of a treatment-pathway initiated with bimekizumab, a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F and IL-17A, in patients with axial spondyloarthritis (axSpA) compared with IL-17Ai's, ixekizumab, and secukinumab, from the NHS Scotland perspective. METHODS: The axSpA treatment-pathway was modeled using a decision tree followed by a lifetime Markov model. The pathway included first- and second-line biologic disease-modifying antirheumatic drugs (bDMARD), followed by best supportive care (bDMARD, nonbiologic). Bimekizumab followed by any bDMARD ("BKZ") was compared with IL-17Ai's: secukinumab 150 mg followed by a blend ("SEC") of dose up-titration to secukinumab 300 mg and any bDMARD, or ixekizumab followed by any bDMARD ("IXE"). Transition to the next therapy was triggered by Bath Ankylosing Spondylitis Disease Activity Index-50% (BASDAI50) non-response or any-cause discontinuation. A published network meta-analysis provided efficacy data. EuroQoL-5-dimensions utilities were derived by mapping from Ankylosing Spondylitis Disease Activity Score. Costs included disease management (linked to functional limitations), biologics acquisition (list prices), administration and monitoring (NHS 2021/22). Discounting was 3.5%/year. Probabilistic results from patients with non-radiographic axSpA and ankylosing spondylitis were averaged to reflect the axSpA disease spectrum. Scenario and sensitivity analyses were performed. RESULTS: The incremental cost-effectiveness ratio (ICER) of BKZ was £24,801/quality-adjusted life-year (QALY) vs. SEC (95% credible interval £24,163-£25,895). BKZ had similar costs (Δ -£385 [-£15,239-£14,468]) and QALYs (Δ 0.039 [-0.748-0.825]) to IXE, with £1,523 (£862-£2,222) net monetary benefit. Conclusions remained unchanged in most scenarios. Results' drivers included BASDAI50 response rate and disease management cost. LIMITATIONS: Results were based on list prices. Data concerning up-titration to secukinumab 300 mg was scarce. CONCLUSIONS: The bimekizumab treatment-pathway represents a cost-effective option across the axSpA disease spectrum in Scotland. Bimekizumab is cost-effective compared to a secukinumab-pathway that includes dose up-titration, and has similar costs and QALYs to an ixekizumab-pathway.

Cost-Effectiveness of Routine Monitoring of Long-Term Conditions in Primary Care: Informing Decision Modelling with a Systematic Review in Hypertension, Type 2 Diabetes and Chronic Kidney Disease.

BACKGROUND: Long-term conditions (LTCs) are major public health problems with a considerable health-related and economic burden. Modelling is key in assessing costs and benefits of different disease management strategies, including routine monitoring, in the conditions of hypertension, type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) in primary care. OBJECTIVE: This review aimed to identify published model-based cost-effectiveness studies of routine laboratory testing strategies in these LTCs to inform a model evaluating the cost effectiveness of testing strategies in the UK. METHODS: We searched the Medline and Embase databases from inception to July 2023; the National Institute for Health and Care Institute (NICE) website was also searched. Studies were included if they were model-based economic evaluations, evaluated testing strategies, assessed regular testing, and considered adults aged >16 years. Studies identified were summarised by testing strategies, model type, structure, inputs, assessment of uncertainty, and conclusions drawn. RESULTS: Five studies were included in the review, i.e. Markov (n = 3) and microsimulation (n = 2) models. Models were applied within T2DM (n = 2), hypertension (n = 1), T2DM/hypertension (n = 1) and CKD (n = 1). Comorbidity between all three LTCs was modelled to varying extents. All studies used a lifetime horizon, except for a 10-year horizon T2DM model, and all used quality-adjusted life-years as the effectiveness outcome, except a TD2M model that used glycaemic control. No studies explicitly provided a rationale for their selected modelling approach. UK models were available for diabetes and CKD, but these compared only a limited set of routine monitoring tests and frequencies. CONCLUSIONS: There were few studies comparing routine testing strategies in the UK, indicating a need to develop a novel model in all three LTCs. Justification for the modelling technique of the identified studies was lacking. Markov and microsimulation models, with and without comorbidities, were used; however, the findings of this review can provide data sources and inform modelling approaches for evaluating the cost effectiveness of testing strategies in all three LTCs.

Clinical effectiveness of point of care tests for diagnosing urinary tract infection: a systematic review.

BACKGROUND: Point of care tests (POCTs) have the potential to improve the urinary tract infection (UTI) diagnostic pathway, as they can provide a diagnosis quickly in near-patient settings, and some also identify causative pathogens/antimicrobial sensitivity. OBJECTIVES: To assess the clinical impact, accuracy, and technical characteristics of POCT for diagnosing UTI. METHODS OF DATA SYNTHESIS: Narrative summary and bivariate random effects meta-analyses to estimate summary sensitivity and specificity. DATA SOURCES: Five electronic databases, two clinical trial registries, study reports and review reference lists, and websites. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials/non-randomized studies and diagnostic test accuracy studies published since 2000. PARTICIPANTS: People with suspected UTI. TESTS: Rapid tests (results <40 minutes): Astrego PA-100 system, Lodestar DX, Uriscreen, UTRiPLEX. Culture tests (results <24 hours): Flexicult Human, ID Flexicult, Diaslide, Dipstreak, Chromostreak, Uricult, Uricult Trio, Uricult Plus. REFERENCE STANDARD: Any. ASSESSMENT OF RISK OF BIAS: Risk of Bias-2, Quality Assessment of Diagnostic Accuracy Studies-2, Quality Assessment of Diagnostic Accuracy Studies-C. RESULTS: Two randomized controlled trials evaluated Flexicult Human (one against standard care; one against ID Flexicult). No difference was reported in antibiotic use concordant with culture results (OR 0.84 95% CI 0.58-1.20) or appropriate antibiotic prescribing (OR 1.44 95% CI 1.03-1.99). Initial antibiotic prescribing was lower with Flexicult than standard care (OR 0.56 95% CI 0.35-0.88). No difference for other measures of antibiotic use, symptom duration, patient enablement, or resource use. Fifteen studies reported accuracy data. Limited data were available, with most POCT evaluated in single studies or not evaluated at all. Uriscreen (four studies), Uricult Trio (three studies), Flexicult Human (four studies), and ID Flexicult (two studies) had modest sensitivity and specificity. POCTs were easier to use and interpret than standard culture. CONCLUSIONS: There is currently insufficient evidence to support the use of POCTs in UTI diagnosis. Due to the rapid development of POCT, this review should be updated regularly.

Identifying the Optimum Strategy for Identifying Adults and Children With Celiac Disease: A Cost-Effectiveness and Value of Information Analysis.

OBJECTIVES: Celiac disease (CD) is thought to affect around 1% of people in the United Kingdom, but only approximately 30% are diagnosed. The aim of this work was to assess the cost-effectiveness of strategies for identifying adults and children with CD in terms of who to test and which tests to use. METHODS: A decision tree and Markov model were used to describe testing strategies and model long-term consequences of CD. The analysis compared a selection of pre-test probabilities of CD above which patients should be screened, as well as the use of different serological tests, with or without genetic testing. Value of information analysis was used to prioritize parameters for future research. RESULTS: Using serological testing alone in adults, immunoglobulin A (IgA) tissue transglutaminase (tTG) at a 1% pre-test probability (equivalent to population screening) was most cost-effective. If combining serological testing with genetic testing, human leukocyte antigen combined with IgA tTG at a 5% pre-test probability was most cost-effective. In children, the most cost-effective strategy was a 10% pre-test probability with human leukocyte antigen plus IgA tTG. Value of information analysis highlighted the probability of late diagnosis of CD and the accuracy of serological tests as important parameters. The analysis also suggested prioritizing research in adult women over adult men or children. CONCLUSIONS: For adults, these cost-effectiveness results suggest UK National Screening Committee Criteria for population-based screening for CD should be explored. Substantial uncertainty in the results indicate a high value in conducting further research.

Comparison of indirect treatment methods in migraine prevention to address differences in mode of administration.

Aim: Indirect treatment comparisons (ITCs) are anchored on a placebo comparator, and the placebo response may vary according to drug administration route. Migraine preventive treatment studies were used to evaluate ITCs and determine whether mode of administration influences placebo response and the overall study findings. Materials & methods: Change from baseline in monthly migraine days produced by monoclonal antibody treatments (subcutaneous, intravenous) was compared using fixed-effects Bayesian network meta-analysis (NMA), network meta-regression (NMR), and unanchored simulated treatment comparison (STC). Results: NMA and NMR provide mixed, rarely differentiated results between treatments, whereas unanchored STC strongly favors eptinezumab over other preventive treatments. Conclusion: Further investigations are needed to determine which ITC best reflects the impact of mode of administration on placebo.

A network meta-analysis of immunotherapy-based treatments for advanced nonsquamous non-small cell lung cancer.

Introduction: In the absence of head-to-head trials comparing immunotherapies for advanced nonsquamous non-small-cell lung cancer (NsqNSCLC), a network meta-analysis (NMA) was conducted to compare the relative efficacy of these treatments. Materials & methods: A systematic literature review of randomized controlled trials evaluating first-line-to-progression and second-line treatments for advanced NsqNSCLC informed Bayesian NMAs for overall survival (OS) and progression-free survival (PFS) end points. Results: Among first-line-to-progression treatments, pembrolizumab + pemetrexed + platinum showed the greatest OS benefit versus other regimens and a PFS benefit versus all but three regimens. Among second-line treatments, an OS benefit was seen for atezolizumab, nivolumab and pembrolizumab versus docetaxel. Conclusion: Pembrolizumab + pemetrexed + platinum showed the maximum OS benefit in the first-line setting. In the second-line setting, anti-PD-1/anti-PD-L1 monotherapies were better than docetaxel.

Defining the optimum strategy for identifying adults and children with coeliac disease: systematic review and economic modelling.

BACKGROUND: Coeliac disease is an autoimmune disorder triggered by ingesting gluten. It affects approximately 1% of the UK population, but only one in three people is thought to have a diagnosis. Untreated coeliac disease may lead to malnutrition, anaemia, osteoporosis and lymphoma. OBJECTIVES: The objectives were to define at-risk groups and determine the cost-effectiveness of active case-finding strategies in primary care. DESIGN: (1) Systematic review of the accuracy of potential diagnostic indicators for coeliac disease. (2) Routine data analysis to develop prediction models for identification of people who may benefit from testing for coeliac disease. (3) Systematic review of the accuracy of diagnostic tests for coeliac disease. (4) Systematic review of the accuracy of genetic tests for coeliac disease (literature search conducted in April 2021). (5) Online survey to identify diagnostic thresholds for testing, starting treatment and referral for biopsy. (6) Economic modelling to identify the cost-effectiveness of different active case-finding strategies, informed by the findings from previous objectives. DATA SOURCES: For the first systematic review, the following databases were searched from 1997 to April 2021: MEDLINE® (National Library of Medicine, Bethesda, MD, USA), Embase® (Elsevier, Amsterdam, the Netherlands), Cochrane Library, Web of Science™ (Clarivate™, Philadelphia, PA, USA), the World Health Organization International Clinical Trials Registry Platform ( WHO ICTRP ) and the National Institutes of Health Clinical Trials database. For the second systematic review, the following databases were searched from January 1990 to August 2020: MEDLINE, Embase, Cochrane Library, Web of Science, Kleijnen Systematic Reviews ( KSR ) Evidence, WHO ICTRP and the National Institutes of Health Clinical Trials database. For prediction model development, Clinical Practice Research Datalink GOLD, Clinical Practice Research Datalink Aurum and a subcohort of the Avon Longitudinal Study of Parents and Children were used; for estimates for the economic models, Clinical Practice Research Datalink Aurum was used. REVIEW METHODS: For review 1, cohort and case-control studies reporting on a diagnostic indicator in a population with and a population without coeliac disease were eligible. For review 2, diagnostic cohort studies including patients presenting with coeliac disease symptoms who were tested with serological tests for coeliac disease and underwent a duodenal biopsy as reference standard were eligible. In both reviews, risk of bias was assessed using the quality assessment of diagnostic accuracy studies 2 tool. Bivariate random-effects meta-analyses were fitted, in which binomial likelihoods for the numbers of true positives and true negatives were assumed. RESULTS: People with dermatitis herpetiformis, a family history of coeliac disease, migraine, anaemia, type 1 diabetes, osteoporosis or chronic liver disease are 1.5-2 times more likely than the general population to have coeliac disease; individual gastrointestinal symptoms were not useful for identifying coeliac disease. For children, women and men, prediction models included 24, 24 and 21 indicators of coeliac disease, respectively. The models showed good discrimination between patients with and patients without coeliac disease, but performed less well when externally validated. Serological tests were found to have good diagnostic accuracy for coeliac disease. Immunoglobulin A tissue transglutaminase had the highest sensitivity and endomysial antibody the highest specificity. There was little improvement when tests were used in combination. Survey respondents (n = 472) wanted to be 66% certain of the diagnosis from a blood test before starting a gluten-free diet if symptomatic, and 90% certain if asymptomatic. Cost-effectiveness analyses found that, among adults, and using serological testing alone, immunoglobulin A tissue transglutaminase was most cost-effective at a 1% pre-test probability (equivalent to population screening). Strategies using immunoglobulin A endomysial antibody plus human leucocyte antigen or human leucocyte antigen plus immunoglobulin A tissue transglutaminase with any pre-test probability had similar cost-effectiveness results, which were also similar to the cost-effectiveness results of immunoglobulin A tissue transglutaminase at a 1% pre-test probability. The most practical alternative for implementation within the NHS is likely to be a combination of human leucocyte antigen and immunoglobulin A tissue transglutaminase testing among those with a pre-test probability above 1.5%. Among children, the most cost-effective strategy was a 10% pre-test probability with human leucocyte antigen plus immunoglobulin A tissue transglutaminase, but there was uncertainty around the most cost-effective pre-test probability. There was substantial uncertainty in economic model results, which means that there would be great value in conducting further research. LIMITATIONS: The interpretation of meta-analyses was limited by the substantial heterogeneity between the included studies, and most included studies were judged to be at high risk of bias. The main limitations of the prediction models were that we were restricted to diagnostic indicators that were recorded by general practitioners and that, because coeliac disease is underdiagnosed, it is also under-reported in health-care data. The cost-effectiveness model is a simplification of coeliac disease and modelled an average cohort rather than individuals. Evidence was weak on the probability of routine coeliac disease diagnosis, the accuracy of serological and genetic tests and the utility of a gluten-free diet. CONCLUSIONS: Population screening with immunoglobulin A tissue transglutaminase (1% pre-test probability) and of immunoglobulin A endomysial antibody followed by human leucocyte antigen testing or human leucocyte antigen testing followed by immunoglobulin A tissue transglutaminase with any pre-test probability appear to have similar cost-effectiveness results. As decisions to implement population screening cannot be made based on our economic analysis alone, and given the practical challenges of identifying patients with higher pre-test probabilities, we recommend that human leucocyte antigen combined with immunoglobulin A tissue transglutaminase testing should be considered for adults with at least a 1.5% pre-test probability of coeliac disease, equivalent to having at least one predictor. A more targeted strategy of 10% pre-test probability is recommended for children (e.g. children with anaemia). FUTURE WORK: Future work should consider whether or not population-based screening for coeliac disease could meet the UK National Screening Committee criteria and whether or not it necessitates a long-term randomised controlled trial of screening strategies. Large prospective cohort studies in which all participants receive accurate tests for coeliac disease are needed. STUDY REGISTRATION: This study is registered as PROSPERO CRD42019115506 and CRD42020170766. FUNDING: This project was funded by the National Institute for Health and Care Research ( NIHR ) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 44. See the NIHR Journals Library website for further project information.

WHAT IS THE PROBLEM?: Around 1 in 100 people in the UK has coeliac disease. It develops when the immune system attacks the lining of the gut after eating gluten. It is thought that only one in three people with coeliac disease is currently diagnosed. Without treatment, people with coeliac disease are at an increased risk of anaemia, osteoporosis and cancer. Treatment is a lifelong gluten-free diet. Diagnosing coeliac disease is difficult. Some people have minimal or non-specific symptoms, such as pain, indigestion or bloating, so knowing who to test is tricky. WHAT DID WE DO?: We wanted to establish who should be tested for coeliac disease, what tests should be used and whether or not invasive testing (a gut biopsy) is necessary for everyone. We looked at existing studies and data from general practices, and conducted an online survey, and brought everything together in an economic (cost) analysis. WHAT DID WE FIND?: Using individual symptoms is not helpful to identify people who may have coeliac disease. People with coeliac disease are more likely to have a combination of symptoms. People with anaemia, type 1 diabetes, osteoporosis, thyroid disorders, immunoglobulin A deficiency, Down syndrome, Turner syndrome or a family history of coeliac disease are more likely to have coeliac disease and should be offered tests. Common blood tests for coeliac disease are very accurate, particularly when used in combination with genetic testing. Blood tests alone can be used for diagnosis for some people. Others will need a biopsy to confirm the diagnosis. Whether or not this is needed depends on their risk of coeliac disease: whether or not they have symptoms and whether or not they have a condition that puts them at higher risk. Shared decision-making is important for individuals considering an invasive test, depending on how certain they want to be about their diagnosis before starting a gluten-free diet.

Cost-Effectiveness Analysis of Prostate Cancer Screening in the UK: A Decision Model Analysis Based on the CAP Trial.

BACKGROUND AND OBJECTIVE: Most guidelines in the UK, Europe and North America do not recommend organised population-wide screening for prostate cancer. Prostate-specific antigen-based screening can reduce prostate cancer-specific mortality, but there are concerns about overdiagnosis, overtreatment and economic value. The aim was therefore to assess the cost effectiveness of eight potential screening strategies in the UK. METHODS: We used a cost-utility analysis with an individual-based simulation model. The model was calibrated to data from the 10-year follow-up of the Cluster Randomised Trial of PSA Testing for Prostate Cancer (CAP). Treatment effects were modelled using data from the Prostate Testing for Cancer and Treatment (ProtecT) trial. The participants were a hypothetical population of 10 million men in the UK followed from age 30 years to death. The strategies were: no screening; five age-based screening strategies; adaptive screening, where men with an initial prostate-specific antigen level of < 1.5 ng/mL are screened every 6 years and those above this level are screened every 4 years; and two polygenic risk-stratified screening strategies. We assumed the use of pre-biopsy multi-parametric magnetic resonance imaging for men with prostate-specific antigen ≥ 3 ng/mL and combined transrectal ultrasound-guided and targeted biopsies. The main outcome measures were projected lifetime costs and quality-adjusted life-years from a National Health Service perspective. RESULTS: All screening strategies increased costs compared with no screening, with the majority also increasing quality-adjusted life-years. At willingness-to-pay thresholds of £20,000 or £30,000 per quality-adjusted life-year gained, a once-off screening at age 50 years was optimal, although this was sensitive to the utility estimates used. Although the polygenic risk-stratified screening strategies were not on the cost-effectiveness frontier, there was evidence to suggest that they were less cost ineffective than the alternative age-based strategies. CONCLUSIONS: Of the prostate-specific antigen-based strategies compared, only a once-off screening at age 50 years was potentially cost effective at current UK willingness-to-pay thresholds. An additional follow-up of CAP to 15 years may reduce uncertainty about the cost effectiveness of the screening strategies.

Network Meta-analysis on Disconnected Evidence Networks When Only Aggregate Data Are Available: Modified Methods to Include Disconnected Trials and Single-Arm Studies while Minimizing Bias.

BACKGROUND: Network meta-analysis (NMA) requires a connected network of randomized controlled trials (RCTs) and cannot include single-arm studies. Regulators or academics often have only aggregate data. Two aggregate data methods for analyzing disconnected networks are random effects on baseline and aggregate-level matching (ALM). ALM has been used only for single-arm studies, and both methods may bias effect estimates. METHODS: We modified random effects on baseline to separate RCTs connected to and disconnected from the reference and any single-arm studies, minimizing the introduction of bias. We term our modified method reference prediction. We similarly modified ALM and extended it to include RCTs disconnected from the reference. We tested these methods using constructed data and a simulation study. RESULTS: In simulations, bias for connected treatments for ALM ranged from -0.0158 to 0.051 and for reference prediction from -0.0107 to 0.083. These were low compared with the true mean effect of 0.5. Coverage ranged from 0.92 to 1.00. In disconnected treatments, bias of ALM ranged from -0.16 to 0.392 and of reference prediction from -0.102 to 0.40, whereas coverage of ALM ranged from 0.30 to 0.82 and of reference prediction from 0.64 to 0.94. Under fixed study effects for disconnected evidence, bias was similar, but coverage was 0.81 to 1.00 for reference prediction and 0.18 to 0.76 for ALM. Trends of similar bias but greater coverage for reference prediction with random study effects were repeated in constructed data. CONCLUSIONS: Both methods with random study effects seem to minimize bias in treatment connected to the reference. They can estimate treatment effects for disconnected treatments but may be biased. Reference prediction has greater coverage and may be recommended overall. HIGHLIGHTS: Two methods were modified for network meta-analysis on disconnected networks and for including single-arm observational or interventional studies in network meta-analysis using only aggregate data and for minimizing the bias of effect estimates for treatments only in trials connected to the reference.Reference prediction was developed as a modification of random effects on baseline that keeps analyses of trials connected to the reference separately from those disconnected from the reference and from single-arm studies. The method was further modified to account for correlation in trials with more than 2 arms and, under random study effects, to estimate variance in heterogeneity separately in connected and disconnected evidence.Aggregate-level matching was extended to include trials disconnected from the reference, rather than only single-arm studies. The method was further modified to separately estimate treatment effects and heterogeneity variance in the connected and disconnected evidence and to account for the correlation between arms in trials with more than 2 arms.Performance was assessed using a constructed data example and simulation study.The methods were found to have similar, and sometimes low, bias when estimating the relative effects for disconnected treatments, but reference prediction with random study effects had the greatest coverage.The use of reference prediction with random study effects for disconnected networks is recommended if no individual patient data or alternative real-world evidence is available.

A clinical tool to identify older women with back pain at high risk of osteoporotic vertebral fractures (Vfrac): a population-based cohort study with exploratory economic evaluation.

BACKGROUND: osteoporotic vertebral fractures (OVFs) identify people at high risk of future fractures, but despite this, less than a third come to clinical attention. The objective of this study was to develop a clinical tool to aid health care professionals decide which older women with back pain should have a spinal radiograph. METHODS: a population-based cohort of 1,635 women aged 65+ years with self-reported back pain in the previous 4 months were recruited from primary care. Exposure data were collected through self-completion questionnaires and physical examination, including descriptions of back pain and traditional risk factors for osteoporosis. Outcome was the presence/absence of OVFs on spinal radiographs. Logistic regression models identified independent predictors of OVFs, with the area under the (receiver operating) curve calculated for the final model, and a cut-point was identified. RESULTS: mean age was 73.9 years and 209 (12.8%) had OVFs. The final Vfrac model comprised 15 predictors of OVF, with an AUC of 0.802 (95% CI: 0.764-0.840). Sensitivity was 72.4% and specificity was 72.9%. Vfrac identified 93% of those with more than one OVF and two-thirds of those with one OVF. Performance was enhanced by inclusion of self-reported back pain descriptors, removal of which reduced AUC to 0.742 (95% CI: 0.696-0.788) and sensitivity to 66.5%. Health economic modelling to support a future trial was favourable. CONCLUSIONS: the Vfrac clinical tool appears to be valid and is improved by the addition of self-reported back pain symptoms. The tool now requires testing to establish real-world clinical and cost-effectiveness.

Efficacy and safety of first-line therapies in EGFR-mutated advanced non-small-cell lung cancer: a network meta-analysis.

Aim: To evaluate the comparative efficacy and safety of identified first-line therapies for patients with EGFR mutation-positive (EGFRm+) advanced non-small-cell lung cancer (NSCLC), with a focus on ramucirumab + erlotinib. Methods: In the absence of head-to-head studies, a Bayesian network meta-analysis was conducted using randomized clinical trial data to evaluate first-line systemic therapies with erlotinib/gefitinib as the reference treatment. Results: For progression-free survival, ramucirumab + erlotinib was comparable to osimertinib and dacomitinib in the primary analysis. Conclusion: The analysis showed ramucirumab + erlotinib efficacy to be comparable to best-in-class treatment options for previously untreated patients with EGFRm+ advanced NSCLC. Registration information: PROSPERO ID: CRD42020136247.

Systematic Review of Cost-Effectiveness Models in Prostate Cancer: Exploring New Developments in Testing and Diagnosis.

OBJECTIVES: Recent innovations in prostate cancer diagnosis include new biomarkers and more accurate biopsy methods. This study assesses the evidence base on cost-effectiveness of these developments (eg, Prostate Health Index and magnetic resonance imaging [MRI]-guided biopsy) and identifies areas of improvement for future cost-effectiveness models. METHODS: A systematic review using the National Health Service Economic Evaluation Database, MEDLINE, Embase, Health Technology Assessment databases, National Institute for Health and Care Excellence guidelines, and United Kingdom National Screening Committee guidance was performed, between 2009 and 2021. Relevant data were extracted on study type, model inputs, modeling methods and cost-effectiveness conclusions, and results narratively synthesized. RESULTS: A total of 22 model-based economic evaluations were included. A total of 11 compared the cost-effectiveness of new biomarkers to prostate-specific antigen testing alone and all found biomarkers to be cost saving. A total of 8 compared MRI-guided biopsy methods to transrectal ultrasound-guided methods and found MRI-guided methods to be most cost-effective. Newer detection methods showed a reduction in unnecessary biopsies and overtreatment. The most cost-effective follow-up strategy in men with a negative initial biopsy was uncertain. Many studies did not model for stage or grade of cancer, cancer progression, or the entire testing and treatment pathway. Few fully accounted for uncertainty. CONCLUSIONS: This review brings together the cost-effectiveness literature for novel diagnostic methods in prostate cancer, showing that most studies have found new methods to be more cost-effective than standard of care. Several limitations of the models were identified, however, limiting the reliability of the results. Areas for further development include accurately modeling the impact of early diagnostic tests on long-term outcomes of prostate cancer and fully accounting for uncertainty.

Costs and Cost-Effectiveness of User-Testing of Health Professionals' Guidelines to Reduce the Frequency of Intravenous Medicines Administration Errors by Nurses in the United Kingdom: A Probabilistic Model Based on Voriconazole Administration.

AIM: In the UK, injectable medicines are often prepared and administered by nurses following the Injectable Medicines Guide (IMG). Our earlier study confirmed a higher frequency of correct administration with user-tested versus standard IMG guidelines. This current study aimed to model the cost-effectiveness of user-testing. METHODS: The costs and cost-effectiveness of user-testing were explored by modifying an existing probabilistic decision-analytic model. The adapted model considered administration of intravenous voriconazole to hospital inpatients by nurses. It included 11 error types, their probability of detection and level of harm. Model inputs (including costs) were derived from our previous study and other published data. Monte Carlo simulation using 20,000 samples (sufficient for convergence) was performed with a 5-year time horizon from the perspective of the 121 NHS trusts and health boards that use the IMG. Sensitivity analyses were undertaken for the risk of a medication error and other sources of uncertainty. RESULTS: The net monetary benefit at £20,000/quality-adjusted life year was £3,190,064 (95% credible interval (CrI): -346,709 to 8,480,665), favouring user-testing with a 96% chance of cost-effectiveness. Incremental cost-savings were £240,943 (95% CrI 43,527-491,576), also favouring user-tested guidelines with a 99% chance of cost-saving. The total user testing cost was £6317 (95% CrI 6012-6627). These findings were robust to assumptions about a range of input parameters, but greater uncertainty was seen with a lower medication error risk. CONCLUSIONS: User-testing of injectable medicines guidelines is a low-cost intervention that is highly likely to be cost-effective, especially for high-risk medicines.

Multilevel and Quasi Monte Carlo Methods for the Calculation of the Expected Value of Partial Perfect Information.

The expected value of partial perfect information (EVPPI) provides an upper bound on the value of collecting further evidence on a set of inputs to a cost-effectiveness decision model. Standard Monte Carlo estimation of EVPPI is computationally expensive as it requires nested simulation. Alternatives based on regression approximations to the model have been developed but are not practicable when the number of uncertain parameters of interest is large and when parameter estimates are highly correlated. The error associated with the regression approximation is difficult to determine, while MC allows the bias and precision to be controlled. In this article, we explore the potential of quasi Monte Carlo (QMC) and multilevel Monte Carlo (MLMC) estimation to reduce the computational cost of estimating EVPPI by reducing the variance compared with MC while preserving accuracy. We also develop methods to apply QMC and MLMC to EVPPI, addressing particular challenges that arise where Markov chain Monte Carlo (MCMC) has been used to estimate input parameter distributions. We illustrate the methods using 2 examples: a simplified decision tree model for treatments for depression and a complex Markov model for treatments to prevent stroke in atrial fibrillation, both of which use MCMC inputs. We compare the performance of QMC and MLMC with MC and the approximation techniques of generalized additive model (GAM) regression, Gaussian process (GP) regression, and integrated nested Laplace approximations (INLA-GP). We found QMC and MLMC to offer substantial computational savings when parameter sets are large and correlated and when the EVPPI is large. We also found that GP and INLA-GP were biased in those situations, whereas GAM cannot estimate EVPPI for large parameter sets.

Matching-Adjusted Indirect Comparison of Crisaborole Ointment 2% vs. Topical Calcineurin Inhibitors in the Treatment of Patients with Mild-to-Moderate Atopic Dermatitis.

INTRODUCTION: Crisaborole topical ointment, 2%, is a nonsteroidal, topical anti-inflammatory phosphodiesterase-4 (PDE4) inhibitor that is approved for the treatment of mild-to-moderate atopic dermatitis (AD). The objective of the current analysis was to compare the efficacy of crisaborole 2% relative to pimecrolimus 1%, tacrolimus 0.03% and tacrolimus 0.1% in patients aged ≥ 2 years with mild-to-moderate AD by comparing improvement in Investigator's Static Global Assessment scores ( (ISGA scores of 0/1 indicating "clear or almost clear"). ISGA was selected as the primary efficacy outcome given the US Food and Drug Administration's recommendations on the use of ISGA for assessment of global severity in AD and to align with efficacy measurements in the crisaborole registration trials. Safety endpoints could not be analyzed due to differences in outcome definitions across studies. METHODS: Efficacy of crisaborole was evaluated using individual patient data (IPD) from two pivotal phase III randomized controlled trials (RCTs), and efficacy of comparators was evaluated using published RCTs included in a previous network meta-analysis. Vehicle controls were not comparable due to differences in ingredients and population imbalance and, therefore, an unanchored matching-adjusted indirect comparison (MAIC) was used, which reweighted IPD for crisaborole to estimate absolute response in comparator populations. RESULTS: The odds of achieving an improvement in ISGA score was higher with crisaborole 2% versus pimecrolimus 1% (odds ratio [OR] 2.03; 95% confidence interval [CI] 1.45-2.85; effective sample size = 627, reduced from 1021; p value < 0.001) and for crisaborole 2% versus tacrolimus 0.03% (OR 1.50; 95% CI 1.09-2.05; effective sample size = 311, reduced from 1021; p = 0.012). CONCLUSION: The unanchored MAIC suggests that the odds of achieving an improvement in ISGA score is greater with crisaborole 2% than with pimecrolimus 1% or tacrolimus 0.03% in patients aged ≥ 2 years with mild-to-moderate AD. These results are consistent with findings from the previously published network meta-analysis, which used a different methodology for performing indirect treatment comparisons.