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© 2018 ISPOR–The Professional Society for Health Economics and Outcomes Research Background: Clinical use of next-generation sequencing (NGS) tests has been increasing, but few studies have examined their economic value. Several studies have noted that there are methodological challenges to conducting economic evaluations of NGS tests. Objective: Our objective was to examine key methodological challenges for conducting economic evaluations of NGS tests, prioritize these challenges for future research, and identify how studies have attempted solutions to address these challenges. Methods: We identified challenges for economic evaluations of NGS tests using prior literature and expert judgment of the co-authors. We used a modified Delphi assessment to prioritize challenges, based on importance and probability of resolution. Using a structured literature review and article extraction we then assessed whether published economic evaluations had addressed these challenges. Results: We identified 11 challenges for conducting economic evaluations of NGS tests. The experts identified three challenges as the top priorities for future research: complex model structure, timeframe, and type of analysis and comparators used. Of the 15 published studies included in our literature review, four studies described specific solutions relevant to five of the 11 identified challenges. Conclusions: Major methodological challenges to economic evaluations of NGS tests remain to be addressed. Our results can be used to guide future research and inform decision-makers on how to prioritize research on the economic assessment of NGS tests.

Background Next-generation sequencing (NGS) technologies have seen variable adoption in the clinic. This is partly due to a lack of clinical and economic studies, with the latter increasingly challenged to examine patient preferences for health and nonhealth outcomes (e.g., false-positive rate). Objectives To conduct a structured review of studies valuing patients’ preference-based utility for NGS outcomes, to highlight identified methodological challenges, and to consider how studies addressed identified challenges. Methods We searched MEDLINE (PubMed), Embase (Ovid), and Web of Science for published studies examining outcomes from health care decisions informed by NGS. We focused our search on direct elicitations of preference-based utility. We reviewed included studies and qualitatively grouped and summarized stated challenges and solutions by theme. Results Eleven studies were included. Most of them (n = 6) used discrete choice experiments to value utility. We categorized challenges into four themes: 1) valuing the full range of NGS outcomes, 2) accounting for accuracy and uncertainty surrounding effectiveness, 3) allowing for simultaneous multiple and cascading risks, and 4) incorporating downstream consequences. Studies found strong evidence of utility for NGS information, regardless of health improvement. Investigators addressed challenges by simplifying complex choices, by including health outcomes alongside nonhealth outcomes, and by using multiple elicitation techniques. Conclusions The breadth and complexity of NGS-derived information makes the technology a unique and challenging application for utility valuation. Failing to account for the utility or disutility of NGS-related nonhealth outcomes may lead to overinvestment or underinvestment in NGS, and so there is a need for research addressing unresolved challenges.

We conducted a systematic literature review to summarize the current health economic evidence for whole-exome sequencing (WES) and whole-genome sequencing (WGS). Relevant studies were identified in the EMBASE, MEDLINE, Cochrane Library, EconLit and University of York Centre for Reviews and Dissemination databases from January 2005 to July 2016. Publications were included in the review if they were economic evaluations, cost studies, or outcome studies. Thirty-six studies met our inclusion criteria. These publications investigated the use of WES and WGS in a variety of genetic conditions in clinical practice, the most common being neurological or neurodevelopmental disorders. Study sample size varied from a single child to 2,000 patients. Cost estimates for a single test ranged from $555 to $5,169 for WES and from $1,906 to $24,810 for WGS. Few cost analyses presented data transparently and many publications did not state which components were included in cost estimates. The current health economic evidence base to support the more widespread use of WES and WGS in clinical practice is very limited. Studies that carefully evaluate the costs, effectiveness, and cost-effectiveness of these tests are urgently needed to support their translation into clinical practice.

© the authors, 2018. Background: Antimicrobial resistance (AMR), a major public health threat, is strongly associated with human antibiotic consumption. Influenza-like illnesses (ILI) account for substantial inappropriate antibiotic use; patient understanding and expectations probably play an important role. Aim: This study aimed to investigate what drives patient expectations of antibiotics for ILI and particularly whether AMR awareness, risk preferences (attitudes to taking risks with health) or time preferences (the extent to which people prioritise good health today over good health in the future) play a role. Methods: In 2015, a representative online panel survey of 2,064 adults in the United Kingdom was asked about antibiotic use and effectiveness for ILI. Explanatory variables in multivariable regression included AMR awareness, risk and time preferences and covariates. Results: The tendency not to prioritise immediate gain over later reward was independently strongly associated with greater awareness that antibiotics are inappropriate for ILI. Independently, believing antibiotics were effective for ILI and low AMR awareness significantly predicted reported antibiotic use. However, 272 (39%) of those with low AMR awareness said that the AMR information we provided would lead them to ask a doctor for antibiotics more often, significantly more than would do so less often, and in contrast to those with high AMR awareness (p < 0.0001). Conclusion: Information campaigns to reduce AMR may risk a paradoxical consequence of actually increasing public demand for antibiotics. Public antibiotic stewardship campaigns should be tested on a small scale before wider adoption.

Clopidogrel is an antiplatelet drug given to patients before and after having a percutaneous coronary intervention (PCI). Genomic variants in the CYP2C19 gene are associated with variable enzyme activities affecting drug metabolism and hence, patients with reduced or increased enzymatic function have increased risk of bleeding. We conducted a cost-effectiveness analysis to compare a pharmacogenomics versus a non-pharmacogenomics-guided clopidogrel treatment for coronary artery syndrome patients undergoing PCI in the Spanish healthcare setting. A total of 549 patients diagnosed with coronary artery disease followed by PCI were recruited. Dual antiplatelet therapy was administrated to all patients from 1 to 12 months after PCI. Patients were classified into two groups: the Retrospective group was treated with clopidogrel based on the clinical routine practice and the Prospective group were initially genotyped for the presence of CYP2C19 variant alleles before treatment with those carrying more than one CYP2C19 variant alleles given prasugrel treatment. We collected data on established clinical and health outcome measures, including, per treatment arm: the percentage of patients that suffered from (a) myocardial infraction, (b) major bleeding and minor bleeding, (c) stroke, (d) the number of hospitalization days, and (e) the number of days patients spent in Intensive Care Unit. Our primary outcome measure for the cost-effectiveness analysis was Quality Adjusted Life Years (QALYs). To estimate the treatment cost for each patient, individual data on its resource used were combined with unit price data, obtained from Spanish national sources. The analysis predicts a survival of 0.9446 QALYs in the pharmacogenomics arm and 0.9379 QALYs in the non-pharmacogenomics arm within a 1-year horizon. The cumulative costs per patient were €2971 and €3205 for the Prospective and Retrospective groups, respectively. The main cost driver of total cost in both arms was hospitalization costs. The incremental cost-effectiveness ratio (ICER) was negative indicating that the PGx was a dominant option. Our data show that pharmacogenomics-guided clopidogrel treatment strategy may represent a cost-effective choice compared with non-pharmacogenomics-guided strategy for patients undergoing PCI.

Introduction Standard treatment for neovascular age-related macular degeneration (nAMD) is intravitreal injections of anti-VEGF drugs. Following multiple injections, nAMD lesions often become quiescent but there is a high risk of reactivation, and regular review by hospital ophthalmologists is the norm. The present trial examines the feasibility of community optometrists making lesion reactivation decisions.Methods The Effectiveness of Community vs Hospital Eye Service (ECHoES) trial is a virtual trial; lesion reactivation decisions were made about vignettes that comprised clinical data, colour fundus photographs, and optical coherence tomograms displayed on a web-based platform. Participants were either hospital ophthalmologists or community optometrists. All participants were provided with webinar training on the disease, its management, and assessment of the retinal imaging outputs. In a balanced design, 96 participants each assessed 42 vignettes; a total of 288 vignettes were assessed seven times by each professional group.The primary outcome is a participant’s judgement of lesion reactivation compared with a reference standard. Secondary outcomes are the frequency of sight threatening errors; judgements about specific lesion components; participant-rated confidence in their decisions about the primary outcome; cost effectiveness of follow-up by optometrists rather than ophthalmologists.Discussion This trial addresses an important question for the NHS, namely whether, with appropriate training, community optometrists can make retreatment decisions for patients with nAMD to the same standard as hospital ophthalmologists. The trial employed a novel approach as participation was entirely through a web-based application; the trial required very few resources compared with those that would have been needed for a conventional randomised controlled clinical trial.

A long-running debate surrounds the equivalence of the welfarist and extra-welfarist approaches to economic evaluation. There is a growing belief that the extra-welfarist approach may not necessarily provide all the information that decisionmakers require in certain contexts, e.g. evaluation of complex interventions. As the number of these interventions being evaluated increases, it is crucial that the most appropriate economic evaluation approach is used to enable decisionmakers to be confident in their adoption decisions. We conducted a literature review to evaluate the potential for the choice of economic evaluation approach to impact on the adoption decisions recommended by economic evaluation studies. We found that for every five studies applying both approaches, one shows limited or no concordance in economic evaluation results: the different approaches suggest conflicting adoption decisions, and there is no pattern to which approach provides the most convincing adoption evidence. Only one study in ten indicates which results will best inform adoption decisions. We conclude that the choice of approach can significantly impact on the adoption decisions recommended by economic evaluation studies, with conflicting results creating confusion over whether or not interventions provide good value for money. Health economists rarely provide sufficient guidance to decisionmakers to alleviate this confusion.

BackgroundAnaemia, coagulopathic bleeding and transfusion are strongly associated with organ failure, sepsis and death following cardiac surgery.ObjectiveTo evaluate the clinical effectiveness and cost-effectiveness of medical devices used as diagnostic and therapeutic tools for the management of anaemia and bleeding in cardiac surgery.Methods and resultsWorkstream 1 – in the COagulation and Platelet laboratory Testing in Cardiac surgery (COPTIC) study we demonstrated that risk assessment using baseline clinical factors predicted bleeding with a high degree of accuracy. The results from point-of-care (POC) platelet aggregometry or viscoelastometry tests or an expanded range of laboratory reference tests for coagulopathy did not improve predictive accuracy beyond that achieved with the clinical risk score alone. The routine use of POC tests was not cost-effective. A systematic review concluded that POC-based algorithms are not clinically effective. We developed two new clinical risk prediction scores for transfusion and bleeding that are available as e-calculators. Workstream 2 – in the PAtient-SPecific Oxygen monitoring to Reduce blood Transfusion during heart surgery (PASPORT) trial and a systematic review we demonstrated that personalised near-infrared spectroscopy-based algorithms for the optimisation of tissue oxygenation, or as indicators for red cell transfusion, were neither clinically effective nor cost-effective. Workstream 3 – in the REDWASH trial we failed to demonstrate a reduction in inflammation or organ injury in recipients of mechanically washed red cells compared with standard (unwashed) red cells.LimitationsExisting studies evaluating the predictive accuracy or effectiveness of POC tests of coagulopathy or near-infrared spectroscopy were at high risk of bias. Interventions that alter red cell transfusion exposure, a common surrogate outcome in most trials, were not found to be clinically effective.ConclusionsA systematic assessment of devices in clinical use as blood management adjuncts in cardiac surgery did not demonstrate clinical effectiveness or cost-effectiveness. The contribution of anaemia and coagulopathy to adverse clinical outcomes following cardiac surgery remains poorly understood. Further research to define the pathogenesis of these conditions may lead to more accurate diagnoses, more effective treatments and potentially improved clinical outcomes.Study registrationCurrent Controlled Trials ISRCTN20778544 (COPTIC study) and PROSPERO CRD42016033831 (systematic review) (workstream 1); Current Controlled Trials ISRCTN23557269 (PASPORT trial) and PROSPERO CRD4201502769 (systematic review) (workstream 2); and Current Controlled Trials ISRCTN27076315 (REDWASH trial) (workstream 3).FundingThis project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full inProgramme Grants for Applied Research; Vol. 5, No. 17. See the NIHR Journals Library website for further project information.

Background: Resource-use measurement by patient recall is characterized by inconsistent methods and a lack of validation. A validated standardized resource-use measure could increase data quality, improve comparability between studies and reduce research burden.Aim: To identify a minimum set of core resource-use items that should be included in a standardized adult instrument for UK health economic evaluation from a provider perspective.Methods: Health economists with experience of UK-based economic evaluations were recruited to participate in an electronic Delphi survey. Respondents were asked to rate 60 resource-use items (e.g. medication names) on a scale of 1 to 9 according to the importance of the item in a generic context. Items considered less important according to predefined consensus criteria were dropped and a second survey was developed. In the second round, respondents received the median score and their own score from round 1 for each item alongside summarized comments and were asked to re-rate items. A final project team meeting was held to determine the recommended core set.Results: 45 participants completed round 1. 26 items were considered less important and dropped, 34 items were retained for the second round and no new items were added. 42 respondents completed round 2 (93.3%), and greater consensus was observed. Following the final meeting, a list of 10 core items was selected with further items identified as suitable for ‘bolt-on’ questionnaire modules.Conclusions: The consensus on 10 items considered important in a generic context suggests that a standardized instrument for core resource-use items is feasible.

Background and Aims There is uncertainty regarding the optimal management of endoscopically invisible (flat) low-grade dysplasia in ulcerative colitis. Such a finding does not currently provide an automatic indication for colectomy; however, a recommendation of surveillance instead of surgery is controversial. The aim of this study was to determine the clinical and cost-effectiveness of colonoscopic surveillance versus colectomy for endoscopically invisible low-grade dysplasia of the colon in ulcerative colitis. Methods A Markov model was used to evaluate the costs and health outcomes of surveillance and surgery over a 20-year timeframe. Outcomes evaluated were life years gained and quality-adjusted life years (QALYs). Cohorts of patients aged 25 to 75 were modeled, including estimates from a validated surgical risk calculator and considering none, 1, or both of 2 key comorbidities: heart failure and obstructive airway disease. Results Surveillance is associated with more life years and QALYs compared with surgery from age 61 for those with no comorbidities, age 51 for those with 1 comorbidity and age 25 for those with 2 comorbidities. At the current United Kingdom National Institute for Health and Care Excellence threshold of $25,800 per QALY, ongoing surveillance was cost-effective at age 65 in those without comorbidities and at age 60 in those with either 1 or more comorbidities. Conclusions Surveillance can be recommended from age 65 for those with no comorbidities; however, in younger patients with typical postsurgical quality of life, colectomy may be more effective clinically and more cost-effective. The results were sensitive to the colorectal cancer incidence rate in patients under surveillance and to quality of life after surgery.

In an environment of limited health care resources, it is crucial for health care systems which provide blood transfusion to have accurate and comprehensive information on the costs of transfusion, incorporating not only the costs of blood products, but also their administration. Unfortunately, in many countries accurate costs for administering blood are not available. Our study aimed to generate comprehensive estimates of the costs of administering transfusions for the UK National Health Service.A detailed microcosting study was used to cost two key inputs into transfusion: transfusion laboratory and nursing inputs. For each input, data collection forms were developed to capture staff time, equipment, and consumables associated with each step in the transfusion process. Costing results were combined with costs of blood product wastage to calculate the cost per unit transfused, separately for different blood products. Data were collected in 2014/15 British pounds and converted to US dollars.A total of 438 data collection forms were completed by 74 staff. The cost of administering blood was $71 (£49) per unit for red blood cells, $84 (£58) for platelets, $55 (£38) for fresh-frozen plasma, and $72 (£49) for cryoprecipitate.Blood administration costs add substantially to the costs of the blood products themselves. These are frequently incurred costs; applying estimates to the blood components supplied to UK hospitals in 2015, the annual cost of blood administration, excluding blood products, exceeds $175 (£120) million. These results provide more accurate estimates of the total costs of transfusion than those previously available.

Background Single gene tests to predict whether cancers respond to specific targeted therapies are performed increasingly often. Advances in sequencing technology, collectively referred to as next generation sequencing (NGS), mean the entire cancer genome or parts of it can now be sequenced at speed with increased depth and sensitivity. However, translation of NGS into routine cancer care has been slow. Healthcare stakeholders are unclear about the clinical utility of NGS and are concerned it could be an expensive addition to cancer diagnostics, rather than an affordable alternative to single gene testing. Methods and findings We validated a 46-gene hotspot cancer panel assay allowing multiple gene testing from small diagnostic biopsies. From 1 January 2013 to 31 December 2013, solid tumour samples (including non-small-cell lung carcinoma [NSCLC], colorectal carcinoma, and melanoma) were sequenced in the context of the UK National Health Service from 351 consecutively submitted prospective cases for which treating clinicians thought the patient had potential to benefit from more extensive genetic analysis. Following histological assessment, tumour-rich regions of formalin-fixed paraffin-embedded (FFPE) sections underwent macrodissection, DNA extraction, NGS, and analysis using a pipeline centred on Torrent Suite software. With a median turnaround time of seven working days, an integrated clinical report was produced indicating the variants detected, including those with potential diagnostic, prognostic, therapeutic, or clinical trial entry implications. Accompanying phenotypic data were collected, and a detailed cost analysis of the panel compared with single gene testing was undertaken to assess affordability for routine patient care. Panel sequencing was successful for 97% (342/351) of tumour samples in the prospective cohort and showed 100% concordance with known mutations (detected using cobas assays). At least one mutation was identified in 87% (296/342) of tumours. A locally actionable mutation (i.e., available targeted treatment or clinical trial) was identified in 122/351 patients (35%). Forty patients received targeted treatment, in 22/40 (55%) cases solely due to use of the panel. Examination of published data on the potential efficacy of targeted therapies showed theoretically actionable mutations (i.e., mutations for which targeted treatment was potentially appropriate) in 66% (71/107) and 39% (41/105) of melanoma and NSCLC patients, respectively. At a cost of £339 (US$449) per patient, the panel was less expensive locally than performing more than two or three single gene tests. Study limitations include the use of FFPE samples, which do not always provide high-quality DNA, and the use of “real world” data: submission of cases for sequencing did not always follow clinical guidelines, meaning that when mutations were detected, patients were not always eligible for targeted treatments on clinical grounds. Conclusions This study demonstrates that more extensive tumour sequencing can identify mutations that could improve clinical decision-making in routine cancer care, potentially improving patient outcomes, at an affordable level for healthcare providers., Sarah Wordsworth and colleagues study the feasibility of employing next-generation sequencing of tumor DNA in clinical practice., Author summary Why was this study done? Healthcare planners and oncologists require real world evidence that next generation sequencing (NGS) technologies improve gene mutation detection and enable more appropriate use of targeted drug therapies. With a range of genomic testing options available for cancer patients, we need to know whether healthcare systems can afford to implement cancer panels in routine clinical care, even if they are effective. What did the researchers do and find? This study assessed a 46-gene hotspot cancer panel assay allowing multiple gene testing of small diagnostic cancer biopsies in the context of the UK National Health Service. Tumour samples (including non-small-cell lung cancer, melanoma, and colorectal carcinoma) from 351 patients who treating clinicians thought might benefit from more extensive genetic analysis underwent NGS using the panel. A clinical report was produced with a median turnaround time of seven working days that indicated all mutations detected, including those with potential diagnostic, prognostic, therapeutic, or clinical trial entry implications. Clinical data were collected for patients whose tumour samples underwent sequencing in order to assess changes to clinical management resulting from this test. An accompanying detailed cost analysis was performed to determine the affordability of the panel compared to existing single gene testing options. The panel demonstrated at least one mutation in 87% (296/342) of successfully sequenced tumours. Forty patients in this cohort received targeted treatments on the basis of genetic data obtained using the panel. For 22 of these patients, there was no alternative genetic test available locally to produce this data. Mutation detection with the panel costs £339 (US$449) per patient, compared with single gene testing ranging from £71 to £141 (US$94–US$187) per test, depending on the mutation type. If more than two or three genes are examined (depending on the cancer type), using the panel is less expensive than single gene testing. What do these findings mean? The panel assay is a useful method to identify genetic mutations in tumours that can extend the range of therapeutic options available to patients. In terms of costs and affordability, the panel may be a justifiable option if 2–3 or more genes need to be examined. Further data need to be collected on the clinical outcomes of patients accessing drugs as a result of more extensive sequencing data outside the scope of single gene/mutation tests. In addition to supporting routine clinical care, the panel can be used to support research studies where treatment choices are genetically determined.

BackgroundEvery year approximately 5000–9000 patients are admitted to a hospital with diarrhoea, which in up to 90% of cases has a non-infectious cause. As a result, single rooms are ‘blocked’ by patients with non-infectious diarrhoea, while patients with infectious diarrhoea are still in open bays because of a lack of free side rooms. A rapid test for differentiating infectious from non-infectious diarrhoea could be very beneficial for patients.ObjectiveTo evaluate MassCode multiplex polymerase chain reaction (PCR) for the simultaneous diagnosis of multiple enteropathogens directly from stool, in terms of sensitivity/specificity to detect four common important enteropathogens:Clostridium difficile,Campylobacterspp.,Salmonellaspp. and norovirus.DesignA retrospective study of fixed numbers of samples positive forC. difficile(n = 200),Campylobacterspp. (n = 200),Salmonellaspp. (n = 100) and norovirus (n = 200) plus samples negative for all these pathogens (n = 300). Samples were sourced from NHS microbiology laboratories in Oxford and Leeds where initial diagnostic testing was performed according to Public Health England methodology. Researchers carrying out MassCode assays were blind to this information. A questionnaire survey, examining current practice for infection control teams and microbiology laboratories managing infectious diarrhoea, was also carried out.SettingMassCode assays were carried out at Oxford University Hospitals NHS Trust. Further multiplex assays, carried out using Luminex, were run on the same set of samples at Leeds Teaching Hospitals NHS Trust. The questionnaire was completed by various NHS trusts.Main outcome measuresSensitivity and specificity to detectC. difficile,Campylobacterspp.,Salmonellaspp., and norovirus.ResultsNucleic acids were extracted from 948 clinical samples using an optimised protocol (200Campylobacterspp., 199C. difficile, 60S. enterica, 199 norovirus and 295 negative samples; some samples contained more than one pathogen). Using the MassCode assay, sensitivities for each organism compared with standard microbiological testing ranged from 43% to 94% and specificities from 95% to 98%, with particularly poor performance forS. enterica. Relatively large numbers of unexpected positives not confirmed with quantitative PCR were also observed, particularly forS. enterica,Giardia lambliaandCryptosporidiumspp. As the results indicated thatS. entericadetection might provide generic challenges to other multiplex assays for gastrointestinal pathogens, the Luminex xTag®gastrointestinal assay was also run blinded on the same extracts (937/948 remaining) and on re-extracted samples (839/948 with sufficient material). ForCampylobacterspp.,C. difficileand norovirus, high sensitivities (> 92%) and specificities (> 96%) were observed. ForS. enterica, on the original MassCode/Oxford extracts, Luminex sensitivity compared with standard microbiological testing was 84% [95% confidence interval (CI) 73% to 93%], but this dropped to 46% on a fresh extract, very similar to MassCode, with a corresponding increase in specificity from 92% to 99%. Overall agreement on the per-sample diagnosis compared with combined microbiology plus PCR for the main four/all pathogens was 85.6%/64.7%, 87.0%/82.9% and 89.8%/86.8% for the MassCode assay, Luminex assay/MassCode extract and Luminex assay/fresh extract, respectively. Luminex assay results from fresh extracts implied that 5% of samples did not represent infectious diarrhoea, even though enteropathogens were genuinely present. Managing infectious diarrhoea was a significant burden for infection control teams (taking 21% of their time) and better diagnostics were identified as having major potential benefits for patients.ConclusionsOverall, the Luminex xTag gastrointestinal panel showed similar or superior sensitivity and specificity to the MassCode assay. However, on fresh extracts, this test had low sensitivity to detect a key enteric pathogen,S. enterica; making it an unrealistic option for most microbiology laboratories. Extraction efficiency appears to be a major obstacle for nucleic acid-based tests for this organism, and possibly the whole Enterobacteriaceae family. To improve workflows in service microbiology laboratories, to reduce workload for infection control practitioners, and to improve outcomes for NHS patients, further research on deoxyribonucleic acid-based multiplex gastrointestinal diagnostics is urgently needed.FundingThe Health Technology Assessment programme of the National Institute for Health Research.

One of the functions of the reformed Cancer Drugs Fund in England is as a managed access fund, providing conditional funding for cancer drugs where there is uncertainty in the economic case, and where that uncertainty can be addressed by data collection during two years' use in the NHS. Our study characterises likely sources of such uncertainty, through a review of recent NICE Technology Appraisals.Discussions of uncertainty in NICE Appraisal Committees were extracted from published Single Technology Appraisals of cancer drugs, 2014-2016, and categorised inductively. The location of the comments within the structured Appraisal document was used as a proxy for the degree of concern shown by the Committee.Twenty-nine appraisals were analysed, of which 23 (79%) were recommended for funding. Six main sources of uncertainty were identified. Immaturity of survival data, and issues relating to comparators, were common sources of uncertainty regardless of degree of concern. Uncertainties relating to quality of life, and the patient population in the trial, were discussed frequently but rarely occurred in the more uncertain appraisals. Concerns with trial design, and cost uncertainty, were less common, but a high proportion contributed to the most uncertain appraisals. Funding decisions were not driven by uncertainty in the evidence base, but by the expected cost per QALY relative to acceptance thresholds, and the resultant level of uncertainty in the decision.The reformed CDF is an improvement on its predecessor. However the main types of uncertainty seen in recent cancer appraisals will not readily be resolved solely by 2 years' RWD collection in the reformed CDF; where there are no ongoing trials to provide longer-term data, randomised trials rather than RWD may be needed to fully resolve questions of relative efficacy. Other types of uncertainty, and concerns with generalisability, may be more amenable to the RWD approach, and it is these that we expect to be the focus of data collection arrangements in the reformed CDF.

Background. We assessed whether a near-infrared spectroscopy (NIRS)-based algorithm for the personalized optimization of cerebral oxygenation during cardiopulmonary bypass combined with a restrictive red cell transfusion threshold would reduce perioperative injury to the brain, heart, and kidneys. Methods. In a randomized controlled trial, participants in three UK centres were randomized with concealed allocation to a NIRS (INVOS 5100; Medtronic Inc., Minneapolis, MN, USA)-based patient-specific' algorithm that included a restrictive red cell transfusion threshold (haematocrit 18%) or to a generic' non-NIRS-based algorithm (standard care). The NIRS algorithm aimed to maintain cerebral oxygenation at an absolute value of > 50% or at > 70% of baseline values. The primary outcome for the trial was cognitive function measured up to 3 months postsurgery. Results. The analysis population comprised eligible randomized patients who underwent valve or combined valve surgery and coronary artery bypass grafts using cardiopulmonary bypass between December 2009 and January 2014 (n=98 patient-specific algorithm; n=106 generic algorithm). There was no difference between the groups for the three core cognitive domains (attention, verbal memory, and motor coordination) or for the non-core domains psychomotor speed and visuo-spatial skills. The NIRS group had higher scores for verbal fluency; mean difference 3.73 (95% confidence interval 1.50, 5.96). Red cell transfusions, biomarkers of brain, kidney, and myocardial injury, adverse events, and health-care costs were similar between the groups. Conclusions. These results do not support the use of NIRS-based algorithms for the personalized optimization of cerebral oxygenation in adult cardiac surgery. Clinical trial registration.http://www.controlled-trials.com, ISRCTN 23557269.

BackgroundUncertainty about optimal red blood cell transfusion thresholds in cardiac surgery is reflected in widely varying transfusion rates between surgeons and cardiac centres.ObjectiveTo test the hypothesis that a restrictive compared with a liberal threshold for red blood cell transfusion after cardiac surgery reduces post-operative morbidity and health-care costs.DesignMulticentre, parallel randomised controlled trial and within-trial cost–utility analysis from a UK NHS and Personal Social Services perspective. We could not blind health-care staff but tried to blind participants. Random allocations were generated by computer and minimised by centre and operation.SettingSeventeen specialist cardiac surgery centres in UK NHS hospitals.ParticipantsPatients aged > 16 years undergoing non-emergency cardiac surgery with post-operative haemoglobin InterventionsParticipants in the liberal group were eligible for transfusion immediately after randomisation (post-operative haemoglobin Main outcome measuresThe primary outcome was a composite outcome of any serious infectious (sepsis or wound infection) or ischaemic event (permanent stroke, myocardial infarction, gut infarction or acute kidney injury) during the 3 months after randomisation. Events were verified or adjudicated by blinded personnel. Secondary outcomes included blood products transfused; infectious events; ischaemic events; quality of life (European Quality of Life-5 Dimensions); duration of intensive care or high-dependency unit stay; duration of hospital stay; significant pulmonary morbidity; all-cause mortality; resource use, costs and cost-effectiveness.ResultsWe randomised 2007 participants between 15 July 2009 and 18 February 2013; four withdrew, leaving 1000 and 1003 in the restrictive and liberal groups, respectively. Transfusion rates after randomisation were 53.4% (534/1000) and 92.2% (925/1003). The primary outcome occurred in 35.1% (331/944) and 33.0% (317/962) of participants in the restrictive and liberal groups [odds ratio (OR) 1.11, 95% confidence interval (CI) 0.91 to 1.34;p = 0.30], respectively. There were no subgroup effects for the primary outcome, although some sensitivity analyses substantially altered the estimated OR. There were no differences for secondary clinical outcomes except for mortality, with more deaths in the restrictive group (4.2%, 42/1000 vs. 2.6%, 26/1003; hazard ratio 1.64, 95% CI 1.00 to 2.67;p = 0.045). Serious post-operative complications excluding primary outcome events occurred in 35.7% (354/991) and 34.2% (339/991) of participants in the restrictive and liberal groups, respectively. The total cost per participant from surgery to 3 months postoperatively differed little by group, just £182 less (standard error £488) in the restrictive group, largely owing to the difference in red blood cells cost. In the base-case cost-effectiveness results, the point estimate suggested that the restrictive threshold was cost-effective; however, this result was very uncertain partly owing to the negligible difference in quality-adjusted life-years gained.ConclusionsA restrictive transfusion threshold is not superior to a liberal threshold after cardiac surgery. This finding supports restrictive transfusion due to reduced consumption and costs of red blood cells. However, secondary findings create uncertainty about recommending restrictive transfusion and prompt a new hypothesis that liberal transfusion may be superior after cardiac surgery. Reanalyses of existing trial datasets, excluding all participants who did not breach the liberal threshold, followed by a meta-analysis of the reanalysed results are the most obvious research steps to address the new hypothesis about the possible harm of red blood cell transfusion.Trial registrationCurrent Controlled Trials ISRCTN70923932.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 20, No. 60. See the NIHR Journals Library website for further project information.

BackgroundPatients with neovascular age-related macular degeneration (nAMD) usually attend regular reviews, even when the disease is quiescent. Reviews are burdensome to health services, patients and carers.ObjectivesTo compare the proportion of correct lesion classifications made by community-based optometrists and ophthalmologists from vignettes of patients; to estimate the cost-effectiveness of community follow-up by optometrists compared with follow-up by ophthalmologists in the Hospital Eye Service (HES); to ascertain views of patients, their representatives, optometrists, ophthalmologists and clinical commissioners on the proposed shared care model.DesignCommunity-based optometrists and ophthalmologists in the HES classified lesions from vignettes comprising clinical information, colour fundus photographs and optical coherence tomography images. Participants’ classifications were validated against experts’ classifications (reference standard).SettingInternet-based application.ParticipantsOphthalmologists had to have ≥ 3 years post-registration experience in ophthalmology, have passed part 1 of the Royal College of Ophthalmologists, Diploma in Ophthalmology or equivalent examination, and have experience in the age-related macular degeneration service. Optometrists had to be fully qualified, be registered with the General Optical Council for ≥ 3 years and not be participating in nAMD shared care.InterventionsThe trial sought to emulate a conventional trial in comparing optometrists’ and ophthalmologists’ decision-making, but vignettes, not patients, were assessed; therefore, there were no interventions. Participants received training prior to assessing vignettes.Main outcome measuresPrimary outcome – correct classification of the activity status of a lesion based on a vignette, compared with a reference standard. Secondary outcomes – frequencies of potentially sight-threatening errors, participants’ judgements about specific lesion components, participant-rated confidence in their decisions and cost-effectiveness of follow-up by community-based optometrists compared with HES ophthalmologists.ResultsIn total, 155 participants registered for the trial; 96 (48 in each professional group) completed training and main assessments and formed the analysis population. Optometrists and ophthalmologists achieved 1702 out of 2016 (84.4%) and 1722 out of 2016 (85.4%) correct classifications, respectively [odds ratio (OR) 0.91, 95% confidence interval (CI) 0.66 to 1.25;p = 0.543]. Optometrists’ decision-making was non-inferior to ophthalmologists’ with respect to the pre-specified limit of 10% absolute difference (0.298 on the odds scale). Frequencies of sight-threatening errors were similar for optometrists and ophthalmologists [57/994 (5.7%) vs. 62/994 (6.2%), OR 0.93, 95% CI 0.55 to 1.57;p = 0.789]. Ophthalmologists assessed lesion components as present less often than optometrists and were more confident about their lesion classifications than optometrists. The mean care-pathway cost for assessment was very similar by group, namely £397.33 for ophthalmologists and £410.78 for optometrists. The optometrist-led monitoring reviews were slightly more costly and less effective than ophthalmologist-led reviews, although the differences were extremely small. There was consensus that optometrist-led monitoring has the potential to reduce clinical workload and be more patient-centred. However, potential barriers are ophthalmologists’ perceptions of optometrists’ competence, the need for clinical training, the ability of the professions to work collaboratively and the financial feasibility of shared care for Clinical Commissioning Groups.ConclusionsThe ability of optometrists to make nAMD retreatment decisions from vignettes is non-inferior to that of ophthalmologists. Various barriers to implementing shared cared for nAMD were identified.Future work recommendationsThe Effectiveness, cost-effectiveness and acceptability of Community versus Hospital Eye Service follow-up for patients with neovascular age-related macular degeneration with quiescent disease (ECHoES) study web application was robust and could be used for future training or research. The benefit of reducing HES workload was not considered in the economic evaluation. A framework of programme budgeting and marginal analysis could explicitly explore the resource implications of shifting resources within a given health service area, as the benefit of reducing HES workload was not considered in the economic evaluation. Future qualitative research could investigate professional differences of opinion that were identified in multidisciplinary focus groups.Trial registrationCurrent Controlled Trials ISRCTN07479761.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 20, No. 80. See the NIHR Journals Library website for further project information.

Objectives To assess the cost-effectiveness of optometrist-led follow-up monitoring reviews for patients with quiescent neovascular age-related macular degeneration (nAMD) in community settings (including high street opticians) compared with ophthalmologist-led reviews in hospitals. Design A model based cost-effectiveness analysis with a 4-week time horizon, based on a ‘virtual’ non-inferiority randomised trial designed to emulate a parallel group design. Setting A virtual internet-based clinical assessment, conducted at community optometry practices, and hospital ophthalmology clinics. Participants Ophthalmologists with experience in the age-related macular degeneration service; fully qualified optometrists not participating in nAMD shared care schemes. Interventions The participating optometrists and ophthalmologists classified lesions from vignettes and were asked to judge whether any retreatment was required. Vignettes comprised clinical information, colour fundus photographs and optical coherence tomography images. Participants’ classifications were validated against experts’ classifications (reference standard). Resource use and cost information were attributed to these retreatment decisions. Main Outcome Measures Correct classification of whether further treatment is needed, compared with a reference standard. Results The mean cost per assessment, including the subsequent care pathway, was £411 for optometrists and £397 for ophthalmologists: a cost difference of £13 (95% CI: -£18, £45). Optometrists were non-inferior to ophthalmologists with respect to the overall percentage of lesions correctly assessed (difference: -1.0%; 95% CI: -4.5%, 2.5%). Conclusions In the base case analysis, the slightly larger number of incorrect retreatment decisions by optometrists led to marginally and non-significantly higher costs. Sensitivity analyses that reflected different practices across eye hospitals indicate that shared care pathways between optometrists and ophthalmologists can be identified which may reduce demands on scant hospital resources, although in light of the uncertainty around differences in outcome and cost it remains unclear whether the differences between the two care pathways are significant in economic terms.

OBJECTIVE: To assess the incremental cost and cost-effectiveness of a restrictive versus a liberal red blood cell transfusion threshold after cardiac surgery.DESIGN: A within-trial cost-effectiveness analysis with a 3-month time horizon, based on a multicentre superiority randomised controlled trial from the perspective of the National Health Service (NHS) and personal social services in the UK.SETTING: 17 specialist cardiac surgery centres in UK NHS hospitals.PARTICIPANTS: 2003 patients aged >16 years undergoing non-emergency cardiac surgery with a postoperative haemoglobin of INTERVENTIONS: Restrictive (transfuse if haemoglobin MAIN OUTCOME MEASURES: Health-related quality of life measured using the EQ-5D-3L to calculate quality-adjusted life years (QALYs).RESULTS: The total costs from surgery up to 3 months were £17 945 and £18 127 in the restrictive and liberal groups (mean difference is -£182, 95% CI -£1108 to £744). The cost difference was largely attributable to the difference in the cost of red blood cells. Mean QALYs to 3 months were 0.18 in both groups (restrictive minus liberal difference is 0.0004, 95% CI -0.0037 to 0.0045). The point estimate for the base-case cost-effectiveness analysis suggested that the restrictive group was slightly more effective and slightly less costly than the liberal group and, therefore, cost-effective. However, there is great uncertainty around these results partly due to the negligible differences in QALYs gained.CONCLUSIONS: We conclude that there is no clear difference in the cost-effectiveness of restrictive and liberal thresholds for red blood cell transfusion after cardiac surgery.TRIAL REGISTRATION NUMBER: ISRCTN70923932; Results.

Background and Objectives Several countries have included medium-chain acyl-CoA dehydrogenase deficiency (MCADD) in their newborn screening programs. However, the sensitivity of the programs cannot be estimated directly as only individuals with a positive result undergo a definitive diagnostic test. We propose a framework to overcome this limitation and estimate the prevalence of disease, sensitivity of screening, and its yield relative to no screening. Study Design and Setting A Bayesian model simultaneously combined available prevalence data on the most common mutation of MCADD (c.985A>G) in screened and nonscreened populations using the relationship between true and apparent prevalence of disease. Data originated from screening pilots in England, disease surveillance studies, and published literature. Model validity and consistency were formally checked. Results True prevalence of c.985A>G homozygotes in England was 6.2 per 100,000 individuals, and the sensitivity of the screening program was 94% (95% confidence interval [CI]: 74, 100%) compared with a detection rate in nonscreened areas of 48% (95% CI: 30, 68%) by age of 5 years. Hence, the screening program detected 47% (95% CI: 30, 60%) additional cases compared with no screening. Conclusion The sensitivity of the screening program in England was high and our estimation approach could be adapted to inform other jurisdictions, rare diseases, and newborn screening programs.

Aims: To explore the cost-effectiveness of alternative methods of screening family members for hypertrophic cardiomyopathy (HCM), the most common monogenic cardiac disorder and the most frequent cause of sudden cardiac death (SCD) in young people.Methods and results: Economic decision model comparing cascade screening by genetic, as opposed to clinical methods. The incremental cost per life year saved was €14 397 for the cascade genetic compared with the cascade clinical approach. Genetic diagnostic strategies are more likely to be cost-effective than clinical tests alone. The costs for cascade molecular genetic testing were slightly higher than clinical testing in the short run, but this was largely because the genetic approach is more effective and identifies more individuals at risk.Conclusion: The use of molecular genetic information in the diagnosis and management of HCM is a cost-effective approach to the primary prevention of SCD in these patients.

The number of economic evaluations conducted on a multinational basis is increasing. Therefore, techniques are required to compare the results of such studies in a meaningful manner. This paper explores different approaches to comparing across country cost data applied to a European study of dialysis therapy for end-stage renal disease. A price and volume index is created at the level of the individual health care technology and compared to an exchange rate conversion and published purchasing power parities (PPPs). Both exchange rate and PPP conversions when published rates are used fail to accurately reflect the true resource use of the applied health care example. These differences can be related to specific issues of input mix and price variation. Alternatively, the use of technology specific PPPs provided a more robust approach for international comparisons and also have the potential for use in multi-centre economic evaluations within the same country.

Background: Somatic mutations are important determinants of cancer behaviour and response to therapy. However, molecular testing in this context has a relatively low profile within the clinical community, despite publicity surrounding targeted therapies such as Herceptin. Aims: As the testing process affects many stakeholders, especially oncologists, this paper examines current test request patterns and views of such testing. Methods: A postal questionnaire was mailed to 582 UK oncologists and haematologists, achieving a 20% response rate. Results: The survey revealed that immunohistochemistry and fluorescent in situ hybridisation are the most commonly requested tests (used by 70% and 55% of respondents, respectively), especially for breast cancer. Availability of suitable treatment options is the main factor influencing the decision to test (selected by 62% of respondents). Respondents were generally positive about future demand for immunohistochemistry, fluorescent in situ hybridisation, microarray analysis and DNA-based tests, but uncertain about the prospects for microsatellite instability and ploidy testing. Conclusions: Overall, respondents thought that somatic mutation testing could have a significant and positive effect on oncology and haematology departments and patient care, especially with better treatment and tumour classification. However, lack of supportive scientific evidence and funding were considered key barriers to widespread testing. Further research is clearly required on both the resource implications of this increase in demand and the best model of service delivery to ensure the most efficient use of health service resources.

Summary Background Advances in molecular and genomic testing for patients with suspected infectious diarrhoea are on the horizon. It is important to understand how infection control and microbiology departments currently operate with respect to the management of these patients in order to assess the implications of more widespread diagnostic testing. However, there are few data available on current practice in this context. Aim To describe current infection control and microbiologist practice across England with respect to the management of patients with suspected infectious diarrhoea. Methods Hospitals in England completed three questionnaires on current testing practice in this context. Questionnaire design was informed by current practice within the Oxford University Hospitals group. Findings Forty-one percent of hospitals completed at least one questionnaire. A notable proportion of staff time was devoted to the management of patients with suspected infectious diarrhoea. Staff training was generally good, but compliance with policy documents was only 80%. Cleaning and isolation policies varied across hospitals, suggesting that either these were not evidence-based, or that the evidence base is weak. There was more agreement on outbreak definitions, management, and cohorting policies. Stool-testing decisions were mainly driven by patient characteristics, whereas strain typing was infrequently used (except to investigate Clostridium difficile infections). Multiple practical difficulties associated with patient management were identified, along with a clear appetite for more widespread genomic diagnostic testing. Conclusion Managing patients with suspected infectious diarrhoea is a major burden in England. Advances in testing practice in this context could have significant clinical and economic impacts.

Accurate resource-use measurement is challenging within an economic evaluation, but is a fundamental requirement for estimating efficiency. Considerable research effort has been concentrated on the appropriate measurement of outcomes and the policy implications of economic evaluation, while methods for resource-use measurement have been relatively neglected. Recently, the Database of Instruments for Resource Use Measurement (DIRUM) was set up at http://www.dirum.org to provide a repository where researchers can share resource-use measures and methods. A workshop to discuss the issues was held at the University of Birmingham in October 2011. Based on material presented at the workshop, this article highlights the state of the art of UK instruments for resource-use data collection based on patient recall. We consider methodological issues in the design and analysis of resource-use instruments, and the challenges associated with designing new questionnaires. We suggest a method of developing a good practice guideline, and identify some areas for future research. Consensus amongst health economists has yet to be reached on many aspects of resource-use measurement. We argue that researchers should now afford costing methodologies the same attention as outcome measurement, and we hope that this Current Opinion article will stimulate a debate on methods of resource-use data collection and establish a research agenda to improve the precision and accuracy of resource-use estimates.

Thresholds for red blood cell transfusion following cardiac surgery vary by hospital and surgeon. The TITRe2 multi-centre randomised controlled trial aims to randomise 2000 patients from 17 United Kingdom centres, and tests the hypothesis that a restrictive transfusion threshold will reduce postoperative morbidity and health service costs compared to a liberal threshold. Patients consent to take part in the study pre-operatively but are only randomised if their haemoglobin falls below 9g/dL during their post-operative hospital stay. The primary outcome is a binary composite outcome of any serious infectious or ischaemic event in the first three months after randomisation. Many challenges have been encountered in the set-up and running of the study.

PURPOSE: To compare the efficacy and safety of ranibizumab and bevacizumab intravitreal injections to treat neovascular age-related macular degeneration (nAMD). DESIGN: Multicenter, noninferiority factorial trial with equal allocation to groups. The noninferiority limit was 3.5 letters. This trial is registered (ISRCTN92166560). PARTICIPANTS: People >50 years of age with untreated nAMD in the study eye who read =25 letters on the Early Treatment Diabetic Retinopathy Study chart. METHODS: We randomized participants to 4 groups: ranibizumab or bevacizumab, given either every month (continuous) or as needed (discontinuous), with monthly review. MAIN OUTCOME MEASURES: The primary outcome is at 2 years; this paper reports a prespecified interim analysis at 1 year. The primary efficacy and safety outcome measures are distance visual acuity and arteriothrombotic events or heart failure. Other outcome measures are health-related quality of life, contrast sensitivity, near visual acuity, reading index, lesion morphology, serum vascular endothelial growth factor (VEGF) levels, and costs. RESULTS: Between March 27, 2008 and October 15, 2010, we randomized and treated 610 participants. One year after randomization, the comparison between bevacizumab and ranibizumab was inconclusive (bevacizumab minus ranibizumab -1.99 letters, 95% confidence interval [CI], -4.04 to 0.06). Discontinuous treatment was equivalent to continuous treatment (discontinuous minus continuous -0.35 letters; 95% CI, -2.40 to 1.70). Foveal total thickness did not differ by drug, but was 9% less with continuous treatment (geometric mean ratio [GMR], 0.91; 95% CI, 0.86 to 0.97; P = 0.005). Fewer participants receiving bevacizumab had an arteriothrombotic event or heart failure (odds ratio [OR], 0.23; 95% CI, 0.05 to 1.07; P = 0.03). There was no difference between drugs in the proportion experiencing a serious systemic adverse event (OR, 1.35; 95% CI, 0.80 to 2.27; P = 0.25). Serum VEGF was lower with bevacizumab (GMR, 0.47; 95% CI, 0.41 to 0.54; P

We aim to establish whether it is ever appropriate to conduct cost-minimisation analysis (CMA) rather than cost-effectiveness analysis.We perform a literature review to examine how the use of CMA has changed since Briggs & O'Brien announced its death in 2001. Examples of simulated and trial data are presented: firstly to illustrate the advantages and disadvantages of CMA in the context of non-inferiority trials and those finding no significant difference in efficacy and secondly to assess whether CMA gives biased results.We show that CMA is still used and will bias measures of uncertainty, causing overestimation or underestimation of the value of information and the probability that treatment is cost-effective. Although bias will be negligible for non-inferiority studies comparing treatments that differ enormously in cost, it is generally necessary to collect and analyse data on costs and efficacy (including utilities) to assess this bias. Cost-effectiveness analysis (including evaluation of the joint distribution of costs and benefits) is almost always required to avoid biased estimation of uncertainty. The remit of CMA in trial-based economic evaluation is therefore even narrower than previously thought, suggesting that CMA is not only dead but should also be buried.

Background: Treating patients admitted to critical care with severe pneumonia requires timely intervention with an effective antibiotic. This reduces the risk of dying of pneumonia and minimises complications associated with a prolonged stay in critical care. Objective: To compare the cost-effectiveness of meropenem 1 g/8 h with piperacillin/tazobactam 4.5 g/8 h for treating pneumonia in UK critical care. Methods: A Markov model was built to estimate lifetime costs and quality-adjusted life years (QALYs) of using meropenem versus piperacillin/tazobactam to treat severe pneumonia. Estimates of effectiveness, utility weights and costs were obtained from published sources. Probabilistic sensitivity analysis was conducted to address uncertainty in the model results. Results: Cost of treating a patient with severe pneumonia was estimated as £19,026 with meropenem and £19,978 with piperacillin/tazobactam, respectively. QALYs gained were 4.768 with meropenem and 4.654 with piperacillin/tazobactam. Probabilistic sensitivity analysis showed meropenem to be consistently less costly and more effective than piperacillin/tazobactam. Conclusion: The additional efficacy of meropenem translates into more patients surviving critical care and leaving this high-cost service more quickly than if they had been treated with piperacillin/ tazobactam. As meropenem is more effective and less expensive than piperacillin/tazobactam at treating patients with severe pneumonia, it is the dominant treatment option. © 2011 Springer-Verlag.

OBJECTIVE: To compare the effectiveness of meropenem with cefepime and piperacillin/tazobactam in the absence of direct comparisons in randomised controlled trials. DATA SOURCES: Two previously conducted systematic reviews, one comparing the carbapenems (ertapenem and imipenem/cilastatin) versus 4th-generation cephalosporins (cefepime) or antipseudomonal penicillins (piperacillin/tazobactam), and the other comparing the carbapenems (imipenem/cilastatin versus meropenem), were updated to provide the basis for this mixed treatment comparison. Searching was completed in April 2007. No restriction was placed on language of publication. STUDY SELECTION AND DATA EXTRACTION: Randomised controlled trials of adult patients hospitalised with infection and treated with a carbapenem or cefepime or piperacillin/tazobactam. Two reviewers independently assessed the papers against the inclusion/exclusion criteria and for methodological quality with any differences in opinion adjudicated by a third party. Two reviewers independently extracted data on clinical response, bacteriological response, mortality, and adverse events. DATA SYNTHESIS: A mixed treatment comparison meta-analysis using Bayesian Markov Chain Monte Carlo simulation was used to perform the indirect comparison. The dataset comprised 34 trials: four comparing ertapenem versus piperacillin/tazobactam, one imipenem/cilastatin versus cefepime, 26 imipenem/cilastatin versus meropenem, three imipenem/cilastatin versus piperacillin/tazobactam. We calculated odds ratios (OR) using imipenem/cilastatin as the common comparator. Meropenem was associated with the highest probability of being the most effective treatment for clinical response (OR 1.52, 95% credible interval [CrI] 1.23-1.87) and bacteriological response (OR 1.45, 95% CrI 1.15-1.80) with a reduced risk of serious adverse events (overall: OR 0.88, 95% CrI 0.76-1.02; serious adverse events leading to withdrawal: OR 0.73, 95% CrI 0.42-1.20; and GI-related: OR 0.76, 95% CrI 0.55-1.02). There was little difference between the three carbapenems and cefepime on all-cause mortality. CONCLUSIONS: This mixed treatment comparison suggests meropenem has substantial advantages over cefepime, ertapenem, imipenem/cilastatin and piperacillin/tazobactam in the treatment of hospitalised patients with infection.

Genetic testing in health care can provide information to help with disease prediction, diagnosis, prognosis, and treatment. Assessing the clinical utility of genetic testing requires a process to value and weight different outcomes. This article discusses the relative merits of different economic measures and methods to inform recommendations relative to genetic testing for risk of disease, including cost-effectiveness analysis and cost-benefit analysis. Cost-effectiveness analyses refer to analyses that calculate the incremental cost per unit of health outcomes, such as deaths prevented or life-years saved because of some intervention. Cost-effectiveness analyses that use preference-based measures of health state utility such as quality-adjusted life-years to define outcomes are referred to as cost-utility analyses. Cost-effectiveness analyses presume that health policy decision makers seek to maximize health subject to resource constraints. Cost-benefit analyses can incorporate monetary estimates of willingness-to-pay for genetic testing, including the perceived value of information independent of health outcomes. These estimates can be derived from contingent valuation or discrete choice experiments. Because important outcomes of genetic testing do not fit easily within traditional measures of health, cost-effectiveness analyses do not necessarily capture the full range of outcomes of genetic testing that are important to decision makers and consumers. We recommend that health policy decision makers consider the value to consumers of information and other nonhealth attributes of genetic testing strategies.

This chapter begins by outlining why health economics is an important discipline in discussions concerning the use of genomic information in health care. It then provides the reader with an overview of some of the key concepts addressed by health economics and describes one of the main methods used by health economists to evaluate healthcare interventions: economic evaluation. The chapter then moves on to provide examples of where health economics has been applied to genomics, including diagnostics, treatment, and disease prevention. Challenges faced by the health economics discipline in evaluating genomics interventions are then described, which include methodological challenges and issues related to evidence generation and reimbursement mechanisms. Finally, the chapter outlines some of the policy implications of using health economics in genomics.

Background: Genetics clinical practice has paid limited attention to non-inherited aspects of cancer, namely mutations occurring during carcinogenesis. These somatic mutations are likely to be the primary determinants of cancer behaviour and treatment response, with a recent example being Her2/Neu gene status and response to Herceptin in breast cancer. Aim: To assess the feasibility of widespread testing of tumours by surveying UK histopathology and genetics laboratories. Methods: The questionnaire asked: which of the common cancers or other malignancies are routinely assessed; which molecular and cytogenetic methods are used; who orders and funds testing; what is the future demand for somatic testing; and what are the barriers to widespread testing? Results: Of 50 laboratories surveyed, 33 responded, 22 of which are currently using molecular tests. The survey shows that the most common tests are immunohistochemistry, fluorescence in-situ hybridisation and DNA testing of somatic mutations. Most laboratories predict testing will increase over the next 10 years, particularly for DNA testing using microarrays. Respondents perceived the main barriers to expanding molecular testing were a lack of laboratory funding and scientific evidence and testing not considered an NHS priority. Conclusion: These results provide important information for healthcare commissioners faced with managing demand for molecular testing of cancers.

Array based comparative genomic hybridisation (aCGH) is a powerful technique for detecting clinically relevant genome imbalance and can offer 40 to > 1000 times the resolution of karyotyping. Indeed, idiopathic learning disability (ILD) studies suggest that a genome-wide aCGH approach makes 10–15% more diagnoses involving genome imbalance than karyotyping. Despite this, aCGH has yet to be implemented as a routine NHS service. One significant obstacle is the perception that the technology is prohibitively expensive for most standard NHS clinical cytogenetics laboratories. To address this, we investigated the cost-effectiveness of aCGH versus standard cytogenetic analysis for diagnosing idiopathic learning disability (ILD) in the NHS. Cost data from four participating genetics centres were collected and analysed. In a single test comparison, the average cost of aCGH was £442 and the average cost of karyotyping was £117 with array costs contributing most to the cost difference. This difference was not a key barrier when the context of follow up diagnostic tests was considered. Indeed, in a hypothetical cohort of 100 ILD children, aCGH was found to cost less per diagnosis (£3,118) than a karyotyping and multi-telomere FISH approach (£4,957). We conclude that testing for genomic imbalances in ILD using microarray technology is likely to be cost-effective because long-term savings can be made regardless of a positive (diagnosis) or negative result. Earlier diagnoses save costs of additional diagnostic tests. Negative results are cost-effective in minimising follow-up test choice. The use of aCGH in routine clinical practice warrants serious consideration by healthcare providers.

This study compared genetic nurse counsellors with standard services for breast cancer genetic risk counselling services in two regional genetics centres, in Grampian region, North East Scotland and in Cardiff, Wales. Women referred for genetic counselling were randomised to an initial genetic counselling appointment with either a genetic nurse counsellor (intervention) or a clinical geneticist (current service, control). Participants completed postal questionnaires before, immediately after the counselling episode and 6 months later to assess anxiety, general health status, perceived risk and satisfaction. A parallel economic evaluation explored factors influencing cost-effectiveness. The two concurrent randomised controlled equivalence trials were conducted and analysed separately. In the Grampian trial, 289 patients (193 intervention, 96 control) and in the Wales trial 297 patients (197 intervention and 100 control) returned a baseline questionnaire and attended their appointment. Analysis suggested at least likely equivalence in anxiety (the primary outcome) between the two arms of the trials. The cost per counselling episode was 11.54 UK pounds less for nurse-based care in the Grampian trial and 12.50 UK pounds more for nurse-based care in Cardiff. The costs were sensitive to the grade of doctor (notionally) replaced and the extent of consultant supervision required by the nurse. In conclusion, care based on genetic nurse counsellors was not significantly different from conventional cancer genetic services in both trial locations.

Objectives: Recent policy recommendations for cervical screening include liquid-based cytology. This new approach could improve laboratory throughput, reducing the waiting time for test results. New guidelines also standardize the interval for screening, with women aged 25–50 offered screening every 3 years and women aged 50–64 every 5 years. Quantitative evidence on the preferences of women for alternative screening programs is limited; this study, therefore, elicits such preferences.Methods: A postal questionnaire using a discrete choice experiment was mailed to 2,000 women in the Tayside Health Board region of Scotland.Results: A response rate of 44 percent from those women who had previously had a smear was achieved. Women had a significant positive preference for reductions in recall rates and waiting time for results. Women preferred more frequent screening, particularly those aged 50+. Expected reductions in the chance of recall from the conventional Pap smear to the new liquid-based cytology were associated with a willingness to pay of £41. Women aged 50+ would be willing to pay £42 to increase the frequency of screening from every 5 to every 3 years. Service characteristics did not influence screening participation.Conclusions: Guidance to move to liquid-based cytology will meet women's preferences for fewer repeat cervical smears and should reduce waiting time for results. However, proposals to increase screening intervals for those aged 50+ are inconsistent with the preferences for this age group. From a policy perspective, our study results suggest that the changes in attributes of the service such as unsatisfactory smear rates and frequency of screening, will improve service efficiency without affecting participation rates.

© The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. STUDY QUESTION: What is the impact of different age and BMI groups on total investigation and treatment costs in women attending a secondary/tertiary care fertility clinic? summary answer: Women in their early to mid-30s and women with normal BMI had higher cumulative investigation and treatment costs, but also higher probability of live birth. WHAT IS KNOWN ALREADY: Female age and BMI have been used as criteriafor rationing publically funded fertility treatments. Populationbased data on the costs of investigating and treating infertility are lacking. study design, size an d duration: A retrospective cohort study of 2463 women was conducted in a single secondary/tertiary care fertility clinic in Aberdeen, Scotland from 1998 to 2008. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants included all women living in a defined geographical area referred from primary care to a specialized fertility clinic over an 11-year period. Women were followed up for 5 years or until live birth if this occurred sooner. Mean discounted cumulative National Health Service costs (expressed in 2010/2011 GBP) offertility investigations, treatments (including all types of assisted reproduction), and pregnancy (including delivery episode) and neonatal admissions were calculated and summarized by age ( 35.00kg/m). Further multivariate modelling was carried out to estimate the impact of age and BMI on investigation and treatment costs and live birth outcome, adjusting for covariates predictive of the treatment pathway and live birth. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 2463 women referred, 1258 (51.1%) had a live birth within 5 years, with 694 (55.1%) of these being natural conceptions. The live birth rate was highest among women in the youngest age group (64.3%), and lowest in those aged.40 years (13.4%). Overall live birth rates were generally lower in women with BMI.30 kg/m.The total costs of investigations were generally highest among women younger than 30 years (£491 in those with normal BMI),whilsttreatmentcoststendedtobehigherin31-35 year olds (£1,840 in those with normal BMI). Multivariate modelling predicted a cost increase associated with treatment which was highest among women in the lowest BMI group (across all ages), and also highest among women aged 31-35 years. The increase in the predicted probability of live birth with exposure to treatment was consistent across age and BMI categories (∼ 10%), except in the oldest age group where a slightly smaller increase in the probability of live birth was observed. The ratio of increased costs to the increased probability of live birth in women who were treated increased markedly in women over the age of 40 years, but tended to fall as BMI increased within all age groups. limitations and reason for caution: Our results, based on retrospective observational data from a single centre, have limited generalizability and are not free from clinician and clinic selection bias which can influence the choice of treatments as well as their costs. WIDER IMPLICATIONS OF THE FINDINGS: Spontaneous live birth rates were particularly high in younger women with unexplained infertility, suggesting that expectant management is a reasonable option in this group. The policy of not over-investigating older women and offering early treatment where appropriate still incurred the highest costs per additional live birth associated with treatment, owing to the lower probability of treatment success. The increased additional cost for each live birth associated with treatment for women with decreasing BMI across all age groups, suggests that it may be possible to identify a more targeted approach to treatment. STUDY FUNDING/COMPETING INTEREST(S): This study was partly funded by an NHS endowment grant (Grant Number 12/48) and D.J.M. by a Chief Scientist Office Postdoctoral Fellowship (Ref PDF/12/06). There are no conflicts of interest to declare.

Objective To assess the incremental cost and costeffectiveness of continuous and discontinuous regimens of bevacizumab (Avastin) and ranibizumab (Lucentis) for neovascular age-related macular degeneration (nAMD) from a UK National Health Service (NHS) perspective. Design A within-trial cost-utility analysis with a 2-year time horizon, based on a multicentre factorial, noninferiority randomised controlled trial. Setting 23 hospital ophthalmology clinics. Participants 610 patients aged ≥50 years with untreated nAMD in the study eye. Interventions 0.5 mg ranibizumab or 1.25 mg bevacizumab given continuously (monthly) or discontinuously (as-needed) for 2 years. Main outcome measures Quality-adjusted life-years (QALYs). Results Total 2-year costs ranged from £3002/patient ($4700; 95% CI £2601 to £3403) for discontinuous bevacizumab to £18 590/patient ($29 106; 95% CI £18 258 to £18 922) for continuous ranibizumab. Ranibizumab was significantly more costly than bevacizumab for both continuous (+£14 989/patient ($23 468); 95% CI £14 522 to £15 456; p Conclusions Ranibizumab is not cost-effective compared with bevacizumab, being substantially more costly and producing little or no QALY gain. Discontinuous bevacizumab is likely to be the most cost-effective of the four treatment strategies evaluated in this UK trial, although there is a 37% chance that continuous bevacizumab is cost-effective.

Several countries include medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, a rare autosomal recessive disease, in their newborn screening programmes despite prevalence uncertainty. We estimated the frequency of its most common mutation, c.985A>G, tested for regional differences and compared screening and genotype frequencies. We identified 43 studies reporting the frequency of c.985A>G over 10 million individuals, and pooled frequency data using a novel Bayesian approach. We found significant variation in the frequency of the mutation across regions supporting a reported founder effect. The proportion of c.985A>G homozygotes was highest in Western Europe with 4.1 (95%CI: 2.8-5.6) per 100,000 individuals, then the New World (3.2, 95%CI: 2.0-4.7), Southern (1.2, 95%CI: 0.6-2.0) and Eastern European regions (0.9, 95%CI: 0.5-1.7). No cases with the mutation were identified in Asian and Middle Eastern regions. Significant differences were found in some countries between the genotype and screening allele frequency of c.985A>G. Our predictions could inform the frequency of the mutation by region and our approach could apply to other genetic conditions. © 2013 John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.

Costs and benefits of cervical screening IV: valuation by women of the cervical screening programme Objectives: To assess the value of the cervical smear test to women, taking account of the positive and negative aspects of the cervical screening service. Design: A postal survey. Setting: Tayside Health Board region of Scotland. Participants: A sample of 2000 women aged 20–59. Main outcome measures: Maximum willingness to pay (WTP) for a cervical smear test. Results: Women were prepared to pay £50.20 per smear on a 3-yearly basis. Willingness to pay was positively related to income, but unrelated to age and whether or not the respondent had previously had a smear. Conclusions: Previous studies have estimated the cost per screen or cost per life year saved by cervical screening. This study used the economic instrument of WTP to take account of other potential (dis)benefits to women. The value women place on having a smear was more than the cost to the National Health Service (NHS) of providing the service. The output of a WTP study is potentially useful at the policy level. Future work should explore both the value of alternative approaches to cervical screening, and the value of competing health care interventions.

Genomic interventions could enable improved disease stratification and individually tailored therapies. However, they have had a limited impact on clinical practice to date due to a lack of evidence, particularly economic evidence. This is partly because health economists are yet to reach consensus on whether existing methods are sufficient to evaluate genomic technologies. As different approaches may produce conflicting adoption decisions, clarification is urgently required. This article summarizes the methodological issues associated with conducting economic evaluations of genomic interventions.A structured literature review was conducted to identify references that considered the methodological challenges faced when conducting economic evaluations of genomic interventions.Methodological challenges related to the analytical approach included the choice of comparator, perspective and timeframe. Challenges in costing centered around the need to collect a broad range of costs, frequently, in a data-limited environment. Measuring outcomes is problematic as standard measures have limited applicability, however, alternative metrics (e.g., personal utility) are underdeveloped and alternative approaches (e.g., cost-benefit analysis) underused. Effectiveness data quality is weak and challenging to incorporate into standard economic analyses, while little is known about patient and clinician behavior in this context. Comprehensive value of information analyses are likely to be helpful.Economic evaluations of genomic technologies present a particular challenge for health economists. New methods may be required to resolve these issues, but the evidence to justify alternative approaches is yet to be produced. This should be the focus of future work in this field.

Background: Bevacizumab has been suggested to have similar effectiveness to ranibizumab for treatment of neovascular age-related macular degeneration. The Inhibition of VEGF in Age-related choroidal Neovascularisation (IVAN) trial was designed to compare these drugs and different regimens. Here, we report the findings at the prespecified 2-year timepoint. Methods: In a multicentre, 2×2 factorial, non-inferiority randomised trial, we enrolled adults aged at least 50 years with active, previously untreated neovascular age-related macular degeneration and a best corrected distance visual acuity (BCVA) of at least 25 letters from 23 hospitals in the UK. Participants were randomly assigned (1:1:1:1) to intravitreal injections of ranibizumab (0·5 mg) or bevacizumab (1·25 mg) in continuous (every month) or discontinuous (as needed) regimens, with monthly review. Study participants and clinical assessors were masked to drug allocation. Allocation to continuous or discontinuous treatment was masked up to 3 months, at which point investigators and participants were unmasked. The primary outcome was BCVA at 2 years, with a prespecified non-inferiority limit of 3·5 letters. The primary safety outcome was arterial thrombotic event or hospital admission for heart failure. Analyses were by modified intention to treat. This trial is registered, number ISRCTN92166560. Findings: Between March 27, 2008, and Oct 15, 2010, 628 patients underwent randomisation. 18 were withdrawn; 610 received study drugs (314 ranibizumab; 296 bevacizumab) and were included in analyses. 525 participants reached the visit at 2 years: 134 ranibizumab in continuous regimen, 137 ranibizumab in discontinuous regimen, 127 bevacizumab in continuous regimen, and 127 bevacizumab in discontinuous regimen. For BCVA, bevacizumab was neither non-inferior nor inferior to ranibizumab (mean difference -1·37 letters, 95% CI -3·75 to 1·01; p=0·26). Discontinuous treatment was neither non-inferior nor inferior to continuous treatment (-1·63 letters, -4·01 to 0·75; p=0·18). Frequency of arterial thrombotic events or hospital admission for heart failure did not differ between groups given ranibizumab (20 [6%] of 314 participants) and bevacizumab (12 [4%] of 296; odds ratio [OR] 1·69, 95% CI 0·80-3·57; p=0·16), or those given continuous (12 [4%] of 308) and discontinuous treatment (20 [7%] of 302; 0·56, 0·27-1·19; p=0·13). Mortality was lower with continuous than discontinuous treatment (OR 0·47, 95% CI 0·22-1·03; p=0·05), but did not differ by drug group (0·96, 0·46-2·02; p=0·91). Interpretation: Ranibizumab and bevacizumab have similar efficacy. Reduction in the frequency of retreatment resulted in a small loss of efficacy irrespective of drug. Safety was worse when treatment was administered discontinuously. These findings highlight that the choice of anti-VEGF treatment strategy is less straightforward than previously thought. Funding: UK National Institute for Health Research Health Technology Assessment programme. © 2013 Chakravarthy et al. Open Access article distributed under the terms of CC BY-NC-SA.

Background Bariatric and metabolic surgery is used as a treatment for patients with severe and complex obesity. However, there is a need to improve outcome selection and reporting in bariatric surgery trials. A Core Outcome Set (COS), an agreed minimum set of outcomes reported in all studies of a specific condition, may achieve this. Here, we present the development of a COS for BARIAtric and metabolic surgery Clinical Trials—the BARIACT Study. Methods and Findings Outcomes identified from systematic reviews and patient interviews informed a questionnaire survey. Patients and health professionals were surveyed three times and asked to rate the importance of each item on a 1–9 scale. Delphi methods provided anonymised feedback to participants. Items not meeting predefined criteria were discarded between rounds. Remaining items were discussed at consensus meetings, held separately with patients and professionals, where the COS was agreed. Data sources identified 2,990 outcomes, which were used to develop a 130-item questionnaire. Round 1 response rates were moderate but subsequently improved to above 75% for other rounds. After rounds 2 and 3, 81 and 14 items were discarded, respectively, leaving 35 items for discussion at consensus meetings. The final COS included nine items: “weight,” “diabetes status,” “cardiovascular risk,” “overall quality of life (QOL),” “mortality,” “technical complications of the specific operation,” “any re-operation/re-intervention,” “dysphagia/regurgitation,” and “micronutrient status.” The main limitation of this study was that it was based in the United Kingdom only. Conclusions The COS is recommended to be used as a minimum in all trials of bariatric and metabolic surgery. Adoption of the COS will improve data synthesis and the value of research data. Future work will establish methods for the measurement of the outcomes in the COS., Karen Coulman and colleagues present a core outcome set developed by patients and health professionals for BARIAtric and metabolic surgery Clinical Trials (BARIACT).