Molecular testing for Lynch syndrome in people with colorectal cancer: systematic reviews and economic evaluation

This is the final version of the article. Available from the publisher via the DOI in this record.BACKGROUND: Inherited mutations in deoxyribonucleic acid (DNA) mismatch repair (MMR) genes lead to an increased risk of colorectal cancer (CRC), gynaecological cancers and other cancers, known as Lynch syndrome (LS). Risk-reducing interventions can be offered to individuals with known LS-causing mutations. The mutations can be identified by comprehensive testing of the MMR genes, but this would be prohibitively expensive in the general population. Tumour-based tests - microsatellite instability (MSI) and MMR immunohistochemistry (IHC) - are used in CRC patients to identify individuals at high risk of LS for genetic testing. MLH1 (MutL homologue 1) promoter methylation and BRAF V600E testing can be conducted on tumour material to rule out certain sporadic cancers. OBJECTIVES: To investigate whether testing for LS in CRC patients using MSI or IHC (with or without MLH1 promoter methylation testing and BRAF V600E testing) is clinically effective (in terms of identifying Lynch syndrome and improving outcomes for patients) and represents a cost-effective use of NHS resources. REVIEW METHODS: Systematic reviews were conducted of the published literature on diagnostic test accuracy studies of MSI and/or IHC testing for LS, end-to-end studies of screening for LS in CRC patients and economic evaluations of screening for LS in CRC patients. A model-based economic evaluation was conducted to extrapolate long-term outcomes from the results of the diagnostic test accuracy review. The model was extended from a model previously developed by the authors. RESULTS: Ten studies were identified that evaluated the diagnostic test accuracy of MSI and/or IHC testing for identifying LS in CRC patients. For MSI testing, sensitivity ranged from 66.7% to 100.0% and specificity ranged from 61.1% to 92.5%. For IHC, sensitivity ranged from 80.8% to 100.0% and specificity ranged from 80.5% to 91.9%. When tumours showing low levels of MSI were treated as a positive result, the sensitivity of MSI testing increased but specificity fell. No end-to-end studies of screening for LS in CRC patients were identified. Nine economic evaluations of screening for LS in CRC were identified. None of the included studies fully matched the decision problem and hence a new economic evaluation was required. The base-case results in the economic evaluation suggest that screening for LS in CRC patients using IHC, BRAF V600E and MLH1 promoter methylation testing would be cost-effective at a threshold of £20,000 per quality-adjusted life-year (QALY). The incremental cost-effectiveness ratio for this strategy was £11,008 per QALY compared with no screening. Screening without tumour tests is not predicted to be cost-effective. LIMITATIONS: Most of the diagnostic test accuracy studies identified were rated as having a risk of bias or were conducted in unrepresentative samples. There was no direct evidence that screening improves long-term outcomes. No probabilistic sensitivity analysis was conducted. CONCLUSIONS: Systematic review evidence suggests that MSI- and IHC-based testing can be used to identify LS in CRC patients, although there was heterogeneity in the methods used in the studies identified and the results of the studies. There was no high-quality empirical evidence that screening improves long-term outcomes and so an evidence linkage approach using modelling was necessary. Key determinants of whether or not screening is cost-effective are the accuracy of tumour-based tests, CRC risk without surveillance, the number of relatives identified for cascade testing, colonoscopic surveillance effectiveness and the acceptance of genetic testing. Future work should investigate screening for more causes of hereditary CRC and screening for LS in endometrial cancer patients. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016033879. FUNDING: The National Institute for Health Research Health Technology Assessment programme.Funding for this study was provided by the Health Technology Assessment programme of the National Institute for Health Researc

Are prices of new dwellings different? A spectral analysis of UK property vintages

The work makes two contributions to Hui’s (2011) dynamic house price classification. First, a house price ripple in cycles from Modern to Older dwellings is revealed and, second, as New housing is shown to have lower volatility than the other two. Using spectral analysis, it is argued that there is a 7½-year repeat buyer-second-hand cycle and a five year, first time buyer-New housing cycle, common to three house price vintages. These cycles reinforce each other every fifteen years, which corresponds with a Minsky super-cycle in housing finance. The equity of the owner-occupier is fortified by higher house prices whereas new builds extract embedded equity from the market. Government should support builders and facilitate access to market to first time buyers and through programmes like Help-to-Buy 1. However, to address the greater price instability that should follow, Government should impose a capital gains tax on the house seller

The changing nature of labour regulation: the distinctiveness of the National Agreement for the Engineering Construction Industry

The article addresses the changing nature of labour regulation through analysis of the National Agreement for the Engineering Construction Industry, originating in 1981. It shows how multiple spatial regulatory scales, the changing coalitions of actors involved, employer and client engagement and labour agency have been critical to National Agreement for the Engineering Construction Industry's survival

Poor numeracy skills are associated with glycaemic control in Type 1 diabetes.

To assess the numeracy and literacy skills of individuals with Type 1 diabetes and determine if there is a relationship with achieved glycaemic control independent of their duration of diabetes, diabetes education, demographic and socio-economic factors

Exclusionary employment in Britain’s broken labour market

There is growing evidence of the problematic nature of the UK’s ‘flexible labour market’ with rising levels of in-work poverty and insecurity. Yet successive Governments have stressed that paid work is the route to inclusion, focussing attention on the divide between employed and unemployed. Past efforts to measure social exclusion have tended to make the same distinction. The aim of this paper is to apply Levitas et al’s (2007) framework to assess levels of exclusionary employment, i.e. exclusion arising directly from an individual’s labour market situation. Using data from the Poverty and Social Exclusion UK survey, results show that one in three adults in paid work is in poverty, or in insecure or poor quality employment. One third of this group have not seen any progression in their labour market situation in the last five years. The policy focus needs to shift from ‘Broken Britain’ to Britain’s broken labour market

Putting victims first? : a critique of Coalition anti-social behaviour policy

Anti-social behaviour (ASB) policy was not pursued by the Conservative–Liberal Democrat Coalition government with the same vigour as their New Labour predecessors. Where developments did take place a clear shift in emphasis was apparent, with the needs of ASB victims elevated to the forefront of policy. This article critically appraises two major developments that showcase the Coalition government’s attempts to overhaul ASB policy to ‘put victims first’, namely: the changes to call handling and case management processes, and the Community Trigger, which forces the authorities to review their responses to complaints of ASB in circumstances where victims feel they have been ignored. These particular policies aim to prioritise victims’ needs; however, it is argued the new victim-focus: is diluted by competing Coalition ASB agendas, demonstrates little connection between rhetoric and reality, provides limited redress for all victims and fails to coalesce with established attempts to tackle perpetrators of ASB

Self-reported knowledge, correct knowledge and use of UK drinking guidelines among a representative sample of the English population

Aims: Promotion of lower risk drinking guidelines is a commonly used public health intervention with various purposes, including communicating alcohol consumption risks, informing drinkers' decision-making and, potentially, changing behaviour. UK drinking guidelines were revised in 2016. To inform potential promotion of the new guidelines, we aimed to examine public knowledge and use of the previous drinking guidelines, including by population subgroup. Methods: A demographically representative, cross-sectional online survey of 2100 adults living in England in July 2015 (i.e. two decades after adoption of previous guidelines and prior to introduction of new guidelines). Univariate and multivariate logistic regressions examined associations between demographic variables, alcohol consumption (AUDIT-C), smoking, and knowledge of health conditions and self-reported knowledge and use of drinking guidelines. Multinomial logistic regression examined the same set of variables in relation to accurate knowledge of drinking guidelines (underestimation, accurate-estimation, overestimation). Results: In total, 37.8% of drinkers self-reported knowing their own-gender drinking guideline, of whom 66.2% gave an accurate estimate. Compared to accurate estimation, underestimation was associated with male gender, lower education and AUDIT-C score, while overestimation was associated with smoking. Few (20.8%) reported using guidelines to monitor drinking at least sometimes. Drinking guideline use was associated with higher education, overestimating guidelines and lower AUDIT-C. Correctly endorsing a greater number of health conditions as alcohol-related was associated with self-reported knowledge of guidelines, but was not consistently associated with accurate estimation or use to monitor drinking. Conclusions: Two decades after their introduction, previous UK drinking guidelines were not well known or used by current drinkers. Those who reported using them tended to overestimate recommended daily limits. SHORT SUMMARY: We examined public knowledge and use of UK drinking guidelines just before new guidelines were released (2016). Despite previous guidelines being in place for two decades, only one in four drinkers accurately estimated these, with even fewer using guidelines to monitor drinking. Approximately 8% of drinkers overestimated maximum daily limits

Brexit: human resourcing implications

Purpose: Three years on from the Brexit vote, while it remains a central topic for debate in the media, there has been limited discussion about the human resource (HR) implications. The purpose of this paper is to provide theoretical evaluation and informed discussion, distilled into four interconnected propositions, on how employee resourcing as a HR practice may be impacted following actual Brexit decisions. Design/methodology/approach: Drawing on the employee resourcing literature, the paper adopts a discursive approach which examines how the UK’s decision to exit the European Union will affect HR practice. The paper draws comparison with the global recession since 2008, a similarly unprecedented development in its discussion of employee resourcing practices and draws parallels which may help to inform the future of HR practices in the UK, because of Brexit. Findings: This paper offers a set of propositions; the flow of talent into the UK may become more restricted and reinvigorate the “war for talent” that followed the effects of the global financial crisis on the UK. To attract and retain workers in relatively lower-skilled roles, employers may be faced with a need to re-skill such roles and adopt more flexible working arrangements. Finally, to meet skilled employment requirements, removal of restrictions to recruit from within the European Economic Area may trigger increased global migration of skilled workers. Originality/value: This paper contributes to the discussions regarding the implications of Brexit for HR practice by offering propositions to shape future research agendas

New national alcohol guidelines in the UK: public awareness, understanding and behavioural intentions

Background: Alcohol consumption places a significant burden on the NHS and is an important risk factor for cancer, associated with 12 800 UK cases/year. New alcohol guidelines were published in 2016, taking into account the increasing evidence of the health harms of alcohol. Methods: A survey of the UK drinker population (n = 972) was conducted 1 week before and 1 month after the release of the guidelines to capture drinking habits, guideline awareness and intended behaviour change. Results: Overall, 71% were aware of the new alcohol guidelines, however, just 8% knew what the recommended limits were. Higher socioeconomic groups were more likely to know these limits (ABC1 = 9% versus C2DE = 4%, P = 0.009). Participants who recognized the message that alcohol causes cancer were more likely to correctly identify the new guidelines (message recognition = 12% versus no recognition = 6%, P = 0.004); and were more likely to self-report an intention to reduce their alcohol consumption (message recognition = 10% versus no recognition = 6%, P = 0.01). Conclusion: The majority of the population knew the guidelines had been updated, however, communication of the new limits needs to be improved. Raising awareness of the links between alcohol and cancer may improve understanding of alcohol guidelines and could prompt behaviour change for those motivated to reduce their alcohol consumption

An observational study of Donor Ex Vivo Lung Perfusion in UK lung transplantation: DEVELOP-UK

Background: Many patients awaiting lung transplantation die before a donor organ becomes available. Ex vivo lung perfusion (EVLP) allows initially unusable donor lungs to be assessed and reconditioned for clinical use. Objective: The objective of the Donor Ex Vivo Lung Perfusion in UK lung transplantation study was to evaluate the clinical effectiveness and cost-effectiveness of EVLP in increasing UK lung transplant activity. Design: A multicentre, unblinded, non-randomised, non-inferiority observational study to compare transplant outcomes between EVLP-assessed and standard donor lungs. Setting: Multicentre study involving all five UK officially designated NHS adult lung transplant centres. Participants: Patients aged ≥ 18 years with advanced lung disease accepted onto the lung transplant waiting list. Intervention: The study intervention was EVLP assessment of donor lungs before determining suitability for transplantation. Main outcome measures: The primary outcome measure was survival during the first 12 months following lung transplantation. Secondary outcome measures were patient-centred outcomes that are influenced by the effectiveness of lung transplantation and that contribute to the health-care costs. Results: Lungs from 53 donors unsuitable for standard transplant were assessed with EVLP, of which 18 (34%) were subsequently transplanted. A total of 184 participants received standard donor lungs. Owing to the early closure of the study, a non-inferiority analysis was not conducted. The Kaplan–Meier estimate of survival at 12 months was 0.67 [95% confidence interval (CI) 0.40 to 0.83] for the EVLP arm and 0.80 (95% CI 0.74 to 0.85) for the standard arm. The hazard ratio for overall 12-month survival in the EVLP arm relative to the standard arm was 1.96 (95% CI 0.83 to 4.67). Patients in the EVLP arm required ventilation for a longer period and stayed longer in an intensive therapy unit (ITU) than patients in the standard arm, but duration of overall hospital stay was similar in both groups. There was a higher rate of very early grade 3 primary graft dysfunction (PGD) in the EVLP arm, but rates of PGD did not differ between groups after 72 hours. The requirement for extracorporeal membrane oxygenation (ECMO) support was higher in the EVLP arm (7/18, 38.8%) than in the standard arm (6/184, 3.2%). There were no major differences in rates of chest radiograph abnormalities, infection, lung function or rejection by 12 months. The cost of EVLP transplants is approximately £35,000 higher than the cost of standard transplants, as a result of the cost of the EVLP procedure, and the increased ECMO use and ITU stay. Predictors of cost were quality of life on joining the waiting list, type of transplant and number of lungs transplanted. An exploratory model comparing a NHS lung transplant service that includes EVLP and standard lung transplants with one including only standard lung transplants resulted in an incremental cost-effectiveness ratio of £73,000. Interviews showed that patients had a good understanding of the need for, and the processes of, EVLP. If EVLP can increase the number of usable donor lungs and reduce waiting, it is likely to be acceptable to those waiting for lung transplantation. Study limitations include small numbers in the EVLP arm, limiting analysis to descriptive statistics and the EVLP protocol change during the study. Conclusions: Overall, one-third of donor lungs subjected to EVLP were deemed suitable for transplant. Estimated survival over 12 months was lower than in the standard group, but the data were also consistent with no difference in survival between groups. Patients receiving these additional transplants experience a higher rate of early graft injury and need for unplanned ECMO support, at increased cost. The small number of participants in the EVLP arm because of early study termination limits the robustness of these conclusions. The reason for the increased PGD rates, high ECMO requirement and possible differences in lung injury between EVLP protocols needs evaluation