A new method for model-based health economic evaluation utilising and extending moment-generating functions

This is the author accepted manuscript. The final version is available from SAGE Publications via the DOI in this record.The dataset associated with this article is located in ORE at: https://doi.org/10.24378/exe.643Background Health economic evaluations frequently include projections for lifetime costs and health effects using modelling frameworks such as Markov modelling or discrete event simulation (DES). Markov models typically cannot represent events whose risk is determined by the length of time spent in state (sojourn time) without the use of tunnel states. DES is very flexible, but introduces Monte Carlo variation which can significantly limit the complexity of model analyses. Methods We present a new methodological framework for health economic modelling which is based on, and extends, the concept of moment-generating functions (MGFs) for time-to-event random variables. When future costs and health effects are discounted, MGFs can be used to very efficiently calculate the total discounted life years spent in a series of health states. Competing risks are incorporated into the method. This method can also be used to calculate discounted costs and health effects when these payoffs are constant per unit time, one-off or exponential with regard to time. MGFs are extended to additionally support costs and health effects which are polynomial with regard to time (as in a commonly used model of population norms for EQ-5D utility). Worked example A worked example is used to demonstrate application of the new method in practice, and to compare it to Markov modelling and DES. Results are compared in terms of convergence and accuracy, and computation times are compared. R code and an Excel workbook are provided. Conclusions The MGF method can be applied to health economic evaluations in the place of Markov modelling or DES and has certain advantages over both

Development of theory-based health messages: three-phase programme of formative research

Online health behaviour interventions have great potential but their effectiveness may be hindered by a lack of formative and theoretical work. This paper describes the process of formative research to develop theoretically and empirically based health messages that are culturally relevant and can be used in an online intervention to promote healthy lifestyle behaviours among new university students. Drawing on the Theory of Planned Behaviour, a three-phase programme of formative research was conducted with prospective and current undergraduate students to identify (i) modal salient beliefs (the most commonly held beliefs) about fruit and vegetable intake, physical activity, binge drinking and smoking, (ii) which beliefs predicted intentions/behaviour and (iii) reasons underlying each of the beliefs that could be targeted in health messages. Phase 1, conducted with 96 pre-university college students, elicited 56 beliefs about the behaviours. Phase 2, conducted with 3026 incoming university students, identified 32 of these beliefs that predicted intentions/behaviour. Phase 3, conducted with 627 current university students, elicited 102 reasons underlying the 32 beliefs to be used to construct health messages to bolster or challenge these beliefs. The three-phase programme of formative research provides researchers with an example of how to develop health messages with a strong theoretical- and empirical base for use in health behaviour change interventions

Cost-effectiveness of the Manchester approach to identifying Lynch syndrome in women with endometrial cancer

This is the final version. Available on open access from MDPI via the DOI in this recordLynch syndrome (LS) is a hereditary cancer syndrome responsible for 3% of all endometrial cancer and 5% in those aged under 70 years. It is unclear whether universal testing for LS in endometrial cancer patients would be cost-effective. The Manchester approach to identifying LS in endometrial cancer patients uses immunohistochemistry (IHC) to detect mismatch repair (MMR) deficiency, incorporates testing for MLH1 promoter hypermethylation, and genetic testing for pathogenic MMR variants. We aimed to assess the cost-effectiveness of the Manchester approach based on primary research data from clinical practice in Manchester. The PETALS study informed estimates of diagnostic performances for a number of different strategies. A recent microcosting study was adapted and used to estimate diagnostic costs. A Markov model was used to predict long-term costs and health outcomes (measured in quality-adjusted life years, QALYs) for individuals and their relatives. Bootstrapping and probabilistic sensitivity analysis were used to estimate the uncertainty in cost-effectiveness. The Manchester approach dominated other reflex testing strategies when considering diagnostic costs and Lynch syndrome cases identified. When considering long-term costs and QALYs the Manchester approach was the optimal strategy, costing £5459 per QALY gained (compared to thresholds of £20,000 to £30,000 per QALY commonly used in the NHS). Cost-effectiveness is not an argument for restricting testing to younger patients or those with a strong family history. Universal testing for Lynch syndrome in endometrial cancer patients is expected to be cost-effective in the UK NHS, and the Manchester approach is expected to be the optimal testing strategy.Medical Research Council (MRC)National Institute for Health Research (NIHR

A Tomato of the Floating World: Assembling Inle Lake's Cultural Ecology

This thesis offers an object-oriented ethnography of Inle Lake's floating tomatoes. Based on 18 months of ethnographic fieldwork and using the theoretical and methodological framework of assemblage, I investigate the relationship between the Inle tomato and the wider cultural ecology of Inle Lake. I focus on what the tomato reveals about the networks and relations that constitute the social, ecological, economic and political landscapes of Inle Lake. I argue that the tomato-assemblage is a complex configuration of precariously held together ecological, sociocultural, political and economic relations that are constituted by interactions between environments, markets, technologies, knowledges and power. I suggest that following the tomato-assemblage and its entanglements denaturalizes superficial perceptions of a "less-than-human" nature and reimagines a cultural ecology of Inle Lake that is shaped by contestation. I make the tomato-assemblage visible from a variety of vantage points that highlight how the overall configuration is brought into being and how there are often differing perspectives of connection and disconnect dependent on subject position. These vantage points explore the tomato as a material and symbolic linkage to ethnic territory; an attraction within the regional economy of tourism; a system of labour; a commodity valued in affective ways; a product of agricultural biotechnology; and an environmental threat. By ethnographically exploring the tensions involved in how this assemblage is held together I demonstrate that the cultural ecology of Inle Lake is not fixed, nor stable, but rather contingent on its parts and the ways in which they interact with each other. This research has implications for not only ongoing theoretical debates around the importance of centering the non-human in anthropological studies of human society and culture, but also for opening up alternative approaches to understanding topics of ethnicity, economy and ecology in Myanmar

Methods for modelling the cost-effectiveness of interventions for prostate cancer: a systematic review - Protocol

This is a protocol for a systematic review of methods for modelling the cost-effectiveness of interventions for prostate cancer. It will aim to identify and bring together all health economic modelling studies in prostate cancer, to inform the subsequent development of a whole disease model for prostate cancer. This protocol is being deposited prospectively. The following review activities have been completed at the time of depositing: Bibliographic database search strategies designed (MEDLINE, Embase, NHSEED, HTA) Bibliographic database searches conducted and results combined into an EndNote library prepared for screening Random sample of 100 citations selected for pilot screening No further review activities have been initiated or completed at time of depositing

A systematic review and economic evaluation of intraoperative tests [RD-100i one-step nucleic acid amplification (OSNA) system and Metasin test] for detecting sentinel lymph node metastases in breast cancer.

This is the final version of the review. Available from NIHR via the DOI in this record.BACKGROUND: In breast cancer patients, sentinel lymph node biopsy is carried out at the same time as the removal of the primary tumour to postoperatively test with histopathology for regional metastases in the sentinel lymph node. Those patients with positive test results are then operated on 2-4 weeks after primary surgery to remove the lymph nodes from the axilla (axillary lymph node dissection, ALND). New molecular tests RD-100i [one-step nucleic acid amplification (OSNA); based on messenger RNA amplification to identify the cytokeratin-19 (CK19) gene marker] (Sysmex, Norderstedt, Germany) and Metasin (using the CK19 and mammaglobin gene markers) (Cellular Pathology, Princess Alexandra Hospital NHS Trust, Harlow, UK) are intended to provide an intraoperative diagnosis, thereby avoiding the need for postoperative histopathology and, in positive cases, a second operation for ALND. OBJECTIVE: To evaluate the clinical effectiveness and cost-effectiveness of using OSNA and Metasin in the NHS in England for the intraoperative diagnosis of sentinel lymph nodes metastases, compared with postoperative histopathology, the current standard. DATA SOURCES: Electronic databases including MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, The Cochrane Library and the Health Economic Evaluations Database as well as clinical trial registries, grey literature and conference proceedings were searched up to July 2012. REVIEW METHODS: A systematic review of the evidence was carried out using standard methods. Single-gate studies were used to estimate the accuracy of OSNA with histopathology as the reference standard. The cost-effectiveness analysis adapted an existing simulation model of the long-term costs and health implications of early breast cancer diagnostic outcomes. The model accounted for the costs of an extended first operation with intraoperative testing, the loss of health-related quality of life (disutility) from waiting for postoperative test results, disutility and costs of a second operation, and long-term costs and disutility from lymphoedema related to ALND, adjuvant therapy, locoregional recurrence and metastatic recurrence. RESULTS: A total of 724 references were identified in the searches, of which 17 studies assessing test accuracy were included in the review, 15 on OSNA and two on Metasin. Both Metasin studies were unpublished. OSNA sensitivity of 84.5% [95% confidence interval (CI) 74.7% to 91.0%] and specificity of 91.8% (95% CI 87.8% to 94.6%) for patient nodal status were estimated in a meta-analysis of five studies [unadjusted for tissue allocation bias (TAB)]. At these values and a 20% node-positive rate, OSNA resulted in lifetime discounted cost-savings of £498 and a quality-adjusted life-year (QALY) loss of 0.048 relative to histopathology, that is, £4324 saved per QALY lost. The most favourable plausible scenario for OSNA in terms of the node-positive rate (range 10-40%), diagnostic accuracy values (91.3% sensitivity and 94.2% specificity, from three reports that adjusted for TAB), the costs of histopathology, OSNA and second surgery, and long-term costs and utilities resulted in a maximum saving per QALY lost of £10,500; OSNA sensitivity and specificity would need to be ≥ 95% for this figure to be ≥ £20,000. LIMITATIONS: There is limited evidence on the diagnostic test accuracy of intraoperative tests. The quality of information on costs of resource utilisation during the diagnostic pathway is low and no evidence exists on the disutility of waiting for a second surgery. No comparative studies exist that report clinical outcomes of intraoperative diagnostic tests. These knowledge gaps have more influence on the decision than current uncertainty in the performance of postoperative histopathology in standard practice. CONCLUSIONS: One-step nucleic acid amplification is not cost-effective for the intraoperative diagnosis of sentinel lymph node metastases. OSNA is less accurate than histopathology and the consequent loss of health benefits in this patient group is not compensated for by health gains elsewhere in the health system that may be obtained with the cost-savings made. The evidence on Metasin is insufficient to evaluate its cost-effectiveness. STUDY REGISTRATION: This study is registered as PROSPERO CRD42012002889. FUNDING: The National Institute for Health Research Health Technology Assessment programme

A model-based assessment of the cost-utility of strategies to identify Lynch syndrome in early-onset colorectal cancer patients.

This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this record.BACKGROUND: Lynch syndrome is an autosomal dominant cancer predisposition syndrome caused by mutations in the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2. Individuals with Lynch syndrome have an increased risk of colorectal cancer, endometrial cancer, ovarian and other cancers. Lynch syndrome remains underdiagnosed in the UK. Reflex testing for Lynch syndrome in early-onset colorectal cancer patients is proposed as a method to identify more families affected by Lynch syndrome and offer surveillance to reduce cancer risks, although cost-effectiveness is viewed as a barrier to implementation. The objective of this project was to estimate the cost-utility of strategies to identify Lynch syndrome in individuals with early-onset colorectal cancer in the NHS. METHODS: A decision analytic model was developed which simulated diagnostic and long-term outcomes over a lifetime horizon for colorectal cancer patients with and without Lynch syndrome and for relatives of those patients. Nine diagnostic strategies were modelled which included microsatellite instability (MSI) testing, immunohistochemistry (IHC), BRAF mutation testing (methylation testing in a scenario analysis), diagnostic mutation testing and Amsterdam II criteria. Biennial colonoscopic surveillance was included for individuals diagnosed with Lynch syndrome and accepting surveillance. Prophylactic hysterectomy with bilateral salpingo-oophorectomy (H-BSO) was similarly included for women diagnosed with Lynch syndrome. Costs from NHS and Personal Social Services perspective and quality-adjusted life years (QALYs) were estimated and discounted at 3.5% per annum. RESULTS: All strategies included for the identification of Lynch syndrome were cost-effective versus no testing. The strategy with the greatest net health benefit was MSI followed by BRAF followed by diagnostic genetic testing, costing £5,491 per QALY gained over no testing. The effect of prophylactic H-BSO on health-related quality of life (HRQoL) is uncertain and could outweigh the health benefits of testing, resulting in overall QALY loss. CONCLUSIONS: Reflex testing for Lynch syndrome in early-onset colorectal cancer patients is predicted to be a cost-effective use of limited financial resources in England and Wales. Research is recommended into the cost-effectiveness of reflex testing for Lynch syndrome in other associated cancers and into the impact of prophylactic H-BSO on HRQoL.NIH

Azacitidine for treating acute myeloid leukaemia with more than 30% bone marrow blasts: A Single Technology Appraisal

Report commissioned by the NIHR HTA ProgrammeThis report was commissioned by the NIHR HTA Programme as project number 15/64/10

Low-dose computed tomography for lung cancer screening in high risk populations: a systematic review and economic evaluation

This is the final version. Available from NIHR Journals Library via the DOI in this record.The dataset associated with this article is located in ORE at: https://doi.org/10.24378/exe.564Background Diagnosis of lung cancer frequently occurs in its later stages. Low-dose computed tomography (LDCT) could detect lung cancer early. Objectives To estimate the effectiveness and cost-effectiveness of LDCT lung cancer screening in high risk populations. Methods Clinical effectiveness A systematic review of randomised controlled trials (RCTs) comparing LDCT screening programmes with usual care (no screening) or other imaging screening programme (such as chest X-ray (CXR)) was conducted. Bibliographic sources included MEDLINE, Embase, Web of Science and the Cochrane Library. Meta-analyses, including network meta-analyses, were performed. Cost-effectiveness An independent economic model employing discrete event simulation and using a natural history model calibrated to results from a large RCT was developed. There were twelve different population eligibility criteria and four intervention frequencies (single screen, triple screen, annual screening and biennial screening) and a no screening control arm. Results Clinical effectiveness Twelve RCTs were included, four of which currently contribute evidence on mortality. Meta-analysis of these demonstrated that LDCT with up to 9.80 years of follow-up was associated with a non-statistically significant decrease in lung cancer mortality (pooled RR 0.94, 95% CI 0.74 to 1.19). The findings also showed that LDCT screening demonstrated a non-statistically significant increasein all-cause mortality. Given the considerable heterogeneity detected between studies for both outcomes, the results should be treated with caution. Network meta-analysis including six RCTs was performed to assess the relative effectiveness of LDCT, CXR and usual care. The results showed that LDCT was ranked as the best screening strategy in terms of lung cancer mortality reduction. CXR had a 99.7% probability of being the worst intervention with usual care intermediate. Cost-effectiveness Screening programmes are predicted to be more effective than no screening, reduce lung cancer mortality and result in more lung cancer diagnoses. Screening programmes also increase costs. Screening for lung cancer is unlikely to be cost-effective at a threshold of £20,000/QALY, but may be cost-effective at a threshold of £30,000/QALY. The incremental cost-effectiveness ratio for a single screen in smokers aged 60–75 years with at least a 3% risk of lung cancer is £28,169 per QALY. Sensitivity and scenario analyses were conducted. Screening was only cost-effective at a threshold of £20,000/QALY in a minority of analyses. Limitations Clinical effectiveness The largest of the included RCTs compared LDCT with CXR screening rather than no screening. Cost-effectiveness A representative cost to the NHS of lung cancer has not been recently estimated according to key variables such as stage at diagnosis. Certain costs associated with running a screening programme have not been included. Conclusions LDCT screening may be clinically effective in reducing lung cancer mortality but there is considerable uncertainty. There is evidence that a single round of screening could be considered cost-effective at conventional thresholds, but there is significant uncertainty about the effect on costs and the magnitude of benefits. Future work Effectiveness and cost-effectiveness estimates should be updated with the anticipated results from several ongoing RCTs (particularly NELSON).This report was commissioned by the NIHR Health Technology Assessment Programme as project number 14/151/0

Preferences for genetic testing to predict risk of developing hereditary cancer: A systematic review of discrete choice experiments

This is the final version. Available from SAGE Publications via the DOI in this record. Background. Understanding service user preferences is key to effective health care decision making and efficient resource allocation. It is of particular importance in the management of high-risk patients in whom predictive genetic testing can alter health outcomes. Purpose. This review aims to identify the relative importance and willingness to pay for attributes of genetic testing in hereditary cancer syndromes. Data Sources. Searches were conducted in Medline, Embase, PsycINFO, HMIC, Web of Science, and EconLit using discrete choice experiment (DCE) terms combined with terms related to hereditary cancer syndromes, malignancy synonyms, and genetic testing. Study Selection. Following independent screening by 3 reviewers, 7 studies fulfilled the inclusion criteria, being a DCE investigating patient or public preferences related to predictive genetic testing for hereditary cancer syndromes. Data Extraction. Extracted data included study and respondent characteristics, DCE attributes and levels, methods of data analysis and interpretation, and key study findings. Data Synthesis. Studies covered colorectal, breast, and ovarian cancer syndromes. Results were summarized in a narrative synthesis and the quality assessed using the Lancsar and Louviere framework. Limitations. This review focuses only on DCE design and testing for hereditary cancer syndromes rather than other complex diseases. Challenges also arose from heterogeneity in attributes and levels. Conclusions. Test effectiveness and detection rates were consistently important to respondents and thus should be prioritized by policy makers. Accuracy, cost, and wait time, while also important, showed variation between studies, although overall reduction in cost may improve uptake. Patients and the public would be willing to pay for improved detection and clinician over insurance provider involvement. Future studies should seek to contextualize findings by considering the impact of sociodemographic characteristics, health system coverage, and insurance policies on preferences