Modelling cost-effective strategies for minimising socioeconomic inequalities in colorectal cancer screening outcomes in England.

Colorectal cancer (CRC) incidence and mortality is higher in socioeconomically deprived groups for a variety of reasons, but is exacerbated by poorer screening uptake. However, many strategies for improving screening participation exist. This analysis aimed to model the impact of screening on CRC inequalities in England and then compare different strategies for increasing participation, to determine the most cost-effective methods for reducing screening-induced inequalities. An existing health economic model, Microsimulation Model in Cancer of the Bowel was adapted. Screening-eligible individuals were simulated to investigate the impact of screening on CRC inequalities. Following this, four strategies for promoting screening participation were compared: 1) annual re-invitation of screening non-participants; 2) a national media advertising campaign; 3) text message reminders for non-participants; 4) health promotion in deprived populations. Cost-effectiveness, CRC outcomes, resource impacts and effects on CRC inequalities were assessed. Inequalities analysis was based on age-standardised CRC mortality by socioeconomic group. Screening was found to be highly cost-effective but CRC inequalities increased as screening effectiveness improved. Annual re-invitation of non-participants was most cost-effective for promoting particiption (incremental cost-effectiveness ratio = £4404 per quality-adjusted life-year), reducing CRC mortality (11,129 deaths averted), and reducing screening-induced inequality (slope of inequalities reduced from 20.80 to 19.38), although it required 42% more screening kits to be sent out. Other strategies were cost-effective compared with screening alone, and improved CRC outcomes, but had varying impacts on inequalities. Whilst bowel cancer screening increases socioeconomic inequalities in CRC mortality, effective and cost-effective strategies are available for mitigating screening-induced inequalities.

Optimizing the Design of a Repeated Fecal Immunochemical Test Bowel Cancer Screening Programme With a Limited Endoscopy Capacity From a Health Economic Perspective.

OBJECTIVES: In 2016, it was announced that the fecal immunochemical test (FIT) would replace the guaiac fecal occult blood test in the UK Bowel Cancer Screening Programme. England has limited endoscopy capacity. This study informed decision making by determining the most cost-effective FIT screening strategy (age range, frequency, and FIT threshold) under a constrained endoscopy capacity. METHODS: An economic model with a colorectal cancer natural history component was used to model 60 221 screening strategies with first screening at age 50 to 60 years, screening interval of 1 to 6 years, 3+ screening episodes, and FIT integer threshold of 20 to 180 µg hemoglobin/g feces. Screening strategies requiring the same endoscopy capacity were compared to determine the characteristics of the most cost-effective strategies. RESULTS: With 50 000 annual screening referral colonoscopies, the 20 most cost-effective strategies had a starting age of 50 to 53 years, 2-yearly screening, 7 or 8 rounds of screening, and FIT threshold of 127 to 166. Compared with a 2-yearly screening interval, screening less frequently (3-, 4-, 5-, or 6-yearly) with a more sensitive FIT was less cost-effective. CONCLUSIONS: The UK Bowel Cancer Screening Programme should use a 2-yearly FIT screening interval. When endoscopy capacity increases, the screening starting age should be reduced first followed by reducing the FIT threshold. These findings are relevant for other colorectal cancer screening programs with constrained endoscopy capacity.

British Society of Gastroenterology/Association of Coloproctology of Great Britain and Ireland/Public Health England post-polypectomy and post-colorectal cancer resection surveillance guidelines.

These consensus guidelines were jointly commissioned by the British Society of Gastroenterology (BSG), the Association of Coloproctology of Great Britain and Ireland (ACPGBI) and Public Health England (PHE). They provide an evidence-based framework for the use of surveillance colonoscopy and non-colonoscopic colorectal imaging in people aged 18 years and over. They are the first guidelines that take into account the introduction of national bowel cancer screening. For the first time, they also incorporate surveillance of patients following resection of either adenomatous or serrated polyps and also post-colorectal cancer resection. They are primarily aimed at healthcare professionals, and aim to address:Which patients should commence surveillance post-polypectomy and post-cancer resection?What is the appropriate surveillance interval?When can surveillance be stopped? two or more premalignant polyps including at least one advanced colorectal polyp (defined as a serrated polyp of at least 10 mm in size or containing any grade of dysplasia, or an adenoma of at least 10 mm in size or containing high-grade dysplasia); or five or more premalignant polyps The Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument provided a methodological framework for the guidelines. The BSG's guideline development process was used, which is National Institute for Health and Care Excellence (NICE) compliant.two or more premalignant polyps including at least one advanced colorectal polyp (defined as a serrated polyp of at least 10 mm in size or containing any grade of dysplasia, or an adenoma of at least 10 mm in size or containing high-grade dysplasia); or five or more premalignant polyps The key recommendations are that the high-risk criteria for future colorectal cancer (CRC) following polypectomy comprise either:two or more premalignant polyps including at least one advanced colorectal polyp (defined as a serrated polyp of at least 10 mm in size or containing any grade of dysplasia, or an adenoma of at least 10 mm in size or containing high-grade dysplasia); or five or more premalignant polyps This cohort should undergo a one-off surveillance colonoscopy at 3 years. Post-CRC resection patients should undergo a 1 year clearance colonoscopy, then a surveillance colonoscopy after 3 more years.

External Validation of a Colorectal Cancer Model Against Screening Trial Long-Term Follow-Up Data.

BACKGROUND: The University of Sheffield School of Health and Related Research (ScHARR) Bowel Cancer Screening Model has been used previously to make decisions about colorectal cancer screening strategies in England. OBJECTIVES: The objective of this study was to perform an external validation of the ScHARR model against long-term follow-up data about colorectal cancer (CRC) incidence and mortality reductions due to screening, from the Nottingham trial of guaiac faecal occult blood testing for CRC, and the UK Flexible Sigmoidoscopy Screening Trial. METHODS: The ScHARR model was adapted prior to validation to reflect the setting of each trial in terms of population characteristics, details of screening and surveillance programs, uptake of screening, and further investigations and study follow-up. The impact of using current versus historical CRC incidence and mortality data in the validation was also examined by carrying out a series of analyses in which historical data from different years was included in the model. RESULTS: The ScHARR model was able to predict CRC incidence and mortality rate/hazard ratios from both trials to well within the 95% confidence intervals in the observed data. While it was less accurate in predicting absolute incidence and mortality rates, modeling historical incidence and mortality data enabled these predictions to be improved considerably. CONCLUSION: The ScHARR model is able to replicate the long-term relative benefit from screening observed in 2 large-scale UK-based screening trials and can therefore be considered to be an appropriate tool to facilitate decision making around the English bowel cancer screening program.

Factors associated with completion of bowel cancer screening and the potential effects of simplifying the screening test algorithm.

BACKGROUND: The primary colorectal cancer screening test in England is a guaiac faecal occult blood test (gFOBt). The NHS Bowel Cancer Screening Programme (BCSP) interprets tests on six samples on up to three test kits to determine a definitive positive or negative result. However, the test algorithm fails to achieve a definitive result for a significant number of participants because they do not comply with the programme requirements. This study identifies factors associated with failed compliance and modifications to the screening algorithm that will improve the clinical effectiveness of the screening programme. METHODS: The BCSP Southern Hub data for screening episodes started in 2006-2012 were analysed for participants aged 60-69 years. The variables included age, sex, level of deprivation, gFOBt results and clinical outcome. RESULTS: The data set included 1,409,335 screening episodes; 95.08% of participants had a definitively normal result on kit 1 (no positive spots). Among participants asked to complete a second or third gFOBt, 5.10% and 4.65%, respectively, failed to return a valid kit. Among participants referred for follow up, 13.80% did not comply. Older age was associated with compliance at repeat testing, but non-compliance at follow up. Increasing levels of deprivation were associated with non-compliance at repeat testing and follow up. Modelling a reduction in the threshold for immediate referral led to a small increase in completion of the screening pathway. CONCLUSIONS: Reducing the number of positive spots required on the first gFOBt kit for referral for follow-up and targeted measures to improve compliance with follow-up may improve completion of the screening pathway.

Cost-effectiveness of screening for ovarian cancer amongst postmenopausal women: a model-based economic evaluation.

BACKGROUND: The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) was the biggest ovarian cancer screening trial to date. A non-significant effect of screening on ovarian cancer was reported, but the authors noted a potential delayed effect of screening, and suggested the need for four years further follow-up. There are no UK-based cost-effectiveness analyses of ovarian cancer screening. Hence we assessed the lifetime outcomes associated with, and the cost-effectiveness of, screening for ovarian cancer in the UK, along with the value of further research. METHODS: We performed a model-based economic evaluation. Effectiveness data were taken from UKCTOCS, which considered strategies of multimodal screening (MMS), ultrasound screening (USS) and no screening. We conducted systematic reviews to identify the remaining model inputs, and performed a rigorous and transparent prospective evaluation of different methods for extrapolating the effect of screening on ovarian cancer mortality. We considered costs to the UK healthcare system and measured effectiveness using quality-adjusted life years (QALYs). We used value of information methods to estimate the value of further research. RESULTS: Over a lifetime, MMS and USS were estimated to be both more expensive and more effective than no screening. USS was dominated by MMS, being both more expensive and less effective. Compared with no screening, MMS cost on average £419 more (95% confidence interval £255 to £578), and generated 0.047 more QALYs (0.002 to 0.088). The incremental cost-effectiveness ratio (ICER) comparing MMS with no screening was £8864 per QALY (£2600 to £51,576). Alternative extrapolation methods increased the ICER, with the highest value being £36,769 (£13,888 to dominated by no screening). Using the UKCTOCS trial horizon, both MMS and USS were dominated by no screening, as they produced fewer QALYs at a greater cost. The value of research into eliminating all uncertainty in long-term effectiveness was estimated to be worth up to £20 million, or approximately £5 million for four years follow-up. CONCLUSIONS: Screening for ovarian cancer with MMS is both more effective and more expensive than not screening. Compared to national willingness to pay thresholds, lifetime cost-effectiveness is promising, but there remains considerable uncertainty regarding extrapolated long-term effectiveness.

Estimating the Cost-Effectiveness of Implementation: Is Sufficient Evidence Available?

BACKGROUND: Timely implementation of recommended interventions can provide health benefits to patients and cost savings to the health service provider. Effective approaches to increase the implementation of guidance are needed. Since investment in activities that improve implementation competes for funding against other health generating interventions, it should be assessed in term of its costs and benefits. OBJECTIVE: In 2010, the National Institute for Health and Care Excellence released a clinical guideline recommending natriuretic peptide (NP) testing in patients with suspected heart failure. However, its implementation in practice was variable across the National Health Service in England. This study demonstrates the use of multi-period analysis together with diffusion curves to estimate the value of investing in implementation activities to increase uptake of NP testing. METHODS: Diffusion curves were estimated based on historic data to produce predictions of future utilization. The value of an implementation activity (given its expected costs and effectiveness) was estimated. Both a static population and a multi-period analysis were undertaken. RESULTS: The value of implementation interventions encouraging the utilization of NP testing is shown to decrease over time as natural diffusion occurs. Sensitivity analyses indicated that the value of the implementation activity depends on its efficacy and on the population size. CONCLUSIONS: Value of implementation can help inform policy decisions of how to invest in implementation activities even in situations in which data are sparse. Multi-period analysis is essential to accurately quantify the time profile of the value of implementation given the natural diffusion of the intervention and the incidence of the disease.

Distributional cost-effectiveness analysis of health care programmes--a methodological case study of the UK Bowel Cancer Screening Programme.

This paper presents an application of a new methodological framework for undertaking distributional cost-effectiveness analysis to combine the objectives of maximising health and minimising unfair variation in health when evaluating population health interventions. The National Health Service bowel cancer screening programme introduced in 2006 is expected to improve population health on average and to worsen population health inequalities associated with deprivation and ethnicity--a classic case of 'intervention-generated inequality'. We demonstrate the distributional cost-effectiveness analysis framework by examining two redesign options for the bowel cancer screening programme: (i) the introduction of an enhanced targeted reminder aimed at increasing screening uptake in deprived and ethnically diverse neighbourhoods and (ii) the introduction of a basic universal reminder aimed at increasing screening uptake across the whole population. Our analysis indicates that the universal reminder is the strategy that maximises population health, while the targeted reminder is the screening strategy that minimises unfair variation in health. The framework is used to demonstrate how these two objectives can be traded off against each other, and how alternative social value judgements influence the assessment of which strategy is best, including judgements about which dimensions of health variation are considered unfair and judgements about societal levels of inequality aversion.

Effectiveness and cost-effectiveness of an awareness campaign for colorectal cancer: a mathematical modeling study.

BACKGROUND: A campaign to increase the awareness of the signs and symptoms of colorectal cancer (CRC) and encourage self-presentation to a GP was piloted in two regions of England in 2011. Short-term data from the pilot evaluation on campaign cost and changes in GP attendances/referrals, CRC incidence, and CRC screening uptake were available. The objective was to estimate the effectiveness and cost-effectiveness of a CRC awareness campaign by using a mathematical model which extrapolates short-term outcomes to predict long-term impacts on cancer mortality, quality-adjusted life-years (QALYs), and costs. METHODS: A mathematical model representing England (aged 30+) for a lifetime horizon was developed. Long-term changes to cancer incidence, cancer stage distribution, cancer mortality, and QALYs were estimated. Costs were estimated incorporating costs associated with delivering the campaign, additional GP attendances, and changes in CRC treatment. RESULTS: Data from the pilot campaign suggested that the awareness campaign caused a 1-month 10 % increase in presentation rates. Based on this, the model predicted the campaign to cost £5.5 million, prevent 66 CRC deaths and gain 404 QALYs. The incremental cost-effectiveness ratio compared to "no campaign" was £13,496 per QALY. Results were sensitive to the magnitude and duration of the increase in presentation rates and to disease stage. CONCLUSIONS: The effectiveness and cost-effectiveness of a cancer awareness campaign can be estimated based on short-term data. Such predictions will aid policy makers in prioritizing between cancer control strategies. Future cost-effectiveness studies would benefit from campaign evaluations reporting as follows: data completeness, duration of impact, impact on emergency presentations, and comparison with non-intervention regions.

Using resource modelling to inform decision making and service planning: the case of colorectal cancer screening in Ireland.

BACKGROUND: Organised colorectal cancer screening is likely to be cost-effective, but cost-effectiveness results alone may not help policy makers to make decisions about programme feasibility or service providers to plan programme delivery. For these purposes, estimates of the impact on the health services of actually introducing screening in the target population would be helpful. However, these types of analyses are rarely reported. As an illustration of such an approach, we estimated annual health service resource requirements and health outcomes over the first decade of a population-based colorectal cancer screening programme in Ireland. METHODS: A Markov state-transition model of colorectal neoplasia natural history was used. Three core screening scenarios were considered: (a) flexible sigmoidoscopy (FSIG) once at age 60, (b) biennial guaiac-based faecal occult blood tests (gFOBT) at 55-74 years, and (c) biennial faecal immunochemical tests (FIT) at 55-74 years. Three alternative FIT roll-out scenarios were also investigated relating to age-restricted screening (55-64 years) and staggered age-based roll-out across the 55-74 age group. Parameter estimates were derived from literature review, existing screening programmes, and expert opinion. Results were expressed in relation to the 2008 population (4.4 million people, of whom 700,800 were aged 55-74). RESULTS: FIT-based screening would deliver the greatest health benefits, averting 164 colorectal cancer cases and 272 deaths in year 10 of the programme. Capacity would be required for 11,095-14,820 diagnostic and surveillance colonoscopies annually, compared to 381-1,053 with FSIG-based, and 967-1,300 with gFOBT-based, screening. With FIT, in year 10, these colonoscopies would result in 62 hospital admissions for abdominal bleeding, 27 bowel perforations and one death. Resource requirements for pathology, diagnostic radiology, radiotherapy and colorectal resection were highest for FIT. Estimates depended on screening uptake. Alternative FIT roll-out scenarios had lower resource requirements. CONCLUSIONS: While FIT-based screening would quite quickly generate attractive health outcomes, it has heavy resource requirements. These could impact on the feasibility of a programme based on this screening modality. Staggered age-based roll-out would allow time to increase endoscopy capacity to meet programme requirements. Resource modelling of this type complements conventional cost-effectiveness analyses and can help inform policy making and service planning.

Calibrating Natural History of Cancer Models in the Presence of Data Incompatibility: Problems and Solutions.

The calibration of cancer natural history models is often challenged by a lack of representative calibration targets, forcing modellers to rely on potentially incompatible datasets. Using a microsimulation colorectal cancer model as an example, the purposes of this paper are to (1) highlight the reasons for uncertainty in calibration targets, (2) illustrate practical and generalisable approaches for dealing with incompatibility in calibration targets, and (3) discuss the importance of future research in the area of incorporating uncertainty in calibration. The low quality of data and differences in populations, outcome definitions, and healthcare systems may result in incompatibility between the model and the data. Acknowledging reasons for data incompatibility allows assessment of the risk of incompatibility before calibrating the model. Only a few approaches are available to address data incompatibility, for instance addressing biases in calibration targets and their adjustment, relaxing the goodness-of-fit metric, and validation of the calibration targets to the data not used in the calibration. However, these approaches lack explicit comparison and validation, and so more research is needed to describe the nature and causes of indirect uncertainty (i.e. uncertainty that cannot be expressed in absolute quantitative forms) and identify methods for managing this uncertainty in healthcare modelling.

Granulocyte colony-stimulating factors for febrile neutropenia prophylaxis following chemotherapy: systematic review and meta-analysis.

BACKGROUND: Febrile neutropenia (FN) occurs following myelosuppressive chemotherapy and is associated with morbidity, mortality, costs, and chemotherapy reductions and delays. Granulocyte colony-stimulating factors (G-CSFs) stimulate neutrophil production and may reduce FN incidence when given prophylactically following chemotherapy. METHODS: A systematic review and meta-analysis assessed the effectiveness of G-CSFs (pegfilgrastim, filgrastim or lenograstim) in reducing FN incidence in adults undergoing chemotherapy for solid tumours or lymphoma. G-CSFs were compared with no primary G-CSF prophylaxis and with one another. Nine databases were searched in December 2009. Meta-analysis used a random effects model due to heterogeneity. RESULTS: Twenty studies compared primary G-CSF prophylaxis with no primary G-CSF prophylaxis: five studies of pegfilgrastim; ten of filgrastim; and five of lenograstim. All three G-CSFs significantly reduced FN incidence, with relative risks of 0.30 (95% CI: 0.14 to 0.65) for pegfilgrastim, 0.57 (95% CI: 0.48 to 0.69) for filgrastim, and 0.62 (95% CI: 0.44 to 0.88) for lenograstim. Overall, the relative risk of FN for any primary G-CSF prophylaxis versus no primary G-CSF prophylaxis was 0.51 (95% CI: 0.41 to 0.62). In terms of comparisons between different G-CSFs, five studies compared pegfilgrastim with filgrastim. FN incidence was significantly lower for pegfilgrastim than filgrastim, with a relative risk of 0.66 (95% CI: 0.44 to 0.98). CONCLUSIONS: Primary prophylaxis with G-CSFs significantly reduces FN incidence in adults undergoing chemotherapy for solid tumours or lymphoma. Pegfilgrastim reduces FN incidence to a significantly greater extent than filgrastim.

Cost-effectiveness of granulocyte colony-stimulating factor prophylaxis for febrile neutropenia in breast cancer in the United Kingdom.

OBJECTIVE: We report a cost-effectiveness evaluation of granulocyte colony-stimulating factors (G-CSFs) for the prevention of febrile neutropenia (FN) after chemotherapy in the United Kingdom (UK). METHODS: A mathematical model was constructed simulating the experience of women with breast cancer undergoing chemotherapy. Three strategies were modeled: primary prophylaxis (G-CSFs administered in all cycles), secondary prophylaxis (G-CSFs administered in all cycles after an FN event), and no G-CSF prophylaxis. Three G-CSFs were considered: filgrastim, lenograstim, and pegfilgrastim. Costs were taken from UK databases and utility values from published sources. A systematic review provided data on G-CSF efficacy. Probabilistic sensitivity analyses examined the effects of uncertainty in model parameters. RESULTS: In the UK, base-case analysis with a willingness-to-pay (WTP) threshold of £20K per quality-adjusted life year gained and also using list prices, the most cost-effective strategy was primary prophylaxis with pegfilgrastim for a patient with baseline FN risk greater than 38%, secondary prophylaxis with pegfilgrastim for baseline FN risk 11% to 37%, and no G-CSFs for baseline FN risk less than 11%. Using a WTP threshold of £30K and list prices, primary prophylaxis with pegfilgrastim was cost-effective for baseline FN risks greater than 29%. In all analyses, pegfilgrastim dominated filgrastim and lenograstim. Sensitivity analyses demonstrated that higher WTP threshold, younger age, earlier stage at diagnosis, or reduced G-CSF prices result in G-CSF prophylaxis being cost-effective at lower baseline FN risk levels. CONCLUSION: Pegfilgrastim was the most cost-effective G-CSF. The most cost-effective strategy (primary or secondary prophylaxis) was dependent on the FN risk level for an individual patient, patient age and stage at diagnosis, and G-CSF price.

Consistency between direct and indirect trial evidence: is direct evidence always more reliable?

OBJECTIVES: To present a case study involving the reduction in incidence of febrile neutropenia (FN) after chemotherapy with granulocyte colony-stimulating factors (G-CSFs), illustrating difficulties that may arise when following the common preference for direct evidence over indirect evidence. METHODS: Evidence of the efficacy of treatments was identified from two previous systematic reviews. We used Bayesian evidence synthesis to estimate relative treatment effects based on direct evidence, indirect evidence, and both pooled together. We checked for inconsistency between direct and indirect evidence and explored the role of one specific trial using cross-validation. A subsequent review identified further studies not available at the time of the original analysis. We repeated the analyses on the enlarged evidence base. RESULTS: We found substantial inconsistency in the original evidence base. The median odds ratio of FN for primary pegfilgrastim versus no primary G-CSF was 0.06 (95% credible interval: 0.02-0.19) based on direct evidence, but 0.27 (95% credible interval: 0.13-0.53) based on indirect evidence (P value for consistency hypothesis 0.027). The additional trials were consistent with the earlier indirect, rather than the direct, evidence, and there was no inconsistency between direct and indirect estimates in the updated evidence. The earlier inconsistency was due to one trial comparing primary pegfilgrastim with no primary G-CSF. Predictive cross-validation showed that this study was inconsistent with the evidence as a whole and with other trials making this comparison. CONCLUSIONS: Both the Cochrane Handbook and the NICE Methods Guide express a preference for direct evidence. A more robust strategy, which is in line with the accepted principles of evidence synthesis, would be to combine all relevant and appropriate information, whether direct or indirect.

Should colorectal cancer screening start at different ages for men and women? Cost-effectiveness analysis for a resource-constrained service.

BACKGROUND: Men have a greater risk of colorectal cancer (CRC) than women, but population screening currently starts at the same age for both sexes. AIM: This analysis investigates whether, in a resource-constrained setting, it would be more effective and cost-effective for men and women to start screening for CRC at different ages. METHODS AND RESULTS: An economic modeling analysis was carried out using the Microsimulation Model in Cancer of the Bowel to compare sex-stratification against screening everyone from the same age, taking an English National Health Service perspective. Screening men from age 56 and women from age 60, rather than screening everyone from age 58 using a Fecal Immunochemical Test (FIT) threshold of 120 µg/g is expected to produce an additional 0.0004 QALYs for a cost of £0.55 per person at model start (Incremental Cost-effectiveness Ratio = £1392), and to reduce CRC cases and mortality by 25 and 19 per 100 000 people respectively, while using a similar amount of screening resources. Probabilistic sensitivity analysis indicates a 61% probability that sex-stratification is more cost-effective than screening everyone at age 58. Similar benefits of sex-stratification are found at other FIT thresholds, but become negligible if mean screening start age is reduced to 50. CONCLUSION: Where resources are constrained and it is not feasible to screen everyone from the age of 50, starting screening earlier in men than women is likely to be more cost-effective and gain more health benefits overall than strategies where men and women start screening at the same age.

The Costs and Benefits of Risk Stratification for Colorectal Cancer Screening Based On Phenotypic and Genetic Risk: A Health Economic Analysis.

Population-based screening for colorectal cancer is an effective and cost-effective way of reducing colorectal cancer incidence and mortality. Many genetic and phenotypic risk factors for colorectal cancer have been identified, leading to development of colorectal cancer risk scores with varying discrimination. However, these are not currently used by population screening programs. We performed an economic analysis to assess the cost-effectiveness, clinical outcomes, and resource impact of using risk-stratification based on phenotypic and genetic risk, taking a UK National Health Service perspective. Biennial fecal immunochemical test (FIT), starting at an age determined through risk-assessment at age 40, was compared with FIT screening starting at a fixed age for all individuals. Compared with inviting everyone from age 60, using a risk score with area under the receiver operating characteristic curve of 0.721 to determine FIT screening start age, produces 418 QALYs, costs £247,000, and results in 218 fewer colorectal cancer cases and 156 fewer colorectal cancer deaths per 100,000 people, with similar FIT screening invites. There is 96% probability that risk-stratification is cost-effective, with net monetary benefit (based on £20,000 per QALY threshold) estimated at £8.1 million per 100,000 people. The maximum that could be spent on risk-assessment and still be cost-effective is £114 per person. Lower benefits are produced with lower discrimination risk scores, lower mean screening start age, or higher FIT thresholds. Risk-stratified screening benefits men more than women. Using risk to determine FIT screening start age could improve the clinical outcomes and cost effectiveness of colorectal cancer screening without using significant additional screening resources. PREVENTION RELEVANCE: Colorectal cancer screening is essential for early detection and prevention of colorectal cancer, but implementation is often limited by resource constraints. This work shows that risk-stratification using genetic and phenotypic risk could improve the effectiveness and cost-effectiveness of screening programs, without using substantially more screening resources than are currently available.

Electronic clinical decision support tool for assessing stomach symptoms in primary care (ECASS): a feasibility study.

OBJECTIVE: To determine the feasibility of a definitive trial in primary care of electronic clinical decision support (eCDS) for possible oesophago-gastric (O-G) cancer. DESIGN AND SETTING: Feasibility study in 42 general practices in two regions of England, cluster randomised controlled trial design without blinding, nested qualitative and health economic evaluation. PARTICIPANTS: Patients aged 55 years or older, presenting to their general practitioner (GP) with symptoms associated with O-G cancer. 530 patients (mean age 68 years, 58% female) participated. INTERVENTION: Practices randomised 1:1 to usual care (control) or to receive a previously piloted eCDS tool for suspected cancer (intervention), for use at the discretion of the GPs, supported by a theory-based implementation package and ongoing support. We conducted semistructured interviews with GPs in intervention practices. Recruitment lasted 22 months. OUTCOMES: Patient participation rate, use of eCDS, referrals and route to diagnosis, O-G cancer diagnoses; acceptability to GPs; cost-effectiveness. Participants followed up 6 months after index encounter. RESULTS: From control and intervention practices, we screened 3841 and 1303 patients, respectively; 1189 and 434 were eligible, 392 and 138 consented to participate. Ten patients (1.9%) had O-G cancer. eCDS was used eight times in total by five unique users. GPs experienced interoperability problems between the eCDS tool and their clinical system and also found it did not fit with their workflow. Unexpected restrictions on software installation caused major problems with implementation. CONCLUSIONS: The conduct of this study was hampered by technical limitations not evident during an earlier pilot of the eCDS tool, and by regulatory controls on software installation introduced by primary care trusts early in the study. This eCDS tool needed to integrate better with clinical workflow; even then, its use for suspected cancer may be infrequent. Any definitive trial of eCDS for cancer diagnosis should only proceed after addressing these constraints. TRIAL REGISTRATION NUMBER: ISRCTN125595588.

A New Approach for Sampling Ordered Parameters in Probabilistic Sensitivity Analysis.

BACKGROUND: Probabilistic sensitivity analysis (PSA) in cost-effectiveness analysis involves sampling a large number of realisations of an economic model. For some parameters, we may be uncertain around the true mean values of the variables, but the ordering of the values is known. Typical sampling approaches lack either statistical or clinical validity. For example, sampling using a common number generator results in extreme dependence, and independent sampling can lead to realisations with incorrect ordering. METHODS: We propose a new sampling approach for ordered parameters, the difference method (DM) approach, which samples the parameters of interest via a difference parameter. If the parameters of interest are bounded, it involves transforming the variables so that they are unbounded and then sampling via the difference parameter. We have provided a Microsoft Excel workbook to implement the method. The proposed approach is illustrated with an example sampling ordered parameters for utility and cost. RESULTS: The DM approach has a number of advantages when comparing with the typical approaches used in practice. It generates PSA samples that have similar summary statistics as the given values in our examples, while maintaining the constraint that one value was greater than another. The method also implies plausible positive correlation between the two ordered variables. CONCLUSIONS: Both clinical and statistical validity should be checked when producing PSA samples. The DM approach should be considered as a solution to potential problems in generating PSA samples for ordered parameters.

The association between long-term conditions and uptake of population-based screening for colorectal cancer: results from two English cohort studies.

INTRODUCTION: Uptake of screening for colorectal cancer (CRC) can reduce mortality, and population-based screening is offered in England. To date, there is little evidence on the association between having a long-term condition (LTC) and CRC screening uptake. The objective of this study was to examine the association between having an LTC and uptake of CRC screening in England with the guaiac fecal occult blood test, with a particular focus on common mental disorders. METHODS: The study was a preregistered secondary analysis of two cohorts: first, a linked data set between the regional Yorkshire Health Study (YHS) and the National Health Service National Bowel Cancer Screening Program (BCSP, years 2006-2014); second, the national English Longitudinal Study of Ageing (ELSA, years 2014-2015). Individuals eligible for BCSP screening who participated in either the YHS (7,142) or ELSA Wave 7 (4,099) were included. Study registration: ClinicalTrials.gov, number NCT02503969. RESULTS: In both the cohorts, diabetes was associated with lower uptake (YHS odds ratio [OR] for non-uptake 1.35, 95% CI 1.03-1.78; ELSA 1.33, 1.03-1.72) and osteoarthritis was associated with increased uptake (YHS 0.75, 0.57-0.99; ELSA 0.76, 0.62-0.93). After controlling for broader determinants of health, there was no evidence of significantly different uptake for individuals with common mental disorders. CONCLUSION: Two large independent cohorts provided evidence that uptake of CRC screening is lower among individuals with diabetes and higher among individuals with osteoarthritis. Further work should compare barriers and facilitators to screening among individuals with either of these conditions. This study also demonstrates the benefits of data linkage for improving clinical decision-making.