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Objective To evaluate the benefit of combining polygenic risk scores with the QCancer-10 (colorectal cancer) prediction model for non-genetic risk to identify people at highest risk of colorectal cancer. Design Population based cohort study. Setting Data from the UK Biobank study, collected between March 2006 and July 2010. Participants 434 587 individuals with complete data for genetics and QCancer-10 predictions were included in the QCancer-10 plus polygenic risk score modelling and validation cohorts. Main outcome measures Prediction of colorectal cancer diagnosis by genetic, non-genetic, and combined risk models. Using data from UK Biobank, six different polygenic risk scores for colorectal cancer were developed using LDpred2 polygenic risk score software, clumping, and thresholding approaches, and a model based on genome-wide significant polymorphisms. The top performing genome-wide polygenic risk score and the score containing genome-wide significant polymorphisms were combined with QCancer-10 and performance was compared with QCancer-10 alone. Case-control (logistic regression) and time-to-event (Cox proportional hazards) analyses were used to evaluate risk model performance in men and women. Results Polygenic risk scores derived using the LDpred2 program performed best, with an odds ratio per standard deviation of 1.584 (95% confidence interval 1.536 to 1.633), and top age and sex adjusted C statistic of 0.733 (95% confidence interval 0.710 to 0.753) in logistic regression models in the validation cohort. Integrated QCancer-10 plus polygenic risk score models out-performed QCancer-10 alone. In men, the integrated LDpred2 model produced a C statistic of 0.730 (0.720 to 0.741) and explained variation of 28.2% (26.3 to 30.1), compared with 0.693 (0.682 to 0.704) and 21.0% (18.9 to 23.1) for QCancer-10 alone. In women, the C statistic for the integrated LDpred2 model was 0.687 (0.673 to 0.702) and explained variation was 21.0% (18.7 to 23.7), compared with 0.645 (0.631 to 0.659) and 12.4% (10.3 to 14.6) for QCancer-10 alone. In the top 20% of individuals at highest absolute risk, the sensitivity and specificity of the integrated LDpred2 models for predicting colorectal cancer diagnosis was 47.8% and 80.3% respectively in men, and 42.7% and 80.1% respectively in women, with increases in absolute risk in the top 5% of risk in men of 3.47-fold and in women of 2.77-fold compared with the median. Illustrative decision curve analysis indicated a small incremental improvement in net benefit with QCancer-10 plus polygenic risk score models compared with QCancer-10 alone. Conclusions Integrating polygenic risk scores with QCancer-10 modestly improves risk prediction over use of QCancer-10 alone. Given that QCancer-10 data can be obtained relatively easily from health records, use of polygenic risk score in risk stratified population screening for colorectal cancer currently has no clear justification. The added benefit, cost effectiveness, and acceptability of polygenic risk scores should be carefully evaluated in a real life screening setting before implementation in the general population.

The emergence of next-generation genomic sequencing (NGS) tests for use in clinical care has generated widespread interest around the globe, but little is known about the availability and funding of these tests worldwide. We examined NGS availability across world regions and countries, with a particular focus on availability of three key NGS tests—Whole-Exome Sequencing or Whole-Genome Sequencing for diagnosis of suspected genetic diseases such as intellectual disability disorders or rare diseases, non-invasive prenatal testing for common genetic abnormalities in fetuses and tumor sequencing for therapy selection and monitoring of cancer treatment. We found that these NGS tests are available or becoming available in every major region of the world. This includes both high-income countries with robust genomic programmes such as the USA and the UK, and growing availability in countries with upper-middle-income economies. We used exploratory case studies across three diverse health care systems (publicly funded/national (UK), publicly funded/provincial (Canada) and mixed private/public system (USA)) to illustrate the funding challenges and approaches used to address those challenges that might be adopted by other countries. We conclude by assessing what type of data and initiatives will be needed to better track and understand the use of NGS around the world as such testing continues to expand.

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.

OBJECTIVES: To compare the ability of ophthalmologists versus optometrists to correctly classify retinal lesions due to neovascular age-related macular degeneration (nAMD).DESIGN: Randomised balanced incomplete block trial. Optometrists in the community and ophthalmologists in the Hospital Eye Service classified lesions from vignettes comprising clinical information, colour fundus photographs and optical coherence tomographic images. Participants' classifications were validated against experts' classifications (reference standard).SETTING: Internet-based application.PARTICIPANTS: Ophthalmologists with experience in the age-related macular degeneration service; fully qualified optometrists not participating in nAMD shared care.INTERVENTIONS: The trial emulated a conventional trial comparing optometrists' and ophthalmologists' decision-making, but vignettes, not patients, were assessed. Therefore, there were no interventions and the trial was virtual. Participants received training before assessing vignettes.MAIN OUTCOME MEASURES: Primary outcome-correct classification of the activity status of a lesion based on a vignette, compared with a reference standard. Secondary outcomes-potentially sight-threatening errors, judgements about specific lesion components and participants' confidence in their decisions.RESULTS: In total, 155 participants registered for the trial; 96 (48 in each group) completed all assessments and formed the analysis population. Optometrists and ophthalmologists achieved 1702/2016 (84.4%) and 1722/2016 (85.4%) correct classifications, respectively (OR 0.91, 95% CI 0.66 to 1.25; p=0.543). Optometrists' decision-making was non-inferior to ophthalmologists' with respect to the prespecified limit of 10% absolute difference (0.298 on the odds scale). Optometrists and ophthalmologists made similar numbers of sight-threatening errors (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 classifications than optometrists.CONCLUSIONS: Optometrists' ability to make nAMD retreatment decisions from vignettes is not inferior to ophthalmologists' ability. Shared care with optometrists monitoring quiescent nAMD lesions has the potential to reduce workload in hospitals.TRIAL REGISTRATION NUMBER: ISRCTN07479761; pre-results registration.

Introduction Ongoing surveillance is a potential treatment strategy in the UK National Health Service (NHS) for ulcerative colitis patients who are diagnosed with low-grade dysplasia (LGD) of the flat mucosa, with no associated endoscopically visible lesion. However, given the increased cancer risk following a finding of flat LGD, the costs associated with long-term surveillance and the likely eventual need for surgery, immediate proctocolectomy for flat LGD may both improve health outcomes and also save healthcare costs. The aim of this study was to establish the cost-effectiveness of ongoing surveillance versus immediate surgery for this patient group in the UK NHS. Method Economic modelling was used to address this decision problem. A Markov model was constructed in which cohort analysis was used to evaluate costs and health outcomes for patients aged from 25–75 years with none, one or two comorbidities affecting surgical risk. Two outcome measures were used: life years and quality adjusted life years (QALYs). The model reflected current UK clinical practice, considered a timeframe of 20 years and adopted a health service perspective. Incremental cost-effectiveness ratios for surveillance versus surgery were calculated. One-way sensitivity analysis was used to establish the key model parameters, while probabilistic sensitivity analysis and cost-effectiveness acceptability curves were used to quantify the overall decision uncertainty. Results Ongoing surveillance was cost-effective at a threshold of £30,000/QALY gained at age 62 in the presence of no comorbidities, age 60 in the presence of one comorbidity and at age 51 in the presence of two comorbidities. These results are sensitive to both the colorectal cancer incidence rate for patients under surveillance and to the quality of life in remission post-surgery. There is, however, uncertainty around the results in some age groups: the probability of surveillance being cost-effective is 56.6% at age 65 in the presence of neither of the comorbidities considered (Table 1). Conclusion This study represents the first economic evaluation of surveillance versus surgery in this patient population. As such, this study adds clarity to a decision around which best practice is currently uncertain, and clearly demonstrates which factors are most important for decision-making in this area. Ongoing surveillance may be a cost-effective strategy in this patient population, but only in specific patient subgroups (older patients with multiple comorbidities). In younger patients with fewer comorbidities, surgery likely saves healthcare costs and improves health outcomes. Disclosure of interest None Declared.