BACKGROUND:National guidelines recommend English women between 30 and 49 years with moderate/high risk of breast cancer (BC) be offered screening and prevention interventions. Identification  largely relies on family history-based criteria amongst women self-presenting in primary care. We aimed to understand the preference for different potential risk assessment strategies in this population. METHODS:A cross-sectional survey including a discrete choice experiment. Risk assessments were defined using six attributes, including initiation strategy, eligibility for a full/detailed risk assessment, components of the risk assessment, including multifactorial risk assessment based on the BOADICEA/CanRisk model, and sensitivity. Coefficients from conditional logistic regression were used to estimate preference for different risk assessment approaches compared to current care. RESULTS:Participants (n = 893) preferred alternative approaches for risk assessments over current care, particularly where all eligible women were proactively invited and more above-average risk women were correctly identified. All but one of 21 risk assessment approaches was preferred, with the most favoured approaches having a probability of being preferred over current care >92%. Education level and ethnicity potentially impacted the strength of participant priorities. CONCLUSIONS:Offering multifactorial BC risk assessments to younger women in primary care, especially the most proactive and broad approaches, would be acceptable and preferred over current practice.

Objectives: To quantify the harms participants are willing to accept for varying benefits from cancer screening following provision of information. Methods: We conducted an online discrete choice experiment with two samples of the UK public. Attributes were number of cancer diagnoses and deaths prevented (benefits) and overdiagnoses, false positives and false negatives (harms) for a population who are/are not screened for an unspecified cancer over their lifetimes. After selecting the best-fitting conditional logistic regression model for each sample, we used latent class analysis to investigate preference heterogeneity and calculated the probability that each class/group would take up screening with different benefit and harm levels. Results: In total, 1018 participants completed the discrete choice experiment. Cancer deaths prevented was the most important attribute, followed by the number of false positively/negatively detected cancers; cancers prevented and overdiagnosed were deemed relatively unimportant. Three latent classes were identified. The largest class (approximately two-thirds) chiefly opted for screening, focusing on deaths prevented; this group would strongly prefer screening participation even with harms only (probability 76%-92%). Approximately a quarter of each sample traded off benefits and harms; this group would likely take up screening with outcomes like those of colorectal screening (68%-87%). Conclusions: A minority of the public express preferences for screening that are influenced by trading-off potential benefits/ harms, but most have strong preferences for cancer screening, focusing on the associated reduction of cancer deaths. The find-ings emphasise public health responsibility in appraising or generating evidence on benefits and harms to support decisions about the introduction or modification of screening programmes.

Objective To understand the importance and potential impact on uptake of different attributes of risk-based innovations in the context of risk-stratified healthcare for cancer screening and symptomatic diagnosis.Design The online survey comprised a discrete choice experiment (DCE) in which participants chose between two risk assessment options or to opt out of risk stratification. There were six attributes: test method, type (genetic or non-genetic), location, frequency, sensitivity and specificity. Participants were randomly allocated to consider the choice in an asymptomatic or symptomatic context.Setting Members of the public in the UK.Participants 1202 participants completed the DCE.Outcome measures Conditional logistic regression and latent class analysis informed modelling of predicted preferences for a range of innovations with different features.Results Overall, participants preferred risk assessments over opting out and prioritised sensitivity, with test method and specificity also important. Genetic and non-invasive tests were favoured. With sensitivity and specificity of 80% or better, participants would be more likely to take up a risk assessment than not. Comparing the asymptomatic and symptomatic contexts, 65% and 73% of participants would be very likely to participate regardless of the innovation used, and 29% and 13% of participants might participate depending on the method, sensitivity and specificity. A minority showed strong dislike of risk-based innovations, particularly within screening.Conclusions There are high levels of public support for risk-based innovations within risk-stratified cancer healthcare, especially for referral decision-making and using genetic and non-invasive tests. Optimising risk-based innovations is needed to engage those whose participation is contingent on test methods and performance metrics.

INTRODUCTION:Patients with chronic limb-threatening ischaemia (CLTI) are often prescribed clopidogrel in order to reduce their risk of major adverse limb and cardiovascular events. Clopidogrel is metabolised by the CYP2C19 enzyme and genetic variations in CYP2C19 are common. These variants can influence an individual's ability to metabolise clopidogrel to its active metabolite. Few studies have investigated the relationship between patient genotype and outcomes in vascular surgery. This work aims to establish the relationship between patient genotype and outcomes after revascularisation in patients with CLTI who are prescribed clopidogrel. It will consider whether pharmacogenetics can be used to ensure patients are prescribed effective medications to optimise their outcomes. METHODS AND ANALYSIS:This is an observational cohort study of patients undergoing lower limb surgical, endovascular or hybrid revascularisation for CLTI at Manchester University NHS Foundation Trust. Patients taking clopidogrel post-procedure, as well as those prescribed a non-clopidogrel based medication regimen, will be recruited prior to or shortly after revascularisation. Patients will undergo CYP2C19 genotyping and will be followed up using online records. The study has 90% power to detect 114 amputations with a target sample size of 483 participants. The primary outcomes are risk of amputation at 1 year and a composite endpoint for the risk of major adverse limb events (MALE) or death from any cause at 1 year. Secondary outcomes are risk of MALE at 1 year, risk of major adverse cardiovascular events (MACE) or death from any cause at 1 year, death within 30 days of revascularisation, minor re-interventions at 1 year, total number of re-interventions at 1 year and rate of systemic or gastrointestinal bleed at 1 year.Risk of amputation, MALE and MACE will be analysed using Cox models. All remaining outcomes will be analysed using negative binomial models. Potential competing events for the risk of amputation will be investigated as part of a sensitivity analysis. Patients given a non-clopidogrel-based medication will be compared as an additional analysis. ETHICS AND DISSEMINATION:Manchester University Research Ethics Committee approval obtained as part of the Implementing Pharmacogenetics to Improve Prescribing (IPTIP) trial process (IRAS 305751). The results of the study will be published in a peer-reviewed journal and presented at international conferences. REGISTRATION:This work is a sub-protocol for the IPTIP study which is registered as ISRCTN14050335.

Introduction The National Health Service Cervical Screening Programme (NHSCSP) currently involves a healthcare professional collecting a cervical sample in a healthcare setting. This method of screening has barriers associated with access to screening appointments and the poor acceptability of the speculum examination. Primary screening through HPV testing has led to the development of self-sampling screening methods including vaginal and urine self-sampling, with many UK studies comparing these screening methods with the current NHSCSP. It is not known what features of self-sampling influence individuals’ preferences and cervical screening uptake. To understand these preferences, we plan to undertake a discrete choice experiment (DCE). This protocol aims to describe the steps taken to design the DCE and the proposed approach to fielding the DCE to identify preferences for different sampling approaches in cervical screening.Methods and analysis An online survey comprising a DCE was designed to understand preferences of individuals for self-sampling methods within the NHSCSP. Attributes and levels for the DCE were generated through an iterative process including a literature review of qualitative studies about self-sampling cervical screening methods, input from cervical screening clinical experts and a patient and public involvement group (n=6). A D-efficient design was used to create choice sets for the DCE survey. Regression-based analysis will be used to estimate the impact of each attribute and level on individual choices.Ethics and dissemination This study has been approved by The University of Manchester Proportionate Research Ethics Committee (2024-20767-37669). The results of the DCE will be submitted for publication in a relevant peer review journal and the results will be presented at national and international conferences.Data statement There are no data associated with this protocol. The data produced by this study and analysis scripts will be made available in a public repository following publication of the study.

Pharmacogenetic testing in the United Kingdom’s National Health Service (NHS) has historically been reactive in nature, undertaken in the context of single gene-drug relationships in specialist settings. Using a discrete choice experiment we aimed to identify healthcare professional preferences for development of a pharmacogenetic testing service in primary care in the NHS. Respondents, representing two professions groups (general practitioners or pharmacists), completed one of two survey versions, asking them to select their preferred pharmacogenetic testing service in the context of a presentation of low mood or joint pain. Responses from 235 individuals were included. All respondents preferred pharmacogenetic testing over no testing, though preference heterogeneity was identified. Both professional groups, but especially GPs, were highly sensitive to service design, with uptake varying depending on the service offered. This study demonstrates uptake of a pharmacogenetic testing service is impacted by service design and highlights key areas which should be prioritised within future initiatives.

Introduction. This study aimed to understand the impact of alternative modes of information provision on the stated preferences of a sample of the public for attributes of newborn bloodspot screening (NBS) in the United Kingdom. Methods. An online discrete choice experiment survey was designed using 4 attributes to describe NBS (effect of treatment on the condition, time to receive results, whether the bloodspot is stored, false-positive rate). Survey respondents were randomized to 1 of 2 survey versions presenting the background training materials using text from a leaflet (leaflet version) or an animation (animation version). Heteroskedastic conditional logistic regression was used to estimate the effect of mode of information provision on error variance. Results. The survey was completed by 1,000 respondents (leaflet = 525; animation = 475). Preferences for the attributes in the DCE were the same in both groups, but the group receiving the animation version had 9% less error variance in their responses. Respondents completing the animation version gave higher ratings compared with the leaflet version in terms of ease of perceived understanding. Subgroup analysis suggested that the animation was particularly effective at reducing error variance for women (20%), people with previous children (16.5%), and people between the ages of 35 and 45 y (11.8%). Limitations. This study used simple DCE with 4 attributes, and the results may vary for more complex choice questions. Conclusion. This study provides evidence that that supplementing the information package offered to parents choosing to take part in NBS with an animation may aid them their decision making. Further research would be needed to test the animation in the health system. Implications. Researchers designing DCE should carefully consider the design of their training materials to improve the quality of data collected. Highlights Prior to completing a discrete choice experiment about newborn bloodspot screening, respondents were shown information using either a leaflet-based or animated format. Respondents receiving information using an animation version reported that the information was slightly easier to understand and exhibited 9% less error variance in expressing their preferences for a newborn screening program. Using the animation version to present information appeared to have a larger impact in reducing the error variance of responses for specific respondents including women, individuals with children, individuals between the ages of 35 and 45 y, and individuals educated to degree level.

Decision-makers require knowledge of the strengths and weaknesses of decision-analytic models used to evaluate healthcare interventions to be able to confidently use the results of such models to inform policy. A number of aspects of model validity have previously been described, but no systematic approach to assessing the validity of a model has been proposed. This study aimed to consolidate the different aspects of model validity into a step-by-step approach to assessing the strengths and weaknesses of a decision-analytic model. A pre-defined set of steps were used to conduct the validation process of an exemplar early decision-analytic-model-based cost-effectiveness analysis of a risk-stratified national breast cancer screening programme [UK healthcare perspective; lifetime horizon; costs (£; 2021)]. Internal validation was assessed in terms of descriptive validity, technical validity and face validity. External validation was assessed in terms of operational validation, convergent validity (or corroboration) and predictive validity. The results outline the findings of each step of internal and external validation of the early decision-analytic-model and present the validated model (called ‘MANC-RISK-SCREEN’). The positive aspects in terms of meeting internal validation requirements are shown together with the remaining limitations of MANC-RISK-SCREEN. Following a transparent and structured validation process, MANC-RISK-SCREEN has been shown to have satisfactory internal and external validity for use in informing resource allocation decision-making. We suggest that MANC-RISK-SCREEN can be used to assess the cost-effectiveness of exemplars of risk-stratified national breast cancer screening programmes (NBSP) from the UK perspective. A step-by-step process for conducting the validation of a decision-analytic model was developed for future use by health economists. Using this approach may help researchers to fully demonstrate the strengths and limitations of their model to decision-makers.

Pharmacogenetic-guided prescribing can lead to more accurate medicine selection and dosing, improving patient outcomes and leading to better use of health care budgets. Loss-of-function variants in CYP2C19 influence an individual's ability to metabolize clopidogrel, increasing the risk of secondary vascular events following ischemic stroke and percutaneous coronary intervention. In acute clinical contexts, centralized laboratory-based testing is too slow to inform timely clinical decision-making. This work reports the development and analytical validation of the Genedrive CYP2C19 ID Kit, which provides rapid point-of-care genotyping from a buccal swab in approximately 1 hour. Buccal samples were collected from a total of 204 individuals between September 2023 and July 2024, alongside a blood or saliva sample for comparison with laboratory testing. In the final cohort of 202 patients, all point-of-care results were concordant with laboratory testing. In this assessment, the sensitivity and specificity of the CYP2C19 ID Kit was 100% (95% CI, 95.0%-100%) and 100% (95% CI, 97.2%-100%), respectively. The failure rate of the CYP2C19 ID Kit was 0.98%. This study confirms the analytical validity of the Genedrive CYP2C19 ID Kit. The Genedrive system is able to provide an accurate, rapid, noninvasive alternative to standard laboratory testing and can be used as a point-of-care test in the clinical environment.

Enhanced horizon scanning for emerging treatments has identified that both haemophilia A and haemophilia B pathways will be enriched with a range of new medicines with varying benefit-risk profiles. Patient and clinician views on the balance of the benefits and risks associated with emerging therapies will affect their use for the treatment of haemophilia, while also introducing the need for effective communication strategies to enable informed patient-clinician decision-making.

AbstractPopulation screening for breast cancer (BC) is currently offered in the UK for women aged 50 to 71 with the aim of reducing mortality. There is additional screening within the national programme for women identified as having a very high risk of BC. There is growing interest in further risk stratification in breast screening, which would require a whole population risk assessment and the subsequent offer of screening tailored to the individual’s risk. Some women would be offered more intensive screening than others or no screening. This might provide a better balance of screening benefits and harms for each individual than the current population age-based programme alone. The UK National Screening Committee (UK NSC) is considering using decision-analytic and other models to evaluate different risk stratification screening strategies and identify remaining gaps in evidence. This paper reports the proceedings of a UK NSC workshop where experts in the field discussed both risk prediction models, as well as decision-analytic models providing a benefit-harm analysis/economic evaluation of risk-stratified screening programmes (see Table 1). The aim of the meeting was to present and discuss the current work of experts, including some data which had not been published at the time of the meeting, to inform the UK NSC. The workshop was not intended to present a balanced evaluation of how to deliver screening in future. Areas for further work identified included methods for comparing models to assess accuracy, the optimum risk assessment tools, the digital screening infrastructure, acceptability of stratification, choice of screening test and reducing inequalities. A move to risk stratification of the whole programme would require a careful phased introduction with continuing assessment of real-world evidence during deployment.

Introduction Patients with chronic limb threatening ischaemia (CLTI) are often prescribed clopidogrel in order to reduce their risk of major adverse limb and cardiovascular events. Clopidogrel is metabolised by the CYP2C19 enzyme, and genetics variations in CYP2C19 are common. These variants can influence an individual's ability to metabolise clopidogrel to its active metabolite. This work aims to establish the relationship between patient genotype and outcomes after revascularisation in patients with CLTI who are prescribed clopidogrel. It will consider whether pharmacogenetics can be used to ensure patients are prescribed effective medications to optimise their outcomes. Methods and analysis This is a prospective observational cross-sectional study of patients undergoing lower limb surgical, endovascular or hybrid revascularisation for CLTI. Patients taking clopidogrel post-procedure, as well as those prescribed a non-clopidogrel based medication regimen, will be recruited prior to or shortly after revascularisation. Patients will undergo CYP2C19 genotyping and will be followed-up using online records. Ethics and dissemination Manchester University Research Ethics Committee approval as obtained was part of the Implementing Pharmacogenetics to Improve Prescribing (IPTIP) trial process (IRAS 305751). The results of the study will be published in a peer-review journal and presented at international conferences. Registration This work is a sub-protocol for the IPTIP study which is registered as [ISRCTN14050335][1]. ### Competing Interest Statement Competing interests John McDermott and William Newman are co-founders of Fava Health. The other authors have no competing interests. ### Funding Statement Funding Kerry Burke, John McDermott (JHM), William Newman (WGN) and Stuart Wright (SJW) receive grant support from the NHSE Network of Excellence in Pharmacogenetics. JHM and WGN receive grant funding from the BBSRC (BB/X003442/1), Manchester NIHR HealthTech Research Centre, Manchester NIHR BRC (NIHR203308) and Innovate UK (10058536) JHM is funded by National Institute for Health and Care Research (NIHR) Doctoral Fellowship Award (NIHR 301748). SJW is supported by a Wellcome Trust Early-Career Award (226922/Z/23/Z). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Manchester University Research Ethics Committee gave ethical approval for this work as part of the Implementing Pharmacogenetics to Improve Prescribing (IPTIP) trial process (IRAS 305751). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes An anonymised version of the genetic dataset will be stored in a data repository with no limitations on access or use. Genotype data will be deposited in the Figshare repository (https://figshare.com/) at the end of the study following publication. Data will be open access and will be entirely anonymised, with no study ID. [1]: /external-ref?link_type=ISRCTN&access_num=ISRCTN14050335

Background: Pharmacogenetic-guided prescribing can be used to improve the safety and effectiveness of medicines. There are several approaches by which this intervention might be implemented in clinical practice, which will vary depending on the health system and clinical context. Aim: To understand the clinical utility of panel-based pharmacogenetic testing in patients admitted acutely to hospital and to establish variables that predict if an individual might benefit from the intervention. Design: A cross-sectional study recruiting patients admitted acutely to hospital. Methods Participants underwent panel-based pharmacogenetic testing, and their genetic results were analysed in their context of the medicines they had been exposed to as an inpatient. The primary outcome was the proportion of patients with clinically actionable gene-drug interactions. Individual variables that predict the clinical utility of pharmacogenetic testing were established via logistic regression. Results: Genetic and prescribing data were available for 482 inpatients (55% male; median age 61.2 years; range: 18-96), 97.9% of whom carried a pharmacogenetic result of interest. During their admission, 79.5% of patients were exposed to a medicine for which there is pharmacogenetic prescribing guidance available. Just under one in seven individuals (13.7%) had a clinically actionable gene-drug interaction. Increasing age (>50 years) was positively correlated with the likelihood (2.7-fold increased risk) of having a clinically actionable interaction. Conclusions: These findings demonstrate the potential scale, and potential clinical utility, of pharmacogenetic testing as an intervention, highlighting the need to develop infrastructure to support healthcare professionals make use of this emerging tool.

It is well known that healthcare resource constraints influence the capacity to deliver care, affecting both the costs and outcomes of medical interventions. If these constraints are not adequately accounted for in economic evaluations, there may be a lack of understanding regarding the full impact of implementing health technologies, leading to decisions being made with suboptimal information. This paper offers an overview of the types of healthcare resource constraints and their potential effects, and introduces a framework grounded in operations research and health economics principles, outlining the methodological considerations for incorporating resource constraints into economic evaluations. Drawing from a literature review and advisory group feedback, three categories of resource constraints were identified: single-use resource constraints, reusable resource constraints and patient throughput constraints. The proposed framework outlines a comprehensive set of steps necessary for effectively incorporating constraints into health economic evaluations and details specific approaches and methodological considerations for each stage to ensure a more accurate and realistic assessment of health interventions. This paper also aims to raise awareness among payers and decision-makers with regards to the limitations of technology evaluations in a resource-constrained health system. Specifically, it suggests that health technology assessment agencies ought to offer guidance on incorporating constraints into the submissions they receive. Moreover, it advocates for a more comprehensive economic evaluation in economic assessments to fully capture an intervention's value.

Objective:Lower extremity arterial disease (LEAD) is a prevalent condition that produces a significant burden on health care systems. Patients with LEAD have an increased risk of major adverse cardiovascular events as well as major adverse limb events. Despite significant variation in guidance on antiplatelet therapy for LEAD worldwide, many governing bodies recommend clopidogrel as the preferred single anti-platelet agent. Clopidogrel is also used frequently in post-revascularization regimens, either as a single agent or as part of dual antiplatelet therapy. Clopidogrel is a thienopyridine prodrug that is metabolized in the liver by the CYP2C19 enzyme. Genetic variations in CYP2C19 are common and can influence an individual's ability to metabolize clopidogrel to its active metabolite. Methods:This work completes a narrative review of the literature to consider whether CYP2C19 genetic testing should be routinely implemented in patients who are to be prescribed clopidogrel to improve outcomes in patients with LEAD. Results:Recent advances in both cardiac and stroke medicine have demonstrated a role for patient genotyping to identify poor clopidogrel metabolizers and adopt alternative therapeutic strategies in these patient groups. This approach has been shown to improve clinical outcomes and has been incorporated into national and international guidance. Research studies suggest an association between CYP2C19 loss of function alleles and adverse outcomes in patients with LEAD taking clopidogrel. Conclusions:The introduction of a precision medicine strategy in vascular surgery may have the potential to significantly improve clinical outcomes in this complex group of patients with multiple comorbidities.

AimsGenetic testing can be used to improve the safety and effectiveness of commonly prescribed medicines—a concept known as pharmacogenetics. This study aimed to quantify members of the UK public's preferences for a pharmacogenetic service to be delivered in primary care in the National Health Service.MethodsMembers of the UK population were surveyed via an online panel company. Respondents completed 1 of 2 survey versions, asking respondents to select their preferred pharmacogenetic testing service in the context of a presentation of low mood or pain. A conditional logit model was estimated, before the best functional form for the dataset was identified. Preference heterogeneity was identified via latent class analysis. Coefficients from the final selected models were used to estimate uptake in the context of different hypothetical pharmacogenetic services.ResultsResponses from 1993 individuals were included in the analysis. There were no differences observed in preference between the 2 clinical scenarios. Conditional logit analysis, using maximum likelihood estimation, indicated that respondents preferred to have noninvasive tests and wanted their data to be shared between different healthcare organizations to guide future prescribing. There was a preference for regional over national data sharing initiatives, and respondents preferred to have access to their data. Predicted uptake varied considerably, ranging from 51% to >99%, depending on design of the service.ConclusionThis study identifies public preferences for a pharmacogenetic testing service and demonstrates how predicted uptake can be impacted by relatively minor adaptations. This highlights areas for prioritization during development of future pharmacogenetic services.

Background Economic evaluations have suggested that risk-stratified breast cancer screening may be cost-effective but have used assumptions to estimate the cost of risk prediction. The aim of this study was to identify and quantify the resource use and associated costs required to introduce a breast cancer risk-stratification approach into the English national breast screening program. Methods A micro-costing study, conducted alongside a cohort-based prospective trial (BC-PREDICT), identified the resource use and cost per individual (£; 2021 price year) of providing a risk-stratification strategy at a woman’s first mammography. Costs were calculated for 3 risk-stratification approaches: Tyrer-Cuzick survey, Tyrer-Cuzick with Volpara breast-density measurement, and Tyrer-Cuzick with Volpara breast-density measurement and testing for 142 single nucleotide polymorphisms (SNP). Costs were determined for the intervention as implemented in the trial and in the health service. Results The cost of providing the risk-stratification strategy was calculated to be £16.45 for the Tyrer-Cuzick survey approach, £21.82 for the Tyrer-Cuzick with Volpara breast-density measurement, and £102.22 for the Tyrer-Cuzick with Volpara breast-density measurement and SNP testing. Limitations This study did not use formal expert elicitation methods to synthesize estimates. Conclusion The costs of risk prediction using a survey and breast density measurement were low, but adding SNP testing substantially increases costs. Implementation issues present in the trial may also significantly increase the cost of risk prediction. Implications This is the first study to robustly estimate the cost of risk-stratification for breast cancer screening. The cost of risk prediction using questionnaires and automated breast density measurement was low, but full economic evaluations including accurate costs are required to provide evidence of the cost-effectiveness of risk-stratified breast cancer screening. Highlights Economic evaluations have suggested that risk-stratified breast cancer screening may be a cost-effective use of resources in the United Kingdom. Current estimates of the cost of risk stratification are based on pragmatic assumptions. This study provides estimates of the cost of risk stratification using 3 strategies and when these strategies are implemented perfectly and imperfectly in the health system. The cost of risk stratification is relatively low unless single nucleotide polymorphisms are included in the strategy.

Background: People who have experienced a stroke are at high risk of recurrent strokes. Clopidogrel is prescribed to people who have had a non-cardioembolic stroke. There is evidence that clopidogrel is not effective for patients with CYP2C19 loss-of-function alleles. Pharmacogenetic testing is a potential strategy to identify such patients and guide prescription of appropriate antiplatelet treatment. This study aimed to provide an early estimate of the cost-effectiveness of using a point-of-care pharmacogenetic CYP2C19 test in the UK National Health System. Methods: A decision-analytic model comprising a linked decision tree and Markov model were created in R comparing pharmacogenetic testing with current prescribing practice. In the pharmacogenetic testing arm, patients identified to have one of three loss-of-function alleles were prescribed modified-release dipyridamole and aspirin or aspirin alone. Indicative data were sourced from reviews of the literature supported by expert consultation to select the most appropriate value for the input parameters. The healthcare costs (£;2021) and quality adjusted life years resulting from each strategy were estimated and the incremental cost-effectiveness of testing calculated. Deterministic threshold analysis and probabilistic sensitivity analysis (PSA) was conducted to account for uncertainty in the parameter estimates. Results: The pharmacogenetic testing strategy generated 0.107 additional QALYs per patient tested and saved £512. Pharmacogenetic testing dominated current prescribing practice. The results were robust to extreme changes in key input variables. The PSA suggested that there was a 77% chance that pharmacogenetic testing would be cost-effective with a 62% chance it is cost-saving. Conclusions : A point-of-care pharmacogenetic test to guide prescription of clopidogrel for people who have experienced a stroke has the potential to provide a significant health gain by preventing secondary strokes and may save resources in the health system. This early economic analysis has also informed the direction for future research.

Background Risk stratification as a routine part of the NHS Breast Screening Programme (NHSBSP) could provide a better balance of benefits and harms. We developed BC-Predict, to offer women when invited to the NHSBSP, which collects standard risk factor information; mammographic density; and in a sub-sample, a Polygenic Risk Score (PRS). Methods Risk prediction was estimated primarily from self-reported questionnaires and mammographic density using the Tyrer–Cuzick risk model. Women eligible for NHSBSP were recruited. BC-Predict produced risk feedback letters, inviting women at high risk (≥8% 10-year) or moderate risk (≥5–<8% 10-year) to have appointments to discuss prevention and additional screening. Results Overall uptake of BC-Predict in screening attendees was 16.9% with 2472 consenting to the study; 76.8% of those received risk feedback within the 8-week timeframe. Recruitment was 63.2% with an onsite recruiter and paper questionnaire compared to <10% with BC-Predict only ( P < 0.0001). Risk appointment attendance was highest for those at high risk (40.6%); 77.5% of those opted for preventive medication. Discussion We have shown that a real-time offer of breast cancer risk information (including both mammographic density and PRS) is feasible and can be delivered in reasonable time, although uptake requires personal contact. Preventive medication uptake in women newly identified at high risk is high and could improve the cost-effectiveness of risk stratification. Trial registration Retrospectively registered with clinicaltrials.gov (NCT04359420).