Towards implementation of comprehensive breast cancer risk prediction tools in health care for personalised prevention.

Advances in knowledge about breast cancer risk factors have led to the development of more comprehensive risk models. These integrate information on a variety of risk factors such as lifestyle, genetics, family history, and breast density. These risk models have the potential to deliver more personalised breast cancer prevention. This is through improving accuracy of risk estimates, enabling more effective targeting of preventive options and creating novel prevention pathways through enabling risk estimation in a wider variety of populations than currently possible. The systematic use of risk tools as part of population screening programmes is one such example. A clear understanding of how such tools can contribute to the goal of personalised prevention can aid in understanding and addressing barriers to implementation. In this paper we describe how emerging models, and their associated tools can contribute to the goal of personalised healthcare for breast cancer through health promotion, early disease detection (screening) and improved management of women at higher risk of disease. We outline how addressing specific challenges on the level of communication, evidence, evaluation, regulation, and acceptance, can facilitate implementation and uptake.

How can we address the uncertainties regarding the potential clinical utility of polygenic score-based tests?

As common low penetrance variants associated with diseases are uncovered, attempts continue to be made to harness this knowledge for improving healthcare. Polygenic scores have been developed as the mechanism by which knowledge of common variants can be used to investigate genetic contributions to disease risk. They serve as a biomarker to provide an estimate of the genetic liability for a particular disease. Discussion continues as to whether polygenic scores are a useful biomarker and their readiness for incorporation into clinical and public health practice. In this paper, we investigate the key challenges that need to be addressed, in the description and assessment of the clinical utility of polygenic score-based tests for use in clinical and public health practice.

The risk of developing many common diseases, such as heart disease is influenced by both genetic and lifestyle factors. Polygenic scores (PGS) are one way of assessing an individual's risk of developing certain diseases. There is still uncertainty as to whether and how to use PGS for individual care. Much of this is because it is unclear as to whether tests that give a PGS can provide useful information for the care of individuals and patients as part of prevention or healthcare pathways. In this paper, we describe some of the challenges that need to be addressed, so that we can move forward and better understand when and how to use these tests for population and individual benefit.

Optimising Exome Prenatal Sequencing Services (EXPRESS): a study protocol to evaluate rapid prenatal exome sequencing in the NHS Genomic Medicine Service.

Background: Prenatal exome sequencing (ES) for the diagnosis of fetal anomalies was implemented nationally in England in October 2020 by the NHS Genomic Medicine Service (GMS). is the GMS is based around seven regional Genomic Laboratory Hubs (GLHs). Prenatal ES has the potential to significantly improve NHS prenatal diagnostic services by increasing genetic diagnoses and informing prenatal decision-making. Prenatal ES has not previously been offered routinely in a national healthcare system and there are gaps in knowledge and guidance. Methods: Our mixed-methods evaluation commenced in October 2020, aligning with the start date of the NHS prenatal ES service . Study design draws on a framework developed in previous studies of major system innovation. There are five interrelated workstreams. Workstream-1 will use interviews and surveys with professionals, non-participant observations and documentary analysis to produce in-depth case studies across all GLHs. Data collection at multiple time points will track changes over time. In Workstream-2 qualitative interviews with parents offered prenatal ES will explore experiences and establish information and support needs. Workstream-3 will analyse data from all prenatal ES tests for nine-months to establish service outcomes (e.g. diagnostic yield, referral rates, referral sources). Comparisons between GLHs will identify factors (individual or service-related) associated with any variation in outcomes. Workstream-4 will identify and analyse practical ethical problems. Requirements for an effective ethics framework for an optimal and equitable service will be determined. Workstream-5 will assess costs and cost-effectiveness of prenatal ES versus standard tests and evaluate costs of implementing an optimal prenatal ES care pathway. Integration of findings will determine key features of an optimal care pathway from a service delivery, parent and professional perspective. Discussion: The proposed formative and summative evaluation will inform the evolving prenatal ES service to ensure equity of access, high standards of care and benefits for parents across England.

BACKGROUND: Prenatal exome sequencing is a new test that is offered through the NHS Genomic Medicine Service. Prenatal exome sequencing is offered to pregnant women when ultrasound scans suggest that their baby may have a genetic condition that cannot be diagnosed using standard tests. If a genetic condition is diagnosed this can give parents important information about the outlook for their baby. It can also help with their decisions about whether to continue or end the pregnancy, pregnancy management, post-birth care and future pregnancies. STUDY METHODS: The aim of this study is to evaluate the prenatal exome sequencing service. To do this we will; 1. Study how prenatal exome sequencing is delivered across England using surveys and interviews with professionals.2. Interview parents to ask what they think of prenatal exome sequencing and how support and information could be improved3. Look at how many parents have prenatal exome sequencing and the test results. We will look carefully at who has access to the test and whether any particular groups are less likely to be offered testing.4. Conduct workshops with health professionals and parents to identify any practical or ethical problems that arise when prenatal exome sequencing is offered.5. Look at the cost of prenatal exome sequencing and compare it to the cost of other tests that are offered to diagnose genetic conditions in pregnancy.6. Gather our findings together to make recommendations for best practice. Patient and Public Involvement: A patient and public Involvement, engagement and participation (PPIEP) advisory group will work closely with the research team to design the study and develop study materials. They will also help us understand our findings to make sure the information and recommendations that come out of our research will be helpful to parents and the NHS.

Understanding polygenic models, their development and the potential application of polygenic scores in healthcare.

The use of genomic information to better understand and prevent common complex diseases has been an ongoing goal of genetic research. Over the past few years, research in this area has proliferated with several proposed methods of generating polygenic scores. This has been driven by the availability of larger data sets, primarily from genome-wide association studies and concomitant developments in statistical methodologies. Here we provide an overview of the methodological aspects of polygenic model construction. In addition, we consider the state of the field and implications for potential applications of polygenic scores for risk estimation within healthcare.

Risk stratification, genomic data and the law.

Risk prediction models have a key role in stratified disease prevention, and the incorporation of genomic data into these models promises more effective personalisation. Although the clinical utility of incorporating genomic data into risk prediction tools is increasingly compelling, at least for some applications and disease types, the legal and regulatory implications have not been examined and have been overshadowed by discussions about clinical and scientific utility and feasibility. We held a workshop to explore relevant legal and regulatory perspectives from four EU Member States: France, Germany, the Netherlands and the UK. While we found no absolute prohibition on the use of such data in those tools, there are considerable challenges. Currently, these are modest and result from genomic data being classified as sensitive data under existing Data Protection regulation. However, these challenges will increase in the future following the implementation of EU Regulations on data protection which take effect in 2018, and reforms to the governance of the manufacture, development and use of in vitro diagnostic devices to be implemented in 2022. Collectively these will increase the regulatory burden placed on these products as risk stratification tools will be brought within the scope of these new Regulations. The failure to respond to the challenges posed by the use of genomic data in disease risk stratification tools could therefore prove costly to those developing and using such tools.

Uptake, outcomes, and costs of implementing non-invasive prenatal testing for Down's syndrome into NHS maternity care: prospective cohort study in eight diverse maternity units.

OBJECTIVE:  To investigate the benefits and costs of implementing non-invasive prenatal testing (NIPT) for Down's syndrome into the NHS maternity care pathway. DESIGN:  Prospective cohort study. SETTING:  Eight maternity units across the United Kingdom between 1 November 2013 and 28 February 2015. PARTICIPANTS:  All pregnant women with a current Down's syndrome risk on screening of at least 1/1000. MAIN OUTCOME MEASURES:  Outcomes were uptake of NIPT, number of cases of Down's syndrome detected, invasive tests performed, and miscarriages avoided. Pregnancy outcomes and costs associated with implementation of NIPT, compared with current screening, were determined using study data on NIPT uptake and invasive testing in combination with national datasets. RESULTS:  NIPT was prospectively offered to 3175 pregnant women. In 934 women with a Down's syndrome risk greater than 1/150, 695 (74.4%) chose NIPT, 166 (17.8%) chose invasive testing, and 73 (7.8%) declined further testing. Of 2241 women with risks between 1/151 and 1/1000, 1799 (80.3%) chose NIPT. Of 71 pregnancies with a confirmed diagnosis of Down's syndrome, 13/42 (31%) with the diagnosis after NIPT and 2/29 (7%) after direct invasive testing continued, resulting in 12 live births. In an annual screening population of 698 500, offering NIPT as a contingent test to women with a Down's syndrome screening risk of at least 1/150 would increase detection by 195 (95% uncertainty interval -34 to 480) cases with 3368 (2279 to 4027) fewer invasive tests and 17 (7 to 30) fewer procedure related miscarriages, for a non-significant difference in total costs (£-46 000, £-1 802 000 to £2 661 000). The marginal cost of NIPT testing strategies versus current screening is very sensitive to NIPT costs; at a screening threshold of 1/150, NIPT would be cheaper than current screening if it cost less than £256. Lowering the risk threshold increases the number of Down's syndrome cases detected and overall costs, while maintaining the reduction in invasive tests and procedure related miscarriages. CONCLUSIONS:  Implementation of NIPT as a contingent test within a public sector Down's syndrome screening programme can improve quality of care, choices for women, and overall performance within the current budget. As some women use NIPT for information only, the Down's syndrome live birth rate may not change significantly. Future research should consider NIPT uptake and informed decision making outside of a research setting.

Implications of using whole genome sequencing to test unselected populations for high risk breast cancer genes: a modelling study.

BACKGROUND: The decision to test for high risk breast cancer gene mutations is traditionally based on risk scores derived from age, family and personal cancer history. Next generation sequencing technologies such as whole genome sequencing (WGS) make wider population testing more feasible. In the UK's 100,000 Genomes Project, mutations in 16 genes including BRCA1 and BRCA2 are to be actively sought regardless of clinical presentation. The implications of deploying this approach at scale for patients and clinical services are unclear. In this study we aimed to model the effect of using WGS to test an unselected UK population for high risk BRCA1 and BRCA2 gene variants to inform the debate around approaches to secondary genomic findings. METHODS: We modelled the test performance of WGS for identifying pathogenic BRCA1 and BRCA2 mutations in an unselected hypothetical population of 100,000 UK women, using published literature to derive model input parameters. We calculated analytic and clinical validity, described potential health outcomes and highlighted current areas of uncertainty. We also performed a sensitivity analysis in which we re-ran the model 100,000 times to investigate the effect of varying input parameters. RESULTS: In our models WGS was predicted to identify correctly 93 pathogenic BRCA1 mutations and 151 BRCA2 mutations in 120 and 200 women respectively, resulting in an analytic sensitivity of 75.5-77.5 %. Of 244 women with identified pathogenic mutations, we estimated that 132 (range 121-198) would develop breast cancer, so could potentially be helped by intervention. We also predicted that breast cancer would occur in 41 women (range 36-62) incorrectly identified with no pathogenic mutations and in 12,460 women without BRCA1 or BRCA2 mutations. There was considerable uncertainty about the penetrance of mutations in people without a family history of disease and the appropriate threshold of absolute disease risk for clinical action, which impacts on judgements about the clinical utility of intervention. CONCLUSIONS: This simple model demonstrates the need for robust processes to support the testing for secondary genomic findings in unselected populations that acknowledge levels of uncertainty about the clinical validity and clinical utility of testing positive for a cancer risk gene.

Points to consider for prioritizing clinical genetic testing services: a European consensus process oriented at accountability for reasonableness.

Given the cost constraints of the European health-care systems, criteria are needed to decide which genetic services to fund from the public budgets, if not all can be covered. To ensure that high-priority services are available equitably within and across the European countries, a shared set of prioritization criteria would be desirable. A decision process following the accountability for reasonableness framework was undertaken, including a multidisciplinary EuroGentest/PPPC-ESHG workshop to develop shared prioritization criteria. Resources are currently too limited to fund all the beneficial genetic testing services available in the next decade. Ethically and economically reflected prioritization criteria are needed. Prioritization should be based on considerations of medical benefit, health need and costs. Medical benefit includes evidence of benefit in terms of clinical benefit, benefit of information for important life decisions, benefit for other people apart from the person tested and the patient-specific likelihood of being affected by the condition tested for. It may be subject to a finite time window. Health need includes the severity of the condition tested for and its progression at the time of testing. Further discussion and better evidence is needed before clearly defined recommendations can be made or a prioritization algorithm proposed. To our knowledge, this is the first time a clinical society has initiated a decision process about health-care prioritization on a European level, following the principles of accountability for reasonableness. We provide points to consider to stimulate this debate across the EU and to serve as a reference for improving patient management.

Evaluation of non-invasive prenatal testing (NIPT) for aneuploidy in an NHS setting: a reliable accurate prenatal non-invasive diagnosis (RAPID) protocol.

BACKGROUND: Non-invasive prenatal testing (NIPT) for aneuploidies is now available through commercial companies in many countries, including through private practice in the United Kingdom (UK). Thorough evaluation of service delivery requirements are needed to facilitate NIPT being offered more widely within state funded healthcare systems such as the UK's National Health Service (NHS). Successful implementation will require the development of laboratory standards, consideration of stakeholder views, an analysis of costs and development of patient and health professional educational materials. METHODS/DESIGN: NIPT will be offered in an NHS setting as a contingent screening test. Pregnant woman will be recruited through six maternity units in England and Scotland. Women eligible for Down's syndrome screening (DSS) will be informed about the study at the time of booking. Women that choose routine DSS will be offered NIPT if they have a screening risk ≥ 1:1000. NIPT results for trisomy 21, 18, 13 will be reported within 7-10 working days. Data on DSS, NIPT and invasive testing uptake, pregnancy outcomes and test efficacy will be collected. Additional data will be gathered though questionnaires to a) determine acceptability to patients and health professionals, b) evaluate patient and health professional education, c) assess informed choice in women accepting or declining testing and d) gauge family expenses. Qualitative interviews will also be conducted with a sub-set of participating women and health professionals. DISCUSSION: The results of this study will make a significant contribution to policy decisions around the implementation of NIPT for aneuploidies within the UK NHS. The laboratory standards for testing and reporting, education materials and counselling strategies developed as part of the study are likely to underpin the introduction of NIPT into NHS practice. NIHR PORTFOLIO NUMBER: 13865.

'Personalized medicine': what's in a name?

Over the last decade genomics and other molecular biosciences have enabled new capabilities that, according to many, have the potential to revolutionize medicine and healthcare. These developments have been associated with a range of terminologies, including 'precision', 'personalized', 'individualized' and 'stratified' medicine. In this article, based on a literature review, we examine how the terms have arisen and their various meanings and definitions. We discuss the impact of the new technologies on disease classification, prevention and management. We suggest that although genomics and molecular biosciences will undoubtedly greatly enhance the power of medicine, they will not lead to a conceptually new paradigm of medical care. What is new is the portfolio of modern tools that medicine and healthcare can use for better targeted approaches to health and disease management, and the sociopolitical contexts within which these tools are applied.

A framework for the prioritization of investment in the provision of genetic tests.

BACKGROUND: The UK Genetic Testing Network (UKGTN) established a process for the evaluation of genetic tests for entry onto the National Health Service (NHS) Directory of Molecular Genetic Testing. The Network requested the development and piloting of a prioritization framework that could be used for the commissioning of genetic tests by the NHS. METHODS: A selected working group developed and piloted a multi-criteria prioritization process using 10 genetic tests evaluated by the UKGTN. RESULTS: The framework was able to rank the 10 genetic tests used in the pilot. The rankings were also consistent with the commissioning recommendations for these genetic tests by the UKGTN. CONCLUSION: A set of criteria for the prioritization of genetic tests has been developed. The results from the pilot suggest that the methodology is valid and robust but requires considerable resources to implement. Further development of the process is needed before the framework could be used to influence commissioning decisions for clinical genetic services in the NHS.

Evaluation of genetic tests for susceptibility to common complex diseases: why, when and how?

Recent research into the human genome has generated a wealth of scientific knowledge and increased both public and professional interest in the concept of personalised medicine. Somewhat unexpectedly, in addition to increasing our understanding about the genetic basis for numerous diseases, these new discoveries have also spawned a burgeoning new industry of 'consumer genetic testing'. In this paper, we present the principles learnt though the evaluation of tests for single gene disorders and suggest a comparable framework for the evaluation of genetic tests for susceptibility to common complex diseases. Both physicians and the general public will need to be able to assess the claims made by providers of genetic testing services, and ultimately policy-makers will need to decide if and when such tests should be offered through state funded healthcare systems.

HER2 status in breast cancer--an example of pharmacogenetic testing.

The development of new drugs and associated pharmacogenetic tests will provide an increasing number of challenges to health care systems. In particular, how to evaluate their benefits, prioritize for commissioning purposes and implement a service to provide them in a timely manner. This paper presents an overview of HER2 testing for trastuzumab (Herceptin) treatment in breast cancer cases. Immunohistochemistry and fluorescence in situ hybridization laboratory techniques are described and their HER2 testing performances are compared. Future options for the national provision of HER2 testing by the National Health Service in the UK are also discussed.

How can genetic tests be evaluated for clinical use? Experience of the UK Genetic Testing Network.

The UK Department of Health supported the establishment of the UK Genetic Testing Network (UKGTN) in 2002. The UKGTN is a collaborative network of NHS molecular genetic laboratories that offer tests for human single gene germ-line disorders. Its objective is to provide high quality and equitable services for patients and their families who require genetic advice, diagnosis and management. The UKGTN has developed a 'Gene Dossier' process to evaluate genetic tests and recommend which tests will be provided by the National Health Service. This paper describes the UKGTN organisation and the 'Gene Dossier' process. A brief review of the UKGTN genetic test evaluation experience is presented.

The evaluation of genetic tests.

Scientific advances in genetics and molecular biology have been very successful in advancing our knowledge of biological mechanisms in health and disease, and in catalysing a variety of technological innovations. The number of genetic tests available has consequently increased exponentially over the last few years. Their development has not been accompanied by processes and systems to evaluate these tests in a proper and formal manner to establish their clinical validity and utility. A framework for the evaluation of genetic tests has been developed. This paper reviews the current practice of genetic test evaluation, highlighting the limitations and future challenges in this area of public health.

Array-based comparative genomic hybridization for investigating chromosomal abnormalities in patients with learning disability: systematic review meta-analysis of diagnostic and false-positive yields.

PURPOSE: Array-based comparative genomic hybridization is increasingly being used in patients with learning disability, in addition to existing cytogenetic techniques. This paper reports the results of an evaluation of this emerging technology and discusses the challenges faced in conducting the evaluation. METHODS: Systematic review and meta-analysis of studies investigating patients with learning disability and dysmorphic features in whom conventional cytogenetic analysis has proven negative. Conventional indices of clinical validity could not be calculated, and we use an alternative, based on the extent to which array-based comparative genomic hybridization met its clinical objectives. RESULTS: Seven studies (462 patients) were included. The overall diagnostic yield of causal abnormalities was 13% (95% confidence interval: 10-17%; heterogeneity test statistic I = 0%), and the overall number needed to test was eight (95% confidence interval: 6-10). The false-positive yield of noncausal abnormalities ranged from 5% to 67%, although this range was only 5% to 10% in six of the studies. CONCLUSION: Although promising, there is insufficient evidence to recommend introduction of this test into routine clinical practice. A number of important technical questions need answering, such as optimal array resolution, which clones to include, and the most appropriate platforms. A thorough assessment of clinical utility and cost-effectiveness compared with existing tests is also required.