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.

Mainstreaming of genomic medicine in gastroenterology, present and future: a nationwide survey of UK gastroenterology trainees.

OBJECTIVE: Genomics and personalised medicine are increasingly relevant for patients with gastroenterological conditions. We aim to capture the current state of genomics training in gastroenterology to review current understanding, clinical experience and long-term educational needs of UK trainees. DESIGN AND SETTING: A web-based nationwide survey of all UK gastroenterology specialty trainees was conducted in 2017. RESULTS: 100 trainees (14% of UK gastroenterology trainees) completed this survey. Only 9% and 16% of respondents believe that their local training programme adequately prepares them for the future clinical practice using genomic medicine and personalised medicine, respectively. Barriers identified include the need for greater trainee education (95%), inadequate clinical guidance to base interventions on the results of genomic testing (53%), concerns over misinterpretation by patients (43%) and overuse/misuse of testing by clinicians (34%).Survey respondents felt prepared to perform HFE genotyping (98%), assess TPMT status (97%) and interpret HLA subtyping for suspected coeliac disease (85%). However, only a minority felt prepared to perform the following investigations: polyposis screening (34%), hereditary pancreatitis screening (30%), testing for Lynch yndrome (33%) and KRAS testing for colorectal cancer (20%).Most respondents would support holding dedicated training days on genomic medicine (83%), formal training provisions for the mainstreaming of genomic testing (64%), an update to the UK gastroenterology specialty training curriculum and examinations (57%) and better-defined referral pathways for local genomic services (91%). CONCLUSION: Most gastroenterology trainees in this survey feel ill equipped to practise genomic and personalised medicine as consultants. We propose specific revisions to the UK gastroenterology specialty curriculum that addresses trainees needs.

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.

Genomics education for medical professionals - the current UK landscape.

Genomics education in the UK is at an early stage of development, and its pace of evolution has lagged behind that of the genomics research upon which it is based. As a result, knowledge of genomics and its applications remains limited among non-specialist clinicians. In this review article, we describe the complex landscape for genomics education within the UK, and highlight the large number and variety of organisations that can influence, direct and provide genomics training to medical professionals. Postgraduate genomics education is being shaped by the work of the Health Education England (HEE) Genomics Education Programme, working in conjunction with the Joint Committee on Genomics in Medicine. The success of their work will be greatly enhanced by the full cooperation and engagement of the many groups, societies and organisations involved with medical education and training (such as the royal colleges). Without this cooperation, there is a risk of poor coordination and unnecessary duplication of work. Leadership from an organisation such as the HEE Genomics Education Programme will have a key role in guiding the formulation and delivery of genomics education policy by various stakeholders among the different disciplines in medicine.

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.

Do Health Professionals Need Additional Competencies for Stratified Cancer Prevention Based on Genetic Risk Profiling?

There is growing evidence that inclusion of genetic information about known common susceptibility variants may enable population risk-stratification and personalized prevention for common diseases including cancer. This would require the inclusion of genetic testing as an integral part of individual risk assessment of an asymptomatic individual. Front line health professionals would be expected to interact with and assist asymptomatic individuals through the risk stratification process. In that case, additional knowledge and skills may be needed. Current guidelines and frameworks for genetic competencies of non-specialist health professionals place an emphasis on rare inherited genetic diseases. For common diseases, health professionals do use risk assessment tools but such tools currently do not assess genetic susceptibility of individuals. In this article, we compare the skills and knowledge needed by non-genetic health professionals, if risk-stratified prevention is implemented, with existing competence recommendations from the UK, USA and Europe, in order to assess the gaps in current competences. We found that health professionals would benefit from understanding the contribution of common genetic variations in disease risk, the rationale for a risk-stratified prevention pathway, and the implications of using genomic information in risk-assessment and risk management of asymptomatic individuals for common disease prevention.

Systematic review and meta-analysis to estimate the birth prevalence of five inherited metabolic diseases.

Many newborn screening programmes now use tandem mass spectrometry in order to screen for a variety of diseases. However, countries have embraced this technology with a differing pace of change and for different conditions. This has been facilitated by the ability of this diagnostic method to limit analysis to specific metabolites of interest, enabling targeted screening for particular conditions. MS/MS was introduced in 2009 in England to implement newborn bloodspot screening for medium chain acyl-CoA dehydrogenase deficiency (MCADD) raising the possibility of screening for other inherited metabolic disorders. Recently, a pilot screening programme was conducted in order to evaluate the health and economic consequences of screening for five additional inherited metabolic disorders in England. As part of this study we conducted a systematic review and meta-analysis to estimate the birth prevalence of these conditions: maple syrup urine disease, homocystinuria (pyridoxine unresponsive), glutaric aciduria type I, isovaleric acidaemia and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency including trifunctional protein deficiency. We identified a total of 99 studies that were able to provide information on the prevalence of one or more of the disorders. The vast majority of studies were of screening programmes with some reporting on clinically detected cases.

'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.

What ethical and legal principles should guide the genotyping of children as part of a personalised screening programme for common cancer?

Increased knowledge of the gene-disease associations contributing to common cancer development raises the prospect of population stratification by genotype and other risk factors. Individual risk assessments could be used to target interventions such as screening, treatment and health education. Genotyping neonates, infants or young children as part of a systematic programme would improve coverage and uptake, and facilitate a screening package that maximises potential benefits and minimises harms including overdiagnosis. This paper explores the potential justifications and risks of genotyping children for genetic variants associated with common cancer development within a personalised screening programme. It identifies the ethical and legal principles that might guide population genotyping where the predictive value of the testing is modest and associated risks might arise in the future, and considers the standards required by population screening programme validity measures (such as the Wilson and Jungner criteria including cost-effectiveness and equitable access). These are distinguished from the normative principles underpinning predictive genetic testing of children for adult-onset diseases-namely, to make best-interests judgements and to preserve autonomy. While the case for population-based genotyping of neonates or young children has not yet been made, the justifications for this approach are likely to become increasingly compelling. A modified evaluative and normative framework should be developed, capturing elements from individualistic and population-based approaches. This should emphasise proper communication and genuine parental consent or informed choice, while recognising the challenges associated with making unsolicited approaches to an asymptomatic group. Such a framework would be strengthened by complementary empirical research.

Health needs assessment for congenital anomalies in middle-income countries: Examining the case for neural tube defects in Brazil.

Recent economic improvement in Brazil has been reflected in better maternal-child health indicators, with decreases in infant and perinatal mortality. However, under-five mortality due to congenital disorders remained unchanged, and congenital disorders have become the second leading cause of infant mortality. In the present study, we used the PHG Foundation Health Needs Assessment (HNA) Toolkit with the objective of first assessing the burden of disease caused by neural tube defects (NTDs) in Brazil and the impact of interventions already put in place to address the burden, and second to evaluate and prioritize further interventions and policies required for its prevention and treatment. The results from these two components of the HNA process are described in this paper. The published literature was reviewed to identify studies of NTDs (prevalence; morbidity; prenatal, perinatal, and postnatal mortality; treatment or prevention). Data on indicators of maternal and child health were obtained directly from the Brazilian Ministry of Health, through the online Live Births Information System (SINASC) and from the Mortality Information System (SIM). Descriptive analyses included reports of the rates of NTD in liveborns, fetal, and infant deaths. Differences between folic acid flour pre-fortification (2001-2004) and post-fortification (2006-2010) periods were expressed as prevalence rate ratios. Around 20 % of fetal deaths were related to congenital disorders with approximately 5 % of those being NTDs. For infant mortality, congenital disorders were notified in approximately 15 % of cases, with NTDs present in 10 % of the malformed children. Although statistically significant, the prevalence rate ratio (PRR) for spina bifida in live births was only 0.937 (95 % confidence interval (CI) 0.884-0.994), a decrease of 6.3 % when comparing the pre and post-fortification periods. The impact of fortification seemed to be more visible in fetal deaths due to anencephaly (PRR = 0.727, 95 % CI 0.681-0.777) and for spina bifida (PRR = 0.700, 95 % CI 0.507-0.967) with associated decreases of 27.3 and 30 %. The lower impact of folic acid fortification in Brazil, compared to other Latin-American countries, can be due to differences in dietary habits, concentration of folic acid in flour, as well as characteristic population ethnic composition. The HNA led to the identification of the needs to be addressed in Brazil, including the improvement of reporting congenital disorders within the nationwide birth certification system, and revision of the policy of flour folic acid fortification.

Life insurance: genomic stratification and risk classification.

With the development and increasing accessibility of new genomic tools such as next-generation sequencing, genome-wide association studies, and genomic stratification models, the debate on genetic discrimination in the context of life insurance became even more complex, requiring a review of current practices and the exploration of new scenarios. In this perspective, a multidisciplinary group of international experts representing different interests revisited the genetics and life insurance debate during a 2-day symposium 'Life insurance: breast cancer research and genetic risk prediction seminar' held in Quebec City, Canada on 24 and 25 September 2012. Having reviewed the current legal, social, and ethical issues on the use of genomic information in the context of life insurance, the Expert Group identified four main questions: (1) Have recent developments in genomics and related sciences changed the contours of the genetics and life insurance debate? (2) Are genomic results obtained in a research context relevant for life insurance underwriting? (3) Should predictive risk assessment and risk stratification models based on genomic data also be used for life insurance underwriting? (4) What positive actions could stakeholders in the debate take to alleviate concerns over the use of genomic information by life insurance underwriters? This paper presents a summary of the discussions and the specific action items recommended by the Expert Group.

Familial hypercholesterolaemia: a pressing issue for European health care.

The recent European Atherosclerosis Society (EAS) guidelines for the management of familial hypercholesterolaemia (FH) succinctly reiterate the under-diagnosis and poor management of this common genetic disorder, which is associated with greatly increased mortality from coronary heart disease (CHD), especially in young people. The prevalence of FH is thought to be between 1/500 and 1/200, and thus in Europe 1.8-4.5 million individuals have FH. In most European countries including the UK, fewer than 15% of cases have been identified to date, amounting to over 100,000 undiagnosed cases in the UK alone. There are a number of issues that have impeded the implementation of FH diagnostic and management guidelines in Europe; here, we briefly review the current situation in the UK, and propose ways to start to break down implementation barriers that may be applicable across Europe. Despite guidelines by the UK National Institute of Health and Clinical Excellence (NICE) published in 2008 that recommend genetic testing of index cases and cascade screening of their family members, and the recent NICE Quality Standards for management of FH (QS41), there has been little action towards systematic diagnosis in England despite implementation of systematic screening programmes in Scotland, Wales, Northern Ireland and in other selected countries in Europe. This is surprising because early treatment with statins provides an effective and cheap treatment that reduces mortality to near that found in the normolipidaemic population. With increasing emphasis on preventive medicine and genetic diagnosis across the medical specialties, FH is a clear example of how new genome technologies can - and should - be deployed now for the benefit of patients.

Systematic review of birth prevalence of neural tube defects in India.

BACKGROUND: Neural tube defects are one of the most prevalent congenital anomalies. Data on the total birth prevalence, live birth and stillbirth prevalence of neural tube defects in India are lacking. The objective of this study is to conduct a systematic review of birth prevalence of neural tube defects in India and compare it with existing estimates. METHODS: A PubMed search identified 463 articles, of which 19 articles were eligible for inclusion in the review. Meta-analysis was used to estimate the overall birth prevalence of neural tube defects and to investigate the variation among studies identified by this review. RESULTS: The 19 articles reported a total of 308,387 births, among which 1310 cases of neural tube defects were reported, giving an overall birth prevalence of 4.1 per 1000 (95% confidence interval [CI], 3.1-5.4). The live birth and stillbirth prevalence of neural tube defects was 1.3 per 1000 births (95% CI, 0.9-1.8) and 1.7 per 1000 births (95% CI, 0.7-4.0), respectively. Among the neural tube defects, the reported prevalence of anencephaly was highest at 2.1 per 1000 births (95% CI, 1.6-2.8) followed by spina bifida at 1.9 per 1000 births (95% CI, 1.4-2.7). CONCLUSION: The systematic review suggests that neural tube defects contribute to a significant number of live births and stillbirths in India, suggesting that preconception folic acid supplementation should be an essential element of reproductive health services.

Public health implications from COGS and potential for risk stratification and screening.

The PHG Foundation led a multidisciplinary program, which used results from COGS research identifying genetic variants associated with breast, ovarian and prostate cancers to model risk-stratified prevention for breast and prostate cancers. Implementing such strategies would require attention to the use and storage of genetic information, the development of risk assessment tools, new protocols for consent and programs of professional education and public engagement.

Incorporating genomics into breast and prostate cancer screening: assessing the implications.

Individual risk prediction and stratification based on polygenic profiling may be useful in disease prevention. Risk-stratified population screening based on multiple factors including a polygenic risk profile has the potential to be more efficient than age-stratified screening. In this article, we summarize the implications of personalized screening for breast and prostate cancers. We report the opinions of multidisciplinary international experts who have explored the scientific, ethical, and logistical aspects of stratified screening. We have identified (i) the need to recognize the benefits and harms of personalized screening as compared with existing screening methods, (ii) that the use of genetic data highlights complex ethical issues including discrimination against high-risk individuals by insurers and employers and patient autonomy in relation to genetic testing of minors, (iii) the need for transparency and clear communication about risk scores, about harms and benefits, and about reasons for inclusion and exclusion from the risk-based screening process, and (iv) the need to develop new professional competences and to assess cost-effectiveness and acceptability of stratified screening programs before implementation. We conclude that health professionals and stakeholders need to consider the implications of incorporating genetic information in intervention strategies for health-care planning in the future.