Polygenic susceptibility to breast cancer and implications for prevention.

The knowledge of human genetic variation that will come from the human genome sequence makes feasible a polygenic approach to disease prevention, in which it will be possible to identify individuals as susceptible by their genotype profile and to prevent disease by targeting interventions to those at risk. There is doubt, however, regarding the magnitude of these genetic effects and thus the potential to apply them to either individuals or populations. We have therefore examined the potential for prediction of risk based on common genetic variation using data from a population-based series of individuals with breast cancer. The data are compatible with a log-normal distribution of genetic risk in the population that is sufficiently wide to provide useful discrimination of high- and low-risk groups. Assuming all of the susceptibility genes could be identified, the half of the population at highest risk would account for 88% of all affected individuals. By contrast, if currently identified risk factors for breast cancer were used to stratify the population, the half of the population at highest risk would account for only 62% of all cases. These results suggest that the construction and use of genetic-risk profiles may provide significant improvements in the efficacy of population-based programs of intervention for cancers and other diseases.

Regulating direct-to-consumer genetic tests: what is all the fuss about?

The number of genetic tests available direct-to-consumer has burgeoned over the last few years, prompting numerous calls for tighter regulation of these services. However, there is a lack of consensus about the most appropriate and achievable level of regulation, particularly given the global nature of the market. By consideration of potential for direct and indirect harms caused by genetic susceptibility or genomic profiling tests, in this study we offer an overarching framework that we believe to be feasible for the regulation of direct-to-consumer genetic tests and likely to be relevant to other forms of predictive testing. We suggest that just five key requirements would adequately protect the consumer: a proportionate set of consent procedures; formal laboratory accreditation; evidence of a valid gene-disease association; appropriately qualified staff to interpret the test result; and consumer protection legislation to prevent false or misleading claims.

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.

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.

Conceptual issues for screening in the genomic era - time for an update?

BACKGROUND: Screening tests are ubiquitous in modern medicine; however a consensus view on the criteria that distinguish screening from clinical testing remains strangely elusive. although numerous definitions of screening have been suggested, there is considerable variation amongst them, leading to confusion and disagreement amongst clinicians and public health professionals alike. In light of developments in genomics, the question of what screening entails is becoming increasingly pressing. METHODS: We evaluated the concepts underlying definitions of screening versus clinical testing and investigated their ethical implications. RESULTS: We suggest that just two key concepts underlie screening: first, screening tests are performed in asymptomatic individuals and, second, they are generally offered to individuals who otherwise believe themselves to be healthy (with respect to the disease being screened for). all the other characteristics commonly invoked to describe screening - including the systematic use of rapid tests for risk stratification within a particular population - can be better categorised as either practical requirements or by-products of screening programmes rather than screening tests. CONCLUSIONS: We emphasise the need to differentiate between opportunistic screening and clinical testing because of the differing prior probability of disease and thus the differing ethical burden of responsibility placed upon the physician in each scenario. Physicians need to appreciate the shifting moral burden placed upon them in relation to reactive clinical testing versus proactive screening, and the different legal obligations that may ensue.

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.

Ensuring the appropriate use of genetic tests.

Ensuring the correct use of genetic tests is an important challenge for health-policy makers. Many new genetic tests will identify susceptibility to common diseases or adverse drug responses. Some will lead to new prevention opportunities, but others will have minimal clinical value. Statutory regulation alone cannot guarantee appropriate use. Other strategies, including resource allocation and matters related to clinical governance - such as practice-guideline development and health-provider education - are also important.

Genetic tests and their evaluation: can we answer the key questions?

The rapid pace of research in the field of genetics has already yielded many benefits. The development of new genetic tests is one such example. Before there can be widespread uptake of these tests they need to be evaluated to confirm the benefits of their use. The authors review some of the key features of the evaluation of diagnostic tests focusing on analytical and clinical validity. Test properties such as sensitivity, specificity, likelihood ratios, positive and negative predictive values, and how they relate to molecular genetic testing are discussed. Associated issues such as the concepts of disease definition, imperfect reference standards, and false positives are also explored. The authors suggest possible approaches to addressing some of the problems identified.

High "population attributable fraction" for coronary heart disease mortality among relatives in monogenic familial hypercholesterolemia.

PURPOSE: To estimate "population attributable fraction" (PAF) for coronary heart disease (CHD) mortality in a population of first-degree relatives of patients with monogenic familial hypercholesterolemia (FH) compared with the PAF for hypercholesterolemia in the general population. METHODS: PAF was calculated as [f(R - 1)/[1 + f(R - 1)]], where f is the frequency of the risk factor (hypercholesterolemia) and R is the relative risk for the association of hypercholesterolemia and CHD death. For FH relatives, f was assumed to be 50%, based on a fully penetrant, dominant mode of inheritance, and R values were obtained from the prospective Simon Broome Register data. PAFs for hypercholesterolemia and CHD death in the general population were based on the Framingham risk equations for the 95th percentile of cholesterol and CHD mortality. RESULTS: Over all ages, 44% and 57% of 5-year CHD mortality could potentially be prevented among male and female first-degree relatives in FH families, respectively, by cholesterol reduction. In contrast, values for 5-year CHD death for hypercholesterolemia in the general population were uniformly lower at all ages, with overall 5% and 10% of fatal CHD prevented among men and women, respectively. CONCLUSION: These results strongly support the view that family based testing strategies of relatives of probands with monogenic hypercholesterolemia, followed by effective lipid lowering drug treatment, is a highly effective way of reducing CHD deaths among these relatives.

Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review.

The clinical phenotype of heterozygous familial hypercholesterolemia (FH) is characterized by increased plasma levels of total cholesterol and low density lipoprotein cholesterol, tendinous xanthomata, and premature symptoms of coronary heart disease. It is inherited as an autosomal dominant disorder with homozygotes having a more severe phenotype than do heterozygotes. FH can result from mutations in the low density lipoprotein receptor gene (LDLR), the apolipoprotein B-100 gene (APOB), and the recently identified proprotein convertase subtilisin/kexin type 9 gene (PCSK9). To date, over 700 variants have been identified in the LDLR gene. With the exception of a small number of founder populations where one or two mutations predominate, most geographically based surveys of FH subjects show a large number of mutations segregating in a given population. Studies of the prevalence of FH would be improved by the use of a consistent and uniformly applied clinical definition. Because FH responds well to drug treatment, early diagnosis to reduce atherosclerosis risk is beneficial. Cascade testing of FH family members is cost effective and merits further research. For screening to be successful, public health and general practitioners need to be aware of the signs and diagnosis of FH and the benefits of early treatment.

Familial hypercholesterolemia and coronary heart disease: a HuGE association review.

Familial hypercholesterolemia (FH) is an autosomal disorder characterized by increased levels of total cholesterol and low density lipoprotein cholesterol. The FH clinical phenotype has been shown to be associated with increased coronary heart disease and premature death. Mutations in the low density lipoprotein receptor gene (LDLR) can result in the FH phenotype, and there is evidence that receptor-negative mutations result in a more severe phenotype than do receptor-defective mutations. Mutations in the apolipoprotein B-100 gene (APOB) can result in a phenotype that is clinically indistinguishable from familial hypercholesterolemia, and mutations in this gene have also been shown to be associated with coronary heart disease. Preliminary research indicates that the FH phenotype is influenced by other genetic and environmental factors; however, it is not clear if these are synergistic interactions or simply additive effects.