Next-generation sequencing in the clinic: are we ready?

We are entering an era in which the cost of clinical whole-genome and targeted sequencing tests is no longer prohibitive to their application. However, currently the infrastructure is not in place to support both the patient and the physicians that encounter the resultant data. Here, we ask five experts to give their opinions on whether clinical data should be treated differently from other medical data, given the potential use of these tests, and on the areas that must be developed to improve patient outcome.

Revealing the results of whole-genome sequencing and whole-exome sequencing in research and clinical investigations: some ethical issues.

The introduction of new sequencing technologies whole-genome sequencing (WGS) and whole-exome sequencing (WES) that are much less finely targeted than previous genetic tests has resulted in ethical debate about what should be done with clinically significant findings that may arise during the sequencing process. In this piece we argue that, in addition to whether the finding has been intentionally sought or arises incidentally, the ethical issues concerning what should be done with WES and WGS findings are also influenced by whether sequencing occurs in a clinical or research setting. We argue that decisions about the disclosure of WGS and WES findings generated in the clinical context are much less ethically contentious than decision making about the feedback of research results. We conclude by calling for greater transparency about the purpose of sample collection, more explicit protocols for transitioning between research and clinical contexts and patients and research participants to be warned of the potential for incidental findings to be generated, their potential significance and the actions that might be taken as a result.

A road map for efficient and reliable human genome epidemiology.

Networks of investigators have begun sharing best practices, tools and methods for analysis of associations between genetic variation and common diseases. A Network of Investigator Networks has been set up to drive the process, sponsored by the Human Genome Epidemiology Network. A workshop is planned to develop consensus guidelines for reporting results of genetic association studies. Published literature databases will be integrated, and unpublished data, including 'negative' studies, will be captured by online journals and through investigator networks. Systematic reviews will be expanded to include more meta-analyses of individual-level data and prospective meta-analyses. Field synopses will offer regularly updated overviews.

Recommendations for returning genomic incidental findings? We need to talk!

The American College of Medical Genetics and Genomics recently issued recommendations for reporting incidental findings from clinical whole-genome sequencing and whole-exome sequencing. The recommendations call for evaluating a specific set of genes as part of all whole-genome sequencing/whole-exome sequencing and reporting all pathogenic variants irrespective of patient age. The genes are associated with highly penetrant disorders for which treatment or prevention is available. The effort to generate a list of genes with actionable findings is commendable, but the recommendations raise several concerns. They constitute a call for opportunistic screening, through intentional effort to identify pathogenic variants in specified genes unrelated to the clinical concern that prompted testing. Yet for most of the genes, we lack evidence about the predictive value of testing, genotype penetrance, spectrum of phenotypes, and efficacy of interventions in unselected populations. Furthermore, the recommendations do not allow patients to decline the additional findings, a position inconsistent with established norms. Finally, the recommendation to return adult-onset disease findings when children are tested is inconsistent with current professional consensus, including other policy statements of the American College of Medical Genetics and Genomics. Instead of premature practice recommendations, we call for robust dialogue among stakeholders to define a pathway to normatively sound, evidence-based guidelines.

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.

EuroGentest: DNA-based testing for heritable disorders in Europe.

OBJECTIVES: Regarding the recent attention to develop policies regarding the provision of clinical genetic testing services, access to, acceptance, utilisation and regulation of genetic services was investigated in selected European countries as well as one non-European country. METHODS: Data were collected on the basis of relevant international reports and sources accessible via the internet, from self- designed, internationally administered surveys and with the help of a panel of experts from European countries participating in several workshops as well as from National European Societies of Human Genetics. RESULTS: A selection of divergent health care systems was reviewed and compared (e.g. Finland, Germany, Portugal, Sweden, UK, France, Italy, Spain, Czech Republic, Lithuania and Serbia/Montenegro). For the evaluation of clinical validity and utility of genetic testing, background information was provided focussing on DNA-based testing for heritable disorders with a strong genetic component (usually due to the action of a single gene). CONCLUSIONS: There is great heterogeneity in genetic testing services among the countries surveyed. It is premature to mandate that genetic testing provided by clinical services meets professional standards regarding clinical validity and utility, because there is to date no consensus within the scientific community and among health care providers to what extent clinical validity and utility can and need to be assessed. Points to consider in the process of developing such standards are proposed.

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.

Will genomics widen or help heal the schism between medicine and public health?

We discuss the "schism" between medicine and public health in light of advances in genomics and the expected evolution of health care toward personalized treatment and prevention. Undoubtedly, genomics could deepen the divide between the two worlds, but it also represents an important and perhaps unique opportunity for healing the schism, given the volume of new scientific discoveries and their potential applications in all areas of health and disease. We argue that the integration of genomics into health care and disease prevention requires a strong medicine-public health partnership in the context of a population approach to a translational research agenda that includes four overlapping areas: (1) a joint focus on prevention-a traditional public health concern but now a promise of genomics in the realm of individualized primary prevention and early detection, (2) a population perspective, which requires a large amount of population-level data to validate gene discoveries for clinical applications, (3) commitment to evidence-based knowledge integration with thousands of potential genomic applications in practice, and (4) emphasis on health services research to evaluate outcomes, costs, and benefits in the real world. A strong medicine-public health partnership in the genomics era is needed for the translation of all scientific discoveries for the benefit of population health.

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.

Pharmacogenetics: policy needs for personal prescribing.

Pharmacogenetics involves genetic testing of individual patients to guide drug treatment. Proponents argue that pharmacogenetics will achieve major gains in drug safety and efficacy, and revolutionise marketing. Pharmacogenetics also raises several policy concerns, including the need for sound information for clinical decision-making on drug-genetic test combinations. Currently, the pharmacogenetics science base and the rate of emergence of clinical applications are uncertain. Most commentary on pharmacogenetics focuses on new compounds, yet older drugs cause most adverse events. Test regulation in the USA appears fundamentally different from Europe, where evidence of safety or efficacy may not be required. Genetics research is needed as part of post-marketing surveillance systems. In routine clinical practice, computer-based health records with relevant decision support systems will also be needed. Without health policy action, pharmacogenetics could produce a new generation of poorly evaluated tests and drugs, with medicine becoming significantly less evidence-based, leading to rising costs, patient hazard and exclusions of drug-related 'genetic minorities' from evaluated treatments.

Pharmacogenetics and public policy: expert views in Europe and North America.

The new genetics is stimulating the development of genetic testing of patients to help choose the best drug, adjust doses and avoid side effects. Proponents say that this personalized medicine will revolutionize drug development and healthcare. In a series of group meetings, 48 leading experts from regulatory agencies, industry, academia and consumer interests gave their opinions on the public policy priorities. Most believed that pharmacogenetics would have a clear impact on care within 15 years and that a public policy response was needed. The establishment of a good clinical evidence base should be a priority, together with addressing the needs of drug response gene minorities. A total of 72% also believed that postmarketing surveillance systems should be collecting DNA from patients experiencing moderate or severe adverse events.

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.