Christine Patch

How can the evaluation of genetic tests be enhanced? Lessons learned from the ACCE framework and evaluating genetic tests in the United Kingdom

Advances in genetic technology are increasing the availability of genetic tests, not only for rare single gene disorders, but also for common diseases such as breast and colo-rectal cancer. Before there can be widespread uptake of these tests, they must be evaluated to confirm the benefits of their use. But how should genetic tests be evaluated, given the speed at which new tests are emerging? One highly influential approach is the analytic validity, clinical validity, clinical utility and ethical, legal and social issues (ACCE) framework, which has provided a benchmark for the evaluation of genetic tests. The approach has been adopted and adapted by the United Kingdom Genetic Testing Network, with the help of the Public Health Genetics Unit in Cambridge, to evaluate new genetic tests for use in the National Health Service. We discuss a number of conceptual, methodological, and practical issues concerning the evaluation of genetic tests, based on lessons learned from applying the ACCE framework and from the UK experience, and make a number of recommendations to further strengthen the evaluation of genetic tests.

Use of Antihypertensive Medications and Mortality of Patients With Autosomal Dominant Polycystic Kidney Disease: A Population-Based Study

BACKGROUND This study aimed to estimate the association between antihypertensive therapy and mortality in patients with autosomal dominant polycystic kidney disease (ADPKD). STUDY DESIGN Cohort study. SETTING & PARTICIPANTS Participants with ADPKD from the UK General Practice Research Database older than 15 years between 1991 and 2008. PREDICTORS Use of 5 major classes of antihypertensive drug. OUTCOMES Deaths, new renal replacement therapy events. MEASUREMENTS Random-effects Poisson models were adjusted for age, sex, year of entry into the cohort, calendar year, prevalent coronary heart disease, stroke, diabetes, hyperlipidemia, and lipid-lowering therapy. RESULTS From 1991-2008, there were 2,085 cases of ADPKD, with 1,877 contributing person-time for ages older than 15 years. In 1991, antihypertensive drugs were not prescribed for 68% of participants, which decreased to 38% by 2008. The proportion for which 1 class of antihypertensive drug was prescribed increased from 19% in 1991 to 24% in 2008; 2 classes, from 11% to 22%; 3 classes, from 2% to 11%; and 4 or 5 classes, from 1% to 5%. In 1991, drugs acting on the renin-angiotensin system were prescribed for only 7% of participants; by 2008, this had increased to 46%. There was evidence of a trend toward decreasing mortality as the number of antihypertensive drug classes prescribed in a year increased. For participants with 3 classes of drugs prescribed, the incident rate ratio was 0.11 (95% CI, 0.05-0.21; P < 0.001). Each annual increment in year of entry into the cohort was associated with a 6% (95% CI, 2%-10%; P = 0.008) decrease in mortality. LIMITATIONS Reported associations might be accounted for by unmeasured or incompletely measured confounders. These might include changes in other aspects of medical care for patients with ADPKD. CONCLUSION Increasing coverage and intensity of antihypertensive therapy is associated with decreasing mortality in people with ADPKD.

Developing a policy for paediatric biobanks: principles for good practice.

The participation of minors in biobank research can offer great benefits for science and health care. However, as minors are a vulnerable population they are also in need of adequate protective measures when they are enrolled in research. Research using biobanked biological samples from children poses additional ethical issues to those raised by research using adult biobanks. For example, small children have only limited capacity, if any, to understand the meaning and implications of the research and to give a documented agreement to it. Older minors are gradually acquiring this capacity. We describe principles for good practice related to the inclusion of minors in biobank research, focusing on issues related to benefits and subsidiarity, consent, proportionality and return of results. Some of these issues are currently heavily debated, and we conclude by providing principles for good practice for policy makers of biobanks, researchers and anyone involved in dealing with stored tissue samples from children. Actual implementation of the principles will vary according to different jurisdictions.

Genetic horoscopes: is it all in the genes? Points for regulatory control of direct-to-consumer genetic testing

The development of tests for genetic susceptibility to common complex diseases has raised concerns. These concerns relate to evaluation of the scientific and clinical validity and utility of the tests, quality assurance of laboratories and testing services, advice and protection for the consumer and the appropriate regulatory and policy response. How these concerns are interpreted and addressed is an ongoing debate. If the possibility of using the discoveries from genomic science to improve health is to be realised without losing public confidence, then improvements in the evaluation and mechanisms for control of supply of tests may be as important as the science itself.

Factors affecting the clinical use of non-invasive prenatal testing: a mixed methods systematic review

Non‐invasive prenatal testing has been in clinical use for a decade; however, there is evidence that this technology will be more widely applied within the next few years. Guidance is therefore required to ensure that the procedure is offered in a way that is evidence based and ethically and clinically acceptable. We conducted a systematic review of the current relevant literature to ascertain the factors that should be considered when offering non‐invasive prenatal testing in a clinical setting. We undertook a systematic search of relevant databases, journals and reference lists, and from an initial list of 298 potential papers, identified 11 that were directly relevant to the study. Original data were extracted and presented in a table, and the content of all papers was analysed and presented in narrative form. Four main themes emerged: perceived attributes of the test, regulation and ethical issues, non‐invasive prenatal testing in practice and economic considerations. However, there was a basic difference in the approach of actual or potential service users, who were very positive about the benefits of the technology, compared with other research participants, who were concerned with the potential moral and ethical outcomes of using this testing method. Recommendations for the appropriate use of non‐invasive prenatal testing are made.

Genetic Testing and Common Disorders: How to Assess Relevance and Possibilities

In recent years, the attention of the genomics and genetics research community has shifted toward understanding the basis of common disorders. The spectacular growth of genome-wide association studies has shed new light on the variants influencing risk factors. Understanding pathogenesis and etiology, and finding new ways to prevent and treat those diseases are major challenges. In the era of genomics, a promise of personalized prevention and drug treatment is presented, which many people meet with enthusiasm but which others call into question. The Public and Professional Policy Committee (PPPC) of the European Society of Human Genetics (ESHG), EuroGentest and the Institute for Prospective Technological Studies (IPTS) convened to discuss the relevance and possibilities of genetic testing for common disorders. Currently (in 2010), the genetics research community is skeptical about the possibilities of genetic susceptibility testing and screening contributing significantly to the improvement of the quality of health care. Meanwhile, some applications of very limited clinical utility have become available directly to consumers. Recently, the PPPC published critical recommendations on policy concerning DTC genetic testing (EJHG, 25 August 2010). When considering the potential of new genomic developments for a public health perspective, this Background Document takes the spectrum ranging from monogenic disorders on the one hand to common complex disorders on the other hand into account. It is argued that associations between genetic variants and disease risks of clinical relevance have been established, for instance for hereditary breast and ovarian cancer, colon cancer, diabetes mellitus (MODY subtypes), thrombosis, cardiovascular disorders, celiac disease and Alzheimers disease. Although these examples relate to the monogenic subforms of common disease, they can nevertheless be used to reflect on the possibilities and relevant obstacles in using the new genetics in public health. The deliberations, reflected in the final Background Document, have led to the below recommendations from the PPPC concerning the pitfalls and possibilities of genetic testing in common disorders. A draft of both the Background Document and Recommendations has been distributed and posted on the web during the summer of 2009 to elicit further comments. The PPPC and the Board of the ESHG approved the final version. This final text is considered to reflect the views of the European human genetics scientific and professional community.

Comparison of genotypic and phenotypic strategies for population screening in hemochromatosis: Assessment of anxiety, depression, and perception of health

Purpose: Hemochromatosis is a treatable disorder with a major genetic predisposition. It provides an example in which genotypic and phenotypic strategies for screening may be compared. We previously showed noninferiority of uptake of a genotypic population screening strategy for hemochromatosis compared with a phenotypic strategy. In this article we present the psychologic effects of each strategy.Methods: A sample of 3000 individuals from primary care were randomly allocated to a phenotypic or genotypic screening strategy for hemochromatosis, and the 939 individuals who accepted screening provide the sample for this article. Standardized assessments of anxiety, general health, and depression were made at invitation, testing, result-giving, and 6 months.Results: Screening did not lead to significant changes in the self-rated assessments of anxiety, depression, and general health over time, and there were no significant differences between the two screening strategies. The unemployed or permanently disabled had lower ratings of health and higher anxiety and depression.Conclusion: The two screening strategies appeared to cause little adverse psychologic disturbance in the short term, and there was no difference between the two strategies This study provides some empiric data to support arguments against “genetic exceptionalism” and suggests that genetic testing when used for population screening for a treatable disease has few adverse effects.

Using a community of practice to develop standards of practice and education for genetic counsellors in Europe

The profession of genetic counselling is developing in Europe in response to the increased need for genetic healthcare. Standards of education and professional practice are needed to ensure that patients are provided with genetic counselling of an appropriate quality. However, such standards need to be relevant to practitioners in many different national and healthcare settings. In order to develop appropriate standards and a code of practice to guide professionals in Europe, we formed a community of practice that includes genetic nurses and counsellors, plus other interested health professionals, from 23 European countries. With reference to the European core competences for genetic counsellors, the members of the network developed a set of professional standards for practice, educational standards and a code of practice. It is strongly suggested that the title genetic counsellor should become a protected title in Europe and that practitioners are educated via a master level degree in genetic counselling. These standards have been approved by the members of the network and the existing professional national societies for genetic nurses and counsellors. They provide a foundation for building the profession of genetic counselling in Europe and for provision of equitable care across European countries. Further work is now needed to ensure that appropriate educational opportunities exist to train practitioners and that clinical teams utilise the expertise of these professionals appropriately to enhance the care offered to families at risk of or affected by genetic conditions.

Applied genetics in healthcare : a handbook for specialist practitioners

1. Introduction to Genetic Healthcare 2. Foundations in Genetic Science 3. Working Practically in Genetic Healthcare 4. Working Professionally in Genetic Healthcare 5. Working to Support Families 6. Working as an Educator for Families and Professionals 7. Working as a Researcher 8. Autosomal-Dominant Inheritance 9. Autosomal-Recessive Inheritance 10. X-linked Inheritance 11. Familial Cancer 12. Chromosomal and Non-Traditional Patterns of Inheritance 13. Multifactorial Inheritance and Common Diseases

Building the Genetic Counsellor Profession in the United Kingdom: Two Decades of Growth and Development

The United Kingdom (UK) is comprised of England, Scotland, Wales and Northern Ireland and the current population is approximately 62 million (Office for National Statistics 2012). Healthcare, including genetic services and appropriate testing, is provided to all citizens free at the point of service, via a National Health Service (NHS) funded through taxation (National Health Service Choices 2012). All UK citizens have a named general practitioner who is responsible for their overall healthcare. Individuals and families in every part of the UK have access to genetic services. These are staffed by multi-disciplinary teams comprising mainly medical geneticists and genetic counsellors; the regional NHS genetics laboratories are either integrated with or very closely aligned to the clinical centres. Within the regional genetics centres, a comprehensive service is provided that includes prenatal genetics, and general, metabolic and cancer genetics relating to both paediatric and adult care (Department of Health 2010). Specialist training exists for medical geneticists, genetic counsellors and laboratory geneticists. Many clients are referred to the genetic service by a primary care practitioner (doctor, nurse or midwife working in a primary care setting, such as a community clinic), although in some cases another specialist will refer. Medical genetics clinics were first established in 1946 (Harper et al. 2010), although there was huge expansion in the provision of genetic services during the 1980’s, when testing using recombinant DNA became feasible in the clinical setting. With this expansion, a number of specialist nurses were employed to support the work of medical geneticists, obtaining the necessary knowledge and skills informally through observing colleagues. At the end of the 1980’s, ten of these practitioners met at a scientific meeting and formed the Association of Genetic Nurses and Counsellors (initially called the Genetic Nurses and Social Workers Association). In 1992 an Education Working Group was formed by members of that association and two studies were undertaken to document the role and scope of practice of genetic nurses (Skirton et al. 1997). Building on that study, the first formal recommendations for the education required for genetic nurses or counsellors were made (Skirton et al. 1998).