Background and purpose
During the years prior to the turn of the century, scientific and medical attention for genetic disorders was mainly focused on understanding rare single-gene disorders, such as Huntington's disease, Duchenne muscular dystrophy, and cystic fibrosis (CF), as well as chromosomal abnormalities. The medical specialty of clinical genetics was established in the 1980s and 1990s in many European countries to diagnose these kinds of rare disorders and to counsel patients and families.
In recent years, the attention of the genomics and genetics research community has shifted toward understanding the basis of common complex disorders. Common diseases are diseases frequently encountered in health care. Some cases of common disorders are characterized by a strong influence of germline mutations in a single gene; these will be referred to as ‘monogenic subtypes'. In many cases common disorders have a multifactorial etiology: they are caused by several genes and environmental factors, involving gene–gene and/or gene–environment interactions. We will use the term ‘complex disease' to indicate diseases with variable etiology, including multifactorial etiology as well as monogenic subsets. When discussing ‘susceptibility genes' in this document, we refer to genetic variants with low predictive value. We need to admit, however, that no generally accepted threshold for categorizing predictive value levels exists. Researchers nowadays study the myriad of genetic polymorphisms that have been identified during and since the Human Genome Project. The spectacular growth of genome-wide association studies1 has shed new light on which of these variants represent risk factors for common diseases. Understanding the pathogenesis and etiology, and finding new ways to prevent and treat those diseases are major challenges. The traits or diseases under study include coronary artery disease, myocardial infarction, stroke, peripheral artery disease, obesity, type 1 diabetes, type 2 diabetes, breast cancer, cervical cancer, colorectal cancer, prostate cancer, celiac disease, bipolar disorder, Crohn's disease, and many more. Should incorporation of these research results into current clinical and public health practice become possible, then researchers and practitioners have to be prepared for the way in which this changes their daily routine.2, 3, 4, 5, 6, 7, 8
The clinical management of information about frequently occurring DNA variants that lead to moderate increases in risks for common diseases requires a different approach from that of the significantly increased genetic risks for numerous rare health problems. Translation of research findings to useful health-care applications appears to be lagging behind. Implementation of useful research findings may take years or decades. Meanwhile, some applications of very limited clinical utility have become available directly to the consumers. Difficulties with the translation of research findings need to be understood and addressed if genetics and genomics research is to fulfil its promises towards improving diagnosis, treatment, and prevention. 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. The implementation in health care of genetic tests that are considered useful should overcome several thresholds.
Health promotion and disease prevention for the population at large has been the domain of public health professionals; yet, public health approaches have thus far not taken into account genetic risk factors and often not even family history.9 So far, advice on lifestyle, physical activity, and nutrition has been developed in a one-size-fits-all approach.6 The era of genomics presents the promise of personalized prevention and drug treatment, which has been met with enthusiasm by many people, but called into question by others.10
In the light of these new developments in research, there is a pressing need to assess the possibilities for and implications of genetic testing and screening in common diseases (pertaining to multifactorial disorders as well as monogenic subtypes) from both a clinical and a societal perspective. As with genetic testing in rare mendelian disorders, these assessments should comprise analytic validity, clinical validity, clinical utility, and ethical, legal and social issues,11, 12 as well as health economic aspects. Should a genetic test for a common disease have sufficiently high clinical utility in a specific setting, and should implementation in health care be potentially worthwhile, then the framework for its implementation has to be determined: clinical genetics, medical specialist care, primary care, as a genetic screening program, or as a commercial offer. Currently, as far as common disorders are concerned, testing for monogenic subtypes has mainly been implemented in health care.
In Europe, a shared understanding of and opinion about these developments needs to be established among human and clinical geneticists to enable them to inform future policy making by the European Union (EU) and member states. For this purpose, information was gathered in a background document as input for an expert workshop in Seville, 8–10 October 2007, on ‘Clinical validity and utility of genetic susceptibility testing in common disorders'.
In reflecting on the shift in the field of research from rare monogenic to common disorders with a genetic component, this document is a follow-up on several documents and initiatives that have aimed at documenting and harmonizing genetic testing services in Europe.13, 14, 15, 16, 17, 18, 19, 20 Because of shared interests and complementary expertise, it is a collaborative initiative of three parties: the Public and Professional Policy Committee (PPPC) of the European Society of Human Genetics (ESHG), EuroGentest, and the Institute for Prospective Technological Studies (IPTS). The PPPC is involved in setting professional standards for human and clinical genetics and in issuing recommendations for national and European policy regarding genetic services. EuroGentest is a EU-funded Network of Excellence (NoE) that aims at the standardization and harmonization of genetic testing services and at improving the overall quality of genetic services offered within the EU. This includes both the establishment of procedures and guidelines for the validation of methods and technologies and the provision of quality-assured information sources to medical professionals, as well as proper utilization of genetic services. The IPTS is one of the seven scientific institutes of the European Commission's Joint Research Centre (JRC). It informs EU policy making on issues with a socioeconomic and a scientific or technological dimension.
After the Seville workshop, to enable further discussion on some genetic epidemiological issues, a workshop was organized in September 2008 in Amsterdam. The background document was revised into its present form on the basis of comments by participants of both meetings and other experts, some of whom are active in the EU-funded Public Health Genomic European Network (PHGEN, http://www.phgen.eu) project and the international GRAPH-Int (http://www.graphint.org) consortium that was established under the Canadian Public Health Agency. These organizations have been established to promote, at both the European and the global level, responsible and effective translation of genome-based knowledge and technologies into public policy and public health services.
Suggestions were incorporated in the background document, and during the process the PPPC discussed the recommendations. A draft of the background document and recommendations were distributed and posted on the web during the summer of 2009 to elicit further comments. After this procedure the draft was revised. The PPPC and the Board of the ESHG approved the final version. This final text is expected to reflect the views of the European human genetics scientific and professional community.
Scope and limitations
In this document we will discuss genetic testing and common disorders from a health-care perspective. New possibilities for genetic testing confront health-care workers with the question of whom to test and which test to use. This document focuses on genetic testing and screening in common disorders. The term ‘common disorder' is used for disorders that individually have a high impact on public health. Examples of common disorders include cardiovascular disease (CVD), stroke, diabetes, cancer, dementia, and depression. For a health-care practitioner – unlike a geneticist or an epidemiologist – it may not be clear whether a common disorder is due to one gene with a high risk of serious disease, or due to a combination of several genes and several environmental factors. For disorders in which both etiologies exist, both monogenic and multifactorial, the etiology can be thought of as ‘complex'. Mendelian diseases can have a complex etiology too: one major gene, many modifying genes, and a series of environmental factors. This is not what we mean by ‘complex' in the present document.
Common complex diseases are at present being redefined as a series of diseases with similar symptoms but variable etiology: a few genes, many genes, interactions between genes, many environmental factors, etc. The main difference between ‘complex' and ‘monogenic or Mendelian' is that in a Mendelian or monogenic disorder an alteration in one gene is a prerequisite for passing the threshold to develop the disorder, although the effect of the mutation could, in some cases, be modulated by genetic variants in other genes or epigenetic events caused by environment, life style, etc, while in complex disorders both whether one will develop disease and the severity are modulated by the complex etiology. In Mendelian diseases one crosses the threshold to disease due to one gene; in complex diseases different factors are needed for crossing the threshold. Between these two extremes there are a series of combinations, for example, the BRCA1 or BRCA2 genes, wherein carrying a mutation will bring an individual close to the threshold but other genes and/or environmental factors to push one over it, that is, to cause disease (cancer in this case). Mendelian diseases can be used as an example for common complex diseases, to generate insights into etiological pathways and into avenues for the potential implementation of specific programs in health care. For common complex disorders, genetics and genomics research promises to personalize medicine. Instead of a one-size-fits-all approach, the disorders may be stratified to etiologically different subgroups that also differ according to prognosis and response to treatment and prevention. Lessons learned from rare monogenic conditions may help tailor health care for common complex disorders. Personalizing or tailoring health care will in practice often lead to stratified health care, distinguishing between several groups, while treatment on an individual level is rare.
Different definitions of ‘genetic', ‘screening', and ‘testing' exist. For the purpose of this document we will use genetic (susceptibility) ‘testing' in a broad sense, while we use genetic (susceptibility) ‘screening' for a systematic, proactive offer to members of a certain group of individuals. Screening may be a well-organized public health program, usually aiming at a low risk population. ‘Genetic' testing will be defined as the analysis of DNA or biomarkers for the evaluation of one or more genetic risk factors for a particular disease or disease group.
In health care, genetic screening has to be distinguished from genetic testing because the setting and implications are different. Genetic testing traditionally is carried out on patients or family members who, for whatever reason, have taken the initiative to seek professional advice. Thus, in a health-care setting, testing may provide a health professional with relevant information for diagnosis, prognosis, disease management, and/or further treatment of an individual patient. Genetic testing is also sometimes used in a broader, more comprehensive sense. Genetic tests may be used in genetic screening programs.
Genetic screening traditionally refers to explicit and systematic programs directed either at whole populations of asymptomatic individuals or at subpopulations in which risk is known to be increased or in which the specific phase of life merits screening, such as in the case of pregnant women or newborns. It may be relevant to distinguish between different types of target groups and, furthermore, to distinguish between this systematic approach (eg, as in public health programs) and the situation in which asymptomatic (or low-risk) persons are offered a test (eg, on the internet). Just as in screening, the recent possibilities for direct-to-consumer genetic testing may be used by asymptomatic persons. Although these tests may be chosen for recreational purposes (such as ancestry testing), they may yield (sometimes unsought) medically relevant information. Commercial genetic testing or screening may be aimed at a broad range of disorders, ranging from traits and common disorders to rare and serious disorders.
In some cases, however, also in the regular health-care setting of a doctor–patient relationship, a more systematic offering of tests may be introduced. This is the case when testing becomes a standard regime for a certain patient group. Testing for mutations in breast cancer tumor tissue provides a good example of such a systematic approach, which can therefore be regarded as a form of genetic screening. In this document, we will indicate specifically which aspects of screening (such as low-risk group, systematic approach) are implied when we refer to screening.
In genetic screening, tests may be offered to individuals by a health-care agency or a physician, which may give the public the impression that these tests are imposed upon people. The ethical dilemmas are magnified and the responsibilities of the physicians are correspondingly greater.21 The genetic nature of a disorder can result in risk implications for the blood relatives of the screened person, even though they may not have been included in the screening programs, nor perhaps wish to be included.
When Wilson and Jungner22 formulated their classic list of screening criteria for the World Health Organisation (WHO) in 1968, the possibility of offering treatment was deemed to be an essential prerequisite for offering a sound screening program. Since then, many refinements of these criteria have been formulated, for instance, as regards treatability. Especially in the case of genetic screening, an added aim may be to offer information and options regarding reproductive choices, reducing risk by preventive measures such as changing health behavior, or planning of life events.
Genetic screening for common complex disorders would ideally offer options concerning preventive strategies related to lifestyle, medication, or interventions such as regular monitoring (for example, of biochemical markers in serum, such as cholesterol levels, monitoring of organ function, detecting early premalignant changes, etc). However, the discriminatory power of genetic screening to identify who should or should not be offered particular lifestyle advice or medical interventions remains disputed, especially for ‘susceptibility genes' that confer a low relative risk and have a low predictive value.
When using the term ‘susceptibility' testing or screening, it can be debated what level of risk might be implied.23 The definition in the previous section does not refer to a specific level of risk. A clear-cut distinction between susceptibility testing (indicating a moderately increased risk) and predictive or presymptomatic testing (indicating a severely increased risk) cannot be given. In principle, testing for relatively high penetrant genes, such as BRCA1 or BRCA2 (indicating a lifetime risk of developing hereditary breast cancer of between 60 to 85%), could be regarded as a form of susceptibility testing, and, most notably, in the United States the term ‘susceptibility testing' is also used for these highly penetrant disorders. In practice, however, those kinds of informative tests are considered to be on the predictive side, pertaining to highly penetrant monogenic disorders and monogenic subforms of common disorders, whereas the term ‘susceptibility testing' is reserved for relatively lower predictive values associated with common disorders.
This document reviews and discusses current biomedical, epidemiological, ethical, social scientific, public health, health economic, and health technology assessment (HTA) literature on genetic testing and screening in common disorders, as well as documentation on regulatory and policy issues.
A search was performed in PubMed–medline and the Social Science Citation Index using keywords relevant to genetic susceptibility and testing or screening for common disorders. In addition, references from relevant articles were selected. Especially reviews, reports, position papers, and editorials were considered. Reports on HTAs concerning genetic susceptibility testing were also used. For this purpose, several databases accessible via the internet were surveyed and the relevant literature on the topic of (economic) evaluation of testing services was reviewed (see Appendix C).
Given the two poles of rare, often severe, monogenic disorders caused by highly penetrant genotypes on the one hand and polygenic, multifactorial (complex) common disorders associated with genotypes of low penetrance on the other hand, this document focuses upon the common disorders associated with genotypes of higher or low penetrance: in particular, those conditions where the public health implications need to be considered – that is, at which level of clinical utility tests should be made available and how they should be implemented in practice. For many common disorders, monogenic subtypes exist, including certain forms of cancer (most notably colon cancer and breast and ovarian cancer). It appears worthwhile exploring to what extent health-care practices developed for these disorders may help identify challenges for the future implementation of knowledge of the human genome into health care.24 Learning from health care for monogenic disorders and monogenic subtypes may help to decide on potential avenues of implementation or non-implementation in health care.
A limitation of this document is the absence or scarcity of information on molecular pathways, population genetic data, test performance, and social, psychological, ethical and health economic data, and experience regarding susceptibility testing. Furthermore, the settings in which tests are piloted or marketed are constantly changing. As Calnan et al25 note: ‘New technologies rarely emerge fully formed at their optimum effectiveness and lowest cost; rather they develop in situation, as clinicians master new techniques and the existing technology is tweaked and modified to suit the clinical context…the cost of a new technology may fall rapidly as development costs are covered, uptake rates increase, and the healthcare provider reorganises to provide the service more efficiently. All of this happens a considerable way down the implementation pathway.' Therefore, the data we could obtain for this background document may prove to be of limited value. However, science progresses rapidly, and genome-wide association studies are revealing associations between common disorders and genetic variants at a fast pace, which urges a common understanding of, and vision for, the possibilities of genetic testing and screening in common complex disorders.
For this reason, we will make use of analogies with existing forms of testing and screening, including testing and screening for monogenic subtypes of common complex disorders, whenever this seems appropriate. Special cases such as hemochromatosis (monogenic, yet not highly penetrant) and familial hypercholesterolemia (FH; monogenic, highly prevalent, but only one out of many risk factors for CVD) will also be discussed. The health care provided for these disorders in various countries and health centers falls outside the scope of clinical genetics, and could guide our thinking about future genetic testing and screening in common complex disorders.
This document will not consider germline prenatal or preconceptional testing, nor testing of biomarkers for tumor recurrence, but it will discuss testing of mutations in tumor tissue, since this may reveal susceptibility to certain forms of therapy. Also, pharmacogenomic applications will not be discussed in depth, although some examples will be given of pharmacogenomic testing.
In the next section, the terrain of common complex disorders is introduced. Different assessment frames for genetic testing and screening are discussed. The section following that examines the aims and strategies for genetic testing and screening in common disorders and discusses some examples of current testing and screening in Europe. The section ‘The economic evaluation of genetic tests' discusses the cost–benefit relation of different types of tests and screening strategies and how they could be used in the clinic in a cost-effective way. The subsequent section addresses the ethical, legal, and social issues of testing and screening in common disorders. The last section addresses regulatory and intellectual property issues in the EU as well as the United States.