Definitions of Genetic Testing (Jorge Sequeiros and Bárbara Guimarães)

Aim

The document from an European Commission Expert Group (25 Recommendations on the Ethical, Legal and Social Implications of Genetic Testing, 2004) establishes, as its very first recommendation, the need to define explicitly what is meant by genetic testing, whenever the term is used, and the need to develop a consensus definition that is globally applicable.

That document suggests that a definition should be developed globally by several public and private bodies involved (including the World Health Organisation, the Organisation for Economic Co-operation and Development, the European Commission, the International Federation of Human Genetic Societies, and the International Conference on Harmonisation), and states that the EC should take initiative.

The expert group used for its recommendations a broad definition for genetic testing, i.e. any test that yields genetic data, unambiguously revealing underlying DNA information, either germ-line or somatic and where the nature/technology of the test is not important, but the information derived.

In spite of including information on somatic cell mutations in its broad definition, and acknowledging its importance for identification of disease mechanisms and pathways, disease classification and identification of targets for new medicines, the expert group addressed in its recommendations only data related to transmissible germinal changes, pertaining to heritable diseases or traits.

The need for an agreement of a common definition was also identified at the meeting with EU Member States representatives. The network with Member States should also be seen as a follow up of the expert group.

The present document results directly from that recommendation and aims at contributing to the discussion of such consensus definition and of its applicability. It also aims at comparing the definitions provided by a number of organizations with the recommendations they issue and/or the practices they pursue.

Scope

We have been reviewing definitions of genetic testing mainly from international or transnational organizations, and national and international associations of professionals, consumers and industry, but also from many other public and private entities at the academic, medical, laboratory, ethical, legal and societal level, including scientific societies and lay organizations. We have included, for comparison and for completeness, documents from some of the most authorized experts in the field.

We have identified 78 institutions/organizations. We have finished analysing the 153 documents collected (mainly online) for definitions of genetic testing (and other related definitions). A total of 65 organizations have been reviewed for their definitions. These include European Organizations: European Commission, Council of Europe, CoE-CDBI, European Parliament, IPTS-JRC; Genetics Professional Organizations: IFHGS, ACMG, ESHG, ESHRE, ASHG, CORN, SACGHS, Association of Genetic Nurses & Counsellors, UK; HGAC; HGSA; NSGC; UKGTN; American Board of Genetic Counselling; Nuffield Trust; International/Transnational Organizations: OECD, WHO, UNESCO, WMA, HUGO, CIOMS; International Soc. Nurses; Patient/Consumers Organizations: EuropaBio, Genetic Alliance; EPPOSI: Eurodis; GIG; GeneWatch; Regulating Agencies: CDC, ICH, HGC, FDA; National Institutions: NIH (SACGT), NCI; Insurance Organizations: NAHU; Human Rights Associations: ACLU; DPI; Medical Pathologists Organizations: CAP/AMP; RCP; Ethics Organizations: ACGT, Nuffield Council for Bioethics; European Churches Commission; EGE in Science and New Technologies; SIBI; Professionals Health Organizations: Health Council of the Netherlands; British Medical Association; American Society of Pediatrics Committee in Bioethics; AMA; ICMR; NHGRI; Pharmaceutical Industry: ABPI, GSK; Roche; Genzyme; Research Funding Agencies: Welcome Trust; MRC,UK; Prominent Authors: Peter Harper; Neil Holtzman; Other Organizations: EJHG, HGP; Gene Tests; Parliamentary Office of Science and Technology (POST); President’s Commission for the study of ethical problems in Medicine and Biomedical and behavioral research Feb 1983.

We now intend to analyse a few other organizations associated with these main groups, search for other organizations, like Law Professional Organizations and look for more recent documents from all the organizations above mentioned (see Table 2). We also plan to analyse all documents reviewed with NVIVO 7 software.

Background

We are living in the Genetic era, cloning, genetic testing, the sequencing of the human genome are now part of everyone’s vocabulary and reality. However, these sudden developments are equally astonishing and frightening. Most people although amazed, feel that don’t know enough about them. And intelligible concepts are necessary to calm society and improve health care. Thus, these accomplishments must be understood by everyone particularly by health professionals and patients.

Since the year 2000, when an initial sequencing of the human genome was completed, new discoveries promised new developments in the prevention, diagnose and treatment of numerous diseases.

This hasty progress carries several ethical questions and razes complex debates about the social, economic and legal consequences. Reflection is required so these new technologies can be use to the profit of health improvements. (Ref)

As referred before, in response to the new genetic reality, the European Commission Expert Group wrote a document entitled 25 Recommendations on the Ethical, Legal and Social Implications of Genetic Testing, 2004 where established, as its first recommendation, the need to define explicitly what is meant by genetic testing, whenever the term is used, and the need to develop a consensus definition that is globally applicable.

The fact is, nowadays, only specific groups understand the implications of genetic services, those are the groups directly implied by these services - health professionals and patients. (Ref) Nevertheless, as the expert group explains, these services will be part of National Health Services and public and health professionals need to be certain about the implications and the concepts associated with genetic services and genetic testing.

An EuroGentest work-package was created in this context in an attempt to respond to these developments.

As referred in the next section (obstacles and limitations), during the EuroGentest Workshop Unit 3, 21-22 September that occur in Porto, European experts debated the theme and realize that a consensus definition was probably impossible to achieve. This is due to the fact that different contexts demand different definitions.

Meanwhile the necessity to clarify the message is a reality that urges to respond.

The present document intends to present different definitions of Genetic testing (or related definitions) and to identify trends, differences and ideas presented by national international, health, patient and genetics associations.

Obstacles and Limitations

While there is a consensus about the need of clearness, the creation of a global definition of Genetic Testing, seems to divide experts in the area.

During the EuroGentest Workshop Unit 3 (Porto, 21-22 September 2006), a complex debate occur dividing opinions about the obligation and importance of developing a new working definition. As some experts pointed out, there is a risk of creating just one definition in a universe of several others.

Another question has to be razed; there are numerous different contexts where genetic testing may have different meanings and implications. Should we develop a group of definitions? Or, perhaps, after the Porto meeting, we ought to select a new approach for this work. Instead of another definition or group of definitions (context dependent), we should concentrate in collecting a list of factors that should be included in any definition of genetic testing.

Preliminary analysis

The definitions currently used for genetic testing are extremely variable, as expected. Nevertheless, there seems to be some patterns as to the items and areas that are covered, as well as to the aim with which they are produced (e.g., patient interest groups and consumers versus insurers, genetics organizations versus pathologists associations, ethical bodies versus commercial labs, etc.). In one area, legislation, are definitions more inconsistent than in any other, and too often at stake with one another.

Definitions range from the strict view of being synonymous to DNA-based testing, to any source that can provide unambiguous genetic information (thus covering some instances of ‘non-classic’ genetic tests, physical examination in some cases and family history). In spite of its variable nomenclature and phrasing, most types of DNA testing, particularly if related to a heritable disorder, performed in a medical context, and either in affected persons, or a healthy individual or foetus, seems to gather some consensus.

Items variably included in the definition of genetic testing are linked to the methods used for testing or to derive genetic information, its purpose, and the material analyzed:

• DNA-based testing ± cytogenetics and biochemical data
• Mendelian fully-penetrant traits ± susceptibility genes
• disease testing ± drug response
• testing for medical conditions ± identity forensic testing
• germline ± somatic mutations
• direct mutation detection ± linkage analysis
• clinical ± research purposes
• individual data ± family history
• patients, families, or population screening
• variable life-cycle timings (PGD and prenatal)
• various methods and target materials

The definition of genetic testing relies heavily on the concept of genetic information. We have thus tried to list first possible sources of genetic information (Table 1).

As referred before, Table 2 shows some of the prestigious and authoritative organizations and authors that are being surveyed for definitions of genetic testing. We then provide an overview of the wide variability among definitions given by these organizations or individuals, according to our interpretation of which of the previous items are covered or not in those definitions (Table 3). The definitions used are given and referenced as an appendix.

We have tried to analyse also, in the form of comments, the intent and the purpose for which those definitions were made (very often, working definitions with very specific aims are produced). For the Table 2 and for the proposal of a consensus definition, however, the actual content (not the intent) of each definition was taken into consideration (as if they were to be used out of the context in which they were cited). Nevertheless, this work had to rely, to a certain extent, on the interpretation we have made of that definition. Whenever available, explanatory notes or examples following a definition were used for the analysis of its content.

While some sources are concerned with and try to define genetic testing, others are clearly more interested in genetic information, i.e., more with the results or the information extracted, than with the methodologies used to derive it. Thus, patients and civil rights associations, as well as ethical and legal organizations, tend to use broad definitions of genetic testing (information), while insurers and non-genetics professional associations tend to prefer narrower definitions.

Discussion

Items usually included in the definition of genetic testing

Definitions of genetic testing were found to include (1) usually: medical applications, diagnostic, presymptomatic and complex disease testing, prenatal diagnosis and PGD, Mendelian traits and genetic predispositions, and DNA-based testing; (2) only sometimes: drug response, carrier testing, population genetic screening, somatic mutations, cytogenetic tests, RNA and other metabolites; and (3) rarely: non-medical applications, scientific research, identity testing, other polymorphic traits, routine blood tests, physical exam and family history.

Clues for discussion of definitions of genetic testing

In order to define genetic testing, we need beforehand to define clearly what a ‘test’ is ("uses an assay for a particular purpose, puts assay into a context", Ron Zimmern). Can we include subsidiary exams, physical examination and family history as particular forms of a genetic test, in cases where they can provide unambiguous information (at least with the same predictive value of most DNA-based tests)?

It is also clear that it is the information derived, not the testing methods used that will be important for any consensus definition. This should address the predictive value of the information, and include sources of genetic information other than DNA-based testing.

On the other hand, there seems to be a need for context-dependent definitions (e.g., insurance and reimbursement policy; legislation for data protection and discrimination, ethical recommendations; genetics and other professionals guidelines; somatic vs. germinal mutations).

The question rises, then, if it will ever be possible to have a consensus definition of genetic testing. Could we have and propose 2-3 ‘contextual’ definitions, instead?

It may also be important for this purpose to make a distinction between genetic information and DNA-based information. Some of these questions are graphically displayed in Fig. 1.

Finally, when addressing a definition of genetic testing, should we not address also other related definitions (e.g., genetic screening, diagnostic, predictive, presymptomatic, pharmacogenetics/pharmacogenomic tests)?

We are planning to survey EuroGentest participants about these questions, using a questionnaire that is being revised for that purpose.

It would also be interesting to compare also definitions contained in the legislation of European (and other) countries, what will be dome at a later time, together with Unit 2.

Appendix

EUROPEAN ORGANIZATIONS

European Commission (STRATA Group on Genetic Testing)

Genetic test: A broad definition was used for genetic testing, i.e. “any test that yields genetic data”. Any test which yields genetic data. More specifically a genetic test detects the presence or absence of, or change in, a particular gene or chromosome, including variants or other inherited polymorphic traits that are not necessarily diagnostic of disease. They also include biochemical tests for gene products such as enzymes and other proteins.

G enetic data or information relate to inherited or acquired properties that are transmitted during cell division and that affect subsequent generations of offspring (“germinal genetic data”) or cells and tissues (“somatic genetic data”). Genetic data comprise: data describing structural properties of DNA (nucleotide sequence or chemical modifications of nucleotides); or data describing properties of other biological markers (RNA, proteins, metabolites, other biological constituents) that are the direct consequence of the underlying DNA template’s structure.

Medical genetic testing: The application of genetic testing to derive information relevant to healthcare: disease risk, prediction, disease diagnosis, disease prognosis, disease treatment and reproductive choices.

Non-medical genetic testing: The application of genetic testing for all purposes that do not have a medical aspect, manly for the purpose of identification, e.g. paternity and forensic testing, or the identification of the presence of animal and plant materials.

Biochemical genetic test: The analysis of human proteins or other molecules predominantly used to detect gene products showing genetic variations or mutations.

Diagnostic test: A test providing primarily information about an existing condition and its prognosis. However, it is possible. Although uncommon, that a test applied to diagnose a particular disorder may provide predictive information about another disorder.

Pharmacogenetics: The study and understanding of the genetic variation between individuals underlying differential response to drug treatment (efficacy or adverse reactions).

The term comes from the words pharmacology and genetics and describes the interaction of pharmaceuticals and genetics.

Like other forms of genetic testing, the concept of pharmacogenetics encompasses the use of information encoded in patient’s DNA to help predict their responses to medicines and thereby enhance the effectiveness and safety of medicines for individual patients.

It is important that pharmacogenetics is not confused with genetic testing for rare monogenetic disease diagnosis or prediction.

References:

• 25 Recommendations on the Ethical, Legal and Social Implications of Genetic Testing:
  http://ec.europa.eu/comm/research/conferences/2004/genetic/pdf/recommendations_en.pdf
• Ethical, Legal and Social Aspects of Genetic Testing: research, development and clinical applications, STRATA Group on Genetic Testing, 2005:
  http://europa.eu.int/comm/research/conferences/2004/genetic/pdf/report_en.pdf]

European Commission

Prenatal screening consists in the extended application of risk assessment procedures to populations of pregnant women rather than to individuals.

Prenatal screening raises additional ethical issues namely in terms of public health policy.

Preconceptional testing or screening allows individuals to be aware of specific genetic risks to their offspring. It could involve the development of simple-to-use genetic testing kits, which raise ethical issues regarding the management of information by the individuals.

Preimplantation diagnosis (PID) consists of analysing the genetic components of very early embryos in vitro. This allows the transfer of embryos of a particular sex or genotype to the woman’s uterus, thereby greatly reducing the need to consider termination of pregnancy for couples at risk of transmitting genetic diseases. PID is currently at the experimental stage of clinical trials. Compared with PND, PID, which requires in vitro fertilization raises additional ethical question.

Genetic testing in this context means the use of a scientific test to obtain information on some aspects of the genetic status of a person, indicative of a present or future medical problem. In this context of employment, “genetic testing” incorporates “genetic screening” and “genetic monitoring”.

Genetic screening in this context means the use of a scientific test to determine whether a person possesses particular variant forms of one or more genes in his/her genome.

Genetic monitoring in this context means the examination at regular intervals, for chromosomal abnormalities in samples of cells from a person who may be at risk, in their employment, of exposure to agents which cause genetic damage.

Non-DNA based genetic screening – the definition of genetic screening need not be restricted to tests carried out directly on an individual’s DNA (…) For the purposes of this Opinion, any test that evaluates specific genes or gene products that may be indicators of a persons genetic status are considered to be Genetic Tests.

Family medical histories – as family medical histories can provide information on a person’s genetic status, which may have predictive value for future health as significant as laboratory performed genetic test, these are included within our definition of genetic tests.

References:

• Ethical Aspects of Prenatal Diagnosis (Opinion of the Group Advisers on the Ethical Implications of Biotechnology to the European Commission):
  http://europa.eu.int/comm/european_group_ethics/gaieb/en/opinion6.pdf
• Opinion on the Ethical Aspects of Genetic testing in the Workplace (The European Group on Ethics in Science and New Technologies to the European Commission) July 2003 (EGE):
  http://europa.eu.int/comm/european_group_ethics/docs/avis18EN.pdf]

Council of Europe - Committee of Ministers

Genetic testing and screening can be carried out at different levels, such as on chromosomes, genes (DNA), proteins, organs or a given individual, and can be complemented with aspects of the family history. The essential distinction between genetic diagnosis and genetic screening is that the latter is not initiated by the individual who is its subject, but by the provider of the screening service. For the purposes of this Recommendation, the term "genetic tests for health care purposes" refers to tests which serve: to diagnose and classify a genetic disease; to identify unaffected carriers of a defective gene in order to counsel them about the risk of having affected children; to detect a serious genetic disease before the clinical onset of symptoms in order to improve the quality of life by using secondary preventive measures and/or to avoid giving birth to affected offspring; to identify persons at risk of contracting a disease where both a defective gene and a certain lifestyle are important as causes of the disease. The term "genetic diagnosis" refers to tests carried out to diagnose a presumed ailment on an individual or several members of a family in the framework of a family study; the term "genetic screening" refers to genetic tests carried out on a population as a whole or a subset of it without previous suspicion that the tested individuals may carry the trait.

Any genetic testing and screening procedure should be accompanied by appropriate counselling, both before and after the procedure. Such counselling must be non-directive. The information to be given should include the pertinent medical facts, the results of tests, as well as the consequences and choices. It should explain the purpose and the nature of the tests and point out possible risks. It must be adapted to the circumstances in which individuals and families receive genetic information. Everything should be done to provide, where necessary, continuing support for the tested persons

Reference:

• Recommendation R(92)3 of the Committee of Ministers yo Member States on Genetic Testing and Screening for Health Care Purposes, 10 Feb 1992:
  http://www1.umn.edu/humanrts/instree/coerecr92-3.html

Council of Europe - Steering Committee on Bioethics (CDBI), 2003

The provisions of this section apply to genetic tests on a living person or materials removed from a living person performed in order to diagnose a genetic disease or disorder and/or to determine whether the person possesses one or more genetic traits which may lead that person to develop a disease or a disorder in the future or may result in a disease or disorder if transmitted to that person’s progeny or which are relevant to medical treatment. Predictive genetic tests: Tests which are predictive of genetic diseases or disorders or which serve either to identify a person as a carrier of a gene responsible for a disease or disorder, or to detect a genetic predisposition or susceptibility to a disease or disorder may be performed only for health purposes or for scientific research linked to health purposes. Genetic screening for health purposes: The provisions of this section apply to specific tests offered for health purposes in an authorised programme, to an entire population or section of a population in order to identify asymptomatic persons with an increased risk of developing a genetic disease or disorder or transmitting such a disease or disorder to his or her descendants.

Reference:

• Working Party On Human Genetics (CDBI-CO-GT4), Working document on the applications of genetics for health purposes, 2003:
  http://www.coe.int/t/e/legal_affairs/legal_cooperation/bioethics/activities/human_genetics/INF(2003)3E_Wkgdoc_genetics.pdf

Council of Europe - Steering Committee on Bioethics (CDBI), 2005

Genetic tests: (A - scope not limited to tests aiming at obtaining health related information, but including also for example behavioural and performance tests) Tests involving analysis of human biological samples and aiming specifically to determine genetic characteristics of a person which are transmissible to his or her descendants. Analysis refers to chromosomal analysis, DNA or RNA analysis, or analysis on any other elements enabling to obtain information which are equivalent to those, in determining genetic characteristics transmissible to descendants. The Protocol does not apply to genetic tests carried out on the human embryo or foetus; genetic tests carried out for research purposes; genetic tests carried out for identification purposes.

or (B - scope limited to tests aiming at obtaining health related information) Tests involving analysis of human biological samples and aiming specifically to determine health related genetic characteristics of a person which are transmissible to descendants. Analysis refers to chromosomal analysis, DNA or RNA analysis, or analysis on any other element enabling to obtain information which are equivalent to those, in determining genetic characteristics which are transmissible to descendants. The Protocol does not apply to genetic tests carried out on the human embryo or foetus; to genetic tests carried out for research purposes; to genetic tests carried out for identification purposes.

Proposal from the Secretariat for the Explanatory Report. The notion of “genetic test” is based here on two elements: its method and its objective. It is to be understood as a procedure including removal of human biological material, where relevant, as well as the analysis of personal information obtained therefrom. This procedure involves analysis of biological samples and aims specifically to determine [health related] genetic characteristics of a person which are hereditary or acquired at embryonic stage, or which appear during lifetime but affect gametes and therefore are transmissible to descendants.

The Protocol also covers further use of tests results, including in fields other than health. The analyses of biological samples are most often cytogenetic analyses on chromosomes, or molecular analyses concerning DNA, RNA or products of expression of genes. However, tests using any other method of analysis on biological samples enabling to obtain information which are equivalent to those obtained by the methods referred to here above for the determination of [health related] genetic characteristics transmissible to descendants are also considered to be covered by the Protocol. [This would exclude tests aiming to obtain information on pathological genetic modification acquired during lifetime by only certain somatic cells due for example to external factors in the environment.] This would exclude as such collection of genetic information through family history.

The Protocol covers any genetic test carried out on a person whether leaving or dead, or on human biological material, [in particular] in the fields of health, employment and insurance. This includes diagnostic, predictive or healthy carrier tests as well as pharmacogenetic tests. Genetic tests offered in the framework of a genetic screening programme are also covered.

The Protocol does not however cover [genetic tests on the human embryo and foetus], genetic tests carried out for research purposes and genetic tests carried out for identification purposes such as filiation or for forensic inquiries, when not for medical purposes.

Genetic services - The goals of these services are to respond to the needs of individuals and families wishing to know whether they are at risk of developing or transmitting a disease or disorder with a genetic component, or who are faced with such disease or disorder. This includes in particular providing information and genetic counselling, carrying out genetic testing and interpreting results, ensuring care for the person concerned and their family, namely preventive care, as well as the training of persons involved in genetic services.

Predictive test - The expression “predictive test”, in accordance with Article 12 of the Convention on Human Rights and Biomedicine, refers to a test which is predictive of genetic diseases or which serves either to identify the subject as a carrier of a gene responsible for a disease or to detect a genetic predisposition or susceptibility to a disease. The predictive nature of the information obtained with predictive genetic testing, the psychological impact of knowledge of genetic risk for the person concerned, the possible implications for family members, and the often difficult decisions to make for the person concerned, including where appropriate in relation to procreation choices, make appropriate genetic counselling particularly important for such tests. This also applies to any other test with similar consequences for procreation choices or important implications for family members.

Genetic counselling - The notion of “genetic counselling” is to be understood here as a communication and support process aiming to enable individuals and, where appropriate, families, to make informed choices with regard to a genetic test and its implications.

It includes the obligatory provision of information prior to requesting consent or authorisation as required in paragraph 1. It also includes an offer of support before and, if appropriate after the test, to the person concerned allowing him or her to “handle” the implications of the test and its results, including, where appropriate, communication to family members of information relevant to their health, or procreation choices.

Genetic counselling is an individualised and non directive process taking into account, in particular, the psychological and familial context of the person concerned and involving an exchange between him or her and the person providing the counselling. This support process may therefore vary in form and extent depending on the test considered but also on the particular significance of the information that the test is likely to provide for the person concerned or for members of his or her family.

Reference:

• CDBI (2004) 14 REV2 - Draft Protocol on genetic testing: revised proposals [ Restricted]

European Parliament

Pharmacogenetics - determining differences in individual reactions to drugs

Pharmacogenomics – development of customised drugs – "personal pills"

Genetic tests - many tests have already been developed to identify or confirm rare genetic diseases. However, whereas until a few years ago there were only a handful of genetic tests for a small number of hereditary diseases, today, as a result of the impetus provided by academic and commercial laboratories, there are tests for cystic fibrosis, Huntington’s chorea, muscular dystrophy, and, moreover, a great many non-hereditary degenerative diseases – the symptoms of which can appear in youth or adulthood – such as, for example, diabetes, cancer, cardiovascular diseases, high blood pressure, and Alzheimer’s disease. Genetic tests give incontestable prognoses where some diseases are concerned but in many other cases reveal no more than a predisposition that can be influenced by external factors such as environment, diet, and lifestyle. Genetic tests can be carried out for various purposes:

• postnatal diagnostics is used to diagnose a disease, determine the probability that an infant will develop a given disease, the onset of which does not occur until later in life, and detect genetic alterations that increase the predisposition to some illnesses such as certain tumours and cardiovascular disorders;
• antenatal diagnostics is used to diagnose a genetic disease or condition in a foetus;
• preimplant diagnostics, an alternative to antenatal diagnosis, is used to diagnose a genetic disease or condition in an embryo before it is implanted in the uterus (it is an application of in vitro insemination).

Embryonal chromosome analysis using the technique of preimplant genetic diagnosis (PGD) makes it possible to ensure that embryos will not be implanted if they have abnormal chromosomes and cannot survive. PGD enables selected, i.e. undeformed, embryos to be implanted and avoids the abortions that might otherwise follow a conventional antenatal diagnosis at an advanced stage of pregnancy (after the third month in the case of amniocentesis). It offers an alternative to the normal antenatal diagnosis methods, especially in cases where parents are at high risk of having a child with severe genetic diseases. It can be used to detect many singlegene disorders. Data and reports relating to the findings of PGD are compiled at world level. The PGD Consortium, a body which works in collaboration with the European Society of Human Reproduction and Embryology (ESHRE), published the most recent findings last summer. Over 200 babies have been born with the aid of this technique (see papers read by Professors Devroy and Hovatta at the temporary committee meeting of 27 March 2001). PGD has undoubted advantages over conventional antenatal diagnostic techniques, in which diagnosis is carried out in about the third month of gestation, whereas PGD enables an eight-cell embryo to be analysed when it is as little as three days old. Conventional techniques require samples consisting of many cells, whereas in PGD the diagnosis can be confined to just a few (from one to three). Furthermore, the findings resulting from conventional techniques are not known until a couple of weeks after the tests, whereas the findings of PGD are available within about two days (see paper read by Prof. Devroy at the temporary committee meeting of 27 March 2001).

Merely from the above description of the technique it is plain to see that PGD entails different ethical implications from conventional diagnostic techniques for a couple who decide to have an abortion in the light of the diagnosis. PGD methods have prompted disquiet on account of the possibility that people might want ‘made to measure’ children with particular traits such as intelligence or a gift for music. However, leaving aside the possible objection that ethics has yet to address these questions, it is technically completely impossible to identify such characteristics in embryos (see paper read by Prof. Hovatta on 27 March 2001).

Gene therapy - Gene therapy is designed to correct anomalous gene function. It is termed somatic gene therapy when it is used on body cells (blood, organs, etc.) – the main applications are in oncology, cardiovascular medicine, and the treatment of genetic diseases – and the genes inserted will not be passed on to succeeding generations. It is termed germinal gene therapy when it is practised on reproductive cells (oocytes and spermatozoa) or embryos. In this case the change will be passed on to offspring.

Genetic medicine - Unlike gene therapy, genetic medicine does not act upon or permanently alter cell functions. Most of the new medicines are aimed at more easily reachable targets, generally proteins and enzymes on the surface of a cell or in its cytoplasm. They will be more efficacious but have less potent side effects and will act on the body in a much more selective way. Doses will be personalised on the basis of pharmacogenetic tests (papers by Prof. Neri and Mr Goodfellow – meeting of 26 April 2001). Backed by knowledge of the patient’s predispositions, these medicines will prevent the disease rather than curing the symptoms.

Pharmacogenetics - Pharmacogenetics studies how genetic differences influence the variable reactions of individual patients to drugs administered to them (papers by Prof. Neri and Mr Goodfellow – meeting of 26 April 2001). The ultimate goal will be to devise a personalised therapy.

Genetic data - Genetic data are regarded as highly specific information. They can reveal important facts not just about the person examined, but also about the members of his or her family and, in the final analysis, have a great impact on individual lives and lifestyles, not least as regards decisions to have children. The legal framework for data protection covers matters such as confidentiality, anonymity, commercial exploitation, access to information, insurance, employers, and so forth. It might be necessary to update Directive 95/46/EC on the protection of individuals with regard to the processing of personal data and on the free movement of such data.

Predictive genetic tests - Tests which are predictive of genetic diseases or which serve either to identify the subject as a carrier of a gene responsible for a disease or to detect a genetic predisposition or susceptibility to a disease may be performed only for heath purposes or for scientific research linked to health purposes, and subject to appropriate genetic counselling.

(Council of Europe Convention on Human Rights and Biomedicine 1997 – similar definition-based on)

Reference:

• Report on the ethical, legal, economic and social implications of human genetics, Temporary Committee on Human genetics and other New technologies in Modern Medicine (European Parliament, 2001)
  http://europa.eu.int/comm/research/biosociety/pdf/pe_genetics.pdf

IPTS-JRC

Genetic testing (working definition) is used to identify variations in the DNA sequence that correlate with a disease or higher risk to develop a disease. This type of test can be used for diagnosis before any symptoms of disease are recognisable and to determine the personal risk for certain multifactorial diseases. Thus, the results of genetic testing can have far reaching effects on an individual’s life.

There exist slightly different definitions of “genetic testing”, regarding the comprehensiveness of what is subsumed under this term. Against the background of reported problems in the field of genetic testing, the working definition used by OECD is adopted for further discussions: “Genetic testing is testing for variations in germline DNA sequences, or for products/effects arising from changes in heritable sequences, which are predictive of significant health effects.” The study targeted only molecular DNA testing for diagnosis of hereditary diseases, excluding other types of diagnostic tests, such as cytogenetics or biochemical testing. Pharmacogenetics falls also beyond the scope of the study.

Genetic tests as defined above can be applied serving the following purposes:

Diagnostic testing: This is the most common reason for a request for a genetic test triggered by a patient presenting clinical signs or symptoms suspected to have a genetic cause. In this case, the test is performed to confirm, refine or exclude a clinical diagnosis. In many cases the test is widely used as an exclusion test with a low probability of a positive diagnosis (an example is a test for fragile-X disease on children with learning difficulty).

Predictive testing: To estimate the risk to a person with no symptoms of developing a genetic disorder in the future. Usually two forms of predictive testing are distinguished, presymptomatic and predisposition testing: Presymptomatic testing looks for a mutation (or alteration) in a healthy individual, which, if present, will almost certainly lead to occurrence of symptoms. This type of testing is most applicable to adult-onset genetic conditions like Huntington’s chorea. Adults may have no symptoms of disease at the time of the test but there might be a suspicion of high risk of inheriting a genetic condition from a parent. A minority of individuals in this situation seek predictive information through a genetic test.

Predisposition testing looks for gene mutations that provide a probability of occurrence of the disorder (e.g. mutations in the genes BRCA 1 and 2 provide certain susceptibility for breast cancer, but a positive test result does not indicate a 100% risk of developing breast cancer). Many common human diseases – cardiovascular disease, diabetes, atopy, Alzheimer disease – appear to be multifactorial, i.e. are susceptible to a number of genetic and environmental influences. The search for the genetic components of these conditions is currently a major research undertaking, with enormous commercial implications.

Carrier testing: Clarification of presence of a gene mutation for a recessively inherited or Xlinked disorder that will not affect the person but could eventually affect his/her relatives. The test result might be important for reproductive decisions. Carrier testing in children where the test has no implication for their own health has been controversial with many geneticists arguing that the possibility of testing should be delayed until an age when a child can give informed consent for the test.

Prenatal testing: Clarification if the foetus carries certain mutations or alterations responsible for hereditary diseases. Prenatal testing for Down syndrome and related conditions usually results from increased risk either because of maternal age or following a pregnancy screen by ultrasonography or a biochemical test of the mother’s blood. Prenatal diagnosis for single gene disorders is comparatively rare. It is mainly requested where parents are at high risk and have direct experience of a serious genetic condition in their own child or in a close relative. A close liaison between obstetric and genetic services is desirable since parents may choose to end pregnancies shown to be at high risk of a genetic condition after a test. Genetic screening: Predictive testing, prenatal testing and carrier testing can also be offered systematically at the population level. Genetic screening may be concerned with the general population or with sub-populations defined on the basis of their risk. Population screening programs are usually decided on and organised by health authorities at the national or regional level. The only well-established screening programmes are newborn screening programmes: Testing of new-born shortly after birth for specific disorders such as phenylketonuria, galactosemia, congenital hypothyroidism. Biochemical genetic testing of newborn infants is recommended for some monogenic conditions and is carried out in specialist neonatal screening laboratories.

Preimplantation genetic diagnosis (PGD) follows an in vitro fertilisation procedure. Genetic testing is carried out on one or two cells removed from the early embryo. Embryos shown by the PIGD test not to have a genetic mutation for the condition examined are then implanted in the uterus to attempt to establish a pregnancy. The scope and range of testing in the context of this study were circumscribed to diagnosis of health effects but there are many other common applications of these techniques.

Pharmacogenetics, which refers to the identification of DNA variants (polymorphisms) that are related to the variability in drug response, is amongst these other applications of genetic testing with a potentially massive expansion. Adverse drug responses currently account for many hospitalisations and deaths per year. On average in Europe, up to 7% of hospital patients receiving medication experience severe side effects and it is thought that pharmacogenetic testing could reduce this incidence and may contribute to the development of individualised prescription of medicines, or the assurance of the 'right medicine for the right patient'.

Another type of DNA-based testing is carried out for disease sub-typing, for example in oncology laboratories to characterize different types of cancer. The mutations that are under investigation in these cases are most often so-called somatic changes, which arise in a specific tissue, causing a clone of cells to proliferate. These techniques are also used in the identity testing for forensic and criminal law applications, to establish or disprove paternity and to confirm family relationships in immigration applications.

This type of testing is currently widespread and occurs in both the public and private sectors. Areas of related activity that are economically important and share technologies include genetic testing in non-human areas to promote animal health and food safety and regulation, for example testing for permissible levels of genetically modified organisms in food products. Performing a molecular genetic test is a complex process comprising multiple steps: the assignment of the correct indication for sampling, administrative steps, the sample analysis and the writing of a correct and informative report.

Genetic counselling is a communication and educational process to inform the patient and family members on benefits and risks of genetic tests, the limitations and meaning of results. It is meant to inform but also to help the individuals and their families to cope with information gained from testing (including psychological and social implication). Counselling is extremely important considering the wrong or exaggerated expectations connected with genetic testing often reported in the media. Genetic tests are often perceived as being a very accurate method of predicting the future health status of an individual, but depending on what is being tested the accuracy of predicting the future health status might vary profoundly.

The role of the counsellor is critical in giving this information to the patient. The quality of genetic testing cannot be considered isolated from either the type and quality of laboratory reporting, or the quality for the counselling that the patient receives pre-and post-test.

Genetic testing services include not only the actual technical performance of a genetic test ate the lab bench but also the referral system, the accuracy of test results and their correct reporting, proper handling of samples and data (in terms of informed consent and privacy) and also pre and post-test counselling. When discussing quality and harmonization, all these aspects should be taken into consideration (Nys, H et al, Genetic testing patients’ rights, insurance and employment. A survey of regulations in the European Union, 2002, European Commission:Brussels p.154).

Reference:

• IPTS-JRC and ESTO, Towards quality assurance and harmonisation of genetic testing services in the EU, 2003:
  http://www.orpha.net/docs/genetictesting.pdf

INTERNATIONAL/TRANSNATIONAL ORGANIZATIONS

UNESCO

Genetic testing: a procedure to detect the presence or absence of, or change in, a particular gene or chromosome, including an indirect test for a gene product or other specific metabolite that is primarily indicative of a specific genetic change.

Human genetic data: information about heritable characteristics of individuals obtained by analysis of nucleic acids or by other scientific methods.

Human proteomic data: Information pertaining to an individual’s proteins including their expression, modification and interaction.

Biological samples: Any sample of biological material (for example blood, skin and bone cells or blood plasma) in which nucleic acids are present and which contains the characteristic genetic make-up of an individual.

Genetic screening: Large-scale systematic genetic testing offered in a programme to a population or subsection thereof intended to detect genetic characteristics in asymptomatic people.

Genetic counselling: A procedure to explain the possible implications of the findings of genetic testing or screening, its advantages and risks and where applicable to assist the individual in the long-term handling of the consequences; It takes place before and after genetic testing and screening.

Genetic counselling should be non-directive, culturally adapted and consistent with the best interest of the person concerned.

Reference

• International Declaration on Human Genetic Data, 2003: http://portal.unesco.org/en/ev.php-URL_ID=17720&URL_DO=DO_PRINTPAGE&URL_SECTION=201.html (modified from ACGT and NCB)

UNESCO

Genetic counselling provides the link between genetic technologies, several of which have been acquired through the Human Genome Project, and patient care. It can be defined as a communication process which involves diagnosis, explanation and options.

Definitions of genetic counselling. The definitions given concur that it is a communication of information about diagnosed genetic conditions, in a way which allows to make a decision, as autonomous as possible, and safeguarding the emotional and ethical character of the person who asks for the consultation. While defined as based on a physician-patient relationship in many countries, the complexity of genetic counselling has led to a new profession of genetic counsellors who are not physicians, especially in North-America.

• UNITED STATES OF AMERICA: A communication process which involves diagnosis, explanations and options (as in all medical consultation). In genetic counselling there is a stronger need for detail, especially in the explanations and options, for which empathetic and emotional support are an essential part. Counsellors are involved in the ethics of the "people’s right to know".
• UNITED KINGDOM: Counselling entails precision of diagnosis, the estimation of risks, and a supportive role to ensure that those who are given information are enable to benefit from it and from the interventions that are available.
• ITALY: The objective, methods and indications of genetic consultation are:
• Objective: to provide information to patients (and/or blood relations of a patient) at risk of contracting a disease that may be hereditary on:
  • consequence of pathology in question
  • probability of contracting and transmitting it
  • possibility of keeping it in check and treating it
• Methods:
  • construction and analysis of pedigree
  • calculation of the risk of recurrence (Mendelian or empirical)
  • estimation of the consanguinity coefficient
  • more specific analysis
• When is counselling indicated:
  • known or presumed illness in patient or family
  • congenital malformation
  • mental retardation
  • consanguinity
  • recurrent miscarriage, infertility
• CHILE: A medical process of communication between a physician and a consultant (counselee) where scientific knowledge, data and facts are exchanged in order to provide a framework to understand the genetic problem of the patient and the family.
• ARGENTINA: Better called "genetic advising" - a useful tool in preventive medicine.
• ZAIRE: Information on eventual pathology, not therapeutic but predictive.

Reference

• Genetic Counselling - UNESCO 1995:
  http://portal.unesco.org/shs/en/file_download.php/e5ec8f48c2de32a26171790bbdda05eccounsellingCIB3_en.pdf]

World Health Organization (WHO) - 1

Genetic testing: DNA analysis to determine the carrier status of an individual; to diagnose a present disease in the individual; or to determine the individual’s genetic predisposition to developing a particular condition in the future.

DNA genetic testing involves the analysis of DNA in order to determine the presence of a gene associated with a particular disease. In general, there are four kinds of genetic tests: Carrier testing determines if the person tested, who does not himself have the disease, carries a gene for the disease. If two carriers have a child together, there is a high probability that their offspring will have the disease. Prenatal testing determines whether a foetus is affected with a genetic abnormality causing a particular condition. Embryos may also be tested during in vitro fertilization before being surgically implanted into the womb; this is called pre-implantation diagnosis. For technical reasons, the latter method is not widely practised. Diagnostic testing determines whether the tested individual in fact has a particular genetic condition or a genetic predisposition for acquiring the condition later in life. Predictive testing determines the presence in asymptomatic individuals of an abnormal gene that will lead to a disease in the future, or of a genetic predisposition for acquiring the condition later in life, in interaction with environmental factors.

Reference:

• Genetics, genomics and the patenting of DNA Review of potential implications for health in developing countries, WHO 2005:
  http://www.who.int/genomics/FullReport.pdf

World Health Organization (WHO) - 2

Genetic Counselling is the provision of accurate, full and unbiased information in a caring, professional relationship that offers guidance, but allows individuals and families to come to their own decisions. Counselling is essential before any genetic testing is carried out and should continue afterwards if the results entail choices for the person and family tested.

Genetic Counselling should be available to all, and should be as non-directive as possible.

Genetic Counselling - Non-directive counselling has two major elements. The first is the provision of accurate, full and unbiased information that individuals and families may use in making decisions. The second is an understanding, empathic relationship that offers guidance and helps people to work towards their own decisions.

In non-directive counselling, the professional avoids purposely slanting information that may lead people to do what the counsellor thinks best, individuals and families must depend on the counsellor as a source of accurate information, and usually have no way of discovering when information is biased. Non-directive counselling does not mean presenting information and then abandoning individuals and families to make their own decisions without help. Most people may want to talk with someone who will listen to their concerns, help them to express and understand their own values, and help them to work towards their own decisions. Non-directive counsellors do not tell people what to do; decisions are those of the individuals and the families. The counsellor should, as much as possible, support all decisions.

Genetic Screening refers to tests offered to a population group to identify asymptomatic people at an increased risk from a particular adverse outcome. Examples are phenylalanine screening for phenylketonuria in newborn babies, as the use of maternal serum biochemical markers in pregnant women to screen for foetuses with Down syndrome. In all cases, individuals whose screens indicate that they are at risk must be offered a definitive diagnostic test.

Genetic Testing is the analysis of the status of a particular gene. A genetic test may establish:

• A specific diagnosis of a genetic condition in a symptomatic individual
• The certainty that a particular condition will develop in an individual who is asymptomatic at the time of the testing (presymptomatic diagnosis), or c) the presence of a genetic predisposition to develop a particular complex disease such as cancer or cardiovascular disease.

Presymptomatic testing refers to identification of healthy individuals who may have inherited a gene for a late onset disease, and if so will develop the disorder if they live long enough (e.g. Huntington disease).

Susceptibility testing identifies healthy individuals who may have inherited a genetic predisposition that puts them an increased risk of developing a multifactorial disease, such as heart disease, Alzheimer disease or cancer but who, even so, may never develop the disease in question.

Presymptomatic testing in the absence of therapeutic options should be available if the following conditions are met:

• The information provided by testing will be used to prevent harm to the person tested, or to spouse, family, prospective children or others.
• The person is fully informed about the limitations of testing, including possibilities of uninformative results and inability to predict exact age of onset or (sometimes) severity of symptoms.
• The person (or legally authorized representative)is mentally capable of giving consent.
• Testing is accompanied by a counselling programme of appropriate length and intensity for the disorder.

Prenatal diagnosis of genetic disorders and foetal anomalies has expanded significantly for hundreds of conditions through DNA analysis of foetal cells and the increased use of ultrasound and maternal serum biochemical screening (amniocentesis). The purpose of prenatal diagnosis is to rule out the presence in the foetus of a particular medical condition for which the pregnancy is at an increased risk. This information is provided to the couple to assist in their decision-making process regarding the available options, such as carrying the pregnancy to term, preparing for a difficult delivery and for special newborn care, or terminating the pregnancy. Genetic counselling is particular important prior to prenatal diagnosis and, after a result indicating an affected foetus, to secure fully informed choices.

Genetic information has the unusual character of being both individual and familial; it can provide important details about the health status of the patient, but often suggests something about the health status of blood relatives.

References:

• Proposed International Guidelines on Ethical issues on Medical Genetics and Genetic Services – WHO 1998:
  http://www.who.int/genomics/publications/en/ethicalguidelines1998.pdf
• Quality and Safety in Genetic testing: An Emerging Concern (WHO):
  http://www.who.int/genomics/policy/quality_safety/en/print.html]

OECD (Ad-Hoc Working Definition)

Pharmacogenetics refers to the identification of genetic mutations and of polymorphisms involved in or responsible for variability in drug response, including drug metabolism and disposition and the development of what is often described as "the right medicine for the right patient".

The terms " pharmaco-genomics" and " pharmaco-genetics" are often used interchangeably. However, pharmaco-genomics refers to the application of molecular tools to R&D, including, but not limited to, d