Quality & Safety in Genetic Testing: An Emerging Concern
Genetic tests are available in a growing number of countries, for an expanding set of conditions. It is essential that this increased use be accompanied by appropriate oversight. Because of the very nature of genetic information itself, and the variable prognostic value of currently available tests, maintaining quality standards for genetic tests poses particular challenges. Countries have responded in different ways to these challenges, however a great deal of work remains to improve, and build upon, existing frameworks.
Quality Assurance in Genetic Testing?
Quality Throughout the Testing Process
Determining the Validity of a Genetic Test
Formulating a Regulatory Structure for Genetic Tests
Genetic Testing and Society
Collaboration in Maintaining Quality of Genetic Tests
The Evolution of Quality Assurance in an Uncertain Genomic Future
Although on a global level, genetic tests are not yet widely available, their use is expanding.In those countries where their application is well developed, we can learn some important lessons about how to anticipate and address issues relating to their quality and ethical acceptability. Traditionally, genetic tests existed to detect single-gene disorders. This is because tests for single-gene disorders are generally easier to develop, more reliable and more accurate than test for multi-gene disorders. In recent years, thanks to the Human Genome Project and our growing understanding of the exact role of genes in human disease, genetic tests have been developed for a number of conditions that are the product of complex interaction among genes and environmental factors. These tests are often of more questionable prognostic value, because it is far less clear in many cases what role genetics plays in these conditions, and thus how truly predictive such tests can be. Even for extensively researched conditions, like some forms of cancer, often the best that can be offered to patients is information about their susceptibility -- that is, their probability or risk of developing the condition sometime in the future. This means that, as scientific knowledge evolves and services are developed, the process of interpreting genetic tests, communicating their meaning to patients, and providing clinically useful guidance is likely to become more challenging.
Quality is a broad concept that should apply to all aspects of the process of administering a genetic test, from the point of deciding whether or not a genetic test is warranted, to making sense of the information provided by the test. Clearly, it is essential that the test itself yield accurate results, and that the laboratory be competent to perform tests to an acceptable standard. But in addition to the analytic phase of testing (i.e. the actual process of performing the test), the clinical interface with the patient is equally critical to the process of ensuring quality testing. Prior to performing the test, within the pre-analytic phase, counselling must be administered to inform the patient of the range of options and possible outcomes, and consent must be obtained to conduct the test. In both cases, standards should exist to determine the qualifications of the individual providing counselling and what constitutes appropriate consent. After the test, during the post-analytic phase, the results of the test must be interpreted, and the patient must be appropriately counselled regarding available interventions and existing support structures, even in cases where there is no possible cure or therapy. Major life decisions- such as whether or not to carry a foetus to term or whether or not to undergo prophylactic surgery, for instance- often depend on the results of genetic tests. Testing accuracy is essential, and must go hand in hand with a clinical foundation of communication and interaction between the patient and the health professional.
The approach to quality must be multi-tiered, encompassing several elements both within the clinical and laboratory settings. It is helpful to distinguish some elements of the process that are central to maintaining quality assurance. The following has been proposed as one way of conceptualizing the various issues, to help determine overall efficacy of a test:
- Analytic validity refers to the ability of the laboratory test to distinguish the trait that it was designed to measure (in the case of genetic testing, the presence of an abnormal gene variant). Analytic validity must be safeguarded by making sure the physical test itself has been assessed for effectiveness. Many laboratories use tests developed on-site within the laboratory, which can make standardizing the quality of these tests difficult. Additionally, the clinical laboratories performing the tests must be competent and effective in performing these tests. It is important that standardized samples be readily available against which to judge tested materials, and that active external proficiency testing programs be established, with special care taken to include rare genetic disorders in testing schemes.
- Clinical validity describes the test's ability to predict a given clinical outcome. Within genetic testing this is particularly relevant, as tests often yield results that indicate the "chance" or probability that an illness will manifest itself in the individual, rather than providing a highly definite diagnosis. Therefore, it is important that the test results are meaningful. This depends on practitioners' ability to adequately explain the implications of a positive or negative result to patients, including the possibility of error. For example, a test for Huntington's Disease has strong clinical validity, because a positive test indicates almost certain development of the disease in later life, while a test for mutations in the BRCA 1 gene (which can indicate a predisposition for breast and prostate cancer) have less clinical validity, because they indicate increased risk, or a predisposition to developing the disease. 
- Clinical utility indictates whether a test results in information that can be used to develop a clinical intervention. While some genetic tests provide clinically "useful" information that can inform patients and help them to make choices that could improve health outcomes, many conditions with a significant genetic component currently have no cure or treatment. In a narrow sense, tests for such disorders have low clinical utility, because no medical intervention exists to treat the condition. However, the absence of therapy or cure does not mean that knowledge of a disease or predisposition has no value. In many cases, the quality of life of individuals with inherited disorders can be improved by social interventions, such as special education, therapy or family counselling. In the case of more complex disorders, like cancer or diabetes, which may have an element of genetic risk, knowledge of genetic predisposition could encourage lifestyle choices that improve long-term health outcomes. In any case, it is important to appreciate that the consequences of genetic tests often include social and psychological effects for the patient and his or her family, that also need support and attention. This reaffirms the importance of specialists such as geneticists and genetic counsellors as well as primary care practitioners, and their role in informing patients and conveying test results clearly.
In addressing issues of quality in genetic testing, one must consider what it ultimately means to interpret test results accurately and fairly, and who determines the standards to which the professionals, from lab technicians to counsellors, should be held. Additionally, one must determine how, and by whom, these standards are maintained or enforced. Indeed, these are questions to which answers are still being developed, both at national and international levels. Although many countries have recognized the need for structures to address quality assurance in genetic testing, a regulatory vacuum is widely recognized to exist. Some jurisdictions, such as the United States and many European countries, are relatively advanced in developing and coordinating the various institutions involved in setting standards at different levels of the process. However, even these countries have yet to succeed in fully integrating what continues to be a somewhat fragmented structure. The Organization for Economic Development and Cooperation (OECD), the European Commission (EC) and the World Health Organization (WHO) have been working together in recent years to develop consensus around international standards and best practices for ensuring the quality of genetic services in their member countries; however, there remains much work to do to finalize and implement their recommendations. Several developed countries have not yet enacted regulations based on recommendations from international, professional, and governmental sources; moreover, it is unclear how closely laboratories currently adhere to voluntary standards.Generally, governmental bodies enact statutory regulations, but jurisdictions such as the European Union may have a difficult time standardizing government regulation across national borders. Nevertheless, it is essential to respect national and social differences on regulatory structures when developing a set of guidelines. There is little available literature on regulation of genetic testing in developing countries; however, there is evidence in some countries, like South Africa, that genetic testing quality regulations are in the early stages of development
As countries, both at the national and international levels, grapple with quality and safety issues in genetic testing, even in their narrowest technical sense, they must also take into account the broader questions about the ethical and social implications of genetic testing programs. 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. There are important questions to consider about who should have access to a patient's genetic information, and under what conditions. A child may argue that she is entitled to know whether her mother was the carrier of particular gene that she is likely to have inherited. An employer, or an insurer, may likewise claim that she ought to have access to genetic information, since it has predictive power with regard to future illnesses. The risk of abuse of genetic information imposes certain obligations on providers of tests to protect patients by putting in place structures that insure that only authorized individuals or organisations may gain access to it.
Obtaining consent from a patient before undertaking a clinical procedure is recognized as a critical part of providing acceptable medical services, both genetic and otherwise. Ensuring that a patient's consent is truly informed means being able to clearly communicate the benefit, risk, and outcomes of a genetic test, including its psychological and social impact. Genetic tests are often employed in the context of reproductive decision-making, which means that the issues raised intersect with a range of considerations relating to women's choice and reproductive rights, among others. Many of these concerns have been highlighted in the literature, though they are not always addressed under the rubric of "quality" or "safety". The World Health Organization is among those that have attempted to create guidelines incorporating ethical and social concerns. At the national level, these issues are being addressed in some settings, insofar as countries are taking a growing interest in providing counselling services and other support structures for patients, and implementing procedures and technologies to protect patient information. While many of these concerns are wider than quality and patient safety, in that they often depend on factors outside of what the system can adequately provide (such as empowering women), they are nevertheless fundamental to assuring the overall quality and safety of genetic testing.
Genetic testing oversight involves a number of organizations, both within and outside of the public sphere. In general, the government plays a leading role in developing regulations to define safety mechanisms for genetic tests, and outlines statutory requirements for the development and usage of these tests. Often, this can involve several governmental bodies: in the United States, for example, the Federal Food and Drug Administration (FDA) regulates the development of new tests; the Centers for Medicare and Medicaid Services determine genetic laboratory accreditation; the Centers for Disease Control and Prevention (CDC) conduct research on current oversight; and the Secretary of Health and Human Services plays a directive role in how regulation develops. Beyond that, other actors also play a part, including the private sector and professional organizations, which offer laboratories external quality assurance schemes in order to provide laboratories with feedback on their testing procedures, and by providing clinical geneticists with guidelines and best practice standards. Additionally, international organizations, such as the OECD, can play a role in building consensus and developing standards, for example, by directing regulatory development and integration across international borders. However, not all countries currently have all the pieces of this regulatory infrastructure in place, and even if they do, they are not always well co-ordinated; usually, however, there is involvement at least by the national department of health, and likely one or more professional organizations.
Regulation of genetic testing, much like genetic testing itself, is in its formative period. Many challenges still have yet to be overcome. Quality at each phase of the testing process, expansion of rare genetic disease detection capability, as well as social questions of discrimination and stigma, access to genetic information by third-parties, and patient access to care, are among many issues that have yet to be fully addressed. Nevertheless, strides have been made to develop appropriate regulation, particularly in the developed world, and these early efforts have shown that an integrated approach is necessary and should involve many actors, from professional organizations at the national level to international policy making organizations, including WHO. All these entities have an important role to play in the formation and the dynamic development of standards, both statutory and voluntary, and must continue to be alert to the constantly changing landscape of genetic testing.
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