Source: https://www.nature.com/articles/gim2016189?error=cookies_not_supported&code=bc9d705b-42a8-4bf2-b52d-29dc4dbfb433
Timestamp: 2019-04-20 15:30:54+00:00

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Public variant databases support the curation, clinical interpretation, and sharing of genomic data, thus reducing harmful errors or delays in diagnosis. As variant databases are increasingly relied on in the clinical context, there is concern that negligent variant interpretation will harm patients and attract liability. This article explores the evolving legal duties of laboratories, public variant databases, and physicians in clinical genomics and recommends a governance framework for databases to promote responsible data sharing.
Human variant databases support the aggregation, curation, and sharing of data on disease-associated variants.1,2,3,4 Variant databases not only curate the literature but also facilitate access to unpublished variant classifications generated in diagnostic laboratories. Making this information available to laboratories, clinicians, and patients supports accurate and timely diagnosis, which in turn improves clinical outcomes. Indeed, public variant databases are increasingly relied on during genomic testing to clarify the clinical significance of variants in support of diagnosis or targeted treatment.5 For clinically oriented databases, harm to patients resulting from misinterpretation is a central ethical and legal concern. Previous ethical/legal discussion concerning variant databases has focused on other concerns such as privacy, commercialization, and database sustainability.6,7,8 Building on existing guidance, we outline the ethical—and potentially legal—duties of databases to ensure the quality, accuracy, and currency of variant data and recommend best practices to manage legal risk through transparency and contractual frameworks.
A third tier, “Curation Space,” is undergoing development and will facilitate expert curation of individual (case)-level data by credentialed users.
We begin by reviewing a 2016 lawsuit (Williams v. Athena) in the United States involving allegations of negligent variant interpretation by a genetic testing laboratory. Because the outcome of this case is not yet known, our discussion is based largely on allegations made by the plaintiff. These claims have not yet been proven in court. Nonetheless, this case illustrates the kinds of patient harms and liability concerns that may arise in the context of genomic testing and variant interpretation. Variant databases now complement the efforts of laboratories to curate and interpret variants. Curation is the collection (from various sources), annotation, and maintenance of variant data.10 Interpretation is the evaluation of the evidence regarding a linkage between a genetic variant and a disease or condition and making an assertion about that linkage (or lack thereof).10 In light of Williams v. Athena, might databases also have legal duties toward patients to ensure the quality and currency of variant data? What ethical, and potentially legal, standards apply to their activities? Finally, what steps can variant databases take to ensure that laboratories submit high-quality data and that physicians use databases responsibly?
Williams V. Athena: Negligent Variant Interpretation?
The facts alleged in Williams v. Athena—a lawsuit pending in a South Carolina federal court—illustrate the serious harm that could potentially arise from variant misinterpretation. Because the outcome of this case is not yet known, our discussion is largely based on claims made by the plaintiff.11 The case concerns the death of Christian Jacob Millare, born in 2005. The plaintiff alleges the following events occurred: Christian started to have seizures after vaccination at 4 months and was prescribed a standard treatment of anticonvulsants. In 2007, Christian’s DNA was submitted to the Athena laboratory to test him for Dravet syndrome, a severe form of epilepsy associated with mutations in the SCN1A gene. A positive result would have led to a change in treatment because conventional anticonvulsants exacerbate seizures in patients with Dravet syndrome. The 2007 test report from Athena concluded that Christian had a “variant of unknown significance.” Christian continued to receive the standard treatment until experiencing a fatal seizure in January 2008. It was only in 2015 that the laboratory company issued a revised report listing Christian’s variant as pathogenic (without citing new evidence). In the resulting wrongful death lawsuit, the plaintiff alleges that Athena negligently interpreted the clinical validity of Christian’s SCNA1 mutation.
A central issue in this case is who is legally responsible for variant interpretation: the laboratory or the physician?12 A laboratory’s traditional responsibility is for the accuracy of the test, including the handling of samples and reporting of results. Physicians are responsible for interpreting the clinical significance of a test result in the context of a particular patient. To do so, a physician needs to remain current regarding the meaning and limitations of test results. However, this division of responsibility between physicians and laboratories has increasingly blurred in the genomics age.13 Laboratories are now expected to aid in variant interpretation and to update patients or their physicians when interpretations change. Current regulations and guidelines require laboratories and their directors to provide physicians with adequate documentation to support interpretation, such as the level of existing knowledge of the variants and a description of the supporting evidence14,15 (42 CFR 493.1445(e)(8)). Some suggest that the duties of physicians should be limited to reasonable interpretations based on the laboratory report.16 In fact, it is difficult to conceive how any laboratory or physician alone can stay abreast of the current genomic state of knowledge. Variant databases support variant interpretation but further blur respective responsibilities between submitting laboratories, variant databases, and physicians.
Williams v. Athena also illustrates how issues of interpretation can bleed into issues of communication. There is some controversy in the case regarding who received the test result and how it was communicated. Standards for reporting genetic results are another area of uncertainty, especially for variants of unknown significance.16 By analogy, variant databases should be careful about how they present variant data and should provide transparent information about data provenance and the processes used in interpretation. Finally, the relationship between interpretation and communication also raises issues about causation.20 In addition to fault, Williams must prove the misclassification caused premature death. This proof is hindered by the intervention of a physician (was it reasonable for Christian’s physician to base a treatment decision on the report?), which may break the chain of causation and scientific uncertainty (would a change of treatment have prevented the fatal seizure?).21 These uncertainties over causation are even more pronounced for misclassified data sharing through a variant database.
A database performing expert curation and classification does seem more likely to be liable for negligent interpretation than a database acting as a mere conduit. The Public Research Space of the BRCA Exchange, for example, provides public access to BRCA variant calls and classifications that are as comprehensive as possible and drawn from many databases. The variants reported will have been classified by someone, often an expert panel, such as a laboratory-associated expert team (such as the GeneDx or InVitae or Ambry team) or one of the national or regional BRCA testing laboratories. In these cases, the database should make the provenance of the variant data clear and clarify that the responsibility for the interpretation rests primarily with the submitting laboratory or database. In contrast, the BRCA Exchange Consensus Space “shows variants curated and classified by an international expert panel, the ENIGMA consortium, to assess their pathogenicity (associated disease risk).” This information is presented as more reliable.
The purpose of and intended audience for a database should be clearly established and prominently displayed.8 The BRCA Exchange describes its aim to “Create a curated list of BRCA variants, interpreted by expert consensus, to enable, without dictating, accurate clinical care.” Transparent descriptions of the data provenance and quality are also important representations from a liability perspective.
Variant databases share classifications published in the scientific literature as well as classifications submitted directly by clinical laboratories. Direct submission of variant data by clinical laboratories makes data available that would not otherwise reach the public domain. In such cases, variant databases should establish a submission policy or submission agreement to clarify respective responsibilities. The pros of submission agreements are that they can impose contractual accountability on submitters for the quality of data and for meeting legal requirements and ethical standards. The ClinVar database submission policy, for example, requires classifications to be made according to a comprehensive review of evidence consistent with, or more thorough than, current practice guidelines.23 A submission click-wrap agreement requires submitters to attest that they have the right to submit data for unrestricted access and that the data are accurate. Database managers should be aware of the limits of these agreements. Strict submission requirements may discourage the voluntary submission of data. They may also shift responsibility to the database to hold submitters accountable for meeting the requirements.
Liability disclaimers: exclude liability for harm resulting from reliance on inaccurate information. Legal disclaimers are found in a variety of medical contexts. When liability cannot be disclaimed, user agreements may instead aim to limit liability or remedies.
Indemnities: users agree to indemnify the database for costs or liability stemming from the user’s actions.
No warranty: the database makes no representations, warranties, or assurances that the data are accurate, current, or fit for purpose (e.g., diagnosis).
No medical advice: the user agrees to not make diagnostic decisions based solely on the information in the repository without consulting a health-care professional with the relevant expertise.
The Human Variome project has developed a standard text for database disclaimers based on common elements in existing disclaimers. It notifies users of appropriate uses and includes language to limit the liability of submitters, curators, and managers.25 The effectiveness of user agreements to modify the obligations of clinicians, who are the primary audience for variant databases, may be limited. Clinicians are already held to professional standards and are expected to be up to date with the current state of knowledge (and its limitations). The validity of liability disclaimers may also be uncertain, particularly when data are made available online and internationally. In many jurisdictions, there are limits on liability disclaimers (e.g., it may be illegal to disclaim liability for recklessness or negligence resulting in bodily harm). In addition, a simple notification on a public website may not be sufficient to form a legal agreement; some form of click-wrap/click-through agreement may be required. Even when use agreements have a limited impact on legal obligations, they are still important to clarify the respective responsibilities of submitters, databases, and users.
Cotton RG, Al Aqeel AI, Al-Mulla F, et al.; members of the Human Variome Project Data Collection from Clinics, Data Collection from Laboratories and Publication, Credit and Incentives Working Groups. Capturing all disease-causing mutations for clinical and research use: toward an effortless system for the Human Variome Project . Genet Med 2009;11:843–849.
Plazzer JP, Macrae F. DNA variant databases: current state and future directions . Methods Mol Biol 2014;1168:263–273.
Johnston JJ, Biesecker LG. Databases of genomic variation and phenotypes: existing resources and future needs . Hum Mol Genet 2013;22(R1):R27–R31.
Brookes AJ, Robinson PN. Human genotype-phenotype databases: aims, challenges and opportunities . Nat Rev Genet 2015;16:702–715.
Bennetts B, Caramins M, Hsu A, et al. Quality standards for DNA sequence variation databases to improve clinical management under development in Australia . Appl Transl Genom 2014;3:54–57.
Knoppers BM, Laberge CM. Ethical guideposts for allelic variation databases . Hum Mutat 2000;15:30–35.
Cotton RG, Sallée C, Knoppers BM. Locus-specific databases: from ethical principles to practice . Hum Mutat 2005;26:489–493.
Povey S, Al Aqeel AI, Cambon-Thomsen A, et al.; Ethics Committee of the Human Genome Organization (HUGO). Practical guidelines addressing ethical issues pertaining to the curation of human locus-specific variation databases (LSDBs) . Hum Mutat 2010;31:1179–1184.
Global Alliance for Genomics and Health (GA4GH). A federated ecosystem for sharing genomic, clinical data , Science 2016;352:1278–1280.
US Food and Drug Administration. Use of Public Human Genetic Variant Databases to Support Clinical Validity for Next Generation Sequencing (NGS)-Based In Vitro Diagnostics: Draft Guidance for Stakeholders and Food and Drug Administration Staff”, 8 July 2016. http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM509837.pdf. Accessed 6 September 2016.
Plaintiff’s Complaint, Williams v. Quest Diagnostics, Inc., (S.C. Ct. C.P.) (24 February 2016).
Wagner JK. Litigating the accountability of clinical genomics laboratories . Genomics Law Report. 31 May 2016). http://www.genomicslawreport.com/index.php/2016/05/31/litigating-the-accountability-of-genomics-laboratories/.
Shirts BH, Parker LS. Changing interpretations, stable genes: responsibilities of patients, professionals, and policy makers in the clinical interpretation of complex genetic information . Genet Med 2008;10:778–783.
Richards CS, Bale S, Bellissimo DB, et al.; Molecular Subcommittee of the ACMG Laboratory Quality Assurance Committee. ACMG recommendations for standards for interpretation and reporting of sequence variations: revisions 2007 . Genet Med 2008;10:294–300.
Richards S, Aziz N, Bale S, et al.; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology . Genet Med 2015;17:405–424.
Ray T. Mother’s negligence suit against Quest’s Athena could broadly impact genetic testing labs . Genome Web. 14 March 2016. https://www.genomeweb.com/molecular-diagnostics/mothers-negligence-suit-against-quests-athena-could-broadly-impact-genetic.
US Food and Drug Administration. Laboratory developed tests. 17 November 2015. http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm407296.htm.
Harkin LA, McMahon JM, Iona X, et al.; Infantile Epileptic Encephalopathy Referral Consortium. The spectrum of SCN1A-related infantile epileptic encephalopathies . Brain 2007;130(Pt 3):843–852.
Global Alliance for Genomics and Health. Response to FDA Draft Guidance (NGS testing & Public Variant Databases). 6 October 2016. https://genomicsandhealth.org/files/public/GA4GH%20Consultation%20-%20FDA%20Draft%20Guidance_6Oct2016_v1.1.pdf.
Marchant GE, Lindor RA. Personalized medicine and genetic malpractice . Genet Med 2013;15:921–922.
Ray T. Quest, Athena make moves in wrongful death lawsuit . Genome Web. 1 April 2016.
Traynor M. Information liability and the challenges of law reform. In: Winn JK (ed). Consumer Protection in the Age of the Information Economy. Ashgate Publishing: Aldershot, UK, 2006.
National Center for Biotechnology Information. Guidelines for applying for review status in ClinVar. http://www.ncbi.nlm.nih.gov/clinvar/docs/review_guidelines/. Accessed 30 January 2015.
Hurwitz B. Legal and political considerations of clinical practice guidelines . BMJ 1999;318:661–664.
Human Variome Project. Disclaimer Statements for Gene/Disease Specific Databases. 2014. HVP/GL/002-01/EN. http://www.humanvariomeproject.org/assets/hvp-guidelines/HVP-GL-002-01-EN-Disclaimer_Statements_for_GDSDBs.pdf.
Dewey FE, Grove ME, Pan C, et al. Clinical interpretation and implications of whole-genome sequencing . JAMA 2014;311:1035–1045.
Amendola LM, Jarvik GP, Leo MC, et al. Performance of ACMG-AMP Variant-Interpretation Guidelines among Nine Laboratories in the Clinical Sequencing Exploratory Research Consortium . Am J Hum Genet 2016;98:1067–1076.
Funding for this research was provided through the Can-SHARE project supported by Genome Quebec, Genome Canada, the government of Canada, the Ministère de l’Économie, Innovation et Exportation du Québec, and the Canadian Institutes of Health Research (fund 141210). Funding for RC-D was provided by P50 HG003391 from the National Human Genome Research Institute and FasterCures, a Center of the Milken Institute.

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