Whole Genome Sequencing and Incidental Findings in Clinical Laboratory Settings

1. Whole Genome Sequencing and Incidental Findings in Clinical Laboratory Settings Mark E. Sobel, MD, PhD Executive Officer, Intersociety Council for Pathology Information Executive Officer, American Society for Investigative Pathology Executive Officer Emeritus, Association for Molecular Pathology mesobel@asip.org Eighth Meeting of the CEER Investigators, NHGRI October 16, 2012

2. Definitions and Acronyms • Whole Genome Sequencing (WGS) • Whole Genome Analysis (WGA) • Next-generation Sequencing (NGS) • Whole Exome Sequencing (WES)

3. Incidental Findings An incidental finding is a finding concerning an individual in the course of conducting research that has potential health or reproductive importance and is discovered in the course of conducting research, but is beyond the aims of the study and is not anticipated in the research protocol. Susan M. Wolf, et al. (2012). Genetics in Medicine, 12: 361-384. What about incidental findings that occur in the course of clinical testing? Especially WGS!

4. CLIA ‘88 • Clinical Laboratory Improvement Amendment • The following analytical characteristics must be documented: • Accuracy • Precision • Analytical sensitivity • Analytical specificity • Reportable range • Reference intervals (normal values) • Any other performance characteristic required for test performance

5. Test Validity • Is the test accurate? • False positives? • False negatives? • Clinical Validity – does it test for the stated disease or syndrome? • Clinical Utility • Is there a treatment? • Does it help select treatment • Are there preventive measures that can be taken?

6. CLIA ‘88 Upon a patient’s request, the laboratory may provide access to completed test reports that, using the laboratory’s authentication process, can be identified as belonging to the patient.

7. Proposed Rule 42 CFR Part 493 September 14, 2011 Centers for Medicare & Medicaid Services (CMS) According to the HIT Policy Committee, CLIA regulations are perceived by some stakeholders as imposing barriers to the exchange of health information. While individuals can obtain test results through the ordering provider, the advent of certain health reform concepts (e.g., individualized medicine and an individual’s active involvement in his or her own health care) may be best served by revisiting the CLIA limitations on the disclosure of laboratory test results.

8. Proposed Rule 42 CFR Part 493 Retain the existing provisions that provide for release of test reports to authorized persons…. Amend the Health Insurance Portability and Accountability Act of 1996 (HIPAA) Privacy Rule to provide individuals the right to receive their test reports directly from laboratories by removing the exceptions for CLIA-certified laboratories and CLIA-exempt laboratories.

9. Clinical Diagnostic Genome Sequencing The introduction of high-throughput, next-generation sequencing (NGS) in 2005 heralded a critical and transformative step in the history of DNA sequencing.

10. This report of the Whole Genome Analysis group of the Association for Molecular Pathology illuminates the opportunities and challenges associated with clinical diagnostic genome sequencing. With the reality of clinical application of next-generation sequencing, technical aspects of molecular testing can be accomplished at greater speed and with higher volume, while much information is obtained. Although this testing is a next logical step for molecular pathology laboratories, the potential impact on the diagnostic process and clinical correlations is extraordinary and clinical interpretation will be challenging. We review the rapidly evolving technologies; provide application examples; discuss aspects of clinical utility, ethics, and consent; and address the analytic, postanalytic, and professional implications. (J Mol Diagn 2012, 14:525540; http://dx.doi.org/10.1016/j.jmoldx.2012.04.006)

11. NGS Platforms Although the NGS platforms differ in design and specific chemistries, they are fundamentally related by a paradigm in which sequencing of spatially separated, clonally amplified DNA templates or single DNA molecules is performed in a massively parallel manner.

12. NGS Technology All NGS technologies offer the ability to simultaneously sequence thousands to millions of relatively short nucleic acid sequences in parallel. They can provide orders of magnitude more information, at competitive costs, when large regions of the genome are sequenced.

13. Advantages of NGS Technology • Individual sequencing assays based on capillary electrophoresis tend to be: • Expensive • Laborious • Less comprehensive, necessitating serial gene-by-gene testing to identify causative mutation(s)

14. Informed Consent and Ethical Considerations • The capacity to perform large-scale sequencing on the human genome presents unique challenges regarding the provision of informed consent, particularly in deciding on the level of detail that needs to be shared. • No specific guidance exists, and each institution offering such testing is deriving its own policies. • With genome testing by NGS, the perceived and real potential risks are magnified compared with genetic tests that target only one gene at a time.

15. Bioinformatics Requirements • Major computations performed with NGS data: • Data assembly with base calling at the level of individual reads • Alignment of the assembled sequence to a reference sequence • Variant calling

16. Variant Calling • Different computational analyses devoted to SNPs, small indels, structural variants or large indels, copy number variants • Generation of an unprecedented amount of medical data that result in special informatics needs and require tools for data management, storage, analysis, and archiving • Manage the large data set without error and to ensure proper quality and documentation.

17. Electronic Health Record • Reporting of NGS test results raises several issues: • Ordering of the test • Receiving a document that summarizes the clinical interpretation • Storage of the interpretation

18. Presidential Commission for the Study of Bioethical Issues Washington, DC October 2012 http://www.bioethics.gov

19. Basic Ethical Principles • Ideal of respect for persons • Public beneficence • Responsible stewardship • Intellectual freedom and responsibility • Democratic deliberation • Justice and fairness

20. Recommendations • Recommendation 1.1 • Funders of WGS research, managers of research, clinical, and commercial databases, and policy makers should maintain or establish clear policies defining acceptable access to and permissible uses of WGS data. These policies should promote opportunities for models of data sharing by individuals who want to share their WGS data with clinicians, researchers, or others.

21. Recommendations • Recommendation 1.2 • Federal and state governments should ensure a consistent floor of privacy protections covering WGS data regardless of how they were obtained. These policies should protect individual privacy by prohibiting unauthorized WGS without the consent of the individual from whom the sample came.

22. Recommendations • Recommendation 2.1 • Funders of WGS research, managers of research, clinical, and commercial databases, and policy makers should ensure the security of WGS data. • Recommendation 2.2 • Funders of WGS research, managers of research, clinical, and commercial databases, and policy makers must outline to donors or suppliers of specimens acceptable access to and permissible use of identifiable WGS data.

23. Recommendations • Recommendation 2.3 • Relevant federal agencies should continue to invest in initiatives to ensure that third-party entrustment of WGS data, particularly when these data are interpreted to generate health-related information, complies with relevant regulatory schemes such as HIPAA and other data privacy and security requirements. Best practices for keeping data secure should be shared across the industry to create a solid foundation of knowledge upon which to maximize public trust.

24. Recommendations • Recommendation 3.1 • Researchers and clinicians should evaluate and adopt robust and workable consent processes that allow research participants, patients, and others to understand who has access to their WGS and other data generated…., and to know how these data might be used in the future. Consent processes should ascertain participant or patient preferences at the time the samples are obtained.

25. Recommendations • Recommendation 3.2 • The federal OHRP or a designated central organizing federal agency should establish clear and consistent guidelines for informed consent forms for research conducted by those under the purview of the Common Rule that involves WGS. Informed consent forms should: • Briefly describe WGS and WGA • State how the data will be used in the present study, and state, to the extent feasible, how the data might be used in the future • Explain the extent to which the individual will have control over future data use • Define benefits, potential risks, and state that their might be unknown future risks • State what data and information might be returned to the individual

26. Recommendations • Recommendation 3.3 • Researchers, clinicians, and commercial WGS entities must make individuals aware that incidental findings are likely to be discovered in the course of WGS. The consent process should convey whether these findings will be communicated, the scope of communicated findings, and to whom the findings will be communicated.

27. Recommendations • Recommendation 3.4 • Funders of WGS research should support studies to evaluate proposed frameworks for offering return of incidental findings and other research results derived from WGS. Funders should also investigate the related preferences and expectations of the individuals contributing samples and data to genomic research and undergoing WGS in clinical care, research, or commercial contexts.

28. Recommendations • Recommendation 4.1 • Funders of WGS research, relevant clinical entities, and the commercial sector should facilitate explicit exchange of information between genomic researchers and clinicians, while maintaining robust data protection safeguards, so that WGS and health data can be shared to advance genomic medicine.

29. Recommendations • Recommendation 4.2 • Policy makers should promote opportunities for the public to benefit from WGS research. Further, policy makers and the research community should promote opportunities for the exploration of alternative models of the relationship between researchers and research participants, including participatory models that promote collaborative relationships.

30. Recommendations • Recommendation 5 • The federal government should facilitate access to the numerous scientific advances generated through its investments in WGS to the broadest group of persons possible to ensure that all persons who could benefit from these developments have the opportunity to do so.