A Balanced Look at the Implications of Genomic (and Other “Omics”) Testing for Disease Diagnosis and Clinical Care
2. The Promise of Genomic Methods
3. Research Experiments, Clinical Testing and Genomic Testing
3.1. Research Assays and Methods
3.2. Clinical Tests
3.3. Genomic Testing
4. Quality Assurance in the Genome Sequencing Era
- (a) Guidelines for Clinical NGS ImplementationInitial laboratory guidelines for clinical diagnostic NGS testing have been established and published by several laboratory professional organizations. These include initiatives by professional organizations, such as the Association for Molecular Pathology (AMP)  and the American College of Medical Genetics and Genomics (ACMG) [30,31], as well as those by entities, such as the Clinical Laboratory Standards Institute (CLSI) and the Division of Laboratory Science and Standards at the Centers for Disease Control (CDC) . These efforts are expected eventually to result in consistent recommendations for the clinical validation process of NGS testing, as well as for performance metrics and genomic reference materials for clinical use.
- (b) Checks and Balances: The College of American Pathologists Checklist for NGS TestingThe College of American Pathologists (CAP), a CMS-approved accrediting organization, has recently developed a new set of checklist requirements that are specific to NGS, which advances greater standardization in clinical NGS testing. CAP checklists are available to subscribing laboratories and cover key aspects of laboratory function: policies, procedures and pre-analytical, analytical and post-analytical aspects of clinical testing. There is a customized checklist for every section of a clinical laboratory, as well as a general checklist that applies to all sections. During a laboratory inspection, CAP inspectors use these checklists in their evaluation process, to assess whether laboratories follow regulations and practice guidelines and operate at a quality level that is worthy of CAP accreditation and CLIA certification. The NGS section of the molecular checklist contains a set of requirements for both the analytical wet bench processes, as well as for the various bio-informatics steps required for data analysis and annotation. Even though these requirements are not rigidly prescriptive, they highlight key points that must be considered when documenting the reliability and usefulness of clinical NGS testing methods. Many medical centers are within the second year or third of carrying out such testing and therefore have undergone inspection of their genomic or next-generation DNA sequencing assays by CAP or other groups that carry out inspections of CLIA-certified laboratories. Feedback from inspectors and participant laboratories will be very useful for identifying the areas in which checklists need to be revised or made more detailed, explicit or prescriptive, as well as for highlighting the more difficult or uncertain areas in genome sequence data gathering, interpretation and reporting. Some evaluation of the thoroughness of inspections in this new area and the knowledge and qualifications of the inspectors selected for this task will also be warranted as part of the laboratory medicine profession’s due diligence in incorporating these new testing methods into mainstream clinical testing.
- (c) Assay Validation RequirementsThe assay validation conducted before a test is offered clinically documents that a test is consistently and accurately detecting what it claims to be able to identify. CLIA regulations (Code of Federal Regulations § 493.1253 (b) (2)) stipulate that certain core analytical characteristics must be assessed and documented. These include accuracy, precision, analytical sensitivity, analytical specificity, reportable range, reference intervals (normal values) and any other performance characteristic required for test performance (e.g., carryover, dilutions and calculations). The same parameters should be applied to NGS testing, which ranges in scope from single genes or mutation panels to genome sequencing. Limitations of sequence library generation and interpretation, including poorer quality analysis of repetitive sequence regions, less reliable detection or inability to detect certain categories of variation (e.g., insertions, deletions, and other structural variants), inadequately covered regions and similar problems should be reflected and noted in descriptions of the testing method. During the validation process, every single step of NGS must be evaluated, including sample library preparation, clonal fragment amplification, sequencing and all steps of the analysis.A key need for NGS assay development and validation is the availability of well-characterized “gold-standard” reference materials. Fortunately, there are several public efforts and commercial products that are beginning to meet this need. As an example, the National Institute of Standards and Technology (NIST), with the Genome in a Bottle Consortium, has developed well-characterized single genome reference material for SNVs and small insertions and deletions . Continued support of these and related efforts are needed to generate additional reference genomes and other reference materials for additional applications (e.g., somatic variants).
- (d) Interpretation and Reporting of NGS ResultsThe ACMG has previously published recommendations for the interpretation and reporting of sequence variations for heritable disease, and updates to these recommendations that include interpretation and reporting of NGS-derived sequence changes are expected to be released soon . Additional recommendations will likely be required for other applications (e.g., somatic mutation testing in cancer, pharmacogenetic variation). Despite the advances in sequencing technology, many of the key principles of interpretation still apply. SNP databases and disease-related collections of sequence variants are immensely helpful in variant annotation and interpretation, but there are significant issues that prevent them from being reliably used for clinical diagnostic purposes. Many population databases contain individuals that have developed or will develop disease, and many of the disease-specific databases include benign variants. This underscores the importance of centralized efforts to generate clinical-grade variant databases, such as ClinVar .The final formal interpretation of NGS results, their official posting into the patient’s medical record and their translation into clinical care by the physicians responsible for doing that requires interdisciplinary collaboration, whereby pathologists, geneticists and other laboratory professionals become even more directly involved with others in the healthcare team, in order to ensure accurate diagnostic information for individual patients in the context of their disease phenotype.
- (e) Proficiency Testing for NGS AssaysApart from the creation of NGS-specific checklist items, the CAP is in the process of developing NGS proficiency testing products, which are expected to become available in the near future. No other NGS proficiency testing is available in the U.S. from CMS or a CMS-approved accrediting organization. However, laboratories are required to participate in proficiency testing at least twice per year, and this requirement is currently met by alternative assessment. The purpose of such proficiency testing is to be a central quality assessment tool that is an integral component of laboratory inspections and regulatory requirements. To this end, laboratories commonly perform a blinded proficiency testing exchange with other laboratories.
Assessing the Utility of Genomic Information in Clinical Patient Care
5. Physician Education and Training
6. Ethical and Privacy Considerations
Quality of Patient Information and Informed Consent
7. Guiding Principles for Clinical Genomic and Other “Omic” Testing
Box 1. Guiding principles for clinical genomic and other “omic” testing:
- Clinical laboratory testing is an integral component of patient care and is held to different standards than research testing not used to guide clinical care.
- Clinical genomic testing requires extra effort to be dedicated to designing the informed consent and patient education processes.
- Education of physicians and other care-givers about genomic testing methods will be critical for appropriate use and maximal patient benefit.
- The use of less-extensively validated genomic testing approaches for clinical care ordinarily should progress in a graded manner from use in “innovative care” settings, followed by use in clinical research settings, before being added to “standard” clinical laboratory testing.
- Individual and institutional conflicts of interest in clinical genomic testing must be identified and managed.
- These guiding principles also apply to efforts to introduce other clinical “omics” testing into clinical care (such as transcriptomes, proteomes, metabolomes and microbiomes).
- Clinical genomic and other “omic” data and methodologies should, to the greatest extent possible, be shared openly with the wider medical and research communities, to accelerate the pace of medical discovery and to increase the quality and reproducibility of clinical genomic data analysis.
- (a) Clinical Laboratory Testing Is an Integral Component of Patient Care and Is Held to Different Standards than Research Testing Not Used to Guide Clinical CareClinical laboratory testing, regardless of the assay methodology or test complexity, is done to guide patient care decisions, including making diagnoses, counseling patients regarding their prognosis or their future risk of developing disease, guiding management of the patient’s condition and making recommendations about reproductive or life style choices. Multidisciplinary committees of clinician specialists and clinical laboratory geneticists, guided by recommendations from medical specialty organizations, as well as other sources of information, may be best able to decide which new genomic tests or applications are sufficiently well-supported by evidence in the scientific literature to be adapted for clinical use.Any implementation of clinical genomic testing must, of course, comply fully with all relevant laws and regulations governing laboratory tests and, in the United States of America, meet the standards of the professional bodies, such as the College of American Pathologists (CAP) and/or ASHI (the American Society for Histocompatibility and Immunogenetics) that, together with The Joint Commission, have been deemed the status to inspect clinical laboratories on behalf of the Centers for Medicare and Medicaid Services (CMS) to ensure that requirements for CLIA certification are met and all medical tests, including genomic tests, are being carried out responsibly.
- (b) Clinical Genomic Testing Requires Extra Effort to be Dedicated to Designing the Informed Consent and Patient Education ProcessesPatients must be able to obtain sufficient information about the potential value, future implications and limitations of genomic testing so as to be able to give informed consent if they choose to “opt-in” to the use of such tests for their care. Patient education about genomic test results will help to ensure that any subsequent clinical decision-making is carried out as an informed collaborative process between the patient and their physician. In many cases, this may require additional time to be spent by hospital personnel with the patient to ensure that they understand what is measured and what is interpreted from genomic tests. It is likely that the development of additional educational resources for patients will be necessary for this process. As with almost any other clinical interaction with patients, the use of genomic testing should be done only on the basis of a patient decision to “opt-in”, rather than as a default pathway from which patients need to “opt-out”.
- (c) Education of Physicians and Other Care-Givers about Genomic Testing Methods will be Critical for Appropriate Use and Maximal Patient BenefitMedical centers and healthcare organizations should consider establishing a set of resources, including a service staffed by individuals with training in molecular genetic pathology, medical genetics and genetic counseling, to educate and advise medical personnel about the proper selection of genetic tests and the appropriate interpretation of their results. The need for such a resource has been highlighted by a recent study performed at a large reference laboratory, which documented a strikingly high rate of inappropriate selection of genetic tests (e.g., ordering the incorrect test, ordering tests that were not needed or ordering suboptimal tests given the clinical question being asked). Approximately 26% of all requests for complex genetic testing for heritable disease were changed following review . These misorders result in unnecessary costs to the healthcare system and, more importantly, may result in significant clinical consequences (e.g., failure or delays in receiving necessary testing, receiving incidental or secondary findings that were not requested or desired).If clinical findings indicate that genomic tests could be helpful for the care of a particular patient, integrated “tumor board”-style meetings are particularly important in evaluating whether genomic sequencing methods should be applied for the care of that individual patient and for discussing the results and implications of the new genomic data for that patient’s care, particularly in challenging cases. It is still an open question as to how the cost of physician and other professional time and effort will be compensated for such diagnostic conferences, but the trend toward health system payments based on patient outcomes rather than the sheer volume of clinical work performed in a patient’s care may be compatible with such new efforts, if genomic testing contributes significantly to optimal diagnostic and management decisions and the cost-effectiveness of caring for individuals and populations in coming years.
- (d) The Use of Less-Extensively Validated Genomic Testing Approaches for Clinical Care Ordinarily Should Progress in a Graded Manner from Use in “Innovative Care” Settings, Followed by Use in Clinical Research Settings, before being Added to “Standard” Clinical Laboratory TestingIt is likely that a range of different approaches or applications of “genomic” testing will continue to be proposed by physician scientists and other medical investigators, spanning a wide range of different kinds of measurements and interpretations, with widely-varying levels of evidence for their actual clinical utility in different clinical contexts. There are preexisting good models for incorporating innovative clinical methods into practice, and these can be applied to the evaluation of genomic tests supported by various levels of prior evidence. For applications of “genomic” technology that measure already well-established genetic variants with clear clinical significance, typically by replacing older Sanger DNA sequencing assays, rapid incorporation into clinically and analytically validated molecular genetic pathology testing in the CLIA-certified clinical laboratories is advisable. The results of such sequence interpretation are applied for clinical decision-making in the same manner as equivalent results obtained using prior testing methods.When the clinical value of genomic testing is not well established, but few or no other adequate diagnostic testing options exist, then, as with other types of “innovative clinical care” adopted by medical centers, the application of these tools on very limited numbers of patients for specific purposes at the discretion of the clinician can be considered. If genomic testing will be applied systematically on multiple subjects, without established evidence of clinical utility, it should be carried out in the context of a clinical research study with the accompanying human subject protections and regulations associated with this activity. This would, of course, include obtaining informed consent from the patient for the research, following an explicit and detailed discussion of the limitations of the novel test as a basis for making clinical decisions or healthcare recommendations, the kinds of unexpected (and in some cases, unwanted by the patient) test results that could be reported to the patient and their physician and additional confirmatory testing that would be required before making clinical decisions based on the results of the novel test.As genomic testing and interpretation methods are validated by ongoing clinical research studies and evidence accumulates for the clinical utility of particular approaches in a given clinical context, some testing and interpretation methods would become sufficiently mature to join the list of “standard” laboratory tests that can be ordered for individual patients by clinicians without the additional safeguards and consultations described above. To the extent that patient informed consent permits, the data and interpreted results of genomic tests should be stored in databases that will permit additional research and discovery to proceed and derive additional clinical insights and knowledge from the testing process.
- (e) Individual and Institutional Conflicts of Interest in Clinical Genomic Testing must be Identified and ManagedConflicts of interest are a serious concern for physicians and others responsible for patient care, and the current period of great discovery and commercial interest in clinical genomics has presented opportunities for physician-scientists and others to become involved in the commercialization of new genomic testing or interpretation methods. All physicians and healthcare institutions must be vigilant to ensure that such potential conflicts of interest do not lead to inappropriate decisions about the kinds of testing approaches to pursue or not to pursue. Individual conflicts of interest, where a faculty member or physician has a financial stake in a private company and/or intellectual property related to genomic testing and analysis methods, are similar to those that apply to the use of other medical technologies, pharmaceuticals and devices. Institutional conflicts of interest are those where the healthcare organization or those directing it could influence decisions about which kinds of diagnostic testing would be used for the care of patients, either to encourage the use of particular test methods, instruments, analytical systems or outsourcing to particular genomic testing to particular companies, or else the avoidance of particular tests or companies. Information about any such potential conflicts should be publicly available, as well as scrutinized and managed within the organization, to ensure and document the propriety and ethical behavior of all participants.
- (f) These Guiding Principles also Apply to Efforts to Introduce Other Clinical “Omics” Testing into Clinical Care (Such as Transcriptomes, Proteomes, Metabolomes and Microbiomes).The improvement in NGS-based sequencing methods over the past five years has resulted in dramatic decreases in the cost per base of DNA sequence. Initially, these technologies revolutionized research endeavors, but clinical laboratories rapidly adopted these technologies. Other related complex testing using NGS or other technologies in the research setting shows significant potential clinical utility. These methods and technologies include RNA sequencing (complementary DNA sequencing), proteomics, metabolomics and metagenomics, as well as functional genomic studies. We suggest that these guiding principles for genomic testing can also be applied to the incorporation of other complex clinical laboratory testing into patient care when sufficient evidence is available to support clinical utility.
- (g) Clinical Genomic and Other “Omic” Data and Methodologies Should, to the Greatest Extent Possible, be Shared Openly with the Wider Medical and Research Communities, to Accelerate the Pace of Medical Discovery and to Increase the Quality and Reproducibility of Clinical Genomic Data AnalysisWith many technological advances, there are opportunities for private enrichment, as well as the creation of new public resources. The balance between these two components can shape the pace of adoption and the ultimate impact of the technology; the history of the development of the Internet and the role of “open source” contributions to it show the key impact that communities with some element of altruism or public spiritedness can have on the success of a technology. The recent U.S. Supreme Court ruling in AMP v. Myriad Genetics, Inc. , which determined that human genes themselves are not able to be patented, and the preceding ruling in Mayo Collaborative Services v. Prometheus Laboratories, Inc. , which found that correlations between measured analytes and medical interpretations of such data do not qualify as patentable inventions, may have somewhat decreased the likelihood that private companies will attempt to use litigation to deter testing for particular human gene mutations . These rulings may increase the likelihood that individual companies may try to amass, and keep in private hands, human genetic information and clinical interpretations as trade secrets. In spite of this possibility, there is now an opportunity for medical centers and other healthcare institutions to cooperate in sharing data, interpretations and analysis methods, to speed the identification of correlations between genomic sequences and disease risks, prognosis and treatment outcomes. Currently, the initial frameworks for such data sharing and coordination efforts are promising, but medical organizations and, particularly, their patients will benefit from further joint activity in the public domain that advances clinical genomics  and that can serve as a counter-balance to siloed, competitive, inward-looking efforts (whether in academic or commercial settings).
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Boyd, S.D.; Galli, S.J.; Schrijver, I.; Zehnder, J.L.; Ashley, E.A.; Merker, J.D. A Balanced Look at the Implications of Genomic (and Other “Omics”) Testing for Disease Diagnosis and Clinical Care. Genes 2014, 5, 748-766. https://doi.org/10.3390/genes5030748
Boyd SD, Galli SJ, Schrijver I, Zehnder JL, Ashley EA, Merker JD. A Balanced Look at the Implications of Genomic (and Other “Omics”) Testing for Disease Diagnosis and Clinical Care. Genes. 2014; 5(3):748-766. https://doi.org/10.3390/genes5030748Chicago/Turabian Style
Boyd, Scott D., Stephen J. Galli, Iris Schrijver, James L. Zehnder, Euan A. Ashley, and Jason D. Merker. 2014. "A Balanced Look at the Implications of Genomic (and Other “Omics”) Testing for Disease Diagnosis and Clinical Care" Genes 5, no. 3: 748-766. https://doi.org/10.3390/genes5030748