Following the general sessions, participants formed three breakout groups in concurrent discussion sessions during the remainder of May 20 and early morning of May 21. Because of the broad scope of the discussion, each breakout group was charged to address a subset of the issues and also ensure that overlapping issues were adequately considered by participants with expertise needed.

Breakout Group A - Promoting Quality Testing. This group was charged to develop recommendations for actions needed and identify issues to be further discussed for promoting and assuring the quality of rare disease tests in clinical settings and laboratories providing patient testing for rare diseases and conditions. Topics addressed by this group included:

• Strengths and weaknesses of current strategies and approaches to assessing and evaluating the quality of laboratory testing for rare diseases;
• Applicability of available guidelines for assessing and evaluating quality of rare disease testing, recognizing that formal or standard proficiency testing (PT) or external quality assessment (EQA) programs are not available for the majority of the rare disease tests;
• Issues related to international test referrals or cross-border testing, recognizing that currently for many rare conditions, a patient specimen has to be sent to another country to be tested;
• Data needs for assessing the quality of current testing, identifying areas needing improvement, and developing recommendations and strategies for best practices;
• Responsibilities of laboratories in listing, announcing, or advertising their testing services; and
• Appropriate roles of government, laboratories, professional organizations, industry, academic institutions, healthcare providers, patients, and others in promoting quality rare disease testing.

Breakout Group B - Transferring Tests from Research Phase to Clinical Use. Group B was charged to develop recommendations for translating genetic findings into clinical testing, taking into consideration stages from clinical research, disease gene identification, test development, through validation and implementation in patient care. Discussion of this group focused on the following issues:

• Strengths and limitations of current mechanisms for moving potential tests from the research phase to clinical use;
• Networking approaches needed to facilitate and encourage translation;
• Validation of newly developed rare disease tests during each step of the translation process, from patient classification, gene identification, test or test system development, through implementation in clinical laboratory setting or as part of a public health program;
• Data collection and compilation needed to facilitate research translation, test validation, and review or evaluation of new tests;
• Impact of technology on research translation and test availability;
• Oversight and gatekeepers needed to ensure quality of each step of the translation process; and
• Roles of government, investigators, professional organizations, industry, academic institutions, healthcare providers, patients, research participants, and others in the translation process.

Breakout Group C - Access, Data, and Educational Needs. This group was charged to develop recommendations on systems and mechanisms needed to improve the availability of, access to, and information dissemination for rare disease testing. Issues considered by this group included:

• Needs and challenges in ensuring continued availability of quality rare disease testing, recognizing that individual rare disease tests are often available from a single or only a few laboratories and from laboratories primarily conducting research;
• Mechanisms that can be explored to assist in implementation and provision of testing;
• Improving coverage and reimbursement for rare disease genetic tests;
• Mechanisms needed for data collection, assessment, and synthesis to aid in evidence-based decision making by oversight agencies, insurers, and other data users;
• Educational needs and roles of all stakeholders in improving public knowledge of quality testing; and
• Practical mechanisms for information dissemination and education.

Subsequent to the breakout discussion, participants returned to a general session to hear the reports from each breakout group and to provide additional input. All three group reports were received with enthusiasm. Recommendations were made by each group regarding the areas of needs to be addressed, actions needed; issues to be further discussed, and key organizations for the suggested activities. A number of overarching premises and consensus were recognized in addition to recommendations for specific aspects of rare disease testing.

III-A. Premises

1. Clinically available genetic tests and research translation efforts needed to develop clinical testing services are woefully behind the pace of basic discoveries in genetics and genomics.
2. High quality testing is the goal of all phases of the translation process, from the research phase to clinical laboratories.

III-B. General Recommendations

1. Affirmation of CLIA standards for tests used for clinical purposes. When test results are to be shared with patients, research participants, or their healthcare providers, whether during clinical research, transition of potential tests from research to clinical use, or the clinical testing phase, the entire testing process, including specimen collection and processing, analytical procedures, and result reporting, should be performed by CLIA-certified laboratories.
2. Education is needed regarding CLIA and other requirements for releasing individual-specific results in clinical research. Research investigators, laboratory directors, clinicians, pathologists, patients and families, research participants, and other users of laboratory services should be considered the target audience. It is important to have strategies in place and consensus on the teaching materials before initiating the educational activities, to minimize adverse effect on access to testing. With assistance from CMS and CDC, professional organizations and funding agencies should take a leading role in the development of educational programs and teaching aids and in information disseminating.
3. Provide education for IRBs regarding CLIA and the role that IRBs should have in safeguarding the release of individual test results in clinical research. OHRP should lead this activity, with assistance from CMS, CDC, funding agencies, and professional organizations to develop educational strategies, materials, and process.
4. Develop mechanisms and guidelines for determining the clinical readiness of a potential test. Issues to be further explored include how newly developed rare disease tests should be validated, and how analytic validity, clinical validity, and clinical utility should be established for rare disease tests with an often limited patient population.
5. Establish mechanisms and strategies to promote quality data collection during each step of test development through clinical application, in order to 1) facilitate translation of potential tests to the clinical setting, 2) improve result interpretation and use in patient management, 3) assess impact and benefits of testing on health outcomes, and 4) improve access to quality testing.

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III-C. Recommendations for Promoting Quality Rare Disease Testing

Recommendations in this area were developed by Breakout Group A and reported by Drs. Patricia Charache and Carol Greene. After considering strengths and weaknesses of current strategies to assuring quality testing, applicability of available guidelines for quality assessment, data needs, and actions needed for promoting quality rare disease testing, the group made the following recommendations:

Strengths and Weaknesses of Current and Proposed Approaches

1. The Johns Hopkins University approach. The group discussed the approach presented by Dr. Patricia Charache and considered a model in which all research laboratories providing specific information back to patients or research subjects become CLIA-certified. It was agreed that this model would ensure basic quality laboratory practices and compliance with applicable regulatory requirements; however, its broader transferability is unknown since it requires strong institutional commitment and close collaboration with a department. In addition, there are both real and perceived barriers, such as the risk of discontinuing testing services, the lack of resources needed for implementation, as well as laboratory personnel and leadership issues.
2. New York State Program. The group agreed that the New York State program provides peer review of method validation, assures quality performance of laboratory testing, and enables quality assessment in association with laboratory surveys.
3. Partnerships for CLIA laboratories to provide confirmatory testing for mutations found in non-CLIA laboratories. A general concern was expressed for the likelihood of false negative results associated with this approach, since only positive findings are sent for confirmation. The group discussed various specific approaches under this model, and felt that some are evidently not in compliance with CLIA while others need further review and input from the oversight programs to determine their appropriateness. In addition, this model does not solve the problem of research laboratories desiring or being expected by research participants to share both negative and positive test results.
4. The proposed European approach based on benchmarking. It was agreed that if appropriate benchmarks for each phase of the testing process can be determined, they will be useful to set internationally acceptable standards for rare disease testing and cross-border test referrals. However, concerns were expressed about difficulties in developing appropriate benchmarks for rare disease testing.
5. Test referral to non-US laboratories. It was agreed that sending specific rare disease tests to non-US laboratories is currently necessary but also problematic; therefore, standards are needed both for specimen shipping and tracking documentation and for the validity and quality of the testing. In addition, CLIA requirements, US and international privacy regulations, and other requirements may impose restrictions both on cross-border test referrals and on obtaining information necessary for test selection, result interpretation and reporting. The group also noted that certain "borderless" laboratories may be able to facilitate sending specimens and test results across borders and may provide a model for addressing transborder testing; however, the use of these laboratories can be problematic when contact information for the testing laboratory is not provided and test results are transcribed or edited on the report issued to the referring institution.
6. The pediatric oncology group model. The group recognized the success of this model in setting guidelines that maintain the quality of clinical services and research investigations. It was agreed that further information on this model is needed to understand how it might apply to and be helpful for the rare disease testing community.

Areas of Needs

1. Guidance and quality indicators need to be developed for all testing phases, i.e., the pre-analytical, analytical, and post-analytical phases of rare disease testing. These guidelines need to be achievable and reasonable.
2. When test results are to be shared with patient(s) or provider(s), the pre-analytical, analytical, and post-analytical phases of testing should be performed by a CLIA-certified laboratory or an equivalent laboratory if the test is referred to a non-US laboratory.
3. Multiple approaches may be required to address the needs for quality testing while maintaining access to testing services, in recognition that
   • CLIA requirements are minimum standards and not comprehensive for rare disease genetic testing;
   • Requiring CLIA certification precludes referring tests to many foreign laboratories offering rare disease tests not available within US;
   • CLIA requirements and other guidelines inadequately address key pre-analytical and (especially) post-analytical factors pertaining to test interpretation and result reporting; and
   • CLIA certification is inadequately enforced, known to, or understood by research laboratories performing patient care testing.
4. Mechanisms need to be developed to ensure accuracy of both positive and negative test results, in light of the growing services to confirm mutations identified by non CLIA-certified laboratories. Models to consider may include 1) research laboratories attaining CLIA certification, 2) partnering between research and CLIA laboratories, and 3) partnering between clinical laboratories.
5. In developing quality assurance strategies, non-DNA-based rare disease genetic testing should be considered in addition to molecular tests.
6. In considering efforts to improve the availability of rare disease testing, the inherent challenges of translational research and development of clinical services need to be recognized to avoid setting unrealistic expectations and to promote development of appropriate strategies and approaches.
7. Recommendations and action items suggested need to be followed through.

Recommended Next Steps

1. Define quality standards for rare disease genetic testing through the following actions:
   

   a.	Establish specific requirements for genetic testing under CLIA. HHS should accelerate its current pace in developing the proposed CLIA regulation for genetic testing.
   b.	Establish quality indicators appropriate for rare disease testing, recognizing the limited availability of disease information, laboratories performing testing, quality control materials, and external quality assessment programs. The group agreed that this is an especially challenging area, and suggested that ACMG take the lead in collaboration with CDC.
   c.	Establish validation guidelines for rare disease genetic tests and criteria for evaluating their analytical and clinical validity. The group agreed that this is also an especially difficult issue, and can be addressed in concert with (b) above.
   d.	Establish standardized generic (i.e., not disease-specific) protocols for results reporting and for pre-analytic issues. ACMG could take a lead here in partnership with other standard-setting organizations, such as the College of American Pathologists, the Association for Molecular Pathologists (AMP), New York State, NCCLS, and with help from the Clinical Laboratory Improvement Advisory Committee (CLIAC).
   e.	Enhance data collection and analysis, probably by a central facility to allow data sharing and genotype-phenotype correlation. Initiatives from major mutation databases, such as those affiliated with the Human Genome Variation Society (HGVS), should be supported. CDC and NIH should work closely to expand current efforts and develop evaluation and monitoring systems.

2. Further explore cross-border testing issues with international partners, especially with respect to international and US privacy regulations, CLIA certification, and overarching issues regarding assuring quality of global rare disease testing. The group suggested that CDC convene international colleagues to address these issues and develop strategies for moving forward.
3. Evaluate adequacy of current strategies to monitor testing and laboratory quality, and collect data on current practices and outcomes to 1) help identify problems, 2) suggest possible solutions, and 3) forecast and track impact of solutions on quality and access. The group felt that such assessment studies are critical for quality improvement but was unable to identify a specific group to lead in this area.
4. Provide education for IRBs, researchers, laboratories, and users of laboratory services regarding CLIA and other requirements to promote quality testing, as stated in Overarching Recommendations 2 and 3.

Issues to Be Further Discussed

1. What role professional organizations, government, and other players can play in setting quality standards or accreditation programs for rare disease testing? The group felt various models should be considered, including the European benchmark model, the Johns Hopkins University strategies, and the New York State approach.
2. How practical mechanisms should be established to balance quality and access/availability of testing - to ensure quality without imposing undue burden or restrictions on testing access, and to enhance availability and access without compromising quality? The group felt this is a critical issue that needs to be further discussed in conjunction with the recommendation on CLIA compliance for all patient testing, to determine which strategies will be useful and which will be counterproductive.
3. How should criteria be established for determining whether a rare disease test is appropriate for use in clinical settings? The group considered several options, including adoption of arbitrary criteria for test acceptability if the test identifies a defined percentage of known mutations for the disease or detects mutations in a specific patient population. However, the group also recognized the obligation to provide patients with access to testing that can generate helpful information for their families, even if limited information is available regarding penetrance and sensitivity due to the rarity of the disease.
4. To what extent should quality assurance strategies focus on the laboratory and to what extent should they focus on the test? The group felt a two-pronged approach would be needed and recognized the need to have further discussion on how the two aspects could complement each other in assuring quality testing.
5. How should strategies be developed to assure appropriate result interpretation and patient counseling without excluding qualified professionals or specialists? The group discussed the New York State approach and the Johns Hopkins University model, in which the institution determines whether non-pathology laboratories may provide patient testing based on their qualifications. It was felt that if guidance were to be set forth by professional organizations or the government, appropriate expertise should be recognized to avoid disruption of quality service.
6. It was agreed that data are needed in the following areas in order to make more specific recommendations:

   a.	Practice assessment on current rare disease testing;
   b.	Information and better understanding of practices and problems in the pre- and post-analytic phases, including informed consent, information provided in test reports, and other considerations;
   c.	Information on personnel in laboratories performing rare disease testing;
   d.	Information on both tests and laboratories offering rare genetic disease testing that are not listed on GeneTests:
   e.	Information on research laboratories releasing patient-specific test information and their concerns, to help i) develop practical educational means for CLIA compliance, ii) understand the impact on access associated with enforcing CLIA, and iii) minimize adverse impact without compromising quality;
   f.	Practices within academic institutions in tracking laboratories doing rare disease testing and encouraging them to have quality assurance measures in place, to assist in exploration of funding needs and mechanisms.

7. A pilot generic or methodology-based proficiency testing project should be considered for rare disease tests not included in available PT/EQA programs.
8. Explore models of "equivalency" determination by CLIA for foreign laboratories.
9. Convene working group of international partners to consider cross-border issues relating to international test referral and sharing of information for clinical and research purposes, including consideration for privacy (HIPAA and other national and international privacy rules), CLIA, and international trade issues.
10. To promote quality patient testing in clinical research, develop a requirement for NIH grant applications, e.g., a checkbox, to ensure test performance in CLIA-certified laboratories if results are to be released to research participants or their healthcare providers.
11. Activities are needed to make the currently available educational resources more visible.
12. Consider implications of all strategies and policies proposed for non-DNA based tests.
13. Should there be a mechanism for monitoring the announcements and advertisements laboratories make regarding their testing services? The group was concerned about the inability to know the quality, reliability, or validity of the tests advertised, and felt further discussion is needed on responsibilities of laboratories for truth in advertising.

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III-D. Recommendations for Transferring Tests from Research Phase to Clinical Use

Recommendations in this aspect was developed by Breakout Group B, which was charge to consider issues related to translational research and moving potential tests from research phase to clinical setting. Discussion of this was moderated by Drs. Joann Boughman, Steve Groft, and Giovanna Spinella. Dr. Boughman summarized the following recommendations and issues identified by the group:

Recommendations

1. Affirmation of CLIA standards when tests are used for clinical purposes, as stated in Overarching Recommendation 1. In conducting clinical research or during transition of potential tests from the research phase to clinical use, when individual-specific test results are shared with patients, research participants, or their healthcare professionals, the entire testing process, including specimen collection and processing, analytical steps, and result reporting, should be performed by CLIA-certified laboratories. Approaches to consider may include research laboratories becoming CLIA-certified or partnership between research and clinical laboratories so that clinical testing is performed by the clinical/CLIA-certified laboratory.
2. Enhance infrastructure to gain momentum to facilitate the rare disease translational process. The following needs were identified for the research and clinical areas respectively:
   1) For the research community:
   • More obvious support mechanisms for translational research;
   • Education of researchers regarding CLIA requirements for laboratories providing patient testing and other requirements pertaining to releasing individual-specific results in clinical research;
   • Mechanisms for developing partnerships between research and clinical laboratories, including, for example, providing possible contacts and a list of laboratories that could function as a resource;
   • Education and training for IRBs and institutions to improve understanding of CLIA requirements and the role of IRBs in safeguarding the translational process;
   • NIH ORD, ASHG, and ACMG should consider organizing and/or sponsoring activities to address some of these needs; OHRP should take the lead for IRB education.
   2) For the clinical community:
   • Resources and funding mechanisms in response to requests from research laboratories. The NIH model that Dr. Gahl presented could be considered as a practical approach in support of the needs of the NIH clinical research programs as well as individual laboratories.
   • Network/database of resource laboratories, to facilitate the following activities:
     • "Match making" capabilities among clinical laboratories, research laboratories, and advocacy groups regarding test needs and stage of development;
     • Access to mutation databases to allow genotype -phenotype correlation;
     • Appropriate quality assurance mechanisms within the network for confirmation or backup services and quality control/quality improvement purposes;
     • Data sharing between and among research and clinical laboratories to improve interpretation and utility of test results.
   • NIH ORD, HRSA, and AHRQ consider organizing and/or sponsoring activities to address these needs.
3. Set forth professional guidance for transferring potential tests from research to clinical use. Guidance might be needed from different professional organizations, including ASHG, ACMG, AMP and organizations representing pathologists, to address the needs and issues specific for their members.

1. Establishment of Rare Disease Testing Networks to include both DNA-based and biochemical testing for genetic diseases. It was suggested that a steering committee be formed to include representatives from government agencies, professional organizations, and patient advocacy groups; and that stakeholders include laboratorians, clinicians, researchers, advocacy groups, payers, and other users. A $5,000 contribution was proposed for founding members to initiate the network activities. Initial activities of the network should include:

   1)	Communication and coordination - members of the network and the steering committee will need to get together to discuss steps needed to move tests that are only available on a research basis to clinical testing.
   2)	Engage researchers - establish a web-based resource to provide information on how to contact and make request to the network and to serve as an educational mechanism.
   3)	Develop process and guidelines for validating rare disease tests and for establishing the analytical validity, clinical validity, and clinical utility of rare disease testing.
   4)	Data pooling - use information from mutation databases and clinical correlation studies to compile data needed to facilitate research translation and test validation. The need for general or specific data format will be considered to aid in determination of genotype-phenotype correlation with a small number of positive cases.
   5)	Seek additional support for continuation, enhancement, and formalization of the network, through grant applications, response to RFAs, and other mechanisms.

2. Development and dissemination of meeting materials to involve additional stakeholders and engage the broader community.
3. Planning for a follow-up conference to convert recommendations developed into projects and action items; and develop recommendation for issues that need to be further addressed.
4. Development of professional guidelines for transferring potential tests from research phase to clinical setting.

1. Incentives for data sharing. It was recognized that incentives need to be established to encourage data sharing between and among research and clinical laboratories. Incentives could include authorship on publications but the scope and options need to be more broadly considered.
2. Determination of if or when a test is ready for clinical use. It was recognized that the transition point is when individual-specific test information is released, and that currently the decision is left to laboratories to make. Therefore, issues that need to be further explored include how newly developed rare disease tests should be validated, and how analytic utility, clinical validity, and clinical utility should be established for rare disease tests when the number of positive cases and families is often limited or very small.
3. Non DNA-based rare disease testing. It was recognized that availability of quality, accessible non DNA-based rare disease testing, such as biochemical genetic testing, also need to be improved; but there are specific challenges in transferring biochemical tests from research to clinical use. These challenges may be further discussed at the next conference.

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III-E. Recommendations on Access, Data, and Educational Needs

Recommendations in these areas were developed by Breakout Group C, after discussing issues regarding the needs and challenges in ensuring continued availability of quality rare disease testing, improving coverage and reimbursement, data collection, and practical mechanisms for information dissemination and education. Dr. Roberta Pagon and Andy Faucett moderated and reported the discussion of this group. Among the recommendations and needs identified are the following:

Overarching Needs

1. Education is needed for researchers regarding their role in ensuring quality of the continuum from bench to bedside, for providers on test availability and appropriate use, for IRB groups on their role in safeguarding the research and clinical interface, for patient groups on setting appropriate expectations for potential or available testing, and for all groups on the availability, quality and efficacy of testing.
2. Partnerships need to be modeled and eventually required and encouraged by funding agencies to build relationships between investigators, clinical labs, patient groups, clinicians and payers that allow two-way learning. Professional organizations could create a pool of willing groups to participate in pilot projects. As a short term goal, funding agencies should require patient testing that is part of a clinical research study to be performed in CLIA-certified laboratories, with assistance of IRB review.

Recommendations on Improving Access to Rare Disease Testing
The group spent considerable time discussing access and decided to focus on pre-market, market and post-market factors that affect access:

1. Pre-market phase. The group discussed issues affecting public awareness of potential tests, which could deter understanding of a potential test's clinical utility and integration to clinical care. The following recommendations were developed to address the needs in the pre-market phase:

   a.	The cost of test development needs to be subsidized and business models showing how this can be accomplished need to be publicized.
   b.	Models on how to show clinical validity and utility with limited populations need to be developed.
   c.	Models of linking research laboratories with clinical laboratories in same or other institutions can be considered, to help promote a shift from all-service laboratories to niche laboratories specializing in particular rare disease tests.
   d.	Funding agencies should consider including data collection on clinical validity and utility as an important goal in supporting research associated with development of new tests.
   e.	Biobanks and repositories of patient samples need to be encouraged to facilitate test development, test validation and data collection.

2. Market phase. The gatekeeper-consultant systems need to be strengthened to direct healthcare providers to the right test performed by a qualified and experienced laboratory.

   a.	Strategies need to be developed to help determine whether the appropriate test is available and make the information available to healthcare providers.
   b.	The advantages and disadvantages of free-standing laboratories and university-based or academic laboratories need to be explored. When a test is only available from an academic laboratory, it is often not covered by insurers because the laboratory is "out of the network". Efforts need to be considered to improve coverage and reimbursement for such "niche" tests, and to explore strategies for laboratories offering these tests to become "in-network" providers.
   c.	Education outreach should be considered for provider representatives and case managers from the insurance industry on rare disease test availability and use.

3. Post Market phase. The group identified the following needs:

   a.	Involve primary care and other healthcare providers in the process to obtain data for evidence-based outcomes associated with quality testing; and
   b.	Create an expectation that healthcare providers should provide adequate clinical information with test request to enable appropriate interpretation and utilization of test results in patient management.

Recommendation on Mechanisms and Infrastructures Needed
The group considered mechanisms needed for determining when a test is ready for clinical use, for making test information available to healthcare providers, for assessing the impact of the test result on patient care, and for addressing the cost and reimbursement issues. The following next steps were recommended as a result of the discussion:

1. Develop a transition model for moving potential tests from research phase to clinical use.

   a.	Federal research funding agencies need to develop the expectation and the process for such transition to include efforts of research laboratories, clinical laboratories, and patient support groups to enhance data collection.
   b.	Expert groups should be developed to set guidance for test readiness and data collection for rare diseases. Past examples that can be considered include newborn screening programs, experience of the Ataxia Molecular Diagnostic Testing Group, prenatal maternal serum screening programs, and the Tay-Sachs screening program.
   c.	Develop strategies to bring together the needs and interests in a potential test with the expertise and resources for test development, to facilitate the determination of its clinical readiness and to move the transition process forward. The group recognized the significant role that patient advocacy groups can have during this process.

2. Develop mechanisms for providing test information to healthcare providers. It was agreed that MD Consult or similar resources used by clinicians should be considered as possible mechanisms. In addition, the group recommended that professional organizations, particularly the American College of Physicians, the American Academy of Pediatricians, the Society of General Internal Medicine, and other professional groups representing healthcare users of laboratory services should be encouraged to develop guidelines regarding genetic testing for their memberships.
3. Develop mechanisms for determining how test results influence patient care and health outcome. It was agreed that data collection on clinical impact needs to be incorporated in the process of bringing a test to market. The group suggested exploring a "zero sum" model to bring all interested parties and stakeholders together to jointly develop approaches that are practical and beneficial for all parties. Focused discussion on this issue is recommended for the next meeting.
4. Strategies to address the cost issues. It was recognized that costs of clinical tests are highly influenced by liability concerns and that federal legislation similar to that for childhood and adolescent immunization might be needed to provide cost relief. The group recommended exploring a proposal that might reduce liability, by forming a network of laboratories to enable inter-laboratory comparison, service back-up, and other quality assurance measures.
5. Strategies to improve reimbursement schedule. It was pointed out that coverage and reimbursement for a new test can be influenced by public pressure, standards of care, and available data on clinical validity and utility. The group agreed that redefining billing codes to replace the current one-size-fits-all system is a long term goal; however, the need was recognized to reflect the value of rare disease genetic testing and associated clinical services through billing codes. The group recommended developing ways to educate payers about rare disease testing and why costs may be higher, and then refining standards of care as payers start providing coverage and their understanding of the tests evolves.