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    Researchers define best practices of genome sequencing for patients with rare diseases

Genome sequencing has shown promise in becoming a first-tier diagnostic test for patients with rare genetic disorders, but standards addressing the definition and deployment of a best-in-class test are lacking.

Two recent manuscripts published in npj Genomic Medicine present consensus recommendations on clinical genome sequencing analytical validation and clinical utility to diagnose patients with suspected genetic diseases, including practical advice for optimizing test development, validating practices and ongoing quality management.

Mayo Clinic researchers Hutton Kearney, Ph.D.; Eric Klee, Ph.D.; Brendan Lanpher, M.D.; and Ross Rowsey, Ph.D. represent Mayo in the Medical Genome Initiative. The initiative includes leading health care and research organizations in the U.S. and Canada focused on expanding access to high-quality clinical genome sequencing for genetic diseases by publishing best practice recommendations.

As the Mayo steering committee lead for the Medical Genome Initiative, Dr. Kearney leads Mayo's clinical genome testing development.

"Our aim was to present consensus recommendations on genome sequencing to reduce the burden on laboratories introducing genome sequencing into the clinical practice, and support safe and effective genome testing for the diagnosis of genetic diseases," says Dr. Kearney.

Consortium evaluates current state of genome testing

Consortium members provided insight into the current state of genomic testing at each of their institutions, as well as current laboratory practices across sites. They focused on providing practical advice for test development optimization, validation practices and ongoing quality management to deploy genome sequencing tests:

  • Although the stage is set for widespread adoption of genome sequencing, technical challenges remain, including workflow and test limitations that may affect the efficacy of genome sequencing.
  • Standards that address the definition and deployment practices of a best-in-class clinical genomic testing need to be fully defined.
  • Professional bodies have made progress in providing guidance for clinical test validation and best practices for benchmarking, with reference standards and recommended accuracy measures beginning to emerge.
  • There are often different but equally valid approaches to the analytical validation of genome sequencing tests.
  • The rapid advancement of genetic testing is continually being updated and improved. As a result, laboratories are often at different stages of implementation.

Collaboration and communication are key

Members of the consortium agreed that collaborative efforts and communication within and among research and health care institutions are essential to establishing guidelines and standards to increase access to high-quality genome sequencing, while minimizing patient risk.

Dr. Rowsey, a Mayo clinical lab director, leads a team within the Medical Genome Initiative working to launch the genome sequencing test.

"It's important to establish clear consensus around many of the analytical principles that define a valid clinical genome test," says Dr. Rowsey. "We also recommend endorsing genome sequencing as a viable first-tier test for children and adults with rare disorders."

Toolkit for measuring and evaluating the clinical utility of genomic sequencing for patients

In the clinical utility paper, the Medical Genome Initiative sought to define and provide laboratories, clinicians, researchers, and health care systems with best practices and resources when measuring and evaluating the clinical utility of genomic sequencing. The toolkit offers a flexible, yet structured framework, as well as measurement strategies to enable the capture of clinical usefulness data.

"We looked at effects on diagnostic thinking, therapeutic management, patient health and nonhealth outcomes, and societal impacts," says Dr. Lanpher, a Mayo clinical geneticist and one of the authors of the study.

Best practices for measuring clinical utility include:

  • Assess the impact on health care provider diagnostic thinking and decision-making. This can include tracking changes in the differential diagnosis; influencing the diagnostic journey, including decisions to use multiple genetic tests and various other diagnostic modalities; changes in prognostic certainty; and timeliness of the diagnostic information.         
  • Weigh therapeutic efficacy. Include all medical recommendations and interventions that follow from a genomic sequencing result. While diagnostic results are more likely to lead to tailored recommendations or interventions, the absence of a pathogenic variant can enhance patient management decisions and also should be captured. Interventions can include therapies targeted to underlying disease mechanisms, supportive therapies, disease-specific monitoring plans, subspecialist referrals and any other resulting changes in management.  
  • Evaluate patient outcome efficacy. Include patient outcomes that may be directly and indirectly affected by the test. Patient outcomes can include health outcomes, such as hospitalization time, hospitalization events, morbidity and survival, and disease-specific outcomes, and nonhealth outcomes, such as knowledge, psychosocial response, personal utility and decision quality.  
  • Gauge societal effects that relate to family effects, societal acceptability and value for money. Benefits of information generated by genome sequencing must be balanced against individual, community, and societal level costs and consequences.

"The consortium expects best practices to continue to evolve," says Dr. Klee. "Although reaching consensus on specific validation-related practice was not always possible, a sentiment shared by all groups was that establishing standards in clinical genome sequencing is difficult but critically important."

Dr. Klee's research focuses on clinical adoption of genetic sequencing by developing and implementing bioinformatics methods to help medical providers interpret results.

Three additional best practice manuscripts are currently in development by the Medical Genome Initiative: test interpretation and reporting, data management and infrastructure, and patient selection; the papers are expected to be published in the near future.

The Mayo Clinic researchers in the consortium represent Mayo Clinic's Center for Individualized Medicine and the Department of Laboratory Medicine and Pathology as part of their work in Mayo Clinic's integrated multidisciplinary practice.

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