Interview with Julie Eggington of Center for Genomic Interpretation

Dr. Eggington co-founded the Center for Genomic Interpretation (CGI) in 2016, which became a nonprofit organization in 2017, with the mission to drive quality in clinical genetics. To accomplish its mission, CGI provides a variety of services to health insurers, laboratories, clinicians and patients. Dr. Eggington is an expert in the initial classification of novel clinical genetic variants, high throughput literature curation, as well as the accurate re-classification of Variants of Uncertain Significance (VUS) through optimized research methods. Dr. Eggington has directed variant classification and reclassification programs at Myriad Genetics, Courtagen, and 23andMe. Read her full bio.

Interview with Julie Eggington of Center for Genomic Interpretation

Q1a: Together with Robert Burton you founded the Center for Genomic Interpretation (CGI), a non-profit organization. Can you tell us more about CGI and the mission behind it?

A: CGI’s mission is to drive quality in clinical genetics and genomics. CGI works primarily with laboratories, health insurance payers, clinicians, and patients/consumers. CGI provides tailored services to educate and support these stakeholders so that more patients/consumers get clinically valid and accurate results.

Q1b: Why is CGI a non-profit organization instead of a for-profit organization? What is the idea behind it?

A: CGI is a 501(c)(3) deep tech humanitarian organization founded in 2017. As an independent and non-profit organization, CGI provides tailored services at reasonable prices to customers who are looking for unbiased technical support and education in the very niche area of commercial clinical genetics and genomics. Since CGI charges for services that are in line with its mission, CGI’s basic operations are self-sustained. To date, CGI has provided services to laboratories and health insurance payers, though CGI is expanding its services to support government policy makers, clinicians and patients/consumers.

CGI’s donor fundraising efforts focus on preparing for CGI’s much larger and longer term goal of making accurate clinical genetic variant classification and reclassification pre-competitive. CGI aims to provide just-in-time variant classification services at scale to commercial and academic laboratories at low cost, so that all labs are capable of providing the highest quality variant classifications and reclassifications to patients and consumers.

Q: What excites you about your work at CGI?

A: I am most excited about the positive patient impact we have in our work. By helping the genetics and genomics labs and health insurance payers implement improved quality initiatives, we get to help many thousands, if not millions, of patients.

Q: What organizations has CGI worked with in the context of genomic data interpretation?

A: We have non-disclosure agreements with all of the commercial labs that we help with genetic variant classification. Most of the labs we currently serve are medium to high volume laboratories wanting to supplement their current pipelines. Though we also support several startup companies.

We have also started helping health insurers on some very particular genomic data interpretation challenges related to true and false positive variant interpretations, where true positives may lead to a precision therapy. For example, RPE65 pathogenic variant interpretations may result in treatment with Luxturna, costing close to one million dollars per treatment.

Also, due to a recent press release made by Blue Shield of California (BSCA), we can now say that BSCA is partnering with CGI on CGI’s ELEVATEGenetics initiative, which is an initiative to provide more transparent and standardized laboratory quality metrics to stakeholders.

Q: Can you tell us more about a specific example?

A: Regarding variant classification, many laboratories have optimized their variant classification work flows to decrease false negative interpretation rates. This often results in the unintended consequence of higher false positive interpretation rates, which have contaminated ClinVar. ClinVar is the most widely used public variant classification database in the USA. False positive variant interpretations can sometimes contribute to erroneous medical procedures and therapies, so many laboratories double check the data behind the classification claims made in ClinVar before using the classifications. Sometimes these labs that are checking out ClinVar classifications will disagree with pathogenic or likely pathogenic consensus classifications. Before issuing a non-consensus report, these labs often ask CGI to independently assess the classifications on variants to see if CGI agrees or disagrees with the consensus classification. CGI’s stringent variant classification and reclassification protocols are well suited for this fact-checking work.

Q: Variant data interpretation has its challenges. How can we improve the interpretation of variant data in that are used in the clinic to diagnose a disease or make treatment patient treatment decisions?

A: CGI views its nonprofit business model as the operational solution to bring accurate variant classifications and reclassifications into the clinic. Accurate variant classification must be evidence based, and clinical scientists must guard against the heavy use of research data which is contaminated by ascertainment bias and publication bias. CGI has developed its own stringent evidenced based process that allows it to provide variant classification as a service to labs for any genes associated with monogenic disease. Also, excellent professional and academic consortia groups continue to publish updates to variant interpretation protocols.

Q: What are some of the biggest challenges the industry is currently facing when it comes to genomic data interpretation, and how will we overcome these challenges?

A: For all but the highest volume boutique commercial laboratories, the cost of accurate variant classification for many sequencing tests exceeds the reimbursement value of those tests. Some labs use venture capital funds to close this gap, and/or take low quality shortcuts to lower costs, or simply stop offering certain genetic tests. CGI is working to fix this in two ways:

  1. CGI is educating health insurers on the true costs of high quality genetic tests, and the benefits of using higher quality tests over lower quality tests. CGI’s ELEVATEGenetics initiative is part of this effort, providing needed transparency to laboratory quality metrics.
  2. CGI is fundraising in order to build out its larger scale and lower cost accurate variant classification service. In this way, CGI will act as a central nonprofit service, providing accurate variant classifications and reclassifications to all labs at a significantly reduced price through a just-in-time model. Due to the scale, and being able to serve many laboratories in a noncompetitive way, CGI will achieve an economy of scale unachievable by any single laboratory, thus driving costs of variant classification down for everybody.
Q: Who is mostly affected by these challenges?

A: Patients are most affected. In some hereditary diseases the false positive rate due to over-interpretation of sequence variants may currently exceed one in every two positive reports. These patients may end up being treated for diseases they do not have, while the diagnostic journey to find their true disease is abandoned.

In rarer cases, false positive variant interpretations may lead to erroneous fetal terminations. This was the case in the early 2000’s with the CFTR I148T variant which was included on the ACMG and ACOG panethnic panel of CFTR pathogenic variants. The variant was later demonstrated to be an interpretation false positive, and is now known to be a somewhat frequent and benign variant in the Indian population.

Q: Is there anything else you would like to share with the PMWC audience?

A: Much of precision medicine relies on accurate interpretation of genetics and genomics data. Unless we are able to improve the current quality of genetic variant interpretation in the industry, precision medicine will not advance at the rate we all hope it will. CGI is dedicated to fixing quality and accuracy problems in clinical genetics and genomics. CGI is always thrilled to receive donations in order to help patients get accurate results, and to help both established and start up commercial companies succeed with high quality offerings. So please support the Center for Genomic Interpretation in its mission to drive quality in clinical genetics.