This article has been changed to provide updated information on the price of HudsonAlpha's WGS testing.
NEW YORK (GenomeWeb) – The founders of Envision Genomics, a spinout from the HudsonAlpha Institute of Biotechnology, are continuing to make a case for clinical whole-genome sequencing as the standard for clinical testing for rare diseases and hereditary cancers, reducing medicine's reliance on multiple point-of-care tests.
Specifically, Envision is targeting a clinical market segment comprising customers who are interested in using WGS but are not sure how to go about doing so. Envision has also developed new variant analysis and interpretation software for the service that will be clinically validated in June this year. The company charges $6,500 for its service which covers sample sequencing through data analysis including Sanger confirmation.
Envision was founded by some of the same researchers that were involved in the widely reported case of six-year old Nicholas Volker at the Medical College of Wisconsin. By sequencing Volker's genome, researchers in MCW's clinical sequencing program identified a mutation in Volker's XIAP gene that indicated that a bone marrow transplant would help treat his severe form of inflammatory bowel disease. In 2015, HudsonAlpha hired several MCW employees for a new Center for Personal Genomics it launched that was focused initially on diagnosing rare disease. HudsonAlpha also opened a genomic medicine clinic later in the year to offer diagnostic WGS for $6,500.
Now some of those HudsonAlpha employees are commercializing their sequencing and analysis expertise under the Envision brand. Howard Jacob is a company founder and also serves as president and CSO. Another founder, Elizabeth Worthey, serves as the company's chief product development officer.
Jacob and others have for some years been pushing for the use of clinical WGS as an alternative to repeated single-purpose tests or gene panels particularly for rare and undiagnosed diseases as well as hereditary cancers. He delivered a keynote at this year's Bio-IT World Conference during which he again argued for the use of WGS in some clinical contexts including specific examples of how his team has used it to help patients.
Envision is focused on "helping other people that want to practice genomic medicine use what they have and leverage what we have," he told GenomeWeb at the conference. "If you are new to the area, which sequencer do you use? Which data storage solution do you use? How do you analyze data? How do you deliver the data?" Without a local genome center to help, he added, "it's a pretty daunting task."
In the clinical arena, gene panels and whole-exome sequencing have dominated much of the discussion around NGS-based medicine. However, although WGS is arguably a much simpler and more streamlined approach to testing, clinical labs still have reservations that, in Envision's view, are not necessarily warranted.
Part of the problem is that a number of misconceptions about WGS have persisted simply because it hasn't been done enough in clinics, according to Jacob. For instance, there are malleable definitions of clinical utility. "You could call 10 physicians in 10 different fields and ask them 'what does clinical utility mean to you?' and [get] a very wide spread [of responses]," he said. There are also concerns about upfront costs of whole-genome sequencing. As a result, genomic medicine in general and WGS in particular are methods of last resort in the clinic that are employed only when all other tests have failed.
Currently labs have to validate and certify multiple gene tests for clinical use. In contrast, WGS would only need to be done once. The challenge would then become reanalyzing the data over and over again. "It just simplifies the world," Jacob argued. "If you are running a clinical laboratory, its one test."
This "one and done" approach is "a completely new model for medicine," Jacob said. "The trick then is to get the physicians comfortable with moving it earlier in the space so we are not spending so much money on all the other ancillary tests and they are getting the information that they need to practice medicine.
In actual clinical practice, "I'm really comfortable with us doing this for rare and undiagnosed disease ... [and] for cancer," he added. "For people that are interested in knowing more about themselves, I think there is also utility for that but then there needs to be a different series of conversations."
To that end, Envision provides an end-to-end solution that covers sequencing, analysis, and even physician and patient education. Although it is a separate entity from HudsonAlpha, Envision is an associated company — the institute owns some shares — and can leverage its infrastructure to grow the business. This means that the company can use HudsonAlpha's IT infrastructure and CLIA-certified sequencing resources, including an Illumina HiSeq X Ten system, to generate data from samples. In total, Envision has the capacity to sequence 15,000 clinical genomes per year, according to Jacob.
It also means that Envision employees can pursue commercial interests whilst retaining their positions at the institute. In addition to his position with Envision, Jacob is also vice president for genomic medicine at HudsonAlpha and chief medical genomics officer for the institute's clinic. Meanwhile, Worthey is also a faculty investigator and informatics director at HudsonAlpha in addition to her role at Envision.
On the software front, the company currently uses an updated version of the same software that the team used at MCW to analyze data from the Volker case and others but it is building an entirely new pipeline from scratch, Worthey told GenomeWeb.
Worthey led the MCW team that developed Envision's analysis software, called CarpeNovo, in late 2009. The MCW team used the software to identify pathogenic mutations in patient samples — the first version of the tool was used to analyze Nik Volker's exome. CarpeNovo offers tools for linking functional, positional, biochemical, and disease-association data to variants, and for doing targeted analysis on genes, gene sets, or regions. Users can also filter variants by chromosome or chromosomal region or search for variants associated with phenotypes that are similar to the phenotype of the patient in question.
Envision developed its new system because it took too long to get an agreement in place with MCW that would allow it to use CarpeNovo, she explained. However, the delay proved to be a blessing because it motivated Worthey's team to build an improved and much faster iteration of the software. The new software — currently called Codi — follows the same principles and offers the same features as its predecessor but runs queries fasters, is able to handle more variants, and offers some new functionality.
Codi is "written specifically for clinical use cases [meaning that] everything from the vcf file to the final clinical report, all of that work and that process is dealt with in a single tool," Worthey told GenomeWeb. It's also designed to be easy to use for clinicians without programming skills or bioinformatics expertise, she said.
Until it launches Codi, Envision is using CarpeNovo for data analysis and interpretation. It has made several updates to the software since it was first developed in 2009. The list of updates includes a way of representing data in a graph, rather than a tabular format, that makes it easier to sift through and identify pathogenic variants. There are also mechanism for users to contribute their variant annotations — information on disease association and pathogenicity — to Envision's underlying database. Those annotations immediately become available to other clinicians who use the company's services.
"That's critical because I can filter [based] on that," Worthey said. For example, if multiple users agree that a given variant is actually a mapping error then others can ignore it when looking at their results, she explained. If, on the other hand, there is conflicting evidence — some clinicians think the variant is pathogenic and others disagree — users could reach out to the parties in question and try to understand the reasoning for their classification. "I could also see the evidence codes that they enter as to why they thought it was pathogenic or likely pathogenic," she said. "I think as we move forward that's the sort of thing that tools … have to be able to do."
The updated version of CarpeNovo also works a lot faster than its predecessor. With its software, Envision can analyze either a full genome or exome in about an hour and half, down from about a week, Worthey said. "One of the things that's interesting is when you do clinical interpretation of a genome you'll maybe end up with 60 variants to look at. When you do a clinical interpretation of an exome for the same individual, you'll have maybe 58," she said. "So the amount of work that goes into the analysis and interpretation isn't that different."
That's because most of the data from the genome gets de-prioritized because clinicians can only interpret variants in their data that have known associations to disease. Still, the handful of additional variants that clinicians get from the genome could be crucial to their patients' care, Worthey noted, and since the interpretation takes about the same time it might be worth doing.
In recent months, she has been involved in detailed twitter discussions — some of which are captured here — with others in the community who do not share Envision's views on using WGS for clinical diagnostics. She plans to publish some numbers from an analysis that she has done that compares clinical exomes and genomes including details on costs and what percentage of cases would not have been diagnosed if clinicians had done exome sequencing instead of WGS, as well as the average monthly costs for patients who don't have a diagnosis.
Besides faster queries, other updated features in Codi will include a pharmacogenetics report as well as a new method of representing data in common diseases, Worthey said. The system also uses a different database technology — CarpeNovo used Oracle but Codi uses MongoDB. Envision also hopes to install instances of Codi at partner sites and try to get the systems to talk to each other similar to what the Global Alliance for Genomics and Health is doing with the Beacon project.
If all goes to according to plan, a single Codi systems will be able to query information stored in another Codi installation elsewhere. Envision is working on setting up a Codi instance at an unnamed partner's site for this purpose, Worthey said.
"The reason that we are doing that is so that you are not biased to what you already think is important," she explained. "If you think about ClinVar, everybody sends the stuff that they think is important into it. But if you didn't have enough knowledge to know that [a variant] was important, you are not going to send it, so nobody else is going to find it and you are not going to generate the knowledge that [something's] important." Setting up communicating Codi systems will let users query data wherever it is located and in a more complete form.
Envision also plans to collaborate with researchers in GA4GH's Beacon project to enable Codi to communicate with beacons as well. It hopes to ultimately build a network of such sites to share variant information with each other. "The goal would be down the road that we can all query each other's systems regardless of whether it's exactly the same tool or not," Worthey said.
Jacob said that Envision has a number of customers on its roster but declined to name specific ones. He did say, however, that clients are asking for the company's help with analyzing data from patients with rare, undiagnosed diseases and also that Envision will soon unveil details about a network of children's hospitals that it is organizing. "We are staying focused on that because rare undiagnosed disease crosses all [medical] sub-specialties," he told GenomeWeb.
Jacob also believes that as more physicians use WGS and perceive its value, its use will spread. This is where physician-to-physician conversations will be critical, he said. So far, feedback from clients who have used the company's services has been positive. "I've yet to have a physician come back and say 'I wish I wouldn't have done that,'" he said. More commonly, their response is "'I'd like to use this sooner.'"