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Sequencing Firm Phosphorus Tests Limits of Comprehensive Consumer Genomics With GeneCompass


NEW YORK – Pushing limits in both breadth and pricing, clinical sequencing firm Phosphorus has launched a new consumer genomics product this month that it believes can meet growing demand for preemptive genetic testing, driven by new models of concierge medicine.

Called GeneCompass, the test analyzes alterations in more than 400 genes, reporting variants that impact cancer risk, predispositions or risks for other diseases, drug response, and traits associated with other aspects of biology, personal health, and "wellness."

Although other tests have become available in recent years that cover much, if not all, the same content, they are usually available in more piecemeal formats. Targets that are firmly medically established are most often ordered by physicians through more traditional lab models and only in specific reimbursed circumstances, while direct-to-consumer tests have been limited to lower risk, and often less validated, genetic associations, or to returning medically relevant results only with the caveat that they should not be acted upon by physicians.

Phosphorus' new product hews most closely in both its design and its physician-involved, consumer ordering process to tests like Color's and Invitae's, which include hereditary cancer, cardiovascular disease risk, and pharmacogenomic content.

Phosphorus CEO Alexander Bisignano said that the goal with GeneCompass was to provide similar or better medically oriented panels, while adding pharmacogenomics targets to match the breadth of market-leading PGx-only tests. Additionally, wellness-oriented targets were included that consumer customers seek out through companies like 23andMe and Ancestry, all at a price close to what those firms charge individually.

"There is definitely a trend that we started seeing about a year or two ago that led to the development of this product, where primary care physicians and physicians at these specialty group practices and startups were saying 'We're integrating genetics into our practice.' But [what that meant is that] they were getting people a 23andMe test."

"To do what we do on one test, [people] have had to stitch together four or five different genetic tests, and that can be over $1,000," Bisignano said.

Phosphorus was launched over four years ago, but its business model was initially focused on B2B, institutional partnerships, and private labeling. "We had a suite of tests ... similar to labs like Inivitae that offer panel-based testing meeting clinical guidelines and typically offered in specialty contexts where there is reimbursement. So, lipid clinics, cardiologists, fertility groups, etc.," Bisignano said.

The firm still offers those panels, and it licenses the chemistry and end-to-end software to other laboratories and practices that are interested in building their own genetic labs to offer tests in house, Bisignano said.

In launching a direct-to-consumer product, the company had to make a few changes.

"Rather than combining all of our panel tests ... we decided to select the genes that are known to have the largest clinical impact," Bisignano said.

The result is the GeneCompass panel, which covers more than 400 genes associated with 16 clinical areas, including cancer, cardiovascular disease, gastrointestinal disorders, neurology, hearing loss, pain management, metabolic health, fitness, and sleep.

To be able to include all of this and maintain a competitive price point, Bisignano said the firm developed in-house bioinformatics that help keep its cost of goods down. "We started verticalizing a lot more that we used to outsource — everything from the alignment process that we did all the way to even some of the secondary and tertiary algorithms that we use to calculate things like HLA typing and CYP2D6 segmental duplication analysis," he said.

Phosphorus also switched from Roche's NimbleGen technology which it used for its panel-based testing, to Twist Bioscience's platform, which Bisignano said has resulted in better uniformity of coverage and the ability to multiplex more samples.

Although Color and Invitae's consumer offerings feature much of the same cancer and cardiovascular content as GeneCompass, Bisignano said the pharmacogenomic panel is significantly larger, though still reflective of clinical guidelines developed by groups like CPIC and PharmGKB.

From there, GeneCompass diverges even further, adding areas beyond oncology and cardiovascular disease.

"We did a pretty big survey of clinical genetics for ... monogenic diseases, and we've added categories ranging from gastrointestinal diseases to endocrinology, hearing loss, vision loss, immunology and infectious disease, metabolic disorders," Bisignano said. The firm also added other categories such as neurology, ophthalmology, pain management, and psychiatry, as well as a reproductive health section covering conditions that could result in female infertility, male infertility, or complications during pregnancy.

The test's added breadth also reflects the fact that Phosphorus doesn't only report classic highly penetrant variants associated with monogenic disease. The firm also reports a category of disease risk across the test's 12 clinical sections that it calls "susceptibility loci," which are higher frequency variants in the population that can cause things ranging from a higher risk for myocardial infarction all the way to aortic aneurysm risks, but don’t necessarily have high penetrance.

Reporting these findings, especially in a direct-to-consumer environment, could be seen as controversial. But Bisignano said Phosphorus has tried to be proactive and cautious about potential risk to customers.

"These are valuable pieces of information, even if they don't have a sort of a definitive disease diagnosis associated with them, so we made the decision to add them. But we specifically do not categorize them the way we do monogenic disease, and we make very clear the difference between those and the conditions that are categorized as monogenic diseases," he said.

The company has also developed a risk rating system based on expert guidance from its internal clinical team and scientific advisory board that allows the firm to report findings as a "high risk, moderate risk or mild risk."

"Between that and then our post-test genetic counseling, we feel that we're actually helping our physicians and our patients to understand" the context, he added.

For example, in the company's test report, a pathogenic variant in the gene GCK would be described as autosomal dominant and is listed as "high risk" within the gastro-endocrinology subsection, while a variant in IL23R is listed as a susceptibility locus for Crohn's disease, with a "mild" risk rating.

In describing "mild risk" findings, the report states that these variants are associated with an "elevated but still low risk."

Other examples of susceptibility loci in the firm's sample report include a variant in APOC1 rated as mild risk for coronary artery disease and another in FTO rated moderate for myocardial infarction.

PGx findings are separated out within the report's 12 disease categories and don't get a risk rating. Neither do "wellness" findings, which have their own separate section.

Although numerous labs have begun to market wellness-oriented consumer genetic tests, the links between genetic alterations and things like athleticism, metabolism, dietary sensitivities, and the need for specific supplements or vitamins are not well established. But Bisignano said that Phosphorus' market research has revealed that both consumers and physicians want this content.

"It's something we decided to do because patient and physician demand is, I think, important. And our thesis was, let's make sure when we put content on here, we make it clear if it's a low association or if it's something that's not going to cause a high risk," he said.

Although he agreed that a lot of the science remains up for debate, he argued that including wellness can potentially capture more individuals with serious and actionable health risks

"If someone's potentially not going to buy this test because they only really want to know if they are a sprinter or an endurance athlete, and that allows us to [get them in the door], to prevent them from having a channelopathy event, that's a huge, huge win," Bisignano said. "That's the holistic view."

One thing Phosphorus does not report is polygenic risk, although it is investigating polygenic risk scores as part of a research study customers can consent to participate in. This multicenter IRB-approved trial is sharing additional content with participants that the company wouldn't report clinically, but considers research-use only, for example PGx associations that don't meet its standards but have early evidence. Polygenic scores haven’t been added yet — but as the company gathers more data the intention is to bring them in.

Part of the goal, Bisignano added, is also to use this cohort to add to the scientific knowledge. "We want to see if we can replicate and strengthen or disprove some of these relationships over time," he said, "because that's one of our big goals as a company, to not just affect clinical outcomes ... but also contribute back to genetic research."

The US Food and Drug Administration has not sought to curb physician-involved consumer tests like Color and Invitae's, nor has it targeted wellness-oriented tests and low-risk health products as long as their claims don't veer into the medical. But it has in recent years intervened with some pharmacogenomic DTC companies.

Bisignano said that the consensus has been that those actions were likely related to the way PGx companies recommended specific treatment actions to ordering physicians. As a result, Phosphorus isn't worried about censure. "We have been pretty hands-off with saying what to do with a drug ... and we always link to the primary research and the PharmGKB reference material, because it really is the physicians that need to make use of this information," he said.

In the longer term, the company does want to work with FDA to see if there is a way to bring a version of GeneCompass through review as an IVD, Bisignano added. "The goal is to get preventative genetics to become sort of normal in healthcare. I think that engaging the FDA will be important for that."

A concern for consumer genomics that has been raised as other tests like 23andMe have sought to offer customers more actionable health information, is that if DTC testing is to serve as a new model of early health intervention, it is one that is far from universally accessible.

Even at a $250 price point, doctors have argued that many individuals are likely to be excluded from seeking out genetic testing to proactively manage their health, whether financially, or because of a lack of knowledge that these options exist.

For the same reasons, many of the same populations are hardly in a position to access the out-of-pocket concierge medical practices where Phosphorus is hoping to capitalize on knowledge of and enthusiasm for preemptive genetic tests being on the rise.

According to Bisignano, while the demand driving development of GeneCompass does come from these specific corners, the company's ultimate hope is that it can help push comprehensive preemptive genetic testing into the standard of care.

"We're [meeting] what we saw as a natural demand in the primary care market amongst thought leaders that I hope one day will be able to trickle to everyone," he said. "And that's the other goal of our study, to try to get data ultimately to make the case that this is better for outcomes and better for the healthcare system from a cost perspective."