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Sanford Health Looks to Improve Rare Disease Dx, Research With Congenica Technology

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CHICAGO – Late last month, UK-based informatics company Congenica and US healthcare system Sanford Health entered into a long-term data partnership to enable clinicians to diagnose rare diseases.

Under this multiyear agreement with both clinical and research components, Sioux Falls, South Dakota-based Sanford Health will apply Congenica's rapid genomic data analysis and clinical decision support technology to help practitioners to unravel the causes of previously diagnosed rare diseases. The partners also will work together to produce insights they hope can lead to the discovery of novel biomarkers and treatments.

In a webinar that Congenica and Sanford hosted March 29, David Pearce, president of innovation, research, and world clinics at Sanford Health, talked about the "diagnostic odyssey" that patients with rare diseases often face, using pediatric epilepsy as an example.

He expounded on that idea in an interview with GenomeWeb.

"The world is littered with examples of people taking six years to get a definitive diagnosis of a rare condition," Pearce said. "If we could get in there much quicker and then try and treat the cause much sooner, we know that's going to have benefits."

Cambridge, UK-based Congenica makes a modular and scalable data analytics tool for annotating and clinically interpreting genomic sequence data to support clinical decision-making.

Congenica CEO David Atkins said last year that the firm planned on moving into clinical care.

Atkins this month said that Sanford represents an ideal scenario for Congenica. "They have scale, they're very sophisticated, but they also have a very complex delivery challenge," the Congenica CEO said.

Community health systems and rural hospitals don't always have specialists that urban academic medical centers do, nor do they have as many people who can interpret and counsel patients on genetic information. Sanford, which has a presence in 26 US states and 10 countries — thanks to the organization's Sanford World Clinics global health program — is this kind of widely dispersed healthcare delivery system.

Congenica claims that its system is as much as 20 times faster with tertiary analysis than standard off-the-shelf analytics tools because it removes much of the manual work.

According to Atkins, the company achieves the increased speed through algorithms, organization of reference databases for fast access, and an interface that is meant to reflect how clinicians make decisions. "Where there's manual intervention, we will lead our users through logical decision-making," he said of the latter.

Atkins expressed a goal of making genomic-based personalized medicine widely accessible and tightly integrated into workflows and " to not have it rely exclusively on very highly trained, very sophisticated users."

"Our focus is making clinical genomics routine and integrated into healthcare," Atkins said. "We're trying to make very complex things very straightforward and simple."

Atkins did say that Sanford has sophisticated users, as well as competent clinical geneticists, but they are concentrated in urban centers. With the end-to-end capabilities and automation that the Congenica platform provides, the health system can offer "relatively complex analysis in a relatively routine manner" to all its clinicians, he said.

Sanford will be using the standard Congenica technology offering.

"But I would say Sanford represents one of the more complex ranges of some patients and customers," Atkins said, welcoming the challenge. "We're delighted that [Sanford] is starting with the most complex cases."

Sanford is going to start by analyzing cases of rare diseases that have been difficult to diagnose, and will be doing so with whole-genome sequencing rather than whole-exome, according to Atkins. There are about 7,000 known rare diseases, affecting an estimated 30 million Americans.

One particular area of interest for Pearce is pediatric epilepsy.

"Epilepsy is a common symptom to many neurological disorders," some rare and some more prevalent, said Pearce, who also is vice chair of the International Rare Diseases Research Consortium. "But the basis of that epilepsy is … going to have some sort of genetic abnormality."

Patients, however, are not always referred for genetic testing, so clinicians put them on a long path of trial and error, often starting with a visit to the emergency room after a seizure, Pearce said. Sanford thus is developing a program to perform whole-exome sequencing for patients presenting in the ER with epilepsy symptoms, in hopes of identifying the underlying cause as early as possible.

"Bottom line is, we need to have the entire sequence for everybody in this cohort, but also a very decent set of controls as well of individuals that are unaffected," he said during the webinar.

"One of the worst-kept secrets is genetic information is really hard to interpret and it's really hard to integrate into a medical record or into a clinical database," Pearce later told GenomeWeb. Congenica is helping with this challenge.

Pearce said that Congenica offers the ability to integrate sequencing interpretation into clinical databases to improve communication between the clinical and genetic sides of diagnostic processes.

"Let's assume if there are 300 individuals in the United States with this rare disease," Pearce said. "We may have a natural history study on them, but they're not all going to have the exact same course of the disease. They may have the same defect in the same gene, but they may have a different mutation that's causing this, and that creates all sorts of different variation with the clinical phenotype."

He said that the Congenica technology platform makes both the genomic and phenotypic components available in the same place for all Sanford clinicians, regardless of location. For this reason, Congenica data is being integrated into Sanford's vast telehealth infrastructure as well.

"Let's take a look at that clinical information, really understanding the seizure component to a number of rare diseases, and then identify the genetic basis of that," Pearce said.

Even when clinicians understand the cause, though, therapeutics are not effective for one-third of patients with epilepsy, both children and adults. Congenica and Sanford see this partnership as an opportunity to discover new drug targets and compounds.

Pearce has a background in rare pediatric brain disease, particularly juvenile Batten disease, in which children inherit two defective copies of the CLN3 gene from their parents. He said that this condition, which can cause impaired vision, learning disabilities, muscle atrophy, seizures, and often death by early adulthood, often takes several years to diagnose.

While at the University of Rochester in the 2000s, Pearce helped put together a registry of a few hundred children in the US known to have juvenile Batten disease, and his research from this registry led to the first clinical trial for this condition. There are still no known direct treatments for the disease.

"Obviously physicians struggle with treating these children just symptomatically because they've never seen it before," Pearce said.

After Pearce moved to Sanford in 2010, he set up a program called CoRDS, which stands for Coordination of Rare Diseases at Sanford, to replicate his earlier Batten work with the help of registries and natural-history studies with similar underlying conditions.

The registries now contain several thousand people and have the backing of patient advocacy groups, Pearce said.

"We have large cohorts of patients with certain diseases in the registry, many of whom only have a clinical diagnosis rather than a genetic diagnosis," Pearce explained. "It's so hard to get a good clinical … and genetic diagnosis on these individuals, because you're often dealing with unknown genes."

For example, a person exhibiting nonconvulsive seizures could have a previous diagnosis of ataxia, but there are many possible causes for such symptoms. Sanford makes its registries available to outside researchers and clinicians in hopes of advancing the sciences.

"We're ready to take the next step, which is we want to have improved diagnosis," Pearce said. "We have a large number of undiagnosed individuals in this rare disease database in terms of the genetic diagnosis."

Atkins noted that Congenica built its capabilities for complex analysis when preparing to provide diagnostic decision support services to the UK National Health Service's Genomic Medicine Service. Congenica was one of four companies picked to provide genomic interpretation services for the first 8,000 patients in the 100,000 Genomes Project that ultimately morphed into the Genomic Medicine Service, and one of two working on rare diseases.

"In some ways, [this system] it's very much a prototype for what David Pearce and Sanford are doing," Atkins said. "When we first met the Sanford team and they laid out the challenge of having a dispersed group of users, uneven skill sets, and, like every institution, resource constraints, we looked at that and we thought that's exactly what we felt."

Atkins said that initial training at Sanford is complete and that the health system is operational on Congenica with patient analysis. "The rollout is very, very simple through cloud deployment," he said.

The next phase, to start in a few months, will involve how to apply the technology in other areas, such as neurology, according to Atkins.

Congenica will be updating its technology with the release of version 3.1 of its genomic analysis platform, planned for May 5. Atkins said that Sanford will be evaluating some of the new features, including improved calling of structural variants and automated allocation of American College of Medical Genetics variant codes.

"Our trajectory of travel with our platform is to continually increase the level of automation, so again to remove the need for high complexity and highly trained users," he said.

Sanford does not have a specific timeline for this research. Pearce said that his team is in the hypothesis-generation stage, and will let the science guide the pace.

Because the organization has a research operation in place, including institutional review boards, Pearce believes that new discoveries can move to pilots and clinical trials fairly quickly.

"We'll be partnering with our colleagues in the clinics," he said. "The beauty of this type of research is if you do make a discovery, you can quickly file through your IRBs to make it actionable."

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