Rady Children’s fast genomic sequencing initiative gains steam

Rapid whole genome sequencing will become more useful, augmented by EHR data, the use of the cloud and comparisons with large databases, says Stephen Kingsmore, MD.

Rady Children’s Hospital-San Diego continues to advance the use of whole genome sequencing, developing a network that makes the services available to more pediatric hospitals and working toward a future that sees it more widely used as a common form of care for children.

The organization has been leading an initiative to use rapid whole genome sequencing (WGS) technology and other advanced computing technologies to improve the speed of the process, enable use of it for more constituencies and advance medical research. Rady is also forming collaborative partnerships across the industry to expand use of sequencing in treatment.

The need is huge – there are an estimated 6,000 rare diseases that have their basis in patients’ genetic makeup. Beyond that, it’s estimated that as many as 25 million Americans are affected by rare and often undiagnosed conditions. Diagnosing rare genetic conditions quickly is particularly crucial in treating young critically ill patients, where shortening the diagnosis to window is crucial to survival, treatment and long-term prognosis.

As such, the initiative at Rady also demonstrates the current and future use of technology – particularly the cloud, electronic health records, standards and more – to cost-effectively solve medical mysteries.

Rady Children’s operates its Institute for Genomic Medicine as a non-profit research organization, that has brought together a team of scientists, researchers and clinicians who focus on preventing, diagnosing, treating and curing childhood disease through genomics and systems medicine research.

Part of its efforts have involved shortening the time needed to conduct WGS. So far, it’s brought the time down to 13.5 hours, continuing to whittle away at its past performance. Just two years ago, it took slightly less than 20 hours to gain results, from the time a rapid WGS order was placed through the facility’s Epic electronic health records system until test results were available in the EHR, said Albert Oriol, vice president and CIO for Rady Children’s.

The use of artificial intelligence and other advanced computing continues to shave time from WGS studies, Oriol noted. That can be crucial for young patients and the clinicians treating them -- patients in a neonatal or pediatric intensive care unit often suffer critical complications or long-lasting side effects that could affect patients the rest of their lives. However, the use of rapid genomic sequencing could focus treatment and shorten NICU or PICU stays, reducing both in-hospital and lifetime costs.

Stephen Kingsmore, MD

Rady Children’s, which started the pediatric genomics initiative in 2016, is offering rapid WGS services to a nationwide network of facilities treating children, with about a hundred organizations participating, said Stephen Kingsmore, MD, president and CEO of the institute. Rady’s is now able to conduct about 100 WGS studies a month.

Moving some of the institute’s capabilities to the cloud can facilitate expansion of genomic sequencing services, Oriol noted. That’s because datasets for sequencing studies, and potential analysis of results, can involve large files and complex computing, he said.

The institute also relies on growing access to large existing databases of genomic research, said Matthew Bainbridge, its principal investigator and associate director of clinical genomics. “There’s been a huge knowledge base gathered over the last six to 10 years,” he said. “We’ve learned much about the strands of genetic diseases, and we’re able to use the data for a certain disease in trying to figure out therapy that would be successful.”

Complex phenotypes can be discerned through sequencing, which can focus treatment. And results can be compared to other known rare mutations, such as those found in the Genome Aggregation Database (gnomAD), which is seeking to aggregate and harmonize exome and genome sequencing data from large projects to make summary data available to scientists.

RCGI lab at Rady Children's (Photo by Earnie Grafton)

Rady is also pursuing relationships with companies to expand its capabilities and grow research opportunities. For example, Pacific Biosciences of California Inc. (PacBio), a leading provider of high-quality, long-read sequencing platforms, and Rady’s Institute for Genomic Medicine are collaborating on a study that aims to identify potential disease-causing genetic variants and increase the solve rates of rare diseases. The study is focused on long-read whole genome sequencing of rare disease cases for which previous short-read whole genome and exome sequencing have yielded no answers. The study, which is currently underway, was able to detect variants that were not identified by short-read sequencing (SRS); of these, an average of 37 were missense mutations in known disease genes. These long reads can detect disease-causing structural and small variants missed by short-read sequencing platforms.

In addition, a research collaboration was announced in July between the Rady institute and Takeda Pharmaceutical Co. to speed up efforts to discover and develop treatments for rare childhood diseases through analysis of the natural progression of some genetic disorders. The organizations say they're hoping to improve the clinical outcomes of young patients who have illnesses emerge during their early years. The effort looks to improve outcomes by providing precise diagnoses and specific treatments as early as possible.

The institute hopes to increase its capacity exponentially as it moves forward. Kingsmore sees a near-term goal of 40,000 to 80,000 rapid WGS studies a year, as well as increasing efforts to develop gene therapies, perhaps reaching about 1,000 genetic therapies in five years. He also expects increased interest from pharmaceutical and life sciences companies that want to develop new genetic therapies.

In the long term, rapid WGS may become a part of standard newborn screening, he believes. "With NICU kids, we want to get them before they enter the NICU. In the long run, there will be less NICU testing; we'll have it done at birth."

"If we're thinking about the future, having all kids sequenced means that the data can follow them around," Bainbridge added. "That would be a huge boon for the phenotype community. We see some really insidious diseases where kids don't have any issues when they're really young, like some cardiac disorders that are undiagnosed when they're really young but have devastating results later.

"The hope is we can do this sequencing a couple weeks before babies are born so we can have all the treatments ready," he added.

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