News Release 

Researchers use machine-learning system to diagnose genetic diseases

Automation yields faster test results to inform personalized medical care

Rady Children's Institute for Genomic Medicine

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IMAGE: An expert in genomic and systems medicine research, Dr. Kingsmore holds the world speed record for achieving the fastest molecular diagnosis using whole genome sequencing in 19.5 hours. view more 

Credit: RCIGM

April 24, 2019-San Diego-Researchers at Rady Children's Institute for Genomic Medicine (RCIGM) have utilized a machine-learning process and clinical natural language processing (CNLP) to diagnose rare genetic diseases in record time. This new method is speeding answers to physicians caring for infants in intensive care and opening the door to increased use of genome sequencing as a first-line diagnostic test for babies with cryptic conditions.

"Some people call this artificial intelligence, we call it augmented intelligence," said Stephen Kingsmore, MD, DSc, President and CEO of RCIGM. "Patient care will always begin and end with the doctor. By harnessing the power of technology, we can quickly and accurately determine the root cause of genetic diseases. We rapidly provide this critical information to intensive care physicians so they can focus on personalizing care for babies who are struggling to survive."

A new study documenting the process was published today in the journal Science Translational Medicine. The workflow and research were led by the RCIGM team in collaboration with leading technology and data-science developers --Alexion, Clinithink, Diploid, Fabric Genomics and Illumina.

Dr. Kingsmore's team has pioneered a rapid Whole Genome Sequencing process to deliver genetic test results to neonatal and pediatric intensive care (NICU/PICU) physicians to guide medical intervention. RCIGM is the research arm of Rady Children's Hospital-San Diego.

By reducing the need for labor-intensive manual analysis of genomic data, the supervised automated pipeline provided significant time-savings. In February 2018, the same team achieved the Guinness World Record™ for fastest diagnosis through whole genome sequencing. Of the automated runs, the fastest times - averaging 19 hours - were achieved using augmented intelligence.

"This is truly pioneering work by the RCIGM team--saving the lives of very sick newborn babies by using AI to rapidly and accurately analyze their whole genome sequence " says Eric Topol, MD, Professor of Molecular Medicine at Scripps Research and author of the new book Deep Medicine.

RCIGM has optimized and integrated several time-saving technologies into a rapid Whole Genome Sequencing (rWGS) process to screen a child's entire genetic makeup for thousands of genetic anomalies from a blood sample.

Key components in the rWGS pipeline come from Illumina, the global leader in DNA sequencing, including Nextera DNA Flex library preparation, whole genome sequencing via the NovaSeq 6000 and the S1 flow cell format. Speed and accuracy are enhanced by Illumina's DRAGEN (Dynamic Read Analysis for GENomics) Bio-IT Platform.

Other pipeline elements include Clinithink's clinical natural language processing platform CliX ENRICH that quickly combs through a patient's electronic medical record to automatically extract crucial phenotype information.

Another core element of the machine learning system is MOON by Diploid. The platform automates genome interpretation using AI to automatically filter and rank likely pathogenic variants. Deep phenotype integration, based on natural language processing of the medical literature, is one of the key features driving this automated interpretation. MOON takes five minutes to suggest the causal mutation out of the 4.5 million variants in a whole genome.

In addition, Alexion's rare disease and data science expertise enabled the translation of clinical information into a computable format for guided variant interpretation.

As part of this study, the genetic sequencing data was fed into automated computational platforms under the supervision of researchers. For comparison and verification, clinical medical geneticists on the team used Fabric Genomics' AI-based algorithms--VAAST and Phevor integrated into the clinical decision support software, OPAL (now called Fabric Enterprise)--to confirm the output of the automated pipeline. Fabric software is part of RCIGM's standard analysis and interpretation workflow.

The study titled "Diagnosis of genetic diseases in seriously ill children by rapid whole-genome sequencing and automated phenotyping and interpretation," found that automated, retrospective diagnoses concurred with expert manual interpretation (97 percent recall, 99 percent precision in 95 children with 97 genetic diseases).

Researchers concluded that genome sequencing with automated phenotyping and interpretation--in a median 20:10 hours--may spur use in intensive care units, thereby enabling timely and precise medical care.

"Using machine-learning platforms doesn't replace human experts. Instead it augments their capabilities," said Michelle Clark, PhD, statistical scientist at RCIGM and the first author of the study. "By informing timely targeted treatments, rapid genome sequencing can improve the outcomes of seriously ill children with genetic diseases."

An estimated four percent of newborns in North America are affected by genetic diseases, which are the leading cause of death in infants. Rare genetic diseases also account for approximately 15 percent of admissions to children's hospitals.

The RCIGM workflow is engineered to speed and scale up genomic data interpretation to reduce the time and cost of whole genome sequencing. The team's goal is to make rWGS accessible and available to any child who needs it.

Increased automation of the process removes a barrier to scaling up clinical use of WGS by reducing the need for time-consuming manual analysis and interpretation of the data by scarce certified clinical medical geneticists. There were fewer than 1,600 of these experts nationwide in 2017, according to the American Board of Medical Genetics and Genomics.

Rady Children's Institute began performing genomic sequencing in July 2016. As of the end of March 2019, the team had completed testing and interpretation of the genomes of more than 750 children. One-third of those children have received a genetic diagnosis with 25 percent of those benefitting from an immediate change in clinical care based on their diagnosis.

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About Rady Children's Institute for Genomic Medicine:

The Institute is leading the way in advancing precision healthcare for infants and children through genomic and systems medicine research. Discoveries at the Institute are enabling rapid diagnosis and targeted treatment of critically ill newborns and pediatric patients at Rady Children's Hospital-San Diego and partnering hospitals. The vision is to expand delivery of this life-saving technology to enable the practice of precision pediatric medicine at children's hospitals across California, the nation and the world. RCIGM is a subsidiary of Rady Children's Hospital and Health Center. Learn more at http://www.RadyGenomics.org. Follow us on Twitter @RadyGenomics.

About Rady Children's Hospital - San Diego:

Rady Children's Hospital-San Diego is a 524-bed pediatric care facility providing the largest source of comprehensive pediatric medical services in San Diego, southern Riverside and Imperial counties. Rady Children's is the only hospital in the San Diego area dedicated exclusively to pediatric healthcare and is the region's only designated pediatric trauma center. In June 2018, U.S. News & World Report ranked Rady Children's among the best children's hospitals in the nation in all ten pediatric specialties the magazine surveyed. Rady Children's is a nonprofit organization that relies on donations to support its mission. For more information, visit http://www.rchsd.org and find us on Facebook, Twitter and Vimeo.

About Illumina

Illumina is improving human health by unlocking the power of the genome. Our focus on innovation has established us as the global leader in DNA sequencing and array-based technologies, serving customers in the research, clinical and applied markets. Our products are used for applications in the life sciences, oncology, reproductive health, agriculture and other emerging segments. To learn more, visit http://www.illumina.com and follow @illumina.

About Alexion

Alexion is a global biopharmaceutical company focused on serving patients and families affected by rare diseases through the innovation, development and commercialization of life- changing therapies. As the global leader in complement biology and inhibition for more than 20 years, Alexion has developed and commercializes two approved complement inhibitor to treat patients with paroxysmal nocturnal hemoglobinuria (PNH) as well as the first and only approved complement inhibitor to treat atypical hemolytic uremic syndrome (aHUS) and anti-acetylcholine receptor (AchR) antibody-positive generalized myasthenia gravis (gMG), and is also developing it for patients with neuromyelitis optica spectrum disorder (NMOSD). Alexion also has two highly innovative enzyme replacement therapies for patients with life- threatening and ultra-rare metabolic disorders, hypophosphatasia (HPP) and lysosomal acid lipase deficiency (LAL-D). In addition, the company is developing several mid-to-late-stage therapies, including a second complement inhibitor, a copper-binding agent for Wilson disease and an anti-neonatal Fc receptor (FcRn) antibody for rare Immunoglobulin G (IgG)-mediated diseases as well as several early-stage therapies, including one for light chain (AL) amyloidosis and a second anti-FcRn therapy. Alexion focuses its research efforts on novel molecules and targets in the complement cascade, and its development efforts on the core therapeutic areas of hematology, nephrology, neurology, and metabolic disorders. Alexion has been named to the Forbes list of the World's Most Innovative Companies seven years in a row and is headquartered in Boston, Massachusetts' Innovation District. The company also has offices around the globe and serves patients in more than 50 countries. Further information about Alexion can be found at: http://www.alexion.com.

About Clinithink

Clinithink's patented CLiX clinical natural language processing (CNLP) platform delivers the deepest, fastest and most accurate analysis of unstructured data across patient populations currently possible - reading and encoding millions of free text documents within any EHR in a matter of hours. CLiX enables rapid extraction of rich phenotype information (output as HPO terms if desired) thereby providing medical professionals with the knowledge they need to quickly and accurately diagnose conditions and plan the most effective treatments. CLiX also fast forwards drug development - ensuring protocols are optimized, patients identified and sites selected in a fraction of the time of manual processing, thus helping Clinithink's life science associates get crucial treatments to market faster. For more information visit http://www.clinithink.com or contact clinithink.com/contact/

About Diploid

Diploid is on a mission to provide clinical labs, hospitals and nationwide sequencing programs with the tools to diagnose every rare disease patient. Its MOON platform is the first software worldwide to use artificial intelligence for autonomous variant interpretation in rare disease diagnostics. Thanks to its use of advanced machine learning and deep phenotype integration, MOON is now widely recognized as the fastest genome interpretation solution, going from whole genome VCF to diagnosis in just minutes. In addition, MOON's autopilot feature enables unsupervised reanalysis of negative cases, making continuous genome interpretation a reality. Learn more at http://www.diploid.com/moon.

About Fabric Genomics

Fabric Genomics is making genomics-driven precision medicine a reality. The company provides clinical-decision support software that enables clinical labs, hospital systems and country-sequencing programs to gain actionable genomic insights, resulting in faster and more accurate diagnoses and reduced turnaround time. Fabric's end-to-end genomic analysis platform incorporates proven AI algorithms, and has applications in both hereditary disease and oncology. Headquartered in Oakland, California, Fabric Genomics was founded by industry veterans and innovators with a deep understanding of bioinformatics, large-scale genomics and clinical diagnostics. To learn more, visit http://www.fabricgenomics.com, and follow us on Twitter, LinkedIn, and Facebook.

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