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The Sequencing Technology Behind The World's Fastest Genetic Diagnosis

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In February 2018, a team at Rady Children's Institute for Genomic Medicine broke the world record for the fastest genetic diagnosis when they delivered a rare disease diagnosis in just 19 hours 30 minutes. This landmark was enabled by close partnership with technology leaders like Illumina, Clinithink and Alexion. We caught up with John Reynders, Vice President, Data Sciences, Genomics, and Bioinformatics at Alexion Pharmaceuticals, to discuss how the record was broken, and why diagnosing rare diseases is important in modern medicine.

Ruairi Mackenzie (RM): What technologies helped Alexion break the record for the fastest genetic disease diagnosis?

John Reynders (JR): In May 2017, Alexion entered into an innovative collaboration with Rady Children’s Institute for Genomic Medicine (RCIGM) to accelerate the diagnosis of critically-ill newborns with rare genetic disorders. This collaboration combines the Institute’s genomic research expertise with Alexion data science and bioinformatics capabilities to advance precision medicine for infants in an intensive care setting.

Under the partnership, Alexion has shared the SmartPanel, a platform developed by Alexion that personalizes and prioritizes suspected rare-disease genes from a patient's next-generation sequenced genome and specific clinical presentation. The RCIGM team is leveraging the SmartPanel in research to establish positive predictive value, enable electronic medical record (EMR) integration for rapid phenotypic extraction and assess overall patient outcomes via earlier diagnosis. The organizations have collaborated on patient and disease characterization, algorithmic modules and scalability with a shared goal of contributing core capabilities to the open source community to accelerate research in the challenging area of pediatric rare-disease diagnosis.

Diagnosing acutely ill pediatric patients is a race against the clock, so it’s essential for physicians to have access to solutions that will provide answers faster and help set the course of treatment. A close collaboration between RCIGM and Alexion as well as several other leading technology and data-science developers — Illumina, Clinithink, Edico Genome, Fabric Genomics and Diploid— enabled the RCIGM team to engineer a seamless process—enhanced by in-house expertise—to deliver analysis and interpretation of life-threatening genetic variations in just 19.5 hours in February 2018. This set a new world record for the fastest genetic diagnosis, an extraordinary achievement when you consider that even today, this process can typically take weeks using traditional manual approaches.

RM: Why is lowering the time for rare disease diagnosis so important?

JR: Eighty percent of rare diseases are genetic, yet the average time from a person’s first symptom to an accurate diagnosis is approximately five years, and for some people it can take up to 20 years. Approximately 50-75 percent of rare diseases affect children, and 30 percent of rare disease patients die before the age of five. 

The current process for diagnosing a rare disease involves manually assessing physicians’ free text notes on a patient’s medical history and symptoms, and then utilizing various computer systems to interpret the data and analyze between 10,000 – 20,000 genomic variations in hopes of identifying ones that indicate a disease. Not only is this a time-intensive and arduous process, but it also lacks standardization.

Rapid diagnosis through genome sequencing can provide definitive answers, allowing physicians to provide timely, targeted treatment that can help prevent a needless diagnostic odyssey and improve medical outcomes. 

RM: Tell us about your recent collaboration with Boston Children’s Hospital. Why are rare diseases important in pediatric care and how will Alexion’s technology help treat these diseases?

JR: In February 2018, Alexion and the Manton Center for Orphan Disease Research, the Innovation and Digital Health Accelerator at Boston Children’s Hospital announced a collaboration to enable rapid and precise diagnoses for patients with suspected rare diseases. The collaboration is focused on creating new sets of computable descriptions of hundreds of diagnosed and undiagnosed patients with rare diseases to train the artificial intelligence engine within Alexion’s 20 Rare-Disease Questions (20RDQ) platform to improve diagnosis speed and accuracy while creating actionable insights and disease intervention options in a clinically meaningful timeframe.

Under the collaboration, Alexion shared its 20RDQ platform, which integrates a comprehensive landscape of rare disease definitions with clinical feature databases to enable a series of guided questions based upon a patient’s medical history and record. When presented with an undiagnosed patient, 20RDQ can help a physician investigate subtle features of the underlying rare disease to converge a diagnosis.

The Manton Center and Innovation Accelerator is combining 20RDQ with internally developed software to create computable descriptions of patients that can be combined with rapid genome sequencing to produce a prioritized list of suspect genetic variants of rare diseases for consideration by a diagnosing physician. 

RM: Will we see the time taken to identify diseases shorten further in coming years?

JR: Through collaborations such as the ones with the Manton Center, Clinithink and the Rady Insitute, we are making accurate rare disease diagnoses much more quickly than we had in the past and we will continue pushing the boundaries of what’s possible with the shared goal of accelerating diagnoses in order to enable the best treatment and outcomes for patients with rare genetic diseases.

John Reynders was speaking to Ruairi J Mackenzie, Science Writer for Technology Networks