Postdoctoral Fellow Rady Children's Institute for Genomic Medicine Rady Children's Institute for Genomic Medicine San Diego, California, United States
Background: Many rare genetic diseases have effective treatments but progress to severe morbidity or mortality if untreated immediately. Physicians are often unfamiliar with treatments for these disorders. Rapid molecular diagnosis may be insufficient to improve outcomes in such cases.
Objective: We describe Genome-to-Treatment (GTRx), a system for automated provisional diagnosis and electronic clinical decision support for such diseases.
Design/Methods: Diagnosis was achieved in 13.5 hours by sequencing library preparation directly from blood (modified Illumina DNA PCR-free prep), 2 x 100 nucleotide whole genome sequencing-by-synthesis (Illumina NovaSeq 6000, SP flowcell, modified recipe), hyperthreaded bioinformatic analysis (Illumina DRAGEN v3.7), natural language processing of electronic health records (CliniThink) and automated interpretation (InVitae MOON or Fabric GEMS) (Table 1).
Results: This method had superior analytic performance for single nucleotide variants (precision, P, 99.8%; recall, R, 99.5%), insertion-deletions (P-99.3%, R-98.1%), structural variants (P-97.7%, R-54.9%) and copy number variants (P-48.4%, R-80.5%) (Table 2). 370 severe genetic diseases with effective treatments were identified by literature review, clinician nomination and WGS experience. Specific interventions (drugs, devices, diets and surgeries) were identified for each by internet and literature searches, and manually curated. Five biochemical geneticists adjudicated the indications, contraindications, efficacy and evidence-of-efficacy of each intervention in each disorder in the context of an ill child in an intensive care unit. The panel had agreement 189 of 190 interventions after discussion. A pipeline integrated 10 genetic disease information resources (including Mendelian Inheritance in Man, Orphanet, Genetics Home Reference, GeneReviews, DrugBank, Genetic and Rare Diseases Information, InXight Drugs and NCBI Gene), and a web resource linked these and management guidance to automated interpretation tools by diagnosis. GTRx provided correct diagnoses and management guidance in four retrospective patients. Prospectively, an infant with encephalopathy was diagnosed in 13.5 hours, enabling timely institution of effective treatment. Conclusion(s): GTRx enables prompt implementation of optimal treatment at population scale in patients receiving intensive care with diseases of unknown etiology, particularly for rapidly progressive genetic diseases in hospitals without full complements of subspecialists.
Authors/Institutions: Mallory J. Owen, Rady Children's Institute for Genomic Medicine, San Diego, California, United States; Narayanan Veeraraghavan, Rady Children's Institute for Genomic Medicine, San Diego, California, United States; Sebastien Lefebvre, Alexion Pharmaceuticals Inc, Boston, Massachusetts, United States; Christian Hansen, Rady Children's Institute for Genomic Medicine, San Diego, California, United States; Bryan Lajoie, Illumina Inc, San Diego, California, United States; Timothy McPhail, Illumina Inc, San Diego, California, United States; Shyamal Mehtalia, Illumina Inc, San Diego, California, United States; David Dimmock, Rady Children's Institute for Genomic Medicine, San Diego, California, United States; Laurie D. Smith, Rady Children's Institute for Genomic Medicine, San Diego, California, United States; Gunter Scharer, Rady Children's Institute for Genomic Medicine, San Diego, California, United States; Rebecca Mardach, Rady Children's Institute for Genomic Medicine, San Diego, California, United States; Mary Willis, Rady Children's Institute for Genomic Medicine, San Diego, California, United States; Annette Feigenbaum, Rady Children's Institute for Genomic Medicine, San Diego, California, United States; Seema Rego, Rady Children's Institute for Genomic Medicine, San Diego, California, United States; Kevin K. Chau, Rady Children's Institute for Genomic Medicine, San Diego, California, United States; Lucitia Van Der Kraan, Rady Children's Institute for Genomic Medicine, San Diego, California, United States; Yan Ding, Rady Children's Institute for Genomic Medicine, San Diego, California, United States; Zhanyang Zhu, Rady Children's Institute for Genomic Medicine, San Diego, California, United States; Shimul Chowdhury, Rady Children's Institute for Genomic Medicine, San Diego, California, United States; Anna-Kaisa Niemi, Rady Children's Hospital San Diego, San Diego, California, United States; Mark Speziale, Rady Children's Hospital San Diego, San Diego, California, United States; Mark Nespeca, Rady Children's Hospital San Diego, San Diego, California, United States; Meredith Wright, Rady Children's Institute for Genomic Medicine, San Diego, California, United States; Martin Reese, Fabric Genomics, Oakland, California, United States; Joe Azure, Fabric Genomics, Oakland, California, United States; Erwin Frise, Fabric Genomics, Oakland, California, United States; Charlene Son Rigby, Fabric Genomics, Oakland, California, United States; Sandy White, Fabric Genomics, Oakland, California, United States; Charlotte A. Hobbs, Rady Children's Institute for Genomic Medicine, San Diego, California, United States; Sheldon Gilmer, Rady Children's Institute for Genomic Medicine, San Diego, California, United States; Gail Knight, Rady Children's Hospital San Diego, San Diego, California, United States; Albert Oriol, Rady Children's Hospital San Diego, San Diego, California, United States; Jerica Lenberg, Rady Children's Institute for Genomic Medicine, San Diego, California, United States; Shareef Nahas, Rady Children's Institute for Genomic Medicine, San Diego, California, United States; Thomas R. Defay, Alexion Pharmaceuticals Inc, Boston, Massachusetts, United States; Jacqueline Weir, Illumina Inc, San Diego, California, United States; Vicki Thomson, Illumina Inc, San Diego, California, United States; Louise Fraser, Illumina Inc, San Diego, California, United States; Sergey Batalov, Rady Children's Institute for Genomic Medicine, San Diego, California, United States; Chris Kunard, Illumina Inc, San Diego, California, United States; Kevin Hall, Illumina Inc, San Diego, California, United States; Stephen Kingsmore, Rady Children's Institute for Genomic Medicine, San Diego, California, United States
