. 2022 Jul 26;13(1):4057.

doi: 10.1038/s41467-022-31446-6.

An automated 13.5 hour system for scalable diagnosis and acute management guidance for genetic diseases

Mallory J Owen^{1

2}, Sebastien Lefebvre³, Christian Hansen^{1

2}, Chris M Kunard⁴, David P Dimmock^{1

2

5}, Laurie D Smith¹, Gunter Scharer¹, Rebecca Mardach^{2

6}, Mary J Willis¹, Annette Feigenbaum^{2

6}, Anna-Kaisa Niemi^{2

6}, Yan Ding^{1

2}, Luca Van Der Kraan^{1

2}, Katarzyna Ellsworth^{1

2}, Lucia Guidugli^{1

2}, Bryan R Lajoie⁴, Timothy K McPhail⁴, Shyamal S Mehtalia⁴, Kevin K Chau^{1

2}, Yong H Kwon^{1

2}, Zhanyang Zhu^{1

2}, Sergey Batalov^{1

2}, Shimul Chowdhury^{1

2

5}, Seema Rego^{1

2}, James Perry^{2

6}, Mark Speziale^{2

6}, Mark Nespeca^{2

6

7}, Meredith S Wright^{1

2

5}, Martin G Reese⁸, Francisco M De La Vega⁸, Joe Azure⁸, Erwin Frise⁸, Charlene Son Rigby⁸, Sandy White⁸, Charlotte A Hobbs^{1

2

6}, Sheldon Gilmer², Gail Knight^{2

6}, Albert Oriol^{1

2}, Jerica Lenberg^{1

2

5}, Shareef A Nahas^{1

2}, Kate Perofsky^{1

2

6}, Kyu Kim^{1

2

6}, Jeanne Carroll^{1

2

6}, Nicole G Coufal^{1

2

6}, Erica Sanford¹, Kristen Wigby^{1

2

6}, Jacqueline Weir⁴, Vicki S Thomson⁴, Louise Fraser⁴, Seka S Lazare⁴, Yoon H Shin⁴, Haiying Grunenwald⁴, Richard Lee⁴, David Jones⁴, Duke Tran⁴, Andrew Gross⁴, Patrick Daigle⁴, Anne Case⁴, Marisa Lue⁴, James A Richardson⁴, John Reynders³, Thomas Defay³, Kevin P Hall⁴, Narayanan Veeraraghavan^{1

2}, Stephen F Kingsmore^{9

10

11}

Affiliations

¹ Rady Children's Institute for Genomic Medicine, San Diego, CA, 92123, USA.
² Rady Children's Hospital, San Diego, CA, 92123, USA.
³ Alexion Pharmaceuticals, Inc., Boston, MA, 02210, USA.
⁴ Illumina, Inc., San Diego, CA, 92122, USA.
⁵ Keck Graduate Institute, Claremont, CA, 91711, USA.
⁶ Department of Pediatrics, University of California San Diego, San Diego, CA, 92093, USA.
⁷ Department of Neuroscience, University of California San Diego, San Diego, CA, 92093, USA.
⁸ Fabric Genomics, Inc., Oakland, CA, 94612, USA.
⁹ Rady Children's Institute for Genomic Medicine, San Diego, CA, 92123, USA. skingsmore@rchsd.org.
¹⁰ Rady Children's Hospital, San Diego, CA, 92123, USA. skingsmore@rchsd.org.
¹¹ Keck Graduate Institute, Claremont, CA, 91711, USA. skingsmore@rchsd.org.

PMID: 35882841
PMCID: PMC9325884
DOI: 10.1038/s41467-022-31446-6

An automated 13.5 hour system for scalable diagnosis and acute management guidance for genetic diseases

Mallory J Owen et al. Nat Commun. 2022.

. 2022 Jul 26;13(1):4057.

doi: 10.1038/s41467-022-31446-6.

Authors

Affiliations

¹ Rady Children's Institute for Genomic Medicine, San Diego, CA, 92123, USA.
² Rady Children's Hospital, San Diego, CA, 92123, USA.
³ Alexion Pharmaceuticals, Inc., Boston, MA, 02210, USA.
⁴ Illumina, Inc., San Diego, CA, 92122, USA.
⁵ Keck Graduate Institute, Claremont, CA, 91711, USA.
⁶ Department of Pediatrics, University of California San Diego, San Diego, CA, 92093, USA.
⁷ Department of Neuroscience, University of California San Diego, San Diego, CA, 92093, USA.
⁸ Fabric Genomics, Inc., Oakland, CA, 94612, USA.
⁹ Rady Children's Institute for Genomic Medicine, San Diego, CA, 92123, USA. skingsmore@rchsd.org.
¹⁰ Rady Children's Hospital, San Diego, CA, 92123, USA. skingsmore@rchsd.org.
¹¹ Keck Graduate Institute, Claremont, CA, 91711, USA. skingsmore@rchsd.org.

PMID: 35882841
PMCID: PMC9325884
DOI: 10.1038/s41467-022-31446-6

Abstract

While many genetic diseases have effective treatments, they frequently progress rapidly to severe morbidity or mortality if those treatments are not implemented immediately. Since front-line physicians frequently lack familiarity with these diseases, timely molecular diagnosis may not improve outcomes. Herein we describe Genome-to-Treatment, an automated, virtual system for genetic disease diagnosis and acute management guidance. Diagnosis is achieved in 13.5 h by expedited whole genome sequencing, with superior analytic performance for structural and copy number variants. An expert panel adjudicated the indications, contraindications, efficacy, and evidence-of-efficacy of 9911 drug, device, dietary, and surgical interventions for 563 severe, childhood, genetic diseases. The 421 (75%) diseases and 1527 (15%) effective interventions retained are integrated with 13 genetic disease information resources and appended to diagnostic reports ( https://gtrx.radygenomiclab.com ). This system provided correct diagnoses in four retrospectively and two prospectively tested infants. The Genome-to-Treatment system facilitates optimal outcomes in children with rapidly progressive genetic diseases.

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Conflict of interest statement

M.G.R., F.D.L.V., C.S.R., J.A., S.W., and E.F. are employees and stockholders of Fabric Genomics, Inc. and have equity holdings and stock options. T.D., J.R., and S.L. are employees of Alexion Pharmaceuticals, Inc. and have equity holdings and stock options. K.P.H., J.A.R., M.L., A.C., P.D., A.G., D.T., D.J., R.L., H.G., S.S.L., Y.H.S., L.F., C.M.K., B.R.L., T.K.M., S.S.M., J.W., and V.S.T. are employees of Illumina, Inc. and have equity holdings and stock options. D.D. received funding from Biomarin (consultant for Pegvaliase trials), Audentes Therapeutics (Scientific Advisory Board), and Ichorion Therapeutics (consultant for mitochondrial disease drugs). M.B. owns stock in Codified Genomics and is a consultant for Baebies Inc. Related to the current work, S.F.K. and S.L. filed provisional patent application 63/209,797, entitled “Method and system for improved management of genetic diseases” with the U.S. Patent and Trademark Office. The remaining authors have no competing interests.

Figures

**Fig. 1. Flow diagrams of the technological components of a 13.5-hour system for automated diagnosis and virtual acute management guidance of genetic diseases by rWGS.**
Innovations described herein are indicated by orange boxes. A The order and duration of laboratory steps and technologies. EHR Electronic Health Record, EDTA EthyleneDiamineTetraAcetic acid, gDNA genomic DeoxyriboNucleic Acid, PCR Polymerase Chain Reaction, QA Quality Assurance, nt Nucleotide, SNV Single Nucleotide Variant, indel insertion-deletion nucleotide variant, SV Structural Variant, CNV Copy Number Variant, GTRx Genome-to-Treatment. B Diagram of the information flow from order placement in the EHR to return of diagnostic results together with specific management guidance for that genetic disease. rWGS Portal: Custom software system for rWGS ordering, accessioning, chain-of-custody, and return of results (v.3.2). LIMS Custom laboratory information management system for rWGS, short tandem repeat profiling, confirmatory testing (Sanger sequencing and Multiplex Ligation-dependent Probe Amplification), and inventory management (L7 informatics). IR Information resource, *: HL7/FHIR or Continuity of Care Documents, †: JSON. ‡: bcl, □: vcf.

**Fig. 2. Flowchart of the development of Genome-To-Treatment (GTRx), a virtual system for acute management guidance for rare genetic diseases.**
Phase 1 - Compilation of a comprehensive gene-genetic disease list for severe, childhood-onset conditions in which an established treatment was available. Phase 2, integration of 13 information resources pertaining to rare genetic diseases. Phase 3, development of the GTRx web resource containing the integrated information resources. Phase 4, automated, artificial intelligence (AI)-based searching and manual curation of published evidence of treatments for each condition by three companies. Phase 5, development of a custom REDCap system for structured assessment of genes, disorders, and therapeutic interventions. Phase 6a, independent manual review of curated interventions and assertions for the first 15 pilot gene-disease pairs by five experts. Phase 6b, primary and secondary reviews of the remaining gene-disease pairs. Phase 7, round-table discussion of records lacking consensus. Phase 8, upload of retained consensus records to the GTRx web resource.

**Fig. 3. GTRx disease, gene, and literature filtering, and final content.**
A A modified PRISMA flowchart showing filtering steps and summarizing results of review of 563 unique disease-gene dyads herein. B Genetic disease types and disease genes featured in the first 100 GTRx genes reviewed herein.

**Fig. 4. Clinical course and diagnostic timeline of two critically ill infants who received 13.5-h rWGS and confirmatory standard diagnostic rWGS.**
Clinical (a and c, dark blue circles) and diagnostic timelines (b and d, light blue circles) of infants AH638 (a, b) and CSD59F (c, d), who received both standard, clinical rWGS and the 13.5-h methods. ED Emergency Department, EEG Electroencephalogram, AI Artificial intelligence, DOL Day of life. Circles with vertical lines indicate interactions between neonatology, genomics, and biochemical genetics.

**Fig. 5. Decreasing cost of research WGS (red line) and time to provisional diagnosis of rapid, clinical WGS (blue line) of WGS, 2005–2021.**
^{, –} (https://www.genome.gov/about-genomics/fact-sheets/Sequencing-Human-Genome-cost). Source data are provided as a Source Data file.

See this image and copyright information in PMC

References

1. Online Mendelian Inheritance in Man. https://www.omim.org/
1. Willig LK, et al. Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of diagnostic and clinical findings. Lancet Respir. Med. 2015;3:377–387. doi: 10.1016/S2213-2600(15)00139-3. - DOI - PMC - PubMed
1. Petrikin JE, et al. The NSIGHT1-randomized controlled trial: rapid whole-genome sequencing for accelerated etiologic diagnosis in critically ill infants. NPJ Genom. Med. 2018;3:6. doi: 10.1038/s41525-018-0045-8. - DOI - PMC - PubMed
1. Farnaes L, et al. Rapid whole-genome sequencing decreases infant morbidity and cost of hospitalization. NPJ Genom. Med. 2018;3:10. doi: 10.1038/s41525-018-0049-4. - DOI - PMC - PubMed
1. Sanford EF, et al. Rapid whole genome sequencing has clinical utility in children in the PICU. Pediatr. Crit. Care Med. 2019;20:1007–1020. doi: 10.1097/PCC.0000000000002056. - DOI - PMC - PubMed

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An automated 13.5 hour system for scalable diagnosis and acute management guidance for genetic diseases

Affiliations

An automated 13.5 hour system for scalable diagnosis and acute management guidance for genetic diseases

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical