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Feasibility of Ultra-Rapid Exome Sequencing in Critically Ill Infants and Children With Suspected Monogenic Conditions in the Australian Public Health Care System

Educational Objective
To understand the value of rapid genomic testing for critically ill pediatric patients with suspected monogenic conditions.
1 Credit CME
Key Points

Question  Can ultra-rapid genomic testing be performed for critically ill pediatric patients in a public health care system?

Findings  This multisite descriptive feasibility study included 12 Australian hospitals and 2 laboratories. Among the 108 critically ill infants and children with suspected monogenic conditions who had ultra-rapid genomic testing, the mean time to genomic test report was 3.3 days and the molecular diagnostic yield was 51%.

Meaning  This study suggests feasibility of ultra-rapid genomic testing in a public setting for critically ill pediatric patients. However, further research is needed to understand its clinical value.

Abstract

Importance  Widespread adoption of rapid genomic testing in pediatric critical care requires robust clinical and laboratory pathways that provide equitable and consistent service across health care systems.

Objective  To prospectively evaluate the performance of a multicenter network for ultra-rapid genomic diagnosis in a public health care system.

Design, Setting, and Participants  Descriptive feasibility study of critically ill pediatric patients with suspected monogenic conditions treated at 12 Australian hospitals between March 2018 and February 2019, with data collected to May 2019. A formal implementation strategy emphasizing communication and feedback, standardized processes, coordination, distributed leadership, and collective learning was used to facilitate adoption.

Exposures  Ultra-rapid exome sequencing.

Main Outcomes and Measures  The primary outcome was time from sample receipt to ultra-rapid exome sequencing report. The secondary outcomes were the molecular diagnostic yield, the change in clinical management after the ultra-rapid exome sequencing report, the time from hospital admission to the laboratory report, and the proportion of laboratory reports returned prior to death or hospital discharge.

Results  The study population included 108 patients with a median age of 28 days (range, 0 days to 17 years); 34% were female; and 57% were from neonatal intensive care units, 33% were from pediatric intensive care units, and 9% were from other hospital wards. The mean time from sample receipt to ultra-rapid exome sequencing report was 3.3 days (95% CI, 3.2-3.5 days) and the median time was 3 days (range, 2-7 days). The mean time from hospital admission to ultra-rapid exome sequencing report was 17.5 days (95% CI, 14.6-21.1 days) and 93 reports (86%) were issued prior to death or hospital discharge. A molecular diagnosis was established in 55 patients (51%). Eleven diagnoses (20%) resulted from using the following approaches to augment standard exome sequencing analysis: mitochondrial genome sequencing analysis, exome sequencing–based copy number analysis, use of international databases to identify novel gene–disease associations, and additional phenotyping and RNA analysis. In 42 of 55 patients (76%) with a molecular diagnosis and 6 of 53 patients (11%) without a molecular diagnosis, the ultra-rapid exome sequencing result was considered as having influenced clinical management. Targeted treatments were initiated in 12 patients (11%), treatment was redirected toward palliative care in 14 patients (13%), and surveillance for specific complications was initiated in 19 patients (18%).

Conclusions and Relevance  This study suggests feasibility of ultra-rapid genomic testing in critically ill pediatric patients with suspected monogenic conditions in the Australian public health care system. However, further research is needed to understand the clinical value of such testing, and the generalizability of the findings to other health care settings.

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Article Information

Corresponding Author: Zornitza Stark, DM, Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, 50 Flemington Rd, Parkville, VIC 3052, Australia (zornitza.stark@vcgs.org.au).

Accepted for Publication: April 23, 2020.

Authors/Members of the Australian Genomics Health Alliance Acute Care Flagship: Sebastian Lunke, PhD; Stefanie Eggers, PhD; Meredith Wilson, MBBS; Chirag Patel, MD; Christopher P. Barnett, MBBS; Jason Pinner, MBBS; Sarah A. Sandaradura, PhD; Michael F. Buckley, PhD; Emma I. Krzesinski, MBChB; Michelle G. de Silva, PhD; Gemma R. Brett, MGenCouns; Kirsten Boggs, MGenCouns; David Mowat, MBBS; Edwin P. Kirk, PhD; Lesley C. Adès, MBBS; Lauren S. Akesson, PhD; David J. Amor, PhD; Samantha Ayres, MGenCouns; Anne Baxendale, GradDipGenetCounsel; Sarah Borrie, MGenCouns; Alessandra Bray, PhD; Natasha J. Brown, PhD; Cheng Yee Chan, MBChB; Belinda Chong, PhD; Corrina Cliffe, BSc, Biomed; Martin B. Delatycki, PhD; Matthew Edwards, MD; George Elakis, BSc; Michael C. Fahey, PhD; Andrew Fennell, MBBChBAO; Lindsay Fowles, PhD; Lyndon Gallacher, MGenCouns; Megan Higgins, MBBS; Katherine B. Howell, PhD; Lauren Hunt, MSc; Matthew F. Hunter, MBChB; Kristi J. Jones, PhD; Sarah King, PhD; Smitha Kumble, MBBS; Sarah Lang, PhD; Maelle Le Moing, MSc; Alan Ma, MBBS; Dean Phelan, PhD; Michael C. J. Quinn, PhD; Anna Richards, MSc; Christopher M. Richmond, MBBS; Jessica Riseley, BSc; Jonathan Rodgers, MBBS; Rani Sachdev, MBBS; Simon Sadedin, PhD; Luregn J. Schlapbach, MD; Janine Smith, MBBS; Amanda Springer, MGenCouns; Natalie B. Tan, MBBS; Tiong Y. Tan, PhD; Suzanna L. Temple, PhD; Christiane Theda, MD; Anand Vasudevan, MBBS; Susan M. White, MBBS; Alison Yeung, MBBS; Ying Zhu, PhD; Melissa Martyn, PhD; Stephanie Best, PhD; Tony Roscioli, PhD; John Christodoulou, PhD; Zornitza Stark, DM.

Affiliations of Authors/Members of the Australian Genomics Health Alliance Acute Care Flagship: Australian Genomics Health Alliance, Parkville, Australia (Lunke, de Silva, Boggs, Ayres, Bray, King, Best, Christodoulou, Stark); Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Melbourne, Australia (Lunke, Eggers, de Silva, Brett, Akesson, Ayres, Brown, Chong, Delatycki, Gallacher, Kumble, Le Moing, Phelan, Richmond, Riseley, Sadedin, N. B. Tan, T. Y. Tan, White, Yeung, Christodoulou, Stark); University of Melbourne, Melbourne, Australia (Lunke, de Silva, Brett, Akesson, Amor, Brown, Delatycki, Gallacher, Howell, T. Y. Tan, Theda, White, Christodoulou, Stark); Sydney Children’s Hospitals Network-Westmead, Sydney, Australia (Wilson, Sandaradura, Boggs, Adès, Bray, Jones, Ma, Smith); University of Sydney, Sydney, Australia (Wilson, Sandaradura, Adès, Jones, Ma, Smith, Christodoulou); Genetic Health Queensland, Royal Brisbane and Women’s Hospital, Brisbane, Australia (Patel, Fowles, Higgins, Hunt, Quinn, Rodgers); Women’s and Children’s Hospital, North Adelaide, Australia (Barnett, Baxendale, Borrie); Sydney Children’s Hospitals Network-Randwick, Sydney, Australia (Pinner, Boggs, Mowat, Kirk, Bray, Sachdev); University of New South Wales, Sydney, Australia (Pinner, Mowat, Kirk, Roscioli); NSW Health Pathology Randwick Genomics Laboratory, Sydney, Australia (Buckley, Kirk, Chan, Cliffe, Elakis, Lang, Richards, Temple, Zhu, Roscioli); Monash Genetics, Monash Health, Melbourne, Australia (Krzesinski, Akesson, Fahey, Fennell, Hunter, Springer, Yeung); Department of Paediatrics, Monash University, Melbourne, Australia (Krzesinski, Fahey, Fennell, Hunter, Springer); Royal Children’s Hospital, Melbourne, Australia (Amor, Howell); Murdoch Children’s Research Institute, Melbourne, Australia (Amor, Howell, Theda, Martyn, Best); Neuroscience Research Australia, University of New South Wales, Sydney, Australia (Chan, Roscioli); Hunter Genetics, Newcastle, Australia (Edwards); Department of Paediatrics, School of Medicine, University of Western Sydney, Sydney, Australia (Edwards); University of Queensland, Brisbane, Australia (Higgins, Hunt); Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide (King); Paediatric Critical Care Research Group, Child Health Research Centre, the University of Queensland and Queensland Children’s Hospital, Brisbane, Australia (Schlapbach); Royal Women’s Hospital, Melbourne, Australia (Theda, Vasudevan); Melbourne Genomics Health Alliance, Melbourne, Australia (Martyn); Australian Institute of Health Innovation, Macquarie University, Sydney (Best).

Author Contributions: Drs Lunke and Stark had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Lunke, Eggers, Barnett, Brett, Hunter, Theda, Martyn, Best, Roscioli, Christodoulou, Stark.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Lunke, Barnett, Brett, Amor, Ayres, Fahey, Schlapbach, White, Martyn, Best, Stark.

Critical revision of the manuscript for important intellectual content: Lunke, Eggers, Wilson, Patel, Barnett, Pinner, Sandaradura, Buckley, Krzesinski, de Silva, Brett, Boggs, Mowat, Kirk, Ades, Akesson, Amor, Baxendale, Schenscher, Bray, Brown, Chan, Chong, Cliffe, Delatycki, Edwards, Elakis, Fahey, Fennell, Fowles, Gallacher, Higgins, Howell, Hunt, Hunter, Jones, King, Kumble, Lang, Le Moing, Ma, Phelan, Quinn, Richards, Richmond, Riseley, Rodgers, Sachdev, Sadedin, Schlapbach, Smith, Springer, N. Tan, T. Tan, Temple, Theda, Vasudevan, White, Yeung, Zhu, Best, Roscioli, Christodoulou, Stark.

Statistical analysis: Lunke, Martyn.

Obtained funding: Lunke, Patel, Pinner, Amor, Hunter, Roscioli, Christodoulou, Stark.

Administrative, technical, or material support: Lunke, Eggers, Wilson, Patel, Barnett, Pinner, Buckley, de Silva, Brett, Boggs, Kirk, Akesson, Ayres, Schenscher, Bray, Brown, Chong, Cliffe, Elakis, Fahey, Fowles, Gallacher, Higgins, Hunt, Hunter, Jones, King, Lang, Le Moing, Phelan, Quinn, Richards, Richmond, Riseley, Sadedin, Springer, N. Tan, Temple, Vasudevan, White, Yeung, Roscioli.

Supervision: Lunke, Wilson, Barnett, Pinner, Buckley, Boggs, Brown, Hunter, Sachdev, T. Tan, Martyn, Best, Roscioli, Christodoulou, Stark.

Conflict of Interest Disclosures: Dr Fahey reported receiving personal fees for providing expert testimony in medicolegal cases; and receiving grants from the Fulbright Foundation. Dr Howell reported receiving personal fees from RogCon Biosciences Inc. Dr Theda reported receiving personal fees from Navi Medical Technologies Pty Ltd, Ventora Pty Ltd, the Royal Children’s Hospital, and Johns Hopkins University. No other disclosures were reported.

Funding/Support: The Australian Genomics Health Alliance (Australian Genomics) project was funded by grant GNT1113531 from the National Health and Medical Research Council Targeted Call for Research, grant 2017-906 from the Royal Children’s Hospital Foundation, and unspecified grants from the Sydney Children’s Hospital Network and the Channel 7 Children’s Research Foundation. The research conducted at the Murdoch Children’s Research Institute was supported by the Victorian government’s operational infrastructure support program.

Role of the Funder/Sponsor: The funders/sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank Andrew Sinclair, PhD (Murdoch Children’s Research Institute), for critically reading the manuscript without receiving compensation.

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