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Multicenter Study
. 2020 Jun 23;323(24):2503-2511.
doi: 10.1001/jama.2020.7671.

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

Australian Genomics Health Alliance Acute Care Flagship; Sebastian Lunke  1   2   3 , Stefanie Eggers  2 , Meredith Wilson  4   5 , Chirag Patel  6 , Christopher P Barnett  7 , Jason Pinner  8   9 , Sarah A Sandaradura  4   5 , Michael F Buckley  10 , Emma I Krzesinski  11   12 , Michelle G de Silva  1   2   3 , Gemma R Brett  2   3 , Kirsten Boggs  1   4   8 , David Mowat  8   9 , Edwin P Kirk  8   9   10 , Lesley C Adès  4   5 , Lauren S Akesson  2   3   11 , David J Amor  3   13   14 , Samantha Ayres  1   2 , Anne Baxendale  7 , Sarah Borrie  7 , Alessandra Bray  1   4   8 , Natasha J Brown  2   3 , Cheng Yee Chan  10   15 , Belinda Chong  2 , Corrina Cliffe  10 , Martin B Delatycki  2   3 , Matthew Edwards  16   17 , George Elakis  10 , Michael C Fahey  11   12 , Andrew Fennell  11   12 , Lindsay Fowles  6 , Lyndon Gallacher  2   3 , Megan Higgins  6   18 , Katherine B Howell  3   13   14 , Lauren Hunt  6   18 , Matthew F Hunter  11   12 , Kristi J Jones  4   5 , Sarah King  1   19 , Smitha Kumble  2 , Sarah Lang  10 , Maelle Le Moing  2 , Alan Ma  4   5 , Dean Phelan  2 , Michael C J Quinn  6 , Anna Richards  10 , Christopher M Richmond  2 , Jessica Riseley  2 , Jonathan Rodgers  6 , Rani Sachdev  8 , Simon Sadedin  2 , Luregn J Schlapbach  20 , Janine Smith  4   5 , Amanda Springer  11   12 , Natalie B Tan  2 , Tiong Y Tan  2   3 , Suzanna L Temple  10 , Christiane Theda  3   14   21 , Anand Vasudevan  21 , Susan M White  2   3 , Alison Yeung  2   11 , Ying Zhu  10 , Melissa Martyn  14   22 , Stephanie Best  1   14   23 , Tony Roscioli  9   10   15 , John Christodoulou  1   2   3   5 , Zornitza Stark  1   2   3
Affiliations
Multicenter Study

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

Australian Genomics Health Alliance Acute Care Flagship et al. JAMA. .

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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Conflict of interest statement

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.

Figures

Figure 1.
Figure 1.. Steps for Non-Rapid Genomic Testing Compared With Ultra-Rapid Genomic Testing
Figure 2.
Figure 2.. Recruitment and Summary of Ultra-Rapid Exome Sequencing Cohort
aOccurred 3 months after the ultra-rapid exome sequencing report and was considered by clinicians to have been influenced by the genomic report. bSome patients had changes in management from more than 1 category.
See this image and copyright information in PMC

Comment in

References

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