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Title: A head-to-head evaluation of the diagnostic efficacy and costs of trio versus singleton exome sequencing analysis.
Austin Authors: Tan, Tiong Yang;Lunke, Sebastian;Chong, Belinda;Phelan, Dean;Fanjul-Fernandez, Miriam;Marum, Justine E;Kumar, Vanessa Siva;Stark, Zornitza;Yeung, Alison;Brown, Natasha J;Stutterd, Chloe;Delatycki, Martin B ;Sadedin, Simon;Martyn, Melissa;Goranitis, Ilias;Thorne, Natalie;Gaff, Clara L;White, Susan M
Affiliation: Murdoch Children's Research Institute, Melbourne, Australia
Department of Pathology, University of Melbourne, Melbourne, Australia
Department of Clinical Genetics, Austin Health, Heidelberg, Victoria, Australia
Victorian Clinical Genetics Services, Melbourne, Australia
Melbourne Genomics Health Alliance, Parkville, Australia
Department of Paediatrics, University of Melbourne, Melbourne, Australia
Issue Date: Dec-2019
Date: 2019-07-18
Publication information: European journal of human genetics : EJHG 2019; 27(12): 1791-1799
Abstract: Diagnostic exome sequencing (ES) can be performed on the proband only (singleton; sES) or with additional samples, often including both biological parents with the proband (trio; tES). In this study we sought to compare the efficiencies of exome sequencing (ES) by trio (tES) versus singleton (sES) approach, determine costs, and identify factors to consider when deciding on optimal implementation strategies for the diagnosis of monogenic disorders. We undertook ES in 30 trios and analysed each proband's sES and tES data in parallel. Two teams were randomly allocated to either sES or tES analysis for each case and blinded to each other's work. Each task was timed and cost analyses were based on time taken and diagnostic yield. We modelled three scenarios to determine the factors to consider in the implementation of tES. sES diagnosed 11/30 (36.7%) cases and tES identified one additional diagnosis (12/30 (40.0%)). tES obviated the need for Sanger segregation, reduced the number of variants for curation, and had lower cost-per-diagnosis when considering analysis alone. When sequencing costs were included, tES nearly doubled the cost of sES. Reflexing to tES in those who remain undiagnosed after sES was cost-saving over tES in all as first-line. This approach requires a large differential in diagnostic yield between sES and tES for maximal benefit given current sequencing costs. tES may be preferable when scaling up laboratory throughput due to efficiency gains and opportunity cost considerations. Our findings are relevant to clinicians, laboratories and health services considering tES over sES.
DOI: 10.1038/s41431-019-0471-9
ORCID: 0000-0001-8455-7778
Journal: European journal of human genetics : EJHG
PubMed URL: 31320747
Type: Journal Article
Appears in Collections:Journal articles

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