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. 2017 Sep 1;171(9):855-862.
doi: 10.1001/jamapediatrics.2017.1755.

Diagnostic Impact and Cost-effectiveness of Whole-Exome Sequencing for Ambulant Children With Suspected Monogenic Conditions

Tiong Yang Tan  1   2   3 , Oliver James Dillon  3 , Zornitza Stark  1   2 , Deborah Schofield  2   4   5 , Khurshid Alam  2   3 , Rupendra Shrestha  4 , Belinda Chong  1 , Dean Phelan  1 , Gemma R Brett  1   2   6 , Emma Creed  1   2   6 , Anna Jarmolowicz  1   2   6 , Patrick Yap  1   2 , Maie Walsh  1   2 , Lilian Downie  1   2 , David J Amor  1   2   3 , Ravi Savarirayan  1   2   3 , George McGillivray  1   2 , Alison Yeung  1   2 , Heidi Peters  3   7 , Susan J Robertson  2   7 , Aaron J Robinson  7 , Ivan Macciocca  1   2 , Simon Sadedin  2 , Katrina Bell  2 , Alicia Oshlack  2   3 , Peter Georgeson  8 , Natalie Thorne  8 , Clara Gaff  3   6   8 , Susan M White  1   2   3
Affiliations

Diagnostic Impact and Cost-effectiveness of Whole-Exome Sequencing for Ambulant Children With Suspected Monogenic Conditions

Tiong Yang Tan et al. JAMA Pediatr. .

Abstract

Importance: Optimal use of whole-exome sequencing (WES) in the pediatric setting requires an understanding of who should be considered for testing and when it should be performed to maximize clinical utility and cost-effectiveness.

Objectives: To investigate the impact of WES in sequencing-naive children suspected of having a monogenic disorder and evaluate its cost-effectiveness if WES had been available at different time points in their diagnostic trajectory.

Design, setting, and participants: This prospective study was part of the Melbourne Genomics Health Alliance demonstration project. At the ambulatory outpatient clinics of the Victorian Clinical Genetics Services at the Royal Children's Hospital, Melbourne, Australia, children older than 2 years suspected of having a monogenic disorder were prospectively recruited from May 1 through November 30, 2015, by clinical geneticists after referral from general and subspecialist pediatricians. All children had nondiagnostic microarrays and no prior single-gene or panel sequencing.

Exposures: All children underwent singleton WES with targeted phenotype-driven analysis.

Main outcomes and measures: The study examined the clinical utility of a molecular diagnosis and the cost-effectiveness of alternative diagnostic trajectories, depending on timing of WES.

Results: Of 61 children originally assessed, 44 (21 [48%] male and 23 [52%] female) aged 2 to 18 years (mean age at initial presentation, 28 months; range, 0-121 months) were recruited, and a diagnosis was achieved in 23 (52%) by singleton WES. The diagnoses were unexpected in 8 of 23 (35%), and clinical management was altered in 6 of 23 (26%). The mean duration of the diagnostic odyssey was 6 years, with each child having a mean of 19 tests and 4 clinical genetics and 4 nongenetics specialist consultations, and 26 (59%) underwent a procedure while under general anesthetic for diagnostic purposes. Economic analyses of the diagnostic trajectory identified that WES performed at initial tertiary presentation resulted in an incremental cost savings of A$9020 (US$6838) per additional diagnosis (95% CI, A$4304-A$15 404 [US$3263-US$11 678]) compared with the standard diagnostic pathway. Even if WES were performed at the first genetics appointment, there would be an incremental cost savings of A$5461 (US$4140) (95% CI, A$1433-A$10 557 [US$1086- US$8004]) per additional diagnosis compared with the standard diagnostic pathway.

Conclusions and relevance: Singleton WES in children with suspected monogenic conditions has high diagnostic yield, and cost-effectiveness is maximized by early application in the diagnostic pathway. Pediatricians should consider early referral of children with undiagnosed syndromes to clinical geneticists.

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Conflict of interest statement

Conflict of Interest Disclosures: None reported.

Figures

Figure 1.
Figure 1.. Actual and Modeled Diagnostic Trajectories of the 44 Children Included in the Study
A, Standard diagnostic pathway without whole-exome sequencing (WES) (counterfactual, no diagnoses). B, Standard diagnostic pathway with WES (actual, with 23 of 44 diagnoses). C, WES applied at first clinical genetics (CG) assessment (counterfactual, 23 of 44 diagnoses). D, WES applied at initial tertiary presentation (counterfactual, 23 of 44 diagnoses).
Figure 2.
Figure 2.. Cost-effectiveness Plane for Standard Diagnostic Pathway Compared With WES Combined With Standard Diagnostic Pathway, WES at First Genetics Appointment, and WES at Initial Tertiary Presentation
To convert Australian dollars to US dollars, multiply by 0.759. WES indicates whole-exome sequencing.
See this image and copyright information in PMC

Comment in

References

    1. Kumar P, Radhakrishnan J, Chowdhary MA, Giampietro PF. Prevalence and patterns of presentation of genetic disorders in a pediatric emergency department. Mayo Clin Proc. 2001;76(8):777-783. - PubMed
    1. McCandless SE, Brunger JW, Cassidy SB. The burden of genetic disease on inpatient care in a children’s hospital. Am J Hum Genet. 2004;74(1):121-127. - PMC - PubMed
    1. Yoon PW, Olney RS, Khoury MJ, Sappenfield WM, Chavez GF, Taylor D. Contribution of birth defects and genetic diseases to pediatric hospitalizations: a population-based study. Arch Pediatr Adolesc Med. 1997;151(11):1096-1103. - PubMed
    1. Miller DT, Adam MP, Aradhya S, et al. . Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86(5):749-764. - PMC - PubMed
    1. Biesecker LG, Green RC. Diagnostic clinical genome and exome sequencing. N Engl J Med. 2014;370(52):2418-2425. - PubMed

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