Should Scotland Provide Genome-wide Sequencing for the Diagnosis of Rare Developmental Disorders? A Cost-effectiveness Analysis

Overview

Journal Eur J Health Econ

Specialty Health Services

Date 2024 Sep 9

PMID 39249625

Authors

Michael Abbott

Mandy Ryan

Rodolfo Hernandez

Lynda McKenzie

Sebastian Heidenreich

Lynne Hocking

Caroline Clark

Morad Ansari

David Moore

Anne Lampe

Ruth McGowan

Jonathan Berg

Zosia Miedzybrodzka

Affiliations

Soon will be listed here.

Abstract

Aims: This study aims to evaluate the cost effectiveness of genetic and genomic testing strategies for the diagnosis of rare developmental disorders in NHS Scotland.

Methods: Six genetic and genomic testing strategies were evaluated using a decision tree model. First-line, second-line and last-resort trio genome sequencing (GS), and second-line and last-resort trio exome sequencing (ES) were compared with standard genetic testing. The cost effectiveness of each strategy was expressed in terms of incremental cost per additional diagnosis. The impact of uncertainty on cost-effectiveness results was explored using deterministic and probabilistic sensitivity analysis.

Results: 2nd-line ES was a cost-saving option, increasing diagnostic yield by 13.9% and decreasing cost by £1027 per trio compared to standard genetic testing. Compared to ES, strategies involving GS increased costs significantly, with only a moderate or zero improvement in diagnostic yield. Sensitivity analysis indicated that significant reductions in cost or improvements in diagnostic yield are required before 1st-line GS becomes cost effective.

Conclusion: 2nd-line ES (after chromosomal microarray; replacing gene panel testing) for the diagnosis of developmental disorders is a cost-saving option for the Scottish NHS. Ongoing economic evaluation is required to monitor the evolving cost and diagnostic yield of GS and ES over time.

References

de Ligt J, Willemsen M, van Bon B, Kleefstra T, Yntema H, Kroes T . Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med. 2012; 367(20):1921-9. DOI: 10.1056/NEJMoa1206524. View

Lionel A, Costain G, Monfared N, Walker S, Reuter M, Hosseini S . Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test. Genet Med. 2017; 20(4):435-443. PMC: 5895460. DOI: 10.1038/gim.2017.119. View

Firth H, Wright C . The Deciphering Developmental Disorders (DDD) study. Dev Med Child Neurol. 2011; 53(8):702-3. DOI: 10.1111/j.1469-8749.2011.04032.x. View

Schwarze K, Buchanan J, Taylor J, Wordsworth S . Are whole-exome and whole-genome sequencing approaches cost-effective? A systematic review of the literature. Genet Med. 2018; 20(10):1122-1130. DOI: 10.1038/gim.2017.247. View

Quenez O, Cassinari K, Coutant S, Lecoquierre F, Le Guennec K, Rousseau S . Detection of copy-number variations from NGS data using read depth information: a diagnostic performance evaluation. Eur J Hum Genet. 2020; 29(1):99-109. PMC: 7852510. DOI: 10.1038/s41431-020-0672-2. View

Muhlbacher A, Sadler A . The Probabilistic Efficiency Frontier: A Framework for Cost-Effectiveness Analysis in Germany Put into Practice for Hepatitis C Treatment Options. Value Health. 2017; 20(2):266-272. DOI: 10.1016/j.jval.2016.12.015. View

Culyer A . Cost-effectiveness thresholds in health care: a bookshelf guide to their meaning and use. Health Econ Policy Law. 2016; 11(4):415-32. DOI: 10.1017/S1744133116000049. View

Johansson P . Is there a meaningful definition of the value of a statistical life?. J Health Econ. 2001; 20(1):131-9. DOI: 10.1016/s0167-6296(00)00073-4. View

Li C, Vandersluis S, Holubowich C, Ungar W, Goh E, Boycott K . Cost-effectiveness of genome-wide sequencing for unexplained developmental disabilities and multiple congenital anomalies. Genet Med. 2020; 23(3):451-460. DOI: 10.1038/s41436-020-01012-w. View

10.

Ewans L, Schofield D, Shrestha R, Zhu Y, Gayevskiy V, Ying K . Whole-exome sequencing reanalysis at 12 months boosts diagnosis and is cost-effective when applied early in Mendelian disorders. Genet Med. 2018; 20(12):1564-1574. DOI: 10.1038/gim.2018.39. View

11.

Howell K, Eggers S, Dalziel K, Riseley J, Mandelstam S, Myers C . A population-based cost-effectiveness study of early genetic testing in severe epilepsies of infancy. Epilepsia. 2018; 59(6):1177-1187. PMC: 5990455. DOI: 10.1111/epi.14087. View

12.

Schofield D, Alam K, Douglas L, Shrestha R, MacArthur D, Davis M . Cost-effectiveness of massively parallel sequencing for diagnosis of paediatric muscle diseases. NPJ Genom Med. 2017; 2. PMC: 5677979. DOI: 10.1038/s41525-017-0006-7. View

13.

Stark Z, Schofield D, Alam K, Wilson W, Mupfeki N, Macciocca I . Prospective comparison of the cost-effectiveness of clinical whole-exome sequencing with that of usual care overwhelmingly supports early use and reimbursement. Genet Med. 2017; 19(8):867-874. DOI: 10.1038/gim.2016.221. View

14.

Yeung A, Tan N, Tan T, Stark Z, Brown N, Hunter M . A cost-effectiveness analysis of genomic sequencing in a prospective versus historical cohort of complex pediatric patients. Genet Med. 2020; 22(12):1986-1993. DOI: 10.1038/s41436-020-0929-8. View

15.

Incerti D, Xu X, Chou J, Gonzaludo N, Belmont J, Schroeder B . Cost-effectiveness of genome sequencing for diagnosing patients with undiagnosed rare genetic diseases. Genet Med. 2021; 24(1):109-118. DOI: 10.1016/j.gim.2021.08.015. View

16.

Wu Y, Balasubramaniam S, Rius R, Thorburn D, Christodoulou J, Goranitis I . Genomic sequencing for the diagnosis of childhood mitochondrial disorders: a health economic evaluation. Eur J Hum Genet. 2021; 30(5):577-586. PMC: 9090793. DOI: 10.1038/s41431-021-00916-8. View

17.

Lavelle T, Feng X, Keisler M, Cohen J, Neumann P, Prichard D . Cost-effectiveness of exome and genome sequencing for children with rare and undiagnosed conditions. Genet Med. 2022; 24(6):1349-1361. DOI: 10.1016/j.gim.2022.03.005. View

18.

Marshall D, Gonzalez J, MacDonald K, Reed Johnson F . Estimating Preferences for Complex Health Technologies: Lessons Learned and Implications for Personalized Medicine. Value Health. 2017; 20(1):32-39. PMC: 5319756. DOI: 10.1016/j.jval.2016.08.737. View

19.

Schofield D, Rynehart L, Shresthra R, White S, Stark Z . Long-term economic impacts of exome sequencing for suspected monogenic disorders: diagnosis, management, and reproductive outcomes. Genet Med. 2019; 21(11):2586-2593. DOI: 10.1038/s41436-019-0534-x. View

20.

Stark Z, Schofield D, Martyn M, Rynehart L, Shrestha R, Alam K . Does genomic sequencing early in the diagnostic trajectory make a difference? A follow-up study of clinical outcomes and cost-effectiveness. Genet Med. 2018; 21(1):173-180. DOI: 10.1038/s41436-018-0006-8. View