Original Title: MSAC application no. 1680

Authors' objectives: To assess the safety, effectiveness and cost-effectiveness of a virtual gene panel-based whole exome analysis (WEA) and copy number variant (CNS) analysis for the diagnosis of a genetic cause of hearing impairment (HI) in children, to inform the Medical Services Advisory Committee.

Authors' results and conclusions: There was no evidence for safety comparisons between children with HI who undergo WEA and those who receive GJB2/GJB6 testing alone. Both the proposed and prior tests are performed on peripheral blood or other easily obtained DNA source such as buccal cells and sampling does not provide any serious risk to the individual. A linked evidence approach was taken to show the effectiveness of WEA for children with HI, as no direct evidence was identified. An incremental increase in diagnostic yield for WEA of 24.8% to 47.5% was reported (when between 120 and 190 genes were analysed). The yield varied partly according to the gene panel size analysed, and also by the level of selection for HI of the tested population (for example the extent of exclusion of syndromic cases), its ethnicity, and test methodology (for example if CNV analysis was performed). One Australian study found that WEA resulted in management changes in approximately 50% of those tested when GJB2/GJB6 was included in the WEA gene panel. Of 59 genetic diagnoses, there were 16 due to a non-syndromic HI variant (16/59 diagnoses, 27.1%). Children diagnosed with syndromic HI went on to other diagnostic or treatment pathways (16/59 diagnoses, 27.1%). The most common management change in the children with a genetic diagnosis was discharge from further testing. There was no change in management for 49.1% of 106 cases (5 syndromic diagnoses, and 47 cases testing negative). There were no health outcomes identified or assessed for WEA for HI. The literature suggests that in the near future, genetic testing may indicate which children will not benefit from a cochlear implant (CI), however there is not sufficient evidence for this outcome as yet. Assessment of the non-health related outcome value of knowing showed that parents valued maximising their child’s health and planning for their future. About a third of parents chose to receive diagnostic results only from WEA when given the option, rather than extended analysis of either actionable or non-actionable health outcome results from WEA. When all linked evidence for Population 1 is considered, there is insufficient evidence for health benefits despite incremental diagnostic yield from WEA. Benefits to families identified are the chance of being discharged from further diagnostic testing, and the value of knowing, which may give certainty and the opportunity to plan for their child’s future. The incremental cost per additional proband and/or carrier identified was AU$1,629.

Authors' recommendations: There was no evidence for safety comparisons between children with HI who undergo WEA and those who receive GJB2/GJB6 testing alone. Both the proposed and prior tests are performed on peripheral blood or other easily obtained DNA source such as buccal cells and sampling does not provide any serious risk to the individual. A linked evidence approach was taken to show the effectiveness of WEA for children with HI, as no direct evidence was identified. An incremental increase in diagnostic yield for WEA of 24.8% to 47.5% was reported (when between 120 and 190 genes were analysed). The yield varied partly according to the gene panel size analysed, and also by the level of selection for HI of the tested population (for example the extent of exclusion of syndromic cases), its ethnicity, and test methodology (for example if CNV analysis was performed). One Australian study found that WEA resulted in management changes in approximately 50% of those tested when GJB2/GJB6 was included in the WEA gene panel. Of 59 genetic diagnoses, there were 16 due to a non-syndromic HI variant (16/59 diagnoses, 27.1%). Children diagnosed with syndromic HI went on to other diagnostic or treatment pathways (16/59 diagnoses, 27.1%). The most common management change in the children with a genetic diagnosis was discharge from further testing. There was no change in management for 49.1% of 106 cases (5 syndromic diagnoses, and 47 cases testing negative). There were no health outcomes identified or assessed for WEA for HI. The literature suggests that in the near future, genetic testing may indicate which children will not benefit from a cochlear implant (CI), however there is not sufficient evidence for this outcome as yet. Assessment of the non-health related outcome value of knowing showed that parents valued maximising their child’s health and planning for their future. About a third of parents chose to receive diagnostic results only from WEA when given the option, rather than extended analysis of either actionable or non-actionable health outcome results from WEA. When all linked evidence for Population 1 is considered, there is insufficient evidence for health benefits despite incremental diagnostic yield from WEA. Benefits to families identified are the chance of being discharged from further diagnostic testing, and the value of knowing, which may give certainty and the opportunity to plan for their child’s future. The incremental cost per additional proband and/or carrier identified was AU$1,629.

Authors' methods: As there was no direct evidence to support WEA for childhood HI, a linked-evidence approach was used to assess whether WEA for childhood hearing loss provides additional information in comparison to GJB2/GJB6 genetic testing. Prior to the start of the systematic review, a research protocol was developed, based on the PICO confirmation ratified by the PICO Advisory Sub-Committee of MSAC. The research protocol was registered a priori with the international prospective register of systematic reviews (PROSPERO) with the registration number CRD42022334693. The medical literature (Embase, Pubmed and the Cochrane library) was searched on 7th April 2022 to identify relevant studies and systematic reviews published since inception of the database to 7th April 2022. The searches were appropriate for determining the diagnostic yield of testing, change in management, and value of knowing for the proposed intervention and comparator for all proposed populations. Medical subject term (MESH/Emtree) headings and free text terms were used for searching and translated between databases. There was no language limit. All study designs were included. However, published case studies or case series reporting outcomes for fewer than three cases or families were excluded during full text appraisal. Studies with populations including >10% consanguineous families were excluded when reporting the diagnostic yield of genetic testing. Titles and abstracts were reviewed by a single reviewer with a random sample of >10% receiving independent assessment by a second reviewer. Full text of articles were appraised by one of two reviewers. There was a high level of concordance between reviewers with conflicts resolved by discussion or a third reviewer. Evidence retrieved from the searches was assessed according to the NHMRC levels of evidence. Where sufficient “high- level” evidence was available, lower-level evidence was not included in the assessment. Evidence relevant to the linked evidence approach was extracted from eligible studies. The quality of included studies was evaluated and reported using the NHLBI4 and modified QUADAS 2 instruments.

Project Status: Completed

URL for project: http://www.msac.gov.au/internet/msac/publishing.nsf/Content/1680-public

URL for protocol: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=334693

Year Published: 2021

URL for published report: http://www.msac.gov.au/internet/msac/publishing.nsf/Content/1680-public

Requestor: Australian Department of Health and Aged Care / Medical Services Advisory Committee (MSAC)

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: Australia

Organisation Name: Adelaide Health Technology Assessment

Contact Address: School of Public Health, Mail Drop 545, University of Adelaide, Adelaide SA 5005, AUSTRALIA, Tel: +61 8 8313 4617

Contact Name: ahta@adelaide.edu.au

Contact Email: ahta@adelaide.edu.au

Copyright: <p>Adelaide Health Technology Assessment (AHTA) on behalf of NICS</p>