Incremental net benefit of whole genome sequencing for newborns and children with suspected genetic disorders: Systematic review and meta-analysis of cost-effectiveness evidence

Nurchis, Mario Cesare; Riccardi, Maria Teresa; Radio, Francesca Clementina; Chillemi, Giovanni; Bertini, E.; Tartaglia, Marco; Cicchetti, Americo; Dallapiccola, Bruno; Damiani, Gianfranco

doi:10.1016/j.healthpol.2022.03.001

Cited by 19 publications

(14 citation statements)

References 49 publications

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“…These elements include: (a) specific inclusion criteria for patient selection and a clinical genetics evaluation, (b) a phenotype‐agnostic analysis of the ES data, followed by manual curation of variants by clinicians, with close collaboration with a bioinformatician, (c) collaborative pursuit of VUS via active and passive processes, (d) communication of diagnoses in well‐defined categories, to make clear the actionability of the results to the patients/families, (e) periodic time‐lapsed reanalysis, as well as “watching” genes via publicly available resources such as PubMed, and (f) capturing the change in diagnoses over time—although it is acknowledged that ES results can change over time, 13 the underlying reasons for these have not been systematically examined. All of these processes have resulted in a current diagnostic yield of 45% (def/likely diagnoses only), compared to the diagnostic yield of 33%–38% in two recent reviews of ES/GS 47,48 . The inclusion of parents in the ES, in most of our patients (94%), also contributes to the higher diagnostic yield.…”

Section: Discussionmentioning

confidence: 80%

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The best of both worlds: Blending cutting‐edge research with clinical processes for a productive exome clinic

Sullivan,

Spillmann,

Schoch

et al. 2023

Clinical Genetics

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Genomic medicine has been transformed by next‐generation sequencing (NGS), inclusive of exome sequencing (ES) and genome sequencing (GS). Currently, ES is offered widely in clinical settings, with a less prevalent alternative model consisting of hybrid programs that incorporate research ES along with clinical patient workflows. We were among the earliest to implement a hybrid ES clinic, have provided diagnoses to 45% of probands, and have identified several novel candidate genes. Our program is enabled by a cost‐effective investment by the health system and is unique in encompassing all the processes that have been variably included in other hybrid/clinical programs. These include careful patient selection, utilization of a phenotype‐agnostic bioinformatics pipeline followed by manual curation of variants and phenotype integration by clinicians, close collaborations between the clinicians and the bioinformatician, pursuit of interesting variants, communication of results to patients in categories that are predicated upon the certainty of a diagnosis, and tracking changes in results over time and the underlying mechanisms for such changes. Due to its effectiveness, scalability to GS and its resource efficiency, specific elements of our paradigm can be incorporated into existing clinical settings, or the entire hybrid model can be implemented within health systems that have genomic medicine programs, to provide NGS in a scientifically rigorous, yet pragmatic setting.

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Section: Discussionmentioning

confidence: 80%

“…All of these processes have resulted in a current diagnostic yield of 45% (def/likely diagnoses only), compared to the diagnostic yield of 33%-38% in two recent reviews of ES/GS. 47,48 The inclusion of parents in the ES, in most of our patients (94%), also contributes to the higher diagnostic yield.…”

Section: Discussionmentioning

confidence: 92%

The best of both worlds: Blending cutting‐edge research with clinical processes for a productive exome clinic

Sullivan,

Spillmann,

Schoch

et al. 2023

Clinical Genetics

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show abstract

“…There is a growing literature on the cost effectiveness of exome and genome sequencing [ 68 , 69 , 70 , 71 ]. The main focus of these publications is on measures of cost-per-diagnosis and the literature does not yet address total effects on cost-of-care.…”

Section: Clinical Implications Of Genetic Testingmentioning

confidence: 99%

Considering the Genetic Architecture of Hypoplastic Left Heart Syndrome

Belmont

2022

JCDD

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Hypoplastic left heart syndrome (HLHS) is among the most severe cardiovascular malformations and understanding its causes is crucial to making progress in prevention and treatment. Genetic analysis is a broadly useful tool for dissecting complex causal mechanisms and it is playing a significant role in HLHS research. However, unlike classical Mendelian disorders where a relatively small number of genes are largely determinative of the occurrence and severity of the disease, the picture in HLHS is complex. De novo single-gene and copy number variant (CNV) disorders make an important contribution, but there is emerging evidence for causal contributions from lower penetrance and common variation. Integrating this emerging knowledge into clinical diagnostics and translating the findings into effective prevention and treatment remain challenges for the future.

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“…Massively parallel sequencing techniques, such as whole‐exome and whole‐genome sequencing (WES/WGS), that map vast parts of persons' DNA all at once, are increasingly being employed in the clinic to clarify medical conditions with a suspected genetic cause. WES provides between 25% and 50% of clinically tested individuals with a definitive diagnosis (Nurchis et al., 2023). While this is a considerable number, some individuals receive no diagnosis or they receive results that are unclear to interpret—so‐called variants of unclear significance (VUSs)—due to limited evidence regarding pathogenicity of the variant.…”

Section: Introductionmentioning

confidence: 99%

Hope, but never expect? Comparing parents' pre‐ and post‐disclosure attitudes toward return of results from diagnostic exome sequencing for their child

Cornelis,

Tibben,

Brilstra

et al. 2024

Molec Gen & Gen Med

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BackgroundCounseling for whole‐exome sequencing (WES) could benefit from aligning parents' pre‐ and post‐disclosure attitudes. A few studies have qualitatively compared parents' pre‐ and post‐disclosure attitudes toward receiving WES results for their child in a diagnostic setting. This study explored these attitudes in the context of children with a developmental delay.MethodsSemi‐structured interviews were conducted with parents (n = 27) of 16 children undergoing diagnostic WES in trio‐analysis, both before and after receiving results.ResultsThree key insights emerged. First, the distinction between hoping and expecting was relevant for shaping parents' experiences with receiving results related to the primary indication. Second, parents of young children whose development of autonomous capacities was uncertain sometimes found themselves in a situation resembling a Catch‐22 when confronted with decisions about unsolicited findings (UFs): an important reason for consenting to WES was to gain a better picture of how the child might develop, but in order to make responsible choices about UFs, some ideas of their child's development is needed. Third, default opt‐ins and opt‐outs helped parents fathom new kinds of considerations for accepting or declining UFs in different categories, thereby aiding decision‐making.ConclusionResults from this study are relevant for counseling and policy development.

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Incremental net benefit of whole genome sequencing for newborns and children with suspected genetic disorders: Systematic review and meta-analysis of cost-effectiveness evidence

Cited by 19 publications

References 49 publications

The best of both worlds: Blending cutting‐edge research with clinical processes for a productive exome clinic

The best of both worlds: Blending cutting‐edge research with clinical processes for a productive exome clinic

Considering the Genetic Architecture of Hypoplastic Left Heart Syndrome

Hope, but never expect? Comparing parents' pre‐ and post‐disclosure attitudes toward return of results from diagnostic exome sequencing for their child

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