Re-analysis of genomic data: An overview of the mechanisms and complexities of clinical adoption

Robertson, Alan J.; Tan, Natalie B; Spurdle, Amanda B.; Metke-Jimenez, Alejandro; Sullivan, Clair; Waddell, Nicola

doi:10.1016/j.gim.2021.12.011

Cited by 34 publications

(48 citation statements)

References 72 publications

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“…While reanalysis of the data can potentially be automated, information technology systems would need to be developed to enable long term tracking of participants. Recent studies using advanced informatics and data mining tools such as machine learning have demonstrated the potential of such approaches (Baker et al, 2019; James et al, 2020; Robertson et al, 2022; Seo et al, 2022; Tan et al, 2020; Zaunseder et al, 2022).…”

Section: Technical and Implementation Challengesmentioning

confidence: 99%

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Newborn screening for neurodevelopmental diseases: Are we there yet?

Chung

Berg

Botkin

et al. 2022

American J of Med Genetics Pt C

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In the US, newborn screening (NBS) is a unique health program that supports health equity and screens virtually every baby after birth, and has brought timely treatments to babies since the 1960's. With the decreasing cost of sequencing and the improving methods to interpret genetic data, there is an opportunity to add DNA sequencing as a screening method to facilitate the identification of babies with treatable conditions that cannot be identified in any other scalable way, including highly penetrant genetic neurodevelopmental disorders (NDD). However, the lack of effective dietary or drugbased treatments has made it nearly impossible to consider NDDs in the current NBS

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Section: Technical and Implementation Challengesmentioning

confidence: 99%

“…Recent studies using advanced informatics and data mining tools such as machine learning have demonstrated the potential of such approaches (Baker et al, 2019;James et al, 2020;Robertson et al, 2022;Seo et al, 2022;Tan et al, 2020;Zaunseder et al, 2022).…”

Section: Technical and Implementation Challengesmentioning

confidence: 99%

Newborn screening for neurodevelopmental diseases: Are we there yet?

Chung

Berg

Botkin

et al. 2022

American J of Med Genetics Pt C

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“…Furthermore, if exome testing was performed for diagnostic purposes, this could simultaneously (or be reanalyzed to) identify pharmacogenetic loci. 46 Our study has a number of limitations. The findings of this analysis are considered preliminary until further evidence from high-quality clinical studies are available, particularly for seizure control and health utilities under genetically guided therapy that were important parameters in our model.…”

Section: Discussionmentioning

confidence: 93%

“…The costs of testing could be decreased dramatically (e.g., with polymerase chain reaction) when pharmacogenomic loci are known and validated. Furthermore, if exome testing was performed for diagnostic purposes, this could simultaneously (or be reanalyzed to) identify pharmacogenetic loci 46 …”

Section: Discussionmentioning

confidence: 99%

Early cost–utility analysis of genetically guided therapy for patients with drug‐resistant epilepsy

et al. 2022

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Objective Existing gene panels were developed to understand the etiology of epilepsy, and further benefits will arise from an effective pharmacogenomics panel for personalizing therapy and achieving seizure control. Our study assessed the cost‐effectiveness of a pharmacogenomics panel for patients with drug‐resistant epilepsy, compared with usual care. Methods A cost–utility analysis was employed using a discrete event simulation model. The microsimulation model aggregated the costs and benefits of genetically guided treatment versus usual care for 5000 simulated patients. The 10‐year model combined data from various sources including genomic databases on prevalence of variants, population‐level pharmaceutical claims on antiseizure medications, published long‐term therapy retention rates, patient‐level cost data, and systematic reviews. Incremental cost per quality‐adjusted life‐year (QALY) gained was computed. Deterministic and probabilistic sensitivity analyses were undertaken to address uncertainty in model parameters. Results The mean cost of the genetically guided treatment option was AU$98 199 compared with AU$95 386 for usual care. Corresponding mean QALYs were 4.67 compared with 4.28 for genetically guided and usual care strategies, respectively. The incremental cost per QALY gained was AU$7381. In probabilistic sensitivity analyses, the incremental cost per QALY gained was AU$6321 (95% uncertainty interval = AU$3604–AU$9621), with a 100% likelihood of being cost‐effective in the Australian health care system. The most influential drivers of the findings were the monthly health care costs associated with reduced seizures, costs when seizures continued, and the quality‐of‐life estimates under genetically guided and usual care strategies. Significance This early economic evaluation of a pharmacogenomics panel to guide treatment for drug‐resistant epilepsy could potentially be cost‐effective in the Australian health care system. Clinical trial evidence is necessary to confirm these findings.

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“…Many molecularly undiagnosed patients (especially those with a characteristic clinical or biochemical phenotype and a negative trio WES) could benefit from progression to WGS. Additionally, re-analysis of WGS data for pathogenic variants ( Costain et al, 2018 ; Deignan et al, 2019 ; Robertson et al, 2022 ) in such cases may be beneficial.…”

Section: Discussionmentioning

confidence: 99%

Intronic variants in inborn errors of metabolism: Beyond the exome

et al. 2022

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Non-coding regions are areas of the genome that do not directly encode protein and were initially thought to be of little biological relevance. However, subsequent identification of pathogenic variants in these regions indicates there are exceptions to this assertion. With the increasing availability of next generation sequencing, variants in non-coding regions are often considered when no causative exonic changes have been identified. There is still a lack of understanding of normal human variation in non-coding areas. As a result, potentially pathogenic non-coding variants are initially classified as variants of uncertain significance or are even overlooked during genomic analysis. In most cases where the phenotype is non-specific, clinical suspicion is not sufficient to warrant further exploration of these changes, partly due to the magnitude of non-coding variants identified. In contrast, inborn errors of metabolism (IEMs) are one group of genetic disorders where there is often high phenotypic specificity. The clinical and biochemical features seen often result in a narrow list of diagnostic possibilities. In this context, there have been numerous cases in which suspicion of a particular IEM led to the discovery of a variant in a non-coding region. We present four patients with IEMs where the molecular aetiology was identified within non-coding regions. Confirmation of the molecular diagnosis is often aided by the clinical and biochemical specificity associated with IEMs. Whilst the clinical severity associated with a non-coding variant can be difficult to predict, obtaining a molecular diagnosis is crucial as it ends diagnostic odysseys and assists in management.

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Re-analysis of genomic data: An overview of the mechanisms and complexities of clinical adoption

Cited by 34 publications

References 72 publications

Newborn screening for neurodevelopmental diseases: Are we there yet?

Newborn screening for neurodevelopmental diseases: Are we there yet?

Early cost–utility analysis of genetically guided therapy for patients with drug‐resistant epilepsy

Intronic variants in inborn errors of metabolism: Beyond the exome

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