Meta-analysis of the diagnostic and clinical utility of genome and exome sequencing and chromosomal microarray in children with suspected genetic diseases

Clark, Michelle M.; Stark, Zornitza; Farnaes, Lauge; Tan, Tiong Yang; White, Susan; Dimmock, David; Kingsmore, Stephen F.

doi:10.1038/s41525-018-0053-8

Cited by 485 publications

(485 citation statements)

References 70 publications

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“…A more recent metaanalysis suggested that "among studies published in 2017, the diagnostic utility of WGS was significantly greater than CMA." The authors also noted that "the diagnostic utility of WGS and WES [whole-exome sequencing] were not significantly different" (Clark et al 2018). Whole-exome sequencing, in contrast to whole-genome sequencing, focuses specifically on the ~1.5-2% of genes that code for proteins.…”

Section: Genetic and Genomic Sequencing Technologiesmentioning

confidence: 99%

“What if There's Something Wrong with Her?”‐How Biomedical Technologies Contribute to Epistemic Injustice in Healthcare

Reynolds¹

2020

The Southern J of Philosophy

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While there is a steadily growing literature on epistemic injustice in healthcare, there are few discussions of the role that biomedical technologies play in harming patients in their capacity as knowers. Through an analysis of newborn and pediatric genetic and genomic sequencing technologies (GSTs), I argue that biomedical technologies can lead to epistemic injustice through two primary pathways: epistemic capture and value partitioning. I close by discussing the larger ethical and political context of critical analyses of GSTs and their broader implications for just and equitable healthcare delivery.

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Section: Genetic and Genomic Sequencing Technologiesmentioning

confidence: 99%

“What if There's Something Wrong with Her?”‐How Biomedical Technologies Contribute to Epistemic Injustice in Healthcare

Reynolds¹

2020

The Southern J of Philosophy

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“…The introduction of genomic technologies into medicine has already had a significant impact on medical care 1. Cancer patients routinely undergo genomic analysis of their tumors to identify potential therapeutic targets;2 unexpected prenatal ultrasound findings lead to microarray testing of the fetal genome;3 and genome sequencing is the diagnostic tool of choice for newborns with serious, otherwise undiagnosable conditions 4. Given the extensive research now under way applying genomic technologies to predictive and diagnostic testing for a multitude of conditions, the role of genomics in medicine is likely to continue its exponential growth.…”

Section: Introductionmentioning

confidence: 99%

On What We Have Learned and Still Need to Learn about the Psychosocial Impacts of Genetic Testing

Parens¹,

Appelbaum²

2019

Hastings Center Report

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Since the start of the program to investigate the ethical, legal, and social implications (ELSI) of the Human Genome Project in 1990, many ELSI scholars have maintained that genetic testing should be used with caution because of the potential for negative psychosocial effects associated with receiving genetic information. More recently, though, some ELSI scholars have produced evidence suggesting that the original ELSI concerns were unfounded, exaggerated, or, at a minimum, misdirected. At least in the contexts that have been most studied, large negative impacts have not been found in the vast majority of people studied. What might explain the discrepancy between the original hypothesized outcomes and the growing impression that large negative effects appear to be few and far between? And if the original predictions of large negative psychosocial effects were simply wrong, is it time for ELSI researchers to move on? Should genetic testing be routinized, and would it be appropriate to relax or abandon the practice of engaging patients in a process of detailed informed consent before they receive genetic information? To confront those questions, we convened a conference entitled “Looking for the Psychosocial Impacts of Genomic Information” to review what is known about the negative impacts of genetic information on a variety of populations and in multiple medical and social contexts, to explore the implications of the findings, and to consider whether future research might benefit from different methods than have been used to date.

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“…Next‐generation sequencing (NGS) is a disruptive technology that provides more comprehensive tests and several‐fold higher diagnostic yields than conventional methods for diagnosing genetic disorders. Looking to the future, deploying NGS‐based whole‐genome sequencing (WGS) as a first tier diagnostic test has the potential to revolutionize the diagnosis of genetic disorders, given that the diagnostic yield of WGS for children suspected of a Mendelian disorder currently averages over 40% and continues to increase with time (Clark et al, ; Scocchia et al, ). Nonetheless, the majority of patients who now undergo WGS after first‐line genomic testing failed to yield an answer remain without a molecular diagnosis.…”

Section: Introductionmentioning

confidence: 99%

CAGI SickKids challenges: Assessment of phenotype and variant predictions derived from clinical and genomic data of children with undiagnosed diseases

et al. 2019

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Whole‐genome sequencing (WGS) holds great potential as a diagnostic test. However, the majority of patients currently undergoing WGS lack a molecular diagnosis, largely due to the vast number of undiscovered disease genes and our inability to assess the pathogenicity of most genomic variants. The CAGI SickKids challenges attempted to address this knowledge gap by assessing state‐of‐the‐art methods for clinical phenotype prediction from genomes. CAGI4 and CAGI5 participants were provided with WGS data and clinical descriptions of 25 and 24 undiagnosed patients from the SickKids Genome Clinic Project, respectively. Predictors were asked to identify primary and secondary causal variants. In addition, for CAGI5, groups had to match each genome to one of three disorder categories (neurologic, ophthalmologic, and connective), and separately to each patient. The performance of matching genomes to categories was no better than random but two groups performed significantly better than chance in matching genomes to patients. Two of the ten variants proposed by two groups in CAGI4 were deemed to be diagnostic, and several proposed pathogenic variants in CAGI5 are good candidates for phenotype expansion. We discuss implications for improving in silico assessment of genomic variants and identifying new disease genes.

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Meta-analysis of the diagnostic and clinical utility of genome and exome sequencing and chromosomal microarray in children with suspected genetic diseases

Cited by 485 publications

References 70 publications

“What if There's Something Wrong with Her?”‐How Biomedical Technologies Contribute to Epistemic Injustice in Healthcare

“What if There's Something Wrong with Her?”‐How Biomedical Technologies Contribute to Epistemic Injustice in Healthcare

On What We Have Learned and Still Need to Learn about the Psychosocial Impacts of Genetic Testing

CAGI SickKids challenges: Assessment of phenotype and variant predictions derived from clinical and genomic data of children with undiagnosed diseases

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