Clinical investigational studies for validation of a next-generation sequencing<i>in vitro</i>diagnostic device for cystic fibrosis testing

Grosu, Daniel S.; Hague, Lynda; Chelliserry, Manjula; Kruglyak, Kristina M.; Lenta, Ross; Klotzle, Brandy; San, Jonathan; Goldstein, Wendy M; Moturi, Sharmili; Devers, Patricia; Woolworth, Julie A.; Peters, Eric; Elashoff, Barbara; Stoerker, Jay; Wolff, Daynna J.; Friedman, Kenneth J.; Highsmith, W. Edward; Lin, Erick; Ong, Frank S

doi:10.1586/14737159.2014.916618

Cited by 24 publications

(17 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[5][6][7][8][9] A number of laboratories have utilized these standards to establish analytical performance metrics for their clinical tests. [10][11][12][13] Validations for targeted disease panels typically include comparison of variant calls to a reference standard, and/or retesting biological specimens containing known pathogenic alterations. [14][15][16] In contrast, validation of WES is typically performed by a methods-based validation approach, which includes comparison of variant calls to reference datasets of genome sequences.…”

Section: Introductionmentioning

confidence: 99%

Novel findings with reassessment of exome data: implications for validation testing and interpretation of genomic data

Gibson

Nesbitt

Cao

et al. 2018

Genetics in Medicine

View full text Add to dashboard Cite

PurposeThe objective of this study was to assess the ability of our laboratory's exome-sequencing test to detect known and novel sequence variants and identify the critical factors influencing the interpretation of a clinical exome test.MethodsWe developed a two-tiered validation strategy: (i) a method-based approach that assessed the ability of our exome test to detect known variants using a reference HapMap sample, and (ii) an interpretation-based approach that assessed our relative ability to identify and interpret disease-causing variants, by analyzing and comparing the results of 19 randomly selected patients previously tested by external laboratories.ResultsWe demonstrate that this approach is reproducible with >99% analytical sensitivity and specificity for single-nucleotide variants and indels <10 bp. Our findings were concordant with the reference laboratories in 84% of cases. A new molecular diagnosis was applied to three cases, including discovery of two novel candidate genes.ConclusionWe provide an assessment of critical areas that influence interpretation of an exome test, including comprehensive phenotype capture, assessment of clinical overlap, availability of parental data, and the addressing of limitations in database updates. These results can be used to inform improvements in phenotype-driven interpretation of medical exomes in clinical and research settings.

show abstract

Section: Introductionmentioning

confidence: 99%

Novel findings with reassessment of exome data: implications for validation testing and interpretation of genomic data

Gibson

Nesbitt

Cao

et al. 2018

Genetics in Medicine

View full text Add to dashboard Cite

show abstract

“…In this tutorial we discussed multiple applications for NGS in clinical oncology including driver identification, detection of resistance mechanisms, quantification of mutational burden, evaluation of tumor gene expression, and diagnosis of germline mutations. The FDA recently approved the Illumina MiSeqDx platform for diagnosis of cystic fibrosis associated mutations, paving the way for approval of NGS‐based tests as CDx assays for oncology indications. In the near term, comprehensive testing of actionable mutations will be accomplished via NGS‐based CDx assays and used to match patients with appropriate targeted therapies.…”

Section: Resultsmentioning

confidence: 99%

“…NGS is already broadly utilized for the detection of germline mutations that cause hereditary illnesses and influence disease risk (e.g., cystic fibrosis) . In the oncology setting, this is particularly useful when sequencing large genes like BRCA1, BRCA2 , and PTEN , or when multiple genes must be tested in the same patient.…”

Section: Applications Of Ngs In Clinical Trials and Clinical Practicementioning

confidence: 99%

The Role of Next‐Generation Sequencing in Enabling Personalized Oncology Therapy

Cummings¹,

Peters²,

Lacroix

et al. 2016

Clinical Translational Sci

View full text Add to dashboard Cite

“…13 The percentage of diagnoses and the rates of new variant detection are remarkably high in existing studies. [14][15][16][17][18] In the comprehensive study of Grosu et al with two different CFTR kits, the success rate of the tests was found to be between 99.7 and 100.0% compared with Sanger sequencing, which was accepted as the reference method. 14 Apparently, this variant (c.4096A > T, I1366F) was mentioned in two previous studies.…”

Section: Discussionmentioning

confidence: 99%

A Novel Pathogenic Variant of the CFTR Gene in a Patient with Cystic Fibrosis Phenotype—c.4096A > T

et al. 2019

View full text Add to dashboard Cite

Cystic fibrosis is a chronic multisystemic disease originating from functional alterations in CFTR (cystic fibrosis transmembrane conductance regulator) protein. To date, more than 300 pathogenic variants have been described in the literature. However, the diagnosis of CF, which was thought to become easier after the CFTR gene was identified, became more complicated due to the enormous amount of variations. In this study, we present a patient whose clinical findings were consistent with cystic fibrosis (CF) and showed a homozygous missense change that is not previously reported in the CFTR gene as pathogenic. In the next-generation sequencing analysis, homozygous c.4096A > T single-nucleotide exchange (I1366F [p.Ile1366Phe], missense) was shown in both alleles of the patient' CFTR gene. According to our database analysis, this variant has not yet been previously reported (VarSome, ClinVar, MutationTaster, Ensembl, dbSNP, PubMed). We do consider the change as pathogenic since the patient's findings were compatible with CF and the data analysis was in favor of pathogenicity. The most recent consensus report published in 2017 emphasized the importance of CFTR gene analysis, and this study emphasizes the difficulties of associating CFTR gene variations with a clinical picture and constitutes a new data on the genotype–phenotype correlation of CFTR variants. Also, considering the frequency of CF (according to World Health Organization data, every 1 out of 2,000–3,000 infants is born with CF in European Union countries and every 1 out of 3,500 in the United States) as well as the increasing rate of molecular studies performed on CF patients worldwide, reporting novel variation has an additional value.

show abstract

Clinical investigational studies for validation of a next-generation sequencingin vitrodiagnostic device for cystic fibrosis testing

Cited by 24 publications

References 41 publications

Novel findings with reassessment of exome data: implications for validation testing and interpretation of genomic data

Novel findings with reassessment of exome data: implications for validation testing and interpretation of genomic data

The Role of Next‐Generation Sequencing in Enabling Personalized Oncology Therapy

A Novel Pathogenic Variant of the CFTR Gene in a Patient with Cystic Fibrosis Phenotype—c.4096A > T

Contact Info

Product

Resources

About