ArticleThe Journal of molecular diagnostics : JMD2019
A Rigorous Interlaboratory Examination of the Need to Confirm Next-Generation Sequencing-Detected Variants with an Orthogonal Method in Clinical Genetic Testing.
Article in The Journal of molecular diagnostics : JMD, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
51 citing papers in PubMed.
- Reproductive Genetic Carrier Screening in Romania: A Couple-Based Study of Pathogenic Molecular Variants.International journal of molecular sciences · 2026Article
- A rare upstream regulatory region mutation in APC presenting as classical familial adenomatous polyposis: A case report and literature review.Experimental and therapeutic medicine · 2026Article
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- Genetic analysis of neurodegenerative diseases.The Journal of clinical investigation · 2026Review
- Paired Exome-Based Comprehensive Genomic Profiling and Germline Genetic Testing for Unselected Patients With Colorectal Cancer in a Multicenter Prospective Study.Gastro hep advances · 2026Article
- The Landscape of Genetic Variation and Disease Risk in Romania: A Single-Center Study of Autosomal Recessive Carrier Frequencies and Molecular Variants.International journal of molecular sciences · 2025Article
- Article
- Analysis ofCirculation. Genomic and precision medicine · 2025Article
- Kabuki and CHARGE syndromes: overlapping symptoms and diagnostic challenges.Einstein (Sao Paulo, Brazil) · 2025Article
- Pathomechanisms of Monoallelic variants in TTN causing skeletal muscle disease.Human molecular genetics · 2024Article
- StratoMod: predicting sequencing and variant calling errors with interpretable machine learning.Communications biology · 2024Article
- Targeted next-generation sequencing analysis in Italian patients with keratoconus.Eye (London, England) · 2024Article
- Disparate Rates of Germline Variants in Cancer Predisposition Genes in African American/Black Compared With Non-Hispanic White Individuals Between 2015 and 2022.JCO precision oncology · 2024Article
- Unexpected Genetic Twists in Patients with Cardiac Devices.Journal of clinical medicine · 2024Article
- The impact of inversions across 33,924 families with rare disease from a national genome sequencing project.American journal of human genetics · 2024Article
- Article
- Genetic determinants of global developmental delay and intellectual disability in Ukrainian children.Journal of neurodevelopmental disorders · 2024Article
- Recommendations for Uniform Variant Calling of SARS-CoV-2 Genome Sequence across Bioinformatic Workflows.Viruses · 2024Article
- Genetic Characterization of Dilated Cardiomyopathy in Romanian Adult Patients.International journal of molecular sciences · 2024Article
- Mutational analysis of theFrontiers in medicine · 2024Article
Corrections and comments
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Authors and funding
10 authors.
Funding
Abstract
Orthogonal confirmation of next-generation sequencing (NGS)-detected germline variants is standard practice, although published studies have suggested that confirmation of the highest-quality calls may not always be necessary. The key question is how laboratories can establish criteria that consistently identify those NGS calls that require confirmation. Most prior studies addressing this question have had limitations: they have been generally of small scale, omitted statistical justification, and explored limited aspects of underlying data. The rigorous definition of criteria that separate high-accuracy NGS calls from those that may or may not be true remains a crucial issue. We analyzed five reference samples and over 80,000 patient specimens from two laboratories. Quality metrics were examined for approximately 200,000 NGS calls with orthogonal data, including 1662 false positives. A classification algorithm used these data to identify a battery of criteria that flag 100% of false positives as requiring confirmation (CI lower bound, 98.5% to 99.8%, depending on variant type) while minimizing the number of flagged true positives. These criteria identify false positives that the previously published criteria miss. Sampling analysis showed that smaller data sets resulted in less effective criteria. Our methodology for determining test- and laboratory-specific criteria can be generalized into a practical approach that can be used by laboratories to reduce the cost and time burdens of confirmation without affecting clinical accuracy.
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