2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Optimized whole genome screening: the impact of variant calling accuracy improvements on curation burden

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The document discusses the impact of variant calling accuracy improvements on the curation burden in optimized whole-genome-based screening. The study focuses on the analysis of representative gene lists for newborn screening and carrier screening panels using different versions of the DRAGEN software. The gene lists are intersected with NISTv4.2.1 and NISTv0.6 samples to generate false positive/false negative data and compare recall and precision for different DRAGEN versions.<br /><br />The results show that there are improvements in sensitivity, false positive/negative rates, recall, and precision for variant calling across different DRAGEN versions. The addition of the multi-genome reference in version 3.7.5 and updates in subsequent versions contribute to decreases in false positive/negative rates. The study also explores the overlap of genes in the screening panels with targeted callers and expansion hunter software.<br /><br />Additionally, the report describes the generation of a reportable range for single nucleotide variants (SNVs) and small insertions/deletions (indels) using machine learning. An artificial intelligence model trained on 39 replicates of 3 samples categorizes regions of the genome as high or low confidence calls, which is then intersected with the screening panels.<br /><br />The authors conclude that there are continuous improvements in variant calling accuracy with DRAGEN, and the addition of targeted callers and expansion hunter allows for the inclusion of "difficult" genes in screening panels. The gene lists, copy number variant calls, and the reportable range for DRAGEN 4.0.3 are provided as supplementary data.<br /><br />Overall, the study highlights the importance of accurate variant calling in genomic screening and the impact of software improvements on analysis workflows.

Asset Subtitle

Presenting Author - Kristen Sund, PhD, MS; Co-Author - Samuel P. Strom, PhD; Co-Author - Pauline Fujita, PhD; Co-Author - Batsal Devkota, PhD; Co-Author - Jennifer Shah, PhD; Co-Author - Nathan Berkowitz, PhD; Co-Author - LeAnne Lovato, PhD; Co-Author - Elliott H. Margulies, PhD; Co-Author - Mitch Bekritsky, PhD;

Meta Tag

Biochemical genetics

Exome sequencing

Gene Localization

Gene Mapping

Genome sequencing

Genomic Methodologies

Metabolic Disorder

NextGen Sequencing

Sequencing

Variant Detection

Co-Author Samuel P. Strom, PhD

Co-Author Pauline Fujita, PhD

Co-Author Batsal Devkota, PhD

Co-Author Jennifer Shah, PhD

Co-Author Nathan Berkowitz, PhD

Co-Author LeAnne Lovato, PhD

Co-Author Elliott H. Margulies, PhD

Co-Author Mitch Bekritsky, PhD

Presenting Author Kristen Sund, PhD, MS

Keywords

variant calling accuracy

curation burden

whole-genome-based screening

gene lists

DRAGEN software

NISTv4.2.1

false positive/negative rates

recall

precision

targeted callers