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An open resource for accurately benchmarking small variant and reference calls

Justin M. Zook
Jennifer McDaniel
Nathan D. Olson
Justin M. Wagner
Hemang Parikh
Haynes Heaton
Sean A. Irvine
Len Trigg
Rebecca Truty
Francisco M. De La Vega
Chunlin Xiao
Stephen Sherry
Marc Salit
Nature Biotechnology, vol. 37 (2019), 561–566


Benchmark small variant calls are required for developing, optimizing and assessing the performance of sequencing and bioinformatics methods. Here, as part of the Genome in a Bottle (GIAB) Consortium, we apply a reproducible, cloud-based pipeline to integrate multiple short- and linked-read sequencing datasets and provide benchmark calls for human genomes. We generate benchmark calls for one previously analyzed GIAB sample, as well as six genomes from the Personal Genome Project. These new genomes have broad, open consent, making this a ‘first of its kind’ resource that is available to the community for multiple downstream applications. We produce 17% more benchmark single nucleotide variations, 176% more indels and 12% larger benchmark regions than previously published GIAB benchmarks. We demonstrate that this benchmark reliably identifies errors in existing callsets and highlight challenges in interpreting performance metrics when using benchmarks that are not perfect or comprehensive. Finally, we identify strengths and weaknesses of callsets by stratifying performance according to variant type and genome context.

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