Bohu Pan, US Food and Drug AdministrationFollow
Luyao Ren, Fudan University
Vitor Onuchic, Illumina Inc.
Meijian Guan, SAS Institute Inc.
Rebecca Kusko, Immuneering Corporation
Steve Bruinsma, Illumina Inc.
Len Trigg, Real Time Genomics
Andreas Scherer, University of Helsinki
Baitang Ning, US Food and Drug Administration
Chaoyang Zhang, University of Southern MississippiFollow
Christine Glidewell-Kenney, Illumina Inc.
Chunlin Xiao, National Institutes of Health
Eric Donaldson, Food and Drug Administration
Fritz J. Sedlazeck, Baylor College of Medicine
Gary Schroth, Illumina Inc.
Gokhan Yavas, US Food and Drug Administration
Haiying Grunenwald, Illumina Inc.
Haodong Chen, Sentieon Inc.
Heather Meinholz, Illumina Inc.
Joe Meehan, US Food and Drug Administration
Jing Wang, National Institute of Metrology
JIngcheng Yang, Fudan University
Jonathan Foox, Weill Cornell Medicine
Jun Shang, Fudan University
Kelci Miclaus, SAS Institute Inc.
Lianhua Dong, National Institute of Metrology
Leming Shi, Fudan University
Marghoob Mohiyuddin, Roche Sequencing Solutions
Mehdi Pirooznia, National Institutes of HealthFollow
Ping Gong, U.S. Army Engineer Research and Development CenterFollow
Rooz Golshani, Illumina Inc.
Russ Wolfinger, SAS Institute Inc.
Samir Lababidi, US Food and Drug Administration
Sayed Mohammed Ebrahim Sahraeian, Roche Sequencing Solutions
Steve Sherry, National Library of Medicine
Tao Han, US Food and Drug Administration
Tieliu Shi, East China Normal UniversityFollow
Wanwan Hou, Fudan University
Weigong Ge, US Food and Drug Administration
Wen Zou, US Food and Drug Administration
Wenjing Guo, Us Food and Drug Administration
Wenjun Bao, SAS Institute Inc.
Wenzhong Xiao, Stanford University
Xiaohui Fan, Zhejiang University
Yoichi Gondo, Tokai University
Ying Yu, Fudan University
Yongmei Zhao, Frederick national Laboratory for Cancer Research
Zhenqiang Su, Takeda Pharmaceuticals
Zhichao Liu, US Food and Drug Administration
Weida Tong, US Food and Drug Administration
Wenming Xiao, US Food and Drug Administration
Justin M. Zook, National Institute of Standards and TechnologyFollow
Yuanting Zeng, Fudan UniversityFollow
Huixiao Hong, US Food and Drug AdministrationFollow

Document Type


Publication Date



Computing Sciences and Computer Engineering


Background: Reproducible detection of inherited variants with whole genome sequencing (WGS) is vital for the implementation of precision medicine and is a complicated process in which each step affects variant call quality. Systematically assessing reproducibility of inherited variants with WGS and impact of each step in the process is needed for understanding and improving quality of inherited variants from WGS.

Results: To dissect the impact of factors involved in detection of inherited variants with WGS, we sequence triplicates of eight DNA samples representing two populations on three short-read sequencing platforms using three library kits in six labs and call variants with 56 combinations of aligners and callers. We find that bioinformatics pipelines (callers and aligners) have a larger impact on variant reproducibility than WGS platform or library preparation. Single-nucleotide variants (SNVs), particularly outside difficult-to-map regions, are more reproducible than small insertions and deletions (indels), which are least reproducible when > 5 bp. Increasing sequencing coverage improves indel reproducibility but has limited impact on SNVs above 30×.

Conclusions: Our findings highlight sources of variability in variant detection and the need for improvement of bioinformatics pipelines in the era of precision medicine with WGS.

Publication Title

Genome Biology



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