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High levels of sample-to-sample variation confound data analysis for non-invasive prenatal screening of fetal microdeletions

Chu, T and Yeniterzi, S and Yatsenko, SA and Dunkel, M and Shaw, PA and Bunce, KD and Peters, DG (2016) High levels of sample-to-sample variation confound data analysis for non-invasive prenatal screening of fetal microdeletions. PLoS ONE, 11 (6).

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Abstract

© 2016 Chu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Our goal was to test the hypothesis that inter-individual genomic copy number variation in control samples is a confounding factor in the non-invasive prenatal detection of fetal microdeletions via the sequence-based analysis of maternal plasma DNA. The database of genomic variants (DGV) was used to determine the "Genomic Variants Frequency" (GVF) for each 50kb region in the human genome. Whole genome sequencing of fifteen karyotypically normal maternal plasma and six CVS DNA controls samples was performed. The coefficient of variation of relative read counts (cv.RTC) for these samples was determined for each 50kb region. Maternal plasma from two pregnancies affected with a chromosome 5p microdeletion was also sequenced, and analyzed using the GCREM algorithm. We found strong correlation between high variance in read counts and GVF amongst controls. Consequently we were unable to confirm the presence of the microdeletion via sequencing of maternal plasma samples obtained from two sequential affected pregnancies. Caution should be exercised when performing NIPT for microdeletions. It is vital to develop our understanding of the factors that impact the sensitivity and specificity of these approaches. In particular, benign copy number variation amongst controls is a major confounder, and their effects should be corrected bioinformatically.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Chu, Ttic19@pitt.eduTIC19
Yeniterzi, S
Yatsenko, SAsay17@pitt.eduSAY17
Dunkel, M
Shaw, PA
Bunce, KD
Peters, DGdgp6@pitt.eduDGP6
Centers: Other Centers, Institutes, or Units > Magee-Women's Research Institute
Date: 1 June 2016
Date Type: Publication
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Journal or Publication Title: PLoS ONE
Volume: 11
Number: 6
DOI or Unique Handle: 10.1371/journal.pone.0153182
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Obstetrics, Gynecology, and Reproductive Sciences
Refereed: Yes
Date Deposited: 22 Dec 2016 16:03
Last Modified: 23 Jun 2018 11:55
URI: http://d-scholarship.pitt.edu/id/eprint/28225

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