Sensitivity of noninvasive prenatal detection of fetal aneuploidy from maternal plasma using shotgun sequencing is limited only by counting statistics

We recently demonstrated noninvasive detection of fetal aneuploidy by shotgun sequencing cell-free DNA in maternal plasma using next-generation high throughput sequencer. However, GC bias introduced by the sequencer placed a practical limit on the sensitivity of aneuploidy detection. In this study,...

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Bibliographic Details
Published in:PloS one 2010-05, Vol.5 (5), p.e10439-e10439
Main Authors: Fan, H Christina, Quake, Stephen R
Format: Article
Language:English
Subjects:
Aneuploidy
Base Composition - genetics
Bias
Bioengineering
Chromosomes
Deoxyribonucleic acid
DNA
DNA sequencing
Female
Fetus - metabolism
Fetuses
Gene sequencing
Genetic disorders
Genetic engineering
Genetics and Genomics/Bioinformatics
Genetics and Genomics/Medical Genetics
Genomes
Humans
Models, Statistical
Nucleotide sequence
Obstetrics/Pregnancy
Plasma
Plasmas (physics)
Poisson Distribution
Pregnancy
Pregnant women
Prenatal development
Prenatal Diagnosis
Sensitivity
Sequence Analysis, DNA - methods
Statistics
Studies
Citations: Items that cite this one
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Summary:We recently demonstrated noninvasive detection of fetal aneuploidy by shotgun sequencing cell-free DNA in maternal plasma using next-generation high throughput sequencer. However, GC bias introduced by the sequencer placed a practical limit on the sensitivity of aneuploidy detection. In this study, we describe a method to computationally remove GC bias in short read sequencing data by applying weight to each sequenced read based on local genomic GC content. We show that sensitivity is limited only by counting statistics and that sensitivity can be increased to arbitrary precision in sample containing arbitrarily small fraction of fetal DNA simply by sequencing more DNA molecules. High throughput shotgun sequencing of maternal plasma DNA should therefore enable noninvasive diagnosis of any type of fetal aneuploidy.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0010439