Combining count- and length-based <i>z</i>-scores leads to improved predictions in non-invasive prenatal testing

Budiš, Jaroslav; Gazdarica, Juraj; Radvánszky, Ján; Szücs, Gábor; Kucharík, Marcel; Striešková, Lucia; Gazdaricova, Iveta; Haršányová, Mária; Ďuriš, František; Minárik, Gabriel; Sekelska, Martina; Nagy, Bálint; Turña, Ján; Szemes, Tomáš

doi:10.1093/bioinformatics/bty806

Cited by 14 publications

(9 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In our previous study, we described non-invasive prenatal test (NIPT) based on analysis of plasma DNA from pregnant women [11,12,13]. This test uses low-coverage massively parallel sequencing of whole-genome for detection of CNV aberrations [14].…”

Section: Introductionmentioning

confidence: 99%

Identification of Structural Variation from NGS-Based Non-Invasive Prenatal Testing

Pös

Budiš

Kubiritova

et al. 2019

IJMS

Self Cite

View full text Add to dashboard Cite

Copy number variants (CNVs) are an important type of human genome variation, which play a significant role in evolution contribute to population diversity and human genetic diseases. In recent years, next generation sequencing has become a valuable tool for clinical diagnostics and to provide sensitive and accurate approaches for detecting CNVs. In our previous work, we described a non-invasive prenatal test (NIPT) based on low-coverage massively parallel whole-genome sequencing of total plasma DNA for detection of CNV aberrations ≥600 kbp. We reanalyzed NIPT genomic data from 5018 patients to evaluate CNV aberrations in the Slovak population. Our analysis of autosomal chromosomes identified 225 maternal CNVs (47 deletions; 178 duplications) ranging from 600 to 7820 kbp. According to the ClinVar database, 137 CNVs (60.89%) were fully overlapping with previously annotated variants, 66 CNVs (29.33%) were in partial overlap, and 22 CNVs (9.78%) did not overlap with any previously described variant. Identified variants were further classified with the AnnotSV method. In summary, we identified 129 likely benign variants, 13 variants of uncertain significance, and 83 likely pathogenic variants. In this study, we use NIPT as a valuable source of population specific data. Our results suggest the utility of genomic data from commercial CNV analysis test as background for a population study.

show abstract

Section: Introductionmentioning

confidence: 99%

Identification of Structural Variation from NGS-Based Non-Invasive Prenatal Testing

Pös

Budiš

Kubiritova

et al. 2019

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…The first part of analysis was performed as described previously in [15,16,17]. Sequencing reads were aligned to the human reference genome (hg19) using Bowtie 2 algorithm [18].…”

Section: Methodsmentioning

confidence: 99%

Adaptable Model Parameters in Non-Invasive Prenatal Testing Lead to More Stable Predictions

Gazdarica

Budiš

Ďuriš

et al. 2019

IJMS

View full text Add to dashboard Cite

Recent advances in massively parallel shotgun sequencing opened up new options for affordable non-invasive prenatal testing (NIPT) for fetus aneuploidy from DNA material extracted from maternal plasma. Tests typically compare chromosomal distributions of a tested sample with a control set of healthy samples with unaffected fetuses. Deviations above certain threshold levels are concluded as positive findings. The main problem with this approach is that the variance of the control set is dependent on the number of sequenced fragments. The higher the amount, the more precise the estimation of actual chromosomal proportions is. Testing a sample with a highly different number of sequenced reads as used in training may thus lead to over- or under-estimation of their variance, and so lead to false predictions. We propose the calculation of a variance for each tested sample adaptively, based on the actual number of its sequenced fragments. We demonstrate how it leads to more stable predictions, mainly in real-world diagnostics with the highly divergent inter-sample coverage.

show abstract

“…A source of such uninformative results is the nature of the statistical testing. If the standard cutoff threshold for the reliable conclusion of healthy samples is a z-score of 2.5, the chance that a healthy sample would achieve a greater z-score is estimated to be around 1.86% 33 . Also, biological reasons such as maternal malignancy, fetoplacental mosaicism, or non-identical vanishing twins may contribute to incorrect predictions of the fetal condition 34– 36 .…”

Section: Cell-free Fetal Dna–based Approachmentioning

confidence: 99%

“…Downstream analysis of cfDNA requires bioinformatic algorithms, many of which are based on detection and quantification of imbalances in allelic count, regional genomic representation, or size distribution (or a combination of these) 50 . Moreover, with the in silico bioinformatic approach, it is possible to significantly increase the accuracy and specificity of genetic tests without additional investment for labware 33, 51 . This highlights the importance and potential of bioinformatics in current NIPT.…”

Section: Bioinformaticsmentioning

confidence: 99%

“…There is also an emerging field of methods that detect structural aberrations on the basis of diversions of fragment length distributions 15 . Additionally, count-based and length-based scores may be combined to achieve better separation between euploid and aneuploid samples 58, 59 and reduction of false-positive and uninformative predictions 33, 60 .…”

Section: Bioinformaticsmentioning

confidence: 99%

See 1 more Smart Citation

Recent trends in prenatal genetic screening and testing

2019

View full text Add to dashboard Cite

Prenatal testing in recent years has been moving toward non-invasive methods to determine the fetal risk for genetic disorders without incurring the risk of miscarriage. Rapid progress of modern high-throughput molecular technologies along with the discovery of cell-free fetal DNA in maternal plasma led to novel screening methods for fetal chromosomal aneuploidies. Such tests are referred to as non-invasive prenatal tests (NIPTs), non-invasive prenatal screening, or prenatal cell-free DNA screening. Owing to many advantages, the adoption of NIPT in routine clinical practice was very rapid and global. As an example, NIPT has recently become a standard screening procedure for all pregnant women in the Netherlands. On the other hand, invasive sampling procedures remain important, especially for their diagnostic value in the confirmation of NIPT-positive findings and the detection of Mendelian disorders. In this review, we focus on current trends in the field of NIPT and discuss their benefits, drawbacks, and consequences in regard to routine diagnostics.

show abstract

Combining count- and length-based z-scores leads to improved predictions in non-invasive prenatal testing

Abstract: Supplementary materials are available at Bioinformatics online.

Cited by 14 publications

References 45 publications

Identification of Structural Variation from NGS-Based Non-Invasive Prenatal Testing

Identification of Structural Variation from NGS-Based Non-Invasive Prenatal Testing

Adaptable Model Parameters in Non-Invasive Prenatal Testing Lead to More Stable Predictions

Recent trends in prenatal genetic screening and testing

Contact Info

Product

Resources

About