Systematic evaluation of NIPT aneuploidy detection software tools with clinically validated NIPT samples

Paluoja, Priit; Teder, Hindrek; Ardeshirdavani, Amin; Bayindir, Baran; Vermeesch, Joris Robert; Salumets, Andres; Krjutškov, Kaarel; Palta, Priit

doi:10.1371/journal.pcbi.1009684

Cited by 7 publications

(11 citation statements)

References 21 publications

(48 reference statements)

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“…papers included as base for Additional file 1 : Table S1). A more detailed, scientific unbiased comparison of capabilities of different NIPT-platforms would be critical, as in the literature it is rarely addressed [ 20 ] or done [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

False-positives and false-negatives in non-invasive prenatal testing (NIPT): what can we learn from a meta-analyses on > 750,000 tests?

Liehr

2022

Mol Cytogenet

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Background Non-invasive prenatal testing (NIPT) has had an incomparable triumph in prenatal diagnostics in the last decade. Over 1400 research articles have been published, predominantly praising the advantages of this test. Methods The present study identified among the 1400 papers 24 original and one review paper, which were suited to re-evaluate the efficacy of > 750,000 published NIPT-results. Special attention was given to false-positive and false-negative result-rates. Those were discussed under different aspects—mainly from a patient-perspective. Results A 27: 1 rate of false-positive compared to false-negative NIPT results was found. Besides, according to all reported, real-positive, chromosomally aberrant NIPT cases, 90% of those would have been aborted spontaneously before birth. These findings are here discussed under aspects like (i) How efficient is NIPT compared to first trimester screening? (ii) What are the differences in expectations towards NIPT from specialists and the public? and (iii) There should also be children born suffering from not by NIPT tested chromosomal aberrations; why are those never reported in all available NIPT studies? Conclusions Even though much research has been published on NIPT, unbiased figures concerning NIPT and first trimester screening efficacy are yet not available. While false positive rates of different NIPT tests maybe halfway accurate, reported false-negative rates are most likely too low. The latter is as NIPT-cases with negative results for tested conditions are yet not in detail followed up for cases with other genetic or teratogenic caused disorders. This promotes an image in public, that NIPT is suited to replace all invasive tests, and also to solve the problem of inborn errors in humans, if not now then in near future. Overall, it is worth discussing the usefulness of NIPT in practical clinical application. Particularly, asking for unbiased figures concerning the efficacy of first trimester-screening compared to NIPT, and for really comprehensive data on false-positive and false-negative NIPT results.

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Section: Discussionmentioning

confidence: 99%

False-positives and false-negatives in non-invasive prenatal testing (NIPT): what can we learn from a meta-analyses on > 750,000 tests?

Liehr

2022

Mol Cytogenet

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“…The Assay Software assessed the log likelihood ratio (LLR) for each target chromosome and each sample to provide a determinant of aneuploidy. The LLR is the probability of a sample being affected by the observed coverage versus the probability of a sample being unaffected given the same observed coverage [ 10 ]. Table 1 represents the high-risk of trisomy and high-risk LLR cut-offs of monosomy line for aneuploidies of clinical indication for NIPS by the Illumina VeriSeqTM NIPT assay software.…”

Section: Methodsmentioning

confidence: 99%

Assessment of Maternal Serum Biochemical Attributes and Fetal Ultrasound Scans in First-Trimester Low-Risk Noninvasive Prenatal-Tested Pregnant Women

Keshari¹,

Kumar²,

Kumar³

et al. 2022

Cureus

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Introduction: The first trimester of pregnancy is marked by several important disrupting changes as a result of complex biological upshot of events required for the development of the fetus. These changes in the biological events result in changes in the maternal serum biomarkers that are associated with fetal growth. The aim of the present study was to evaluate the correlation between the maternal blood biochemical determinants such as pregnancy-associated plasma protein-A (PAPP-A) and alpha fetoprotein (AFP) with ultrasound scans during early pregnancy in the first trimester. Methods: The study included 139 women whose fetus was alive between 11±1 weeks of gestation. The risk of fetal chromosomal abnormalities at first trimester was analyzed by the VeriSeq NIPT Solution v2 platform (Illumina, San Diego, CA, USA) for noninvasive prenatal testing (NIPT) assay. The PAPP-A and AFP levels were evaluated by chemiluminescent immunoassays. The levels of PAPP-A and AFP were correlated with the fetal heart rate (HR), crown rump length (CRL), and nuchal translucency (NT) by Pearson’s correlation analysis. Results: The mean age of the participants was 28.35±3.87 years (minimum=21, maximum=35). The mean AFP and PAPP-A levels in the maternal plasma were 14.76±1.04 ng/mL and 4.37±0.86 mIU/ml respectively. The mean FHR, CRL, and NT were 138±7.62 bpm, 59±3.24 mm, and 2.3±0.61 mm respectively. PAPP-A and AFP significantly (p<0.05) correlated with fetal HR, CRL, and NT at 11±1 weeks of gestation. The mean ratio of AFP:PAPP-A in low-risk pregnancies was 3.37. Conclusions: The maternal serum biochemical attributes correlated well with the fetal ultrasound scans. The findings of the present study can prove to be clinically useful for clinical research, obstetrics, and gynaecology, especially for examinations of first-trimester pregnancies.

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“…The copyright holder for this this version posted September 23, 2022. ; https://doi.org/10.1101/2022.09. 20.22280152 doi: medRxiv preprint [9]. Kucharik et al suggested that for MD NIPT assays, sequencing coverage should be 10-20M RPS, with the exact minimum coverage depending on the fetal DNA fraction and target region length [10].…”

Section: (Which Was Not Certified By Peer Review) Preprintmentioning

confidence: 99%

“…Previous low-coverage WGS based NIPT studies have demonstrated that one of the most important factors of successful NIPT analysis is sequencing coverage (depth) [8]. For full chromosome aneuploidy detection, WisecondorX [8], for example, has shown to accurately operate with coverage of 5 million (M) reads per sample (RPS), while some other tools require coverage of 20M RPS to keep the number of false-negative trisomy calls under clinically acceptable 1% screening test limit [9]. The higher the sequencing coverage, the greater the likelihood of comprehensive and confident genome-wide interrogation and, therefore, more accurate evidence to infer chromosomal or even sub-chromosomal aberrations [9].…”

Section: Introductionmentioning

confidence: 99%

“…For full chromosome aneuploidy detection, WisecondorX [8], for example, has shown to accurately operate with coverage of 5 million (M) reads per sample (RPS), while some other tools require coverage of 20M RPS to keep the number of false-negative trisomy calls under clinically acceptable 1% screening test limit [9]. The higher the sequencing coverage, the greater the likelihood of comprehensive and confident genome-wide interrogation and, therefore, more accurate evidence to infer chromosomal or even sub-chromosomal aberrations [9]. Kucharik et al suggested that for MD NIPT assays, sequencing coverage should be 10-20M RPS, with the exact minimum coverage depending on the fetal DNA fraction and target region length [10].…”

Section: Introductionmentioning

confidence: 99%

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BinDel: detecting clinically relevant fetal genomic microdeletions using low-coverage whole-genome sequencing-based NIPT

Paluoja

Teder

Salumets

et al. 2022

Preprint

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Clinically pathogenic chromosomal microdeletions causing genetic disorders such as DiGeorge syndrome are rare genetic aberrations that can cause clinically relevant fetal and childhood developmental deficiencies. Clinical severity of such deficiencies depend on the exact genomic location and genes affected by the fetal chromosomal aberration. Here we present the BinDel, a novel region-aware microdeletion detection software package developed to infer clinically relevant microdeletion risk in low-coverage whole-genome sequencing NIPT data. To test BinDel, we quantified the impact of sequencing coverage, fetal DNA fraction, and region length on microdeletion risk detection accuracy. We also estimated BinDel accuracy on known microdeletion samples and clinically validated aneuploidy samples. BinDel identified each positive control sample as high risk. We also determined that it is critical to take into account that the sample with a detected high microdeletion risk does not have a full chromosome aneuploidy, as the latter can cause erroneous high microdeletion risk findings. We observed that lower sequencing coverage resulted in reduced microdeletion detection accuracy, and higher fetal fractions considerably increased the microdeletion detection accuracy, with coverage becoming increasingly relevant as fetal DNA fraction decreased. In conclusion, we developed an R package-based software tool BinDel for inferring fetal microdeletion risks, which accurately identified all positive control samples with microdeletion or -duplication aberrations as high-risk samples.

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Systematic evaluation of NIPT aneuploidy detection software tools with clinically validated NIPT samples

Cited by 7 publications

References 21 publications

False-positives and false-negatives in non-invasive prenatal testing (NIPT): what can we learn from a meta-analyses on > 750,000 tests?

False-positives and false-negatives in non-invasive prenatal testing (NIPT): what can we learn from a meta-analyses on > 750,000 tests?

Assessment of Maternal Serum Biochemical Attributes and Fetal Ultrasound Scans in First-Trimester Low-Risk Noninvasive Prenatal-Tested Pregnant Women

BinDel: detecting clinically relevant fetal genomic microdeletions using low-coverage whole-genome sequencing-based NIPT

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