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Statistical Approach to Decreasing the Error Rate of Noninvasive Prenatal Aneuploid Detection caused by Maternal Copy Number Variation.

Zhang H, Zhao YY, Song J, Zhu QY, Yang H, Zheng ML, Xuan ZL, Wei Y, Chen Y, Yuan PB, Yu Y, Li DW, Liang JB, Fan L, Chen CJ, Qiao J - Sci Rep (2015)

Bottom Line: We also introduced a method based on the discrepancy between feto-placental concentrations to help reduce the false-positive ratio.All 106 fetuses with T21, 20 with T18, and three with T13 were tested using our method, with sensitivity of 100% and specificity of 99.97%.In the results, two cases with maternal duplications in chromosome 21, which were falsely predicted as T21 by the previous NIPT method, were correctly classified as normal by our algorithm, which demonstrated the effectiveness of our approach.

View Article: PubMed Central - PubMed

Affiliation: Annoroad Gene Technology Co., Ltd, Beijing, China.

ABSTRACT
Analyses of cell-free fetal DNA (cff-DNA) from maternal plasma using massively parallel sequencing enable the noninvasive detection of feto-placental chromosome aneuploidy; this technique has been widely used in clinics worldwide. Noninvasive prenatal tests (NIPT) based on cff-DNA have achieved very high accuracy; however, they suffer from maternal copy-number variations (CNV) that may cause false positives and false negatives. In this study, we developed an algorithm to exclude the effect of maternal CNV and refined the Z-score that is used to determine fetal aneuploidy. The simulation results showed that the algorithm is robust against variations of fetal concentration and maternal CNV size. We also introduced a method based on the discrepancy between feto-placental concentrations to help reduce the false-positive ratio. A total of 6615 pregnant women were enrolled in a prospective study to validate the accuracy of our method. All 106 fetuses with T21, 20 with T18, and three with T13 were tested using our method, with sensitivity of 100% and specificity of 99.97%. In the results, two cases with maternal duplications in chromosome 21, which were falsely predicted as T21 by the previous NIPT method, were correctly classified as normal by our algorithm, which demonstrated the effectiveness of our approach.

No MeSH data available.


Scatter plot of two fetal concentrations (A) and the density of their differences (B). A) scatter plot showing the differences of two fetal concentrations. The x-axis represents fetal concentrations calculated from chromosome X; the y-axis shows fetal DNA fractions estimated from their aneuploid chromosomes. (B) density of the differences between two fetal concentrations. The blue solid line shows the difference distribution of positive samples. The false-positive samples CT00026 and AC01466 are colored in red and yellow respectively.
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f5: Scatter plot of two fetal concentrations (A) and the density of their differences (B). A) scatter plot showing the differences of two fetal concentrations. The x-axis represents fetal concentrations calculated from chromosome X; the y-axis shows fetal DNA fractions estimated from their aneuploid chromosomes. (B) density of the differences between two fetal concentrations. The blue solid line shows the difference distribution of positive samples. The false-positive samples CT00026 and AC01466 are colored in red and yellow respectively.

Mentions: We found two cases (CT00026 and AC01466) that were classified as false-positive samples according to the FCD results after measuring the differences between two fetal DNA fractions computed from chromosome X and the aneuploid chromosome. Mathematically, two fetal fractions will be better fitted by the linear model y = x, and the difference between the two fetal DNA fractions originates from a normal distribution, which was evident in the true positive trisomy results (Fig. 5). CT00026 was a patient who underwent the NIPT FCAD test at 22 gestational weeks. The Z-score of chromosome 18 was 4.39, indicating a potential trisomy 18; however, the fetal fraction of 12.2% from chromosome X was dramatically different from the 3.5% computed from chromosome 18. This huge contrast resulted in a Zfetal of 4.84 and led this patient to be considered as having a potential false-positive sample.


Statistical Approach to Decreasing the Error Rate of Noninvasive Prenatal Aneuploid Detection caused by Maternal Copy Number Variation.

Zhang H, Zhao YY, Song J, Zhu QY, Yang H, Zheng ML, Xuan ZL, Wei Y, Chen Y, Yuan PB, Yu Y, Li DW, Liang JB, Fan L, Chen CJ, Qiao J - Sci Rep (2015)

Scatter plot of two fetal concentrations (A) and the density of their differences (B). A) scatter plot showing the differences of two fetal concentrations. The x-axis represents fetal concentrations calculated from chromosome X; the y-axis shows fetal DNA fractions estimated from their aneuploid chromosomes. (B) density of the differences between two fetal concentrations. The blue solid line shows the difference distribution of positive samples. The false-positive samples CT00026 and AC01466 are colored in red and yellow respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4632076&req=5

f5: Scatter plot of two fetal concentrations (A) and the density of their differences (B). A) scatter plot showing the differences of two fetal concentrations. The x-axis represents fetal concentrations calculated from chromosome X; the y-axis shows fetal DNA fractions estimated from their aneuploid chromosomes. (B) density of the differences between two fetal concentrations. The blue solid line shows the difference distribution of positive samples. The false-positive samples CT00026 and AC01466 are colored in red and yellow respectively.
Mentions: We found two cases (CT00026 and AC01466) that were classified as false-positive samples according to the FCD results after measuring the differences between two fetal DNA fractions computed from chromosome X and the aneuploid chromosome. Mathematically, two fetal fractions will be better fitted by the linear model y = x, and the difference between the two fetal DNA fractions originates from a normal distribution, which was evident in the true positive trisomy results (Fig. 5). CT00026 was a patient who underwent the NIPT FCAD test at 22 gestational weeks. The Z-score of chromosome 18 was 4.39, indicating a potential trisomy 18; however, the fetal fraction of 12.2% from chromosome X was dramatically different from the 3.5% computed from chromosome 18. This huge contrast resulted in a Zfetal of 4.84 and led this patient to be considered as having a potential false-positive sample.

Bottom Line: We also introduced a method based on the discrepancy between feto-placental concentrations to help reduce the false-positive ratio.All 106 fetuses with T21, 20 with T18, and three with T13 were tested using our method, with sensitivity of 100% and specificity of 99.97%.In the results, two cases with maternal duplications in chromosome 21, which were falsely predicted as T21 by the previous NIPT method, were correctly classified as normal by our algorithm, which demonstrated the effectiveness of our approach.

View Article: PubMed Central - PubMed

Affiliation: Annoroad Gene Technology Co., Ltd, Beijing, China.

ABSTRACT
Analyses of cell-free fetal DNA (cff-DNA) from maternal plasma using massively parallel sequencing enable the noninvasive detection of feto-placental chromosome aneuploidy; this technique has been widely used in clinics worldwide. Noninvasive prenatal tests (NIPT) based on cff-DNA have achieved very high accuracy; however, they suffer from maternal copy-number variations (CNV) that may cause false positives and false negatives. In this study, we developed an algorithm to exclude the effect of maternal CNV and refined the Z-score that is used to determine fetal aneuploidy. The simulation results showed that the algorithm is robust against variations of fetal concentration and maternal CNV size. We also introduced a method based on the discrepancy between feto-placental concentrations to help reduce the false-positive ratio. A total of 6615 pregnant women were enrolled in a prospective study to validate the accuracy of our method. All 106 fetuses with T21, 20 with T18, and three with T13 were tested using our method, with sensitivity of 100% and specificity of 99.97%. In the results, two cases with maternal duplications in chromosome 21, which were falsely predicted as T21 by the previous NIPT method, were correctly classified as normal by our algorithm, which demonstrated the effectiveness of our approach.

No MeSH data available.