Adaptive parameter of standard deviation enhances the power of noninvasive prenatal screens

Abstract

Purpose

Traditional Z-test methods during noninvasive prenatal screens (NIPS) use the fixed parameter of standard deviation (SD), which ignores the influence of actual sequencing read counts of a sample on the results. The aim of this study is to eliminate the influence of the sequencing depth of individual samples on the results and enhance the power of NIPS.

Methods

In this study, we propose an improved NIPS method, which calculates the SD in the Z-score process adaptively according to the actual read count of the test sample. Our approach obtained the SD linear fitting function along with the read count with a large number of reference samples, in which SD and read count fit well. The effectiveness of our enhanced NIPS method was evaluated on three common trisomy syndromes and five recurrent CNV syndromes with 3219 and 6592 samples based on whole genome sequencing of maternal peripheral blood.

Results

A total of 3,219 pregnant samples have been used for validating the proposed method on detecting fetal trisomy syndromes (T13, T18, and T21), in which eight false negative (FN) samples have been corrected as true positive (TP) and eight false positive (FP) samples have been fixed as true negative (TN) with our proposed adaptive-SD method. Another 6592 samples were used to compare the two methods on detecting five recurrent fetal copy number variation (CNV) syndromes, in which the FP samples have decreased from 99 to 39.

Conclusions

Our adaptive-SD NIPS method shows more power on detecting both trisomy syndromes and five recurrent CNVs in the pregnant samples with diverse read counts. Besides, our proposed method contributes to lower FP and FN samples than the traditional Z-test method in NIPS. Our results show that our enhanced NIPS methods are effective in detecting both abnormal fetal trisomy syndromes and recurrent CNV syndromes in pregnant women.

Keywords:

• noninvasive prenatal screen
• Z-test
• adaptive parameter
• trisomy syndrome
• copy number variation

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Additional information

Funding

This study was supported by the National Natural Science Foundation of China [31801043] and Natural Science Foundation of Beijing Municipality [7192187]. The funders had no role in study design, data collection and analysis, interpretation of the results or writing the manuscript.