An adaptive detection method for fetal chromosomal aneuploidy using cell-free DNA from 447 Korean women

作者：Kim Sunshin; Jung HeeJung; Han Sung Hee; Lee SeungJae; Kwon JeongSub; Kim Min Gyun; Chu Hyungsik; Han Kyudong; Kwak Hwanjong; Park Sunghoon; Joo Hee Jae; An Minae; Ha Jungsu; Lee Kyusang; Kim Byung Chul; Zheng Hailing; Zhu Xinqiang; Chen Hongliang^*; Bhak Jong^*

来源：BMC Medical Genomics, 2016, 9(1): 61.

DOI：10.1186/s12920-016-0222-5

• Non-invasive prenatal testing
• Adaptive detection algorithm
• Sequencing
• Circulating fetal DNA
• Trisomy
• Genome

Background: Noninvasive prenatal testing (NIPT) using massively parallel sequencing of cell-free DNA (cfDNA) is increasingly being used to predict fetal chromosomal abnormalities. However, concerns over erroneous predictions which occur while performing NIPT still exist in pregnant women at high risk for fetal aneuploidy. We performed the largest-scale clinical NIPT study in Korea to date to assess the risk of false negatives and false positives using next-generation sequencing.
Methods: A total of 447 pregnant women at high risk for fetal aneuploidy were enrolled at 12 hospitals in Korea. They underwent definitive diagnoses by full karyotyping by blind analysis and received aneuploidy screening at 11-22 weeks of gestation. Three steps were employed for cfDNA analyses. First, cfDNA was sequenced. Second, the effect of GC bias was corrected using normalization of samples as well as LOESS and linear regressions. Finally, statistical analysis was performed after selecting a set of reference samples optimally adapted to a test sample from the whole reference samples. We evaluated our approach by performing cfDNA testing to assess the risk of trisomies 13, 18, and 21 using the sets of extracted reference samples.
Results: The adaptive selection algorithm presented here was used to choose a more optimized reference sample, which was evaluated by the coefficient of variation (CV), demonstrated a lower CV and higher sensitivity than standard approaches. Our adaptive approach also showed that fetal aneuploidies could be detected correctly by clearly splitting the z scores obtained for positive and negative samples.
Conclusions: We show that our adaptive reference selection algorithm for optimizing trisomy detection showed improved reliability and will further support practitioners in reducing both false negative and positive results.

• 出版日期2016-10-3