title: An adaptive detection method for fetal chromosomal aneuploidy using cell-free DNA from 447 Korean women.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: GenomeCare, Suwon, Republic of Korea.
authors.forename: Sunshin
authors.initials: S
authors.lastname: Kim
authors.affiliation: Mirae & Heemang OB/GYN Clinic, Seoul, Republic of Korea.
authors.forename: HeeJung
authors.initials: H
authors.lastname: Jung
authors.affiliation: Seoul Clinical Laboratories (SCL), Yongin, Republic of Korea.
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Han
authors.affiliation: Mirae & Heemang OB/GYN Clinic, Seoul, Republic of Korea.
authors.forename: SeungJae
authors.initials: S
authors.lastname: Lee
authors.affiliation: Mirae & Heemang OB/GYN Clinic, Seoul, Republic of Korea.
authors.forename: JeongSub
authors.initials: J
authors.lastname: Kwon
authors.affiliation: Namujungwon Maternity Hospital, Yangju, Republic of Korea.
authors.forename: Min Gyun
authors.initials: MG
authors.lastname: Kim
authors.affiliation: GN Maternity Hospital, Pyeongtak, Republic of Korea.
authors.forename: Hyungsik
authors.initials: H
authors.lastname: Chu
authors.affiliation: Department of Nanobiomedical Science, BK21 PLUS NBM Global Research Center for, Regenerative Medicine, Dankook University, Cheonan, Republic of Korea.
authors.forename: Kyudong
authors.initials: K
authors.lastname: Han
authors.affiliation: TheragenEtex, Suwon, Republic of Korea.
authors.forename: Hwanjong
authors.initials: H
authors.lastname: Kwak
authors.affiliation: TheragenEtex, Suwon, Republic of Korea.
authors.forename: Sunghoon
authors.initials: S
authors.lastname: Park
authors.affiliation: TheragenEtex, Suwon, Republic of Korea.
authors.forename: Hee Jae
authors.initials: HJ
authors.lastname: Joo
authors.affiliation: GenomeCare, Suwon, Republic of Korea.
authors.forename: Minae
authors.initials: M
authors.lastname: An
authors.affiliation: GenomeCare, Suwon, Republic of Korea.
authors.forename: Jungsu
authors.initials: J
authors.lastname: Ha
authors.affiliation: The Genomics Institute (TGI), BioMedical Engineering, UNIST, Ulsan, 687-798, Republic of Korea.
authors.forename: Kyusang
authors.initials: K
authors.lastname: Lee
authors.affiliation: The Genomics Institute (TGI), BioMedical Engineering, UNIST, Ulsan, 687-798, Republic of Korea.
authors.forename: Byung Chul
authors.initials: BC
authors.lastname: Kim
authors.affiliation: Xiamen Vangenes BioTech, Xiamen, Fujian, China.
authors.forename: Hailing
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Xiamen Vangenes BioTech, Xiamen, Fujian, China.
authors.forename: Xinqiang
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Xiamen Vangenes BioTech, Xiamen, Fujian, China. chenhl@vangenes.com.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Chen
authors.affiliation: GenomeCare, Suwon, Republic of Korea. jongbhak@genomics.org.|The Genomics Institute (TGI), BioMedical Engineering, UNIST, Ulsan, 687-798, Republic of Korea. jongbhak@genomics.org.|Geromics, Ulsan, 687-798, Republic of Korea. jongbhak@genomics.org.|Genome Research Foundation, Osong, Chungbuk, Republic of Korea. jongbhak@genomics.org.
authors.forename: Jong
authors.initials: J
authors.lastname: Bhak
mesh_terms: D000328:Adult; D000465:Algorithms; D000782:Aneuploidy; D002877:Chromosomes, Human / Q000235:genetics*; D004247:DNA / Q000235:genetics*; D005260:Female; D005333:Fetus / Q000378:metabolism*; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D011247:Pregnancy; D056910:Republic of Korea; D017422:Sequence Analysis, DNA; D014314:Trisomy / Q000175:diagnosis / Q000235:genetics; D055815:Young Adult
chemical_list: D004247:DNA
keywords: Adaptive detection algorithm; Circulating fetal DNA; Genome; Non-invasive prenatal testing; Sequencing; Trisomy