Method for non-invasive prenatal screening for aneuploidy

A technology for prenatal screening and aneuploidy, applied in biochemical equipment and methods, instruments, library member identification, etc., can solve problems such as false positives

Pending Publication Date: 2020-02-07
QUEST DIAGNOSTICS INVESTMENTS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Current NIPS methods can produce false-positive results due to biological and technical issues, prompting physicians to prescribe further diagnostic testing through invasive procedures, such as amniocentesis or chorionic villus sampling (CVS), which carry surgery-related Risk of miscarriage and other complications

Method used

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  • Method for non-invasive prenatal screening for aneuploidy
  • Method for non-invasive prenatal screening for aneuploidy
  • Method for non-invasive prenatal screening for aneuploidy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0112] Example 1: Assay Development

[0113] The following sections describe the materials and methods used to perform the NIPS assay of the present invention.

[0114] 1. Patient sample collection

[0115] In one example, for assay development, validation, and validation studies, applicants obtained samples from pregnant women from Sequenom (San Diego, CA), Precision Medicine, and consenting volunteers. For singleton pregnancies, applicants obtained 3,750 samples from Sequenom, 165 samples from Precision Medicine, and 10 samples from volunteers; Sequenom also provided samples from 115 pairs of twin pregnancies. The Sequenom samples are scheduled to be discarded and de-identified before being sent to applicants. Samples from Precision Medicine were obtained with informed consent using their protocol. Volunteers provided written informed consent through signed forms approved by the Western Institutional Review Board, which specifically reviewed and approved the study. Thi...

Embodiment 2

[0145] Example 2: Assay verification and verification

[0146] Once assay performance parameters were established, a series of assay samples were tested, including known unaffected pregnancies and known aneuploid pregnancies. The series of 2,085 samples included trisomy 21 (n=69), trisomy 18 (n=20) and trisomy 13 (n=17). There were no unaffected pregnancies with a Z-score >4 and no affected pregnancies with a Z-score 4 and no affected pregnancies with a Z-score <8.

[0147] As there was no difference in performance between the testing and validation studies, the results were pooled for analysis. The effect of GC correction was minimal for chromosome 21 with normal GC content, intermediate for chromosome 18 with moderate gain and GC content, and greatest for chromosome 13 with highest GC content ( figure 1 ). Using raw data, a Z-score threshold of 4 yielded absolute discrimination between 2,498 unaffected pregnancies and 90 trisomy 21 samples; no unaffected pregnancies had...

Embodiment 3

[0152] Embodiment 3: clinical implementation

[0153] The following section describes the results of the NIPS assay of the invention in an exemplary clinical implementation. In particular, samples from the 10th gestational week were accepted. More than 90% of the samples received were from between the 10th and 15th week of gestation.

[0154] Based on the test and validation results above, for clinical implementation, a Z-score cutoff of ≤4 was used for unaffected pregnancies and >8 for affected pregnancies. A Z score >3 but <8 suggests further investigation. A review of the first 10,000 clinical samples revealed abnormal NIPS results in 180 (1.8%) (Table 1). The overall positive rate of trisomy 21 was 1.0%, trisomy 18 was 0.36%, trisomy 13 was 0.21%, and sex aneuploidy was 0.17%. One sample was positive for the DiGeorge microdeletion, and 2 cases had 2 abnormalities. Of the first 10,713 samples tested, results were unreportable in 94 (0.88%); due to low fetal fraction ...

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Abstract

The present disclosure provides methods for non-invasive prenatal screening (NIPS) of fetal aneuploidies. The present methods are based on analyzing cell-free fetal DNA (cff DNA) found in a pregnant woman's circulation through the next generation sequencing (NGS) technology. Particularly, the present methods analyze the relative abundance of different fetal genomic fragments present in the maternal sample, where the fragments can be aligned to particular chromosomal locations of the fetal genome. The relative abundance information is indicative as to whether a particular chromosome is overrepresented or underrepresented in a fetal genome as compared to normal individuals, and thus can be used to detect fetal aneuploidy. Additionally, methods for increasing the positive predictive values (PPV) of NIPS by excluding false-positive detections are also provided.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit and priority of U.S. Provisional Application No. 62 / 445,196, filed January 11, 2017, the disclosure of which is incorporated herein by reference in its entirety. technical field [0003] The present disclosure provides methods for noninvasive prenatal screening (NIPS) of fetal aneuploidy. The method of the present invention is based on the analysis of cell-free fetal DNA (cff DNA) found in the circulation of pregnant women by next-generation sequencing (NGS) techniques. In particular, the methods of the invention analyze the relative abundance of different fragments of the fetal genome present in the maternal sample, which fragments can be aligned to specific chromosomal locations of the fetal genome. Relative abundance information indicates whether a particular chromosome is over- or under-represented in the fetal genome compared to normal individuals, and thus can be used to detect ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/09G16B20/00C12Q1/68C04B20/04G01N33/53G06F17/18C12Q1/6869G16B20/10
CPCG01N33/5308G01N2800/368C12Q1/6883C12Q2600/156C40B20/04G16B20/10G16B30/10G16B20/20G16B30/20
Inventor C·罗兰R·欧文C·斯特罗姆张克
Owner QUEST DIAGNOSTICS INVESTMENTS INC
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