Marker for detecting and / or diagnosing 21-trisomy syndrome, 18-trisomy syndrome and neural tube defects and application thereof

Abstract

The invention relates to a marker for detecting and / or diagnosing 21-trisomy syndrome, 18-trisomy syndrome and neural tube defects and application of the marker, and belongs to the technical field of medical detection. The marker provided by the invention is selected from one or more of maternal serum D-dimer (D-D), pregnancy related plasma protein A (PAPP-A) and free human chorionic gonadotropin beta subunit (Free beta-hCG). The D-D + PAPP-A + Free beta-hCG model provided by the invention has the highest diagnostic value for 21-trisomy syndrome (DS) and 18-trisomy syndrome (ES), and the combination of D-D and PAPP-A and / or Free beta-hCG can improve the diagnostic value, diagnostic sensitivity and screening effect for neural tube defects (NTD). A new marker and a screening scheme are provided for simultaneously monitoring and diagnosing DS, ES or NTD fetuses of early pregnancy pregnant women in the clinical early stage.

Description

Technical Field

[0001] The present invention relates to the technical field of medical detection, and particularly relates to a marker for detecting and / or diagnosing trisomy 21, trisomy 18, and neural tube defects, and its application. Background Art

[0002] Chromosomal aneuploidy abnormalities are common chromosomal number abnormalities in fetuses, mainly including trisomy 21 (Down's Syndrome, DS), trisomy 18 (Edward's syndrome, ES), trisomy 13 (Patau's Syndrome), supermale syndrome (47, XYY), Klinefelter's Syndrome (47, XXY), Turner's Syndrome (45, X), etc. Among them, the incidence rates of DS and ES in newborns are 1‰ and 1 / 2600 - 1 / 2500 respectively. Neural tube defects (NTD) are congenital birth defect diseases caused by the failure of the embryonic neural tube to close around the 4th week of pregnancy, with an incidence rate of 1‰ in newborns. According to the defect site and clinical manifestations, it can be divided into open neural tube defects (ONTD) and closed neural tube defects, where ONTD includes anencephaly and open spina bifida. There is no effective treatment method for DS and ES after the fetus is born, and some NTDs require multiple surgeries, which will inevitably bring a serious economic burden to families and society. Therefore, it is particularly important to carry out prenatal detection and diagnosis of fetal DS, ES, and NTD.

[0003] Currently, the prenatal detection of fetal DS, ES, and NTD mainly detects indicators such as pregnancy-associated plasma protein A (PAPP-A), free beta subunit of human chorionic gonadotropin (Free β-hCG), fetal nuchal translucency thickness (NT) in the first trimester (9 - 13 +6 weeks), and serum alpha-fetoprotein (AFP), Free β-hCG, unconjugated estriol (uE3), inhibin A (INHIBIN-A), etc. in the second trimester (15 - 20 +6 weeks), and then combines parameters such as the pregnant woman's last menstrual period, gestational week, weight, age, etc., and uses special analysis software for prenatal detection to calculate the risk of having a fetus with DS, ES, or NTD.

[0004] Although the combined indicators of PAPP-A, Freeβ-hCG, and NT in the early pregnancy can detect 80% - 90% of fetal chromosomal aneuploidy abnormalities when the theoretical false positive rate is 5%, in actual clinical work, the detection sensitivity and specificity of the combined indicators of PAPP-A, Freeβ-hCG, and NT are not ideal. In addition, although detecting the AFP level in the second trimester of pregnancy is considered the gold standard for detecting NTD, there are drawbacks such as a delayed detection time, a shortened decision-making time for pregnant women, and untimely clinical intervention when detecting NTD in the second trimester of pregnancy.

[0005] There are no prior art reports on detecting and / or diagnosing fetal DS, ES, and NTD in the early pregnancy. Summary of the Invention

[0006] The object of the present invention is to provide a marker for detecting and / or diagnosing trisomy 21, trisomy 18, and neural tube defects and its application, so as to solve the problems of delayed detection time, shortened decision-making time, untimely clinical intervention, and low sensitivity and specificity in the process of detecting and / or diagnosing fetuses with trisomy 21 (DS), trisomy 18 (ES), and neural tube defects (NTD) in the prior art.

[0007] To achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0008] The present invention provides a marker for detecting and / or diagnosing trisomy 21, trisomy 18, and neural tube defects, and the marker is selected from one or more of maternal serum D-dimer, pregnancy-associated plasma protein A, and free β-subunit of human chorionic gonadotropin.

[0009] The present invention also provides the application of the above-mentioned marker in the preparation of a preparation for detecting and / or diagnosing trisomy 21.

[0010] The present invention also provides the application of the above-mentioned marker in the preparation of a preparation for detecting and / or diagnosing trisomy 18.

[0011] The present invention also provides the application of the above-mentioned marker in the preparation of a preparation for detecting and / or diagnosing neural tube defects.

[0012] The present invention also provides a kit for detecting and / or diagnosing trisomy 21, and the kit includes a reagent for detecting the above-mentioned marker.

[0013] The present invention also provides a kit for detecting and / or diagnosing trisomy 18, and the kit includes a reagent for detecting the above-mentioned marker.

[0014] The present invention also provides a kit for detecting and / or diagnosing neural tube defects, and the kit includes reagents for detecting the markers described above.

[0015] The present invention also provides the use of the kit described above in detecting the content of maternal serum D-dimer for non-disease diagnosis or treatment purposes.

[0016] The present invention also provides the use of the kit described above in detecting the content of pregnancy-associated plasma protein A for non-disease diagnosis or treatment purposes.

[0017] The present invention also provides the use of the kit described above in detecting the content of free beta subunit of human chorionic gonadotropin for non-disease diagnosis or treatment purposes.

[0018] The present invention has the following technical effects and advantages:

[0019] The present invention firstly proposes that the maternal serum D-dimer (D-D) index of pregnant women in the early pregnancy can be used to predict neural tube defects (NTD), and the D-D index is a good marker for diagnosing fetuses with trisomy 21 syndrome (DS), trisomy 18 syndrome (ES), and NTD fetuses, with good specificity, and can be used to screen the risks of fetuses with DS, ES, and NTD fetuses;

[0020] Combining D-D with pregnancy-associated plasma protein A (PAPP-A) and free beta subunit of human chorionic gonadotropin (Freeβ-hCG) can improve the diagnostic value of the risk model for DS and ES. Among them, the D-D + PAPP-A + Freeβ-hCG model calibrated by the AGW index (the index obtained by combining the expected gestational age, gestational age, and maternal weight) has the highest diagnostic value for DS and ES, and is significantly higher than the diagnostic value of the traditional PAPP-A + Freeβ-hCG model for DS and ES;

[0021] Combining D-D with PAPP-A, D-D with Freeβ-hCG, and D-D with PAPP-A + Freeβ-hCG can all improve the diagnostic value, diagnostic sensitivity, and screening effect of the risk model for NTD;

[0022] The present invention can provide new markers and screening programs for clinically monitoring and diagnosing fetuses with DS, ES, or NTD in pregnant women in the early pregnancy at the same time. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 The contents of D-D, PAPP-A, and Freeβ-hCG for each group of pregnant women, where A is the content of D-D for each group of pregnant women, B is the content of PAPP-A for each group of pregnant women, and C is the content of Freeβ-hCG for each group of pregnant women;

[0024] Figure 2 are the ROC curves for diagnosing DS by each risk model;

[0025] Figure 3 are the ROC curves for diagnosing ES by each risk model;

[0026] Figure 4 are the ROC curves for diagnosing NTD by each risk model. Specific implementation manners

[0027] The present invention provides a marker for detecting and / or diagnosing trisomy 21 (DS), trisomy 18 (ES), and neural tube defects (NTD), and the marker is selected from one or more of maternal serum D-dimer (D-D), pregnancy-associated plasma protein A (PAPP-A), and free beta subunit of human chorionic gonadotropin (Freeβ-hCG);

[0028] The marker is any one of the following (1) to (4):

[0029] (1) Maternal serum D-dimer (D-D);

[0030] (2) A combination of maternal serum D-dimer and pregnancy-associated plasma protein A (D-D + PAPP-A);

[0031] (3) A combination of maternal serum D-dimer and free beta subunit of human chorionic gonadotropin (D-D + Freeβ-hCG);

[0032] (4) A combination of maternal serum D-dimer, pregnancy-associated plasma protein A, and free beta subunit of human chorionic gonadotropin (D-D + PAPP-A + Freeβ-hCG).

[0033] The present invention also provides the application of the marker in the preparation of a preparation for detecting and / or diagnosing trisomy 21.

[0034] The present invention also provides the application of the marker in the preparation of a preparation for detecting and / or diagnosing trisomy 18.

[0035] The present invention also provides the application of the marker in the preparation of a preparation for detecting and / or diagnosing neural tube defects.

[0036] The present invention also provides a kit for detecting and / or diagnosing trisomy 21, and the kit includes a reagent for detecting the marker.

[0037] The present invention also provides a kit for detecting and / or diagnosing trisomy 18, and the kit includes a reagent for detecting the marker.

[0038] The present invention also provides a kit for detecting and / or diagnosing neural tube defects, and the kit comprises a reagent for detecting the marker described above.

[0039] The present invention also provides the use of the kit described above in detecting the content of maternal serum D-dimer for non-disease diagnosis or treatment purposes.

[0040] The present invention also provides the use of the kit described above in detecting the content of pregnancy-associated plasma protein A for non-disease diagnosis or treatment purposes.

[0041] The present invention also provides the use of the kit described above in detecting the content of free beta subunit of human chorionic gonadotropin for non-disease diagnosis or treatment purposes.

[0042] The technical solutions provided by the present invention will be described in detail below in conjunction with examples, but they should not be construed as limiting the protection scope of the present invention.

[0043] In the reagent of the present invention, the amniotic fluid cell culture medium is purchased from Shanghai Dart Hill Biotechnology Co., Ltd., the D-D reagent is purchased from BIM Company in the United States, and the PAPP-A / Freeβ-hCG collection kit is purchased from PerkinElmer Company in the United States.

[0044] Example 1: Determination of research subjects

[0045] (1) Determination of the case group and the control group: Retrospective analysis of the data of 396,306 pregnant women who underwent prenatal screening in the prenatal screening clinics of Hangzhou Obstetrics and Gynecology Hospital and Hangzhou Linping Maternal and Child Health Hospital from 2015 to 2023. All pregnancies of 9-13 +6 weeks with singleton pregnancies in the first trimester of pregnant women with 21-trisomy syndrome (DS) fetuses, 18-trisomy syndrome (ES) fetuses, and neural tube defect (NTD) fetuses were included in the preselected cases (a total of 800 cases). Pregnant women who were diagnosed as having DS fetuses, ES fetuses, or NTD fetuses by amniotic fluid cell chromosome karyotype analysis or imaging diagnosis were randomly selected from the preselected cases and included in the case group (a total of 140 cases), corresponding to the DS group (75 cases), the ES group (23 cases), and the NTD group (42 cases) respectively. Pregnant women with normally developing fetuses during the same period were included in the control group (177 cases);

[0046] Among them, the method for diagnosing pregnant women in the case group is as follows: After obtaining the informed consent of the preselected cases, amniocentesis is performed under ultrasonic guidance at 16-22 weeks of pregnancy, 28 mL of amniotic fluid during pregnancy is extracted from each preselected case, and the amniotic fluid cell precipitate is taken after centrifugation and inoculated into the amniotic fluid cell culture medium. Cell culture is carried out at 37 °C and 5% CO2, and the amniotic fluid cell culture medium is changed every 7 days. During this period, the growth of amniotic fluid cells is observed. When the amniotic fluid cells grow vigorously adherent and present polyclonal cells, colchicine is added for harvesting, and then karyotype analysis of amniotic fluid cells is performed, and imaging diagnosis is regularly carried out on preselected cases with positive NTD and some negative cases;

[0047] (2) Inclusion criteria: Referring to the diagnostic criteria formulated by the China Maternal and Child Health Monitoring Network (https: / / www.mchscn.cn / BirthDefectMonitoring-25.html), 47,XX+21 or 47,XY+21 karyotype is diagnosed as DS, 47,XX+18 or 47,XY+18 karyotype is diagnosed as ES, and ONTD (including open spina bifida and anencephaly) and closed neural tube defects are diagnosed as NTD; Preselected cases pregnant with DS fetuses, ES fetuses, and NTD fetuses are included in the case group;

[0048] (3) Exclusion criteria: Pregnant women with twin or multiple pregnancies; Pregnant women with other internal medical diseases such as insulin-dependent diabetes and severe pregnancy complications; Smoking pregnant women; Pregnant women who have undergone in vitro fertilization transplantation; Pregnant women with birth defect fetuses with other chromosomal abnormalities and structural abnormalities other than DS, ES, and NTD; Pregnant women with incomplete data information, etc.;

[0049] This invention has been approved by the Ethics Committee of Hangzhou Obstetrics and Gynecology Hospital, and the approval number is

[2023] -Medical Ethics Review A No. (002).

[0050] Example 2: Marker detection and risk model construction

[0051] (1) Marker detection: 3 mL of fasting venous blood is extracted from pregnant women in the case group and the control group. After standing for 30 min, it is centrifuged at 2500 rpm for 10 min to separate the serum. Referring to the operation instructions of the D-D reagent, the double-antibody one-step sandwich enzyme-linked immunosorbent assay (ELISA) is used to detect the concentration value of maternal serum D-dimer (D-D) in each group of pregnant women; At the same time, referring to the operation instructions of the PAPP-A / Freeβ-hCG collection kit, time-resolved fluorescence assay (DELFIA) is used to detect the concentration values of pregnancy-associated plasma protein A (PAPP-A) and free β-subunit of human chorionic gonadotropin (Freeβ-hCG) in each group of pregnant women;

[0052] (2) Risk model construction: The Beginning Block method of binary logistic regression analysis was used to analyze the concentration values of D-D, PAPP-A, and Freeβ-hCG in each group of pregnant women. At the same time, in order to reduce the diagnostic bias caused by the specificity of the expected delivery age, gestational age, and pregnant women's weight of individual pregnant women, the expected delivery age, gestational age, and pregnant women's weight of each group of pregnant women were combined into the AGW index, and the concentration values of D-D, PAPP-A, and Freeβ-hCG in each group of pregnant women were calibrated, so as to construct a risk model for diagnosing pregnant women with DS fetuses, ES fetuses, and NTD fetuses. Specifically, the single-marker models include the Freeβ-hCG model, PAPP-A model, D-D model, Freeβ-hCG+AGW model, PAPP-A+AGW model, D-D+AGW model; the dual-marker models include the PAPP-A+Freeβ-hCG+AGW model, D-D+Freeβ-hCG+AGW model, D-D+PAPP-A+AGW model; the triple-marker models include the D-D+PAPP-A+Freeβ-hCG+AGW model, D-D+PAPP-A+Freeβ-hCG model;

[0053] (3) Statistical analysis: IBM-SPSS 21.0 was used for statistical processing. The Shapiro-Wilk test was used to test the normality of the data. Skewed data was expressed as the median and 97.5% interval [M(P 2.5 ~P 97.5 )]. The Mann-Whitney U test was used to compare the risk models. According to the receiver operating characteristic curve (ROC), the area under the curve (AUC) and the optimal cut-off value of D-D, PAPP-A, and Freeβ-hCG in each risk model for diagnosing pregnant women with DS fetuses, ES fetuses, and NTD fetuses were calculated. Combined with the 95% confidence interval (95% CI), probability value (P), sensitivity (Se), specificity (Sp), Youden index (YD), positive predictive value (PPV), negative predictive value (NPV), false positive rate (FPR), false negative rate (FNR), positive likelihood ratio (+LR), and negative likelihood ratio (-LR) to evaluate the diagnostic performance of each risk model.

[0054] Example 3: Follow-up after pregnancy

[0055] Doctors followed up each group of pregnant women after pregnancy, filled in the "Hangzhou Prenatal Screening Work Report" and the "Follow-up Registration Form for Pregnancy Outcomes of Pregnant Women with High Risk, Other High Risks, and Low Risk Birth Defects in Hangzhou Prenatal Screening", filled in the "Birth Defect Infant Registration Card" according to the "China Birth Defect Monitoring Program", and followed up and registered the birth defect diagnosis according to the International Classification of Diseases standard (ICD-10).

[0056] Experimental Example 1: Determination of AGW Index of the Research Subjects

[0057] Statistical analysis was performed on the indicators such as the expected delivery age, gestational age, and pregnant women's weight of pregnant women in the case group and the control group. The skewed data of each indicator were expressed as the median and 97.5% interval, and the writing form was M(P 2.5 ~P 97.5 ). The results are shown in Table 1.

[0058] Table 1 Skewed Data of AGW Index of Pregnant Women in Each Group

[0059] Group Number of individuals (cases) Expected age at delivery (years) Gestation age (days) Maternal weight (kg) Control group 177 28.62(23.40～34.45) 90.00(80.00～97.00) 51.00(43.00～66.00) DS group 75 29.88(23.86～34.86) 88.00(73.00～97.00) 54.00(39.90～81.10) ES group 23 29.93(24.56～36.55) 87.00(80.00～96.00) 52.00(42.00～74.34) NTD group 42 30.53(22.19～34.32) 88.00(74.00～97.00) 55.00(42.00～74.56) <![CDATA[χ 2 > —— 19.884 36.984 11.084 P —— <0.001 <0.001 <0.001

[0060] The results showed that the expected delivery age and pregnant women's weight of pregnant women in the DS group, ES group, and NTD group were all higher than those of pregnant women in the control group, and the differences between groups were statistically significant (P<0.05); the gestational age of pregnant women in the DS group, ES group, and NTD group was lower than that of pregnant women in the control group, and the differences between groups were statistically significant (P<0.05).

[0061] Experimental Example 2: Determination of D-D, PAPP-A, and Freeβ-hCG Indexes of the Research Subjects

[0062] The concentration values of D-D, PAPP-A, and Freeβ-hCG of pregnant women in the case group and the control group were measured by the method described in step (1) of Example 2. The skewed data of each indicator were expressed as the median and 97.5% interval, and the writing form was M(P 2.5 ~P 97.5 ). The results are shown in Table 2 and Figure 1 as follows.

[0063] Table 2 Skewed Data of D-D, PAPP-A, and Freeβ-hCG of Pregnant Women in Each Group

[0064] Group Number of individuals (cases) D-D (ng / mL) PAPP-A (mU / L) Free β-hCG (ng / mL) Control group 177 217.86(94.53～368.16) 4390(1620～13610) 51.40(16.13～158.10) DS group 75 239.20(104.43～553.15) 1590(304～6710) 88.5(18.28～385.90) ES group 23 281.71(150.93～513.15) 559(21～3816) 10.70(2.62～69.96) NTD group 42 306.06(145.61～827.51) 2880(81～8228) 43.95(4.97～172.45) <![CDATA[χ 2 > —— 30.221 138.324 87.761 P —— <0.001 <0.001 <0.001

[0065] The results showed that the D-D content of pregnant women in the DS group, ES group, and NTD group was higher than that of pregnant women in the control group, and the differences between groups were statistically significant (P<0.001); the PAPP-A content of pregnant women in the DS group, ES group, and NTD group was lower than that of pregnant women in the control group, and the differences between groups were statistically significant (P<0.001); the Freeβ-hCG content of pregnant women in the DS group was higher than that of pregnant women in the control group, and the Freeβ-hCG content of pregnant women in the ES group was lower than that of pregnant women in the control group, and the differences between groups were statistically significant (P<0.001), while the Freeβ-hCG content of pregnant women in the NTD group was lower than that of pregnant women in the control group, and the difference between groups was not statistically significant (P≥0.05). It shows that the D-D index of pregnant women in the first trimester is a good marker for diagnosing DS fetuses, ES fetuses, and NTD fetuses, and can be used to screen the risks of pregnant women with DS fetuses, ES fetuses, and NTD fetuses.

[0066] Experimental Example 3: Value of Risk Model in Diagnosing DS

[0067] The method described in Example 2 was used to construct a risk model for diagnosing fetuses with DS. Specifically, the single-marker models included the Freeβ-hCG model, PAPP-A model, D-D model, Freeβ-hCG+AGW model, PAPP-A+AGW model, D-D+AGW model; the dual-marker models included the PAPP-A+Freeβ-hCG+AGW model, D-D+Freeβ-hCG+AGW model, D-D+PAPP-A+AGW model; the triple-marker models included the D-D+PAPP-A+Freeβ-hCG+AGW model and D-D+PAPP-A+Freeβ-hCG model. Statistical analysis and evaluation of diagnostic value were performed, and the results are shown in Table 3 and Figure 2 as follows.

[0068] Table 3 Diagnostic Value of Each Risk Model for DS

[0069]

[0070]

[0071] The results showed that among the single-marker models, the AUCs of the D-D model, PAPP-A model, and Freeβ-hCG model for predicting DS fetuses were 0.628, 0.900, and 0.757 respectively, and the 95% CIs were 0.550 - 0.706, 0.855 - 0.945, and 0.689 - 0.825 respectively, all of which were statistically significant (P<0.001). When the cut-off value of the D-D model was 302.92 ng / mL, its sensitivity (Se) and negative predictive value (NPV) were the lowest, but its specificity (Sp) and negative likelihood ratio (-LR) were the highest. After calibration with the AGW index, the AUCs of each risk model increased. Among them, the D-D+PAPP-A+Freeβ-hCG+AGW model had the highest diagnostic value for DS (AUC = 0.934, 95% CI: 0.897 - 0.972, Se = 0.880, Sp = 0.910), the highest positive predictive value (PPV) and positive likelihood ratio (+LR), and the lowest false positive rate (FPR) and false negative rate (FNR). The order of the AUCs of the dual-marker models was PAPP-A+Freeβ-hCG+AGW model > D-D+PAPP-A+AGW model > D-D+Freeβ-hCG+AGW model.

[0072] Experimental Example 4: Value of Risk Model in Diagnosing ES

[0073] The method described in Example 2 was used to construct a risk model for diagnosing the risk of fetuses with ES, specifically: the single-marker models included the Freeβ-hCG model, the PAPP-A model, the D-D model, the Freeβ-hCG+AGW model, the PAPP-A+AGW model, and the D-D+AGW model; the dual-marker models included the PAPP-A+Freeβ-hCG+AGW model, the D-D+Freeβ-hCG+AGW model, and the D-D+PAPP-A+AGW model; the triple-marker models included the D-D+PAPP-A+Freeβ-hCG+AGW model and the D-D+PAPP-A+Freeβ-hCG model. Statistical analysis and diagnostic value evaluation were performed, and the results are shown in Table 4 and Figure 3 as follows.

[0074] Table 4 Diagnostic value of each risk model for ES

[0075]

[0076]

[0077] The results showed that among the single-marker models, the AUCs of the D-D model, the PAPP-A model, and the Freeβ-hCG model for predicting ES fetuses were 0.697, 0.963, and 0.920, respectively, and the 95% CIs were 0.564 - 0.830, 0.922 - 1.000, and 0.850 - 0.991, respectively, all with statistical significance (P<0.05). When the cut-off value of the D-D model was 324.52 ng / mL, its AUC, sensitivity (Se), and negative predictive value (NPV) were the lowest, the specificity (Sp) was higher, and the negative likelihood ratio (-LR) was the highest. After calibration with the AGW index, the AUCs of each risk model increased. Among them, the D-D+PAPP-A+Freeβ-hCG+AGW model had the highest diagnostic value for ES (AUC = 0.993, 95% CI: 0.981 - 1.000), and the negative likelihood ratio (-LR) was the lowest.

[0078] Experimental Example 5: Diagnostic value of the risk model for NTD

[0079] The method described in Example 2 was used to construct a risk model for diagnosing the risk of fetuses with NTD, specifically: the single-marker models included the Freeβ-hCG model, PAPP-A model, D-D model, Freeβ-hCG + AGW model, PAPP-A + AGW model, D-D + AGW model; the dual-marker models included the PAPP-A + Freeβ-hCG + AGW model, D-D + Freeβ-hCG + AGW model, D-D + PAPP-A + AGW model; the triple-marker models included the D-D + PAPP-A + Freeβ-hCG + AGW model, D-D + PAPP-A + Freeβ-hCG model. Statistical analysis and diagnostic value evaluation were carried out, and the results are shown in Table 5 and Figure 4 as follows.

[0080] Table 5 Diagnostic value of each risk model for NTD

[0081]

[0082]

[0083] The results showed that in the single biomarker model, the AUC of the D-D model for predicting NTD fetuses was 0.726, with a 95% CI of 0.632 - 0.820, all of which were statistically significant (P < 0.001). When the cut-off value of the D-D model was 292.86 ng / mL, Se = 0.548, Sp = 0.881, PPV = 0.822, NPV = 0.661, FPR = 0.119, +LR = 4.605, -LR = 0.513; the AUC of the PAPP-A model for predicting NTD fetuses was 0.685, with a 95% CI of 0.594 - 0.776, all of which were statistically significant (P < 0.001); the AUC of the Freeβ-hCG model for predicting NTD fetuses was 0.561, with a 95% CI of 0.459 - 0.663, which was not statistically significant (P > 0.05), so it had no diagnostic value for NTD; the AUCs of the D-D+Freeβ-hCG+AGW model, the D-D+PAPP-A+AGW model, and the D-D+PAPP-A+Freeβ-hCG+AGW model were all 0.887, with 95% CIs all being 0.829 - 0.946, and the Ses were all 0.667, all of which were statistically significant (P < 0.001), indicating that combining D-D with PAPP-A, D-D with Freeβ-hCG, and D-D with PAPP-A+Freeβ-hCG could all improve the diagnostic value of the risk model for NTD; the positive predictive value (PPV) and positive likelihood ratio (+LR) of the D-D+PAPP-A+Freeβ-hCG+AGW model were the highest, and the false positive rate (FPR) was the lowest. And since Freeβ-hCG had no diagnostic value for NTD and the diagnostic value of PAPP-A for NTD was lower than that of D-D, adding Freeβ-hCG, PAPP-A, or Freeβ-hCG+PAPP-A could not improve the diagnostic value of the risk model for NTD.

[0084] As can be seen from the above embodiments, the present invention provides a biomarker for detecting and / or diagnosing trisomy 21, trisomy 18, and neural tube defects and its application. The D-D index of pregnant women in the early pregnancy of the present invention is a good biomarker for diagnosing DS fetuses, ES fetuses, and NTD fetuses. And the D-D+PAPP-A+Freeβ-hCG model calibrated by the AGW index has a significantly higher diagnostic value for DS and ES than the traditional PAPP-A+Freeβ-hCG model. Combining D-D with PAPP-A, D-D with Freeβ-hCG, and D-D with PAPP-A+Freeβ-hCG can all improve the diagnostic value, diagnostic sensitivity, and screening effect of the risk model for NTD.

[0085] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A marker for detecting and / or diagnosing trisomy 21, trisomy 18, and neural tube defects, characterized in that, The biomarker is selected from one or more of maternal serum D-dimer, pregnancy-associated plasma protein A, and free beta subunit of human chorionic gonadotropin.

2. Use of the biomarker according to claim 1 in the preparation of a preparation for detecting and / or diagnosing trisomy 21.

3. Use of the biomarker according to claim 1 in the preparation of a preparation for detecting and / or diagnosing trisomy 18.

4. Use of the biomarker according to claim 1 in the preparation of a preparation for detecting and / or diagnosing neural tube defects.

5. A kit for detecting and / or diagnosing trisomy 21, characterized in that, The kit includes a reagent for detecting the biomarker according to claim 1.

6. A kit for detecting and / or diagnosing trisomy 18 syndrome, characterized in that, The kit includes a reagent for detecting the biomarker according to claim 1.

7. A kit for detecting and / or diagnosing neural tube defects, characterized in that, The kit includes a reagent for detecting the biomarker according to claim 1.

8. Use of the kit according to any one of claims 5 to 7 in detecting the content of maternal serum D-dimer for non-diagnostic or therapeutic purposes.

9. Use of the kit according to any one of claims 5 to 7 in detecting the content of pregnancy-associated plasma protein A for non-diagnostic or therapeutic purposes.

10. Use of the kit according to any one of claims 5 to 7 in detecting the content of free beta subunit of human chorionic gonadotropin for non-diagnostic or therapeutic purposes.

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