CN117031042A - 用于筛查诊断先天性心脏病胎儿的生物标志物及其应用 - Google Patents
用于筛查诊断先天性心脏病胎儿的生物标志物及其应用 Download PDFInfo
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Abstract
本发明公开了一种用于筛查诊断先天性心脏病胎儿的生物标志物及其应用。所述生物标志物包含74种生物标志物或其组合。本发明的生物标志物及基于其构建的用于评估胎儿先天性心脏病风险的系统具有高灵敏度和高特异性的优点,可以为先天性心脏病胎儿产前筛查、早期诊断、干预治疗等提供有利的技术支持,具有广泛的科研和临床价值。
Description
技术领域
本发明属于生物医药技术和诊断领域,具体涉及一种用于筛查诊断先天性心脏病胎儿的生物标志物及其应用,特别地,是一种用于筛查诊断先天性心脏病(CHD)胎儿的母体血液的生物标志物及其应用。
背景技术
先天性心脏病(Congenital heart disease,CHD)是指在胚胎发育时期由于心脏及大血管的形成障碍或发育异常而引起的解剖结构异常,或出生后应自动关闭的通道未能闭合的情形。它是最常见的一类先天性畸形,约占所有活婴的1%,全球每年约有150万婴儿出生时罹患先心病,孕妇产前筛查及胎儿早期诊治尤为重要。
目前,诊断先天性心脏病的常用手段包括以下几个方面:中孕期胎儿超声心动图检查、早孕期胎儿心脏结构筛查、心脏导管造影检查和核磁共振成像(MRI)等。这些方法各具优缺点,比如胎儿超声心动图检查可对胎儿心脏结构及功能进行全面评价,但由于心超检测的最佳时间为孕18-22周,可能错过了最佳的干预时间;心脏导管造影检查诊断先天性心脏病的准确性较高,但可能造成血管损伤或辐射;核磁共振成像属无创技术,无需造影剂即可清楚地显示心脏,可减少射线辐射等对人体的损害,但其具有设备和检查费用昂贵,易产生伪影等缺点。因此,我们迫切的需要新型的生物标志物用以辅助孕早期胎儿疾病的诊断、干预和提早治疗。
蛋白质组学的分析不仅可以高通量识别蛋白质,还可以综合评估在特定时间和病理条件下蛋白质水平的变化情况,这将有助于研究人类疾病的发生发展机制、诊断及预后监测。血液蛋白质分子标志物一般是指可供客观测定和评价的一个普通生理或病理或治疗过程中的某种特征性的生化指标。
发明内容
本发明所要解决的技术问题是为了克服现有技术中缺少可有效辅助胎儿先天性心脏病的早期诊断、干预和治疗的蛋白质分子标志物,提供一种用于筛查诊断先天性心脏病胎儿的生物标志物及其应用。本发明通过检测母体血液或体液中的分子标志物组合表达水平的变化情况,可以在产前辅助诊断胎儿是否患有先天性心脏病,具有高灵敏度和高特异性的优点,具有良好的临床应用前景。
本发明通过以下技术方案解决上述技术问题。
本发明的第一方面提供一种用于诊断或辅助诊断胎儿先天性心脏病的生物标志物,其特征在于,所述生物标志物包含ACLY、AKR1C3、CAPN5、CNDP2、ENOPH1、H2AC4、H2AC6、H2AW、H2BC11、H2BC17、H2BC21、H2BC3、H2BU1、HSP90AA1、HSP90AA5P、KPNB1、MDH2、MYL9、NRP2、PRPF8、PTPRF、RDX、RPL27、S100A7、SAMHD1、AOC2、ARPC4、BAG2、BASP1、CASP14、CEL、CFHR2、CFHR4、CHL1、COLEC10、COTL1、CSN2、EHD1、EPB42、ERAP1、EXOC3、G6PD、GFAP、GZMM、H6PD、HADHB、HSPD1、IRGQ、KLK12、KLK13、KLK7、L1CAM、LIMCH1、LMAN2、NDUFA10、NPM1、NSF、NT5C、PABPC1、PABPC4、PEPD、PF4、PF4V1、RALY、RPS6KA3、SERPINB3、SERPINB4、SERPINE1、SERPINH1、SHMT1、SPARC、TMPRSS12、TPM1、TPM3及其组合中的一种或多种。
本发明的第二方面提供一种检测生物标志物蛋白表达的试剂,所述试剂检测如第一方面所述的生物标志物的蛋白表达。
本发明一些实施方案中,所述试剂可为与所述生物标志物特异性结合,或者与编码所述生物标志物的核酸特异性杂交的生物分子试剂。
本发明中,所述试剂可基于本领域常规技术手段实现对所述标志物组合的表达水平的检测。例如对于抗体,可通过芯片(蛋白质芯片和微流控芯片等)、数字式单分子免疫阵列、ELISA、放射免疫测定法、免疫透射比浊法、免疫组织化学法、Western印迹等检测。
本发明一些较佳实施方案中,所述生物分子试剂选自引物、探针和抗体。
本发明的第三方面提供一种试剂盒,所述试剂盒包括如第二方面所述的试剂。
本发明的第四方面提供一种如第一方面所述的生物标志物、如第二方面所述的试剂或如第三方面所述的试剂盒在制备预测或诊断或辅助诊断胎儿先天性心脏病的试剂或产品中的应用。
本发明一些实施方案中,所述产品包括芯片、试剂盒、试纸和高通量测序平台。
本发明的第五方面提供一种辅助诊断胎儿先天性心脏病的方法,所述方法包括:
定量检测待测样本中生物标志物的蛋白表达水平,并与所述待测样本的来源的个体的临床病理信息关联分析;其中,所述生物标志物为如第一方面所述的生物标志物。
本发明一些实施方案中,所述定量检测为质谱检测或高通量蛋白质组学检测。
本发明一些实施方案中,所述待测样本包括母体血液、尿液、羊水、唾液和胎儿标本。
本发明一些具体实施方案中,所述待测样本为母体血液。
本发明的第六方面提供一种胎儿先天性心脏病风险预测或早期诊断的系统,所述系统包括检测模块和分析判断模块;所述检测模块检测待测样本中的生物标志物的蛋白表达水平,并将蛋白表达水平的数据传输至所述分析判断模块;
所述分析判断模块分析蛋白表达水平的数据,当生物标志物的蛋白表达水平达到预设的阈值时,判断待测样本来源的孕妇的胎儿患先天性心脏病的概率大于不患先天性心脏病的概率;否则判断待测样本来源的孕妇的胎儿患先天性心脏病的概率小于不患先天性心脏病的概率;
其中,所述生物标志物为如第一方面所述的生物标志物。
本发明中,所述阈值可由本领域技术人员或医师根据实际情况进行调整,例如,对于表达下调的生物标志物,其阈值为阴性对照的表达量的1/2。又或者,对于表达上调的生物标志物,其阈值为阴性对照的表达量的2倍。
本发明一些实施方案中,所述系统还包括输出模块,所述输出模块输出所述分析判断模块的判断结果。
本发明的第七方面提供一种计算机可读存储介质,其存储有计算机程序,所述计算机程序被处理器执行时,可实现如第五方面所述的方法的步骤,或者如第六方面所述的系统的功能。
本发明的第八方面提供一种电子设备,其包括存储器和处理器,所述存储器存储有计算机程序,其特征在于,所述处理器用于执行所述计算机程序以实现如第五方面所述的方法的步骤,或者如第六方面所述的系统的功能。
在符合本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:
本发明的74种蛋白生物标志物组合通过实验发现在患有先天性心脏病胎儿的母体血液中表达量存在显著变化,因此可以作为先天性心脏病胎儿的风险预估与检测,根据上述生物标志物组合构建的用于评估胎儿先天性心脏病风险的系统具有高灵敏度和高特异性的优点,可以为先天性心脏病胎儿产前筛查、早期诊断、干预治疗等提供有利的技术支持;并且,可以基于例如母体血浆蛋白的生物标志物研制相应的辅助早期诊断试剂盒,具有广泛的科研价值并为临床诊断、干预治疗等提供了巨大的便利。
附图说明
图1为本发明74种生物标志物的检测结果示意图;
图中:A为生物标志物在训练集中的检测结果,B为生物标志物在内部测试集中的验证结果,C为生物标志物在外部验证集中的检测结果。
图2为预测胎儿先天性心脏病风险的系统的结构示意图;
图中:61为预测或早期诊断胎儿先天性心脏病的系统;51为检测模块;52为分析判断模块;53为输出模块。
图3为电子设备的结构示意图。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
实施例1
实施例中所需的孕9-12周母体外周血液样本分别从上海复旦大学妇产科医院和中国福利院国际和平妇幼保健院两个中心收集,分别得138例和69例样本。本研究的设计和实施由上海复旦大学妇产科医院伦理委员会和中国福利院国际和平妇幼保健院伦理委员会通过伦理投票批准和监督。
采样时记录怀有CHD胎儿的孕妇及怀有正常胎儿的孕妇孕周相等必要数据。
1、分离血浆
采集全血样品,于EDTA抗凝管中颠倒混匀后,使用4℃低温离心机,1,600×g离心10min,离心后收集上清(血浆)至新的EP管中,16,000×g离心10min去除细胞碎片,将血浆分装至离心管中,-80℃冻存备用。
2、孕妇血浆样本前处理
根据制造商的说明,使用高丰度Top14蛋白质去除专用试剂盒(Thermo Fisher,Waltham,MA,USA)去除2μL血浆样本中的高丰度蛋白。向体系中加入浓度为10mM的碳酸氢铵,加适量氨水调整体系的pH至8,将样品95℃孵育3min使蛋白质热变性,冷却至室温后,向体系中加入1μg胰蛋白酶(Trypsin),于37℃下振荡15h,然后向体系中加入10μL氨水停止酶解。将酶解后的肽段样品进行脱盐处理,抽干,冻存于-80℃直至质谱检测。
3、孕妇血浆样本的质谱检测
用Orbitrap Fusion Lumos三合一高分辨质谱系统(Thermo Fisher Scientific,Rockford,USA)和高效液相色谱系统(EASY-nLC 1200,Thermo Fisher)进行检测,并得到该肽样品对应的质谱数据。
采用纳流液相色谱,色谱柱为自制C18色谱柱(150μm ID×15cm, 填料)。柱温箱温度60℃。将干粉状肽段用12μL上样缓冲液(0.1%甲酸的水溶液)复溶,上样量为5μL,以600nL/min的线性15-30%流动相B(ACN和0.1%甲酸)分离多肽,利用75min液相梯度结合数据非依赖性获取(Data Independent Acquisition,DIA)获取质谱检测数据。DIA质谱检测参数设置如下:离子模式为正离子;一级质谱分辨率60K,最大注入时间为50ms,AGC Target为4.0e5,扫描范围为300-1400m/z;二级扫描分辨率15K,获取30个可变隔离窗口,碰撞能量30%,MS2的默认电荷状态设置为3。
4、数据分析
所有数据均使用Firmiana进行处理。Firmiana是一个基于Galaxy系统的工作流,由用户登录界面、原数据、识别与量化、数据分析和知识挖掘等多个功能模块组成。DIA数据使用FragPipe(v12.1)和MSFragger(2.2)对UniProt人蛋白质数据库(于2019.12.17更新,20406个条目)进行搜索。母离子的质量差为20ppm,子离子的质量差为50mmu。最多允许两个漏切位点。搜索引擎将半胱氨酸氨基甲酰甲基化设置为固定修饰,将甲硫氨酸的N-乙酰化和氧化设置为可变修饰。母离子电荷范围设为+2、+3和+4。错误发现率(False DiscoveryRate,FDR)设为1%。使用SpectraST软件将DIA数据的结果合并到参考库中。总共327个库用作参考库。
将所鉴定的肽段定量结果记为所有参考谱库中色谱碎片离子峰面积的平均值。使用无标签的基于强度的绝对定量(Intensity Based Absolute Auantification,iBAQ)方法进行蛋白质定量。发明人计算了峰面积值作为相应蛋白质的一部分。总分数(FOT)用于表示样品中特定蛋白质的标准化丰度。FOT定义为蛋白质的iBAQ除以样品中所有已鉴定蛋白质的总iBAQ。选择具有至少一条专属肽段(unique peptide)且1%FDR的蛋白质进行进一步分析。
5、用于先天性心脏病胎儿早筛的蛋白质生物标志物
构建用于先天性心脏病胎儿早筛蛋白质分子的分类器,包括发现、测试及验证三个阶段。
实施例中将138例先天性心脏病胎儿和正常胎儿的母体血液样本随机分为训练集(Training Set)和内部测试集,训练集中包含随机抽取的103例样本(75%),剩下的35例样本(25%)作为内部测试集。对训练集中的103例样本采用逻辑回归(Logistic Regression)算法进行分类器的构建。逻辑回归的方法为本领域所熟知,其中一种方法可参见Ruczinski,Journal of Computational and Graphical Statistics 12:475-512(2003)。逻辑回归在估计错误率时采用10倍交叉验证法,首先将103例样本随机分为10等分。用其中的9等分样本构建模型,用剩下的10%样本进行测试,如此重复10次,计算测试10次的ROC曲线(Receiver Operating Curve)的平均值。选取平均值排名前74的分子标志物用于后续验证。74种蛋白质分子标志物在训练集中的相对表达水平绘制ROC曲线(Receiver OperatingCurve),AUC=1.000,诊断灵敏度(Sensitivity)100.00%,特异性(Specificity)100.00%(如图1的A所示)。
将这74个蛋白质分子构成的模型用于预测内部测试集,35例内部测试集的AUC=0.902,诊断灵敏度80.00%,特异性85.00%(如图1的B所示)。另外,将上海国妇婴医院的69例孕妇血浆样本设为外部验证集(Validation Set),AUC=1.000,诊断灵敏度100.00%,特异性100.00%(如图1的C所示)。
由上述结果可知,孕妇血浆中的74种蛋白分子标志物(ACLY、AKR1C3、CAPN5、CNDP2、ENOPH1、H2AC4、H2AC6、H2AW、H2BC11、H2BC17、H2BC21、H2BC3、H2BU1、HSP90AA1、HSP90AA5P、KPNB1、MDH2、MYL9、NRP2、PRPF8、PTPRF、RDX、RPL27、S100A7、SAMHD1、AOC2、ARPC4、BAG2、BASP1、CASP14、CEL、CFHR2、CFHR4、CHL1、COLEC10、COTL1、CSN2、EHD1、EPB42、ERAP1、EXOC3、G6PD、GFAP、GZMM、H6PD、HADHB、HSPD1、IRGQ、KLK12、KLK13、KLK7、L1CAM、LIMCH1、LMAN2、NDUFA10、NPM1、NSF、NT5C、PABPC1、PABPC4、PEPD、PF4、PF4V1、RALY、RPS6KA3、SERPINB3、SERPINB4、SERPINE1、SERPINH1、SHMT1、SPARC、TMPRSS12、TPM1、TPM3)联用,可用于先天性心脏病胎儿产前筛查及早期诊断。
实施例2预测或早期诊断胎儿先天性心脏病的系统
预测或早期诊断胎儿先天性心脏病的系统61:检测模块51和分析判断模块52,一些实施方式中还包括输出模块53(图2)。
检测模块51用于检测待测样本中所述生物标志物的蛋白表达水平数据,并将其传输给分析判断模块52。
所述分析判断模块52分析蛋白表达水平的数据,当生物标志物的蛋白表达水平达到预设的阈值时,判断待测样本来源的孕妇的胎儿患先天性心脏病的概率大于不患先天性心脏病的概率;否则判断待测样本来源的孕妇的胎儿患先天性心脏病的概率小于不患先天性心脏病的概率。
输出模块53用于将分析判断模块52中的判断结果以可视化或其他用户友好型方式输出。
进一步地,所述判断结果可以作为医师进行疾病风险评估、诊断的辅助数据。
实施例3电子设备
本实施例提供了一种电子设备,电子设备可以通过计算设备的形式表现(例如可以为服务器设备),包括存储器、处理器及存储在存储器上并可在处理器上运行的计算机程序,其中处理器执行计算机程序时可以实现本发明实施例2中预测或早期诊断胎儿先天性心脏病的方法。
图3示出了本实施例的硬件结构示意图,电子设备9具体包括:
至少一个处理器91、至少一个存储器92以及用于连接不同系统组件(包括处理器91和存储器92)的总线93,其中:
总线93包括数据总线、地址总线和控制总线。
存储器92包括易失性存储器,例如随机存取存储器(RAM)921和/或高速缓存存储器922,还可以进一步包括只读存储器(ROM)923。
存储器92还包括具有一组(至少一个)程序模块924的程序/实用工具925,这样的程序模块924包括但不限于:操作系统、一个或者多个应用程序、其它程序模块以及程序数据,这些示例中的每一个或某种组合中可能包括网络环境的实现。
处理器91通过运行存储在存储器92中的计算机程序,从而执行各种功能应用以及数据处理,例如本发明实施例4的数据分析方法。
电子设备9进一步可以与一个或多个外部设备94(例如键盘、指向设备等)通信。这种通信可以通过输入/输出(I/O)接口95进行。并且,电子设备9还可以通过网络适配器96与一个或者多个网络(例如局域网(LAN),广域网(WAN)和/或公共网络,例如因特网)通信。网络适配器96通过总线93与电子设备9的其它模块通信。应当明白,尽管图中未示出,可以结合电子设备9使用其它硬件和/或软件模块,包括但不限于:微代码、设备驱动器、冗余处理器、外部磁盘驱动阵列、RAID(磁盘阵列)系统、磁带驱动器以及数据备份存储系统等。
应当注意,尽管在上文详细描述中提及了电子设备的若干单元/模块或子单元/模块,但是这种划分仅仅是示例性的并非强制性的。实际上,根据本申请的实施方式,上文描述的两个或更多单元/模块的特征和功能可以在一个单元/模块中具体化。反之,上文描述的一个单元/模块的特征和功能可以进一步划分为由多个单元/模块来具体化。
实施例4计算机可读存储介质
本发明实施例提供了一种计算机可读存储介质,其上存储有计算机程序,程序被处理器执行时实现本发明实施例2中预测或早期诊断胎儿先天性心脏病的方法的步骤。
其中,可读存储介质可以采用的更具体可以包括但不限于:便携式盘、硬盘、随机存取存储器、只读存储器、可擦拭可编程只读存储器、光存储器件、磁存储器件或上述的任意合适的组合。
在可能的实施方式中,本发明还可以实现为一种程序产品的形式,其包括程序代码,当所述程序产品在终端设备上运行时,所述程序代码用于使所述终端设备执行实现本发明实施例2中预测或早期诊断胎儿先天性心脏病的方法的步骤。
其中,可以以一种或多种程序设计语言的任意组合来编写用于执行本发明的程序代码,所述程序代码可以完全地在用户设备上执行、部分地在用户设备上执行、作为一个独立的软件包执行、部分在用户设备上部分在远程设备上执行或完全在远程设备上执行。
本发明涉及的生物标志物:
ACLY:ATP citrate lyase
AKR1C3:aldo-keto reductase family 1member C3
AOC2:amine oxidase copper containing 2
ARPC4:actin related protein 2/3complex subunit 4
BAG2:BAG cochaperone 2
BASP1:brain abundant membrane attached signal protein 1
CAPN5:calpain 5
CASP14:caspase 14
CEL:carboxyl ester lipase
CFHR2:complement factor H related 2
CFHR4:complementfactorHrelated 4
CHL1:cell adhesion molecule L1 like
CNDP2:carnosine dipeptidase 2
COLEC10:collectin subfamily member 10
COTL1:coactosin like F-actin binding protein 1
CSN2:casein beta
EHD1:EH domain containing 1
ENOPH1:enolase-phosphatase 1
EPB42:erythrocyte membrane protein band 4.2
ERAP1:endoplasmic reticulum aminopeptidase 1
EXOC3:exocyst complex component 3
G6PD:glucose-6-phosphate dehydrogenase
GFAP:glial fibrillary acidic protein
GZMM:granzyme M
H2AC4:H2A clustered histone 4
H2AC6:H2A clustered histone 6
H2AW:H2A clustered histone 25
H2BC3:H2B clustered histone 3
H2BC11:H2B clustered histone 11
H2BC17:H2B clustered histone 17
H2BC21:H2B clustered histone 21
H2BU1:H2B.U histone 1
H6PD:hexose-6-phophate dehydrogenase
HADHB:hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complexsubunit beta
HSP90AA1:heat shock protein 90 alpha family class A member 1
HSP90AA5P:heat shock protein 90 alpha family class A member 5,pseudogene
HSPD1:heat shock protein family D member 1
IRGQ:immunity related GTPase Q
KLK7:kallikrein related peptidase 7
KLK12:kallikrein related peptidase 12
KLK13:kallikrein related peptidase 13
KPNB1:karyopherin subunit beta 1
L1CAM:L1 cell adhesion molecule
LIMCH1:LIM and calponin homology domains 1
LMAN2:lectin,mannose binding 2
MDH2:malate dehydrogenase 2
MYL9:myosin light chain 9
NDUFA10:NADH:ubiquinone oxidoreductase subunit A10
NPM1:nucleophosmin 1
NRP2:neuropilin 2
NSF:N-ethylmaleimide sensitive factor
NT5C:5’,3’-nucleotidase,cytosolic
PABPC1:poly(A)binding protein cytoplasmic 1
PABPC4:poly(A)binding protein cytoplasmic 4
PEPD:peptidase D
PF4:platelet factor 4
PF4V1:platelet factor 4 variant 1
PRPF8:pre-mRNA processing factor 8
RALY:heterogeneous nuclear ribonucleoprotein-associated withlethalyellow
RDX:radixin
RPL27:ribosomal protein L27
PTPRF:protein tyrosine phosphatase receptor type F
RPS6KA3:ribosomal protein S6 kinase A3
S100A7:S100 calcium binding protein A7
SAMHD1:SAM and HD domain containing deoxynucleosidetriphosphatetriphosphohydrolase 1
SERPINB3:serpin family B member 3
SERPINB4:serpin family B member 4
SERPINE1:serpin family E member 1
SERPINH1:serpin family H member 1
SHMT1:serine hydroxymethyltransferase 1
SPARC:secreted protein acidic and cysteine rich
TMPRSS12:transmembrane serine protease 12
TPM1:tropomyosin 1
TPM3:tropomyosin 3
Claims (10)
1.一种用于诊断或辅助诊断胎儿先天性心脏病的生物标志物,其特征在于,所述生物标志物包含ACLY、AKR1C3、CAPN5、CNDP2、ENOPH1、H2AC4、H2AC6、H2AW、H2BC11、H2BC17、H2BC21、H2BC3、H2BU1、HSP90AA1、HSP90AA5P、KPNB1、MDH2、MYL9、NRP2、PRPF8、PTPRF、RDX、RPL27、S100A7、SAMHD1、AOC2、ARPC4、BAG2、BASP1、CASP14、CEL、CFHR2、CFHR4、CHL1、COLEC10、COTL1、CSN2、EHD1、EPB42、ERAP1、EXOC3、G6PD、GFAP、GZMM、H6PD、HADHB、HSPD1、IRGQ、KLK12、KLK13、KLK7、L1CAM、LIMCH1、LMAN2、NDUFA10、NPM1、NSF、NT5C、PABPC1、PABPC4、PEPD、PF4、PF4V1、RALY、RPS6KA3、SERPINB3、SERPINB4、SERPINE1、SERPINH1、SHMT1、SPARC、TMPRSS12、TPM1、TPM3及其组合中的一种或多种。
2.一种检测生物标志物蛋白表达的试剂,其特征在于,所述试剂检测如权利要求1所述的生物标志物的蛋白表达;
较佳地,所述试剂为与所述生物标志物特异性结合,或者与编码所述生物标志物的核酸特异性杂交的生物分子试剂;
更佳地,所述生物分子试剂选自引物、探针和抗体。
3.一种试剂盒,其特征在于,所述试剂盒包括如权利要求2所述的试剂。
4.一种如权利要求1所述的生物标志物、如权利要求2所述的试剂或如权利要求3所述的试剂盒在制备预测或诊断或辅助诊断胎儿先天性心脏病的试剂或产品中的应用;
较佳地,所述产品包括芯片、试剂盒、试纸和高通量测序平台。
5.一种辅助诊断胎儿先天性心脏病的方法,其特征在于,所述方法包括:
定量检测待测样本中生物标志物的蛋白表达水平,并与所述待测样本的来源的个体的临床病理信息关联分析;
其中,所述生物标志物为如权利要求1所述的生物标志物。
6.如权利要求5所述的方法,其特征在于,所述定量检测为质谱检测或高通量蛋白质组学检测;和/或,所述待测样本包括母体血液、尿液、羊水、唾液和胎儿标本。
7.一种胎儿先天性心脏病风险预测或早期诊断的系统,其特征在于,所述系统包括检测模块和分析判断模块;所述检测模块检测待测样本中的生物标志物的蛋白表达水平,并将蛋白表达水平的数据传输至所述分析判断模块;
所述分析判断模块分析蛋白表达水平的数据,当生物标志物的蛋白表达水平达到预设的阈值时,判断待测样本来源的孕妇的胎儿患先天性心脏病的概率大于不患先天性心脏病的概率;否则判断待测样本来源的孕妇的胎儿患先天性心脏病的概率小于不患先天性心脏病的概率;
其中,所述生物标志物为如权利要求1所述的生物标志物。
8.如权利要求7所述的系统,其特征在于,所述系统还包括输出模块,所述输出模块输出所述分析判断模块的判断结果。
9.一种计算机可读存储介质,其存储有计算机程序,其特征在于,所述计算机程序被处理器执行时,可实现如权利要求5或6所述的方法的步骤,或者如权利要求7或8所述的系统的功能。
10.一种电子设备,其包括存储器和处理器,所述存储器存储有计算机程序,其特征在于,所述处理器用于执行所述计算机程序以实现如权利要求5或6所述的方法的步骤,或者如权利要求7或8所述的系统的功能。
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