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通讯作者:

石河子大学校级科研项目(ZZZC202062A)通信作者:单红英(1980-),女,新疆石河子人,副主任医师,主要从事生殖医学方面的研究。E-mail:hongyingshan@bjmu.edu.cn

中图分类号:R711.71

文献标识码:A

文章编号:2096-8965(2022)04-0065-14

DOI:10.12287/j.issn.2096-8965.20220409

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目录contents

    摘要

    目的 通过 Meta分析评价血液 miRNA对子宫内膜异位症的诊断价值,确定血液 miRNA作为区分子宫内膜异位症无创性诊断生物标志物。方法 检索中英文数据库从建库至2022年9月关于血液miRNA诊断子宫内膜异位症的相关文献,提取文献数据,采用Stata14.0软件和RevMan 5.4用于数据分析和质量评估。结果 共纳入了24篇相关文献,血液miRNA作为诊断子宫内膜异位症的总灵敏度为0.86,特异性为0.84,阳性似然比为5.3,阴性似然比为0.17,诊断优势比 (Diagnostic odds Rotio,DOR) 为31,曲线下面积 (Area Under the Curve,AUC) 为0.91,进行元回归及亚组分析,血清、亚洲和非洲人群、异位内膜表达上调的miRNA诊断EMs的准确价值较高。结论 血液miRNA可以作为子宫内膜异位症诊断生物标志物,血清中表达上调的miRNA在亚洲和非洲人群中诊断子宫内膜异位症 (Endometriosis,EMs) 的诊断价值较高。

    Abstract

    Objective The value of blood miRNA for the diagnosis of endometriosis was evaluated by Metaanalysis, for which it was identified as a non-invasive diagnostic biomarker to distinguish endometriosis. Methods English and Chinese language databases were searched for relevant literature on blood miRNAs for the diagnosis of endometriosis reported up until September 2022. The appropriate data was derived from the literature and analyzed and assessed using Stata14.0 and RevMan5.4. Results A total of 24 relevant papers were included. As a diagnostic tool for endometriosis, blood miRNA has an overall sensitivity of 0.86, specificity of 0.84, positive likelihood ratio of 5.3, negative likelihood ratio of 0.17, diagnostic odds ratio (DOR) of 31, and area under the curve (AUC) of 0.91. The research featured meta-regression and subgroup analysis, and the upregulation of expression by miRNA in blood serum, Asian and African populations had a higher accuracy value for diagnosing endometriosis. Conclusion Blood miRNAs can thus be used as diagnostic biomarkers for endometriosis, with the miRNAs upregulation in serum expression having a higher diagnostic value for diagnosing endometriosis in Asian and African populations.

  • 0 前言

  • 子宫内膜异位症 (Endometriosis,EMs) 是一种常见的妇科良性疾病,主要是指子宫内膜组织在子宫腔以外的部位生长[1],包括卵巢、输卵管、腹腔等。EMs最常见的临床症状包括慢性盆腔痛、深部性交痛及不孕[2],影响了大约 10% 育龄期妇女[3],部分EMs患者早期无明显临床症状,因此,EMs的真正患病率尚不能确定。EMs 缺乏早期诊断方法,经阴道超声 (Transvaginal Sonography,TVS) 诊断因操作者的不同,结果差异较大;MRI等影像学检查可以识别EMs的深部病灶,但并不能很好诊断出早期浅表病灶[4];血清 CA125 是广泛应用于 EMs 诊断中的无创标志物,其作为单一血清诊断标志物时敏感度较高,但特异度仅有57%。因此,其并不适用于 EMs 的早期诊断[5]。腹腔镜手术是确诊 EMs 的唯一金标准,但腹腔镜作为一种有创的诊断方法,存在创伤大、费用高以及风险较大等缺点,并导致诊断时间延长,可能 4-11 年不等,其中 65% 的患者更可能存在误诊[6]。EMs 发病与诊断之间的延迟导致慢性疼痛持续时间长且加重,并增加不孕症发生概率,甚至导致二次手术[7],严重影响患者的身体及心理健康。因此,急需一种无创生物标志物,提高早期EMs诊断的特异度及敏感度,可以对EMs 患者进行早期诊断,早期治疗,改善其生活质量及相关预后。

  • 液体活检是一种非侵入诊断方法,主要通过检测血液、尿液等体液中的肿瘤来源的蛋白质、核酸和外泌体等循环生物标志物,从而实现疾病的早期诊断,其具有非侵入性、准确性高、易取样等优点[8]。研究表明,miRNA 在 EMs患者中存在差异性表达,主要在血液、唾液以及子宫内膜等相应靶组织中[910]。miRNA 具有高度保守性,不易突变的特征[11],且表达较稳定,基本不受年龄、体重指数 (Body Mass Index,BMI) 等影响。许多研究已经证明了血液 miRNAs 作为 EMs 生物标志物的潜力, EMs 血液中 miRNA 主要包括血清 miRNA 和血浆 miRNA,其具有易获得、损伤小、检测方便的优点[7]。因此,血液中 miRNA 可能成为早期诊断 EMs 的液体活检工具。本研究全面检索血液 miRNA 对EMs的诊断价值文献,并对其进行荟萃分析,探索血液 miRNA 作为 EMs 无创生物学标志物的诊断效能,为EMs患者早期诊断、早期治疗提供依据,改善其预后及生活质量。

  • 1 方法

  • 1.1 文献检索

  • 全面检索中文数据库中国知网 (CNKI)、万方数据、中国生物医学 (CBM) 维普资讯及英文数据库PubMed、Cochrane library、Embase数据库,检索时间自建库至2022年9月,中文检索主题词为“子宫内膜异位症”、“血清miRNA”、“血浆miRNA”以及“血液miRNA”,英文检索主题词和MeSH术语以 “Endometriosis”以及“miRNA”,PubMed检索公式: PuMed:(((((((((((((((((((((((microRNA[Title/Abstract])OR(MicroRNA[Title/Abstract]))OR(miRNAs[Title/ Abstract]))OR(Micro RNA[Title/Abstract]))OR(RNA,Micro[Title/Abstract]))OR(miRNA[Title/Abstract]))OR(Primary MicroRNA[Title/Abstract]))OR(MicroRNA,Primary[Title/Abstract]))OR(Primary miRNA[Title/ Abstract]))OR(miRNA,Primary[Title/Abstract]))OR(pri-miRNA[Title/Abstract]))OR(pri miRNA[Title/ Abstract]))OR(RNA,Small Temporal[Title/Abstract])))OR(Temporal RNA,Small[Title/Abstract]))OR(stRNA [Title/Abstract]))OR(Small Temporal RNA[Title/ Abstract]))OR(pre-miRNA[Title/Abstract]))OR(pre miRNA[Title/Abstract]))OR("MicroRNAs"[Mesh])))OR(miR[Title/Abstract]))OR(mir[Title/Abstract]))AND(("Endometriosis"[Mesh])OR(((Endometrioses [Title/Abstract])OR(Endometrioma[Title/Abstract]))OR(Endometriomas[Title/Abstract])))("microrna"[Title/ Abstract]OR"microrna"[Title/Abstract] OR "miRNAs" [Title/Abstract] OR "micro rna"[Title/Abstract] OR "rna micro"[Title/Abstract] OR "miRNA"[Title/Abstract] OR "primary microrna"[Title/Abstract] OR "microrna primary"[Title/Abstract] OR "primary mirna"[Title/ Abstract] OR "mirna primary"[Title/Abstract] OR "primiRNA"[Title/Abstract] OR "pri-miRNA"[Title/ Abstract] OR(("RNA"[MeSH Terms] OR "RNA"[All Fields])AND "small temporal"[Title/Abstract])OR(("Temporal"[All Fields]OR "temporally"[All Fields]OR "temporals"[AllFields])AND"rnasmall"[Title/Abstract])OR "stRNA"[Title/Abstract] OR "small temporal rna" [Title/Abstract] OR "pre-miRNA"[Title/Abstract] OR "pre-miRNA"[Title/Abstract] OR "MicroRNAs"[MeSH Terms] OR "miR"[Title/Abstract] OR "miR"[Title/ Abstract])AND("Endometriosis"[MeSH Terms] OR("Endometrioses"[Title/Abstract] OR "Endometrioma" [Title/Abstract]OR"Endometriomas"[Title/Abstract]))。

  • CBM 检索公式:(("血液 miRNA"[常用字段:智能] OR "血液 miR-"[常用字段:智能])OR(("血浆 miR-"[常用字段:智能] OR "血清miR-"[常用字段:智能])OR(血浆 miRNA)OR(血清 miRNA)))AND((子宫内异症)OR(内异症)OR("子宫内膜异位症"[不加权:扩展]))

  • 1.2 纳入及排除标准

  • 1.2.1 纳入标准

  • (1) 研究对象:腹腔镜术后诊断为子宫内膜异位症患者。(2) 干预措施:通过微阵列或 (和) RT-PCR 实验检测 EMs 患者血液中 miRNA 的表达,包括血清及血浆。(3) 可直接或间接获得相关诊断数据。

  • 1.2.2 排除标准

  • (1) 有关血液 miRNAs 在其他妇科恶性肿瘤表达。(2) 无腹腔镜病理诊断。(3) 动物实验以及体外细胞实验等基础实验。(4) 重复文献、综述、会议摘要、未公开发表以及无法获取全文数据的文献。

  • 1.3 文献筛选

  • 由两位研究者独立按照纳入与排除标准进行筛选文献和资料提取,并将提取资料进行交叉核对,如有争议由第3位研究者进行协商。提取资料主要包括作者、发表年份、样本量、miRNA、敏感度 (Sensitivity,Se)、特异度 (Specificity,Sp)、曲线下面积 (AUC)、真阳性 (TP)、假阳性 (FP)、真阴性 (TN) 以及假阴性 (FN)。

  • 1.4 质量评价

  • 用诊断实验准确性质量评价工具-2(Quality As⁃ sessment of Diagnostic Accuracy Studies-2,QUADAS-2)对病例的选择、待评价实验、病例流程与进展情况进行偏倚风险与临床适用性的评估。

  • 1.5 统计学方法

  • 使用 Stata14.0 和 RevMan5.4 软件进行数据分析和质量评估,根据敏感度、特异度、样本量以及子宫内膜异位症患病率计算综合敏感度、特异度、阳性似然比 (Positive Likelihood Ratio,LR+)、阴性似然比 (Negative Likelihood Ratio,LR-) 以及诊断性试验比值比 (Diagnostic Odds Ratio,DOR),绘制综合受试者工作曲线 (Summary Receiver Operat⁃ ing Characteristic,SROC)评估曲线下面积(AUC),使用 Spearman 秩检验研究之间是否存在阈值效应, P >0.05,说明不存在阈值效应引起的异质性;非阈值效应产生异质性由 Cochran-Q 值和 I 2 检验值评估,I 2 ≥ 50%认为异质性显著。P <0.1或者I 2 ≥50% 认为异质性显著。

  • 2 结果

  • 2.1 文献检索结果

  • 对数据库进行初步检索,共检索相关中文文献 89篇,英文文献963篇,通过检索参考文献、灰色文献发现 1 篇,进行初步筛选后得到文献 535 篇,阅读标题、摘要后剔除研究内容不吻合498篇,阅读全文后排除 13 篇文献,最终参与 Meta 分析的文献共有24篇。检索流程图如图1。

  • 图1 文献检索流程图

  • 2.2 纳入文献基本特征

  • 共纳入 24 篇相关研究文献,子宫内膜异位症患者1 292名,非子宫内膜异位症患者1 013名。文献基本特征如表1,13篇文献关于血清miRNA,11 篇文献关于血浆 miRNA。纳入文献中共 46 个 miRNA 在 EMs 中表达进行了差异性分析,其中 13 个 miRNA (miR-200c、 miR-199b-3p、 miR-122、 miR-199a、 miR-125-3p、 miR-140-5p、 miR-125b、miR-150、miR-342、miR-451a、miR-122-5p、miR-199-5p、miR-125b-5p) 在EMs中表达上调, 33 个 miRNA (miR-455、 miR-17-5p、 miR-424-5p、 miR-148a、 miR-34a-5p、 miR-224-5、 let-7d-3p、 miR-188-5p、 miR-4741、 miR-3613、 let-7b、 miR-199a-3p、 miR-143-3p、 miR-340-5p、 let-7b-5p、 miR-21-5p、 miR-20a-5p、 miR-103a-3p、 miR-185-5p、 miR-141、 miR-145、 miR-923、 miR-139-3p、 miR-155、 miR-574-3p、 miR-154-5p、 miR-200a、 miR-200b、 let-7d、 miR-20a、miR-22、miR-542-3p、miR-9) 在 EMs中表达下调。纳入文献中 7 个 miRNA (miR-141、 miR-17-5p、 miR-122、 miR-199a、 miR-145、 miR-199a-3p、miR-451a) 诊断价值在多篇文献中进行了描述,9 篇文献对 20 个 miRNA 联合诊断模型进行了描述,因此,纳入文献中共有 78 个相关变量参与Meta分析。

  • 表1 24篇纳入研究的文献基本特征

  • 续表

  • 续表

  • 续表

  • 续表

  • 图2 24篇纳入研究的文献质量评价

  • 2.3 纳入研究质量评价结果

  • 使用RevMan5.4软件根据QUADAS-2量表将纳入研究的 24 篇文献进行质量评价 (见图2)。结果显示所纳入文献总体质量在中高等,在偏倚风险中主要存在病例流程偏倚风险,即纳入文献有部分未能明确指出抽血时间与金标准的判断时间间隔是否合适,在临床适用性方面,所纳入文献质量较高。

  • 2.4 统计分析结果

  • 异质性检验:图3A提示大部分数据位于中心区域,但总的离散度较明显,提示异质性较大,异质性结果分析敏感度I 2 = 85.00(95%CI:82.17~87.84), P = 0.00 和 I 2 = 84.52 (95%CI:81.57~87.47),P = 0.00,总的异质性 I 2 = 99 (95%CI:98~99),P = 0.00。阈值效应引起的异质性相关系数为0.26 (P = 0.07),差异无统计学意义。因此,存在非阈值效应引起的差异性,可采用随机效应模型。

  • 采用随机效应模型得到合并敏感性和特异性分别为0.86(95%CI:0.83~0.88)和0.84(95%CI:0.80~0.87),如图4。LR+和 LR-的总体结果分别为 5.3 (95%CI: 4.1~6.7) 和 0.17 (95%CI: 0.14~0.21), DOR为31 (95%CI:21~46)。总的受试者工作特征 SROC 也显示了 AUC 为 0.91 (95%CI: 0.89~0.94) (见图3B)。

  • Fagan 的列线图和似然比图也可用于评价 miRNA 的临床效用,根据 Fagan 列线 (见图3D),检验前概率为 20%,检验后阳性概率为 57%,PLR 为5,检验后阴性概率为4%,NLR为0.17。似然比图中PLR >10和NLR <0.1是诊断准确性高的指标,如图3C,LR+和LR-的总结点在右下象限,但在所有 miRNA 数据中,位于左上象限的 miRNA (miR-200c、miR-199b-3p+miR-224-5+let-7d-3p、miR-122、miR-199a、miR-145+miR-923+miR-141、miR-125b-5p、miR-199a+miR-122+miR-145+miR-542-3p)诊断价值较高。

  • 2.5 元回归分析和亚组分析

  • 血液 miRNA 诊断性 Meta 分析中异质性较大,进行元回归、亚组检验分析异质性的来源。使用元回归方法评估血液样本、单一或联合 miRNA、种族、EMs 分期以及 miRNA 在异位子宫内膜中表达对异质性的影响 (见图5)。结果显示,敏感度异质性受到血液样本、单一或联合 miRNA、种族、 EMs 分期以及 miRNA 在异位子宫内膜中表达的影响,特异度异质性受到单一或联合 miRNA、种族以及 miRNA 在异位子宫内膜中表达的影响 (见表2)。

  • 图3 (A) 双变量箱线图;(B) 血液miRNA在子宫内膜异位症诊断中SROC曲线;(C) 似然比图;(D) Fagan列线图

  • 图4 血液miRNA在子宫内膜异位症中诊断合并敏感性及特异性的Meta分析

  • 图5 元回归分析异质性影响

  • 元回归结果表明,血液样本、种族以及 miRNA 在 EMs 中的表达是导致异质性的原因。因此对其进行亚组分析 (见表3),评估不同分组血液样本 (血清或血浆)、种族 (亚非洲或欧美洲) 以及miRNA在异位子宫内膜中表达 (上调或下调) 的诊断价值。结果显示,血清 miRNA 比血浆诊断效能高,亚洲和非洲人群诊断准确性高于欧洲和美洲人群,异位内膜中表达上调的 miRNA 较下调的诊断效能有所提高。

  • 2.6 偏倚分析

  • 使用Stata14.0绘制漏斗图检验发表偏倚 (见图6),图形基本对称 (P = 0.25),发表偏倚不显著。

  • 图6 漏斗图

  • 2.7 miR-17-5p的诊断价值

  • 选择重复出现4次及以上的miRNA进行统计分析,确定其对EMs诊断效能。只有miR-17-5p符合要求,其敏感度为 0.84,特异度为 0.78 (LR+ 3.8, LR-0.21,DOR为18,AUC为0.88,I2 = 0)。

  • 表2 元回归的结果

  • 表3 不同分组血液miRNA诊断价值的亚组分析

  • 3 讨论

  • 子宫内膜异位症是一种慢性炎症性疾病,导致育龄期女性长期慢性下腹痛、痛经、深部性交痛、月经异常及不孕等症状[36],临床症状缺乏特异性,尤其在疾病进展的早期阶段,部分患者可没有任何临床症状,导致疾病隐匿期诊断率不高。EMs现有诊断方式血清CA125诊断特异性低,大多用于监测疾病进展及术后随访,阴道超声仅对卵巢型EMs诊断价值较高,MRI 更适于晚期及深部浸润性 EMs,腹腔镜检查其创伤性较大,主要是用于诊断和治疗[37],使得EMs早期诊断率低、诊断时间延长,误诊率较高,严重影响患者身心健康。因此需要一种早期无创性诊断方式提高EMs诊断率。

  • 近年来,体液活检作为一种非侵入诊断方式,较传统腹腔镜活检更加方便、安全。miRNA 作为一种稳定表达的生物学标志物,在多种疾病中诊断价值较高,包括胶质瘤[38]、胃癌[39]、肺癌[40] 以及乳腺癌[41] 等,目前miRNA也已证实可作为多种妇科疾病作为新型生物标志物,如宫颈癌[42]、子宫内膜癌[43] 等。既往研究表明,EMs患者中血液miRNA存在差异性表达,包括血清 miRNA 及血浆 miRNA,血液 miRNA 可作为 EMs 体液活检的一种工具,用于EMs的早期诊断,但相关研究样本量较小,结果存在争议。因此,我们通过对多个小样本血液 miRNA 进行系统的回顾和分析,更加全面搜索相关文献,以评估血液miRNAs对EMs的诊断效能。

  • 本研究对符合纳入标准的相关文献进行 Meta 分析后发现,血液 miRNA 作为 EMs 新型诊断生物标志物,其敏感度为0.86,与血清CA125相近,但特异度为0.84远高于血清CA125,综合诊断价值较高,降低了 EMs的误诊率,提高了其早期诊断率。血液 miRNA 在不同类型 EMs 均存在差异性表达,相比于阴超及MRI诊断更加全面。似然比是评价诊断价值的一个综合性指标,血液 miRNA 的验后概率较验前概率明显升高,提示血液 miRNA 用于诊断 EMs 临床效用增加,证明血液 miRNA 可更加准确全面区分EMs患者与正常女性。

  • 本研究结果提示,血液 miRNA 存在非阈值效应引起的异质性。采用元回归及亚组分析来评价研究异质性来源,元回归结果表明血液样本、种族以及 miRNA 在 EMs 中的表达与异质性有关。对异质性来源相关因素进行亚组分析结果显示血清中表达上调的 miRNA 在亚洲和非洲人群中诊断 EMs 的准确性更高。

  • 虽然许多研究表明 EMs 患者血液 miRNA 存在差异性表达,但并没有指出最合适的 miRNA 作为其诊断生物标志物。一些 miRNA 虽然在多个研究中证实其诊断效能,如miR-17-5p,但并没有在所有研究中证实,需要进一步筛选出一种诊断效能最高的血液 miRNA。本研究提示血清中表达上调的 miRNA 诊断价值更高,可以为未来筛选提供方向。而且现有研究大多基于EMs的疾病发生发展机制的研究,缺乏大规模独立人群实验证实其临床适用性,因此,未来需要确定一种表达上调的血清 miRNA,并进行大规模不同人群、不同环境独立人群的前瞻性随机对照研究,用于子宫内膜异位症的早期诊断。

  • 本研究局限性:(1) 有部分文献原始数据无法获得,存在一定的发表偏倚。(2) 仅纳入了主要在中国以及美国开展的研究,对于其它国家,不同种族人群的研究未进一步验证。(3) 不同 miRNA 可能在EMs中具有不同生物学特性,这可能造成缺乏某一特定的 miRNA 或者确定联合 miRNA 的诊断价值的研究。

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  • 参考文献

    • [1] PEIRIS A N,CHALJUB E,MEDLOCK D.Endometriosis [J].JAMA,2018,320(24):2608.

    • [2] KVASKOFF M,MAHAMAT-SALEH Y,FARLAND L V,et al.Endometriosis and cancer:a systematic review and meta-analysis[J].Hum Reprod Update,2021,27(2):393-420.

    • [3] SHAFRIR A L,FARLAND L V,SHAH D K,et al.Risk for and consequences of endometriosis:a critical epidemiologic review[J].Best Pract Res Clin Obstet Gynaecol,2018,51:1-15.

    • [4] HUDSON Q J,PERRICOS A,WENZL R,et al.Challenges in uncovering non-invasive biomarkers of endometriosis[J].Exp Biol Med(Maywood),2020,245(5):437-447.

    • [5] COUTINHO L M,FERREIRA M C,ROCHA A L L,et al.New biomarkers in endometriosis[J].Adv Clin Chem,2019,89:59-77.

    • [6] TAYLOR H S,KOTLYAR A M,FLORES V A.Endometriosis is a chronic systemic disease:clinical challenges and novel innovations[J].Lancet,2021,397(10276):839-852.

    • [7] ZAFARI N,BAHRAMY A,MAJIDI Z M,et al.MicroRNAs as novel diagnostic biomarkers in endometriosis patients:a systematic review and metaanalysis[J].Expert Rev Mol Diagn,2022,22(4):479-495.

    • [8] DE RUBIS G,RAJEEV KRISHNAN S,BEBAWY M.Liquid biopsies in cancer diagnosis,monitoring,and prognosis[J].Trends in Pharmacological Sciences,2019,40(3):172-186.

    • [9] BENDIFALLAH S,SUISSES S,PUCHAR A,et al.Salivary microRNA signature for diagnosis of endometriosis[J].J Clin Med,2022,11(3):612.

    • [10] ZHAO Y,XU Z H,ZHOU J Z,et al.miR-141 inhibits proliferation,migration and invasion in human hepatocellular carcinoma cells by directly downregulating TGFβR1[J].Oncology Reports,2019,42(5):1656-1666.

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    • [13] LIN C L,ZENG S L,LI M J.miR-424-5p combined with miR-17-5p has high diagnostic efficacy for endometriosis[J].Archives of Gynecology and Obstetrics,2022.

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    • [20] MOUSTAFA S,BURN M,MAMILLAPALLI R,et al.Accurate diagnosis of endometriosis using serum microRNAs[J].American Journal of Obstetrics and Gynecology,2020,223(4):557,e1-557,e11.

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