宏基因组二代测序技术在肺结核诊断中应用价值的meta分析

doi:10.3969/j.issn.1004-583X.2023.05.001

摘要/Abstract

摘要：

目的评价宏基因组二代测序(metagenomic next-generation sequencing,mNGS)应用于不同的临床标本对于肺结核(pulmonary tuberculosis,PTB)的诊断价值。方法计算机检索PubMed、Embase、The Cochrane Library、知网(CNKI)、万方和维普等数据库中于建库至2022年11月公开发表的宏基因组二代测序技术诊断PTB的相关研究,获得的文献经过严格筛选和质量评估,由2名研究人员独立筛选文献, 提取数据,并评估纳入研究偏倚风险之后,采用StataSE16软件和Revman5.3软件进行meta分析。结果纳入符合标准的文献11篇,共计1995例,meta分析结果显示,mNGS检测肺标本诊断PTB的敏感度为70%(95% CI:58%~79%),特异度为99%(95%CI:98%~100%)、阳性似然比(PLR)为106.9(95%CI:31.1~366.6)、阴性似然比(NLR)为0.31(95%CI:0.21~0.43)、诊断比值比(DOR)为350(95%CI:81~1512)、曲线下面积(AUC)为0.97;mNGS检测支气管肺泡灌洗液(broncho alveolar lavage fluid,BALF)诊断PTB敏感度为71%(95%CI:55%~83%),特异度为99%(95%CI:97%~100%), PLR为76.4(95% CI:26.6~218.9),NLR为0.30(95% CI:0.18~0.48),DOR为258(95%CI:75~895)、AUC为0.99;mNGS检测肺组织诊断PTB敏感度为81%(95%CI:69%~89%),特异度为97%(95% CI:88%~99%),PLR为26.0(95%CI:6.6~102.4),NLR为0.19(95%CI:0.11~0.33),DOR为135(95% CI:29~639)、AUC为0.97。结论 mNGS诊断PTB具有较高的应用价值,尤其在痰菌阴性PTB的诊断价值更突出,可作为一种快速诊断PTB的辅助工具。

关键词: 结核, 肺, 宏基因组二代测序, 诊断价值, meta分析

Abstract:

Objective To evaluate the diagnostic value of metagenomic next-generation sequencing (mNGS) technology in different clinical specimens for pulmonary tuberculosis (PTB). Methods Relevant researches on the diagnosis of PTB by using mNGS included in PubMed, Embase, The Cochrane Library, CNKI, Wanfang and Vip and other databases for published from the establishment to November 2022were searched. After strict screening and quality evaluation, the literatures were screened by two researchers independently, followed by data extraction and risk assessment of inclusion study bias. StataSE16 software and Revman5.3 software were used for meta-analysis. Results A total of 11 eligible literature and 1995 patients were included in the meta-analysis. The results showed that the sensitivity and specificity of mNGS for PTB diagnosis in lung specimens was 70% (95% CI: 58%-79%) and 99% (95% CI: 98%-100%), positive likelihood ratio (PLR) was 106.9 (95% CI: 31.1-366.6), negative likelihood ratio(NLR) was 0.31 (95% CI: 0.21-0.43), diagnostic odds ratio(DOR) was 350 (95% CI: 81-1512) and the area under curve(AUC) was 0.97. The sensitivity, specificity, PLR, NLR, DOR, and AUC of mNGS for PTB diagnosis in bronchoalveolar lavage fluid (BALF) were 71% (95% CI: 55%-83%), 99% (95% CI: 97%-100%), 76.4 (95% CI: 26.6-218.9), 0.30 (95% CI: 0.18-0.48), 258 (95% CI: 75-895), and 0.99, respectively. The sensitivity and specificity of mNGS for PTB diagnosis in lung tissues were 81% (95% CI: 69%-89%) and 97% (95% CI: 88%-99%), PLR was 26.0 (95% CI: 6.6-102.4), NLR was 0.19 (95% CI: 0.11-0.33), DOR was 135 (95%CI: 29-639), and AUC was 0.97. Conclusion Application of mNGS technology exerts high diagnostic value for PTB, especially for sputum-negative PTB, which can be used as an auxiliary tool for rapid diagnosis of PTB.

Key words: tuberculosis, pulmonary, metagenomic next-generation sequencing, diagnostic value, meta-analysis

中图分类号:

R521

沃拉孜汗·玛德尼亚提, 迪力夏提·图尔迪麦麦提, 李梦晨, 拜合提尼沙·吐尔地. 宏基因组二代测序技术在肺结核诊断中应用价值的meta分析[J]. 临床荟萃, 2023, 38(5): 389-398.

Wolazihan Madeniyati, Dilixiati Tuerdimaimaiti, Li Mengchen, Baihetinisha Tuerdi. Meta-analysis of the application value of metagenomic next-generation sequencing technology in the diagnosis of pulmonary tuberculosis[J]. Clinical Focus, 2023, 38(5): 389-398.

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链接本文: https://huicui.hebmu.edu.cn/CN/10.3969/j.issn.1004-583X.2023.05.001

https://huicui.hebmu.edu.cn/CN/Y2023/V38/I5/389

图/表 13

图1 文献检索流程图

Fig.1 Flow chart of document retrieval

表1 纳入研究文献特征

Tab.1 Characteristics of included studies

第一作者	年份	PTB组(例)	非PTB组(例)	诊断标准	研究方法	mNGS测序平台	标本类型
Zhou等^[11]	2019	13	14	临床/病原	前瞻性研究	BGISEQ	肺标本
Shi等^[12]	2020	48	62	临床/病原	前瞻性研究	其他	BALF
Chen等^[13]	2020	17	20	临床/病原	回顾性研究	BGISEQ	BALF/肺标本
Jin等^[14]	2020	53	424	临床/病原	回顾性研究	BGISEQ	BALF/肺组织/肺标本
Liu等^[15]	2021	142	111	临床/病原	回顾性研究	BGISEQ	BALF
Zhu等^[16]	2021	46	61	临床/病原	回顾性研究	BGISEQ	BALF/肺组织/肺标本
王春等^[17]	2021	103	24	临床/病原	回顾性研究	BGISEQ	BALF/肺组织/肺标本
孙雯雯等^[18]	2021	100	105	临床/病原	回顾性研究	BGISEQ	肺标本
赵素娥等^[19]	2022	95	60	临床/病原	回顾性研究	未知	BALF
Xu等^[20]	2022	71	23	临床/病原	回顾性研究	其他	BALF
Fu等^[21]	2022	46	357	临床/病原	回顾性研究	其他	肺标本

表2 mNGS检测不同临床标本诊断PTB的四格表数据

Tab.2 Data in four tables for the diagnosis of PTB in different clinical specimens detected by mNGS

标本类型	作者	TP	FP	FN	TN
肺标本	Zhou等^[11]	8	0	5	14
	Chen等^[13]	14	0	3	20
	Jin等^[14]	31	7	22	417
	Zhu等^[16]	41	1	5	60
	王春等^[17]	57	1	46	23
	孙雯雯等^[18]	59	0	41	105
	Fu等^[21]	36	0	10	357
BALF	Shi等^[12]	23	1	25	61
	Chen等^[13]	11	0	3	14
	Jin等^[14]	11	2	10	108
	Liu等^[15]	85	0	57	111
	Zhu等^[16]	29	1	3	45
	王春等^[17]	24	0	17	8
	赵素娥等^[19]	55	0	40	60
	Xu等^[20]	67	0	4	23
肺组织	Jin等^[14]	8	1	1	44
	Zhu等^[16]	12	1	2	14
	王春等^[17]	28	0	8	4

图2 质量评估详细结果

Fig.2 Detailed results of quality assessment

图3 风险偏倚评估图

Fig.3 Risk deviation assessment chart

表3 mNGS在不同标本类型中诊断PTB的参数汇总

Tab.3 Summary of parameters for mNGS diagnostic of PTB in different specimen types

标本类型	敏感度(95% CI)	特异度(95% CI)	PLR(95% CI)	NLR(95% CI)	DOR(95% CI)	AUC(95% CI)
肺标本	70%(58%~79%)	99%(98%~100%)	106.9(31.1~366.6)	0.31(0.21~0.43)	350(81~1512)	0.97(0.95~0.98)
BALF	71%(55%~83%)	99%(97%~100%)	76.4(26.6~218.9)	0.30(0.18~0.48)	258(75~895)	0.99(0.98~1.00)
肺组织	81%(69%~89%)	97%(88%~99%)	26.0(6.6~102.4)	0.19(0.11~0.33)	135(29~639)	0.97(0.95~0.98)

图4 mNGS检测肺标本诊断PTB的灵敏度和特异度森林图

Fig.4 Forest plot of sensitivity and specificity of mNGS detection of lung specimens for the diagnosis of PTB

图5 mNGS检测BALF诊断PTB的灵敏度和特异度森林图

Fig.5 Forest plot of sensitivity and specificity of mNGS detection of BALF for the diagnosis of PTB

图6 mNGS检测肺组织诊断PTB的灵敏度和特异度森林图

Fig.6 Forest plot of sensitivity and specificity of mNGS detection of lung tissue for the diagnosis of PTB

图7 不同标本诊断PTB的SROC曲线 a.mNGS检测肺标本诊断PTB的SROC曲线(图中对应研究编号依次为:①Chen等[13],②Fu等[21],③Jin等[14],④Zhou等[11],⑤Zhu等[16],⑥孙雯雯等[18],⑦王春等[17]);b.mNGS检测BALF诊断PTB的SROC曲线(图中对应研究编号依次为:①Chen 等[13],②jin等[14],③Liu等[15],④Shi等[12],⑤Xu等[20],⑥Zhu等[16],⑦王春等[17],⑧赵素娥等[19]);c.mNGS检测肺组织诊断PTB的SROC曲线(图中对应研究标号依次为:①Jin等[14],②Zhu等[16],③王春等[17])

Fig.7 SROC plot of different specimens for diagnosing PTB a.SROC plot for diagnosing PTB by detecting lung samples with mNGS. b.SROC plot for diagnosing PTB by detecting BALF with mNGS. c.SROC plot for diagnosing PTB by detecting lung tissue with mNGS

表4 mNGS检测 BALF的亚组分析

Tab.4 Subgroup analysis of mNGS detection of BALF

	分组	研究数量	敏感度(95%CI)	P值
研究类型	回顾性分析前瞻性研究	7 1	71%(58%~83%) 67%(54%~79%)	0.674
测序平台	BGISEQ 其他	5 3	70%(52%~88%) 72%(47%~97%)	0.882
痰涂片情况	阴性阳性	2 6	89%(81%~97%) 64%(54%~73%)	<0.05

图8 mNGS检测BALF的敏感性分析 a.拟合优度分析;b.双变量正态性分析;c.影响分析;d.异常值检测,图中对应研究编号依次为:①Chen等[13],②jin等[14],③Liu等[15],④Shi等[12],⑤Xu等[20],⑥Zhu等[16],⑦王春等[17],⑧赵素娥等[19]

Fig.8 Sensitivity analysis of mNGS detection of BALF a.Goodness-of-fit; b.Bivariate normality; c.Influence Analysis; d.Outlier Detection

图9 mNGS检测3种标本的Deeks'漏斗图 a.mNGS检测肺标本诊断PTB的Deeks'漏斗图; b.mNGS检测BALF诊断PTB的Deeks'漏斗图; c.mNGS检测肺组织诊断PTB的Deeks'漏斗图

Fig.9 mNGS detects Deeks' funnel plots of 3 specimens a. Deeks' funnel diagram of mNGS detection of lung specimen for diagnosis of PTB; b. Deeks' funnel diagram of mNGS detection of BALF for diagnosis of PTB; c. Deeks' funnel diagram of mNGS detection of lung tissue for diagnosis of PTB

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