循环线粒体DNA作为危重症预后的生物标记物:Meta分析与试验序贯分析

Circulating mitochondrial DNA as a biomarker in critically ill patients: A meta-analysis and trial sequential analysis

目的 通过Meta分析和试验序贯分析(TSA)系统评价循环线粒体DNA(mtDNA)与危重症预后的关系。方法 计算机检索PubMed、Embase、Cochrane Library、中国知网、维普网、万方数据知识平台等数据库,纳入循环mtDNA与危重症预后关系的横断面研究、病例对照研究及队列研究。检索时间均从建库至2018年10月。采用Stata 12.0软件进行Meta分析,应用TSA v0.9软件进行TSA分析。结果 纳入的15篇研究均为前瞻性队列研究,合计样本量1318例。Meta分析结果显示,循环mtDNA与危重症预后之间存在相关性(SMD=1.08,95%CI 0.66~1.49,P=0.000)。进一步根据mtDNA引物、离心参数、绘制mtDNA标准曲线的DNA来源、样本种类、提取技术、结局类型、疾病类型、年龄进行亚组分析,发现除样本种类、结局类型、疾病类型、年龄外,其余因素对结果均有明显影响。敏感性分析证明该模型稳定可靠。Egger检验表明纳入的研究可能存在发表偏倚(P=0.03)。TSA分析提示在尚未达到期望信息量之前已经获得了肯定的结论。结论 循环mtDNA可以作为危重症预后的生物标记物,但因可能存在发表偏倚,应谨慎看待该结论,期待统一研究方法后通过更多试验予以证实。

Objective To systematically review the association between circulating cell-free mitochondrial DNA(mtDNA)and prognosis in critically ill patients by using Meta-analysis and trial sequential analysis(TSA).Methods The PubMed,Embase,Cochrane Library,CNKI,VIP,and WanFang Data were searched from creating of the database up to October,2018 for crosssectional studies,case-control studies,or cohort studies on the relevance between mtDNA and prognosis in critically ill patients.Then,Meta-analysis and TSA were performed using Stata 12.0 software and TSA v0.9 software.Results A total of 15 prospective cohort studies involves 1318 patients.The results of Meta-analysis showed that mtDNA was associated with prognosis in critically ill patients(SMD=1.08,95%CI 0.66-1.49,P=0.000).Subgroup analysis of mitochondrial DNA specific primer,centrifugal parameters,source of mitochondrial DNA as mtDNA standard curve,types of sample,extraction technology,types of outcome and disease,and age showed that,except for the types of the sample,outcome and disease,and age,results were affected apparently and differently by the rest factors.Sensitivity analysis indicated that the model is stable and reliable.Egger test revealed there were maybe publication bias.And the results of TSA displayed that all of the cumulative Z-curve strode traditional threshold value and TSA threshold value which suggested that affirmative conclusions had been reached,namely mtDNA could predict the prognosis of serious diseases as its biomarker clearly.Conclusions Current evidence suggests that mtDNA in circulation could be considered as a biomarker for the prognosis of severe disease.However,due to possible publication bias,the above conclusions should be treated with caution and it also requires a standard process to extract mtDNA from peripheral blood and more trials to prove it.