基于GIS和WGS的广西肺结核疫情迥异的环境与基因交互作用研究

Tuberculosis(TB) is a chronic respiratory infectious disease caused by mycobacterium tuberculosis complex(MTBC). The reported incidence of new TB cases in Guangxi Zhuang autonomous region is significant higher than the national average level with inter-local heterogeneity. The cost-effectiveness of TB control program is unbalance. The results from previous research implied that the multiple environmental factors and gene polymorphisms of MTBC associated with the TB epidemic. It is difficult for us to interpreted the transmission and development mode of TB with traditional and unidimensional model. It is unclear about the epidemic strains of MTBC and their evolution process in Guangxi. How to allocate the control and prevention resources accurately based on the indicator of environmental and genic effect is an important thing to control TB. We will conduct an environmental-genic interaction research to find out the risk factors of high TB epidemic with specific references for TB control and prevention program. The Geographic Information System(GIS) analysis is used for detecting “Hot spots” and “Cold spots” and constructing independent variables of spatial-temporal dimensions based on optimized modeling. Molecular epidemiology analysis based on Whole Genome Sequencing (WGS) method will be performed for testing multi-level effect and interactions. Finally, we expect the outcome meet our objective of “Classification Guidance” and “One County Share One Strategy”.

肺结核是由结核分枝杆菌引起的慢性呼吸道传染病。广西壮族自治区近5年的结核病报告发病率一直远高于全国平均水平，各地区疫情高低迥异，时空异质性显著，资源的投入与成效不成正比。我们前期研究发现，广西的结核病传播和发病模式具有环境复杂性和结核菌基因多态性，传统的、单一维度的模型己经无法诠释结核病传播和发病特点，广西肺结核流行株的系统进化、传播机制依然不清。如何根据环境和病原学影响因素，采取精准防控措施，成为迫切需要解决的问题。本研究拟从环境和病原体本身入手，通过时空流行病学研究，侦测结核病高发区域（热点）和低发区域（冷点），结合优化时空回归模型筛选出环境因素，在热点和冷点地区建立时空维度自变量；通过基于WGS检测和分析技术的基因组分子流行病学研究建立分子维度自变量，进行多水平模型拟合和交互效应分析，最终找到影响疫情高发的因素，为实现“分类指导”、“一县一策”的结核病精准防控提供科学依据。

广西的结核病疫情仍然很重，且具有空间和细菌基因多态性，传统方法和技术无法解释造成这一特性的原因。因此，本研究建立结核病时空生态学数据库；采取回顾性全人群研究，应用改良的空间不规则扫描技术和时空回归模型实现对结核病高发和低发聚集的精确统计和宏观尺度下的动力学建模；同时，实施前瞻性的现场调查，收集结核病高发和低发聚集区培养阳性结核病例的样本并进行全基因组测序分析，应用FST指数推断基于群体基因结构的结核病传播模式；通过社会接触网络拓扑结构的绘制、病原学信息和环境驱动因素的集合建模，最终构建多层次、多维度的结核病传播动力学模型，为广西结核病防治规划调整、实施和分类指导提供量化依据。通过研究，建立了结核病疫情的时-空动态监测体系，提出宏观层面的疫情监测与处置管理措施；应用分子方差算法和多维尺度模型对疫情高发和低发地区的结核分枝杆菌群体基因结构差异进行比对。从分子层面揭示了结核病的局限流行性，提出冷点地区“外防输入”，热点地区“内防扩散”的防控建议，并将高疫情地区特有菌株的流向作为疫情扩散和防控策略调整的预警。