基于临床信息的新发传染病诊疗系统与基于遗传信息的HBV个体化诊疗信息系统的设计与实现

【作者】 李庆虹；

【导师】 赵达生；

【作者基本信息】 中国人民解放军军事医学科学院 ， 军事预防医学， 2010， 博士

【摘要】 近年来,我国传染病呈现两大特点,一是新发传染病的不断出现,二是已控制的传染病发病率呈逐年上升的趋势。如何防控新发传染病的暴发流行,提高在我国流行的几种主要传染性疾病的防治效果已成为我国传染病防治面临的两大艰巨任务。从2003年的SARS ( Severe Acute Respiratory Syndrome,严重急性呼吸综合征)到近几年的禽流感以及近期的甲型H1N1流感病毒感染事件来看,我国面临着越来越严峻的新发传染病暴发流行的危险,同时也反映出已有的传染病监测预警系统在应对新发传染病暴发流行方面仍有很多不足。尽早地警示新发传染病的出现是控制新发传染病暴发流行的关键,但是由于一些新发传染病从未出现或平时很少发生,一线医务人员很难掌握更多相关知识,加上发病初期警觉不够,很容易造成新发传染病的暴发流行。如何提高一线医务人员对新发传染病的认识,在疾病刚开始出现的时候迅速处理,防止蔓延呢?病毒性肝炎发病率除2005年略低于肺结核外,一直稳居我国甲、乙类传染病之首,近年来其发病率明显增加,主要原因是乙型病毒性肝炎(以下简称乙肝)发病率逐年增高。究其原因可见,HBV(Hepatitis B Virus,乙型肝炎病毒)基因突变引起的耐药性问题常常是导致乙肝治疗失败的重要原因,也是致使乙肝流行和发病率持续上升的关键因素之一。如何帮助一线医务人员在乙肝发病早期,通过一系列的检验分析明确患者基因水平的个体化诊疗信息,判断每个病人的耐药性情况呢?随着计算机信息网络时代的到来以及分子生物学、循证医学、统计分析、数据挖掘、J2EE和关系数据库等技术的发展,通过设计特定的服务功能软件,实现某一疾病的计算机辅助诊断、治疗以及个体化基因水平的耐药性分析已经能够实现。针对以上分析,本课题设计并实现了一套符合我国传染病防治需求的传染病辅助诊疗系统,主要包括两大部分:1、基于临床信息的传染病辅助诊断识别系统;2、以HBV为例建立基于遗传信息的个体化诊疗系统。该系统可以帮助一线医务人员更好的解决传染病防治中面临的两个关键问题:1、迅速判别和处理新发传染病;2、早期明确HBV患者所感染病毒的耐药性特点,采用个体化诊疗方案,提高疗效。1.基于临床信息的新发传染病辅助诊断系统的设计与实现本研究通过对各种新发传染病的调研分析以及我国传染病流行特点,选择目前国内尚未报道的或已有报道但较少见的23种新发传染病进行辅助诊疗系统的研究。完成了以下几方面的工作:(1)建立传染病的完备知识库收集相关传染病及鉴别诊断相关疾病的信息资料,运用循证医学的理念、Meta分析等统计分析方法和数据挖掘技术,对资料进行科学地整理、统计、分析、优化和总结,构建了23种新发传染病及50种常见传染病的相关知识库。依据权威机构的诊断标准,借鉴专家的经验,编写8600余条词条,建立临床诊断指标体系,通过回顾性病例分析进行验证。(2)建立基于知识库的辅助诊断识别系统利用J2EE和关系数据库技术,分析、组合相关数据,建立可查询和可更新的传染病综合信息数据库。利用贝叶斯网络、信息熵理论及多元统计分析方法建立数学评价体系,采用分层引导,逐步启发,以及交互反馈的方式,将医师的临床思维与临床经验通过计算机软件实现对新发传染病临床特征的识别,建立符合临床思维的新发传染病计算机辅助专家智能系统。(3)回故性病例和前瞻性病例的应用分析系统完成后临床回顾性研究314份病例及前瞻性研究186份病例的验证结果分别为:第一诊断符合率61.9%及59.7%;前3位提示率78.1%及77.9%;前5位提示率86.6%及85.4%。本研究建立的新发传染病防、控、诊、治相关的计算机辅助诊断系统和知识库,是国内最早将临床医师临床经验与临床思维,应用于计算机辅助专家智能系统的创建。该系统可协助临床一线人员识别、处理各种新发传染病,并作为各级医务人员、行政管理人员、普通群众的信息交流平台,对规范传染病诊治,普及传染病知识,防止传染病的流行有重要意义。该系统可以直接连接到国家疫情网络系统,弥补我国新发传染病临床监测和预警系统的不足,具有很大的社会效益和潜在的经济效益。2.基于遗传信息的HBV个体化诊疗信息系统的设计与实现HBV基因组有4个主要ORF(Open Reading Frame ,开放读码框架)和相应的调控序列,在感染患者当中,HBV的核苷酸突变频率达到每年105-104次。HBV基因突变可引起其生物学特性变化,包括复制速率、蛋白表达量、抗原表位变化、以及对药物的敏感性的改变。因此,分析研究HBV基因变异特性,可以获得HBV耐药性相关信息。本研究为分析HBV耐药性特点,对乙型病毒性肝炎患者进行较大样本病毒基因测序,分析我国HBV基因变异株特点,建立以我国流行HBV株序列为主的基于网络平台的专业HBV耐药相关突变分析系统,主要完成了以下几方面工作:(1)建立HBV相关综合数据库本数据库收集了302医院传染病研究所检测的6880例乙型病毒性肝炎患者HBV全基因组序列516条,前C/基本核心启动子等基因片段序列11456条,代表性HBV基因组序列克隆613个,以及这些患者的血清样本和相关临床资料。用测序软件分析序列和峰图,从GenBank下载已有HBV全基因组序列,与本课题组测定的全基因及功能基因片段序列一起录入,构成HBVseqBJ数据库的主要序列来源,同时吸取用户上传序列,以进一步丰富数据库资料。构建了包括临床信息库、标本库、序列信息库、文献库、生物信息库在内的HBV相关个体化信息和知识查询系统。该系统支持图片、影像、序列等多种格式的数据录入,具有强大的数据查询、导航、视图分析、汇总功能;支持功能扩展和结构化定制,能够满足医学信息收集与科研中的个性化需求,为HBV研究中的病历收集、预后随访、标本采集、耐药分析等提供强有力的信息化保障。(2)构建基于HBV序列分析的个体化诊疗系统建立HBV耐药性相关生物信息平台,该平台可以在线完成基因分型、突变位点识别、抗原表位分析、耐药位点识别功能。数据库对外开放,用户可通过网上注册索取或提交序列资料、下载功能软件和进行在线分析,通过比对HBV序列对患者临床用药方案提供个体化参考。本系统包括序列比对、基因分型、抗原表位分析和耐药相关突变分析功能。病毒序列比对分析,采用相似性算法以便于找到新的突变;基因分型,采用进化树分析结合相似性算法以提高分析速度;对抗原表位的分析,能够涵盖HBV重叠ORF的相互影响;对耐药相关突变位点的分析,可根据前沿进展不断进行更新调整。本项研究率先在国内建立具有自主知识产权的、以国内HBV基因序列为主的专业HBV序列数据库,在此基础上开发HBV科研信息平台和耐药信息分析系统。数据库高度集成,分析系统分为序列比对模块、基因分型模块、抗原表位分析模块、耐药位点分析模块。通过构建基于网络的HBV科研信息平台和耐药性分析系统,一方面为国内HBV科研协作建立了必要的基础信息平台;另一方面,个体基因耐药性分析结果为一线医务人员制定合理化抗病毒治疗方案提供了个体化遗传信息支持。更多还原

【Abstract】 Human health and social stability are threatened seriously with infection diseases. The ability of prevention and treatment of infection disease has become one of the most important factors evaluating the country’s economic and health care development. In recent years, with the emerging of the origin infectious disease (EID) and the increasing incidence of the controlled infection disease, there are two focal points in the infection disease prevention and treatment in china: first is how to control the emerging infectious disease outbreak, second is how to improve the therapeutic efficacy of the main infectious diseases in china.The world have detected more than 40 kinds of EID, more than 30 kinds of EID have been detected in our country. With the international trade and tourism development and the more and more worming global climate, the threats of EID become heavily year by year. In addition, the uses of biological weapons and bio-terrorist incidents have made the threat of EID even more grievously. From the severe acute respiratory syndrome (SARS) breakout in 2003 till the bird flu and the H1N1flu breakout recently, we can feel that the EID has come nearby. These combats between the mankind and infectious diseases in china made us known the obvious deficiency in EID early warning and response capacity. EID Early warning is one of the most important factors to prevent EID breakout. Since most of the EID hardly ever occurred or even never occurred in china, it is hard for the clinicians to know the detail of each EID and diagnosis them correctly especially in the earlier period. The result is that EID will breakout and spread rapidly. How to improve the diagnosis and treatment level for the EID in clinical medical staff?Viral hepatitis incidence topped in the category A and B infectious diseases in china constantly besides 2005 little lower than pulmonary tuberculosis. In recent years viral hepatitis incidence increased significantly form 2002 to 2007(68.71/100,000～121.33/100,000). The increasing incidence of HBV is the main reason. Drug resistance is the major cause responsible for failure of HBV treatment and also acts as the heavy responsibility for HBV increasing. It takes time for clinicians to distinguish the drug resistance and change the effective drugs for the patience. Is there any method that can help the clinicians catch the drug resistance characteristics of each patience and give the effective treatment strategy in the earlier period of HBV infection?With the development of computer network information, molecular biology, evidence-based medicine, statistical analysis, data mining, J2EE and relational data base technology, it is achievable for us to establish an assistant diagnostic and therapeutic system or drug-resistance analysis system for some specific infection diseases. In view of the two aspects urgent tasks in the field of infectious disease in china, we designed and implemented an assistant computer system. This software can help the medical staff deal with two problems: 1) identify and therapy EID quickly and correctly, prevent EID breakout in the very early period; 2) get enough drug-resistance information for each HBV patient in the early stage and prescribe an effective recipe.1. Design and implement the assistant diagnostic and therapeutic system for EID based on the clinical informationAnalysis all the EIDs world-wide, we choose 23 EIDs which have not been detected or seldom been detected in china to establish the computer identification system. The researches have been done as follows:(1)Estbalish the infection diseases information data baseCollect the data of 23 EIDs and 50 differential diagnosis related diseases, establish a knowledge base. Evidence-based medicine theory, Meta statistical analysis, data mining technology was used for data sorting, analyzing, optimizing and summarizing;According to the experience from the clinical and epidemical experts and the authoritative diagnostic standard, we compiled 8600 terms related to diagnosis. Constructed a set of index system of clinical diagnosis, the stability and veracity of this system were tested by a lot of clinical cases.(2)Establish the assistant diagnostic and therapeutic system for EID based on the information data baseJ2EE and relational database technology were used to establish the general EIDs database which has the interaction, inquirable and renewable functions. Extract the clinical features of EIDs effectively and to establish digitizing diagnostic evolution system which could be identified by computer. Enlightened by the doctor’s clinical experience and thinking, the step by step guiding and analyzing and feedback interaction methods were used to develop the computer-assisted expert intelligent system of EID. Multivariate statistical analysis, information entropy theory and Bayesian network were used to settle the problem of J2EE and R language connection. Thus the software accomplish the conformity of clinical message input system and mathematical evaluation system.(3)Retrospective research and prospective research were used to verify the accuracy of the established systemTo verify the accuracy of the established system, we collected 314 case for retrospective research and 186 cases for prospective research. The result showed that 61.8% and 59.7% coincided with the first diagnosis, 78.1%and 77.9% coincided with the first three diagnosis, 86.6% and 85.4% coincided with the first five diagnosis respectively. The EID assistant diagnostic and therapeutic system was the first clinical thinking embedded software in china. It can help the clinicians identify the EID in time and treat it correctly. It can also act as an interactive platform among the clinicians, the service and the patients. That will play an important role in infection diseases diagnosis and treatment, popularizing infection disease knowledge and epidemic prevention. The significant compatibility of the software can help it connect with the national epidemic situation net directly. This will perfect the national epidemic monitoring and warning system. We can expect that the software can produce the huge economic performance and social performances.2. Design and establish a multifunctional Hepatitis B Virus (HBV) Sequence and Drug Resistance Analysis Information PlatformThere are 4 ORF and correlated regulative sequences in HBV. HBV mutation can induce the biological changes including the copy rate, protein expression quantity, epitope and drugs sensitivities. Based on the large-scale HBV gene sequencing, we try to establish a multifunctional HBV sequence and drug resistance analysis information platform. The researches have been done as follows:(1)Establish HBV related information data baseCollected the blood samples and related clinical information from 6880 HBV patients. It deposited 516 HBV complete genomes,11456 gene fragments,and 613 representative cloned genes. Combined with the gene analysis and HBV whole sequences download from GeneBank, we settled the first HBV seqBJ data base in china, which also have enriching ability by receiving data transfer.Established clinical information data base, sample data base, sequence data base, document data base, biology data base and HBV related knowledge consulting system. The system has a powerful consulting, navigating, analyzing and summarizing functions. It can meet the demand of medical information collection and individuation research requirement.(2)Establish a personal information system based on HBV sequence ananlysisEstablished HBV drug resistance information platform, which fulfilled functions comprised HBV sequence comparison, HBV genotyping/serotyping, the amino acid sequence prediction of S/C/P/X proteins, antigenic epitope analysis and drug resistance analysis. It is a opened data base which made it convenient for the patients and doctors to find the better individual treatment strategies.VirusBlast groupware has the follow functions: sequence comparison, genotyping, antigenic epitope analysis and drug resistance analysis. Comparability numeration was used in sequence comparison for finding novel mutation. Evolutional analysis combined with comparability numeration used in genotyping were helpfully in analysis speeding. Antigenic epitope analysis including the influenced between overlapped ORF in HBV. Drug resistance analysis will be renewed by the updating researches.The study settled a specially HBV gene sequences data base which has the independent intellectual property rights in china for the first time. Based on the data base we established a multifunctional HBV sequence and drug resistance analysis information platform. The platform has advantage to make full use of HBV sequences and related data of Chinese patients for HBV drug-resistant analysis in clinic and HBV virologic study.更多还原