Finite Mixture Models for Mapping Spatially Dependent Disease Counts

A vast literature has recently been concerned with the analysis of variation in disease counts recorded across geographical areas with the aim of detecting clusters of regions with homogeneous behavior. Most of the proposed modeling approaches have been discussed for the univariate case and only very recently spatial models have been extended to predict more than one outcome simultaneously. In this paper we extend the standard finite mixture models to the analysis of multiple, spatially correlated, counts. Dependence among outcomes is modeled using a set of correlated random effects and estimation is carried out by numerical integration through an EM algorithm without assuming any specific parametric distribution for the random effects. The spatial structure is captured by the use of a Gibbs representation for the prior probabilities of component membership through a Strauss‐like model. The proposed model is illustrated using real data (© 2009 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)     

On the Identifiability of Transmission Dynamic Models for Infectious Diseases

Understanding the transmission dynamics of infectious diseases is important for both biological research and public health applications. It has been widely demonstrated that statistical modeling provides a firm basis for inferring relevant epidemiological quantities from incidence and molecular data. However, the complexity of transmission dynamic models presents two challenges: (1) the likelihood function of the models is generally not computable, and computationally intensive simulation-based inference methods need to be employed, and (2) the model may not be fully identifiable from the available data. While the first difficulty can be tackled by computational and algorithmic advances, the second obstacle is more fundamental. Identifiability issues may lead to inferences that are driven more by prior assumptions than by the data themselves. We consider a popular and relatively simple yet analytically intractable model for the spread of tuberculosis based on classical IS6110 fingerprinting data. We report on the identifiability of the model, also presenting some methodological advances regarding the inference. Using likelihood approximations, we show that the reproductive value cannot be identified from the data available and that the posterior distributions obtained in previous work have likely been substantially dominated by the assumed prior distribution. Further, we show that the inferences are influenced by the assumed infectious population size, which generally has been kept fixed in previous work. We demonstrate that the infectious population size can be inferred if the remaining epidemiological parameters are already known with sufficient precision.     

Comparison of Representative Strains of Infectious Hematopoietic Necrosis Virus by Serological Neutralization and Cross-Protection Assays

Infectious hematopoietic necrosis virus (IHNV) is a pathogen of young salmon and trout. Viral epizootics among these fish in private and public rearing facilities have been a problem in the northwestern United States from California to Alaska, and an IHNV vaccine has been sought by the aquaculture experts. Since an IHNV vaccine must be designed to immunize against all viral serotypes, an analysis of IHNV serotypes was made. A large number of viruses from widely separated geographic locations and different fish species had already been placed in one of five electropherotypes by the migration of the virion proteins in sodium dodecyl sulfate-polyacrylamide gels. Also, there was evidence that some of these virus isolates had differences in virulence for chinook salmon, rainbow trout, or kokanee salmon. Previous serological studies with polyclonal rabbit antisera and three IHNV isolates indicated that there was only one serotype (B. B. McCain, J. L. Fryer, and K. S. Pilcher, Proc. Soc. Exp. Biol. Med. 137:1042-1046, 1971). A substantial number of new IHNV isolations have been made since that study, and thus a more extensive comparison was made of 10 different IHNV isolates representing the five electropherotypes. This report shows that the glycoprotein from a single isolate of IHNV can induce a protective immune response in vivo to the five IHNV electropherotypes. Plaque reduction neutralization assays indicated that there was only one serotype. Thus, despite the differences observed in the migration of the structural proteins for IHNV isolated from separate geographic locations and different fish species, only one neutralizing virus type was identified.     

具潜伏期的无免疫型传染病动力学的微分模型

对具潜伏期的无免疫型传染病进行讨论,给出一个常微分模型和一个偏微分模型．     

Development of a Novel Multiplex Immunoassay Multi-cruzi for the Serological Confirmation of Chagas Disease

Background

Chagas disease is due to the parasite Trypanosoma cruzi, a protist disseminated by a Triatome vector. This disease is endemic to Latin America and considered by WHO as one of the 17 world’s neglected diseases. In Europe and in North America, imported cases are also detected, due to migration of population outside of the endemic region. Diagnosis of T. cruzi infection is usually made indirectly by the detection of specific antibodies to T. cruzi antigens. Following initial diagnostic evaluation or screening test (qualifying or discarding blood donation), a confirmation test is performed for samples initially reactive. The test presented in this study aims at the confirmation/refutation of the infectious status of human blood samples and will permit taking appropriate clinical measures.

Methodology/Principal Findings

We designed a novel array of twelve antigens and printed these antigens onto 96-well plates. We tested 248 positive samples T. cruzi, 94 unscreened blood donors’ samples from non-endemic area, 49 seronegative blood donors, 7 false-positive and 3 doubtful samples. The observed reactivities were analyzed to propose a decision-tree algorithm that correctly classifies all the samples, with the potential to discriminate false-positive results and sticky samples. We observed that antibodies levels (Sum of all antigens) was significantly higher for PCR positive than for PCR negative samples in all studied groups with Multi-cruzi.

Conclusion/Significance

The results described in this study indicate that the Multi-cruzi improves the serological confirmation of Chagas disease. Moreover the “sum of all antigens” detected by Multi-cruzi could reflect parasitemia level in patients–like PCR signals does—and could serve as an indicator of parasite clearance in longitudinal follow-ups. Validation of this assay is still required on an independent large collection of well characterized samples including typical false-reactive samples such as Leishmaniasis.     

Multiplex Identification of Antigen-Specific T Cell Receptors Using a Combination of Immune Assays and Immune Receptor Sequencing

Monitoring antigen-specific T cells is critical for the study of immune responses and development of biomarkers and immunotherapeutics. We developed a novel multiplex assay that combines conventional immune monitoring techniques and immune receptor repertoire sequencing to enable identification of T cells specific to large numbers of antigens simultaneously. We multiplexed 30 different antigens and identified 427 antigen-specific clonotypes from 5 individuals with frequencies as low as 1 per million T cells. The clonotypes identified were validated several ways including repeatability, concordance with published clonotypes, and high correlation with ELISPOT. Applying this technology we have shown that the vast majority of shared antigen-specific clonotypes identified in different individuals display the same specificity. We also showed that shared antigen-specific clonotypes are simpler sequences and are present at higher frequencies compared to non-shared clonotypes specific to the same antigen. In conclusion this technology enables sensitive and quantitative monitoring of T cells specific for hundreds or thousands of antigens simultaneously allowing the study of T cell responses with an unprecedented resolution and scale.     

呼吸道传染病治疗中抗体药物的研发进展

呼吸系统疾病影响着全世界数百万人,主要病变发生在气管、支气管、肺部及胸腔,病变轻者多咳嗽、胸痛,重者呼吸困难、缺氧甚至呼吸衰竭,可造成多种并发症,导致患者严重残疾甚至死亡。治疗性抗体的临床使用为肺癌、哮喘以及各类呼吸道传染病等的治疗开辟了新途径。目前已有数十种抗体（antibodies,Abs）获得市场批准,而且还有更多的抗体药物正在临床开发中。这些Abs中的大多数是针对哮喘、肺癌、慢性阻塞性肺病、特发性肺纤维化以及呼吸道传染病等疾病。其中,呼吸道传染病的爆发具有传播迅猛、传染性强的特点,常引发全球关注,如当下肆虐全球的新型冠状病毒肺炎。针对呼吸道传染病的多种Abs为其临床治疗提供了新策略。基于此,综述了已获准和正在临床开发的适用于治疗呼吸道传染病的Abs,通过综述抗体治疗的分子机制、优势和发展趋势,以期为呼吸道传染病治疗中抗体药物的研发提供参考。     

感染性疾病动物模型-观点与思考

感染性疾病动物模型是以导致感染性疾病的病原感染动物,或人工导入病原遗传物质,使动物发生和人类相同疾病、类似疾病、部分疾病改变或机体对病原产生反应,为疾病系统研究、比较医学研究以及抗病原药物和疫苗等研制、筛选和评价提供的模式动物。目前,国内外没有严格的感染性疾病模型的分类标准,但是,感染性病原动物模型的分类明显不同于一般动物模型的分类,因此,本文建议将感染性疾病动物模型按照病原种类特性以及疾病表现程度进行分类,便于规范化应用。     

Development and Application of Two Multiplex Real-Time PCR Assays for the Detection of Mycobacterium ulcerans in Clinical and Environmental Samples

Mycobacterium ulcerans is a slow-growing environmental bacterium that causes a severe skin disease known as Buruli ulcer. PCR has become a reliable and rapid method for the diagnosis of M. ulcerans infection in humans and has been used for the detection of M. ulcerans in the environment. This paper describes the development of a TaqMan assay targeting IS2404 multiplexed with an internal positive control to monitor inhibition with a detection limit of less than 1 genome equivalent of DNA. The assay improves the turnaround time for diagnosis and replaces conventional gel-based PCR as the routine method for laboratory confirmation of M. ulcerans infection in Victoria, Australia. Following analysis of 415 clinical specimens, the new test demonstrated 100% sensitivity and specificity compared with culture. Another multiplex TaqMan assay targeting IS2606 and the ketoreductase-B domain of the M. ulcerans mycolactone polyketide synthase genes was designed to augment the specificity of the IS2404 PCR for the analysis of a variety of environmental samples. Assaying for these three targets enabled the detection of M. ulcerans DNA in soil, sediment, and mosquito extracts collected from an area of endemicity for Buruli ulcer in Victoria with a high degree of confidence. Final confirmation was obtained by the detection and sequencing of variable-number tandem repeat (VNTR) locus 9, which matched the VNTR locus 9 sequence obtained from the clinical isolates in this region. This suite of new methods is enabling rapid progress in the understanding of the ecology of this important human pathogen.     

重要呼吸道传染病智慧化监测预警与有效应对策略探讨

全球新发突发传染病不断出现,特别是新型冠状病毒肺炎疫情暴发,对人类健康和社会发展造成巨大影响.本文通过不同渠道收集有关资料,试图梳理我国呼吸道传染病监测预警发展和现状,探讨采用大数据、区块链、人工智能等高新技术,建立智慧化新发突发呼吸道传染病监测预警平台.运用统一关键数据标准、口径,打通部门之间数据壁垒,建立数据共享机制,实时自动采集与传染病有关的数据信息.利用大数据、人工智能、云计算等技术,建立相关数据模型,强化数据分析应用,达到早期识别和预警,做到遏止突发事件的发生发展和传播.同时,在疫情防控过程中能够实时获得疫情的发生发展趋势,及时提出科学精准的有效防控策略.不断提升我国应对突发公共卫生事件的能力和水平,保障我国生物安全.     

Development of Multiplex PCR Assays for the Identification of the 33 Serotypes of Streptococcus suis

Streptococcus suis is an important zoonotic agent causing severe diseases in pigs and humans. To date, 33 serotypes of S . suis have been identified based on antigenic differences in the capsular polysaccharide. The capsular polysaccharide synthesis (cps) locus encodes proteins/enzymes that are responsible for capsular production and variation in the capsule structures are the basis of S . suis serotyping. Multiplex and/or simplex PCR assays have been developed for 15 serotypes based on serotype-specific genes in the cps gene cluster. In this study, we developed a set of multiplex PCR (mPCR) assays to identify the 33 currently known S . suis serotypes. To identify serotype-specific genes for mPCR, the entire genomes of reference strains for the 33 serotypes were sequenced using whole genome high-throughput sequencing, and the cps gene clusters from these strains were identified and compared. We developed a set of 4 mPCR assays based on the polysaccharide polymerase gene wzy, one of the serotype-specific genes. The assays can identify all serotypes except for two pairs of serotypes: 1 and 14, and 2 and 1/2, which have no serotype-specific genes between them. The first assay identifies 12 serotypes (serotypes 1 to 10, 1/2, and 14) that are the most frequently isolated from diseased pigs and patients; the second identifies 10 serotypes (serotypes 11 to 21 except 14); the third identifies the remaining 11 serotypes (serotypes 22 to 31, and 33); and the fourth identifies a new cps cluster of S . suis discovered in this study in 16 isolates that agglutinated with antisera for serotypes 29 and 21. The multiplex PCR assays developed in this study provide a rapid and specific method for molecular serotyping of S . suis .     

Classifying and Mapping Potential Distribution of Forest Types Using a Finite Mixture Model

The present paper presents the application of a finite mixture model (FMM) to analyze spatially explicit data on forest composition and environmental variables to produce a high-resolution map of their current potential distribution. FMM provides a convenient yet formal setting for model-based clustering. Within this framework, forest data are assumed to come from an underlying FMM, where each mixture component corresponds to a cluster and each cluster is characterized by a different composition of tree species. An important extension of this model is based on including a set of covariates to predict class membership. These covariates can be climatic and topographical parameters as well as geographical coordinates and the class membership of neighbouring plots. FMM was applied to a national forest inventory of Italy consisting of 6,714 plots with a measure of abundance for 27 tree species. In this way, a map of potential forest types was produced. The limitations and usefulness of the proposed modelling approach were analyzed and discussed, comparing the results with an independently derived expert map.     

传染病预防控制国家重点实验室

传染病预防控制国家重点实验室(State Key Laboratory for Infectious Diseases Prevention and Control,SKLID)依托于中国疾病预防控制中心(Chinese Center for Disease Prevention and Control),于2005年3月22日经科技部批准正式成立,进入建设时期。