A Generalized Genetic Random Field Method for the Genetic Association Analysis of Sequencing Data

With the advance of high‐throughput sequencing technologies, it has become feasible to investigate the influence of the entire spectrum of sequencing variations on complex human diseases. Although association studies utilizing the new sequencing technologies hold great promise to unravel novel genetic variants, especially rare genetic variants that contribute to human diseases, the statistical analysis of high‐dimensional sequencing data remains a challenge. Advanced analytical methods are in great need to facilitate high‐dimensional sequencing data analyses. In this article, we propose a generalized genetic random field (GGRF) method for association analyses of sequencing data. Like other similarity‐based methods (e.g., SIMreg and SKAT), the new method has the advantages of avoiding the need to specify thresholds for rare variants and allowing for testing multiple variants acting in different directions and magnitude of effects. The method is built on the generalized estimating equation framework and thus accommodates a variety of disease phenotypes (e.g., quantitative and binary phenotypes). Moreover, it has a nice asymptotic property, and can be applied to small‐scale sequencing data without need for small‐sample adjustment. Through simulations, we demonstrate that the proposed GGRF attains an improved or comparable power over a commonly used method, SKAT, under various disease scenarios, especially when rare variants play a significant role in disease etiology. We further illustrate GGRF with an application to a real dataset from the Dallas Heart Study. By using GGRF, we were able to detect the association of two candidate genes, ANGPTL3 and ANGPTL4, with serum triglyceride.     

Infectious Disease Transmission during Organ and Tissue Transplantation

Infectious disease transmission through organ and tissue transplantation has been associated with severe complications in recipients. Determination of donor-derived infectious risk associated with organ and tissue transplantation is challenging and limited by availability and performance characteristics of current donor epidemiologic screening (e.g., questionnaire) and laboratory testing tools. Common methods and standards for evaluating potential donors of organs and tissues are needed to facilitate effective data collection for assessing the risk for infectious disease transmission. Research programs can use advanced microbiological technologies to define infectious risks posed by pathogens that are known to be transplant transmissible and provide insights into transmission potential of emerging infectious diseases for which transmission characteristics are unknown. Key research needs are explored. Stakeholder collaboration for surveillance and research infrastructure is required to enhance transplant safety.     

Pharmacogenomic technologies: a necessary "luxury" for better global public health?

Background

Pharmacogenomic technologies aim to redirect drug development to increase safety and efficacy of individual care. There is much hope that their implementation in the drug development process will help respond to population health needs, particularly in developing countries. However, there is also fear that novel pharmacogenomic drugs will remain too costly, be designed for the needs of the wealthy nations, and so constitute an unnecessary "luxury" for most populations. In this paper, we analyse the promise that pharmacogenomic technologies hold for improving global public health and identify strategies and challenges associated with their implementation.

Discussion

This paper evaluates the capacity of pharmacogenomic technologies to meet six criteria described by the University of Toronto Joint Centre for Bioethics group: 1) impact of the technology, 2) technology appropriateness, 3) capacity to address local burdens, 4) feasibility to be implemented in reasonable time, 5) capacity to reduce the knowledge gap, and 6) capacity for indirect benefits. We argue that the implementation of pharmacogenomic technologies in the drug development process can positively impact population health. However, this positive impact depends on how and for which purposes the technologies are used. We discuss the potential of these technologies to stimulate drug discovery in the case of rare (orphan diseases) or neglected diseases, but also to reduce acute adverse drug reactions in infectious disease treatment and prevention, which promises to improve global public health.

Conclusions

The implementation of pharmacogenomic technologies may lead to the development of drugs that appear to be a "luxury" for populations in need of numerous interventions that are known to have a demonstrable impact on population health (e.g., secure access to potable water, reduction of social inequities, health education). However, our analysis shows that pharmacogenomic technologies do have the potential to redirect drug development and distribution so as to improve the health of vulnerable populations. Strategies should thus be developed to better direct their implementation towards meeting the needs and responding to the realities of populations of the developing world (i.e., social, cultural and political acceptability, and local health burdens), making pharmacogenomic technologies a necessary "luxury" for global public health.     

Microbial genomics: from sequence to function

The era of genomics (the study of genes and their function) began a scant dozen years ago with a suggestion by James Watson that the complete DNA sequence of the human genome be determined. Since that time, the human genome project has attracted a great deal of attention in the scientific world and the general media; the scope of the sequencing effort, and the extraordinary value that it will provide, has served to mask the enormous progress in sequencing other genomes. Microbial genome sequencing, of particular interest to the community studying emerging infectious diseases, prompted the series of articles presented in the following pages. These articles review technological and scientific advances that have occurred since publication of the Haemophilus influenzae genome sequence in July 1995; that was the first demonstration that an entire genome sequence could be deciphered by a "shotgun" approach, i.e., the sequencing and assembly of random fragments of the genome. This is now the method of choice for sequencing of most other genomes, including human (as performed by Celera Genomics).     

Progress in prevention of infectious disease

Current issues in preventing infectious diseases and their implications for the future are examined, looking broadly at technologies, program strategies, and the growing influence of public and professional attitudes and perceptions in maintaining and achieving infectious disease control. It is concluded that the technologies to control infectious diseases are available, implementation of delivery programs is feasible, and current attitudes of public and professions dampen but should not impede progress. The need for distributing the benefits of available preventive medical technology to the developing world is obvious, but achievements will be difficult and costly. It is equally important for the economically developed countries that have achieved successes in infectious disease prevention to sustain their progress and confront the concerns of public compliance, liability, management, and program support which threaten to hinder progress. Obviously, the needs must be clearly enunciated and the problems solved in order for the job of infectious disease prevention to be done.     

Understanding the natural variability of prion diseases

Prion diseases are a heterogeneous group of disorders with an invariably fatal disease course. Although various etiologies have been proposed it is apparent that at least a subset of these diseases are of infectious nature. An essential part of the infectious agent, termed the prion, is mainly composed of an abnormal isoform (PrP(Sc)) of a host-encoded normal cellular protein (PrP(C)). The molecular details of the pathophysiology of this group of diseases are unclear but the conversion of PrP(C) to PrP(Sc) plays a fundamental role. In all human prion diseases, PrP(Sc) is deposited in the central nervous system. These disorders include sporadic, genetic and acquired Creutzfeldt-Jakob disease. The molecular classification of human prion diseases is important in order to understand underlying disease mechanisms and for the development of novel therapy protocols. Current classification systems are based on the assessment of clinical presentation, genetic investigations, neuropathological findings and biochemical analysis of PrP(Sc).     

DNA测序技术与仪器的发展

由于分子生物学近年来的迅速发展,很多临床实验室开展了分子诊断实验项目。虽然目前由于操作复杂和高昂成本的原因,DNA测序技术尚没有大规模走进临床实验室,但是在众多分子诊断方法中,DNA序列测定和分析无疑是最权威的金标准。DNA测序技术在这几十年来从手工到自动化,从复杂到简单,但是近几年的高通量测序技术使之重新复杂起来,本文将介绍一下DNA测序技术与仪器的历史沿革与最新进展。     

早产儿肺及早产儿肺疾病的影像学评估价值

呼吸系统疾病已成为导致我国早产儿死亡的主要原因之一。由于产前糖皮质激素促胎肺成熟治疗、肺表面活性物质(PS)及各种类型呼吸支持技术等的应用,临床诊治该类疾病的策略日趋成熟,对于早产儿呼吸系统常见疾病的诊治,大多具备各自的指南和临床路径。目前临床对于该领域的研究热点,多集中于早产儿肺及其疾病的基因研究、早期干预方式的选择和精准化诊治等方面。笔者拟就早产儿肺及早产儿肺疾病的病理生理基础、影像学表现及其转归的最新研究进展进行阐述,以探讨影像学检查在早产儿肺及其肺疾病中的临床应用价值,辅助临床实现对早产儿肺疾病的精准化诊治。     

2017—2019年荆州市沙市区学校传染病聚集性疫情特点及影响因素分析

目的 分析学校传染病聚集性疫情特点,探讨相关影响因素,为有针对性地开展风险干预提供依据。方法 采用描述性流行病学分析沙市区学校聚集性疫情流行病学特点,应用logistic回归分析探讨影响疫情发生的相关因素。结果 沙市区中小学校、托幼机构2017—2019年共发生传染病聚集性疫情91起,累计发病732例。疫情涉及47所学校。聚集性疫情所涉病种以流感和水痘疫情为主,10月至次年1月呈现聚集性疫情发病高峰。严格落实晨午检(OR=0.22,95%CI:0.07～0.72)、养成良好洗手习惯(OR=0.16,95%CI: 0.04～0.68)、隔离治疗患病学生(OR=0.14,95%CI:0.04～0.47)等因素为学校传染病聚集性疫情发生的风险保护因素。结论 小学是学校传染病聚集性疫情发生的主要场所,呼吸道传染病是疫情防控的重点,应针对重点因素开展干预。     

布鲁杆菌病发病机制及临床诊治研究进展

布鲁杆菌病是一种人畜共患性传染病,人感染布鲁杆菌由于缺乏特异性的临床症状和体征,极易被误诊为其他疾病。布鲁杆菌感染是目前的研究热点,研究者试图从分子水平阐述其致病机制。另外,布鲁杆菌病临床表现发生一些新变化,呈单一或多个器官或系统受累,临床诊断治疗和预防也有新进展。基于此,文章将对布鲁杆菌致病机制以及布鲁杆菌病的临床变化新特点和诊治等方面作一综述。     

Powerful designs for genetic association studies that consider twins and sibling pairs with discordant genotypes

Genetic association studies are becoming commonplace due to the availability of cost-effective yet sophisticated DNA sequencing and genotyping resources and technologies. In addition, technologies designed to identify molecular and subclinical phenotypes that reflect disease pathogenesis are continually being developed and refined (consider, e.g., imaging technologies, microarray-based gene expression and proteomic platforms, histological analyses of excised tissues, etc.). Unfortunately, the large-scale use of many of these molecular and subclinical phenotyping technologies in genetic association studies is difficult logistically and is currently cost-prohibitive. In this paper, we consider efficient designs for testing the association between particular genetic variations and expensive, yet appropriate, subclinical phenotypes of relevance to a disease that take advantage of twins or sibling pairs discordant for genotypes at the locus (or loci) being tested. We demonstrate that including genotypically discordant twins or siblings in an association study can result in a substantial increase in power over designs that use monozygotic twins or only unrelated individuals. We ultimately argue that, from a practical standpoint, sampling from existing family or twin-based cohorts in which: (1) follow-up studies of a genetic association are warranted in order to assess the in vivo significance of an association with respect to more refined pathological phenotypes; and/or (2) large-scale, genome-wide linkage and association studies have been pursued that have focused on clinical endpoints for which the study subjects have consented to more elaborate follow-up studies, is a powerful way to test associations.     

224例不明原因发热患者病因分析

目的了解某院不明原因发热(FUO)患者病因,及其明确诊断的方法,为临床诊断和治疗FUO提供参考。方法应用血清学、细菌学、分子生物学、骨髓穿刺、组织活检,以及诊断性治疗等方法,对该院2008年1月—2014年7月收治的FUO住院患者进行临床诊断,回顾性分析224例FUO患者病因和最终诊断。结果最终明确病因者189例,占84.38%;未明确者35例,占15.62%。其中感染性疾病、结缔组织病、恶性肿瘤、其他类疾病分别占50.45%、18.75%、9.82%、5.36%。在感染性疾病中,细菌为主要病原体,其次为病毒;结缔组织病以系统性红斑狼疮和结节性多动脉炎为主;恶性肿瘤以血液系统肿瘤为主,而淋巴瘤最常见。189例确诊患者采用病原学检查者占30.16%,病理学检查者占24.34%,其他方法(综合分析)占20.11%。结论感染性疾病、结缔组织病、肿瘤为FUO的主要病因。     

Flea-borne rickettsioses: ecologic considerations.

Ecologic and economic factors, as well as changes in human behavior, have resulted in the emergence of new and the reemergence of existing but forgotten infectious diseases during the past 20 years. Flea-borne disease organisms (e.g., Yersinia pestis, Rickettsia typhi, R. felis, and Bartonella henselae) are widely distributed throughout the world in endemic-disease foci, where components of the enzootic cycle are present. However, flea-borne diseases could reemerge in epidemic form because of changes in vector-host ecology due to environmental and human behavior modification. The changing ecology of murine typhus in southern California and Texas over the past 30 years is a good example of urban and suburban expansion affecting infectious disease outbreaks. In these areas, the classic rat-flea-rat cycle of R. typhi has been replaced by a peridomestic animal cycle involving, e.g., free-ranging cats, dogs, and opossums and their fleas. In addition to the vector-host components of the murine typhus cycle, we have uncovered a second typhuslike rickettsia, R. felis. This agent was identified from the blood of a hospitalized febrile patient and from opossums and their fleas. We reviewed the ecology of R. typhi and R. felis and present recent data relevant to the vector biology, immunology, and molecular characterization and phylogeny of flea-borne rickettsioses.     

Personalized exposure assessment: promising approaches for human environmental health research

New technologies and methods for assessing human exposure to chemicals, dietary and lifestyle factors, infectious agents, and other stressors provide an opportunity to extend the range of human health investigations and advance our understanding of the relationship between environmental exposure and disease. An ad hoc Committee on Environmental Exposure Technology Development was convened to identify new technologies and methods for deriving personalized exposure measurements for application to environmental health studies. The committee identified a "toolbox" of methods for measuring external (environmental) and internal (biologic) exposure and assessing human behaviors that influence the likelihood of exposure to environmental agents. The methods use environmental sensors, geographic information systems, biologic sensors, toxicogenomics, and body burden (biologic) measurements. We discuss each of the methods in relation to current use in human health research; specific gaps in the development, validation, and application of the methods are highlighted. We also present a conceptual framework for moving these technologies into use and acceptance by the scientific community. The framework focuses on understanding complex human diseases using an integrated approach to exposure assessment to define particular exposure-disease relationships and the interaction of genetic and environmental factors in disease occurrence. Improved methods for exposure assessment will result in better means of monitoring and targeting intervention and prevention programs.     

Mobile Phone�Cbased Infectious Disease Surveillance System, Sri Lanka

Because many infectious diseases are emerging in animals in low-income and middle-income countries, surveillance of animal health in these areas may be needed for forecasting disease risks to humans. We present an overview of a mobile phone–based frontline surveillance system developed and implemented in Sri Lanka. Field veterinarians reported animal health information by using mobile phones. Submissions increased steadily over 9 months, with ≈4,000 interactions between field veterinarians and reports on the animal population received by the system. Development of human resources and increased communication between local stakeholders (groups and persons whose actions are affected by emerging infectious diseases and animal health) were instrumental for successful implementation. The primary lesson learned was that mobile phone–based surveillance of animal populations is acceptable and feasible in lower-resource settings. However, any system implementation plan must consider the time needed to garner support for novel surveillance methods among users and stakeholders.     

A functional U‐statistic method for association analysis of sequencing data

Although sequencing studies hold great promise for uncovering novel variants predisposing to human diseases, the high dimensionality of the sequencing data brings tremendous challenges to data analysis. Moreover, for many complex diseases (e.g., psychiatric disorders) multiple related phenotypes are collected. These phenotypes can be different measurements of an underlying disease, or measurements characterizing multiple related diseases for studying common genetic mechanism. Although jointly analyzing these phenotypes could potentially increase the power of identifying disease‐associated genes, the different types of phenotypes pose challenges for association analysis. To address these challenges, we propose a nonparametric method, functional U‐statistic method (FU), for multivariate analysis of sequencing data. It first constructs smooth functions from individuals’ sequencing data, and then tests the association of these functions with multiple phenotypes by using a U‐statistic. The method provides a general framework for analyzing various types of phenotypes (e.g., binary and continuous phenotypes) with unknown distributions. Fitting the genetic variants within a gene using a smoothing function also allows us to capture complexities of gene structure (e.g., linkage disequilibrium, LD), which could potentially increase the power of association analysis. Through simulations, we compared our method to the multivariate outcome score test (MOST), and found that our test attained better performance than MOST. In a real data application, we apply our method to the sequencing data from Minnesota Twin Study (MTS) and found potential associations of several nicotine receptor subunit (CHRN) genes, including CHRNB3, associated with nicotine dependence and/or alcohol dependence.     

Prospects for Emerging Infections in East and Southeast Asia 10 Years after Severe Acute Respiratory Syndrome

It is 10 years since severe acute respiratory syndrome (SARS) emerged, and East and Southeast Asia retain a reputation as a hot spot of emerging infectious diseases. The region is certainly a hot spot of socioeconomic and environmental change, and although some changes (e.g., urbanization and agricultural intensification) may reduce the probability of emerging infectious diseases, the effect of any individual emergence event may be increased by the greater concentration and connectivity of livestock, persons, and products. The region is now better able to detect and respond to emerging infectious diseases than it was a decade ago, but the tools and methods to produce sufficiently refined assessments of the risks of disease emergence are still lacking. Given the continued scale and pace of change in East and Southeast Asia, it is vital that capabilities for predicting, identifying, and controlling biologic threats do not stagnate as the memory of SARS fades.     

Bioinformatics tools and databases for whole genome sequence analysis of Mycobacterium tuberculosis

Tuberculosis (TB) is an infectious disease of global public health importance caused by Mycobacterium tuberculosis complex (MTC) in which M. tuberculosis (Mtb) is the major causative agent. Recent advancements in genomic technologies such as next generation sequencing have enabled high throughput cost-effective generation of whole genome sequence information from Mtb clinical isolates, providing new insights into the evolution, genomic diversity and transmission of the Mtb bacteria, including molecular mechanisms of antibiotic resistance. The large volume of sequencing data generated however necessitated effective and efficient management, storage, analysis and visualization of the data and results through development of novel and customized bioinformatics software tools and databases. In this review, we aim to provide a comprehensive survey of the current freely available bioinformatics software tools and publicly accessible databases for genomic analysis of Mtb for identifying disease transmission in molecular epidemiology and in rapid determination of the antibiotic profiles of clinical isolates for prompt and optimal patient treatment.     

流行病学研究新进展

流行病学是一门方法学与应用科学相融合的学科,预防和控制疾病、促进健康是其学科使命。本研究从传染病、慢性病、系统流行病学、实施性研究和健康医疗大数据5个方面介绍流行病学的新进展。传染病领域的新工程与不断涌现的新技术令人振奋,同时病原体变异的环境影响因素需得到更多重视。慢性病领域需更加重视老年人群共病问题;感染性诱发因素、人体菌群在慢性病发生发展过程中的作用逐渐被揭示。系统流行病学是现代流行病学的新兴分支与重要补充,对实现精准预防具有重要意义。实施性研究是连接医学基础科研与公共卫生实践的桥梁,将为健康中国行动计划的有效落实提供证据支持。健康医疗大数据的发展以数字化公共卫生为基础,为流行病学提供广阔的科研平台和丰富的数据资源,也将推动公共卫生服务管理模式的根本转变。     

Risk assessment for the harmful effects of UVB radiation on the immunological resistance to infectious diseases.

Risk assessment comprises four steps: hazard identification, dose-response assessment, exposure assessment, and risk characterization. In this study, the effects of increased ultraviolet B(UVB, 280-315 nm) radiation on immune functions and the immunological resistance to infectious diseases in rats were analyzed according to this strategy. In a parallelogram approach, nonthreshold mathematical methods were used to estimate the risk for the human population after increased exposure to UVB radiation. These data demonstrate, using a worst-case strategy (sensitive individuals, no adaptation), that exposure for approximately 90 min (local noon) at 40 degrees N in July might lead to 50% suppression of specific T-cell mediated responses to Listeria monocytogenes in humans who were not preexposed to UVB (i.e., not adapted). Additionally, a 5% decrease in the thickness of the ozone layer might shorten this exposure time by approximately 2.5%. These data demonstrate that UVB radiation, at doses relevant to outdoor exposure, may affect the specific cellular immune response to Listeria bacteria in humans. Whether this will also lead to a lowered resistance (i.e.,increased pathogenic load) in humans is not known, although it was demonstrated that UVB-induced immunosuppression in rats was sufficient to increase the pathogenic load. Epidemiology studies are needed to validate and improve estimates for the potential effects of increased UVB exposure on infectious diseases in humans.