New Serological Measures of Infectious Disease Transmission Intensity

 描述(由申请人提供)： 候选人：本杰明·阿诺德 我是加州大学伯克利分校的流行病学家。2009年，我在加州大学伯克利分校获得了生物统计学硕士学位和流行病学博士学位。从那时起，我一直在杰克·科尔福德教授的团队中担任流行病学家。作为一项试金石、多国分组随机试验的协调流行病学家的机会--再加上我的家庭多了两个孩子--导致我推迟了学业。我现在准备好重新开始我的职业生涯，朝着独立调查员的身份迈进。 我的长期职业目标是成为应用新的统计方法的领导者，以确定和评估减轻低收入国家肠道感染和被忽视的热带病(NTDS)负担的干预措施。这项研究的重点和职业目标建立在我的经验和与美国疾病控制中心(CDC)的Patrick Lammie博士日益增长的合作中，该合作始于2013年，并向我介绍了血清流行病学研究。我在流行病学方法、生物统计学和国际实地研究方面的背景使我唯一有资格在统计方法和血清学分析的最新进展之间对传染病流行病学做出重大贡献。 环境：加州大学伯克利分校 为了实现我的职业目标，我制定了一项培训和指导计划，重点是统计学(半参数估计理论和机器学习)和传染病免疫学方面的最新进展。在这两个领域，额外的培训将为我提供重要而独特的机会，为血清流行病学研究做出有意义的贡献，并使我能够作为加州大学伯克利分校一名富有成效的教职员工开始独立的职业生涯。 我已经组建了一个由生物统计学和免疫学方面的高级研究人员组成的多学科指导团队，以支持我的培训、研究和职业目标。Mark van der Laan(生物统计学首席导师)将指导我在半参数方法和机器学习方面的培训。艾伦·哈伯德(生物统计学联合导师)将指导我将这一方法论应用于肠道病原体和NTDS。帕特里克·拉米(CDC免疫学联合导师)将指导我的免疫学培训和研究，他在肠道病原体和NTDS的免疫学方面具有专业知识。 研究：传染病传播的新血清学方法 背景：多重抗原分析的最新进展导致了检测肠道病原体和被忽视的热带疾病(NTDS)的低成本和敏感方法的发展。在用于从抗体反应中得出传播强度测量的统计方法方面还没有相应的进步。从公共卫生的角度来看，将抗体反应转化为传播强度的衡量标准是关键的一步，因为它使我们能够针对最有需要的人群实施干预计划，然后衡量这些计划的有效性。 目的和方法：这项研究的主要目标是建立一个方法学框架，将横断面调查中测量的抗体反应转化为肠道病原体(研究中包括7种病原体，如微小隐孢子虫、产肠毒素大肠杆菌)和被忽视的热带疾病(主要焦点：淋巴丝虫病)的传播强度。我们从两个新颖的角度来实现这一目标。在目标1中，我们借鉴了传染病的“峰移”现象，并假设传播的变化将在特定年龄的抗体反应曲线中检测到。在较低的传播率下，由于活动性感染的减少和频率的降低，所有年龄段的抗体水平应该会下降，从而导致特定年龄段的反应曲线发生整体变化。我们将通过比较肯尼亚、坦桑尼亚和海地不同暴露的幼儿的抗体反应曲线(改善与未改善的饮用水对肠道病原体的影响；大规模给药前后对淋巴丝虫病的影响)来评估该方法。 在目标2中，我们将开发半参数方法，以淋巴丝虫病为例，从可能出现血清逆转的病原体的血清阳性数据中估计感染力(血清转换率)。我们的新方法标志着比以前在这一领域的工作有了很大的进步，因为我们几乎不做建模假设，并允许灵活地控制比较组之间的混淆。我们将通过测量大规模药物管理对淋巴丝虫病感染力的影响来评估海地的方法。对于所有方法，我们将创建用户友好的开源软件，以加快向应用研究的转化。 未来：这个有指导的培训和研究计划代表着我在加州大学伯克利分校走上富有成效和协作的独立之路的自然下一步。它将为更广泛的R01级研究组合奠定基础，将新开发的方法应用于评估干预措施对肠道感染的影响的初步研究研究，并帮助确定目标和监测全球消除非传染性疾病的努力。

 DESCRIPTION (provided by applicant): Candidate: Benjamin Arnold I am an epidemiologist at the University of California, Berkeley. I completed my MA in Biostatistics and a PhD in Epidemiology from UC Berkeley in 2009. Since then, I have worked as an epidemiologist in Professor Jack Colford's group. The opportunity to work as the coordinating epidemiologist for a touchstone, multi-country cluster randomized trial - combined with the addition of two children to my family - led me to delay my academic career. I am now ready to restart my career progress toward independent investigator status. My long-term career goal is to become a leader in the application of novel statistical methods to target and evaluate interventions that reduce the burden of enteric infections and neglected tropical diseases (NTDs) in low-income countries. This research focus and career objective build from my experience and from a growing collaboration with Dr. Patrick Lammie at the US Centers for Disease Control (CDC) that started in 2013 and has introduced me to seroepidemiologic research. My background in epidemiologic methods, biostatistics, and international field research makes me uniquely qualified to make significant contributions to infectious disease epidemiology at the interface between recent advances in statistical methodology and serological assays. Environment: University of California, Berkeley To achieve my career goal, I have developed a training and mentoring plan that focuses on recent advances in statistics (semi-parametric estimation theory and machine learning) and on infectious disease immunology. These are two areas where additional training will open up significant and unique opportunities for me to make meaningful contributions to seroepidemiologic research, and will enable me to launch an independent career as a productive faculty member at UC Berkeley. I have assembled a multidisciplinary mentoring team of senior investigators in biostatistics and immunology to support my training, research, and career objectives. Mark van der Laan (primary mentor, biostatistics) will guide my training in semi-parametric methods and machine learning. Alan Hubbard (co-mentor, biostatistics) will guide my translation of the methodology to applications for enteric pathogens and NTDs. Patrick Lammie (co-mentor at CDC, immunology) will guide my immunology training and research with his expertise in the immunology of enteric pathogens and NTDs Research: New Serological Measures of Infectious Disease Transmission Background: Recent advances in multiplex antigen assays have led to the development of low-cost and sensitive methods to measure enteric pathogens and neglected tropical diseases (NTDs). There have not been commensurate advances in the statistical methods used to derive measures of transmission intensity from antibody response. Translating antibody response into metrics of transmission intensity is a key step from a public health perspective because it enables us to target intervention programs to the populations most in need and then measure the effectiveness of those programs. Aims and Methods: The overarching goal of this research is to develop a methodologic framework to translate antibody response measured in cross-sectional surveys into measures of transmission intensity for enteric pathogens (7 included in the study, e.g., Cryptosporidium parvum, enterotoxigenic E. coli) and neglected tropical diseases (principal focus: lymphatic filariasis). We approach this goal from two novel perspectives. In Aim 1, we draw on the "peak shift" phenomenon for infectious diseases, and hypothesize that changes in transmission will be detectable in the age-specific antibody response curve. At lower transmission, antibody levels should decline across all ages due to fewer and less frequent active infections, leading to an overall shift in the age-specific response curve. We will evaluate the approach by comparing antibody response curves for young children with different exposures (improved vs. unimproved drinking water for enteric pathogens; pre- versus post- mass drug administration for lymphatic filariasis) in large, well characterized cohorts in Kenya, Tanzania, and Haiti. In Aim 2, we will develop semi-parametric methods to estimate the force of infection (seroconversion rate) from seroprevalence data for pathogens where seroreversion is possible, using lymphatic filariasis as an example. Our new approach marks a significant advance over previous work in this area by making few modeling assumptions and by allowing for the flexible control of confounding between comparison groups. We will evaluate the approach in Haiti by measuring the effect of mass drug administration on the force of infection for lymphatic filariasis For all of the methods, we will create user-friendly, open source software to accelerate translation to applied research. The Future: This mentored training and research plan represents a natural next step for me on a productive and collaborative path to independence at UC Berkeley. It will set the stage for a broader R01-level research portfolio that applies the newly developed methods to primary research studies that evaluate the impact of interventions on enteric infections, and help target and monitor global elimination efforts for NTDs.