Structural models and direct and indirect effects of alcohol use on HIV infection

描述（由申请人提供）：本提案的总体目标是使用多个先前存在的NIH资助的数据源来适应、应用和改进新的分析流行病学方法，以表征酒精摄入对人类免疫缺陷病毒（HIV）感染风险的关系并估计其影响。在艾滋病毒流行开始后的20多年里，人们对酒精摄入与艾滋病毒血清转化之间的关系仍然知之甚少。本提案的目的将通过三项前瞻性队列研究来实现，这三项研究是美国国宝：艾滋病与静脉注射经验的联系（ALIVE）队列研究，多中心艾滋病队列研究（MACS）和妇女机构间艾滋病毒研究（WIHS）。我们将调整，应用和完善这些复杂的纵向数据的边缘结构模型，并描述酒精摄入量和HIV血清转换之间的关系;我们将量化酒精摄入量和HIV感染风险的特定变化的影响（例如，完全停止，克/天减半，停止暴食）。具体而言，我们的目标是：1-确定（1a）基于测量的行为、人口统计学和生物医学因素的酒精摄入倾向和模式，以及（1b）探索广义（即，频率和强度）和更细微的（即，加上类型和大小）酒精摄入评估; 2-估计总效应（即，直接和间接）的酒精摄入量和模式对HIV血清转化风险的影响，探索总效应是否被年龄、性别或日历年修改，并量化由于测量误差、未测量的混杂和选择偏倚引起的不确定性; 3-估计联合（即，修正）酒精摄入量和模式以及非法或娱乐性处方药使用对HIV血清转化风险的影响;以及4-探索酒精摄入量和模式对HIV血清转化风险的间接影响，通过随后的（a）危险性行为或（B）测量的免疫功能标志物介导。将个人随机分配到对公众健康很重要的许多特定暴露水平（例如，酒精摄入）是不道德和不切实际的。时变混杂、测量误差、迁移选择偏倚（由于失访）、时变风险行为/免疫功能介导以及效应修改等问题均适用于酒精摄入和HIV血清转换的观察数据，并在本提案中得到解决。拟议的研究与生物医学和公共卫生研究中的真实的长期挑战直接相关。具体而言，研究结果将为制定针对艾滋病毒高危人群的干预措施和公共卫生信息提供必要的证据。总之，本提案描述了一个独特的机会和一个重要的、创新的和具有成本效益的举措，以在一个重要的科学研究领域中全面审查、应用和改进最新的分析方法。公共卫生相关性：拟议中的研究将直接关系到生物医学和公共卫生研究中的真实的长期挑战。首先，它将提供必要的清晰度，了解酒精摄入量和人类免疫缺陷病毒感染之间的关系。其次，它将提供复杂观测数据分析定量方法的创新和详细工作实例。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to use multiple preexisting NIH-funded data sources to adapt, apply and refine novel analytic epidemiologic methods to characterize the relation, and estimate the impact, of alcohol intake on risk of infection with Human Immunodeficiency Virus (HIV). The relation between alcohol intake and HIV seroconversion remains poorly understood >2 decades after the onset of the HIV epidemic. The aims of the present proposal will be undertaken using three prospective cohort studies, which are US national treasures: the AIDS Link to Intravenous Experience (ALIVE) cohort study, the Multicenter AIDS Cohort Study (MACS) and the Women's Interagency HIV Study (WIHS). We will adapt, apply and refine marginal structural models to these complex longitudinal data and characterize the relation between alcohol intake and HIV seroconversion; we will quantify the impact of specified changes in alcohol intake and risk of HIV infection (e.g., complete cessation, halving of grams/day, cessation of binging). Specifically, we aim to: 1-determine the (1a) propensity of alcohol intake and patterns based on measured behavioral, demographic and biomedical factors, and (1b) explore the relation between broad (i.e., frequency and intensity) and more nuanced (i.e., plus type and size) alcohol intake assessments; 2- estimate the total effect (i.e., direct and indirect) of alcohol intake and patterns on risk of HIV seroconversion, explore whether the total effect is modified by age, sex or calendar year, and quantify the uncertainty due to measurement error, unmeasured confounding, and selection bias; 3-estimate the joint (i.e., modifying) effect of alcohol intake and patterns and illicit or recreational prescription drug use on risk of HIV seroconversion; and 4- explore the indirect effects of alcohol intake and patterns on risk of HIV seroconversion, mediated through subsequent (a) risky sexual behavior or (b) measured markers of immune function. Randomization of individuals to specified levels of many exposures important to the public's health (e.g., alcohol intake) is both unethical and impractical. Issues of time-varying confounding, measurement error, emigrative selection bias (due to follow up loss), mediation by time-varying risk behaviors/immune function, and effect modification all apply in force to observational data on alcohol intake and HIV seroconversion and are addressed in this proposal. The proposed research is directly relevant to real, long-standing challenges in biomedical and public health research. Specifically, research findings will provide necessary evidence for the development of targeted interventions and public health messages in persons at-risk for HIV. In summary, the present proposal describes a unique opportunity and a significant, innovative and cost-effective initiative to comprehensively examine, apply and refine start-of-the-art analytic methods in the context of an important scientific field of inquiry. PUBLIC HEALTH RELEVANCE: The proposed research will be directly relevant to real, long-standing challenges in biomedical and public health research in two ways. First, it will provide required clarity in understanding the relation between alcohol intake and Human Immunodeficiency Virus infection. Second, it will provide innovations and detailed worked examples in quantitative methods for complex observational data analysis.