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

描述(由申请人提供)：这项建议的总体目标是使用多个先前存在的由NIH资助的数据源，以适应、应用和改进新的分析流行病学方法，以表征酒精摄入对感染人类免疫缺陷病毒(HIV)风险的关系，并评估其影响。酒精摄入和艾滋病毒血清转换之间的关系仍然知之甚少&在艾滋病毒流行开始20年后。本提案的目的将使用三项前瞻性队列研究，它们是美国的国宝：艾滋病与静脉注射经验的联系(AIVE)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、应用和改进边际结构模型，以适应这些复杂的纵向数据，并表征酒精摄入量和艾滋病毒血清转换之间的关系；我们将量化酒精摄入量的特定变化和艾滋病毒感染风险的影响(例如，完全停止饮酒，每天减半克，停止暴饮暴食)。具体地说，我们的目标是：1-根据测量的行为、人口和生物医学因素确定(1a)酒精摄入倾向和模式，以及(1b)探索广泛(即频率和强度)和更细微(即加上类型和大小)酒精摄入量评估之间的关系；2-估计酒精摄入量和模式对艾滋病毒血清转换风险的总影响(即，直接和间接)，探索总影响是否因年龄、性别或日历年而改变，并量化因测量误差、未测量的混淆和选择偏差而产生的不确定性；3--评估酒精摄入量和模式以及非法或娱乐性处方药使用对艾滋病毒血清转换风险的联合(即修正)影响；以及4--探讨酒精摄入量和模式对艾滋病毒血清转换风险的间接影响，这是通过随后的(A)危险性行为或(B)免疫功能的测量标记物实现的。将个人随机分配到对公众健康很重要的许多暴露(例如酒精摄入量)的特定水平是不道德和不切实际的。时变混杂、测量误差、移民选择偏差(由于跟踪损失)、时变危险行为/免疫功能的调节以及效果修正等问题都适用于酒精摄入量和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真正的、长期存在的挑战直接相关。具体地说，研究结果将为针对艾滋病毒高危人群制定有针对性的干预措施和公共卫生信息提供必要的证据。总之，本提案描述了在一个重要的科学研究领域中全面审查、应用和改进最先进的分析方法的独特机会和重大、创新和具有成本效益的举措。与公共卫生的相关性：拟议的研究将在两个方面与生物医学和公共卫生研究的实际、长期的挑战直接相关。首先，它将为理解酒精摄入和人类免疫缺陷病毒感染之间的关系提供必要的澄清。第二，将在复杂观测数据分析的定量方法方面提供创新和详细的实例。

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.