Causal identification of treatment effects for infectious disease outcomes in interconnected populations is challenging because infection outcomes may be transmissible to others, and treatment given to one individual may affect others' outcomes. Contagion, or transmissibility of outcomes, complicates standard conceptions of treatment interference in which an intervention delivered to one individual can affect outcomes of others. Several statistical frameworks have been proposed to measure causal treatment effects in this setting, including structural transmission models, mediation-based partnership models, and randomized trial designs. However, existing estimands for infectious disease intervention effects are of limited conceptual usefulness: Some are parameters in a structural model whose causal interpretation is unclear, others are causal effects defined only in a restricted two-person setting, and still others are nonparametric estimands that arise naturally in the context of a randomized trial but may not measure any biologically meaningful effect. In this paper, we describe a unifying formalism for defining nonparametric structural causal estimands and an identification strategy for learning about infectious disease intervention effects in clusters of interacting individuals when infection times are observed. The estimands generalize existing quantities and provide a framework for causal identification in randomized and observational studies, including situations where only binary infection outcomes are observed. A semiparametric class of pairwise Cox-type transmission hazard models is used to facilitate statistical inference in finite samples. A comprehensive simulation study compares existing and proposed estimands under a variety of randomized and observational vaccine trial designs.
Understanding the effects of interventions, such as restrictions on community and large group gatherings, is critical to controlling the spread of COVID-19. Susceptible-Infectious-Recovered (SIR) models are traditionally used to forecast the infection rates but do not provide insights into the causal effects of interventions. We propose a spatiotemporal model that estimates the causal effect of changes in community mobility (intervention) on infection rates. Using an approximation to the SIR model and incorporating spatiotemporal dependence, the proposed model estimates a direct and indirect (…
Randomized trials of infectious disease interventions, such as vaccines, often focus on groups of connected or potentially interacting individuals. When the pathogen of interest is transmissible between study subjects, interference may occur: individual infection outcomes may depend on treatments received by others. Epidemiologists have defined the primary causal effect of interest -- called the "susceptibility effect" -- as a contrast in infection risk under treatment versus no treatment, while holding exposure to infectiousness constant. A related quantity -- the "direct effect" -- is define…
Defining and identifying causal intervention effects for transmissible infectious disease outcomes is challenging because a treatment -- such as a vaccine -- given to one individual may affect the infection outcomes of others. Epidemiologists have proposed causal estimands to quantify effects of interventions under contagion using a two-person partnership model. These simple conceptual models have helped researchers develop causal estimands relevant to clinical evaluation of vaccine effects. However, many of these partnership models are formulated under structural assumptions that preclude rea…
RCTs sometimes test interventions that aim to improve existing services targeted to a subset of individuals identified after randomization. Accordingly, the treatment could affect the composition of service recipients and the offered services. With such bias, intention-to-treat estimates using data on service recipients and nonrecipients may be difficult to interpret. This article develops causal estimands and inverse probability weighting (IPW) estimators for complier populations in these settings, using a generalized estimating equation approach that adjusts the standard errors for estimatio…
Cluster randomized trials (CRTs) are a popular design to study the effect of interventions in infectious disease settings. However, standard analysis of CRTs primarily relies on strong parametric methods, usually mixed-effect models to account for the clustering structure, and focuses on the overall intent-to-treat (ITT) effect to evaluate effectiveness. The paper presents two assumption-lean methods to analyze two types of effects in CRTs, ITT effects and network effects among well-known compliance groups. For the ITT effects, we study the overall and the heterogeneous ITT effects among the o…
Inferring causal effects from an observational study is challenging because participants are not randomized to treatment. Observational studies in infectious disease research present the additional challenge that one participant's treatment may affect another participant's outcome, i.e., there may be interference. In this paper recent approaches to defining causal effects in the presence of interference are considered, and new causal estimands designed specifically for use with observational studies are proposed. Previously defined estimands target counterfactual scenarios in which individuals…
Improving the efficiency of infectious disease prevention trials using negative control outcome event times
University of Washington（华盛顿大学）；Fred Hutchinson Cancer Center（弗雷德·哈钦森癌症中心）；Penn State University（宾夕法尼亚州立大学）；Gillings School of Global Public Health, University of North Carolina at Chapel Hill（北卡罗来纳大学教堂山分校吉林斯全球公共卫生学院）
The PROmotion of Breastfeeding Intervention Trial (PROBIT) cluster-randomized a program encouraging breastfeeding to new mothers in hospital centers. The original studies indicated that this intervention successfully increased duration of breastfeeding and lowered rates of gastrointestinal tract infections in newborns. Additional scientific and popular interest lies in determining the causal effect of longer breastfeeding on gastrointestinal infection. In this study, we estimate the expected infection count under various lengths of breastfeeding in order to estimate the effect of breastfeeding…
The pandemic of COVID-19 has caused severe public health consequences around the world. Many interventions of COVID-19 have been implemented. It is of great public health and societal importance to evaluate the effects of interventions in the pandemic of COVID-19. In this paper, with help of synthetic control method, regression discontinuity and a Susceptible-Infected and infectious without isolation-Hospitalized in isolation-Removed (SIHR) model, we evaluate the horizontal and longitudinal effects of stringent interventions implemented in Wenzhou, a representative urban city of China, where s…
Whenever possible, the efficacy of a new treatment, such as a drug or behavioral intervention, is investigated by randomly assigning some individuals to a treatment condition and others to a control condition, and comparing the outcomes between the two groups. Often, when the treatment aims to slow an infectious disease, groups or clusters of individuals are assigned en masse to each treatment arm. The structure of interactions within and between clusters can reduce the power of the trial, i.e. the probability of correctly detecting a real treatment effect. We investigate the relationships amo…
Educational research often studies subjects that are in naturally clustered groups of classrooms or schools. When designing a randomized experiment to evaluate an intervention directed at teachers, but with effects on teachers and their students, the power or anticipated variance for the treatment effect needs to be examined at both levels. If the treatment is applied to clusters, power is usually reduced. At the same time, a cluster design decreases the probability of contamination, and contamination can also reduce power to detect a treatment effect. Designs that are optimal at one level may…
Background. Health economic evaluations of interventions against infectious diseases are commonly based on the predictions of ordinary differential equation (ODE) systems or Markov models (MMs). Standard MMs are static, whereas ODE systems are usually dynamic and account for herd immunity which is crucial to prevent overestimation of infection prevalence. Complex ODE systems including probabilistic model parameters are computationally intensive. Thus, mainly ODE-based models including deterministic parameters are presented in the literature. These do not account for parameter uncertainty. As a…
The increasing threat of emerging infectious diseases and antimicrobial resistance requires more efficient, high-quality research. Perpetual Observational Studies (POS) nested within a clinical research network can improve planning, quality and efficiency of interventional and observational studies, although real-life benefits and challenges need to be assessed. Ecraid (European Clinical Research Alliance on Infectious Diseases) has initiated POS and will monitor the impact for five specific infectious syndromes.
Q-Learning with Clustered-SMART (cSMART) Data: Examining Moderators in the Construction of Clustered Adaptive Interventions
Department of Biostatistics（生物统计学系）；School of Public Health University of Michigan（公共卫生学院）；University of Michigan（密歇根大学）；Department of Learning Health Sciences University of Michigan（学习健康科学系）；Office of Research and Development U.S. Department of Veterans Affairs（美国退伍军人事务部研发办公室）；Department of Family Medicine and Community Health University of Wisconsin Madison WI USA（家庭医学与社区健康系）；University of Wisconsin Madison WI USA（威斯康星大学麦迪逊分校）；Department of Statistics University of Michigan（统计学系）；Survey Research Center Institute for Social Research Ann Arbor MI USA（调查研究中心社会研究研究所）
Infectious disease forecasting is of great interest to the public health community and policymakers, since forecasts can provide insight into disease dynamics in the near future and inform interventions. Due to delays in case reporting, however, forecasting models may often underestimate the current and future disease burden. In this paper, we propose a general framework for addressing reporting delay in disease forecasting efforts with the goal of improving forecasts. We propose strategies for leveraging either historical data on case reporting or external internet-based data to estimate the …
Infectious disease epidemiologists routinely fit stochastic epidemic models to time series data to elucidate infectious disease dynamics, evaluate interventions, and forecast epidemic trajectories. To improve computational tractability, many approximate stochastic models have been proposed. In this paper, we focus on one class of such approximations -- time series Susceptible-Infectious-Removed (TSIR) models. Infectious disease modeling often starts with a homogeneous mixing assumption, postulating that the rate of disease transmission is proportional to a product of the numbers of susceptible…
In repeated measures factorial designs involving clustered units, parametric methods such as linear mixed effects models are used to handle within subject correlations. However, assumptions of these parametric models such as continuity and normality are usually hard to come by in many cases. The homoscedasticity assumption is rather hard to verify in practice. Furthermore, these assumptions may not even be realistic when data are measured in a non-metric scale as commonly happens, for example, in Quality of Life outcomes. In this article, nonparametric effect-size measures for clustered data i…
Sepsis is a life-threatening medical emergency, which is a major cause of death worldwide and the second highest cause of mortality in the United States. Researching the optimal control treatment or intervention strategy on the comprehensive sepsis system is key in reducing mortality. For this purpose, first, this paper improves a complex nonlinear sepsis model proposed in our previous work. Then, bifurcation analyses are conducted for each sepsis subsystem to study the model behaviors under some system parameters. The bifurcation analysis results also further indicate the necessity of control…
