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The rich longitudinal individual level data available from electronic health records (EHRs) can be used to examine treatment effect heterogeneity. However, estimating treatment effects using EHR data poses several challenges, including time-varying confounding, repeated and temporally non-aligned measurements of covariates, treatment assignments and outcomes, and loss-to-follow-up due to dropout. Here, we develop the Subgroup Discovery for Longitudinal Data (SDLD) algorithm, a tree-based algorithm for discovering subgroups with heterogeneous treatment effects using longitudinal data by combining the generalized interaction tree algorithm, a general data-driven method for subgroup discovery, with longitudinal targeted maximum likelihood estimation. We apply the algorithm to EHR data to discover subgroups of people living with human immunodeficiency virus (HIV) who are at higher risk of weight gain when receiving dolutegravir-containing antiretroviral therapies (ARTs) versus when receiving non dolutegravir-containing ARTs.

When drawing causal inferences about the effects of multiple treatments on clustered survival outcomes using observational data, we need to address implications of the multilevel data structure, multiple treatments, censoring and unmeasured confounding for causal analyses. Few off-the-shelf causal inference tools are available to simultaneously tackle these issues. We develop a flexible random-intercept accelerated failure time model, in which we use Bayesian additive regression trees to capture arbitrarily complex relationships between censored survival times and pre-treatment covariates and use the random intercepts to capture cluster-specific main effects. We develop an efficient Markov chain Monte Carlo algorithm to draw posterior inferences about the population survival effects of multiple treatments and examine the variability in cluster-level effects. We further propose an interpretable sensitivity analysis approach to evaluate the sensitivity of drawn causal inferences about treatment effect to the potential magnitude of departure from the causal assumption of no unmeasured confounding. Expansive simulations empirically validate and demonstrate good practical operating characteristics of our proposed methods. Applying the proposed methods to a dataset on older high-risk localized prostate cancer patients drawn from the National Cancer Database, we evaluate the comparative effects of three treatment approaches on patient survival, and assess the ramifications of potential unmeasured confounding. The methods developed in this work are readily available in the $\textsf{R}$ package $\textsf{riAFTBART}$., Comment: 33 pages, 10 figures; 6 tables

The multinomial probit Bayesian additive regression trees (MPBART) framework was proposed by Kindo et al. (KD), approximating the latent utilities in the multinomial probit (MNP) model with BART (Chipman et al. 2010). Compared to multinomial logistic models, MNP does not assume independent alternatives and the correlation structure among alternatives can be specified through multivariate Gaussian distributed latent utilities. We introduce two new algorithms for fitting the MPBART and show that the theoretical mixing rates of our proposals are equal or superior to the existing algorithm in KD. Through simulations, we explore the robustness of the methods to the choice of reference level, imbalance in outcome frequencies, and the specifications of prior hyperparameters for the utility error term. The work is motivated by the application of generating posterior predictive distributions for mortality and engagement in care among HIV-positive patients based on electronic health records (EHRs) from the Academic Model Providing Access to Healthcare (AMPATH) in Kenya. In both the application and simulations, we observe better performance using our proposals as compared to KD in terms of MCMC convergence rate and posterior predictive accuracy., Comment: 23 pages, 12 tables, 6 figures, with appendix, 49 pages total

Pooled testing is widely used for screening for viral or bacterial infections with low prevalence when individual testing is not cost-efficient. Pooled testing with qualitative assays that give binary results has been well-studied. However, characteristics of pooling with quantitative assays were mostly demonstrated using simulations or empirical studies. We investigate properties of three pooling strategies with quantitative assays: traditional two-stage mini-pooling (MP) (Dorfman, 1943), mini-pooling with deconvolution algorithm (MPA) (May et al., 2010), and marker-assisted MPA (mMPA) (Liu et al., 2017). MPA and mMPA test individuals in a sequence after a positive pool and implement a deconvolution algorithm to determine when testing can cease to ascertain all individual statuses. mMPA uses information from other available markers to determine an optimal order for individual testings. We derive and compare the general statistical properties of the three pooling methods. We show that with a proper pool size, MP, MPA, and mMPA can be more cost-efficient than individual testing, and mMPA is superior to MPA and MP. For diagnostic accuracy, mMPA and MPA have higher specificity and positive predictive value but lower sensitivity and negative predictive value than MP and individual testing. Included in this paper are applications to various simulations and an application for HIV treatment monitoring.

The World Health Organization (WHO) guidelines for monitoring the effectiveness of HIV treatment in resource-limited settings (RLS) are mostly based on clinical and immunological markers (e.g., CD4 cell counts). Recent research indicates that the guidelines are inadequate and can result in high error rates. Viral load (VL) is considered the "gold standard", yet its widespread use is limited by cost and infrastructure. In this paper, we propose a diagnostic algorithm that uses information from routinely-collected clinical and immunological markers to guide a selective use of VL testing for diagnosing HIV treatment failure, under the assumption that VL testing is available only at a certain portion of patient visits. Our algorithm identifies the patient subpopulation, such that the use of limited VL testing on them minimizes a pre-defined risk (e.g., misdiagnosis error rate). Diagnostic properties of our proposal algorithm are assessed by simulations. For illustration, data from the Miriam Hospital Immunology Clinic (RI, USA) are analyzed.

Missing data are ubiquitous in medical research. Although there is increasing guidance on how to handle missing data, practice is changing slowly and misapprehensions abound, particularly in observational research. We present a practical framework for handling and reporting the analysis of incomplete data in observational studies, which we illustrate using a case study from the Avon Longitudinal Study of Parents and Children. The framework consists of three steps: 1) Develop an analysis plan specifying the analysis model and how missing data are going to be addressed. An important consideration is whether a complete records analysis is likely to be valid, whether multiple imputation or an alternative approach is likely to offer benefits, and whether a sensitivity analysis regarding the missingness mechanism is required. 2) Explore the data, checking the methods outlined in the analysis plan are appropriate, and conduct the pre-planned analysis. 3) Report the results, including a description of the missing data, details on how the missing data were addressed, and the results from all analyses, interpreted in light of the missing data and the clinical relevance. This framework seeks to support researchers in thinking systematically about missing data, and transparently reporting the potential effect on the study results., Comment: 37 pages, including 3 Figures, 1 table and supplementary material

The timing of antiretroviral therapy (ART) initiation for HIV and tuberculosis (TB) co-infected patients needs to be considered carefully. CD4 cell count can be used to guide decision making about when to initiate ART. Evidence from recent randomized trials and observational studies generally supports early initiation but does not provide information about effects of initiation time on a continuous scale. In this paper, we develop and apply a highly flexible structural proportional hazards model for characterizing the effect of treatment initiation time on a survival distribution. The model can be fitted using a weighted partial likelihood score function. Construction of both the score function and the weights must accommodate censoring of the treatment initiation time, the outcome, or both. The methods are applied to data on 4903 individuals with HIV/TB co-infection, derived from electronic health records in a large HIV care program in Kenya. We use a model formulation that flexibly captures the joint effects of ART initiation time and ART duration using natural cubic splines. The model is used to generate survival curves corresponding to specific treatment initiation times; and to identify optimal times for ART initiation for subgroups defined by CD4 count at time of TB diagnosis. Our findings potentially provide "higher resolution" information about the relationship between ART timing and mortality, and about the differential effect of ART timing within CD4 subgroups., Comment: Published in Biometrics

Evidence supporting the current World Health Organization recommendations of early antiretroviral therapy (ART) initiation for adolescents is inconclusive. We leverage a large observational data and compare, in terms of mortality and CD4 cell count, the dynamic treatment initiation rules for HIV-infected adolescents. Our approaches extend the marginal structural model for estimating outcome distributions under dynamic treatment regimes (DTR), developed in Robins et al. (2008), to allow the causal comparisons of both specific regimes and regimes along a continuum. Furthermore, we propose strategies to address three challenges posed by the complex data set: continuous-time measurement of the treatment initiation process; sparse measurement of longitudinal outcomes of interest, leading to incomplete data; and censoring due to dropout and death. We derive a weighting strategy for continuous time treatment initiation; use imputation to deal with missingness caused by sparse measurements and dropout; and define a composite outcome that incorporates both death and CD4 count as a basis for comparing treatment regimes. Our analysis suggests that immediate ART initiation leads to lower mortality and higher median values of the composite outcome, relative to other initiation rules., Comment: Accepted by Biometrics

Emission control technologies installed on power plants are a key feature of many air pollution regulations in the US. While such regulations are predicated on the presumed relationships between emissions, ambient air pollution, and human health, many of these relationships have never been empirically verified. The goal of this paper is to develop new statistical methods to quantify these relationships. We frame this problem as one of mediation analysis to evaluate the extent to which the effect of a particular control technology on ambient pollution is mediated through causal effects on power plant emissions. Since power plants emit various compounds that contribute to ambient pollution, we develop new methods for multiple intermediate variables that are measured contemporaneously, may interact with one another, and may exhibit joint mediating effects. Specifically, we propose new methods leveraging two related frameworks for causal inference in the presence of mediating variables: principal stratification and causal mediation analysis. We define principal effects based on multiple mediators, and also introduce a new decomposition of the total effect of an intervention on ambient pollution into the natural direct effect and natural indirect effects for all combinations of mediators. Both approaches are anchored to the same observed-data models, which we specify with Bayesian nonparametric techniques. We provide assumptions for estimating principal causal effects, then augment these with an additional assumption required for causal mediation analysis. The two analyses, interpreted in tandem, provide the first empirical investigation of the presumed causal pathways that motivate important air quality regulatory policies.

Binary classification rules based on covariates typically depend on simple loss functions such as zero-one misclassification. Some cases may require more complex loss functions. For example, individual-level monitoring of HIV-infected individuals on antiretroviral therapy (ART) requires periodic assessment of treatment failure, defined as having a viral load (VL) value above a certain threshold. In some resource limited settings, VL tests may be limited by cost or technology, and diagnoses are based on other clinical markers. Depending on scenario, higher premium may be placed on avoiding false-positives which brings greater cost and reduced treatment options. Here, the optimal rule is determined by minimizing a weighted misclassification loss/risk. We propose a method for finding and cross-validating optimal binary classification rules under weighted misclassification loss. We focus on rules comprising a prediction score and an associated threshold, where the score is derived using an ensemble learner. Simulations and examples show that our method, which derives the score and threshold jointly, more accurately estimates overall risk and has better operating characteristics compared with methods that derive the score first and the cutoff conditionally on the score especially for finite samples., Comment: 23 pages, 4 tables, 4 figures

People who inject drugs are an important population to study in order to reduce transmission of blood-borne illnesses including HIV and Hepatitis. In this paper we estimate the HIV and Hepatitis C prevalence among people who inject drugs, as well as the proportion of people who inject drugs who are female in Mauritius. Respondent driven sampling (RDS), a widely adopted link-tracing sampling design used to collect samples from hard-to-reach human populations, was used to collect this sample. The random walk approximation underlying many common RDS estimators assumes that each social relation (edge) in the underlying social network has an equal probability of being traced in the collection of the sample. This assumption does not hold in practice. We show that certain RDS estimators are sensitive to the violation of this assumption. In order to address this limitation in current methodology, and the impact it may have on prevalence estimates, we present a new method for improving RDS prevalence estimators using estimated edge inclusion probabilities, and apply this to data from Mauritius.

For settings with a binary treatment and a binary outcome, instrumental variables can be used to construct bounds on a causal treatment effect. With continuous outcomes, meaningful bounds are more difficult to obtain because the domain of the outcome is typically unrestricted. In this paper, we combine an instrumental variable and subjective assumptions in the context of an obser- vational cohort study of HIV-infected women to construct meaningful bounds on the initial-stage causal effect of antiretroviral therapy on CD4 count. The subjective assumptions are encoded in terms of the potential outcomes that are identified by observed data as well as a sensitivity parameter that captures the impact of unmeasured confounding. Measured confounding is adjusted using the method of inverse probability weighting (IPW). With extra information from an IV, we quantify both the causal treatment effect and the degree of the unmea- sured confounding. We demonstrate our method by analyzing data from the HIV Epidemiology Research Study., Comment: 1 figure

Hepatitis C virus (HCV) coinfection has become one of the most challenging clinical situations to manage in HIV-infected patients. Recently the effect of HCV coinfection on HIV dynamics following initiation of highly active antiretroviral therapy (HAART) has drawn considerable attention. Post-HAART HIV dynamics are commonly studied in short-term clinical trials with frequent data collection design. For example, the elimination process of plasma virus during treatment is closely monitored with daily assessments in viral dynamics studies of AIDS clinical trials. In this article instead we use infrequent cohort data from long-term natural history studies and develop a model for characterizing post-HAART HIV dynamics and their associations with HCV coinfection. Specifically, we propose a joint model for doubly interval-censored data for the time between HAART initiation and viral suppression, and the longitudinal CD4 count measurements relative to the viral suppression. Inference is accomplished using a fully Bayesian approach. Doubly interval-censored data are modeled semiparametrically by Dirichlet process priors and Bayesian penalized splines are used for modeling population-level and individual-level mean CD4 count profiles. We use the proposed methods and data from the HIV Epidemiology Research Study (HERS) to investigate the effect of HCV coinfection on the response to HAART., Comment: Published in at http://dx.doi.org/10.1214/10-AOAS391 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org)