arXiv subjects

Linda Valeri

Publications and source records attributed to Linda Valeri.

13 recordsLinked to original sources

arXiv2025

Missing data in non-stationary multivariate time series from digital studies in Psychiatry

Mobile technology (e.g., mobile phones and wearable devices) provides scalable methods for collecting physiological and behavioral biomarkers in patients' naturalistic settings, as well as opportunities for therapeutic advancements and scientific discoveries regarding the etiology of psychiatric illness. Continuous data collection through mobile devices generates highly complex data: entangled multivariate time series of outcomes, exposures, and covariates. Missing data is a pervasive problem in biomedical and social science research, and Ecological Momentary Assessment (EMA) data in psychiatric research is no exception. However, the complex data structure of multivariate time series and their non-stationary nature make missing data a major challenge for proper inference. Additional historical information included in time series analyses exacerbates the issue of missing data and also introduces problems for confounding adjustment. The majority of existing imputation methods are either designed for stationary time series or for longitudinal data with limited follow-up periods. The limited work on non-stationary time series either focuses on missing exogenous information or ignores the complex temporal dependence among outcomes, exposures, and covariates. We propose a Monte Carlo Expectation Maximization algorithm for the state space model (MCEM-SSM) to effectively handle missing data in non-stationary entangled multivariate time series. We demonstrate the method's advantages over other widely used missing data imputation strategies through simulations of both stationary and non-stationary time series, subject to various missing mechanisms. Finally, we apply the MCEM-SSM to a multi-year smartphone observational study of bipolar and schizophrenia patients to investigate the association between digital social connectivity and negative mood.

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arXiv2025

Individual causal effect estimation accounting for latent disease state modification among bipolar participants in mobile health studies

Individuals with bipolar disorder tend to cycle through disease states such as depression and mania. The heterogeneous nature of disease across states complicates the evaluation of interventions for bipolar disorder patients, as varied interventional success is observed within and across individuals. In fact, we hypothesize that disease state acts as an effect modifier for the causal effect of a given intervention on health outcomes. To address this dilemma, we propose an N-of-1 approach using an adapted autoregressive hidden Markov model, applied to longitudinal mobile health data collected from individuals with bipolar disorder. This method allows us to identify a latent variable from mobile health data to be treated as an effect modifier between the exposure and outcome of interest while allowing for missing data in the outcome. A counterfactual approach is employed for causal inference and to obtain a g-formula estimator to recover said effect. The performance of the proposed method is compared with a naive approach across extensive simulations and application to a multi-year smartphone study of bipolar patients, evaluating the individual effect of digital social activity on sleep duration across different latent disease states.

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arXiv2024

A path-specific effect approach to mediation analysis with time-varying mediators and time-to-event outcomes accounting for competing risks

Not accounting for competing events in survival analysis can lead to biased estimates, as individuals who die from other causes do not have the opportunity to develop the event of interest. Formal definitions and considerations for causal effects in the presence of competing risks have been published, but not for the mediation analysis setting. We propose, for the first time, an approach based on the path-specific effects framework to account for competing risks in longitudinal mediation analysis with time-to-event outcomes. We do so by considering the pathway through the competing event as another mediator, which is nested within our longitudinal mediator of interest. We provide a theoretical formulation and related definitions of the effects of interest based on the mediational g-formula, as well as a detailed description of the algorithm. We also present an application of our algorithm to data from the Strong Heart Study, a prospective cohort of American Indian adults. In this application, we evaluated the mediating role of the blood pressure trajectory (measured during three visits) on the association between arsenic and cadmium, in separate models, with time to cardiovascular disease, accounting for competing risks by death. Identifying the effects through different paths enables us to evaluate the impact of metals on the outcome of interest, as well as through competing risks, more transparently.

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arXiv2024

Causal estimands and identification of time-varying effects in non-stationary time series from N-of-1 mobile device data

Mobile technology (mobile phones and wearable devices) generates continuous data streams encompassing outcomes, exposures and covariates, presented as intensive longitudinal or multivariate time series data. The high frequency of measurements enables granular and dynamic evaluation of treatment effect, revealing their persistence and accumulation over time. Existing methods predominantly focus on the contemporaneous effect, temporal-average, or population-average effects, assuming stationarity or invariance of treatment effects over time, which are inadequate both conceptually and statistically to capture dynamic treatment effects in personalized mobile health data. We here propose new causal estimands for multivariate time series in N-of-1 studies. These estimands summarize how time-varying exposures impact outcomes in both short- and long-term. We propose identifiability assumptions and a g-formula estimator that accounts for exposure-outcome and outcome-covariate feedback. The g-formula employs a state space model framework innovatively to accommodate time-varying behavior of treatment effects in non-stationary time series. We apply the proposed method to a multi-year smartphone observational study of bipolar patients and estimate the dynamic effect of phone-based communication on mood of patients with bipolar disorder in an N-of-1 setting. Our approach reveals substantial heterogeneity in treatment effects over time and across individuals. A simulation-based strategy is also proposed for the development of a short-term, dynamic, and personalized treatment recommendation based on patient's past information, in combination with a novel positivity diagnostics plot, validating proper causal inference in time series data.

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arXiv2024

Measurement Error-Robust Causal Inference via Constructed Instrumental Variables

Measurement error can often be harmful when estimating causal effects. Two scenarios in which this is the case are in the estimation of (a) the average treatment effect when confounders are measured with error and (b) the natural indirect effect when the exposure and/or confounders are measured with error. Methods adjusting for measurement error typically require external data or knowledge about the measurement error distribution. Here, we propose methodology not requiring any such information. Instead, we show that when the outcome regression is linear in the error-prone variables, consistent estimation of these causal effects can be recovered using constructed instrumental variables under certain conditions. These variables, which are functions of only the observed data, behave like instrumental variables for the error-prone variables. Using data from a study of the effects of prenatal exposure to heavy metals on growth and neurodevelopment in Bangladeshi mother-infant pairs, we apply our methodology to estimate (a) the effect of lead exposure on birth length while controlling for maternal protein intake, and (b) lead exposure's role in mediating the effect of maternal protein intake on birth length. Protein intake is calculated from food journal entries, and is suspected to be highly prone to measurement error.

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arXiv2023

Comparison of methods for analyzing environmental mixtures effects on survival outcomes and application to a population-based cohort study

The estimation of the effect of environmental exposures and overall mixtures on a survival time outcome is common in environmental epidemiological studies. While advanced statistical methods are increasingly being used for mixture analyses, their applicability and performance for survival outcomes has yet to be explored. We identified readily available methods for analyzing an environmental mixture's effect on a survival outcome and assessed their performance via simulations replicating various real-life scenarios. Using prespecified criteria, we selected Bayesian Additive Regression Trees (BART), Cox Elastic Net, Cox Proportional Hazards (PH) with and without penalized splines, Gaussian Process Regression (GPR) and Multivariate Adaptive Regression Splines (MARS) to compare the bias and efficiency produced when estimating individual exposure, overall mixture, and interaction effects on a survival outcome. We illustrate the selected methods in a real-world data application. We estimated the effects of arsenic, cadmium, molybdenum, selenium, tungsten, and zinc on incidence of cardiovascular disease in American Indians using data from the Strong Heart Study (SHS). In the simulation study, there was a consistent bias-variance trade off. The more flexible models (BART, GPR and MARS) were found to be most advantageous in the presence of nonproportional hazards, where the Cox models often did not capture the true effects due to their higher bias and lower variance. In the SHS, estimates of the effect of selenium and the overall mixture indicated negative effects, but the magnitudes of the estimated effects varied across methods. In practice, we recommend evaluating if findings are consistent across methods.

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arXiv2022

Testing unit root non-stationarity in the presence of missing data in univariate time series of mobile health studies

The use of digital devices to collect data in mobile health (mHealth) studies introduces a novel application of time series methods, with the constraint of potential data missing at random (MAR) or missing not at random (MNAR). In time series analysis, testing for stationarity is an important preliminary step to inform appropriate later analyses. The augmented Dickey-Fuller (ADF) test was developed to test the null hypothesis of unit root non-stationarity, under no missing data. Beyond recommendations under data missing completely at random (MCAR) for complete case analysis or last observation carry forward imputation, researchers have not extended unit root non-stationarity testing to a context with more complex missing data mechanisms. Multiple imputation with chained equations, Kalman smoothing imputation, and linear interpolation have also been proposed for time series data, however such methods impose constraints on the autocorrelation structure, and thus impact unit root testing. We propose maximum likelihood estimation and multiple imputation using state space model approaches to adapt the ADF test to a context with missing data. We further develop sensitivity analysis techniques to examine the impact of MNAR data. We evaluate the performance of existing and proposed methods across different missing mechanisms in extensive simulations and in their application to a multi-year smartphone study of bipolar patients.

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arXiv2022

State space model multiple imputation for missing data in non-stationary multivariate time series with application in digital Psychiatry

Mobile technology enables unprecedented continuous monitoring of an individual's behavior, social interactions, symptoms, and other health conditions, presenting an enormous opportunity for therapeutic advancements and scientific discoveries regarding the etiology of psychiatric illness. Continuous collection of mobile data results in the generation of a new type of data: entangled multivariate time series of outcome, exposure, and covariates. Missing data is a pervasive problem in biomedical and social science research, and the Ecological Momentary Assessment (EMA) using mobile devices in psychiatric research is no exception. However, the complex structure of multivariate time series introduces new challenges in handling missing data for proper causal inference. Data imputation is commonly recommended to enhance data utility and estimation efficiency. The majority of available imputation methods are either designed for longitudinal data with limited follow-up times or for stationary time series, which are incompatible with potentially non-stationary time series. In the field of psychiatry, non-stationary data are frequently encountered as symptoms and treatment regimens may experience dramatic changes over time. To address missing data in possibly non-stationary multivariate time series, we propose a novel multiple imputation strategy based on the state space model (SSMmp) and a more computationally efficient variant (SSMimpute). We demonstrate their advantages over other widely used missing data strategies by evaluating their theoretical properties and empirical performance in simulations of both stationary and non-stationary time series, subject to various missing mechanisms. We apply the SSMimpute to investigate the association between social network size and negative mood using a multi-year observational smartphone study of bipolar patients, controlling for confounding variables.

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arXiv2021

Bayesian kernel machine regression-causal mediation analysis

Greater understanding of the pathways through which an environmental mixture operates is important to design effective interventions. We present new methodology to estimate natural direct and indirect effects and controlled direct effects of a complex mixture exposure on an outcome through a mediator variable. We implement Bayesian Kernel Machine Regression (BKMR) to allow for all possible interactions and nonlinear effects of (1) the co-exposures on the mediator, (2) the co-exposures and mediator on the outcome, and (3) selected covariates on the mediator and/or outcome. From the posterior predictive distributions of the mediator and outcome, we simulate counterfactuals to obtain posterior samples, estimates, and credible intervals of the mediation effects. Our simulation study demonstrates that when the exposure-mediator and exposure-mediator-outcome relationships are complex, BKMR--Causal Mediation Analysis performs better than current mediation methods. We applied our methodology to quantify the contribution of birth length as a mediator between in utero co-exposure to arsenic, manganese and lead, and children's neurodevelopmental scores, in a prospective birth cohort in Bangladesh. Among younger children, we found a negative (adverse) association between the metal mixture and neurodevelopment. We also found evidence that birth length mediates the effect of exposure to the metal mixture on neurodevelopment for younger children. If birth length were fixed to its $75^{th}$ percentile value, the harmful effect of the metal mixture on neurodevelopment is attenuated, suggesting nutritional interventions to help increase fetal growth, and thus birth length, could potentially block the harmful effect of the metal mixture on neurodevelopment.

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arXiv2021

A multistate approach for mediation analysis in the presence of semi-competing risks with application in cancer survival disparities

We propose a novel methodology to quantify the effect of stochastic interventions on non-terminal time-to-events that lie on the pathway between an exposure and a terminal time-to-event outcome. Investigating these effects is particularly important in health disparities research when we seek to quantify inequities in timely delivery of treatment and its impact on patients survival time. Current approaches fail to account for semi-competing risks arising in this setting. Under the potential outcome framework, we define and provide identifiability conditions for causal estimands for stochastic direct and indirect effects. Causal contrasts are estimated in continuous time within a multistate modeling framework and analytic formulae for the estimators of the causal contrasts are developed. We show via simulations that ignoring censoring in mediator and or outcome time-to-event processes, or ignoring competing risks may give misleading results. This work demonstrates that rigorous definition of the direct and indirect effects and joint estimation of the outcome and mediator time-to-event distributions in the presence of semi-competing risks are crucial for valid investigation of mechanisms in continuous time. We employ this novel methodology to investigate the role of delaying treatment uptake in explaining racial disparities in cancer survival in a cohort study of colon cancer patients.

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arXiv2019

A Cross-validated Ensemble Approach to Robust Hypothesis Testing of Continuous Nonlinear Interactions: Application to Nutrition-Environment Studies

Gene-environment and nutrition-environment studies often involve testing of high-dimensional interactions between two sets of variables, each having potentially complex nonlinear main effects on an outcome. Construction of a valid and powerful hypothesis test for such an interaction is challenging, due to the difficulty in constructing an efficient and unbiased estimator for the complex, nonlinear main effects. In this work we address this problem by proposing a Cross-validated Ensemble of Kernels (CVEK) that learns the space of appropriate functions for the main effects using a cross-validated ensemble approach. With a carefully chosen library of base kernels, CVEK flexibly estimates the form of the main-effect functions from the data, and encourages test power by guarding against over-fitting under the alternative. The method is motivated by a study on the interaction between metal exposures in utero and maternal nutrition on children's neurodevelopment in rural Bangladesh. The proposed tests identified evidence of an interaction between minerals and vitamins intake and arsenic and manganese exposures. Results suggest that the detrimental effects of these metals are most pronounced at low intake levels of the nutrients, suggesting nutritional interventions in pregnant women could mitigate the adverse impacts of in utero metal exposures on children's neurodevelopment.

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arXiv2019

Bayesian data fusion for unmeasured confounding

Bayesian causal inference offers a principled approach to policy evaluation of proposed interventions on mediators or time-varying exposures. We outline a general approach to the estimation of causal quantities for settings with time-varying confounding, such as exposure-induced mediator-outcome confounders. We further extend this approach to propose two Bayesian data fusion (BDF) methods for unmeasured confounding. Using informative priors on quantities relating to the confounding bias parameters, our methods incorporate data from an external source where the confounder is measured in order to make inferences about causal estimands in the main study population. We present results from a simulation study comparing our data fusion methods to two common frequentist correction methods for unmeasured confounding bias in the mediation setting. We also demonstrate our method with an investigation of the role of stage at cancer diagnosis in contributing to Black-White colorectal cancer survival disparities.

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arXiv2018

The Role of Body Mass Index at Diagnosis on Black-White Disparities in Colorectal Cancer Survival: A Density Regression Mediation Approach

The study of racial/ethnic inequalities in health is important to reduce the uneven burden of disease. In the case of colorectal cancer (CRC), disparities in survival among non-Hispanic Whites and Blacks are well documented, and mechanisms leading to these disparities need to be studied formally. It has also been established that body mass index (BMI) is a risk factor for developing CRC, and recent literature shows BMI at diagnosis of CRC is associated with survival. Since BMI varies by racial/ethnic group, a question that arises is whether disparities in BMI is partially responsible for observed racial/ethnic disparities in CRC survival. This paper presents new methodology to quantify the impact of the hypothetical intervention that matches the BMI distribution in the Black population to a potentially complex distributional form observed in the White population on racial/ethnic disparities in survival. We perform a simulation that shows our proposed Bayesian density regression approach performs as well as or better than current methodology allowing for a shift in the mean of the distribution only, and that standard practice of categorizing BMI leads to large biases. When applied to motivating data from the Cancer Care Outcomes Research and Surveillance (CanCORS) Consortium, our approach suggests the proposed intervention is potentially beneficial for elderly and low income Black patients, yet harmful for young and high income Black populations.

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