Considerable interest has recently been focused on studying multiple phenotypes simultaneously in both epidemiological and genomic studies, either to capture the multidimensionality of complex disorders or to understand shared etiology of related disorders. We seek to identify {\em multiple regulators} or predictors that are associated with multiple outcomes when these outcomes may be measured on very different scales or composed of a mixture of continuous, binary, and not-fully-observed elements. We first propose an estimation technique to put all effects on similar scales, and we induce sparsity on the estimated effects. We provide standard asymptotic results for this estimator and show that resampling can be used to quantify uncertainty in finite samples. We finally provide a multiple testing procedure which can be geared specifically to the types of multiple regulators of interest, and we establish that, under standard regularity conditions, the familywise error rate will approach 0 as sample size diverges. Simulation results indicate that our approach can improve over unregularized methods both in reducing bias in estimation and improving power for testing.
We propose a method for summarizing the strength of association between a set of variables and a multivariate outcome. Classical summary measures are appropriate when linear relationships exist between covariates and outcomes, while our approach provides an alternative that is useful in situations where complex relationships may be present. We utilize ensemble machine learning to detect nonlinear relationships and covariate interactions and propose a measure of association that captures these relationships. A hypothesis test about the proposed associative measure can be used to test the strong…
Studies that collect multi-outcome data such as tobacco and alcohol use are becoming increasingly common. In principle, multi-outcomes studies investigate the correlations between outcomes, including, causal links and/or joint distributions. Although there are many methods for studying multivariate outcomes, significant limitations regarding scale and interpretation persist. Here we introduce a model based on the exponential-family for discrete binary outcomes that provides a flexible framework for hypothesis testing of multiple binary outcomes in a computationally efficient fashion.
This work is motivated by the need to accurately model a vector of responses related to pediatric functional status using administrative health data from inpatient rehabilitation visits. The components of the responses have known and structured interrelationships. To make use of these relationships in modeling, we develop a two-pronged regularization approach to borrow information across the responses. The first component of our approach encourages joint selection of the effects of each variable across possibly overlapping groups related responses and the second component encourages shrinkage …
Quantile regression permits describing how quantiles of a scalar response variable depend on a set of predictors. Because a unique definition of multivariate quantiles is lacking, extending quantile regression to multivariate responses is somewhat complicated. In this paper, we describe a simple approach based on a two-step procedure: in the first step, quantile regression is applied to each response separately; in the second step, the joint distribution of the signs of the residuals is modeled through multinomial regression. The described approach does not require a multidimensional definitio…
In many psychometric applications, the relationship between the mean of an outcome and a quantitative covariate is too complex to be described by simple parametric functions; instead, flexible nonlinear relationships can be incorporated using penalized splines. Penalized splines can be conveniently represented as a linear mixed effects model (LMM), where the coefficients of the spline basis functions are random effects. The LMM representation of penalized splines makes the extension to multivariate outcomes relatively straightforward. In the LMM, no effect of the quantitative covariate on the …
We present a multivariate one-sided sensitivity analysis for matched observational studies, appropriate when the researcher has specified that a given causal mechanism should manifest itself in effects on multiple outcome variables in a known direction. The test statistic can be thought of as the solution to an adversarial game, where the researcher determines the best linear combination of test statistics to combat nature's presentation of the worst-case pattern of hidden bias. The corresponding optimization problem is convex, and can be solved efficiently even for reasonably sized observatio…
The so-called gut-brain axis has stimulated extensive research on microbiomes. One focus is to assess the association between certain clinical outcomes and the relative abundances of gut microbes, which can be presented as sub-compositional data in conformity with the taxonomic hierarchy of bacteria. Motivated by a study for identifying the microbes in the gut microbiome of preterm infants that impact their later neurobehavioral outcomes, we formulate a constrained integrative multi-view regression, where the neurobehavioral scores form multivariate response, the sub-compositional microbiome d…
We propose a new prediction method for multivariate linear regression problems where the number of features is less than the sample size but the number of outcomes is extremely large. Many popular procedures, such as penalized regression procedures, require parameter tuning that is computationally untenable in such large-scale problems. We take a different approach, motivated by ideas from simultaneous estimation problems, that performs linear shrinkage on ordinary least squares parameter estimates. Our approach is extremely computationally efficient and tuning-free. We show that it can asympt…
Multivariate meta-analysis is gaining prominence in evidence synthesis research because it enables simultaneous synthesis of multiple correlated outcome data, and random-effects models have generally been used for addressing between-studies heterogeneities. However, coverage probabilities of confidence regions or intervals for standard inference methods for random-effects models (e.g., restricted maximum likelihood estimation) cannot retain their nominal confidence levels in general, especially when the number of synthesized studies is small because their validities depend on large sample appr…
Heterogeneity is a hallmark of many complex diseases. There are multiple ways of defining heterogeneity, among which the heterogeneity in genetic regulations, for example GEs (gene expressions) by CNVs (copy number variations) and methylation, has been suggested but little investigated. Heterogeneity in genetic regulations can be linked with disease severity, progression, and other traits and is biologically important. However, the analysis can be very challenging with the high dimensionality of both sides of regulation as well as sparse and weak signals. In this article, we consider the scena…
Multivariate outcomes are common in pragmatic cluster randomized trials. While sample size calculation procedures for multivariate outcomes exist under parallel assignment, none have been developed for a stepped wedge design. In this article, we present computationally efficient power and sample size procedures for stepped wedge cluster randomized trials (SW-CRTs) with multivariate outcomes that differentiate the within-period and between-period intracluster correlation coefficients (ICCs). Under a multivariate linear mixed model, we derive the joint distribution of the intervention test stati…
Random-effects meta-analyses are very commonly used in medical statistics. Recent methodological developments include multivariate (multiple outcomes) and network (multiple treatments) meta-analysis. Here we provide a new model and corresponding estimation procedure for multivariate network meta-analysis, so that multiple outcomes and treatments can be included in a single analysis. Our new multivariate model is a direct extension of a univariate model for network meta-analysis that has recently been proposed. We allow two types of unknown variance parameters in our model, which represent betw…
We introduce a self-censoring model for multivariate nonignorable nonmonotone missing data, where the missingness process of each outcome is affected by its own value and is associated with missingness indicators of other outcomes, while conditionally independent of the other outcomes. The self-censoring model complements previous graphical approaches for the analysis of multivariate nonignorable missing data. It is identified under a completeness condition stating that any variability in one outcome can be captured by variability in the other outcomes among complete cases. For estimation, we …
Latent Markov (LM) models represent an important tool of analysis of longitudinal data when response variables are affected by time-varying unobserved heterogeneity, which is accounted for by a hidden Markov chain. In order to avoid bias when using a model of this type in the presence of informative drop-out, we propose an event-history (EH) extension of the LM approach that may be used with multivariate longitudinal data, in which one or more outcomes of a different nature are observed at each time occasion. The EH component of the resulting model is referred to the interval-censored drop-out…
Publication bias occurs when the publication of research results depends not only on the quality of the research but also on its nature and direction. The consequence is that published studies may not be truly representative of all valid studies undertaken, and this bias may threaten the validity of systematic reviews and meta-analyses - on which evidence-based medicine increasingly relies. Multivariate meta-analysis has recently received increasing attention for its ability reducing potential bias and improving statistical efficiency by borrowing information across outcomes. However, detectin…
The problem we consider considers estimating a multivariate longitudinal panel data model whose outcomes can be a combination of discrete and continuous variables. This problem is challenging because the likelihood is usually analytically intractable. Our article makes both a methodological contribution and also a substantive contribution to the application. The methodological contribution is to introduce into the panel data literature a particle Metropolis within Gibbs method to carry out Bayesian inference, using a Hamiltonian Monte Carlo (Neal 2011} proposal for sampling the vector of unkno…
We develop Bayesian models for density regression with emphasis on discrete outcomes. The problem of density regression is approached by considering methods for multivariate density estimation of mixed scale variables, and obtaining conditional densities from the multivariate ones. The approach to multivariate mixed scale outcome density estimation that we describe represents discrete variables, either responses or covariates, as discretised versions of continuous latent variables. We present and compare several models for obtaining these thresholds in the challenging context of count data ana…
Identifying compromise solutions across multiple treatment benefit-harm profiles in multivariate network meta-analysis
Institute of Medical Biometry and Statistics, Faculty of Medicine and Medical Center-University of Freiburg（弗赖堡大学医学院医学生物计量与统计研究所）；Oslo Center for Biostatistics and Epidemiology, Department of Biostatistics, University of Oslo（奥斯陆大学生物统计系奥斯陆生物统计与流行病学中心）
The Fay-Herriot model is a standard model for direct survey estimators in which the true quantity of interest, the superpopulation mean, is latent and its estimation is improved through the use of auxiliary covariates. In the context of small area estimation, these estimates can be further improved by borrowing strength across spatial region or by considering multiple outcomes simultaneously. We provide here two formulations to perform small area estimation with Fay-Herriot models that include both multivariate outcomes and latent spatial dependence. We consider two model formulations, one in …
This paper proposes a flexible Bayesian approach to multiple imputation using conditional Gaussian mixtures. We introduce novel shrinkage priors for covariate-dependent mixing proportions in the mixture models to automatically select the suitable number of components used in the imputation step. We develop an efficient sampling algorithm for posterior computation and multiple imputation via Markov Chain Monte Carlo methods. The proposed method can be easily extended to the situation where the data contains not only continuous variables but also discrete variables such as binary and count value…
We propose a novel personalized concept for the optimal treatment selection for a situation where the response is a multivariate vector, that could contain right-censored variables such as survival time. The proposed method can be applied with any number of treatments and outcome variables, under a broad set of models. Following a working semiparametric Single Index Model that relates covariates and responses, we first define a patient-specific composite score, constructed from individual covariates. We then estimate conditional means of each response, given the patient score, correspond to ea…
Small study effects occur when smaller studies show different, often larger, treatment effects than large ones, which may threaten the validity of systematic reviews and meta-analyses. The most well-known reasons for small study effects include publication bias, outcome reporting bias and clinical heterogeneity. Methods to account for small study effects in univariate meta-analysis have been extensively studied. However, detecting small study effects in a multivariate meta-analysis setting remains an untouched research area. One of the complications is that different types of selection process…
Finite Mixtures of Generalized Estimating Equations for Clustering Multivariate Correlated Outcomes
Faculty of Economics, Keio University（庆应义塾大学经济学部）；Research School of Finance, Actuarial Studies and Statistics, The Australian National University（澳大利亚国立大学金融、精算与统计研究学院）
Semiparametric Copula Estimation for Spatially Correlated Multivariate Mixed Outcomes: Analyzing Visual Sightings of Fin Whales from a Line Transect Survey
Tokyo University of Science（东京理科大学）；Meisei University（明海大学）；Keio University（庆应义塾大学）；Institute of Marine Research（海洋研究所）；RIKEN Center for Brain Science（理化学研究所脑科学中心）
Joint modeling of spatially-oriented dependent variables is commonplace in the environmental sciences, where scientists seek to estimate the relationships among a set of environmental outcomes accounting for dependence among these outcomes and the spatial dependence for each outcome. Such modeling is now sought for massive data sets with variables measured at a very large number of locations. Bayesian inference, while attractive for accommodating uncertainties through hierarchical structures, can become computationally onerous for modeling massive spatial data sets because of its reliance on i…
The generalized propensity score (GPS) is an extension of the propensity score for use with quantitative or continuous exposures (e.g., dose of medication or years of education). Current GPS methods allow estimation of the dose-response relationship between a single continuous exposure and an outcome. However, in many real-world settings, there are multiple exposures occurring simultaneously that could be causally related to the outcome. We propose a multivariate GPS method (mvGPS) that allows estimation of a dose-response surface that relates the joint distribution of multiple continuous expo…
Studies of Alzheimer's disease (AD) often collect multiple longitudinal clinical outcomes, which are correlated and predictive of AD progression. It is of great scientific interest to investigate the association between the outcomes and time to AD onset. We model the multiple longitudinal outcomes as multivariate sparse functional data and propose a functional joint model linking multivariate functional data to event time data. In particular, we propose a multivariate functional mixed model (MFMM) to identify the shared progression pattern and outcome-specific progression patterns of the outco…
Mediation analysis seeks to identify and quantify the paths by which an exposure affects an outcome. Intermediate variables which are effected by the exposure and which effect the outcome are known as mediators. There exists extensive work on mediation analysis in the context of models with a single mediator and continuous and binary outcomes. However these methods are often not suitable for multi-omic data that include highly interconnected variables measuring biological mechanisms and various types of outcome variables such as censored survival responses. In this article, we develop a genera…
Mediation analysis is appealing for its ability to improve understanding of the mechanistic drivers of causal effects, but real-world data complexities challenge its successful implementation, including: 1) the existence of post-exposure variables that also affect mediators and outcomes (thus, confounding the mediator-outcome relationship), that may also be 2) multivariate, and 3) the existence of multivariate mediators. Interventional direct and indirect effects (IDE/IIE) accommodate post-exposure variables that confound the mediator-outcome relationship, but currently, no estimator for IDE/I…
Selection of covariates is crucial in the estimation of average treatment effects given observational data with high or even ultra-high dimensional pretreatment variables. Existing methods for this problem typically assume sparse linear models for both outcome and univariate treatment, and cannot handle situations with ultra-high dimensional covariates. In this paper, we propose a new covariate selection strategy called double screening prior adaptive lasso (DSPAL) to select confounders and predictors of the outcome for multivariate treatments, which combines the adaptive lasso method with the…
Joint models for longitudinal and survival data have gained a lot of attention in recent years, with the development of myriad extensions to the basic model, including those which allow for multivariate longitudinal data, competing risks and recurrent events. Several software packages are now also available for their implementation. Although mathematically straightforward, the inclusion of multiple longitudinal outcomes in the joint model remains computationally difficult due to the large number of random effects required, which hampers the practical application of this extension. We present a…
Regional aggregates of health outcomes over delineated administrative units (e.g., states, counties, zip codes), or areal units, are widely used by epidemiologists to map mortality or incidence rates and capture geographic variation. To capture health disparities over regions, we seek "difference boundaries" that separate neighboring regions with significantly different spatial effects. Matters are more challenging with multiple outcomes over each unit, where we capture dependence among diseases as well as across the areal units. Here, we address multivariate difference boundary detection for …
In this paper, we propose a general framework for combining evidence of varying quality to estimate underlying binary latent variables in the presence of restrictions imposed to respect the scientific context. The resulting algorithms cluster the multivariate binary data in a manner partly guided by prior knowledge. The primary model assumptions are that 1) subjects belong to classes defined by unobserved binary states, such as the true presence or absence of pathogens in epidemiology, or of antibodies in medicine, or the "ability" to correctly answer test questions in psychology, 2) a binary …
Multivariate meta-analysis can be adapted to a wide range of situations for multiple outcomes and multiple treatment groups when combining studies together. The within-study correlation between effect sizes is often assumed known in multivariate meta-analysis while it is not always known practically. In this paper, we propose a generic method to approximate the within-study covariance for effect sizes in multivariate meta-analysis and apply this method to the scenarios with multiple outcomes and one outcome with multiple treatment groups respectively.
In many clinical trials, outcomes of interest include binary-valued endpoints. It is not uncommon that a binary-valued outcome is dichotomized from a continuous outcome at a threshold of clinical interest. To reach the objective, common approaches include (a) fitting the generalized linear mixed model (GLMM) to the dichotomized longitudinal binary outcome and (b) imputation method (MI): imputing the missing values in the continuous outcome, dichotomizing it into a binary outcome, and then fitting the generalized linear model for the "complete" data. We conducted comprehensive simulation studie…
