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Mediation analysis aims to assess if, and how, a certain exposure influences an outcome of interest through intermediate variables. This problem has recently gained a surge of attention due to the tremendous need for such analyses in scientific fields. Testing for the mediation effect (ME) is greatly challenged by the fact that the underlying null hypothesis (i.e. the absence of MEs) is composite. Most existing mediation tests are overly conservative and thus underpowered. To overcome this significant methodological hurdle, we develop an adaptive bootstrap testing framework that can accommodate different types of composite null hypotheses in the mediation pathway analysis. Applied to the product of coefficients test and the joint significance test, our adaptive testing procedures provide type I error control under the composite null, resulting in much improved statistical power compared to existing tests. Both theoretical properties and numerical examples of the proposed methodology are discussed. [ABSTRACT FROM AUTHOR]

This article explores the reliability of statistical inference for streaming longitudinal data. The authors argue that previous research's assumption of no abnormal data cases is unrealistic and propose a simulation experiment to evaluate their proposed method's performance in the presence of data contamination. The results indicate that the method is robust against mild contamination but exhibits biases and discrepancies with high contamination. The authors suggest further investigation into the weighting function used to achieve robustness. They conclude that the method is resilient against mild contamination and has potential for practical applications. The authors also acknowledge their funding support. [Extracted from the article]

Stratification is a very commonly used approach in biomedical studies to handle sample heterogeneity arising from, for examples, clinical units, patient subgroups, or missing‐data. A key rationale behind such approach is to overcome potential sampling biases in statistical inference. Two issues of such stratification‐based strategy are (i) whether individual strata are sufficiently distinctive to warrant stratification, and (ii) sample size attrition resulted from the stratification may potentially lead to loss of statistical power. To address these issues, we propose a penalized generalized estimating equations approach to reducing the complexity of parametric model structures due to excessive stratification. Specifically, we develop a data‐driven fusion learning approach for longitudinal data that improves estimation efficiency by integrating information across similar strata, yet still allows necessary separation for stratum‐specific conclusions. The proposed method is evaluated by simulation studies and applied to a motivating example of psychiatric study to demonstrate its usefulness in real world settings. [ABSTRACT FROM AUTHOR]

Directed acyclic mixed graphs (DAMGs) provide a useful representation of network topology with both directed and undirected edges subject to the restriction of no directed cycles in the graph. This graphical framework may arise in many biomedical studies, for example, when a directed acyclic graph (DAG) of interest is contaminated with undirected edges induced by some unobserved confounding factors (eg, unmeasured environmental factors). Directed edges in a DAG are widely used to evaluate causal relationships among variables in a network, but detecting them is challenging when the underlying causality is obscured by some shared latent factors. The objective of this paper is to develop an effective structural equation model (SEM) method to extract reliable causal relationships from a DAMG. The proposed approach, termed structural factor equation model (SFEM), uses the SEM to capture the network topology of the DAG while accounting for the undirected edges in the graph with a factor analysis model. The latent factors in the SFEM enable the identification and removal of undirected edges, leading to a simpler and more interpretable causal network. The proposed method is evaluated and compared to existing methods through extensive simulation studies, and illustrated through the construction of gene regulatory networks related to breast cancer. [ABSTRACT FROM AUTHOR]

Context: Steroids play an important role in fetal development and parturition. Gestational exposures to endocrine-disrupting chemicals (EDCs) affect steroidal milieu and pregnancy outcomes, raising the possibility of steroids serving as biomarkers. Most studies have not addressed the impact of EDC mixtures, which are reflective of real life scenarios.Objective: Assess the association of maternal and neonatal steroids with pregnancy outcomes and early pregnancy EDC levels.Design: Prospective analysis of mother-infant dyads.Setting: University hospital.Participants: 121 mother-infant dyads.Main Outcome Measures: The associations of maternal and neonatal steroidal hormones from 121 dyads with pregnancy outcomes, the associations of first trimester EDCs individually and as mixtures with maternal and neonatal steroids in a subset of 56 dyads and the influence of body mass index (BMI), age, and offspring sex in modulating the EDC associations with steroids were determined.Results: Steroid-specific positive or negative associations with pregnancy measures were evident; many maternal first trimester EDCs were negatively associated with estrogens and positively with androgen/estrogen ratios; EDC-steroid associations were influenced by maternal age, pre-pregnancy BMI, and fetal sex; and EDCs individually and as mixtures showed direct and inverse fetal sex-dependent associations with maternal and neonatal steroids.Conclusions: This proof-of-concept study indicates association of steroids with pregnancy outcomes depending on maternal age, prepregnancy BMI, and fetal sex, with the effects of EDCs differing when considered individually or as mixtures. These findings suggest that steroidal hormonal measures have potential to serve as biomarkers of impact of EDC exposures and pregnancy outcome. [ABSTRACT FROM AUTHOR]

Summary: The paper presents an incremental updating algorithm to analyse streaming data sets using generalized linear models. The method proposed is formulated within a new framework of renewable estimation and incremental inference, in which the maximum likelihood estimator is renewed with current data and summary statistics of historical data. Our framework can be implemented within a popular distributed computing environment, known as Apache Spark, to scale up computation. Consisting of two data‐processing layers, the rho architecture enables us to accommodate inference‐related statistics and to facilitate sequential updating of the statistics used in both estimation and inference. We establish estimation consistency and asymptotic normality of the proposed renewable estimator, in which the Wald test is utilized for an incremental inference. Our methods are examined and illustrated by various numerical examples from both simulation experiments and a real world data analysis. [ABSTRACT FROM AUTHOR]

This paper focuses on analysis of spatiotemporal binary data with absorbing states. The research was motivated by a clinical study on amyotrophic lateral sclerosis (ALS), a neurological disease marked by gradual loss of muscle strength over time in multiple body regions. We propose an autologistic regression model to capture complex spatial and temporal dependencies in muscle strength among different muscles. As it is not clear how the disease spreads from one muscle to another, it may not be reasonable to define a neighborhood structure based on spatial proximity. Relaxing the requirement for prespecification of spatial neighborhoods as in existing models, our method identifies an underlying network structure empirically to describe the pattern of spreading disease. The model also allows the network autoregressive effects to vary depending on the muscles' previous status. Based on the joint distribution derived from this autologistic model, the joint transition probabilities of responses among locations can be estimated and the disease status can be predicted in the next time interval. Model parameters are estimated through maximization of penalized pseudo‐likelihood. Postmodel selection inference was conducted via a bias‐correction method, for which the asymptotic distributions were derived. Simulation studies were conducted to evaluate the performance of the proposed method. The method was applied to the analysis of muscle strength loss from the ALS clinical study. [ABSTRACT FROM AUTHOR]

Combining multiple studies is frequently undertaken in biomedical research to increase sample sizes for statistical power improvement. We consider the marginal model for the regression analysis of repeated measurements collected in several similar studies with potentially different variances and correlation structures. It is of great importance to examine whether there exist common parameters across study-specific marginal models so that simpler models, sensible interpretations, and meaningful efficiency gain can be obtained. Combining multiple studies via the classical means of hypothesis testing involves a large number of simultaneous tests for all possible subsets of common regression parameters, in which it results in unduly large degrees of freedom and low statistical power. We develop a new method of fused lasso with the adaptation of parameter ordering (FLAPO) to scrutinize only adjacent-pair parameter differences, leading to a substantial reduction for the number of involved constraints. Our method enjoys the oracle properties as does the full fused lasso based on all pairwise parameter differences. We show that FLAPO gives estimators with smaller error bounds and better finite sample performance than the full fused lasso. We also establish a regularized inference procedure based on bias-corrected FLAPO. We illustrate our method through both simulation studies and an analysis of HIV surveillance data collected over five geographic regions in China, in which the presence or absence of common covariate effects is reflective to relative effectiveness of regional policies on HIV control and prevention. [ABSTRACT FROM AUTHOR]

Advances in high throughput technology have accelerated the use of hundreds to millions of biomarkers to construct classifiers that partition patients into different clinical conditions. Prior to classifier development in actual studies, a critical need is to determine the sample size required to reach a specified classification precision. We develop a systematic approach for sample size determination in high-dimensional (large [Formula: see text] small [Formula: see text]) classification analysis. Our method utilizes the probability of correct classification (PCC) as the optimization objective function and incorporates the higher criticism thresholding procedure for classifier development. Further, we derive the theoretical bound of maximal PCC gain from feature augmentation (e.g. when molecular and clinical predictors are combined in classifier development). Our methods are motivated and illustrated by a study using proteomics markers to classify post-kidney transplantation patients into stable and rejecting classes. [ABSTRACT FROM AUTHOR]

This paper concerns regression methodology for assessing relationships between multidimensional response variables and covariates that are correlated within a network. To address analytical challenges associated with the integration of network topology into the regression analysis, we propose a hybrid quadratic inference method that uses both prior and data-driven correlations among network nodes. A Godambe information-based tuning strategy is developed to allocate weights between the prior and data-driven network structures, so the estimator is efficient. The proposed method is conceptually simple and computationally fast, and has appealing large-sample properties. It is evaluated by simulation, and its application is illustrated using neuroimaging data from an association study of the effects of iron deficiency on auditory recognition memory in infants. [ABSTRACT FROM AUTHOR]

Merging multiple datasets collected from studies with identical or similar scientific objectives is often undertaken in practice to increase statistical power. This article concerns the development of an effective statistical method that enables to merge multiple longitudinal datasets subject to various heterogeneous characteristics, such as different follow-up schedules and study-specific missing covariates (e.g., covariates observed in some studies but missing in other studies). The presence of studyspecific missing covariates presents great statistical methodology challenge in data merging and analysis. We propose a joint estimating function approach to addressing this challenge, in which a novel nonparametric estimating function constructed via splines-based sieve approximation is utilized to bridge estimating equations from studies with missing covariates to those with fully observed covariates. Under mild regularity conditions, we show that the proposed estimator is consistent and asymptotically normal. We evaluate finite-sample performances of the proposed method through simulation studies. In comparison to the conventional multiple imputation approach, our method exhibits smaller estimation bias. We provide an illustrative data analysis using longitudinal cohorts collected in Mexico City to assess the effect of lead exposures on children's somatic growth. [ABSTRACT FROM AUTHOR]

Spatial-clustered data refer to high-dimensional correlated measurements collected from units or subjects that are spatially clustered. Such data arise frequently from studies in social and health sciences. We propose a unified modeling framework, termed as GeoCopula, to characterize both large-scale variation, and small-scale variation for various data types, including continuous data, binary data, and count data as special cases. To overcome challenges in the estimation and inference for the model parameters, we propose an efficient composite likelihood approach in that the estimation efficiency is resulted from a construction of over-identified joint composite estimating equations. Consequently, the statistical theory for the proposed estimation is developed by extending the classical theory of the generalized method of moments. A clear advantage of the proposed estimation method is the computation feasibility. We conduct several simulation studies to assess the performance of the proposed models and estimation methods for both Gaussian and binary spatial-clustered data. Results show a clear improvement on estimation efficiency over the conventional composite likelihood method. An illustrative data example is included to motivate and demonstrate the proposed method. [ABSTRACT FROM AUTHOR]

. Modelling of spatiotemporal processes has received considerable attention in recent statistical research. However, owing to the high dimensionality of the data, the joint modelling of spatial and temporal processes presents a great computational challenge, in both likelihood-based and Bayesian approaches. We propose a joint composite estimating function approach to estimating spatiotemporal covariance structures. This substantially reduces the computational complexity and is more efficient than existing composite likelihood methods. The novelty of the proposed joint composite estimating function is rooted in the construction of three sets of estimating functions from spatial, temporal and spatiotemporal cross-pairs, which results in overidentified estimating functions. Thus, we form a joint inference function in a spirit that is similar to Hansen's generalized method of moments. We show that under practical scenarios the estimator proposed is consistent and asymptotically normal. Simulation studies prove that our method performs well in finite samples. Finally, we illustrate the joint composite estimating function method by estimating the spatiotemporal dependence structure of airborne particulates (PM10) in the north-eastern USA over a 32-month period. [ABSTRACT FROM AUTHOR]

Merging data from multiple studies has been widely adopted in biomedical research. In this paper, we consider two major issues related to merging longitudinal datasets. We first develop a rigorous hypothesis testing procedure to assess the validity of data merging, and then propose a flexible joint estimation procedure that enables us to analyse merged data and to account for different within-subject correlations and follow-up schedules in different studies. We establish large sample properties for the proposed procedures. We compare our method with meta analysis and generalized estimating equations and show that our test provides robust control of Type I error against both misspecification of working correlation structures and heterogeneous dispersion parameters. Our joint estimating procedure leads to an improvement in estimation efficiency on all regression coefficients after data merging is validated. [ABSTRACT FROM PUBLISHER]

Summary This article presents a new modeling strategy in functional data analysis. We consider the problem of estimating an unknown smooth function given functional data with noise. The unknown function is treated as the realization of a stochastic process, which is incorporated into a diffusion model. The method of smoothing spline estimation is connected to a special case of this approach. The resulting models offer great flexibility to capture the dynamic features of functional data, and allow straightforward and meaningful interpretation. The likelihood of the models is derived with Euler approximation and data augmentation. A unified Bayesian inference method is carried out via a Markov chain Monte Carlo algorithm including a simulation smoother. The proposed models and methods are illustrated on some prostate-specific antigen data, where we also show how the models can be used for forecasting. [ABSTRACT FROM AUTHOR]

This article concerns a new joint modeling approach for correlated data analysis. Utilizing Gaussian copulas, we present a unified and flexible machinery to integrate separate one-dimensional generalized linear models (GLMs) into a joint regression analysis of continuous, discrete, and mixed correlated outcomes. This essentially leads to a multivariate analogue of the univariate GLM theory and hence an efficiency gain in the estimation of regression coefficients. The availability of joint probability models enables us to develop a full maximum likelihood inference. Numerical illustrations are focused on regression models for discrete correlated data, including multidimensional logistic regression models and a joint model for mixed normal and binary outcomes. In the simulation studies, the proposed copula-based joint model is compared to the popular generalized estimating equations, which is a moment-based estimating equation method to join univariate GLMs. Two real-world data examples are used in the illustration. [ABSTRACT FROM AUTHOR]

This article presents a new class of nonnormal linear mixed models that provide an efficient estimation of subject-specific disease progression in the analysis of longitudinal data from the Modification of Diet in Renal Disease (MDRD) trial. This new analysis addresses the previously reported finding that the distribution of the random effect characterizing disease progression is negatively skewed. We assume a log-gamma distribution for the random effects and provide the maximum likelihood inference for the proposed nonnormal linear mixed model. We derive the predictive distribution of patient-specific disease progression rates, which demonstrates rather different individual progression profiles from those obtained from the normal linear mixed model analysis. To validate the adequacy of the log-gamma assumption versus the usual normality assumption for the random effects, we propose a lack-of-fit test that clearly indicates a better fit for the log-gamma modeling in the analysis of the MDRD data. The full maximum likelihood inference is also advantageous in dealing with the missing at random (MAR) type of dropouts encountered in the MDRD data. [ABSTRACT FROM AUTHOR]

Identifying local extrema of expression profiles is one primary objective in some cDNA microarray experiments. To study the replication dynamics of the yeast genome, for example, local peaks of hybridization intensity profiles correspond to putative replication origins. We propose a nonparametric kernel smoothing (NKS) technique to detect local hybridization intensity extrema across chromosomes. The novelty of our approach is that we base our inference procedures on equilibrium points, namely those locations at which the first derivative of the intensity curve is zero. The proposed smoothing technique provides both point and interval estimation for the location of local extrema. Also, this technique can be used to test for the hypothesis of either one or multiple suspected locations being the true equilibrium points. We illustrate the proposed method on a microarray data set from an experiment designed to study the replication origins in the yeast genome, in that the locations of autonomous replication sequence (ARS) elements are identified through the equilibrium points of the smoothed intensity profile curve. Our method found a few ARS elements that were not detected by the current smoothing methods such as the Fourier convolution smoothing. [ABSTRACT FROM AUTHOR]

In the presence of data contamination or outliers, some empirical studies have indicated that the two methods of generalised estimating equations and quadratic inference functions appear to have rather different robustness behaviour. This paper presents a theoretical investigation from the perspective of the influence function to identify the causes for the difference. We show that quadratic inference functions lead to bounded influence functions and the corresponding M‐estimator has a redescending property, but the generalised estimating equation approach does not. We also illustrate that, unlike generalised estimating equations, quadratic inference functions can still provide consistent estimators even if part of the data is contaminated. We conclude that the quadratic inference function is a preferable method to the generalised estimating equation as far as robustness is concerned. This conclusion is supported by simulations and real‐data examples. [ABSTRACT FROM AUTHOR]

We address the matter of determining whether or not missing data in longitudinal studies are ignorable with regard to quasilikelihood or estimating equations approaches. This involves testing for whether or not the zero‐mean property of estimating equations holds true. Chen & Little (1999) proposed testing for significant differences among parameter estimators calculated from sample subsets with different patterns of missing data, whereas we propose a more unified generalised score‐type test. This avoids exhaustive estimation of parameters for each missing‐data pattern, testing instead with a single quadratic score test statistic whether or not there is a common parameter under which the means of all the pattern‐specific estimating equations are zero. Comparisons are made for the two approaches with both simulations and real data examples. [ABSTRACT FROM PUBLISHER]

A letter to the editor is presented in response to the article "Joint Regression Analysis for Discrete Longitudinal Data," by L. Madsen and Y. Fang in the 2010 issue.

Mapping and identifying variants that influence quantitative traits is an important problem for genetic studies. Traditional QTL mapping relies on a variance-components (VC) approach with the key assumption that the trait values in a family follow a multivariate normal distribution. Violation of this assumption can lead to inflated type I error, reduced power, and biased parameter estimates. To accommodate nonnormally distributed data, we developed and implemented a modified VC method, which we call the "copula VC method," that directly models the nonnormal distribution using Gaussian copulas. The copula VC method allows the analysis of continuous, discrete, and censored trait data, and the standard VC method is a special case when the data are distributed as multivariate normal. Through the use of link functions, the copula VC method can easily incorporate covariates. We use computer simulations to show that the proposed method yields unbiased parameter estimates, correct type I error rates, and improved power for testing linkage with a variety of nonnormal traits as compared with the standard VC and the regression-based methods. [ABSTRACT FROM AUTHOR]