Treatment rules based on individual patient characteristics that are easy to interpret and disseminate are important in clinical practice. Properly planned and conducted randomized clinical trials are used to construct individualized treatment rules. However, it is often a concern that trial participants lack representativeness, so it limits the applicability of the derived rules to a target population. In this work, we use data from a single trial study to propose a two-stage procedure to derive a robust and parsimonious rule to maximize the benefit in the target population. The procedure allows a wide range of possible covariate distributions in the target population, with minimal assumptions on the first two moments of the covariate distribution. The practical utility and favorable performance of the methodology are demonstrated using extensive simulations and a real data application.

Estimation of a single Bernoulli parameter using pooled sampling is among the oldest problems in the group testing literature. To carry out such estimation, an array of efficient estimators have been introduced covering a wide range of situations routinely encountered in applications. More recently, there has been growing interest in using group testing to simultaneously estimate the joint probabilities of two correlated traits using a multinomial model. Unfortunately, basic estimation results, such as the maximum likelihood estimator (MLE), have not been adequately addressed in the literature for such cases. In this paper, we show that finding the MLE for this problem is equivalent to maximizing a multinomial likelihood with a restricted parameter space. A solution using the EM algorithm is presented which is guaranteed to converge to the global maximizer, even on the boundary of the parameter space. Two additional closed form estimators are presented with the goal of minimizing the bias and/or mean square error. The methods are illustrated by considering an application to the joint estimation of transmission prevalence for two strains of the Potato virus Y by the aphid

We study the bias of the isotonic regression estimator. While there is extensive work characterizing the mean squared error of the isotonic regression estimator, relatively little is known about the bias. In this paper, we provide a sharp characterization, proving that the bias scales as ( ) up to log factors, where 1 ≤ ≤ 2 is the exponent corresponding to Hölder smoothness of the underlying mean. Importantly, this result only requires a strictly monotone mean and that the noise distribution has subexponential tails, without relying on symmetric noise or other restrictive assumptions.

In many problems, a sensible estimator of a possibly multivariate monotone function may fail to be monotone. We study the correction of such an estimator obtained via projection onto the space of functions monotone over a finite grid in the domain. We demonstrate that this corrected estimator has no worse supremal estimation error than the initial estimator, and that analogously corrected confidence bands contain the true function whenever the initial bands do, at no loss to band width. Additionally, we demonstrate that the corrected estimator is asymptotically equivalent to the initial estimator if the initial estimator satisfies a stochastic equicontinuity condition and the true function is Lipschitz and strictly monotone. We provide simple sufficient conditions in the special case that the initial estimator is asymptotically linear, and illustrate the use of these results for estimation of a G-computed distribution function. Our stochastic equicontinuity condition is weaker than standard uniform stochastic equicontinuity, which has been required for alternative correction procedures. This allows us to apply our results to the bivariate correction of the local linear estimator of a conditional distribution function known to be monotone in its conditioning argument. Our experiments suggest that the projection step can yield significant practical improvements.

We describe a probabilistic PARAFAC/CANDECOMP (CP) factorization for multiway (i.e., tensor) data that incorporates auxiliary covariates, . SupCP generalizes the supervised singular value decomposition (SupSVD) for vector-valued observations, to allow for observations that have the form of a matrix or higher-order array. Such data are increasingly encountered in biomedical research and other fields. We use a novel likelihood-based latent variable representation of the CP factorization, in which the latent variables are informed by additional covariates. We give conditions for identifiability, and develop an EM algorithm for simultaneous estimation of all model parameters. SupCP can be used for dimension reduction, capturing latent structures that are more accurate and interpretable due to covariate supervision. Moreover, SupCP specifies a full probability distribution for a multiway data observation with given covariate values, which can be used for predictive modeling. We conduct comprehensive simulations to evaluate the SupCP algorithm. We apply it to a facial image database with facial descriptors (e.g., smiling / not smiling) as covariates, and to a study of amino acid fluorescence. Software is available at https://github.com/lockEF/SupCP.

In this paper we develop an online statistical inference approach for high-dimensional generalized linear models with streaming data for realtime estimation and inference. We propose an online debiased lasso method that aligns with the data collection scheme of streaming data. Online debiased lasso differs from offline debiased lasso in two important aspects. First, it updates component-wise confidence intervals of regression coefficients with only summary statistics of the historical data. Second, online debiased lasso adds an additional term to correct approximation errors accumulated throughout the online updating procedure. We show that our proposed online debiased estimators in generalized linear models are asymptotically normal. This result provides a theoretical basis for carrying out real-time interim statistical inference with streaming data. Extensive numerical experiments are conducted to evaluate the performance of our proposed online debiased lasso method. These experiments demonstrate the effectiveness of our algorithm and support the theoretical results. Furthermore, we illustrate the application of our method with a high-dimensional text dataset.

Thanks to their simplicity and interpretable structure, autoregressive processes are widely used to model time series data. However, many real time series data sets exhibit non-linear patterns, requiring nonlinear modeling. The threshold Auto-Regressive (TAR) process provides a family of non-linear auto-regressive time series models in which the process dynamics are specific step functions of a thresholding variable. While estimation and inference for low-dimensional TAR models have been investigated, high-dimensional TAR models have received less attention. In this article, we develop a new framework for estimating high-dimensional TAR models, and propose two different sparsity-inducing penalties. The first penalty corresponds to a natural extension of classical TAR model to high-dimensional settings, where the same threshold is enforced for all model parameters. Our second penalty develops a more flexible TAR model, where different thresholds are allowed for different auto-regressive coefficients. We show that both penalized estimation strategies can be utilized in a three-step procedure that consistently learns both the thresholds and the corresponding auto-regressive coefficients. However, our theoretical and empirical investigations show that the direct extension of the TAR model is not appropriate for high-dimensional settings and is better suited for moderate dimensions. In contrast, the more flexible extension of the TAR model leads to consistent estimation and superior empirical performance in high dimensions.

Studying the relationship between covariates based on retrospective data is the main purpose of secondary analysis, an area of increasing interest. We examine the secondary analysis problem when multiple covariates are available, while only a regression mean model is specified. Despite the completely parametric modeling of the regression mean function, the case-control nature of the data requires special treatment and semi-parametric efficient estimation generates various nonparametric estimation problems with multivariate covariates. We devise a dimension reduction approach that fits with the specified primary and secondary models in the original problem setting, and use reweighting to adjust for the case-control nature of the data, even when the disease rate in the source population is unknown. The resulting estimator is both locally efficient and robust against the misspecification of the regression error distribution, which can be heteroscedastic as well as non-Gaussian. We demonstrate the advantage of our method over several existing methods, both analytically and numerically.

A representative model in integrative analysis of two high-dimensional correlated datasets is to decompose each data matrix into a low-rank common matrix generated by latent factors shared across datasets, a low-rank distinctive matrix corresponding to each dataset, and an additive noise matrix. Existing decomposition methods claim that their common matrices capture the common pattern of the two datasets. However, their so-called common pattern only denotes the common latent factors but ignores the common pattern between the two coefficient matrices of these common latent factors. We propose a new unsupervised learning method, called the common and distinctive pattern analysis (CDPA), which appropriately defines the two types of data patterns by further incorporating the common and distinctive patterns of the coefficient matrices. A consistent estimation approach is developed for high-dimensional settings, and shows reasonably good finite-sample performance in simulations. Our simulation studies and real data analysis corroborate that the proposed CDPA can provide better characterization of common and distinctive patterns and thereby benefit data mining.

We study the performance of shape-constrained methods for evaluating immune response profiles from early-phase vaccine trials. The motivating problem for this work involves quantifying and comparing the IgG binding immune responses to the first and second variable loops (V1V2 region) arising in HVTN 097 and HVTN 100 HIV vaccine trials. We consider unimodal and log-concave shape-constrained methods to compare the immune profiles of the two vaccines, which is reasonable because the data support that the underlying densities of the immune responses could have these shapes. To this end, we develop novel shape-constrained tests of stochastic dominance and shape-constrained plug-in estimators of the squared Hellinger distance between two densities. Our techniques are either tuning parameter free, or rely on only one tuning parameter, but their performance is either better (the tests of stochastic dominance) or comparable with the nonparametric methods (the estimators of the squared Hellinger distance). The minimal dependence on tuning parameters is especially desirable in clinical contexts where analyses must be prespecified and reproducible. Our methods are supported by theoretical results and simulation studies.

Bayes estimators are well known to provide a means to incorporate prior knowledge that can be expressed in terms of a single prior distribution. However, when this knowledge is too vague to express with a single prior, an alternative approach is needed. Gamma-minimax estimators provide such an approach. These estimators minimize the worst-case Bayes risk over a set of prior distributions that are compatible with the available knowledge. Traditionally, Gamma-minimaxity is defined for parametric models. In this work, we define Gamma-minimax estimators for general models and propose adversarial meta-learning algorithms to compute them when the set of prior distributions is constrained by generalized moments. Accompanying convergence guarantees are also provided. We also introduce a neural network class that provides a rich, but finite-dimensional, class of estimators from which a Gamma-minimax estimator can be selected. We illustrate our method in two settings, namely entropy estimation and a prediction problem that arises in biodiversity studies.

Recent works have proposed regression models which are invariant across data collection environments [24, 20, 11, 16, 8]. These estimators often have a causal interpretation under conditions on the environments and type of invariance imposed. One recent example, the Causal Dantzig (CD), is consistent under hidden confounding and represents an alternative to classical instrumental variable estimators such as Two Stage Least Squares (TSLS). In this work we derive the CD as a generalized method of moments (GMM) estimator. The GMM representation leads to several practical results, including 1) creation of the Generalized Causal Dantzig (GCD) estimator which can be applied to problems with continuous environments where the CD cannot be fit 2) a Hybrid (GCD-TSLS combination) estimator which has properties superior to GCD or TSLS alone 3) straightforward asymptotic results for all methods using GMM theory. We compare the CD, GCD, TSLS, and Hybrid estimators in simulations and an application to a Flow Cytometry data set. The newly proposed GCD and Hybrid estimators have superior performance to existing methods in many settings.

Hypothesis testing procedures are developed to assess linear operator constraints in function-on-scalar regression when incomplete functional responses are observed. The approach enables statistical inferences about the shape and other aspects of the functional regression coefficients within a unified framework encompassing three incomplete sampling scenarios: (i) partially observed response functions as curve segments over random sub-intervals of the domain; (ii) discretely observed functional responses with additive measurement errors; and (iii) the composition of former two scenarios, where partially observed response segments are observed discretely with measurement error. The latter scenario has been little explored to date, although such structured data is increasingly common in applications. For statistical inference, deviations from the constraint space are measured via integrated -distance between the model estimates from the constrained and unconstrained model spaces. Large sample properties of the proposed test procedure are established, including the consistency, asymptotic distribution and local power of the test statistic. Finite sample power and level of the proposed test are investigated in a simulation study covering a variety of scenarios. The proposed methodologies are illustrated by applications to U.S. obesity prevalence data, analyzing the functional shape of its trends over time, and motion analysis in a study of automotive ergonomics.

The likelihood ratio statistic, with its asymptotic distribution at regular model points, is often used for hypothesis testing. However, the asymptotic distribution can differ at model singularities and boundaries, suggesting the use of a might be problematic nearby. Indeed, its poor behavior for testing near singularities and boundaries is apparent in simulations, and can lead to conservative or anti-conservative tests. Here we develop a new distribution designed for use in hypothesis testing near singularities and boundaries, which asymptotically agrees with that of the likelihood ratio statistic. For two example trinomial models, arising in the context of inference of evolutionary trees, we show the new distributions outperform a .

Envelope method was recently proposed as a method to reduce the dimension of responses in multivariate regressions. However, when there exists missing data, the envelope method using the complete case observations may lead to biased and inefficient results. In this paper, we generalize the envelope estimation when the predictors and/or the responses are missing at random. Specifically, we incorporate the envelope structure in the expectation-maximization (EM) algorithm. As the parameters under the envelope method are not pointwise identifiable, the EM algorithm for the envelope method was not straightforward and requires a special decomposition. Our method is guaranteed to be more efficient, or at least as efficient as, the standard EM algorithm. Moreover, our method has the potential to outperform the full data MLE. We give asymptotic properties of our method under both normal and non-normal cases. The efficiency gain over the standard EM is confirmed in simulation studies and in an application to the Chronic Renal Insufficiency Cohort (CRIC) study.

Recent development in statistical methodology for personalized treatment decision has utilized high-dimensional regression to take into account a large number of patients' covariates and described personalized treatment decision through interactions between treatment and covariates. While a subset of interaction terms can be obtained by existing variable selection methods to indicate relevant covariates for making treatment decision, there often lacks statistical interpretation of the results. This paper proposes an asymptotically unbiased estimator based on Lasso solution for the interaction coefficients. We derive the limiting distribution of the estimator when baseline function of the regression model is unknown and possibly misspecified. Confidence intervals and p-values are derived to infer the effects of the patients' covariates in making treatment decision. We confirm the accuracy of the proposed method and its robustness against misspecified function in simulation and apply the method to STAR*D study for major depression disorder.

This manuscript presents an approach to perform generalized linear regression with multiple high dimensional covariance matrices as the outcome. In many areas of study, such as resting-state functional magnetic resonance imaging (fMRI) studies, this type of regression can be utilized to characterize variation in the covariance matrices across units. Model parameters are estimated by maximizing a likelihood formulation of a generalized linear model, conditioning on a well-conditioned linear shrinkage estimator for multiple covariance matrices, where the shrinkage coefficients are proposed to be shared across matrices. Theoretical studies demonstrate that the proposed covariance matrix estimator is optimal achieving the uniformly minimum quadratic loss asymptotically among all linear combinations of the identity matrix and the sample covariance matrix. Under certain regularity conditions, the proposed estimator of the model parameters is consistent. The superior performance of the proposed approach over existing methods is illustrated through simulation studies. Implemented to a resting-state fMRI study acquired from the Alzheimer's Disease Neuroimaging Initiative, the proposed approach identified a brain network within which functional connectivity is significantly associated with Apolipoprotein E 4, a strong genetic marker for Alzheimer's disease.

Random-effects models are a popular tool for analysing total narrow-sense heritability for quantitative phenotypes, on the basis of large-scale SNP data. Recently, there have been disputes over the validity of conclusions that may be drawn from such analysis. We derive some of the fundamental statistical properties of heritability estimates arising from these models, showing that the bias will generally be small. We show that that the score function may be manipulated into a form that facilitates intelligible interpretations of the results. We go on to use this score function to explore the behavior of the model when certain key assumptions of the model are not satisfied - shared environment, measurement error, and genetic effects that are confined to a small subset of sites. The variance and bias depend crucially on the variance of certain functionals of the singular values of the genotype matrix. A useful baseline is the singular value distribution associated with genotypes that are completely independent - that is, with no linkage and no relatedness - for a given number of individuals and sites. We calculate the corresponding variance and bias for this setting.

Identification of causal relations among variables is central to many scientific investigations, as in regulatory network analysis of gene interactions and brain network analysis of effective connectivity of causal relations between regions of interest. Statistically, causal relations are often modeled by a directed acyclic graph (DAG), and hence that reconstruction of a DAG's structure leads to the discovery of causal relations. Yet, reconstruction of a DAG's structure from observational data is impossible because a DAG Gaussian model is usually not identifiable with unequal error variances. In this article, we reconstruct a DAG's structure with the help of interventional data. Particularly, we construct a constrained likelihood to regularize intervention in addition to adjacency matrices to identify a DAG's structure, subject to an error variance constraint to further reinforce the model identifiability. Theoretically, we show that the proposed constrained likelihood leads to identifiable models, thus correct reconstruction of a DAG's structure through parameter estimation even with unequal error variances. Computationally, we design efficient algorithms for the proposed method. In simulations, we show that the proposed method enables to produce a higher accuracy of reconstruction with the help of interventional observations.

Estimating individualized treatment rules is a central task for personalized medicine. [23] and [22] proposed outcome weighted learning to estimate individualized treatment rules directly through maximizing the expected outcome without modeling the response directly. In this paper, we extend the outcome weighted learning to right censored survival data without requiring either inverse probability of censoring weighting or semiparametric modeling of the censoring and failure times as done in [26]. To accomplish this, we take advantage of the tree based approach proposed in [28] to nonparametrically impute the survival time in two different ways. The first approach replaces the reward of each individual by the expected survival time, while in the second approach only the censored observations are imputed by their conditional expected failure times. We establish consistency and convergence rates for both estimators. In simulation studies, our estimators demonstrate improved performance compared to existing methods. We also illustrate the proposed method on a phase III clinical trial of non-small cell lung cancer.

In this manuscript, we study scalar-on-distribution regression; that is, instances where subject-specific distributions or densities are the covariates, related to a scalar outcome via a regression model. In practice, only repeated measures are observed from those covariate distributions and common approaches first use these to estimate subject-specific density functions, which are then used as covariates in standard scalar-on-function regression. We propose a simple and direct method for linear scalar-on-distribution regression that circumvents the intermediate step of estimating subject-specific covariate densities. We show that one can directly use the observed repeated measures as covariates and endow the regression function with a Gaussian process prior to obtain a closed form or conjugate Bayesian inference. Our method subsumes the standard Bayesian non-parametric regression using Gaussian processes as a special case, corresponding to covariates being Dirac-distributions. The model is also invariant to any transformation or ordering of the repeated measures. Theoretically, we show that, despite only using the observed repeated measures from the true density-valued covariates that generated the data, the method can achieve an optimal estimation error bound of the regression function. The theory extends beyond i.i.d. settings to accommodate certain forms of within-subject dependence among the repeated measures. To our knowledge, this is the first theoretical study on Bayesian regression using distribution-valued covariates. We propose numerous extensions including a scalable implementation using low-rank Gaussian processes and a generalization to non-linear scalar-on-distribution regression. Through simulation studies, we demonstrate that our method performs substantially better than approaches that require an intermediate density estimation step especially with a small number of repeated measures per subject. We apply our method to study association of age with activity counts.