Deductive Derivation and Turing-Computerization of Semiparametric Efficient EstimationFrangakis, Constantine E.; Qian, Tianchen; Wu, Zhenke; Diaz, Ivan
doi: 10.1111/biom.12362pmid: 26237182
SummaryResearchers often seek robust inference for a parameter through semiparametric estimation. Efficient semiparametric estimation currently requires theoretical derivation of the efficient influence function (EIF), which can be a challenging and time-consuming task. If this task can be computerized, it can save dramatic human effort, which can be transferred, for example, to the design of new studies. Although the EIF is, in principle, a derivative, simple numerical differentiation to calculate the EIF by a computer masks the EIF's functional dependence on the parameter of interest. For this reason, the standard approach to obtaining the EIF relies on the theoretical construction of the space of scores under all possible parametric submodels. This process currently depends on the correctness of conjectures about these spaces, and the correct verification of such conjectures. The correct guessing of such conjectures, though successful in some problems, is a nondeductive process, i.e., is not guaranteed to succeed (e.g., is not computerizable), and the verification of conjectures is generally susceptible to mistakes. We propose a method that can deductively produce semiparametric locally efficient estimators. The proposed method is computerizable, meaning that it does not need either conjecturing, or otherwise theoretically deriving the functional form of the EIF, and is guaranteed to produce the desired estimates even for complex parameters. The method is demonstrated through an example.
Treatment Decisions Based on Scalar and Functional Baseline CovariatesCiarleglio, Adam; Petkova, Eva; Ogden, R. Todd; Tarpey, Thaddeus
doi: 10.1111/biom.12346pmid: 26111145
SummaryThe amount and complexity of patient-level data being collected in randomized-controlled trials offer both opportunities and challenges for developing personalized rules for assigning treatment for a given disease or ailment. For example, trials examining treatments for major depressive disorder are not only collecting typical baseline data such as age, gender, or scores on various tests, but also data that measure the structure and function of the brain such as images from magnetic resonance imaging (MRI), functional MRI (fMRI), or electroencephalography (EEG). These latter types of data have an inherent structure and may be considered as functional data. We propose an approach that uses baseline covariates, both scalars and functions, to aid in the selection of an optimal treatment. In addition to providing information on which treatment should be selected for a new patient, the estimated regime has the potential to provide insight into the relationship between treatment response and the set of baseline covariates. Our approach can be viewed as an extension of “advantage learning” to include both scalar and functional covariates. We describe our method and how to implement it using existing software. Empirical performance of our method is evaluated with simulated data in a variety of settings and also applied to data arising from a study of patients with major depressive disorder from whom baseline scalar covariates as well as functional data from EEG are available.
Using Decision Lists to Construct Interpretable and Parsimonious Treatment RegimesZhang, Yichi; Laber, Eric B.; Tsiatis, Anastasios; Davidian, Marie
doi: 10.1111/biom.12354pmid: 26193819
SummaryA treatment regime formalizes personalized medicine as a function from individual patient characteristics to a recommended treatment. A high-quality treatment regime can improve patient outcomes while reducing cost, resource consumption, and treatment burden. Thus, there is tremendous interest in estimating treatment regimes from observational and randomized studies. However, the development of treatment regimes for application in clinical practice requires the long-term, joint effort of statisticians and clinical scientists. In this collaborative process, the statistician must integrate clinical science into the statistical models underlying a treatment regime and the clinician must scrutinize the estimated treatment regime for scientific validity. To facilitate meaningful information exchange, it is important that estimated treatment regimes be interpretable in a subject-matter context. We propose a simple, yet flexible class of treatment regimes whose members are representable as a short list of if–then statements. Regimes in this class are immediately interpretable and are therefore an appealing choice for broad application in practice. We derive a robust estimator of the optimal regime within this class and demonstrate its finite sample performance using simulation experiments. The proposed method is illustrated with data from two clinical trials.
Local-aggregate Modeling for Big Data via Distributed Optimization: Applications to NeuroimagingHu, Yue; Allen, Genevera I.
doi: 10.1111/biom.12355pmid: 26295449
SummaryTechnological advances have led to a proliferation of structured big data that have matrix-valued covariates. We are specifically motivated to build predictive models for multi-subject neuroimaging data based on each subject's brain imaging scans. This is an ultra-high-dimensional problem that consists of a matrix of covariates (brain locations by time points) for each subject; few methods currently exist to fit supervised models directly to this tensor data. We propose a novel modeling and algorithmic strategy to apply generalized linear models (GLMs) to this massive tensor data in which one set of variables is associated with locations. Our method begins by fitting GLMs to each location separately, and then builds an ensemble by blending information across locations through regularization with what we term an aggregating penalty. Our so called, Local-Aggregate Model, can be fit in a completely distributed manner over the locations using an Alternating Direction Method of Multipliers (ADMM) strategy, and thus greatly reduces the computational burden. Furthermore, we propose to select the appropriate model through a novel sequence of faster algorithmic solutions that is similar to regularization paths. We will demonstrate both the computational and predictive modeling advantages of our methods via simulations and an EEG classification problem.
Multiple Kernel Learning with Random Effects for Predicting Longitudinal Outcomes and Data IntegrationChen, Tianle; Zeng, Donglin; Wang, Yuanjia
doi: 10.1111/biom.12343pmid: 26177419
SummaryPredicting disease risk and progression is one of the main goals in many clinical research studies. Cohort studies on the natural history and etiology of chronic diseases span years and data are collected at multiple visits. Although, kernel-based statistical learning methods are proven to be powerful for a wide range of disease prediction problems, these methods are only well studied for independent data, but not for longitudinal data. It is thus important to develop time-sensitive prediction rules that make use of the longitudinal nature of the data. In this paper, we develop a novel statistical learning method for longitudinal data by introducing subject-specific short-term and long-term latent effects through a designed kernel to account for within-subject correlation of longitudinal measurements. Since the presence of multiple sources of data is increasingly common, we embed our method in a multiple kernel learning framework and propose a regularized multiple kernel statistical learning with random effects to construct effective nonparametric prediction rules. Our method allows easy integration of various heterogeneous data sources and takes advantage of correlation among longitudinal measures to increase prediction power. We use different kernels for each data source taking advantage of the distinctive feature of each data modality, and then optimally combine data across modalities. We apply the developed methods to two large epidemiological studies, one on Huntington's disease and the other on Alzheimer's Disease (Alzheimer's Disease Neuroimaging Initiative, ADNI) where we explore a unique opportunity to combine imaging and genetic data to study prediction of mild cognitive impairment, and show a substantial gain in performance while accounting for the longitudinal aspect of the data.
Merging Multiple Longitudinal Studies with Study-Specific Missing Covariates: A Joint Estimating Function ApproachWang, Fei; Song, Peter X.-K.; Wang, Lu
doi: 10.1111/biom.12356pmid: 26193911
SummaryMerging 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 study-specific 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.