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Articles 121 - 150 of 205
Full-Text Articles in Biostatistics
A Weighted Instrumental Variable Estimator To Control For Instrument-Outcome Confounders, Douglas Lehmann, Yun Li, Rajiv Saran, Yi Li
A Weighted Instrumental Variable Estimator To Control For Instrument-Outcome Confounders, Douglas Lehmann, Yun Li, Rajiv Saran, Yi Li
The University of Michigan Department of Biostatistics Working Paper Series
No abstract provided.
Models For Hsv Shedding Must Account For Two Levels Of Overdispersion, Amalia Magaret
Models For Hsv Shedding Must Account For Two Levels Of Overdispersion, Amalia Magaret
UW Biostatistics Working Paper Series
We have frequently implemented crossover studies to evaluate new therapeutic interventions for genital herpes simplex virus infection. The outcome measured to assess the efficacy of interventions on herpes disease severity is the viral shedding rate, defined as the frequency of detection of HSV on the genital skin and mucosa. We performed a simulation study to ascertain whether our standard model, which we have used previously, was appropriately considering all the necessary features of the shedding data to provide correct inference. We simulated shedding data under our standard, validated assumptions and assessed the ability of 5 different models to reproduce the …
The Myth Of Making Inferences For An Overall Treatment Efficacy With Data From Multiple Comparative Studies Via Meta-Analysis, Takahiro Hasegawa, Brian Claggett, Lu Tian, Scott D. Solomon, Marc A. Pfeffer, Lee-Jen Wei
The Myth Of Making Inferences For An Overall Treatment Efficacy With Data From Multiple Comparative Studies Via Meta-Analysis, Takahiro Hasegawa, Brian Claggett, Lu Tian, Scott D. Solomon, Marc A. Pfeffer, Lee-Jen Wei
Harvard University Biostatistics Working Paper Series
Meta analysis techniques, if applied appropriately, can provide a summary of the totality of evidence regarding an overall difference between a new treatment and a control group using data from multiple comparative clinical studies. The standard meta analysis procedures, however, may not give a meaningful between-group difference summary measure or identify a meaningful patient population of interest, especially when the fixed effect model assumption is not met. Moreover, a single between-group comparison measure without a reference value obtained from patients in the control arm would likely not be informative enough for clinical decision making. In this paper, we propose a …
Improved Models For Differential Analysis For Genomic Data, Hong Wang
Improved Models For Differential Analysis For Genomic Data, Hong Wang
Theses and Dissertations--Statistics
This paper intend to develop novel statistical methods to improve genomic data analysis, especially for differential analysis. We considered two different data type: NanoString nCounter data and somatic mutation data. For NanoString nCounter data, we develop a novel differential expression detection method. The method considers a generalized linear model of the negative binomial family to characterize count data and allows for multi-factor design. Data normalization is incorporated in the model framework through data normalization parameters, which are estimated from control genes embedded in the nCounter system. For somatic mutation data, we develop beta-binomial model-based approaches to identify highly or lowly …
Missing Data In Clinical Trial: A Critical Look At The Proportionality Of Mnar And Mar Assumptions For Multiple Imputation, Theophile B. Dipita
Missing Data In Clinical Trial: A Critical Look At The Proportionality Of Mnar And Mar Assumptions For Multiple Imputation, Theophile B. Dipita
College of Graduate Studies: Theses & Dissertations
Randomized control trial is a gold standard of research studies. Randomization helps reduce bias and infer causality. One constraint of these studies is that it depends on participants to obtain the desired data. Whatever the researcher can do, there is a possibility to end up with incomplete data. The problem is more relevant in clinical trials when missing data can be related to the condition under study. The benefits of randomization is compromised by missing data. Multiple imputation is a valid method of treating missing data under the assumption of MAR. Unfortunately this is an unverified assumptions. Current practice advise …
Inequality In Treatment Benefits: Can We Determine If A New Treatment Benefits The Many Or The Few?, Emily Huang, Ethan Fang, Daniel Hanley, Michael Rosenblum
Inequality In Treatment Benefits: Can We Determine If A New Treatment Benefits The Many Or The Few?, Emily Huang, Ethan Fang, Daniel Hanley, Michael Rosenblum
Johns Hopkins University, Dept. of Biostatistics Working Papers
The primary analysis in many randomized controlled trials focuses on the average treatment effect and does not address whether treatment benefits are widespread or limited to a select few. This problem affects many disease areas, since it stems from how randomized trials, often the gold standard for evaluating treatments, are designed and analyzed. Our goal is to learn about the fraction who benefit from a treatment, based on randomized trial data. We consider the case where the outcome is ordinal, with binary outcomes as a special case. In general, the fraction who benefit is a non-identifiable parameter, and the best …
Preparedness Of Hospitals In The Republic Of Ireland For An Influenza Pandemic, An Infection Control Perspective, Mary Reidy, Fiona Ryan, Dervla Hogan, Seán Lacey, Claire Buckley
Preparedness Of Hospitals In The Republic Of Ireland For An Influenza Pandemic, An Infection Control Perspective, Mary Reidy, Fiona Ryan, Dervla Hogan, Seán Lacey, Claire Buckley
Department of Mathematics Publications
When an influenza pandemic occurs most of the population is susceptible and attack rates can range as high as 40–50 %. The most important failure in pandemic planning is the lack of standards or guidelines regarding what it means to be ‘prepared’. The aim of this study was to assess the preparedness of acute hospitals in the Republic of Ireland for an influenza pandemic from an infection control perspective.
C-Learning: A New Classification Framework To Estimate Optimal Dynamic Treatment Regimes, Baqun Zhang, Min Zhang
C-Learning: A New Classification Framework To Estimate Optimal Dynamic Treatment Regimes, Baqun Zhang, Min Zhang
The University of Michigan Department of Biostatistics Working Paper Series
Personalizing treatment to accommodate patient heterogeneity and the evolving nature of a disease over time has received considerable attention lately. A dynamic treatment regime is a set of decision rules, each corresponding to a decision point, that determine that next treatment based on each individual’s own available characteristics and treatment history up to that point. We show that identifying the optimal dynamic treatment regime can be recast as a sequential classification problem and is equivalent to sequentially minimizing a weighted expected misclassification error. This general classification perspective targets the exact goal of optimally individualizing treatments and is new and fundamentally …
Adaptive Enrichment Designs For Randomized Trials With Delayed Endpoints, Using Locally Efficient Estimators To Improve Precision, Michael Rosenblum, Tianchen Qian, Yu Du, Huitong Qiu
Adaptive Enrichment Designs For Randomized Trials With Delayed Endpoints, Using Locally Efficient Estimators To Improve Precision, Michael Rosenblum, Tianchen Qian, Yu Du, Huitong Qiu
Johns Hopkins University, Dept. of Biostatistics Working Papers
Adaptive enrichment designs involve preplanned rules for modifying enrollment criteria based on accrued data in an ongoing trial. For example, enrollment of a subpopulation where there is sufficient evidence of treatment efficacy, futility, or harm could be stopped, while enrollment for the remaining subpopulations is continued. Most existing methods for constructing adaptive enrichment designs are limited to situations where patient outcomes are observed soon after enrollment. This is a major barrier to the use of such designs in practice, since for many diseases the outcome of most clinical importance does not occur shortly after enrollment. We propose a new class …
Bayesian Function-On-Function Regression For Multilevel Functional Data, Mark J. Meyer, Brent A. Coull, Francesco Versace, Paul Cinciripini, Jeffrey S. Morris
Bayesian Function-On-Function Regression For Multilevel Functional Data, Mark J. Meyer, Brent A. Coull, Francesco Versace, Paul Cinciripini, Jeffrey S. Morris
Faculty Journal Articles
Medical and public health research increasingly involves the collection of complex and high dimensional data. In particular, functional data—where the unit of observation is a curve or set of curves that are finely sampled over a grid—is frequently obtained. Moreover, researchers often sample multiple curves per person resulting in repeated functional measures. A common question is how to analyze the relationship between two functional variables. We propose a general function-on-function regression model for repeatedly sampled functional data on a fine grid, presenting a simple model as well as a more extensive mixed model framework, and introducing various functional Bayesian inferential …
Realistic Spiking Neuron Statistics In A Population Are Described By A Single Parametric Distribution, Lauren Crow 9370373
Realistic Spiking Neuron Statistics In A Population Are Described By A Single Parametric Distribution, Lauren Crow 9370373
Undergraduate Research Posters
The spiking of activity of neurons throughout the cortex is random and complicated. This complicated activity requires theoretical formulations in order to understand the underlying principles of neural processing. A key aspect of theoretical investigations is characterizing the probability distribution of spiking activity. This study aims to better understand the statistics of the time between spikes, or interspike interval, in both real data and a spiking model with many time scales. Exploration of the interspike intervals of neural network activity can provide a better understanding of neural responses to different stimuli. We consider different parametric distribution fitting techniques to characterize …
Statistical Inference For The Mean Outcome Under A Possibly Non-Unique Optimal Treatment Strategy, Alexander R. Luedtke, Mark J. Van Der Laan
Statistical Inference For The Mean Outcome Under A Possibly Non-Unique Optimal Treatment Strategy, Alexander R. Luedtke, Mark J. Van Der Laan
U.C. Berkeley Division of Biostatistics Working Paper Series
We consider challenges that arise in the estimation of the value of an optimal individualized treatment strategy defined as the treatment rule that maximizes the population mean outcome, where the candidate treatment rules are restricted to depend on baseline covariates. We prove a necessary and sufficient condition for the pathwise differentiability of the optimal value, a key condition needed to develop a regular asymptotically linear (RAL) estimator of this parameter. The stated condition is slightly more general than the previous condition implied in the literature. We then describe an approach to obtain root-n rate confidence intervals for the optimal value …
Cross-Design Synthesis For Extending The Applicability Of Trial Evidence When Treatment Effect Is Heterogeneous-I. Methodology, Ravi Varadhan, Carlos Weiss
Cross-Design Synthesis For Extending The Applicability Of Trial Evidence When Treatment Effect Is Heterogeneous-I. Methodology, Ravi Varadhan, Carlos Weiss
Johns Hopkins University, Dept. of Biostatistics Working Papers
Randomized controlled trials (RCTs) provide reliable evidence for approval of new treatments, informing clinical practice, and coverage decisions. The participants in RCTs are often not a representative sample of the larger at-risk population. Hence it is argued that the average treatment effect from the trial is not generalizable to the larger at-risk population. An essential premise of this argument is that there is significant heterogeneity in the treatment effect (HTE). We present a new method to extrapolate the treatment effect from a trial to a target group that is inadequately represented in the trial, when HTE is present. Our method …
Interadapt -- An Interactive Tool For Designing And Evaluating Randomized Trials With Adaptive Enrollment Criteria, Aaron Joel Fisher, Harris Jaffee, Michael Rosenblum
Interadapt -- An Interactive Tool For Designing And Evaluating Randomized Trials With Adaptive Enrollment Criteria, Aaron Joel Fisher, Harris Jaffee, Michael Rosenblum
Johns Hopkins University, Dept. of Biostatistics Working Papers
The interAdapt R package is designed to be used by statisticians and clinical investigators to plan randomized trials. It can be used to determine if certain adaptive designs offer tangible benefits compared to standard designs, in the context of investigators’ specific trial goals and constraints. Specifically, interAdapt compares the performance of trial designs with adaptive enrollment criteria versus standard (non-adaptive) group sequential trial designs. Performance is compared in terms of power, expected trial duration, and expected sample size. Users can either work directly in the R console, or with a user-friendly shiny application that requires no programming experience. Several added …
Targeted Maximum Likelihood Estimation Using Exponential Families, Iván Díaz, Michael Rosenblum
Targeted Maximum Likelihood Estimation Using Exponential Families, Iván Díaz, Michael Rosenblum
Johns Hopkins University, Dept. of Biostatistics Working Papers
Targeted maximum likelihood estimation (TMLE) is a general method for estimating parameters in semiparametric and nonparametric models. Each iteration of TMLE involves fitting a parametric submodel that targets the parameter of interest. We investigate the use of exponential families to define the parametric submodel. This implementation of TMLE gives a general approach for estimating any smooth parameter in the nonparametric model. A computational advantage of this approach is that each iteration of TMLE involves estimation of a parameter in an exponential family, which is a convex optimization problem for which software implementing reliable and computationally efficient methods exists. We illustrate …
Variable Selection For Zero-Inflated And Overdispersed Data With Application To Health Care Demand In Germany, Zhu Wang, Shuangge Ma, Ching-Yun Wang
Variable Selection For Zero-Inflated And Overdispersed Data With Application To Health Care Demand In Germany, Zhu Wang, Shuangge Ma, Ching-Yun Wang
COBRA Preprint Series
In health services and outcome research, count outcomes are frequently encountered and often have a large proportion of zeros. The zero-inflated negative binomial (ZINB) regression model has important applications for this type of data. With many possible candidate risk factors, this paper proposes new variable selection methods for the ZINB model. We consider maximum likelihood function plus a penalty including the least absolute shrinkage and selection operator (LASSO), smoothly clipped absolute deviation (SCAD) and minimax concave penalty (MCP). An EM (expectation-maximization) algorithm is proposed for estimating the model parameters and conducting variable selection simultaneously. This algorithm consists of estimating penalized …
Adaptive Pair-Matching In The Search Trial And Estimation Of The Intervention Effect, Laura Balzer, Maya L. Petersen, Mark J. Van Der Laan
Adaptive Pair-Matching In The Search Trial And Estimation Of The Intervention Effect, Laura Balzer, Maya L. Petersen, Mark J. Van Der Laan
U.C. Berkeley Division of Biostatistics Working Paper Series
In randomized trials, pair-matching is an intuitive design strategy to protect study validity and to potentially increase study power. In a common design, candidate units are identified, and their baseline characteristics used to create the best n/2 matched pairs. Within the resulting pairs, the intervention is randomized, and the outcomes measured at the end of follow-up. We consider this design to be adaptive, because the construction of the matched pairs depends on the baseline covariates of all candidate units. As consequence, the observed data cannot be considered as n/2 independent, identically distributed (i.i.d.) pairs of units, as current practice assumes. …
Meta-Analysis Of Social-Personality Psychological Research, Blair T. Johnson, Alice H. Eagly
Meta-Analysis Of Social-Personality Psychological Research, Blair T. Johnson, Alice H. Eagly
CHIP Documents
This publication provides a contemporary treatment of the subject of meta-analysis in relation to social-personality psychology. Meta-analysis literally refers to the statistical pooling of the results of independent studies on a given subject, although in practice it refers as well to other steps of research synthesis, including defining the question under investigation, gathering all available research reports, coding of information about the studies and their effects, and interpretation/dissemination of results. Discussed as well are the hallmarks of high-quality meta-analyses.
Set-Based Tests For Genetic Association In Longitudinal Studies, Zihuai He, Min Zhang, Seunggeun Lee, Jennifer A. Smith, Xiuqing Guo, Walter Palmas, Sharon L.R. Kardia, Ana V. Diez Roux, Bhramar Mukherjee
Set-Based Tests For Genetic Association In Longitudinal Studies, Zihuai He, Min Zhang, Seunggeun Lee, Jennifer A. Smith, Xiuqing Guo, Walter Palmas, Sharon L.R. Kardia, Ana V. Diez Roux, Bhramar Mukherjee
The University of Michigan Department of Biostatistics Working Paper Series
Genetic association studies with longitudinal markers of chronic diseases (e.g., blood pressure, body mass index) provide a valuable opportunity to explore how genetic variants affect traits over time by utilizing the full trajectory of longitudinal outcomes. Since these traits are likely influenced by the joint effect of multiple variants in a gene, a joint analysis of these variants considering linkage disequilibrium (LD) may help to explain additional phenotypic variation. In this article, we propose a longitudinal genetic random field model (LGRF), to test the association between a phenotype measured repeatedly during the course of an observational study and a set …
Genetic Association Testing Of Copy Number Variation, Yinglei Li
Genetic Association Testing Of Copy Number Variation, Yinglei Li
Theses and Dissertations--Statistics
Copy-number variation (CNV) has been implicated in many complex diseases. It is of great interest to detect and locate such regions through genetic association testings. However, the association testings are complicated by the fact that CNVs usually span multiple markers and thus such markers are correlated to each other. To overcome the difficulty, it is desirable to pool information across the markers. In this thesis, we propose a kernel-based method for aggregation of marker-level tests, in which first we obtain a bunch of p-values through association tests for every marker and then the association test involving CNV is based on …
Adapting Data Adaptive Methods For Small, But High Dimensional Omic Data: Applications To Gwas/Ewas And More, Sara Kherad Pajouh, Alan E. Hubbard, Martyn T. Smith
Adapting Data Adaptive Methods For Small, But High Dimensional Omic Data: Applications To Gwas/Ewas And More, Sara Kherad Pajouh, Alan E. Hubbard, Martyn T. Smith
U.C. Berkeley Division of Biostatistics Working Paper Series
Exploratory analysis of high dimensional "omics" data has received much attention since the explosion of high-throughput technology allows simultaneous screening of tens of thousands of characteristics (genomics, metabolomics, proteomics, adducts, etc., etc.). Part of this trend has been an increase in the dimension of exposure data in studies of environmental exposure and associated biomarkers. Though some of the general approaches, such as GWAS, are transferable, what has received less focus is 1) how to derive estimation of independent associations in the context of many competing causes, without resorting to a misspecified model, and 2) how to derive accurate small-sample inference …
Fast Covariance Estimation For High-Dimensional Functional Data, Luo Xiao, David Ruppert, Vadim Zipunnikov, Ciprian Crainiceanu
Fast Covariance Estimation For High-Dimensional Functional Data, Luo Xiao, David Ruppert, Vadim Zipunnikov, Ciprian Crainiceanu
Johns Hopkins University, Dept. of Biostatistics Working Papers
For smoothing covariance functions, we propose two fast algorithms that scale linearly with the number of observations per function. Most available methods and software cannot smooth covariance matrices of dimension J x J with J>500; the recently introduced sandwich smoother is an exception, but it is not adapted to smooth covariance matrices of large dimensions such as J \ge 10,000. Covariance matrices of order J=10,000, and even J=100,000$ are becoming increasingly common, e.g., in 2- and 3-dimensional medical imaging and high-density wearable sensor data. We introduce two new algorithms that can handle very large covariance matrices: 1) FACE: a …
Targeted Maximum Likelihood Estimation For Dynamic And Static Longitudinal Marginal Structural Working Models, Maya L. Petersen, Joshua Schwab, Susan Gruber, Nello Blaser, Michael Schomaker, Mark J. Van Der Laan
Targeted Maximum Likelihood Estimation For Dynamic And Static Longitudinal Marginal Structural Working Models, Maya L. Petersen, Joshua Schwab, Susan Gruber, Nello Blaser, Michael Schomaker, Mark J. Van Der Laan
U.C. Berkeley Division of Biostatistics Working Paper Series
This paper describes a targeted maximum likelihood estimator (TMLE) for the parameters of longitudinal static and dynamic marginal structural models. We consider a longitudinal data structure consisting of baseline covariates, time-dependent intervention nodes, intermediate time-dependent covariates, and a possibly time dependent outcome. The intervention nodes at each time point can include a binary treatment as well as a right-censoring indicator. Given a class of dynamic or static interventions, a marginal structural model is used to model the mean of the intervention specific counterfactual outcome as a function of the intervention, time point, and possibly a subset of baseline covariates. Because …
Balancing Score Adjusted Targeted Minimum Loss-Based Estimation, Samuel D. Lendle, Bruce Fireman, Mark J. Van Der Laan
Balancing Score Adjusted Targeted Minimum Loss-Based Estimation, Samuel D. Lendle, Bruce Fireman, Mark J. Van Der Laan
U.C. Berkeley Division of Biostatistics Working Paper Series
Adjusting for a balancing score is sufficient for bias reduction when estimating causal effects including the average treatment effect and effect among the treated. Estimators that adjust for the propensity score in a nonparametric way, such as matching on an estimate of the propensity score, can be consistent when the estimated propensity score is not consistent for the true propensity score but converges to some other balancing score. We call this property the balancing score property, and discuss a class of estimators that have this property. We introduce a targeted minimum loss-based estimator (TMLE) for a treatment specific mean with …
Optimal Tests Of Treatment Effects For The Overall Population And Two Subpopulations In Randomized Trials, Using Sparse Linear Programming, Michael Rosenblum, Han Liu, En-Hsu Yen
Optimal Tests Of Treatment Effects For The Overall Population And Two Subpopulations In Randomized Trials, Using Sparse Linear Programming, Michael Rosenblum, Han Liu, En-Hsu Yen
Johns Hopkins University, Dept. of Biostatistics Working Papers
We propose new, optimal methods for analyzing randomized trials, when it is suspected that treatment effects may differ in two predefined subpopulations. Such sub-populations could be defined by a biomarker or risk factor measured at baseline. The goal is to simultaneously learn which subpopulations benefit from an experimental treatment, while providing strong control of the familywise Type I error rate. We formalize this as a multiple testing problem and show it is computationally infeasible to solve using existing techniques. Our solution involves a novel approach, in which we first transform the original multiple testing problem into a large, sparse linear …
A Bayesian Regression Tree Approach To Identify The Effect Of Nanoparticles Properties On Toxicity Profiles, Cecile Low-Kam, Haiyuan Zhang, Zhaoxia Ji, Tian Xia, Jeffrey I. Zinc, Andre Nel, Donatello Telesca
A Bayesian Regression Tree Approach To Identify The Effect Of Nanoparticles Properties On Toxicity Profiles, Cecile Low-Kam, Haiyuan Zhang, Zhaoxia Ji, Tian Xia, Jeffrey I. Zinc, Andre Nel, Donatello Telesca
COBRA Preprint Series
We introduce a Bayesian multiple regression tree model to characterize relationships between physico-chemical properties of nanoparticles and their in-vitro toxicity over multiple doses and times of exposure. Unlike conventional models that rely on data summaries, our model solves the low sample size issue and avoids arbitrary loss of information by combining all measurements from a general exposure experiment across doses, times of exposure, and replicates. The proposed technique integrates Bayesian trees for modeling threshold effects and interactions, and penalized B-splines for dose and time-response surfaces smoothing. The resulting posterior distribution is sampled via a Markov Chain Monte Carlo algorithm. This …
Group Testing Regression Models, Boan Zhang
Group Testing Regression Models, Boan Zhang
Department of Statistics: Dissertations, Theses, and Student Research
Group testing, where groups of individual specimens are composited to test for the presence or absence of a disease (or some other binary characteristic), is a procedure commonly used to reduce the costs of screening a large number of individuals. Statistical research in group testing has traditionally focused on a homogeneous population, where individuals are assumed to have the same probability of having a disease. However, individuals often have different risks of positivity, so recent research has examined regression models that allow for heterogeneity among individuals within the population. This dissertation focuses on two problems involving group testing regression models. …
Differential Patterns Of Interaction And Gaussian Graphical Models, Masanao Yajima, Donatello Telesca, Yuan Ji, Peter Muller
Differential Patterns Of Interaction And Gaussian Graphical Models, Masanao Yajima, Donatello Telesca, Yuan Ji, Peter Muller
COBRA Preprint Series
We propose a methodological framework to assess heterogeneous patterns of association amongst components of a random vector expressed as a Gaussian directed acyclic graph. The proposed framework is likely to be useful when primary interest focuses on potential contrasts characterizing the association structure between known subgroups of a given sample. We provide inferential frameworks as well as an efficient computational algorithm to fit such a model and illustrate its validity through a simulation. We apply the model to Reverse Phase Protein Array data on Acute Myeloid Leukemia patients to show the contrast of association structure between refractory patients and relapsed …
Depicting Estimates Using The Intercept In Meta-Regression Models: The Moving Constant Technique, Blair T. Johnson Dr., Tania B. Huedo-Medina Dr.
Depicting Estimates Using The Intercept In Meta-Regression Models: The Moving Constant Technique, Blair T. Johnson Dr., Tania B. Huedo-Medina Dr.
CHIP Documents
In any scientific discipline, the ability to portray research patterns graphically often aids greatly in interpreting a phenomenon. In part to depict phenomena, the statistics and capabilities of meta-analytic models have grown increasingly sophisticated. Accordingly, this article details how to move the constant in weighted meta-analysis regression models (viz. “meta-regression”) to illuminate the patterns in such models across a range of complexities. Although it is commonly ignored in practice, the constant (or intercept) in such models can be indispensible when it is not relegated to its usual static role. The moving constant technique makes possible estimates and confidence intervals at …
Estimation Of A Non-Parametric Variable Importance Measure Of A Continuous Exposure, Chambaz Antoine, Pierre Neuvial, Mark J. Van Der Laan
Estimation Of A Non-Parametric Variable Importance Measure Of A Continuous Exposure, Chambaz Antoine, Pierre Neuvial, Mark J. Van Der Laan
U.C. Berkeley Division of Biostatistics Working Paper Series
We define a new measure of variable importance of an exposure on a continuous outcome, accounting for potential confounders. The exposure features a reference level x0 with positive mass and a continuum of other levels. For the purpose of estimating it, we fully develop the semi-parametric estimation methodology called targeted minimum loss estimation methodology (TMLE) [van der Laan & Rubin, 2006; van der Laan & Rose, 2011]. We cover the whole spectrum of its theoretical study (convergence of the iterative procedure which is at the core of the TMLE methodology; consistency and asymptotic normality of the estimator), practical implementation, simulation …