Estimating what would be an individual's potential response to varying levels of exposure to a treatment is of high practical relevance for several important fields, such as healthcare, economics and public policy. However, existing methods for learning to estimate counterfactual outcomes from observational data are either focused on estimating average dose-response curves, or limited to settings with only two treatments that do not have an associated dosage parameter. Here, we present a novel machine-learning approach towards learning counterfactual representations for estimating individual dose-response curves for any number of treatments with continuous dosage parameters with neural networks. Building on the established potential outcomes framework, we introduce performance metrics, model selection criteria, model architectures, and open benchmarks for estimating individual dose-response curves. Our experiments show that the methods developed in this work set a new state-of-the-art in estimating individual dose-response.
Causal analysis of treatment effects with rigorous experiments is, in many domains, an essential tool for validating interventions. In medicine, prospective experiments, such as RCTs, are the de facto gold standard to evaluate whether a given treatment is efficacious in treating a specific indication across a population @cite_11 @cite_7 . However, performing prospective experiments is expensive, time-consuming, and often not possible for ethical reasons @cite_18 . Historically, there has therefore been considerable interest in developing methodologies for performing causal inference using readily available observational data @cite_27 @cite_24 @cite_19 @cite_15 @cite_1 @cite_33 @cite_17 . The na "ive approach of training supervised models to minimise the observed factual error is in general not a suitable choice for counterfactual inference tasks due to treatment assignment bias and the inability to observe counterfactual outcomes. To address the shortcomings of unsupervised and supervised learning in this setting, several adaptations to established machine-learning methods that aim to enable the estimation of counterfactual outcomes from observational data have recently been proposed @cite_38 @cite_21 @cite_0 @cite_39 @cite_35 @cite_30 @cite_23 @cite_36 . In this work, we build on several of these advances to develop a novel machine-learning framework for estimating individual dose-response.
@cite_30 @cite_38 @cite_18 @cite_35 @cite_33 @cite_7 @cite_36 @cite_21 @cite_1 @cite_17 @cite_39 @cite_24 @cite_19 @cite_27 @cite_0 @cite_23 @cite_15 @cite_11
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Learning individual-level causal effects from observational data, such as inferring the most effective medication for a specific patient, is a problem of growing importance for policy makers. The most important aspect of inferring causal effects from observational data is the handling of confounders, factors that affect both an intervention and its outcome. A carefully designed observational study attempts to measure all important confounders. However, even if one does not have direct access to all confounders, there may exist noisy and uncertain measurement of proxies for confounders. We build on recent advances in latent variable modeling to simultaneously estimate the unknown latent space summarizing the confounders and the causal effect. Our method is based on Variational Autoencoders (VAE) which follow the causal structure of inference with proxies. We show our method is significantly more robust than existing methods, and matches the state-of-the-art on previous benchmarks focused on individual treatment effects. Observational studies are rising in importance due to the widespread accumulation of data in fields such as healthcare, education, employment and ecology. We consider the task of answering counterfactual questions such as, "Would this patient have lower blood sugar had she received a different medication?". We propose a new algorithmic framework for counterfactual inference which brings together ideas from domain adaptation and representation learning. In addition to a theoretical justification, we perform an empirical comparison with previous approaches to causal inference from observational data. Our deep learning algorithm significantly outperforms the previous state-of-the-art. THE ethics of medical experimentation on human subjects has attracted much attention in recent years. There has, however, been rather less attention paid to the special ethical problems and dilemmas posed by the randomized clinical trial. The sheer number of such trials, the risks and costs that they involve, and the dangers that are posed both by permitting and by restricting their use would seem to warrant further ethical analysis of the randomized clinical trial. This article attempts to distinguish some of the major ethical problems posed by the randomized clinical trial, to set out some of the principal considerations . . . We propose a novel approach for inferring the individualized causal effects of a treatment (intervention) from observational data. Our approach conceptualizes causal inference as a multitask learning problem; we model a subject's potential outcomes using a deep multitask network with a set of shared layers among the factual and counterfactual outcomes, and a set of outcome-specific layers. The impact of selection bias in the observational data is alleviated via a propensity-dropout regularization scheme, in which the network is thinned for every training example via a dropout probability that depends on the associated propensity score. The network is trained in alternating phases, where in each phase we use the training examples of one of the two potential outcomes (treated and control populations) to update the weights of the shared layers and the respective outcome-specific layers. Experiments conducted on data based on a real-world observational study show that our algorithm outperforms the state-of-the-art. Abstract Ideally, questions about comparative effectiveness or safety would be answered using an appropriately designed and conducted randomized experiment. When we cannot conduct a randomized experiment, we analyze observational data. Causal inference from large observational databases (big data) can be viewed as an attempt to emulate a randomized experiment-the target experiment or target trial-that would answer the question of interest. When the goal is to guide decisions among several strategies, causal analyses of observational data need to be evaluated with respect to how well they emulate a particular target trial. We outline a framework for comparative effectiveness research using big data that makes the target trial explicit. This framework channels counterfactual theory for comparing the effects of sustained treatment strategies, organizes analytic approaches, provides a structured process for the criticism of observational studies, and helps avoid common methodologic pitfalls. Randomized, controlled trials have become the gold standard of medical knowledge. Yet their scientific and political history offers lessons about the complexity of medicine and disease and the economic and political forces shaping the production and circulation of knowledge. Learning representations for counterfactual inference from observational data is of high practical relevance for many domains, such as healthcare, public policy and economics. Counterfactual inference enables one to answer "What if...?" questions, such as "What would be the outcome if we gave this patient treatment @math ?". However, current methods for training neural networks for counterfactual inference on observational data are either overly complex, limited to settings with only two available treatment options, or both. Here, we present Perfect Match (PM), a method for training neural networks for counterfactual inference that is easy to implement, compatible with any architecture, does not add computational complexity or hyperparameters, and extends to any number of treatments. PM is based on the idea of augmenting samples within a minibatch with their propensity-matched nearest neighbours. Our experiments demonstrate that PM outperforms a number of more complex state-of-the-art methods in inferring counterfactual outcomes across several real-world and semi-synthetic datasets. There is intense interest in applying machine learning to problems of causal inference in fields such as healthcare, economics and education. In particular, individual-level causal inference has important applications such as precision medicine. We give a new theoretical analysis and family of algorithms for predicting individual treatment effect (ITE) from observational data, under the assumption known as strong ignorability. The algorithms learn a "balanced" representation such that the induced treated and control distributions look similar, and we give a novel and intuitive generalization-error bound showing the expected ITE estimation error of a representation is bounded by a sum of the standard generalization-error of that representation and the distance between the treated and control distributions induced by the representation. We use Integral Probability Metrics to measure distances between distributions, deriving explicit bounds for the Wasserstein and Maximum Mean Discrepancy (MMD) distances. Experiments on real and simulated data show the new algorithms match or outperform the state-of-the-art. Recent progress in artificial intelligence has renewed interest in building systems that learn and think like people. Many advances have come from using deep neural networks trained end-to-end in tasks such as object recognition, video games, and board games, achieving performance that equals or even beats that of humans in some respects. Despite their biological inspiration and performance achievements, these systems differ from human intelligence in crucial ways. We review progress in cognitive science suggesting that truly human-like learning and thinking machines will have to reach beyond current engineering trends in both what they learn and how they learn it. Specifically, we argue that these machines should (1) build causal models of the world that support explanation and understanding, rather than merely solving pattern recognition problems; (2) ground learning in intuitive theories of physics and psychology to support and enrich the knowledge that is learned; and (3) harness compositionality and learning-to-learn to rapidly acquire and generalize knowledge to new tasks and situations. We suggest concrete challenges and promising routes toward these goals that can combine the strengths of recent neural network advances with more structured cognitive models. Predicated on the increasing abundance of electronic health records, we investigate the problem of inferring individualized treatment effects using observational data. Stemming from the potential outcomes model, we propose a novel multi-task learning framework in which factual and counterfactual outcomes are modeled as the outputs of a function in a vector-valued reproducing kernel Hilbert space (vvRKHS). We develop a nonparametric Bayesian method for learning the treatment effects using a multi-task Gaussian process (GP) with a linear coregionalization kernel as a prior over the vvRKHS. The Bayesian approach allows us to compute individualized measures of confidence in our estimates via pointwise credible intervals, which are crucial for realizing the full potential of precision medicine. The impact of selection bias is alleviated via a risk-based empirical Bayes method for adapting the multi-task GP prior, which jointly minimizes the empirical error in factual outcomes and the uncertainty in (unobserved) counterfactual outcomes. We conduct experiments on observational datasets for an interventional social program applied to premature infants, and a left ventricular assist device applied to cardiac patients wait-listed for a heart transplant. In both experiments, we show that our method significantly outperforms the state-of-the-art. Abstract We outline a framework for causal inference in settings where assignment to a binary treatment is ignorable, but compliance with the assignment is not perfect so that the receipt of treatment is nonignorable. To address the problems associated with comparing subjects by the ignorable assignment—an “intention-to-treat analysis”—we make use of instrumental variables, which have long been used by economists in the context of regression models with constant treatment effects. We show that the instrumental variables (IV) estimand can be embedded within the Rubin Causal Model (RCM) and that under some simple and easily interpretable assumptions, the IV estimand is the average causal effect for a subgroup of units, the compliers. Without these assumptions, the IV estimand is simply the ratio of intention-to-treat causal estimands with no interpretation as an average causal effect. The advantages of embedding the IV approach in the RCM are that it clarifies the nature of critical assumptions needed for a... Abstract : The results of observational studies are often disputed because of nonrandom treatment assignment. For example, patients at greater risk may be overrepresented in some treatment group. This paper discusses the central role of propensity scores and balancing scores in the analysis of observational studies. The propensity score is the (estimated) conditional probability of assignment to a particular treatment given a vector of observed covariates. Both large and small sample theory show that adjustment for the scalar propensity score is sufficient to remove bias due to all observed covariates. Applications include: matched sampling on the univariate propensity score which is equal percent bias reducing under more general conditions than required for discriminant matching, multivariate adjustment by subclassification on balancing scores where the same subclasses are used to estimate treatment effects for all outcome variables and in all subpopulations, and visual representation of multivariate adjustment by a two-dimensional plot. (Author) There occurs on some occasions a difficulty in deciding the direction of causality between two related variables and also whether or not feedback is occurring. Testable definitions of causality and feedback are proposed and illustrated by use of simple two-variable models. The important problem of apparent instantaneous causality is discussed and it is suggested that the problem often arises due to slowness in recording information or because a sufficiently wide class of possible causal variables has not been used. It can be shown that the cross spectrum between two variables can be decomposed into two parts, each relating to a single causal arm of a feedback situation. Measures of causal lag and causal strength can then be constructed. A generalisation of this result with the partial cross spectrum is suggested. AbstractMany scientific and engineering challenges—ranging from personalized medicine to customized marketing recommendations—require an understanding of treatment effect heterogeneity. In this paper, we develop a non-parametric causal forest for estimating heterogeneous treatment effects that extends Breiman's widely used random forest algorithm. In the potential outcomes framework with unconfoundedness, we show that causal forests are pointwise consistent for the true treatment effect, and have an asymptotically Gaussian and centered sampling distribution. We also discuss a practical method for constructing asymptotic confidence intervals for the true treatment effect that are centered at the causal forest estimates. Our theoretical results rely on a generic Gaussian theory for a large family of random forest algorithms. To our knowledge, this is the first set of results that allows any type of random forest, including classification and regression forests, to be used for provably valid statistical infe... Estimating individualized treatment effects (ITE) is a challenging task due to the need for an individual's potential outcomes to be learned from biased data and without having access to the counterfactuals. We propose a novel method for inferring ITE based on the Generative Adversarial Nets (GANs) framework. Our method, termed Generative Adversarial Nets for inference of Individualized Treatment Effects (GANITE), is motivated by the possibility that we can capture the uncertainty in the counterfactual distributions by attempting to learn them using a GAN. We generate proxies of the counterfactual outcomes using a counterfactual generator, G, and then pass these proxies to an ITE generator, I, in order to train it. By modeling both of these using the GAN framework, we are able to infer based on the factual data, while still accounting for the unseen counterfactuals. We test our method on three real-world datasets (with both binary and multiple treatments) and show that GANITE outperforms state-of-the-art methods. In observational studies with exposures or treatments that vary over time, standard approaches for adjustment of confounding are biased when there exist time-dependent confounders that are also affected by previous treatment. This paper introduces marginal structural models, a new class of causal mo LIST OF ILLUSTRATIONS ix LIST OF TABLES xi ACKNOWLEDGMENTS xiii LIST OF ABBREVIATIONS AND ACRONYMS xvii INTRODUCTION: The Gatekeeper 1 CHAPTER ONE: Reputation and Regulatory Power 33 PART ONE: ORGANIZATIONAL EMPOWERMENT AND CHALLENGE CHAPTER TWO: Reputation and Gatekeeping Authority: The Federal Food, Drug and Cosmetic Act of 1938 and Its Aftermath 73 CHAPTER THREE: The Ambiguous Emergence of American Pharmaceutical Regulation, 1944-1961 118 CHAPTER FOUR: Reputation and Power Crystallized: Thalidomide, Frances Kelsey, and Phased Experiment, 1961-1966 228 CHAPTER FIVE: Reputation and Power Institutionalized: Scientific Networks, Congressional Hearings, and Judicial Affirmation, 1963-1986 298 CHAPTER SIX: Reputation and Power Contested: Emboldened Audiences in Cancer and AIDS, 1977-1992 393 PART TWO: PHARMACEUTICAL REGULATION AND ITS AUDIENCES CHAPTER SEVEN: Reputation and the Organizational Politics of New Drug Review 465 CHAPTER EIGHT: The Governance of Research and Development: Gatekeeping Power, Conceptual Guidance, and Regulation by Satellite 544 CHAPTER NINE: The Other Side of the Gate: Reputation, Power, and Post-Market Regulation 585 CHAPTER TEN: The Detente of Firm and Regulator 635 CHAPTER ELEVEN: American Pharmaceutical Regulation in International Context: Audiences, Comparisons, and Dependencies 686 CHAPTER TWELVE: Conclusion: A Reputation in Relief 727 PRIMARY SOURCES AND ARCHIVAL COLLECTIONS 753 INDEX 759