arXiv subjects

Alejandro Schuler

Publications and source records attributed to Alejandro Schuler.

29 records · Page 2Linked to original sources

arXiv2021

Increasing the efficiency of randomized trial estimates via linear adjustment for a prognostic score

Estimating causal effects from randomized experiments is central to clinical research. Reducing the statistical uncertainty in these analyses is an important objective for statisticians. Registries, prior trials, and health records constitute a growing compendium of historical data on patients under standard-of-care that may be exploitable to this end. However, most methods for historical borrowing achieve reductions in variance by sacrificing strict type-I error rate control. Here, we propose a use of historical data that exploits linear covariate adjustment to improve the efficiency of trial analyses without incurring bias. Specifically, we train a prognostic model on the historical data, then estimate the treatment effect using a linear regression while adjusting for the trial subjects' predicted outcomes (their prognostic scores). We prove that, under certain conditions, this prognostic covariate adjustment procedure attains the minimum variance possible among a large class of estimators. When those conditions are not met, prognostic covariate adjustment is still more efficient than raw covariate adjustment and the gain in efficiency is proportional to a measure of the predictive accuracy of the prognostic model above and beyond the linear relationship with the raw covariates. We demonstrate the approach using simulations and a reanalysis of an Alzheimer's Disease clinical trial and observe meaningful reductions in mean-squared error and the estimated variance. Lastly, we provide a simplified formula for asymptotic variance that enables power calculations that account for these gains. Sample size reductions between 10% and 30% are attainable when using prognostic models that explain a clinically realistic percentage of the outcome variance.

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arXiv2021

Mixed models for repeated measures should include time-by-covariate interactions to assure power gains and robustness against dropout bias relative to complete-case ANCOVA

In randomized trials with continuous-valued outcomes the goal is often to estimate the difference in average outcomes between two treatment groups. However, the outcome in some trials is longitudinal, meaning that multiple measurements of the same outcome are taken over time for each subject. The target of inference in this case is often still the difference in averages at a given timepoint. One way to analyze these data is to ignore the measurements at intermediate timepoints and proceed with a standard covariate-adjusted analysis (e.g. ANCOVA) with the complete cases. However, it is generally thought that exploiting information from intermediate timepoints using mixed models for repeated measures (MMRM) a) increases power and b) more naturally "handles" missing data. Here we prove that neither of these conclusions is entirely correct when baseline covariates are adjusted for without including time-by-covariate interactions. We back these claims up with simulations. MMRM provides benefits over complete-cases ANCOVA in many cases, but covariate-time interaction terms should always be included to guarantee the best results.

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arXiv2021

Designing efficient randomized trials: power and sample size calculation when using semiparametric efficient estimators

Trials enroll a large number of subjects in order to attain power, making them expensive and time-consuming. Sample size calculations are often performed with the assumption of an unadjusted analysis, even if the trial analysis plan specifies a more efficient estimator (e.g. ANCOVA). This leads to conservative estimates of required sample sizes and an opportunity for savings. Here we show that a relatively simple formula can be used to estimate the power of any two-arm, single-timepoint trial analyzed with a semiparametric efficient estimator, regardless of the domain of the outcome or kind of treatment effect (e.g. odds ratio, mean difference). Since an efficient estimator attains the minimum possible asymptotic variance, this allows for the design of trials that are as small as possible while still attaining design power and control of type I error. The required sample size calculation is parsimonious and requires the analyst to provide only a small number of population parameters. We verify in simulation that the large-sample properties of trials designed this way attain their nominal values. Lastly, we demonstrate how to use this formula in the "design" (and subsequent reanalysis) of a real clinical trial and show that fewer subjects are required to attain the same design power when a semiparametric efficient estimator is accounted for at the design stage.

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arXiv2021

Multivariate Probabilistic Regression with Natural Gradient Boosting

Many single-target regression problems require estimates of uncertainty along with the point predictions. Probabilistic regression algorithms are well-suited for these tasks. However, the options are much more limited when the prediction target is multivariate and a joint measure of uncertainty is required. For example, in predicting a 2D velocity vector a joint uncertainty would quantify the probability of any vector in the plane, which would be more expressive than two separate uncertainties on the x- and y- components. To enable joint probabilistic regression, we propose a Natural Gradient Boosting (NGBoost) approach based on nonparametrically modeling the conditional parameters of the multivariate predictive distribution. Our method is robust, works out-of-the-box without extensive tuning, is modular with respect to the assumed target distribution, and performs competitively in comparison to existing approaches. We demonstrate these claims in simulation and with a case study predicting two-dimensional oceanographic velocity data. An implementation of our method is available at https://github.com/stanfordmlgroup/ngboost.

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arXiv2020

Bayesian prognostic covariate adjustment

Historical data about disease outcomes can be integrated into the analysis of clinical trials in many ways. We build on existing literature that uses prognostic scores from a predictive model to increase the efficiency of treatment effect estimates via covariate adjustment. Here we go further, utilizing a Bayesian framework that combines prognostic covariate adjustment with an empirical prior distribution learned from the predictive performances of the prognostic model on past trials. The Bayesian approach interpolates between prognostic covariate adjustment with strict type I error control when the prior is diffuse, and a single-arm trial when the prior is sharply peaked. This method is shown theoretically to offer a substantial increase in statistical power, while limiting the type I error rate under reasonable conditions. We demonstrate the utility of our method in simulations and with an analysis of a past Alzheimer's disease clinical trial.

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arXiv2020

A Causal Machine Learning Framework for Predicting Preventable Hospital Readmissions

Clinical predictive algorithms are increasingly being used to form the basis for optimal treatment policies--that is, to enable interventions to be targeted to the patients who will presumably benefit most. Despite taking advantage of recent advances in supervised machine learning, these algorithms remain, in a sense, blunt instruments--often being developed and deployed without a full accounting of the causal aspects of the prediction problems they are intended to solve. Indeed, in many settings, including among patients at risk of readmission, the riskiest patients may derive less benefit from a preventative intervention compared to those at lower risk. Moreover, targeting an intervention to a population, rather than limiting it to a small group of high-risk patients, may lead to far greater overall utility if the patients with the most modifiable (or preventable) outcomes across the population could be identified. Based on these insights, we introduce a causal machine learning framework that decouples this prediction problem into causal and predictive parts, which clearly delineates the complementary roles of causal inference and prediction in this problem. We estimate treatment effects using causal forests, and characterize treatment effect heterogeneity across levels of predicted risk using these estimates. Furthermore, we show how these effect estimates could be used in concert with the modeled "payoffs" associated with successful prevention of individual readmissions to maximize overall utility. Based on data taken from before and after the implementation of a readmissions prevention intervention at Kaiser Permanente Northern California, our results suggest that nearly four times as many readmissions could be prevented annually with this approach compared to targeting this intervention using predicted risk.

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arXiv2020

NGBoost: Natural Gradient Boosting for Probabilistic Prediction

We present Natural Gradient Boosting (NGBoost), an algorithm for generic probabilistic prediction via gradient boosting. Typical regression models return a point estimate, conditional on covariates, but probabilistic regression models output a full probability distribution over the outcome space, conditional on the covariates. This allows for predictive uncertainty estimation -- crucial in applications like healthcare and weather forecasting. NGBoost generalizes gradient boosting to probabilistic regression by treating the parameters of the conditional distribution as targets for a multiparameter boosting algorithm. Furthermore, we show how the Natural Gradient is required to correct the training dynamics of our multiparameter boosting approach. NGBoost can be used with any base learner, any family of distributions with continuous parameters, and any scoring rule. NGBoost matches or exceeds the performance of existing methods for probabilistic prediction while offering additional benefits in flexibility, scalability, and usability. An open-source implementation is available at github.com/stanfordmlgroup/ngboost.

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arXiv2020

Performance metrics for intervention-triggering prediction models do not reflect an expected reduction in outcomes from using the model

Clinical researchers often select among and evaluate risk prediction models using standard machine learning metrics based on confusion matrices. However, if these models are used to allocate interventions to patients, standard metrics calculated from retrospective data are only related to model utility (in terms of reductions in outcomes) under certain assumptions. When predictions are delivered repeatedly throughout time (e.g. in a patient encounter), the relationship between standard metrics and utility is further complicated. Several kinds of evaluations have been used in the literature, but it has not been clear what the target of estimation is in each evaluation. We synthesize these approaches, determine what is being estimated in each of them, and discuss under what assumptions those estimates are valid. We demonstrate our insights using simulated data as well as real data used in the design of an early warning system. Our theoretical and empirical results show that evaluations without interventional data either do not estimate meaningful quantities, require strong assumptions, or are limited to estimating best-case scenario bounds.

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arXiv2018

A comparison of methods for model selection when estimating individual treatment effects

Practitioners in medicine, business, political science, and other fields are increasingly aware that decisions should be personalized to each patient, customer, or voter. A given treatment (e.g. a drug or advertisement) should be administered only to those who will respond most positively, and certainly not to those who will be harmed by it. Individual-level treatment effects can be estimated with tools adapted from machine learning, but different models can yield contradictory estimates. Unlike risk prediction models, however, treatment effect models cannot be easily evaluated against each other using a held-out test set because the true treatment effect itself is never directly observed. Besides outcome prediction accuracy, several metrics that can leverage held-out data to evaluate treatment effects models have been proposed, but they are not widely used. We provide a didactic framework that elucidates the relationships between the different approaches and compare them all using a variety of simulations of both randomized and observational data. Our results show that researchers estimating heterogenous treatment effects need not limit themselves to a single model-fitting algorithm. Instead of relying on a single method, multiple models fit by a diverse set of algorithms should be evaluated against each other using an objective function learned from the validation set. The model minimizing that objective should be used for estimating the individual treatment effect for future individuals.

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arXiv2017

Synth-Validation: Selecting the Best Causal Inference Method for a Given Dataset

Many decisions in healthcare, business, and other policy domains are made without the support of rigorous evidence due to the cost and complexity of performing randomized experiments. Using observational data to answer causal questions is risky: subjects who receive different treatments also differ in other ways that affect outcomes. Many causal inference methods have been developed to mitigate these biases. However, there is no way to know which method might produce the best estimate of a treatment effect in a given study. In analogy to cross-validation, which estimates the prediction error of predictive models applied to a given dataset, we propose synth-validation, a procedure that estimates the estimation error of causal inference methods applied to a given dataset. In synth-validation, we use the observed data to estimate generative distributions with known treatment effects. We apply each causal inference method to datasets sampled from these distributions and compare the effect estimates with the known effects to estimate error. Using simulations, we show that using synth-validation to select a causal inference method for each study lowers the expected estimation error relative to consistently using any single method.

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arXiv2017

Some methods for heterogeneous treatment effect estimation in high-dimensions

When devising a course of treatment for a patient, doctors often have little quantitative evidence on which to base their decisions, beyond their medical education and published clinical trials. Stanford Health Care alone has millions of electronic medical records (EMRs) that are only just recently being leveraged to inform better treatment recommendations. These data present a unique challenge because they are high-dimensional and observational. Our goal is to make personalized treatment recommendations based on the outcomes for past patients similar to a new patient. We propose and analyze three methods for estimating heterogeneous treatment effects using observational data. Our methods perform well in simulations using a wide variety of treatment effect functions, and we present results of applying the two most promising methods to data from The SPRINT Data Analysis Challenge, from a large randomized trial of a treatment for high blood pressure.

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