Additive models play an essential role in studying non-linear relationships. Despite many recent advances in estimation, there is a lack of methods and theories for inference in high-dimensional additive models, including confidence interval construction and hypothesis testing. Motivated by inference for non-linear treatment effects, we consider the high-dimensional additive model and make inferences for the function derivative. We propose a novel decorrelated local linear estimator and establish its asymptotic normality. The main novelty is the construction of the decorrelation weights, which is instrumental in reducing the error inherited from estimating the nuisance functions in the high-dimensional additive model. We construct the confidence interval for the function derivative and conduct the related hypothesis testing. We demonstrate our proposed method over large-scale simulation studies and apply it to identify non-linear effects in the motif regression problem. Our proposed method is implemented in the R package DLL available from CRAN.

Risk modeling with electronic health records (EHR) data is challenging due to no direct observations of the disease outcome and the high-dimensional predictors. In this paper, we develop a surrogate assisted semi-supervised learning approach, leveraging small labeled data with annotated outcomes and extensive unlabeled data of outcome surrogates and high-dimensional predictors. We propose to impute the unobserved outcomes by constructing a sparse imputation model with outcome surrogates and high-dimensional predictors. We further conduct a one-step bias correction to enable interval estimation for the risk prediction. Our inference procedure is valid even if both the imputation and risk prediction models are misspecified. Our novel way of ultilizing unlabelled data enables the high-dimensional statistical inference for the challenging setting with a dense risk prediction model. We present an extensive simulation study to demonstrate the superiority of our approach compared to existing supervised methods. We apply the method to genetic risk prediction of type-2 diabetes mellitus using an EHR biobank cohort.

Labeling patients in electronic health records with respect to their statuses of having a disease or condition, i.e. case or control statuses, has increasingly relied on prediction models using high-dimensional variables derived from structured and unstructured electronic health record data. A major hurdle currently is a lack of valid statistical inference methods for the case probability. In this paper, considering high-dimensional sparse logistic regression models for prediction, we propose a novel bias-corrected estimator for the case probability through the development of linearization and variance enhancement techniques. We establish asymptotic normality of the proposed estimator for any loading vector in high dimensions. We construct a confidence interval for the case probability and propose a hypothesis testing procedure for patient case-control labelling. We demonstrate the proposed method via extensive simulation studies and application to real-world electronic health record data.

The instrumental variable method consistently estimates the effect of a treatment when there is unmeasured confounding and a valid instrumental variable. A valid instrumental variable is a variable that is independent of unmeasured confounders and affects the treatment but does not have a direct effect on the outcome beyond its effect on the treatment. Two commonly used estimators for using an instrumental variable to estimate a treatment effect are the two stage least squares estimator and the control function estimator. For linear causal effect models, these two estimators are equivalent, but for nonlinear causal effect models, the estimators are different. We provide a systematic comparison of these two estimators for nonlinear causal effect models and develop an approach to combing the two estimators that generally performs better than either one alone. We show that the control function estimator is a two stage least squares estimator with an augmented set of instrumental variables. If these augmented instrumental variables are valid, then the control function estimator can be much more efficient than usual two stage least squares without the augmented instrumental variables while if the augmented instrumental variables are not valid, then the control function estimator may be inconsistent while the usual two stage least squares remains consistent. We apply the Hausman test to test whether the augmented instrumental variables are valid and construct a pretest estimator based on this test. The pretest estimator is shown to work well in a simulation study. An application to the effect of exposure to violence on time preference is considered.