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Instrumental variable methods are among the most commonly used causal inference approaches to deal with unmeasured confounders in observational studies. The presence of invalid instruments is the primary concern for practical applications, and a fast-growing area of research is inference for the causal effect with possibly invalid instruments. This paper illustrates that the existing confidence intervals may undercover when the valid and invalid instruments are hard to separate in a data-dependent way. To address this, we construct uniformly valid confidence intervals that are robust to the mistakes in separating valid and invalid instruments. We propose to search for a range of treatment effect values that lead to sufficiently many valid instruments. We further devise a novel sampling method, which, together with searching, leads to a more precise confidence interval. Our proposed searching and sampling confidence intervals are uniformly valid and achieve the parametric length under the finite-sample majority and plurality rules. We apply our proposal to examine the effect of education on earnings. The proposed method is implemented in the R package RobustIV available from CRAN.

 

Imaging of both the positions and orientations of single fluorophores, termed single-molecule orientation-localization microscopy, is a powerful tool for the study of biochemical processes. However, the limited photon budget associated with single-molecule fluorescence makes high-dimensional imaging with isotropic, nanoscale spatial resolution a formidable challenge. Here we realize a radially and azimuthally polarized multi-view reflector (raMVR) microscope for the imaging of the three-dimensional (3D) positions and 3D orientations of single molecules, with precisions of 10.9 nm and 2.0° over a 1.5-μm depth range. The raMVR microscope achieves 6D super-resolution imaging of Nile red molecules transiently bound to lipid-coated spheres, accurately resolving their spherical morphology, despite refractive-index mismatch. By observing the rotational dynamics of Nile red, raMVR images also resolve the infiltration of lipid membranes by amyloid-beta oligomers without covalent labelling. Finally, we demonstrate 6D imaging of cell membranes, where the orientations of specific fluorophores reveal heterogeneity in membrane fluidity. With its nearly isotropic 3D spatial resolution and orientation measurement precision, we expect the raMVR microscope to enable 6D imaging of molecular dynamics within biological and chemical systems with exceptional detail. 

The ability to predict individualized treatment effects (ITEs) based on a given patient's profile is essential for personalized medicine. We propose a hypothesis testing approach to choosing between two potential treatments for a given individual in the framework of high-dimensional linear models. The methodological novelty lies in the construction of a debiased estimator of the ITE and establishment of its asymptotic normality uniformly for an arbitrary future high-dimensional observation, while the existing methods can only handle certain specific forms of observations. We introduce a testing procedure with the type I error controlled and establish its asymptotic power. The proposed method can be extended to making inference for general linear contrasts, including both the average treatment effect and outcome prediction. We introduce the optimality framework for hypothesis testing from both the minimaxity and adaptivity perspectives and establish the optimality of the proposed procedure. An extension to high-dimensional approximate linear models is also considered. The finite sample performance of the procedure is demonstrated in simulation studies and further illustrated through an analysis of electronic health records data from patients with rheumatoid arthritis.

 

A major challenge in instrumental variable (IV) analysis is to find instruments that are valid, or have no direct effect on the outcome and are ignorable. Typically one is unsure whether all of the putative IVs are in fact valid. We propose a general inference procedure in the presence of invalid IVs, called two-stage hard thresholding with voting. The procedure uses two hard thresholding steps to select strong instruments and to generate candidate sets of valid IVs. Voting takes the candidate sets and uses majority and plurality rules to determine the true set of valid IVs. In low dimensions with invalid instruments, our proposal correctly selects valid IVs, consistently estimates the causal effect, produces valid confidence intervals for the causal effect and has oracle optimal width, even if the so-called 50% rule or the majority rule is violated. In high dimensions, we establish nearly identical results without oracle optimality. In simulations, our proposal outperforms traditional and recent methods in the invalid IV literature. We also apply our method to reanalyse the causal effect of education on earnings.