Addressing Instrument-Outcome Confounding in Mendelian Randomization through Representation Learning

Unobserved confounding is a fundamental challenge in causal inference from observational data. This article develops a mixture-learning perspective, viewing latent confounders as sources of heterogeneity that induce mixture structure in observed data. Under suitable structural and identifiability assumptions, recovering the mixing distribution and component mechanisms enables estimation of interventional distributions and causal estimands. Using variants of Bernoulli mixtures as a running example, we contextualize mixture-learning techniques and their structural assumptions, and connect them to causal inference in panel-data settings, including latent factor models and synthetic interventions.We then consider high-dimensional exponential-family mixtures with dependent outcome trajectories, moving beyond counterfactual means to model counterfactual distributions. We situate this perspective relative to complementary approaches for unobserved confounding. Together, these ideas provide a bridge between mixture learning and causal inference, connecting recent advances in high-dimensional mixture learning to scalable identification and estimation of causal effects while raising new challenges for mixture learning.

Learned representations of high-dimensional multimodal health records are increasingly used to adjust for confounding, yet they are usually trained to reconstruct the data rather than preserve the information that causal identification requires. We study counterfactual outcomes under alternative treatments, including phenotype-specific effects and patient-level counterfactual risk profiles of the kind digital twins provide, and interventional direct and indirect effects under exposure-induced intermediate confounding. We give conditions under which a representation preserves identification and show that interventional mediation is more demanding than counterfactual comparison. We prove that no covariate-only training objective, whether reconstruction, contrastive, or physics-informed, can certify that a representation is sufficient, and that, in a linear structural model, a representation can lose arbitrarily little reconstruction accuracy yet induce arbitrarily large bias. We decompose the error of cross-fitted doubly robust estimators into a first-order representation bias, which neither double robustness nor cross-fitting removes, and a second-order remainder of nuisance-estimation errors, so coverage worsens as the sample size grows when the representation is insufficient. We propose a workflow combining modality-specific variational autoencoders trained outside the estimation sample, cross-fitted doubly robust estimators, locked phenotypes, select-then-confirm pathway analysis, portable representations, and diagnostics for representation insufficiency, exposure leakage, and sensitivity. In simulations, discarding a rare, moderately strong confounder gave indirect-effect intervals with 2% coverage at n = 3,000; reconstruction loss missed the problem, and a simple predictive diagnostic flagged it in every replicate.

Causal discovery with latent confounding is particularly challenging, but a common setting in real-world data. In this work, we focus on linear causal models with latent confounding, represented by acyclic directed mixed graphs (ADMGs). Existing methods that fully identify ADMGs typically assume non-Gaussianity or graphical constraints, such as bow-freeness. In contrast, we propose Linear ADMG Learning (LinADMG), a framework for learning ADMGs for linear causal models through identifiable representation learning. Rather than relying on non-Gaussianity or bow-freeness, LinADMG leverages multi-domain settings to identify the noise variables. We show that the identifiability of the noise variables is sufficient for recovering all direct causal relations, and that, under an additional latent-confounding no-cancellation condition, LinADMG can identify the whole ADMG. We implement LinADMG with four identifiable representation learning approaches from the literature and validate the methods on simulated and semisynthetic datasets.