Sequential Counterfactual Inference for Temporal Clinical Data: Addressing the Time Traveler Dilemma

Deep learning has enabled significant advances in time-series causal inference, yet progress remains constrained by the lack of realistic benchmarks with observable counterfactual outcomes. Existing datasets either rely on real-world observations without ground-truth counterfactuals or on simplified simulations that fail to capture complex causal dynamics. To address this gap, we develop a large-scale benchmark for counterfactual prediction in epidemic time series under dynamic interventions. Unlike existing benchmarks, it supports static and time-varying treatments, as well as both single-policy and multi-policy intervention settings, enabling evaluation of causal inference methods across a broad range of causal inference scenarios. Leveraging a calibrated agent-based model grounded in real-world demographic, mobility, epidemiological, and policy data, we generate realistic counterfactual trajectories across more than 150 U.S. counties. Using this benchmark, we evaluate widely used and state-of-the-art causal inference methods, revealing substantial performance differences and highlighting the challenges of realistic time-series causal reasoning.

Predicting counterfactual outcomes in longitudinal data, where sequential treatment decisions heavily depend on evolving patient states, is critical yet notoriously challenging due to complex time-dependent confounding and inadequate uncertainty quantification in existing methods. We introduce the Causal Diffusion Model (CDM), the first denoising diffusion probabilistic approach explicitly designed to generate full probabilistic distributions of counterfactual outcomes under sequential interventions. CDM employs a novel residual denoising architecture with relational self-attention, capturing intricate temporal dependencies and multimodal outcome trajectories without requiring explicit adjustments (e.g., inverse-probability weighting or adversarial balancing) for confounding. In rigorous evaluation on a pharmacokinetic-pharmacodynamic tumor-growth simulator widely adopted in prior work, CDM consistently outperforms state-of-the-art longitudinal causal inference methods, achieving a 15-30% relative improvement in distributional accuracy (1-Wasserstein distance) while maintaining competitive or superior point-estimate accuracy (RMSE) under high-confounding regimes. By unifying uncertainty quantification and robust counterfactual prediction in complex, sequentially confounded settings, without tailored deconfounding, CDM offers a flexible, high-impact tool for decision support in medicine, policy evaluation, and other longitudinal domains.

Longitudinal treatment decisions from multivariate time-series data require predicting potential outcomes under future treatment sequences in the presence of time-varying confounding, heterogeneous patient dynamics, and limited domain-specific data. Existing longitudinal causal estimators typically address this problem by training a new model for each cohort or simulator. We introduce Causal Longitudinal Prior-Fitted Networks (CausalLongPFN), a prior-fitted network for time-series causal inference in longitudinal treatment-response data and zero-shot in-context counterfactual outcome prediction. The model is pretrained entirely on synthetic episodes sampled from a broad prior over temporal structural causal models, exposing it to treatment-confounder feedback, latent heterogeneity, nonlinear state evolution, delayed effects, and cumulative treatment responses. At test time, CausalLongPFN remains frozen and is used zero-shot: it conditions on support trajectories, a query history, and a planned future treatment sequence, and returns a predictive distribution over future outcomes without gradient updates or propensity-model fitting. Multi-step predictions are obtained by recursively applying the one-step predictor under the specified treatment sequence. We evaluate the model on branchable cancer, HIV, and warfarin benchmarks with ground-truth counterfactual labels, and on factual-only rolling-origin prediction in MIMIC-III ICU trajectories. CausalLongPFN is competitive with domain-trained longitudinal baselines on counterfactual benchmarks and performs strongly on factual MIMIC-III prediction, suggesting that broad synthetic causal pretraining can provide a frozen, amortized alternative for zero-shot longitudinal treatment-response prediction when repeated domain-specific training is costly or impractical.