Curriculum-Aware Interpolate-then-Refine: Learned Physiological Time-Series Imputation under Realistic Missingness

Time-series imputation benchmarks employ uniform random masking and shape-agnostic metrics (MSE, RMSE), implicitly weighting evaluation by regime prevalence. In systems with a dominant attractor -- homeostatic physiology, nominal industrial operation, stable network traffic -- this creates a systematic Stationarity Bias: simple methods appear superior because the benchmark predominantly samples the easy, low-entropy regime where they trivially succeed. We formalize this bias and propose a Stratified Stress-Test that partitions evaluation into Stationary and Transient regimes. Using Continuous Glucose Monitoring (CGM) as a testbed -- chosen for its rigorous ground-truth forcing functions (meals, insulin) that enable precise regime identification -- we establish three findings with broad implications:(i)~Stationary Efficiency: Linear interpolation achieves state-of-the-art reconstruction during stable intervals, confirming that complex architectures are computationally wasteful in low-entropy regimes.(ii)~Transient Fidelity: During critical transients (post-prandial peaks, hypoglycemic events), linear methods exhibit drastically degraded morphological fidelity (DTW), disproportionate to their RMSE -- a phenomenon we term the RMSE Mirage, where low pointwise error masks the destruction of signal shape.(iii)~Regime-Conditional Model Selection: Deep learning models preserve both pointwise accuracy and morphological integrity during transients, making them essential for safety-critical downstream tasks. We further derive empirical missingness distributions from clinical trials and impose them on complete training data, preventing models from exploiting unrealistically clean observations and encouraging robustness under real-world missingness. This framework generalizes to any regulated system where routine stationarity dominates critical transients.

Clinical care often relies on key laboratory indicators, yet real-world patient visits are sparse and tests are ordered irregularly, leading to pervasive missingness. While many imputation methods improve average accuracy, they provide limited guidance on which imputed values are reliable enough for high-stakes downstream use. In this work, we study reliable clinical imputation, aiming to produce accurate imputations while selectively releasing the reliable results, with statistical control over clinically unacceptable errors. To achieve this goal, we propose SafeImpute, a reliable imputation framework for irregular and sparse clinical longitudinal records. SafeImpute constructs an event graph that captures both intra-patient temporal trajectories and inter-patient clinical similarity, and learns imputations with a two-relation GNN and adaptive fusion, regularized by an auxiliary masked reconstruction objective. For reliability guarantees, SafeImpute converts a proxy risk score into conformal p-values and applies the Benjamini--Hochberg procedure to control the false discovery rate (FDR) of unacceptable errors among released imputations at a user-specified tolerance. Experiments on our Mayo Clinic data, the public MIMIC-III and MIMIC-IV datasets show that SafeImpute achieves strong imputation accuracy while providing reliable error control, outperforming diverse baselines in both standard imputation evaluation and FDR-controlled selective-release evaluation.

Laboratory tests in electronic health records are collected irregularly, and the absence of a test order can be as informative as the measurement itself. Such missingness reflects clinicians' decisions and patient physiology, making it important to model it directly rather than treat it as a preprocessing artifact. Here we present a diffusion-based approach for generating clinical time series that jointly models laboratory values and their observation patterns using the public Data Analytics Challenge on Missing Data Imputation (DACMI) benchmark derived from MIMIC-III. To preserve realistic sampling, we align chart times into 4-hour intervals and segment admissions into 7-day windows, producing trajectories that pair each lab value with a corresponding observation indicator. Standard transformations and normalization are applied to stabilize training. Our method extends the TimeDiff framework to learn continuous lab values and discrete missingness patterns through complementary diffusion objectives. Experiments show that the generated data closely match real patient trajectories across individual lab distributions and joint value-missingness embeddings, demonstrating that diffusion models can capture clinically meaningful dependencies between patient physiology and clinicians' testing behavior under MNAR-like (missing-not-at-random) missingness. These preliminary results indicate that our model can serve as an initial component toward developing clinical foundation models. By producing synthetic priors that preserve key physiology-missingness relationships, this work motivates the subsequent training of Prior-Data Fitted Networks capable of leveraging informative missingness, which we will investigate in the extended work.