Informative Missingness to Generate Irregular Clinical Time Series
Authors: Hadi Mehdizavareh, Gabriele Santangelo, Giovanna Nicora, Simon Lebech Cichosz, Arianna Dagliati, Arijit Khan, Riccardo Bellazzi
Organizations: Aalborg University, Aalborg, Denmark · University of Pavia, Pavia, Italy · Bowling Green State University, Bowling Green, Ohio, USA
Abstract
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.
Missing data frequently arises across diverse domains, including time-series and image domains. In the real world, missing occurrences often depend on the unobservable values themselves, which are referred to as Missing Not at Random (MNAR). In this work, we introduce the Missing Pattern Recognized Diffusion Imputation Model (PRDIM), a novel framework that explicitly captures the missing pattern and precisely imputes unobserved values. PRDIM iteratively maximizes the likelihood of the joint distribution for observed values and missing mask under an Expectation-Maximization (EM) algorithm. In this sense, we first employ a pattern recognizer, which approximates the underlying missing pattern and provides guidance during every inference toward more plausible imputations with respect to the missing information. Through extensive experiments, we demonstrate that PRDIM consistently achieves strong imputation performance under MNAR settings across multiple data modalities.
Multimodal irregular time series (MITS) consist of asynchronous and irregularly sampled observations from heterogeneous numerical and textual channels. In healthcare, for example, patients' electronic health records (EHR) include irregular lab measurements and clinical notes. The irregular timing and channel patterns of observations carry predictive signal alongside the numerical values and textual content. LLMs are natural candidates for processing such heterogeneous data, given their extensive pretrained knowledge spanning textual and numerical domains. We introduce MILM (Multimodal Irregular time series Language Model), which represents MITS as time-ordered triplets in Extensible Markup Language (XML) format and fine-tunes an LLM through a two-stage strategy for MITS classification. The first stage trains on value-redacted MITS to predict from sampling patterns alone, and the second stage trains on full MITS to jointly model sampling patterns and observed values. Our two-stage model (MILM-2S) and its single-stage counterpart (MILM-Direct) achieve the best and second-best average performance on multiple EHR datasets. Further value redaction evaluations confirm that sampling patterns carry predictive signal and that MILM-2S learns to exploit them. In the value pending evaluation we introduce, where some values are unavailable at prediction time, MILM-2S outperforms MILM-Direct by a larger margin compared to standard evaluation. For MILM-2S, preserving the time and channel of value-pending observations as additional sampling information further improves in-hospital mortality prediction.
In healthcare, multimodal time series tasks often operate on incomplete observations in practice, for example when ECG segments are lost because electrodes detach or an entire respiratory channel is unavailable during overnight monitoring. Such missingness typically appears in two structurally distinct patterns: within-modality missing, where values are absent within an otherwise observed modality, and modality-level missing, where an entire modality is unavailable. Existing methods typically represent unobserved data implicitly through masks or missing embeddings, without learning instance-specific missing information, and most are designed for only one missingness pattern. A natural approach is to explicitly estimate the missing data; however, existing imputation methods treat missingness uniformly despite their different structural priors, and the imputation process is often isolated from downstream tasks, preventing downstream tasks from guiding imputation toward more informative representations. To address these limitations, we present PAMF, a multimodal time-series framework that explicitly handles different missingness patterns while coupling imputation with downstream prediction through prior-aware flow matching and weight sharing. Specifically, the method initializes the flow-matching source state with type-specific priors to distinguish two missing types. It further connects imputation and classification through architecturally matched encoders with weight sharing, transferring task-relevant representations into the imputation process. Experiments on multiple multimodal healthcare time-series benchmarks show that the proposed method achieves the strongest overall downstream performance across diverse datasets and missing settings compared with existing baselines.