A Causal Inference Approach for Evaluating Diagnostic Tests and AI-Enabled Medical Devices: From Effect Modification to Information-Augmented Decision-Making

Diagnostic medical tests and devices provide useful information for evaluating the potential benefits and risks of therapeutic treatments. However, unlike treatments, their impact on health outcomes is generally indirect because measuring diagnostic information typically does not itself affect patient outcomes, which complicates evaluation of their effectiveness. In this work, we develop a causal inference approach for evaluating diagnostic tests by distinguishing explanatory and pragmatic effectiveness. Explanatory effectiveness evaluates whether a diagnostic test result provides treatment-relevant information beyond baseline covariates by explaining additional treatment-effect heterogeneity, which we characterize using a variance-based treatment-effect variable importance measure. Pragmatic effectiveness evaluates whether incorporating this information into personalized treatment decisions improves expected outcomes, a question central to decision-making for patients, clinicians, and other health care stakeholders. We formalize pragmatic effectiveness as a contrast between expected outcomes under optimal personalized treatment rules defined with and without access to the diagnostic test result. We establish identification of the proposed estimand and provide Targeted Maximum Likelihood Estimation (TMLE) and cross-validated TMLE procedures for nonparametric estimation and inference. Simulation studies and a synthetic colorectal cancer application illustrate the proposed estimands and estimation performance. More broadly, this approach provides a causal inference perspective for evaluating AI-enabled devices by distinguishing their dual roles as information-enrichment and personalized decision-optimization tools, clarifying whether AI improves outcomes by expanding information for downstream decisions, improving the decision rule used to act on that information, or through both pathways.

Causal inference for group-contaminated structured outcomes: observable quotients, lossless reduction and exact randomization inference

Structured potential outcomes such as microscopy images may be recorded after an unknown, unit-specific transformation. If that transformation can depend on treatment, covariates or the intrinsic outcome, raw-coordinate analyses may mix biological effects with acquisition geometry. We study the unrestricted observation model X = Γ . Y(A) and characterize its observable information: a target is uniformly recoverable exactly when it is constant on group orbits, while a Borel maximal invariant retains every measurable invariant target. We then distinguish observability from statistical losslessness. A quotient-faithful reconstruction theorem shows that quotient reduction is sufficient for the full transformed experiment exactly when the conditional law of the raw observation given treatment, covariates and the quotient has a parameter-free version. Conditional Haar contamination on a compact group yields Blackwell equivalence as a special case; it is not imposed in the main model. We also separate independent site-specific product actions from shared diagonal actions and show why componentwise canonicalization can discard relative cross-site information. Under explicit metric and kernel regularity, an approximate-contamination theorem bounds quotient-law Wasserstein error and the induced perturbation of population maximum mean discrepancy. For finite-support multichannel lattice images, we construct a maximal invariant under integer translations and quarter turns, combine its characteristic Gaussian kernel with a complete paired-swap test, and retain the original simulations and RxRx1 HUVEC study. Under the sharp null, the quotient test rejected in 0.052 of simulation replicates; at unit effect strength its power was 0.992. The primary RxRx1 contrast had an enumerated paired-swap p-value of 0.0078.

Expert-Guided g-computation with Large Language Models for Estimating Causal Effects on Timings: Applications to Hospital Quality Improvement

Hospital quality improvement (QI) programs routinely face multiple candidate interventions to optimize hospital flow, but existing methods struggle to estimate and rank the causal effects of such interventions. This work focuses on one of the most standard hospital metrics, the average length of stay (LOS), and its causal estimand, the average time saved. To characterize this causal effect, qualitative approaches rely on expert judgment to map patient trajectories, making them susceptible to cognitive biases; quantitative approaches rely on data-driven models, which fail when interventions are hypothetical with no historical data or have complex causal mechanisms that require clinical reasoning rather than data alone. We propose expert-guided g-computation, or egg-computation, which combines the complementary strengths of both approaches by connecting the Gantt charts commonly used to map patient trajectories with the causal DAG literature. We introduce a causal model over Gantt charts and establish identification using a variant of g-computation that seeks expert input only for components unidentifiable from data. To make egg-computation practical, we develop an LLM-assisted pipeline that reliably scales up expert reasoning. In simulations, egg-computation outperforms conventional causal inference methods when patients have diverse causal structures and intervention mechanisms. In a study of eleven candidate QI interventions at an urban safety-net hospital, the LLM pipeline generated graphs and time-saving estimates highly concordant with those of human experts. Beyond healthcare, egg-computation is a broadly applicable framework for estimating the average time saved for candidate interventions whose causal mechanisms can be represented using Gantt charts.

Causal State-Space Model for Causal Inference: Estimating Longitudinal Individual Treatment Effects

Estimating counterfactual outcomes over time from longitudinal observational data is central to clinical decision support. Existing methods rely on domain confusion -- adversarial training that renders representations invariant to treatment assignment -- yet this invariance creates a mutual information conflict: it suppresses treatment-correlated covariate signals necessary for accurate outcome prediction. We formalise this tension via a Jensen-Shannon divergence bound on counterfactual prediction error and develop two complementary models. CSSD (Causal State-Space model with Direct decoder) adapts selective State Space Models with a parallel multi-step decoder that eliminates accumulated rollout error by producing all prediction horizons simultaneously in a single forward pass. CSSPD (Causal State-Space model with Predictive regularisation and Direct decoder) augments CSSD with Contrastive Predictive Coding and Local Information Maximisation to reinforce temporal predictability in the balancing representation and recover local covariate information destroyed by domain confusion. On MIMIC-III, CSSPD achieves lower counterfactual RMSE than the Causal Transformer at every horizon tau >= 2 at O(T) encoder cost, with gains from 0.02 (2-step) to 0.07 (6-step). On Cancer Simulation across confounding strengths gamma in {0,1,2,3,4}, CSSPD outperforms CT at gamma <= 3 (margins 25.9%--37.0%), and CSSD achieves the lowest overall average RMSE (12.7% reduction over CT), confirming the MI conflict analysis. To our knowledge, this is the first work to formalise the balancing-prediction MI conflict and propose a structured resolution through complementary predictive and information-theoretic training objectives.

From Unsupervised Subgroups to Hypothetical State-Intervention Policies: An Evaluation of Selected Subgrouping Methods in Observational Health Data

Conventional subgroup analyses can yield unstable and difficult-to-interpret conclusions, especially in observational biomedical data where each individual is observed under only one exposure state, true individual treatment effects are unavailable, and causal structure is uncertain. We investigate whether subgroups constructed from pretreatment characteristics, without using exposure, outcome, or estimated treatment-effect information, can serve as interpretable units for budget-constrained policy prioritization. We propose a framework combining causal-discovery-informed covariate selection, discovery-evaluation sample splitting, inductive unsupervised clustering, uncertainty-aware subgroup selection, and held-out doubly robust policy evaluation. We compare K-means, hard, membership-weighted, and stochastic Fuzzy C-means, Bayesian Gaussian mixture models, and a supervised causal-forest-derived CATE-tree comparator. Policies are evaluated under a 70% budget for hypothetical obesity-to-non-obesity and elevated-to-lower-glucose state shifts in the PIMA Indians Diabetes dataset and for a lifetime-smoking-history contrast in NHANES. The highest estimated ungated utilities were 0.799 for the BMI policy using Bayesian GMM, 0.735 for the glucose policy using hard or membership-weighted FCM, and 0.775 for the smoking-history policy using K-means. All paired 95% confidence intervals for policy-risk differences included zero, and no comparison remained statistically significant after Holm adjustment. Bayesian pooling generally preserved ungated allocations, whereas Empirical Bernstein gating was more conservative. Policies with similar estimated utility could nevertheless prioritize different individuals. The findings should be interpreted as assumption-dependent decision-support evidence for hypothetical state contrasts rather than proof of intervention benefit.

PerturbPFN: Probing the Limits of Synthetic Priors in Drug Perturbation Modelling

Predicting cellular responses to unseen chemical perturbations is challenging due to unknown targets and mechanisms, high-dimensional expression responses, and limited experimental coverage of the large small-molecule design space. We propose PerturbPFN, a PFN-style amortized model for unknown-target perturbation prediction under a hierarchical synthetic structural prior. Instead of directly regressing high-dimensional expression responses, PerturbPFN infers a latent system graph, sparse atomic intervention targets, and intervention strengths, then propagates their effects through an SCM decoder. The model is trained entirely on prior-predictive synthetic episodes generated from biologically motivated graph and expression simulators, enabling structured in-context learning without test-time gradient updates. We evaluate PerturbPFN on both real single-cell perturbation data and synthetic benchmarks, covering effect prediction, target identification, and regulatory structure discovery. Our results show that PerturbPFN offers a complementary trade-off to specialized baselines, achieving competitive perturbation prediction with low inference cost while exposing interpretable intermediate estimates of targets, strengths, and system structure.

Demonstration of the common dual-channel feature decoupling characteristic of front-door mediation causal inference methods in whole-slice image classification

Causal inference using front door intervention and multi-instance learning (MIL) has advanced the analysis of Whole Slide Images (WSI) in digital pathology. These methods adjust feature distributions of subtle evidence sub-images to correctly associate them with WSI-level diagnoses. We propose and prove 2 hypotheses for evaluating such methods: 1) Causal inference MIL introduces an independent classification channel that effectively completes WSI classification; 2) Greater difference between features extracted by the new and baseline channels increases effectiveness in eliminating false correlations. This hypothesis describes the core of causal inference MILs: overlaying parallel, independent channels to eliminate false associations between WSI-level diagnostic and non-diagnostic evidence sub-images by increasing deep feature diversity. Based on these hypotheses, we evaluated several causal inference MILs on breast cancer and non-small cell lung cancer datasets. This hypothesis provides a new theoretical perspective for applying causal inference to WSI analysis.

Psych-ECA: A Reproducible Semi-Synthetic Benchmark for Synthetic Control Arms in Longitudinal Psychiatry

External and synthetic control arms (ECAs) are entering psychiatric drug development, but the field lacks a benchmark that evaluates the properties regulators care about: not only how accurately a method reconstructs untreated trajectories, but whether its uncertainty is calibrated, whether it is robust to the informative observation times common in mental-health records (sicker patients are seen more often), and what false-positive rate it induces in go/no-go trial decisions. Real psychiatric trial data (e.g. STAR-D and registry cohorts) require credentialed access and lack ground-truth counterfactuals, so, following established semi-synthetic benchmarks in causal inference (IHDP, ACIC, and the PK-PD tumor-growth simulator), we release Psych-ECA, a fully reproducible generator of longitudinal symptom trajectories for depression (PHQ-9), anxiety (HAM-A), and psychosis (PANSS) with known counterfactual control arms, informative visits, and validated-scale measurement noise. We benchmark eight estimators spanning carry-forward, pooled real-world-data averages, nearest-neighbour matching, linear mixed models, gradient boosting, and the Scribe trajectory-bridge method. Three findings emerge. First, trajectory and flexible machine learning methods achieve the best counterfactual accuracy (about 2.3 PHQ-9 RMSE), outperforming cross-sectional baselines. Second, only Scribe is both accurate and calibrated, achieving 93-96% empirical coverage of nominal 90% prediction intervals, compared with 87-88% for gradient boosting and 62-75% for uncalibrated SDE models. Third, inverse-intensity correction reduces bias under informative sampling, while Scribe's calibrated intervals are the only trajectory method that maintains nominal false-positive rates as informativeness increases. We release all code, data-generation scripts, and random seeds to enable fully reproducible evaluation.

Beyond travel mode: urban context shapes active mobility's mental health effects over time

Active mobility is widely promoted for sustainable and healthier living, but whether it translates into equitable mental health benefits across individuals and places over time remains unknown. Using causal machine learning and causal deep learning in 264168 UK adults, we find substantial inequalities in individualized effects of active mobility on anxiety, depression, and common mental disorders. These inequalities widen over time and are strongly structured by urban context. For example, anxiety risk at follow-up ranges from a 40.6% reduction to a 10.1% increase across individuals, versus a 10.4% reduction to a 0.1% increase at baseline. Benefits are greatest in greener, safer, less polluted, and less deprived neighborhood environments, with 81.8% of individuals experiencing above-average benefits and mean anxiety risk reduced by 26.4%, versus 10.4% of individuals and 7.4% reduction in the least supportive environments. Urban compact form further modifies these effects through nonlinear interactions with neighborhood environments, amplifying benefits only under supportive conditions. Despite these strong environmental gradients, genetic moderation is negligible.

CIPHER: Causal Intervention Pathways for Healthcare Equity and Robustness

Deep learning models for medical diagnosis frequently exhibit substantial performance disparities across sensitive subgroups (e.g., race, sex), even when average accuracy is high. While generative data augmentation offers a route to mitigate this, existing strategies are suboptimal; they typically address only one or two dependency channels between sensitive attributes and image features. We formalize the medical image formation process via a structural causal model, revealing that sensitive attributes actually influence image content through four distinct pathways-a structural complexity neglected by prior works. Based on this insight, we introduce CIPHER (Causal Intervention Pathways for Healthcare Equity and Robustness), a framework designed to systematically intervene on all four causal paths. To achieve this, CIPHER utilizes a diffusion backbone equipped with classifier-free guidance and null-text inversion. This technical design enables the faithful reconstruction of patient-specific anatomy while allowing for the precise, editable synthesis of counterfactuals required to break sensitive dependency chains. We tested CIPHER using chest X-ray and dermoscopy benchmarks across both standard and shifted data distributions. By employing a multi-pathway intervention strategy, our model reduced worst-group disparities by an average of 35.8% compared to disease-conditioned synthesis baselines, while also improving total diagnostic accuracy

AI-Assisted Causal Inference and Mediation Analyses of Environmental and Psychosocial Determinants of Subjective Cognitive Difficulties in the All of Us Research Program

Short-term environmental exposures have been linked to cognitive and behavioral outcomes, although many reported associations may reflect broader geographic and contextual differences. Using longitudinal data from the All of Us Research Program (2018--2024), we linked daily weather and air-pollution exposures to repeated attention-related and subjective cognitive outcomes. Associations were evaluated using pooled, fixed-effects, lagged, and event-study analyses. Additional machine-learning analyses were conducted to explore potential heterogeneity and latent psychosocial structure. Replication analyses were performed using the 2024 Behavioral Risk Factor Surveillance System (BRFSS). Several environmental exposure measures showed small associations with cognitive outcomes in pooled analyses, but most attenuated substantially after accounting for within-location temporal variation. Mediation, sensitivity, and machine-learning analyses yielded similar conclusions. In contrast, mental-health burden, loneliness, and social functioning were consistently associated with subjective cognitive difficulty and exhibited substantially larger effect sizes than environmental exposures. Similar patterns were observed in BRFSS. Exploratory AI-assisted analyses yielded findings broadly consistent with the primary longitudinal analyses. These findings suggest that short-term environmental perturbations may have limited associations with cognitive outcomes after accounting for within-location variation, whereas psychosocial factors appear to be more consistently associated with subjective cognitive burden.

Estimating Treatment Effects for Depression in Longitudinal Therapy Switching Settings

Depression treatment often requires switching medications due to inadequate response or adverse effects. Estimating individualized treatment effects in this setting is challenging because treatment assignment is confounded by patient characteristics, switching induces time-varying selection, and counterfactual outcomes are not observed in follow-up data. Using a proprietary longitudinal major depressive disorder (MDD) clinical trial dataset, we formulate a next-visit counterfactual prediction task to estimate Hamilton Depression Rating Scale (HAMD-17) total scores under alternative treatments. We benchmark 8 estimators, including meta-learners, residual-based methods, and tree-based approaches. Causal Forest (CF) demonstrates the most favorable and consistent performance across all criteria. Our analysis shows that symptom benefits concentrate in specific switch directions, with dose intensification being generally beneficial. Notably, we identify a counterintuitive exception where a lower-intensity regimen outperforms a higher-intensity alternative for specific patient subsets. While crude observational comparisons substantially overstate gains, confounding-adjusted estimates yield modest, actionable magnitudes. These findings provide prospectively testable candidates for clinical decision support in depression care.

The Critical Role of Model Selection in Causal Inference: A Comparative Analysis of Classification Models within the InferBERT Framework for Pharmacovigilance

Distinguishing causal adverse drug events (ADEs) from spurious correlations remains a central challenge in pharmacovigilance. The InferBERT framework integrates transformer models with Do-calculus, but its success hinges on the underlying classification model. This study evaluates the impact of model choice in InferBERT, assessing whether simpler models suffice, if domain-specific pre-training helps, whether scaling to LLMs improves causal detection, and the effect of post-hoc calibration. We performed a comparative study on two benchmarks: Analgesics-induced Acute Liver Failure (AILF) and Tramadol-related Mortalities (TRAM). Four models were evaluated-XGBoost (baseline), ALBERT (original InferBERT), BioBERT (biomedical transformer), and Med-LLaMA (medical LLM)-using 5-fold cross-validation repeated over 20 runs. We measured accuracy, Expected Calibration Error (ECE) pre- and post-isotonic regression, and Jaccard concordance of causal terms with PRR, ROR, and EBGM; significance was tested with paired t-tests. BioBERT achieved the highest accuracy on both datasets, while Med-LLaMA underperformed despite its size and parameter-efficient fine-tuning. Domain-specific pre-training was decisive. Calibration improved ECE but had mixed effects on accuracy and causal discovery. BioBERT's superiority also yielded the strongest concordance with traditional pharmacovigilance signals. These results show that domain-specific pre-training provides a clear advantage over simpler baselines and larger LLMs. Investing in manageable, domain-aware models is more effective for computational pharmacovigilance than simply scaling model size.

Bayesian Networks with Latent Time Embedding for Stage-Aware Causal Modeling of Alzheimer's Disease Progression

Alzheimer's disease (AD) progression is often described through the amyloid-tau-neurodegeneration, or AT(N), cascade. However, most longitudinal models represent this cascade either as a fixed sequence of biomarkers or as a black-box forecasting task. This makes it difficult to determine when biologically guided biomarker relationships influence future regional pathology. In this study, we introduce Bayesian Networks with Latent Time Embedding (BN-LTE), a Bayesian structural framework for stage-aware modeling of AD progression. BN-LTE estimates disease pseudotime from baseline biomarker profiles and constrains directed dependencies according to biologically plausible AT(N) ordering. Posterior spline-varying structural equations are then used to link initial multimodal measurements with future annualized regional tau-PET change. Across repeated subject-disjoint evaluations using ADNI data, BN-LTE shows strong spatial reconstruction of tau progression compared with the included forecasting baselines. Beyond spatial reconstruction, BN-LTE recovers posterior stage-varying AT(N)-constrained effects and identifies a mid-pseudotime window of amyloid sensitivity. This window is supported by model-implied g-formula contrasts, root-adjusted AIPW, mechanism-sensitive ablations, and robustness analyses across spline and prior specifications. Overall, these findings position BN-LTE as a Bayesian structural framework for forecasting tau progression while examining stage-dependent AT(N)-cascade mechanisms in observational longitudinal neuroimaging data. Our code is available at https://github.com/danleneurocom/BN-LTE.

Is It You or Your Environment? A Bayesian Inference Framework for Genomically-Anchored Personalized Physiological Interpretation

Personalized health AI systems face a fundamental cold-start problem: machine learning models for physiological interpretation require weeks of individual behavioral data before they can distinguish constitutional variation from environmentally driven deviation. We propose a solution grounded in causal inference and Bayesian prior design. An individual's genomic profile serves as an exogenous genetic anchor -- a domain-informed, personalized prior that is fixed at conception, immune to reverse causation, and available before a single behavioral observation is collected. The anchor initializes a Bayesian belief state over an individual's physiological set point G-hat = mu + sum(beta_i * g_i), where beta_i are GWAS-derived effect sizes and g_i are risk-allele counts. Each incoming physiological measurement P produces a non-constitutional deviation delta = P - G-hat that separates the signal attributable to environment and state from the constitutionally fixed baseline. As behavioral data accrue, the prior decays according to G-hat_t = w(t)*G-hat_genomic + [1-w(t)]*P-bar_t, transitioning from genome-dominated to empirical-baseline-dominated inference. The same observed HRV of 55 ms generates a suppression hypothesis for a person whose prior predicts 80 ms, and an enhancement hypothesis for a person whose prior predicts 30 ms -- a reversal impossible without a personalized anchor. We develop this architecture across six physiological domains, grading genomic priors by evidence strength, distinguishing robustly replicated anchors (FTO, FADS1/2, FKBP5) from contested candidate genes (SLC6A4, MAOA, DRD2). We address the inference boundary between association, Mendelian randomization, and individual token causation, and define four constraints for deployment: evidence-graded priors, dynamic decay, ancestry-matched effect sizes, and attribution rather than deterministic output.

Estimating Individualized Treatment Effects in Acute Ischemic Stroke with Causal Transformation Models (TRAM-DAG): A Multi-Centre Observational Study with External RCT Validation

Personalized medicine in acute ischemic stroke requires moving beyond average treatment effects (ATE) to individualized treatment effect (ITE) estimates to support treatment decisions. In acute ischemic stroke, mechanical thrombectomy has been shown to be more effective on average than lysis in randomized controlled trials (RCTs), such as the MR CLEAN study. We aim to identify which individual patients benefit most from mechanical thrombectomy compared to lysis. The outcome of interest is the modified Rankin Scale (mRS) at three months, an ordinal measure of functional disability (0: no symptoms, 6: death). We demonstrate that causal transformation models on directed acyclic graphs (TRAM-DAG) can be used for ITE estimation after being fitted on observational MAGIC multi-center stroke patient data. To ensure comparability with the MR CLEAN population, which we use for validation, we train the TRAM-DAG on a MAGIC sub-population with NIHSS at admission >= 6, corresponding to one inclusion criterion of MR CLEAN. The fitted model is then used to estimate ITEs for stroke patients in the MR CLEAN population. While these ITE estimates cannot be confirmed experimentally, we show that their average is consistent with the trial's reported ATE. Furthermore, the ITE estimates correctly rank trial patients by their observed frequency of a good outcome (mRS at three months <= 2). These findings support the use of causal models like TRAM-DAG for personalized decision-making in stroke care and highlight their ability to bridge the gap between observational evidence and clinical trials.

Artemis: Anatomy-Resolved inTervention for Eliminating Multimodal NeuroImage confounderS

Multimodal neuroimaging, integrating functional connectivity from fMRI and structural connectivity from DTI, enables non-invasive analysis of brain networks using graph neural networks. However, demographic factors such as age and sex systematically confound the relationship between brain connectivity and clinical outcomes, causing GNNs to exploit spurious shortcuts rather than learning causally invariant representations. While recent causal GNN methods introduce causality at the graph-modeling level, their causal mechanisms remain domain-agnostic without accounting for the real-world confounders inherent in clinical neuroimaging data. Moreover, brain networks are constructed from atlas-based parcellations where each region exhibits distinct sensitivity to demographic factors, necessitating region-aware adjustment. We propose Artemis, a region-level causal framework that bridges this gap with causal intervention at each brain region independently by learning region-specific confounder representations with lightweight parameters. Our adjustment comprehensively utilized the multimodal functional and structural features for graph reasoning as a plug-in module compatible with arbitrary GNN backbones. Experiments on three benchmarks, ADNI for disease diagnosis, OASIS for dementia staging, and HCP for sex classification, demonstrate consistent improvements over representative GNN-based baselines. Multiple supporting experiments further demonstrate statistical significance and neuroscientific interpretability.

MEC-Cox: Machine-Learning-Assisted Generalized Entropy Calibration for ATT Marginal Hazard-Ratio Estimation

Externally controlled survival trials are increasingly used when concurrent randomized controls are infeasible, particularly in oncology and rare-disease settings with time-to-event endpoints. We target an average-treatment-effect-on-the-treated (ATT)-type marginal hazard-ratio estimand, comparing treatment with counterfactual control in the treated trial population, and estimate it using inverse-probability-weighted (IPW) Cox regression. Valid inference is challenging because IPW Cox regression depends on the weights through both event contributions and risk-set averages, making flexible machine-learning nuisance estimation difficult to incorporate directly. Building on machine-learning-assisted generalized entropy calibration (MEC) by Lee and Kim (2026), we propose MEC-Cox for ATT-weighted IPW Cox regression. The method begins with normalized source-propensity-score odds weights for external controls and then applies Bregman calibration to balance cross-fitted prognostic summaries between external controls and treated trial patients. The calibration basis may include control-survival predictions, Cox linear predictors, penalized-survival-model predictions, or other prognostic-score summaries. MEC-updated weights therefore play a dual role as source-transport and prognostic-score balancing weights. We establish consistency, characterize a calibration-induced efficiency gain, and develop a stacked sandwich variance estimator. Simulations show that MEC-Cox can reduce bias, increase efficiency, and improve coverage through flexible machine-learning-assisted adjustment.

Causal Longitudinal Prior-Fitted Networks for Counterfactual Outcome Prediction

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.

Scalable Counterfactual Risk Estimation for Rare Events in Longitudinal Data

Estimating the causal effect of time-varying treatments on survival outcomes in large observational studies is computationally demanding, particularly when outcomes are rare. While g-formula-based methods such as the iterative conditional expectation (ICE) estimator provide a principled framework for longitudinal causal inference, they become computationally expensive, especially when bootstrap-based variance estimation is required. In addition, outcome rarity at each time point induces severe class imbalance, leading to instability and convergence issues in logistic regression and related models. To address these challenges, we propose a principled subsampling and reweighting strategy for longitudinal survival data that can be applied to a range of existing causal effect estimators in this setting, including the ICE estimator. The proposed method substantially reduces computational burden while preserving consistency and improving estimation stability in rare-outcome settings. We evaluate the method through simulations and validate it using a large-scale EHR cohort study on social and behavioral determinants of health (SBDH) and suicide risk, demonstrating its effectiveness for modeling rare outcomes in longitudinal data.

From Baseline to Follow-Up: Counterfactual Spine DXA Image Synthesis in UK Biobank Using a Causal Hierarchical Variational Autoencoder

Dual-energy X-ray absorptiometry (DXA) is widely used for large-scale skeletal assessment, yet learning controllable and interpretable factor-specific anatomical variation remains challenging. We propose a metadata-conditioned causal hierarchical variational autoencoder (CHVAE) for causally consistent generation of anteroposterior (AP) spine DXA images from the UK Biobank (UKB). The model is trained on 3,743 raw AP spine scans from the first imaging visit and conditioned on basic participant attributes and lumbar morphometry. Causal consistency is evaluated in a baseline-to-follow-up setting using abduction--action--prediction (AAP): latent variables are abducted from baseline images, age is intervened to the repeat-imaging value, and the resulting counterfactual follow-up morphometry is compared with observed repeat-imaging measurements. Results show strong absolute-level agreement for key vertebral morphometry variables under age intervention, supporting intervention-aligned synthesis of anatomically plausible DXA images.

Can Breath Biomarkers Causally Influence Blood Glucose? Investigating VOC-Mediated Modulation in Diabetes

Diabetes is a global health burden, and early detection is critical for timely intervention. This study explores a non-invasive, data-driven framework to identify individuals at risk of diabetes using Volatile Organic Compounds (VOCs) and lifestyle variables. We use causal inference techniques to estimate the impact of VOCs such as acetone, isopropanol, isoprene, and ethanol on blood glucose levels. Additionally, we designed a classifier to distinguish diabetics from non-diabetics using non-invasive markers. We created a risk-based ranking system for individuals in the "gray zone," and identified natural clusters in the population using Gaussian Mixture Model. Our results suggest that specific VOCs exhibit a strong causal influence on glucose levels and that machine learning models can reliably classify and stratify individuals at high risk. This integrated causal-explainable analysis can support the development of tool for non-invasive early screening of diabetes.

Causal Machine Learning Is Not a Panacea: A Roadmap for Observational Causal Inference in Health

Objective: The growing availability of large-scale observational clinical datasets and challenges in conducting randomized controlled trials have spurred enthusiasm in using causal machine learning (ML) for causal inference in observational data. We present a roadmap for applying causal ML to observational data. Materials and methods: We outline the importance of assessing validity assumptions within available data and applying causal ML responsibly for clinical experts using causal ML and ML practitioners with limited clinical expertise. Observations: Despite advances in causal ML, its limitations remain largely under-appreciated across disciplines. This gap in shared knowledge may impact the validity of findings. Discussion: Causal assumptions must be satisfied and modeling choices justified. Otherwise, these approaches risk producing biased or misleading results, with consequences for clinical research and patient care. Conclusion: Causal ML can be a powerful tool for generating causal hypotheses. We provide a template to strengthen the rigor and interpretability of causal analyses.

Joint Treatment Effect Estimation from Incomplete Healthcare Data: Temporal Causal Normalizing Flows with LLM-driven Evolutionary MNAR Imputation

Target trial emulation (TTE) enables causal questions to be studied with observational data when randomized controlled trials (RCTs) are infeasible. Yet treatment-effect methods often address causal estimation, missingness, and temporal structure separately, limiting their robustness in electronic health records (EHRs), where time-varying confounding and missing-not-at-random (MNAR) biomarkers can reach 50%--80%. We propose a two-stage pipeline for treatment effect estimation from incomplete longitudinal EHRs. First, CausalFlow-T, a directed acyclic graph (DAG)-constrained normalizing flow with long short-term memory (LSTM)-encoded patient history, performs exact invertible counterfactual inference, avoiding approximation errors from variational inference and separating confounding through explicit causal structure. Ablations on four synthetic and one semi-synthetic benchmark with known counterfactuals show that DAG constraints and exact inference address distinct failure modes: neither compensates for the other. Second, because CausalFlow-T requires completed inputs, we introduce an LLM-driven evolutionary imputer that proposes executable imputation operators rather than individual entries, and evaluate it with three large language model (LLM) backends, including two open-source models. Across 30%--80% MNAR missingness, this imputer achieves the best pooled rank over biomarker and causal metrics, leading in point-wise accuracy and temporal extrapolation while preserving average treatment effect (ATE) recovery as statistical baselines degrade. On Swiss primary-care EHRs from adults with type 2 diabetes initiating a GLP-1 receptor agonist or SGLT-2 inhibitor, the pipeline estimates a per-protocol weight-loss difference of -0.98 kg [95% CI -1.01, -0.96] favoring GLP-1 receptor agonists, consistent with randomized evidence and obtained from realistically incomplete real-world EHRs.

When Does Gene Regulatory Network Inference Break? A Controlled Diagnostic Study of Causal and Correlational Methods on Single-Cell Data

Despite theoretical advantages, causal methods for Gene Regulatory Network (GRN) inference from single-cell RNA-seq data consistently fail to match or outperform correlation-based baselines in many realistic benchmarks, a persistent puzzle which casts doubt on the value of causality for this task. We argue that existing benchmarks are insufficiently controlled to answer this question because they evaluate on real or semi-real data where multiple pathologies co-occur, confounding failure modes, and obscuring the specific conditions under which different inference methods excel or fail. To address this gap, we introduce a controlled diagnostic framework that isolates seven biologically motivated pathologies (dropout, latent confounders, cell-type mixing, feedback loops, network density, sample size, and pseudotime drift) and measure how six representative methods spanning three inference paradigms degrade as each pathology intensifies. Across 6,120 controlled experiments, we find that causal methods genuinely dominate in clean and structurally favorable regimes, but specific pathologies (notably dropout and latent confounders) selectively neutralize their advantages. We further introduce an error-type decomposition that reveals methods with similar aggregate accuracy commit qualitatively different errors. To probe whether single-pathology effects persist when multiple stressors co-occur, we perform an interaction sweep over the three most impactful pathologies and find that their joint effects are sub-additive, while also exposing density-conditional cross-overs invisible to single-dial analysis. Our findings offer a nuanced understanding of when and why different methods succeed or fail for GRN inference, providing actionable insights for method development and practical guidance for practitioners.

TrialCalibre: A Fully Automated Causal Engine for RCT Benchmarking and Observational Trial Calibration

Real-world evidence (RWE) studies that emulate target trials increasingly inform regulatory and clinical decisions, yet residual, hard-to-quantify biases still limit their credibility. The recently proposed BenchExCal framework addresses this challenge via a two-stage Benchmark, Expand, Calibrate process, which first compares an observational emulation against an existing randomized controlled trial (RCT), then uses observed divergence to calibrate a second emulation for a new indication causal effect estimation. While methodologically powerful, BenchExCal is resource intensive and difficult to scale. We introduce TrialCalibre, a conceptualized multiagent system designed to automate and scale the BenchExCal workflow. Our framework features specialized agents such as the Orchestrator, Protocol Design, Data Synthesis, Clinical Validation, and Quantitative Calibration Agents that coordi-nate the the overall process. TrialCalibre incorpo-rates agent learning (e.g., RLHF) and knowledge blackboards to support adaptive, auditable, and transparent causal effect estimation.

Dialysis Risk Prediction and Treatment Effect Estimation for AKI patients using Longitudinal Electronic Health Records

Progression to dialysis or end-stage renal disease is a rare but clinically important outcome. Clinicians need evidence on how medication exposures influence downstream risk. We constructed a fixed-window EHR cohort (90-day observation, 730-day prediction; N=81401; dialysis/ESRD prevalence: 1.1%) and modeled sequences of diagnoses, procedures, and medications with kidney laboratory trends (creatinine, BUN, eGFR). A transformer-based causal multi-head model was trained to estimate drug- and ingredient-level average treatment effects (ATEs) using counterfactual exposure removal and insertion under a full medication history setup. On test set, predictive performance reached an AUC of 0.694 and PR-AUC of 0.094. At the selected decision threshold (0.883), the model achieved an F1 score of 0.201 with a Brier score of 0.018. Post-hoc causal analyses of lab changes (eGFR, creatinine, BUN) using IPTW, AIPW, naive, and covariate-adjusted OLS methods assessed clinical directionality. Results showed partial protective-direction support for ACE/ARB exposures and worsening-direction signals for loop diuretics.