Daily Papers

Safe Reinforcement Learning (RL) algorithms are typically evaluated under fixed training conditions. We investigate whether training-time safety guarantees transfer to deployment under distribution shift, using diabetes management as a safety-critical testbed. We benchmark safe RL algorithms on a unified clinical simulator and reveal a safety generalization gap: policies satisfying constraints during training frequently violate safety requirements on unseen patients. We demonstrate that test-time shielding, which filters unsafe actions using learned dynamics models, effectively restores safety across algorithms and patient populations. Across eight safe RL algorithms, three diabetes types, and three age groups, shielding achieves Time-in-Range gains of 13--14\% for strong baselines such as PPO-Lag and CPO while reducing clinical risk index and glucose variability. Our simulator and benchmark provide a platform for studying safety under distribution shift in safety-critical control domains. Code is available at https://github.com/safe-autonomy-lab/GlucoSim and https://github.com/safe-autonomy-lab/GlucoAlg.

Deep learning models achieve state-of-the art results in predicting blood glucose trajectories, with a wide range of architectures being proposed. However, the adaptation of such models in clinical practice is slow, largely due to the lack of uncertainty quantification of provided predictions. In this work, we propose to model the future glucose trajectory conditioned on the past as an infinite mixture of basis distributions (i.e., Gaussian, Laplace, etc.). This change allows us to learn the uncertainty and predict more accurately in the cases when the trajectory has a heterogeneous or multi-modal distribution. To estimate the parameters of the predictive distribution, we utilize the Transformer architecture. We empirically demonstrate the superiority of our method over existing state-of-the-art techniques both in terms of accuracy and uncertainty on the synthetic and benchmark glucose data sets.

Continuous glucose monitoring (CGM) provides a dense view of daily metabolic physiology, yet existing generic time-series and CGM-specific foundation models often encode glucose traces as entangled single-stream sequences, leaving the distinct temporal structure of glycemic dynamics only implicitly modeled. We present GlucoFM, a lightweight CGM foundation model that aligns irregular recordings to a 24-hour chronological grid, preserves observation masks, and decomposes glucose dynamics into slow physiological state and transient event streams, capturing low-frequency glycemic baselines and short-term deviations that may reflect acute physiological responses or sensor artifacts. GlucoFM is pretrained on 109,066 hours of unlabeled CGM recordings from 477 subjects with two complementary objectives: masked contextual latent prediction over fused daily representations and temporal dynamics prediction over state and event streams. Across four diverse cohorts and seven clinical prediction tasks, GlucoFM achieves the strongest subject-disjoint linear-probing performance among evaluated baselines, improving average PR-AUC by 4.1 points over the best CGM-specific foundation model. Its gains are most pronounced on core metabolic outcomes, leading PR-AUC on all diabetes-risk and β-cell dysfunction tasks and on 3 of 4 insulin-resistance tasks. GlucoFM also achieves the best overall cross-dataset transfer performance and strong few-shot adaptation among evaluated methods, and consistent gains when aggregating multiple days for subject-level prediction, highlighting physiology-aware decomposition as an effective inductive bias for transferable CGM representation learning.

Precise glucose level monitoring is critical for people with diabetes to avoid serious complications. While there are several methods for continuous glucose level monitoring, research on maintenance devices is limited. To mitigate the gap, we provide a novel neural control system for continuous glucose monitoring and management that uses differential predictive control. Our approach, led by a sophisticated neural policy and differentiable modeling, constantly adjusts insulin supply in real-time, thereby improving glucose level optimization in the body. This end-to-end method maximizes efficiency, providing personalized care and improved health outcomes, as confirmed by empirical evidence.

Continuous Glucose Monitoring (CGM) can detect early metabolic subphenotypes (insulin resistance, IR; β-cell dysfunction), but population-scale deployment faces two coupled problems. First, the same physiological state appears through multiple views (CGM time series, venous OGTT, Glucodensity summaries), so single-view representations fail to transfer when deployment shifts the modality or setting. Second, baselines perform inconsistently across these shifts. Both problems point to one remedy: representations that abstract away from any single view to capture higher-level temporal and distributional structure. We propose CGM-JEPA, a self-supervised pretraining framework which predicts masked latent representations rather than raw values, yielding abstraction that transfers across modalities. X-CGM-JEPA adds a masked Glucodensity cross-view objective for complementary distributional information. We pretrain on sim389k unlabeled CGM readings from 228 subjects and evaluate on two clinical cohorts (N=27 and N=17 public-release subsets) across three regimes (cohort generalization, venous-to-CGM transfer, home CGM) under 20-iteration times 2-fold cross-validation. X-CGM-JEPA ranks first or second on AUROC for both endpoints across all three regimes while no baseline does, exceeding the strongest baseline by up to +6.5 pp in cohort generalization and +3.6 pp in venous-to-CGM transfer (paired Wilcoxon, p<0.001). Under modality shift, it matches mean AUROC while redistributing toward weaker subgroups (ethnicity AUROC gap shrinks 25-54%); on sparse in-domain venous data, the distributional view lifts label-aware clustering (ARI +39%, NMI +40%). Code and weights: https://github.com/cruiseresearchgroup/CGM-JEPA

Postprandial hyperglycemia, marked by the blood glucose level exceeding the normal range after meals, is a critical indicator of progression toward type 2 diabetes in prediabetic and healthy individuals. A key metric for understanding blood glucose dynamics after eating is the postprandial area under the curve (PAUC). Predicting PAUC in advance based on a person's diet and activity level and explaining what affects postprandial blood glucose could allow an individual to adjust their lifestyle accordingly to maintain normal glucose levels. In this paper, we propose GlucoLens, an explainable machine learning approach to predict PAUC and hyperglycemia from diet, activity, and recent glucose patterns. We conducted a five-week user study with 10 full-time working individuals to develop and evaluate the computational model. Our machine learning model takes multimodal data including fasting glucose, recent glucose, recent activity, and macronutrient amounts, and provides an interpretable prediction of the postprandial glucose pattern. Our extensive analyses of the collected data revealed that the trained model achieves a normalized root mean squared error (NRMSE) of 0.123. On average, GlucoLense with a Random Forest backbone provides a 16% better result than the baseline models. Additionally, GlucoLens predicts hyperglycemia with an accuracy of 74% and recommends different options to help avoid hyperglycemia through diverse counterfactual explanations. Code available: https://github.com/ab9mamun/GlucoLens.

We present DM-Bench, the first benchmark designed to evaluate large language model (LLM) performance across real-world decision-making tasks faced by individuals managing diabetes in their daily lives. Unlike prior health benchmarks that are either generic, clinician-facing or focused on clinical tasks (e.g., diagnosis, triage), DM-Bench introduces a comprehensive evaluation framework tailored to the unique challenges of prototyping patient-facing AI solutions in diabetes, glucose management, metabolic health and related domains. Our benchmark encompasses 7 distinct task categories, reflecting the breadth of real-world questions individuals with diabetes ask, including basic glucose interpretation, educational queries, behavioral associations, advanced decision making and long term planning. Towards this end, we compile a rich dataset comprising one month of time-series data encompassing glucose traces and metrics from continuous glucose monitors (CGMs) and behavioral logs (e.g., eating and activity patterns) from 15,000 individuals across three different diabetes populations (type 1, type 2, pre-diabetes/general health and wellness). Using this data, we generate a total of 360,600 personalized, contextual questions across the 7 tasks. We evaluate model performance on these tasks across 5 metrics: accuracy, groundedness, safety, clarity and actionability. Our analysis of 8 recent LLMs reveals substantial variability across tasks and metrics; no single model consistently outperforms others across all dimensions. By establishing this benchmark, we aim to advance the reliability, safety, effectiveness and practical utility of AI solutions in diabetes care.

Diabetes is a chronic condition, considered one of the civilization diseases, that is characterized by sustained high blood sugar levels. There is no doubt that more and more people is going to suffer from diabetes, hence it is crucial to understand better its biological foundations. The essential processes related to the control of glucose levels in the blood are: glycolysis (process of breaking down of glucose) and glucose synthesis, both taking place in the liver. The glycolysis occurs during feeding and it is stimulated by insulin. On the other hand, the glucose synthesis arises during fasting and it is stimulated by glucagon. In the paper we present a Petri net model of glycolysis and glucose synthesis in the liver. The model is created based on medical literature. Standard Petri nets techniques are used to analyse the properties of the model: traps, reachability graphs, tokens dynamics, deadlocks analysis. The results are described in the paper. Our analysis shows that the model captures the interactions between different enzymes and substances, which is consistent with the biological processes occurring during fasting and feeding. The model constitutes the first element of our long-time goal to create the whole body model of the glucose regulation in a healthy human and a person with diabetes.

High quality real world datasets are essential for advancing data driven approaches in type 1 diabetes (T1D) management, including personalized therapy design, digital twin systems, and glucose prediction models. However, progress in this area has been limited by the scarcity of publicly available datasets that offer detailed and comprehensive patient data. To address this gap, we present AZT1D, a dataset containing data collected from 25 individuals with T1D on automated insulin delivery (AID) systems. AZT1D includes continuous glucose monitoring (CGM) data, insulin pump and insulin administration data, carbohydrate intake, and device mode (regular, sleep, and exercise) obtained over 6 to 8 weeks for each patient. Notably, the dataset provides granular details on bolus insulin delivery (i.e., total dose, bolus type, correction specific amounts) features that are rarely found in existing datasets. By offering rich, naturalistic data, AZT1D supports a wide range of artificial intelligence and machine learning applications aimed at improving clinical decision making and individualized care in T1D.

Diabetes mellitus affects over 537 million adults worldwide and remains a major challenge in preventive healthcare. Existing machine-learning studies primarily formulate diabetes prediction as a binary classification problem, while subtype-oriented analysis and glycaemic-cognitive associations remain comparatively underexplored. We present a reproducible three-stage machine learning framework for diabetes detection, subtype-oriented clustering, and metabolic-cognitive association analysis. In Stage 1, five supervised classifiers together with a stacking ensemble are benchmarked on the NCSU Diabetes Dataset using stratified five-fold cross-validation and evaluation metrics including ROC-AUC, balanced accuracy, recall, and F1-score. SVM-RBF and Logistic Regression achieve the highest ROC-AUC (0.825 pm 0.026), while Random Forest achieves the highest accuracy (0.762 pm 0.030). SHAP explainability identifies Glucose, BMI, and Age as the dominant predictive biomarkers. In Stage 2, silhouette-validated K-Means clustering (k=2, silhouette approx 0.116) is applied to confirmed diabetic cases using Glucose, Insulin, and Age, recovering clinically plausible subtype-oriented partitions without requiring ground-truth subtype labels. In Stage 3, statistical analysis of the Ohio Longitudinal Cognitive Dataset (n=373) reveals a significant positive association between glycaemic control and cognitive function (ρ_s = 0.208, p = 5.29 times 10^{-5}), which survives Holm correction. The findings support the utility of statistically grounded and interpretable ML pipelines for reproducible diabetes analytics and subtype-aware exploratory analysis.

Background: Type 1 diabetes (T1D) has seen a rapid evolution in management technology and forms a useful case study for the future management of other chronic conditions. Further development of this management technology requires an exploration of its real-world use and the potential of additional data streams. To facilitate this, we contribute the BrisT1D Dataset to the growing number of public T1D management datasets. The dataset was developed from a longitudinal study of 24 young adults in the UK who used a smartwatch alongside their usual T1D management. Findings: The BrisT1D dataset features both device data from the T1D management systems and smartwatches used by participants, as well as transcripts of monthly interviews and focus groups conducted during the study. The device data is provided in a processed state, for usability and more rapid analysis, and in a raw state, for in-depth exploration of novel insights captured in the study. Conclusions: This dataset has a range of potential applications. The quantitative elements can support blood glucose prediction, hypoglycaemia prediction, and closed-loop algorithm development. The qualitative elements enable the exploration of user experiences and opinions, as well as broader mixed-methods research into the role of smartwatches in T1D management.

Accurate nutrition estimation helps people make informed dietary choices and is essential in the prevention of serious health complications. We present NutriBench, the first publicly available natural language meal description nutrition benchmark. NutriBench consists of 11,857 meal descriptions generated from real-world global dietary intake data. The data is human-verified and annotated with macro-nutrient labels, including carbohydrates, proteins, fats, and calories. We conduct an extensive evaluation of NutriBench on the task of carbohydrate estimation, testing twelve leading Large Language Models (LLMs), including GPT-4o, Llama3.1, Qwen2, Gemma2, and OpenBioLLM models, using standard, Chain-of-Thought and Retrieval-Augmented Generation strategies. Additionally, we present a study involving professional nutritionists, finding that LLMs can provide more accurate and faster estimates. Finally, we perform a real-world risk assessment by simulating the effect of carbohydrate predictions on the blood glucose levels of individuals with diabetes. Our work highlights the opportunities and challenges of using LLMs for nutrition estimation, demonstrating their potential to aid professionals and laypersons and improve health outcomes. Our benchmark is publicly available at: https://mehak126.github.io/nutribench.html

Diabetes, resulting from inadequate insulin production or utilization, causes extensive harm to the body. Existing diagnostic methods are often invasive and come with drawbacks, such as cost constraints. Although there are machine learning models like Classwise k Nearest Neighbor (CkNN) and General Regression Neural Network (GRNN), they struggle with imbalanced data and result in under-performance. Leveraging advancements in sensor technology and machine learning, we propose a non-invasive diabetes diagnosis using a Back Propagation Neural Network (BPNN) with batch normalization, incorporating data re-sampling and normalization for class balancing. Our method addresses existing challenges such as limited performance associated with traditional machine learning. Experimental results on three datasets show significant improvements in overall accuracy, sensitivity, and specificity compared to traditional methods. Notably, we achieve accuracies of 89.81% in Pima diabetes dataset, 75.49% in CDC BRFSS2015 dataset, and 95.28% in Mesra Diabetes dataset. This underscores the potential of deep learning models for robust diabetes diagnosis. See project website https://steve-zeyu-zhang.github.io/DiabetesDiagnosis/

Masked autoencoders (MAEs) are increasingly applied to electronic health records (EHR) for learning general-purpose representations that support diverse clinical tasks. However, existing approaches typically rely on uniform random masking, implicitly assuming all features are equally predictable. In reality, laboratory tests exhibit substantial heterogeneity in volatility: some biomarkers (e.g., sodium) remain stable, while others (e.g., lactate) fluctuate considerably and are more difficult to model. Clinically, volatile biomarkers often signal acute pathophysiology and require more sophisticated modeling to capture their complex temporal patterns. We propose a volatility-aware pretraining strategy, Coefficient of Variation Masking (CV-Masking), that adaptively adjusts masking probabilities according to the intrinsic variability of each feature. Combined with a value-only masking objective aligned with clinical workflows, CV-Masking yields systematic improvements over random and variance-based strategies. Experiments on a large panel of laboratory tests show that CV-Masking enhances reconstruction, improves downstream predictive performance, and accelerates convergence, producing more robust and clinically meaningful EHR representations.

Structured tabular data dominates clinical medicine, yet existing benchmarks fail to reflect real-world properties like complex survey sampling, demographic oversampling, and subgroup fairness. We introduce the NHANES Accelerometry Cardiometabolic Benchmark, derived from NHANES 2003-2006, comprising 1,381 adults with hip-worn accelerometry, fasting laboratory biomarkers, dietary intake, and anthropometrics. We evaluate three tabular learning methods -- ridge regression, XGBoost, and the foundation model TabPFN v2 -- to predict glycated haemoglobin (HbA1c), fasting triglycerides, and C-reactive protein (CRP) from activity phenotypes and lifestyle covariates. TabPFN v2 achieves the best overall performance (HbA1c R^2=0.156, CRP R^2=0.383), while triglycerides remain largely unpredictable (R^2 < 0.05), consistent with known genetic dominance. We apply split conformal prediction to generate distribution-free 90% prediction intervals and evaluate demographic coverage equity across sex and race/ethnicity subgroups. Marginal coverage aligns with the 90% target for CRP and HbA1c but falls below for triglycerides. At the subgroup level, we observe localized undercoverage (e.g., HbA1c for Mexican American participants), illustrating the gap between marginal guarantees and the conditional coverage required for clinical fairness. Code and data are at https://github.com/felizzi/nhanes-accel-cardiometabolic-benchmark.

Blazars, a class of active galactic nuclei (AGN) powered by supermassive black holes, are known for their remarkable variability across multiple timescales and wavelengths. With advancements in both ground- and space-based telescopes, our understanding of AGN central engines has significantly improved. However, the mechanisms driving this variability remain elusive, and continue to fascinate both theorists and observers alike. The primary objective of this study is to constrain the X-ray variability properties of the TeV blazar PKS 2155-304. We conduct a comprehensive X-ray spectral and timing analysis, focusing on both long-term and intra-day variability. This analysis uses data from 22 epochs of XMM-Newton EPIC-pn observations, collected over 15 years (2000-2014). To investigate the variability of the source, we applied both timing and spectral analyses. For the timing analysis, we estimated fractional variability, variability amplitude, minimum variability timescales, flux distribution, and power spectral density (PSD). In the spectral analysis, we fitted the X-ray spectra using power-law, log-parabola, and broken power-law (BPL) models to determine the best-fitting parameters. Additionally, we studied the hardness ratio (HR). We observed moderate intra-day variability in most of the light curves. Seven out of the twenty-two observations showed a clear bimodal flux distribution, indicating the presence of two distinct flux states. Our analysis revealed a variable power-law PSD slope. Most HR plots did not show significant variation with flux, except for one observation (OBSID 0124930501), where HR increased with flux (Count/s). The fitted X-ray spectra favored the BPL model for the majority of observations. The findings of this work shed light on the intraday variability of blazars, providing insights into the non-thermal jet processes that drive the observed flux variations.

Objective digital data is scarce yet needed in many domains to enable research that can transform the standard of healthcare. While data from consumer-grade wearables and smartphones is more accessible, there is critical need for similar data from clinical-grade devices used by patients with a diagnosed condition. The prevalence of wearable medical devices in the diabetes domain sets the stage for unique research and development within this field and beyond. However, the scarcity of open-source datasets presents a major barrier to progress. To facilitate broader research on diabetes-relevant problems and accelerate development of robust computational solutions, we provide the DiaTrend dataset. The DiaTrend dataset is composed of intensive longitudinal data from wearable medical devices, including a total of 27,561 days of continuous glucose monitor data and 8,220 days of insulin pump data from 54 patients with diabetes. This dataset is useful for developing novel analytic solutions that can reduce the disease burden for people living with diabetes and increase knowledge on chronic condition management in outpatient settings.

Deep learning is often criticized by two serious issues which rarely exist in natural nervous systems: overfitting and catastrophic forgetting. It can even memorize randomly labelled data, which has little knowledge behind the instance-label pairs. When a deep network continually learns over time by accommodating new tasks, it usually quickly overwrites the knowledge learned from previous tasks. Referred to as the {\it neural variability}, it is well-known in neuroscience that human brain reactions exhibit substantial variability even in response to the same stimulus. This mechanism balances accuracy and plasticity/flexibility in the motor learning of natural nervous systems. Thus it motivates us to design a similar mechanism named {\it artificial neural variability} (ANV), which helps artificial neural networks learn some advantages from ``natural'' neural networks. We rigorously prove that ANV plays as an implicit regularizer of the mutual information between the training data and the learned model. This result theoretically guarantees ANV a strictly improved generalizability, robustness to label noise, and robustness to catastrophic forgetting. We then devise a {\it neural variable risk minimization} (NVRM) framework and {\it neural variable optimizers} to achieve ANV for conventional network architectures in practice. The empirical studies demonstrate that NVRM can effectively relieve overfitting, label noise memorization, and catastrophic forgetting at negligible costs. Code: \url{https://github.com/zeke-xie/artificial-neural-variability-for-deep-learning.

The identification of heterogeneous treatment effects (HTE) across subgroups is of significant interest in clinical trial analysis. Several state-of-the-art HTE estimation methods, including causal forests, apply recursive partitioning for non-parametric identification of relevant covariates and interactions. However, the partitioning criterion is typically based on differences in absolute risk. This can dilute statistical power by masking variation in the relative risk, which is often a more appropriate quantity of clinical interest. In this work, we propose and implement a methodology for modifying causal forests to target relative risk, using a novel node-splitting procedure based on exhaustive generalized linear model comparison. We present results from simulated data that suggest relative risk causal forests can capture otherwise undetected sources of heterogeneity. We implement our method on real-world trial data to explore HTEs for liraglutide in patients with type 2 diabetes.

Scientific discovery in digital health requires converting continuous physiological signals from wearable devices into clinically actionable biomarkers. We introduce CoDaS (AI Co-Data-Scientist), a multi-agent system that structures biomarker discovery as an iterative process combining hypothesis generation, statistical analysis, adversarial validation, and literature-grounded reasoning with human oversight using large-scale wearable datasets. Across three cohorts totaling 9,279 participant-observations, CoDaS identified 41 candidate digital biomarkers for mental health and 25 for metabolic outcomes, each subjected to an internal validation battery spanning replication, stability, robustness, and discriminative power. Across two independent depression cohorts, CoDaS surfaced circadian instability-related features in both datasets, reflected in sleep duration variability (DWB, ρ= 0.252, p < 0.001) and sleep onset variability (GLOBEM, ρ= 0.126, p < 0.001). In a metabolic cohort, CoDaS derived a cardiovascular fitness index (steps/resting heart rate; ρ= -0.374, p < 0.001), and recovered established clinical associations, including the hepatic function ratio (AST/ALT; ρ= -0.375, p < 0.001), a known correlate of insulin resistance. Incorporating CoDaS-derived features alongside demographic variables led to modest but consistent improvements in predictive performance, with cross-validated ΔR^2 increases of 0.040 for depression and 0.021 for insulin resistance. These findings suggest that CoDaS enables systematic and traceable hypothesis generation and prioritization for biomarker discovery from large-scale wearable data.

Building Virtual Cells that can accurately simulate cellular responses to perturbations is a long-standing goal in systems biology. A fundamental challenge is that high-throughput single-cell sequencing is destructive: the same cell cannot be observed both before and after a perturbation. Thus, perturbation prediction requires mapping unpaired control and perturbed populations. Existing models address this by learning maps between distributions, but typically assume a single fixed response distribution when conditioned on observed cellular context (e.g., cell type) and the perturbation type. In reality, responses vary systematically due to unobservable latent factors such as microenvironmental fluctuations and complex batch effects, forming a manifold of possible distributions for the same observed conditions. To account for this variability, we introduce PerturbDiff, which shifts modeling from individual cells to entire distributions. By embedding distributions as points in a Hilbert space, we define a diffusion-based generative process operating directly over probability distributions. This allows PerturbDiff to capture population-level response shifts across hidden factors. Benchmarks on established datasets show that PerturbDiff achieves state-of-the-art performance in single-cell response prediction and generalizes substantially better to unseen perturbations. See our project page (https://katarinayuan.github.io/PerturbDiff-ProjectPage/), where code and data will be made publicly available (https://github.com/DeepGraphLearning/PerturbDiff).

Dynamic treatment regimes (DTRs) are personalized, adaptive, multi-stage treatment plans that adapt treatment decisions both to an individual's initial features and to intermediate outcomes and features at each subsequent stage, which are affected by decisions in prior stages. Examples include personalized first- and second-line treatments of chronic conditions like diabetes, cancer, and depression, which adapt to patient response to first-line treatment, disease progression, and individual characteristics. While existing literature mostly focuses on estimating the optimal DTR from offline data such as from sequentially randomized trials, we study the problem of developing the optimal DTR in an online manner, where the interaction with each individual affect both our cumulative reward and our data collection for future learning. We term this the DTR bandit problem. We propose a novel algorithm that, by carefully balancing exploration and exploitation, is guaranteed to achieve rate-optimal regret when the transition and reward models are linear. We demonstrate our algorithm and its benefits both in synthetic experiments and in a case study of adaptive treatment of major depressive disorder using real-world data.

Longitudinal modelling of Alzheimer's disease progression is clinically useful only if it can describe not just the most likely next diagnosis, but how a patient may evolve over time and how reliable that forecast is. Most deep learning approaches reduce this problem to single-step classification, treating cognitively normal, mild cognitive impairment, and dementia as flat categories while providing limited insight into how uncertainty accumulates across future visits. We propose a probabilistic framework that combines ordinal diagnosis prediction, multi-horizon trajectory generation, and decomposed uncertainty estimation. A Temporal Fusion Transformer encoder is adapted with a CORAL ordinal output layer, asymmetric loss weighting, and converter oversampling to respect disease-stage ordering and improve sensitivity to MCI-to-dementia transitions. Conditioned on the learned patient-context representation, an autoregressive Mixture Density Network generates five-year probabilistic trajectories for diagnosis state, CDR Sum of Boxes, MMSE orientation, and hippocampal volume. On ADNI, the model outperforms linear, recurrent, and transformer baselines for next-visit diagnosis prediction, with the strongest gains on MCI-versus-dementia discrimination. Generated trajectories achieve near-nominal 90% credible interval coverage, widening uncertainty across the forecast horizon, and biomarker dynamics consistent with expected Alzheimer's disease progression. We further separate aleatoric from epistemic uncertainty using analytic mixture variance and a five-member bootstrap ensemble, which provides the strongest encoder diversity and output-level epistemic signal. Epistemic uncertainty is higher for rare progression archetypes, MCI and dementia patients, and under external evaluation on OASIS-3, where it increases alongside prediction error.

Interrogating the evolution of biological changes at early stages of life requires longitudinal profiling of molecules, such as DNA methylation, which can be challenging with children. We introduce a probabilistic and longitudinal machine learning framework based on multi-mean Gaussian processes (GPs), accounting for individual and gene correlations across time. This method provides future predictions of DNA methylation status at different individual ages while accounting for uncertainty. Our model is trained on a birth cohort of children with methylation profiled at ages 0-4, and we demonstrated that the status of methylation sites for each child can be accurately predicted at ages 5-7. We show that methylation profiles predicted by multi-mean GPs can be used to estimate other phenotypes, such as epigenetic age, and enable comparison to other health measures of interest. This approach encourages epigenetic studies to move towards longitudinal design for investigating epigenetic changes during development, ageing and disease progression.

Molecules are frequently represented as graphs, but the underlying 3D molecular geometry (the locations of the atoms) ultimately determines most molecular properties. However, most molecules are not static and at room temperature adopt a wide variety of geometries or conformations. The resulting distribution on geometries p(x) is known as the Boltzmann distribution, and many molecular properties are expectations computed under this distribution. Generating accurate samples from the Boltzmann distribution is therefore essential for computing these expectations accurately. Traditional sampling-based methods are computationally expensive, and most recent machine learning-based methods have focused on identifying modes in this distribution rather than generating true samples. Generating such samples requires capturing conformational variability, and it has been widely recognized that the majority of conformational variability in molecules arises from rotatable bonds. In this work, we present VonMisesNet, a new graph neural network that captures conformational variability via a variational approximation of rotatable bond torsion angles as a mixture of von Mises distributions. We demonstrate that VonMisesNet can generate conformations for arbitrary molecules in a way that is both physically accurate with respect to the Boltzmann distribution and orders of magnitude faster than existing sampling methods.

Alzheimer's disease (AD) is a degenerative brain disease impairing a person's ability to perform day to day activities. The clinical manifestations of Alzheimer's disease are characterized by heterogeneity in age, disease span, progression rate, impairment of memory and cognitive abilities. Due to these variabilities, personalized care and treatment planning, as well as patient counseling about their individual progression is limited. Recent developments in machine learning to detect hidden patterns in complex, multi-dimensional datasets provides significant opportunities to address this critical need. In this work, we use unsupervised and supervised machine learning approaches for subtype identification and prediction. We apply machine learning methods to the extensive clinical observations available at the Alzheimer's Disease Neuroimaging Initiative (ADNI) data set to identify patient subtypes and to predict disease progression. Our analysis depicts the progression space for the Alzheimer's disease into low, moderate and high disease progression zones. The proposed work will enable early detection and characterization of distinct disease subtypes based on clinical heterogeneity. We anticipate that our models will enable patient counseling, clinical trial design, and ultimately individualized clinical care.

When deploying machine learning models in high-stakes real-world environments such as health care, it is crucial to accurately assess the uncertainty concerning a model's prediction on abnormal inputs. However, there is a scarcity of literature analyzing this problem on medical data, especially on mixed-type tabular data such as Electronic Health Records. We close this gap by presenting a series of tests including a large variety of contemporary uncertainty estimation techniques, in order to determine whether they are able to identify out-of-distribution (OOD) patients. In contrast to previous work, we design tests on realistic and clinically relevant OOD groups, and run experiments on real-world medical data. We find that almost all techniques fail to achieve convincing results, partly disagreeing with earlier findings.

Diabetes is a chronic disease that poses a significant global health burden, and optimizing diabetes management requires multi-stakeholder collaboration. Large language models (LLMs) have shown promise in various healthcare scenarios, but their effectiveness across a diverse range of diabetes tasks remains unproven. In this study, we introduced a framework to train and validate diabetes-specific LLMs. We first developed a comprehensive data processing pipeline that includes data collection, filtering, augmentation and refinement. This approach contributes to creating a high-quality, diabetes-specific dataset, and several evaluation benchmarks entirely from scratch. Utilizing the collected training dataset, we fine-tuned a diabetes-specific LLM family that demonstrated state-of-the-art proficiency in understanding and processing various diabetes tasks compared to other LLMs. Furthermore, clinical studies showed the potential applications of our models in diabetes care, including providing personalized healthcare, assisting medical education, and streamlining clinical tasks. In conclusion, our study introduced a framework to develop and evaluate a diabetes-specific LLM family, and highlighted its potential to enhance clinical practice and provide personalized, data-driven support for diabetes support when facing different end users. The code is provided via GitHub at https://github.com/waltonfuture/Diabetica.

For safety, medical AI systems undergo thorough evaluations before deployment, validating their predictions against a ground truth which is assumed to be fixed and certain. However, this ground truth is often curated in the form of differential diagnoses. While a single differential diagnosis reflects the uncertainty in one expert assessment, multiple experts introduce another layer of uncertainty through disagreement. Both forms of uncertainty are ignored in standard evaluation which aggregates these differential diagnoses to a single label. In this paper, we show that ignoring uncertainty leads to overly optimistic estimates of model performance, therefore underestimating risk associated with particular diagnostic decisions. To this end, we propose a statistical aggregation approach, where we infer a distribution on probabilities of underlying medical condition candidates themselves, based on observed annotations. This formulation naturally accounts for the potential disagreements between different experts, as well as uncertainty stemming from individual differential diagnoses, capturing the entire ground truth uncertainty. Our approach boils down to generating multiple samples of medical condition probabilities, then evaluating and averaging performance metrics based on these sampled probabilities. In skin condition classification, we find that a large portion of the dataset exhibits significant ground truth uncertainty and standard evaluation severely over-estimates performance without providing uncertainty estimates. In contrast, our framework provides uncertainty estimates on common metrics of interest such as top-k accuracy and average overlap, showing that performance can change multiple percentage points. We conclude that, while assuming a crisp ground truth can be acceptable for many AI applications, a more nuanced evaluation protocol should be utilized in medical diagnosis.

When humans read or listen, they make implicit commonsense inferences that frame their understanding of what happened and why. As a step toward AI systems that can build similar mental models, we introduce GLUCOSE, a large-scale dataset of implicit commonsense causal knowledge, encoded as causal mini-theories about the world, each grounded in a narrative context. To construct GLUCOSE, we drew on cognitive psychology to identify ten dimensions of causal explanation, focusing on events, states, motivations, and emotions. Each GLUCOSE entry includes a story-specific causal statement paired with an inference rule generalized from the statement. This paper details two concrete contributions. First, we present our platform for effectively crowdsourcing GLUCOSE data at scale, which uses semi-structured templates to elicit causal explanations. Using this platform, we collected a total of ~670K specific statements and general rules that capture implicit commonsense knowledge about everyday situations. Second, we show that existing knowledge resources and pretrained language models do not include or readily predict GLUCOSE's rich inferential content. However, when state-of-the-art neural models are trained on this knowledge, they can start to make commonsense inferences on unseen stories that match humans' mental models.

Most papers caution against using predictive models for disease stratification based on unselected radiomic features, as these features are affected by contouring variability. Instead, they advocate for the use of the Intraclass Correlation Coefficient (ICC) as a measure of stability for feature selection. However, the direct effect of segmentation variability on the predictive models is rarely studied. This study investigates the impact of segmentation variability on feature stability and predictive performance in radiomics-based prediction of Triple-Negative Breast Cancer (TNBC) subtype using Magnetic Resonance Imaging. A total of 244 images from the Duke dataset were used, with segmentation variability introduced through modifications of manual segmentations. For each mask, explainable radiomic features were selected using the Shapley Additive exPlanations method and used to train logistic regression models. Feature stability across segmentations was assessed via ICC, Pearson's correlation, and reliability scores quantifying the relationship between feature stability and segmentation variability. Results indicate that segmentation accuracy does not significantly impact predictive performance. While incorporating peritumoral information may reduce feature reproducibility, it does not diminish feature predictive capability. Moreover, feature selection in predictive models is not inherently tied to feature stability with respect to segmentation, suggesting that an overreliance on ICC or reliability scores for feature selection might exclude valuable predictive features.

Electroencephalography (EEG) is a cornerstone of brain-computer interfaces and clinical neuroscience, yet deep learning models are typically trained and evaluated under a single, unreported preprocessing pipeline. We formalize preprocessing choices as a counterfactual intervention space and show that EEG predictions are surprisingly unstable under this space: across six datasets spanning four paradigms, up to 42% of trial-level predictions flip when only the preprocessing changes, a variability that standard uncertainty methods do not explicitly quantify because they condition on a fixed preprocessing pipeline. We provide three tools to make this instability measurable, decomposable, and reducible. First, a Walsh-Hadamard decomposition of the 2^7 pipeline space reveals that sensitivity is near-additive in practice under the binary intervention design, enabling efficient step-by-step optimization. Second, we introduce Preprocessing Uncertainty (PU), a per-trial diagnostic that captures a dimension of instability complementary to model-based confidence. Third, we study Normalized Adaptive PGI (NA-PGI), a graph-structured regularizer that exploits the compositional structure of preprocessing interventions as one mitigation strategy with clear scope conditions.

Machine learning (ML) holds great potential for accurately forecasting treatment outcomes over time, which could ultimately enable the adoption of more individualized treatment strategies in many practical applications. However, a significant challenge that has been largely overlooked by the ML literature on this topic is the presence of informative sampling in observational data. When instances are observed irregularly over time, sampling times are typically not random, but rather informative -- depending on the instance's characteristics, past outcomes, and administered treatments. In this work, we formalize informative sampling as a covariate shift problem and show that it can prohibit accurate estimation of treatment outcomes if not properly accounted for. To overcome this challenge, we present a general framework for learning treatment outcomes in the presence of informative sampling using inverse intensity-weighting, and propose a novel method, TESAR-CDE, that instantiates this framework using Neural CDEs. Using a simulation environment based on a clinical use case, we demonstrate the effectiveness of our approach in learning under informative sampling.

We derive an expression for the variation between parallel trajectories in phenotypic evolution, extending the well known result that predicts the mean evolutionary path in adaptive dynamics or quantitative genetics. We show how this expression gives rise to the notion of fluctuation domains - parts of the fitness landscape where the rate of evolution is very predictable (due to fluctuation dissipation) and parts where it is highly variable (due to fluctuation enhancement). These fluctuation domains are determined by the curvature of the fitness landscape. Regions of the fitness landscape with positive curvature, such as adaptive valleys or branching points, experience enhancement. Regions with negative curvature, such as adaptive peaks, experience dissipation. We explore these dynamics in the ecological scenarios of implicit and explicit competition for a limiting resource.

Gaussian process (GP) regression provides a strategy for accelerating saddle point searches on high-dimensional energy surfaces by reducing the number of times the energy and its derivatives with respect to atomic coordinates need to be evaluated. The computational overhead in the hyperparameter optimization can, however, be large and make the approach inefficient. Failures can also occur if the search ventures too far into regions that are not represented well enough by the GP model. Here, these challenges are resolved by using geometry-aware optimal transport measures and an active pruning strategy using a summation over Wasserstein-1 distances for each atom-type in farthest-point sampling, selecting a fixed-size subset of geometrically diverse configurations to avoid rapidly increasing cost of GP updates as more observations are made. Stability is enhanced by permutation-invariant metric that provides a reliable trust radius for early-stopping and a logarithmic barrier penalty for the growth of the signal variance. These physically motivated algorithmic changes prove their efficacy by reducing to less than a half the mean computational time on a set of 238 challenging configurations from a previously published data set of chemical reactions. With these improvements, the GP approach is established as, a robust and scalable algorithm for accelerating saddle point searches when the evaluation of the energy and atomic forces requires significant computational effort.

High-throughput screening techniques are commonly used to obtain large quantities of data in many fields of biology. It is well known that artifacts arising from variability in the technical execution of different experimental batches within such screens confound these observations and can lead to invalid biological conclusions. It is therefore necessary to account for these batch effects when analyzing outcomes. In this paper we describe RxRx1, a biological dataset designed specifically for the systematic study of batch effect correction methods. The dataset consists of 125,510 high-resolution fluorescence microscopy images of human cells under 1,138 genetic perturbations in 51 experimental batches across 4 cell types. Visual inspection of the images alone clearly demonstrates significant batch effects. We propose a classification task designed to evaluate the effectiveness of experimental batch correction methods on these images and examine the performance of a number of correction methods on this task. Our goal in releasing RxRx1 is to encourage the development of effective experimental batch correction methods that generalize well to unseen experimental batches. The dataset can be downloaded at https://rxrx.ai.

Gravitational waves from asymmetric mass-ratio black-hole binaries carry unique information about their astrophysical environment. For instance, the Laser Interferometer Space Antenna (LISA) could potentially measure the amplitude and slope of gas torques in binaries embedded in the accretion disks of Active Galactic Nuclei, helping differentiate competing accretion disk models. However, this relies on simplified analytic models, which do not account for the stochastic variability of torques seen in hydrodynamic simulations. In this work, we use hydrodynamic simulations to create gravitational waveforms for extreme and intermediate mass-ratio inspirals in the LISA band. We then analyze these simulated waveforms using simpler templates that assume analytic torques, without stochastic time variability. By performing realistic Bayesian parameter estimation, we find no bias at 90% confidence in the binary parameters; however, estimates of accretion disk parameters, such as torque amplitude and slope, may be biased. Typically, the posterior distribution is centered around the average value of the torques, but when stochastic variability is large, the posterior can indicate no torques, even though they are present in the simulation. Our results suggest that while simplified analytic torque models work well for estimating binary parameters, caution is needed when using them to infer properties of the accretion disk. This work moves towards a more realistic assessment of one of the LISA science objectives, i.e., probing the properties of the astrophysical environments of black holes.

Human medical data can be challenging to obtain due to data privacy concerns, difficulties conducting certain types of experiments, or prohibitive associated costs. In many settings, data from animal models or in-vitro cell lines are available to help augment our understanding of human data. However, this data is known for having low etiological validity in comparison to human data. In this work, we augment small human medical datasets with in-vitro data and animal models. We use Invariant Risk Minimisation (IRM) to elucidate invariant features by considering cross-organism data as belonging to different data-generating environments. Our models identify genes of relevance to human cancer development. We observe a degree of consistency between varying the amounts of human and mouse data used, however, further work is required to obtain conclusive insights. As a secondary contribution, we enhance existing open source datasets and provide two uniformly processed, cross-organism, homologue gene-matched datasets to the community.

Since their discovery, AGN light curves are known to be intrinsically variable. In the optical/UV band, this variability is consistent with correlated or red noise and is particularly well described by the damped random walk (DRW) model. In this work, we evaluate the feasibility of a new method for identifying spatially unresolved couples of AGN through a fully Bayesian time-domain analysis of the observed light curves (LCs). More specifically, we check whether observed LCs are better described by a single DRW, which we interpret as emitted by a single massive black hole (MBH), or a pair of independent DRWs, generated by a pair of MBHs. We test the method on mock LCs associated with a single MBH and pairs generated with different cadences and lengths of observational campaigns. We constrained the occurrence of false positives, that is, the percentage of single MBH LCs that show substantial evidence in favour of the unresolved MBH pair scenario, finding a fraction of 0.2% and 0.59% in the even and uneven sampling scenarios. We discuss how well the method recovers the model parameters, showing that about 51% and 7% of the simulated LCs have all the recovered parameters within 20% of their true values in our best scenario of evenly sampled LCs for the single MBH and MBH pair scenarios, respectively. We finally study the region of the parameter space in which the detection of an MBH pair is possible, finding that such objects can be correctly identified if the timescales of the process describing the noise are very different, with a ratio smaller than ~0.2, and the variability amplitudes are similar, with their ratio bigger than ~0.2. When limiting to such a region of the parameter space, the fraction of pairs with all the recovered parameters within 20% of the injected values increases up to about 14% and 8% for evenly and unevenly sampled LCs, respectively.

A ubiquitous feature of data of our era is their extra-large sizes and dimensions. Analyzing such high-dimensional data poses significant challenges, since the feature dimension is often much larger than the sample size. This thesis introduces robust and computationally efficient methods to address several common challenges associated with high-dimensional data. In my first manuscript, I propose a coherent approach to variable screening that accommodates nonlinear associations. I develop a novel variable screening method that transcends traditional linear assumptions by leveraging mutual information, with an intended application in neuroimaging data. This approach allows for accurate identification of important variables by capturing nonlinear as well as linear relationships between the outcome and covariates. Building on this foundation, I develop new optimization methods for sparse estimation using nonconvex penalties in my second manuscript. These methods address notable challenges in current statistical computing practices, facilitating computationally efficient and robust analyses of complex datasets. The proposed method can be applied to a general class of optimization problems. In my third manuscript, I contribute to robust modeling of high-dimensional correlated observations by developing a mixed-effects model based on Tsallis power-law entropy maximization and discussed the theoretical properties of such distribution. This model surpasses the constraints of conventional Gaussian models by accommodating a broader class of distributions with enhanced robustness to outliers. Additionally, I develop a proximal nonlinear conjugate gradient algorithm that accelerates convergence while maintaining numerical stability, along with rigorous statistical properties for the proposed framework.

Is it possible to perform linear regression on datasets whose labels are shuffled with respect to the inputs? We explore this question by proposing several estimators that recover the weights of a noisy linear model from labels that are shuffled by an unknown permutation. We show that the analog of the classical least-squares estimator produces inconsistent estimates in this setting, and introduce an estimator based on the self-moments of the input features and labels. We study the regimes in which each estimator excels, and generalize the estimators to the setting where partial ordering information is available in the form of experiments replicated independently. The result is a framework that enables robust inference, as we demonstrate by experiments on both synthetic and standard datasets, where we are able to recover approximate weights using only shuffled labels. Our work demonstrates that linear regression in the absence of complete ordering information is possible and can be of practical interest, particularly in experiments that characterize populations of particles, such as flow cytometry.

This paper introduces a structural equation formulation that gives rise to a new family of quasi-periodic Gaussian processes, useful to process a broad class of natural and physiological signals. The proposed formulation simplifies generation and forecasting, and provides hyperparameter estimates, which we exploit in a convergent and consistent iterative estimation algorithm. A bootstrap approach for standard error estimation and confidence intervals is also provided. We demonstrate the computational and scaling benefits of the proposed approach on a broad class of problems, including water level tidal analysis, CO_{2} emission data, and sunspot numbers data. By leveraging the structural equations, our method reduces the cost of likelihood evaluations and predictions from O(k^2 p^2) to O(p^2), significantly improving scalability.

In order to fully harness the potential of machine learning, it is crucial to establish a system that renders the field more accessible and less daunting for individuals who may not possess a comprehensive understanding of its intricacies. The paper describes the design of a system that integrates AutoML, XAI, and synthetic data generation to provide a great UX design for users. The system allows users to navigate and harness the power of machine learning while abstracting its complexities and providing high usability. The paper proposes two novel classifiers, Logistic Regression Forest and Support Vector Tree, for enhanced model performance, achieving 96\% accuracy on a diabetes dataset and 93\% on a survey dataset. The paper also introduces a model-dependent local interpreter called MEDLEY and evaluates its interpretation against LIME, Greedy, and Parzen. Additionally, the paper introduces LLM-based synthetic data generation, library-based data generation, and enhancing the original dataset with GAN. The findings on synthetic data suggest that enhancing the original dataset with GAN is the most reliable way to generate synthetic data, as evidenced by KS tests, standard deviation, and feature importance. The authors also found that GAN works best for quantitative datasets.