We propose a novel method of understanding disease transformation from a healthy baseline with biomarker-level explainability. By modeling the biomarker covariance matrices of healthy controls and disease states, the perturbation can be individually characterized to accomplish mechanistic explanations of disease trajectories, both at a molecular level and for individual patients. Given a cohort of n patients each measured on p biomarkers, we define the biomarker "Hamiltonian" H = X^T X / n \in R^{p \times p}, where X \in R^{n \times p} is the covariant biomarker matrix. The eigenvectors of H define a set of normal modes of biomarker coordination, and the eigenvalues quantify the energy carried by each mode. In the healthy state, the reference Hamiltonian H_0 governs this structure where disease perturbs H_0 by an additive operator ΔH, thus shifting eigenvalues and rotating eigenvectors in proportion to the severity of pathological disruption. We formalize this framework, derive the spectral change given a disease perturbation, and demonstrate that the projection of a newly diagnosed patient's cumulative biomarker covariance structure onto disease-discriminant eigenmodes constitutes an optimal prognostic statistic for greater precision in disease prognosis. This work serves as a veritable white paper with application across a panoply of disease frameworks from cancer to neurodegenerative disorders.

This manuscript contains preprint of a chapter under consideration for inclusion in the forthcoming third edition of {\em Cover and Thomas's Elements of Information Theory}, posted with permission from Wiley. The table of contents EIT-3 ToC of the new edition can be found at: https://docs.google.com/document/d/1L-m4oQEJw1PJhoxBeMwrrBD8S_HmvzMEkPbYvS24980/edit?usp=sharing . For feedback, please contact abbas@ee.stanford.edu Learning and information theory intersect in both model training and the characterization of fundamental performance limits. This manuscript provides a concise and accessible treatment of the first intersection, requiring only basic background in information theory and statistics at the senior undergraduate or first-year graduate level. End-of-chapter exercises make the material well suited for classroom use as well as self-study. The chapter focuses on the role of divergence measures in model training, with examples ranging from linear and logistic regression to autoregressive models, variational autoencoders, diffusion models, generative adversarial networks, and score-based models. It introduces the evidence lower bound (ELBO), $f$\!-divergences, and the Fisher divergence. In particular, the treatment of the generative diffusion model provides a more systematic and explicit derivation than is typical in the literature.

Conformal prediction provides distribution-free predictive intervals with finite-sample marginal coverage. However, achieving conditional validity and interval efficiency (in terms of short interval length) remains challenging, particularly in complex settings with heteroskedasticity, skewed responses, or estimation errors. We propose a conformal-style calibration method for responses obtained by the probability integral transform (PIT) of the conditional cumulative distribution function (CDF) estimated via neural networks to construct a finite-sample-adjusted percentile interval with the shortest length determined by the estimated conditional CDF. Calibrating in PIT space is effective because PIT values are asymptotically feature-independent when the CDF estimator is accurate, which mitigates feature-dependent miscoverage and improves conditional calibration. On the other hand, our percentile calibration adapts to the empirical PIT distribution, which is robust against a possibly imperfect estimation of the conditional CDF. We prove the finite-sample marginal coverage property of the proposed method and show its asymptotic conditional coverage under mild consistency conditions. Experiments on diverse synthetic and real-world benchmarks demonstrate better conditional calibration and substantially shorter intervals than existing methods.

Donor-level disease classification from single-cell RNA sequencing (scRNA-seq) requires strict donor-aware cross-validation: naive pipelines that split cells randomly conflate training and test donors, inflating reported performance through pseudoreplication. We present a donor-aware benchmark evaluating three feature representations across two independent IBD cohorts: centered log-ratio (CLR) transformed cell-type composition, GatedStructuralCFN dependency embeddings, and scVI variational autoencoder latent embeddings. The cohorts are the SCP259 ulcerative colitis atlas (UC vs. Healthy, n=30 donors, 51 cell types) and the Kong 2023 Crohn's disease atlas (CD vs. Healthy, n=71 donors, 55-68 cell types across three intestinal regions). Compartment-stratified CLR composition achieves AUROC 0.956 +/- 0.061 on SCP259; GatedStructuralCFN on the same features achieves 0.978 +/- 0.050. In the Kong cohort, CFN achieves its best performance in the colon region (0.960 +/- 0.055 after feature filtering), exceeding linear CLR (0.900 +/- 0.100), while terminal ileum classification is dominated by linear models (CatBoost CLR 0.967 +/- 0.075 vs. CFN 0.811 +/- 0.164). Cross-dataset transfer (CD->UC, four shared cell types) achieves AUC 0.833 with XGBoost CLR; the reverse direction performs at chance. CFN edge stability analysis shows that compartment-wise composition eliminates spurious unit-sum-induced instability present in global composition (Jaccard 0.026 vs. top-20 recurrence 1.0). CFN shows a consistent numerical advantage over linear models in the colon region of CD (AUROC 0.960 vs. 0.900), though no inter-method comparison reached statistical significance at n<=34 donors per region. Compartment-aware feature construction is critical for both classification performance and structural interpretability. Code: https://github.com/Jonathan-321/sfn-scrna-study

We provide a unified theoretical analysis of Linear Discriminant Analysis with simultaneous multilabel scatter matrix formulations and Stiefel orthogonality constraints. Our contributions span both algebraic structure and statistical guarantees. On the algebraic side, we characterize the rank of the multilabel between-class scatter matrix, showing that the effective discriminant dimensionality can strictly exceed the classical single-label bound of $C-1$; we establish a multilabel partition of variance and prove that all four Fisher objectives are equivalent under the $W^\top S_t^{ML} W = I_r$ constraint while characterizing their divergence under the Stiefel constraint; and we prove a two-sided label-distance preservation bound relating projected distances to Hamming distances in label space. On the statistical side, we establish a finite-sample $O(k_{\max}\sqrt{d\log d/n}/gap_r)$ bound on the subspace estimation error under sub-Gaussian noise with a matching $Ω(σ^2 d/(n\,gap_r))$ minimax lower bound, establishing a near-minimax-optimal rate (matching up to logarithmic and $k_{\max}$ factors) for multilabel discriminant subspace estimation. We further provide high-probability distance concentration, robustness guarantees under label interactions, and a regularization analysis preserving the spectral structure when $d \gg n$. All results are verified numerically on synthetic data generated from the linear label-effect model, covering both the algebraic identities and the multilabel-specific quantities ($k_{\max}$, $κ(S_t^{ML})$, $\|Γ/n\|_2$, $Δ_r$) that govern the statistical bounds. The numerical experiments are designed as a sanity check for the theorems rather than as an empirical benchmark; evaluation on real multilabel datasets is left to future work targeting application-oriented venues.

In many classification settings, the class of primary interest is underrepresented, leading to imbalanced data problems that arise in applications such as rare disease detection and fraud identification. In these contexts, identifying a potential positive instance typically triggers costly follow-up actions, such as medical imaging or detailed transaction inspection, which are subject to limited operational capacity. Motivated by this setting, we consider classification problems where data may arrive sequentially and decisions must be made under constraints on the number of instances that can be selected for further analysis. We propose a classification framework that explicitly controls the rate of positive predictions, enforcing a user-defined bound on the proportion of observations classified as belonging to the minority class while maximizing detection performance. The approach can be implemented using standard learning methods and naturally extends to online settings, where decisions are taken in real time. We show that incorporating capacity constraints leads to substantial improvements over classical approaches, including resampling techniques such as SMOTE, which do not directly control the selection rate.

The goal of this thesis is to investigate the structural properties of certain sequential problems in order to bring the solutions closer to a practical use. In the first part, we put a special emphasis on structures that can be represented as graphs on actions. In the second part, we study the large action spaces that can be of exponential size in the number of base actions or even infinite. For graph bandits, we consider the settings of smoothness of rewards (spectral bandits), side observations, and influence maximization. For large structured domains, we cover kernel bandits, polymatroid bandits, bandits for function optimization (including unknown smoothness), and infinitely many-arms bandits. The thesis aspires to be a survey of the author's contributions on graph and structured bandits.

We develop graph-based methods for semi-supervised learning based on label propagation on a data similarity graph. When data is abundant or arrive in a stream, the problems of computation and data storage arise for any graph-based method. We propose a fast approximate online algorithm that solves for the harmonic solution on an approximate graph. We show, both empirically and theoretically, that good behavior can be achieved by collapsing nearby points into a set of local representative points that minimize distortion. Moreover, we regularize the harmonic solution to achieve better stability properties. We also present graph-based methods for detecting conditional anomalies and apply them to the identification of unusual clinical actions in hospitals. Our hypothesis is that patient-management actions that are unusual with respect to the past patients may be due to errors and that it is worthwhile to raise an alert if such a condition is encountered. Conditional anomaly detection extends standard unconditional anomaly framework but also faces new problems known as fringe and isolated points. We devise novel nonparametric graph-based methods to tackle these problems. Our methods rely on graph connectivity analysis and soft harmonic solution. Finally, we conduct an extensive human evaluation study of our conditional anomaly methods by 15 experts in critical care.

Bayesian predictive inference propagates parameter uncertainty to quantities of interest through the posterior-predictive distribution. In practice, this is typically performed using a two-stage procedure: first approximating the posterior distribution of model parameters, and then propagating posterior samples through the predictive model via Monte Carlo simulation. This sequential workflow can be computationally demanding, particularly for high-fidelity models such as those governed by partial differential equations. We propose a variational Bayesian framework that directly targets the posterior-predictive distribution and jointly learns variational approximations of both the posterior and the corresponding predictive distribution. The formulation introduces a variational upper bound on the Kullback--Leibler divergence together with moment-based regularization terms. The variational distributions are trained in an amortized manner, shifting computational effort to an offline stage and enabling efficient online inference. Numerical experiments ranging from analytical benchmarks to a finite-element solid mechanics problem demonstrate that the proposed method achieves more accurate predictive distributions than conventional two-stage variational inference, while substantially reducing the cost of online predictive inference.

Multi Armed Bandit (MAB) algorithms are a cornerstone of reinforcement learning and have been studied both theoretically and numerically. One of the most commonly used implementation uses a softmax mapping to prescribe the optimal policy and served as the foundation for downstream algorithms, including REINFORCE. Distinct from vanilla approaches, we consider here the L2 regularized softmax policy gradient where a quadratic term is subtracted from the mean reward. Previous studies exploiting convexity failed to identify a suitable theoretical framework to analyze its convergence when the regularization parameter vanishes. We prove here theoretical convergence results and confirm empirically that this regime makes the L2 regularization numerically advantageous on standard benchmarks.