User embeddings play a crucial role in user engagement forecasting and personalized services. Recent advances in sequence modeling have sparked interest in learning user embeddings from behavioral data. Yet behavior-based user embedding learning faces the unique challenge of dynamic user modeling. As users continuously interact with the apps, user embeddings should be periodically updated to account for users' recent and long-term behavior patterns. Existing methods highly rely on stateless sequence models that lack memory of historical behavior. They have to either discard historical data and use only the most recent data or reprocess the old and new data jointly. Both cases incur substantial computational overhead. To address this limitation, we introduce User Stateful Embedding (USE). USE generates user embeddings and reflects users' evolving behaviors without the need for exhaustive reprocessing by storing previous model states and revisiting them in the future. Furthermore, we introduce a novel training objective named future W-behavior prediction to transcend the limitations of next-token prediction by forecasting a broader horizon of upcoming user behaviors. By combining it with the Same User Prediction, a contrastive learning-based objective that predicts whether different segments of behavior sequences belong to the same user, we further improve the embeddings' distinctiveness and representativeness. We conducted experiments on 8 downstream tasks using Snapchat users' behavioral logs in both static (i.e., fixed user behavior sequences) and dynamic (i.e., periodically updated user behavior sequences) settings. We demonstrate USE's superior performance over established baselines. The results underscore USE's effectiveness and efficiency in integrating historical and recent user behavior sequences into user embeddings in dynamic user modeling.

Effective DNA embedding remains crucial in genomic analysis, particularly in scenarios lacking labeled data for model fine-tuning, despite the significant advancements in genome foundation models. A prime example is metagenomics binning, a critical process in microbiome research that aims to group DNA sequences by their species from a complex mixture of DNA sequences derived from potentially thousands of distinct, often uncharacterized species. To fill the lack of effective DNA embedding models, we introduce DNABERT-S, a genome foundation model that specializes in creating species-aware DNA embeddings. To encourage effective embeddings to error-prone long-read DNA sequences, we introduce Manifold Instance Mixup (MI-Mix), a contrastive objective that mixes the hidden representations of DNA sequences at randomly selected layers and trains the model to recognize and differentiate these mixed proportions at the output layer. We further enhance it with the proposed Curriculum Contrastive Learning (C$^2$LR) strategy. Empirical results on 18 diverse datasets showed DNABERT-S's remarkable performance. It outperforms the top baseline's performance in 10-shot species classification with just a 2-shot training while doubling the Adjusted Rand Index (ARI) in species clustering and substantially increasing the number of correctly identified species in metagenomics binning. The code, data, and pre-trained model are publicly available at https://github.com/Zhihan1996/DNABERT_S.

Self-supervised learning (SSL) as an effective paradigm of representation learning has achieved tremendous success on various curated datasets in diverse scenarios. Nevertheless, when facing the long-tailed distribution in real-world applications, it is still hard for existing methods to capture transferable and robust representation. Conventional SSL methods, pursuing sample-level uniformity, easily leads to representation learning disparity where head classes dominate the feature regime but tail classes passively collapse. To address this problem, we propose a novel Geometric Harmonization (GH) method to encourage category-level uniformity in representation learning, which is more benign to the minority and almost does not hurt the majority under long-tailed distribution. Specially, GH measures the population statistics of the embedding space on top of self-supervised learning, and then infer an fine-grained instance-wise calibration to constrain the space expansion of head classes and avoid the passive collapse of tail classes. Our proposal does not alter the setting of SSL and can be easily integrated into existing methods in a low-cost manner. Extensive results on a range of benchmark datasets show the effectiveness of GH with high tolerance to the distribution skewness.

Robust reinforcement learning (RL) aims to find a policy that optimizes the worst-case performance in the face of uncertainties. In this paper, we focus on action robust RL with the probabilistic policy execution uncertainty, in which, instead of always carrying out the action specified by the policy, the agent will take the action specified by the policy with probability $1-\rho$ and an alternative adversarial action with probability $\rho$. We establish the existence of an optimal policy on the action robust MDPs with probabilistic policy execution uncertainty and provide the action robust Bellman optimality equation for its solution. Furthermore, we develop Action Robust Reinforcement Learning with Certificates (ARRLC) algorithm that achieves minimax optimal regret and sample complexity. Furthermore, we conduct numerical experiments to validate our approach's robustness, demonstrating that ARRLC outperforms non-robust RL algorithms and converges faster than the robust TD algorithm in the presence of action perturbations.

Decoding the linguistic intricacies of the genome is a crucial problem in biology, and pre-trained foundational models such as DNABERT and Nucleotide Transformer have made significant strides in this area. Existing works have largely hinged on k-mer, fixed-length permutations of A, T, C, and G, as the token of the genome language due to its simplicity. However, we argue that the computation and sample inefficiencies introduced by k-mer tokenization are primary obstacles in developing large genome foundational models. We provide conceptual and empirical insights into genome tokenization, building on which we propose to replace k-mer tokenization with Byte Pair Encoding (BPE), a statistics-based data compression algorithm that constructs tokens by iteratively merging the most frequent co-occurring genome segment in the corpus. We demonstrate that BPE not only overcomes the limitations of k-mer tokenization but also benefits from the computational efficiency of non-overlapping tokenization. Based on these insights, we introduce DNABERT-2, a refined genome foundation model that adapts an efficient tokenizer and employs multiple strategies to overcome input length constraints, reduce time and memory expenditure, and enhance model capability. Furthermore, we identify the absence of a comprehensive and standardized benchmark for genome understanding as another significant impediment to fair comparative analysis. In response, we propose the Genome Understanding Evaluation (GUE), a comprehensive multi-species genome classification dataset that amalgamates $28$ distinct datasets across $7$ tasks, with input lengths ranging from $70$ to $1000$. Through comprehensive experiments on the GUE benchmark, we demonstrate that DNABERT-2 achieves comparable performance to the state-of-the-art model with $21 \times$ fewer parameters and approximately $56 \times$ less GPU time in pre-training.

Background: Computational drug repurposing is a cost- and time-efficient approach that aims to identify new therapeutic targets or diseases (indications) of existing drugs/compounds. It is especially critical for emerging and/or orphan diseases due to its cheaper investment and shorter research cycle compared with traditional wet-lab drug discovery approaches. However, the underlying mechanisms of action (MOAs) between repurposed drugs and their target diseases remain largely unknown, which is still a main obstacle for computational drug repurposing methods to be widely adopted in clinical settings. Results: In this work, we propose KGML-xDTD: a Knowledge Graph-based Machine Learning framework for explainably predicting Drugs Treating Diseases. It is a two-module framework that not only predicts the treatment probabilities between drugs/compounds and diseases but also biologically explains them via knowledge graph (KG) path-based, testable mechanisms of action (MOAs). We leverage knowledge-and-publication based information to extract biologically meaningful "demonstration paths" as the intermediate guidance in the Graph-based Reinforcement Learning (GRL) path-finding process. Comprehensive experiments and case study analyses show that the proposed framework can achieve state-of-the-art performance in both predictions of drug repurposing and recapitulation of human-curated drug MOA paths. Conclusions: KGML-xDTD is the first model framework that can offer KG-path explanations for drug repurposing predictions by leveraging the combination of prediction outcomes and existing biological knowledge and publications. We believe it can effectively reduce "black-box" concerns and increase prediction confidence for drug repurposing based on predicted path-based explanations, and further accelerate the process of drug discovery for emerging diseases.

Learning with noisy labels has become imperative in the Big Data era, which saves expensive human labors on accurate annotations. Previous noise-transition-based methods have achieved theoretically-grounded performance under the Class-Conditional Noise model (CCN). However, these approaches builds upon an ideal but impractical anchor set available to pre-estimate the noise transition. Even though subsequent works adapt the estimation as a neural layer, the ill-posed stochastic learning of its parameters in back-propagation easily falls into undesired local minimums. We solve this problem by introducing a Latent Class-Conditional Noise model (LCCN) to parameterize the noise transition under a Bayesian framework. By projecting the noise transition into the Dirichlet space, the learning is constrained on a simplex characterized by the complete dataset, instead of some ad-hoc parametric space wrapped by the neural layer. We then deduce a dynamic label regression method for LCCN, whose Gibbs sampler allows us efficiently infer the latent true labels to train the classifier and to model the noise. Our approach safeguards the stable update of the noise transition, which avoids previous arbitrarily tuning from a mini-batch of samples. We further generalize LCCN to different counterparts compatible with open-set noisy labels, semi-supervised learning as well as cross-model training. A range of experiments demonstrate the advantages of LCCN and its variants over the current state-of-the-art methods.

The remarkable success of deep learning is built on a large amount of labeled data. Data annotation in real-world scenarios often suffers from annotation ambiguity. To address annotation ambiguity, partial label learning allows multiple candidate labels to be annotated for each training instance, which can be widely used in web mining (Luo & Orabona, 2010), automatic image annotations (Zeng et al., 2013; Chen et al., 2018), ecoinformatics (Liu & Dietterich, 2012), and crowdsourcing (Gong et al., 2018). For example, a movie clip may contain several characters talking to each other, with some of them appearing in a screenshot. Although we can obtain scripts and dialogues that indicate the names of the characters, we cannot directly confirm the real name of each face in the screenshot (see Figure 7(a)). A similar scenario arises for recognizing faces from news images, where we can obtain the names of the people from the news descriptions but cannot establish a one-to-one correspondence with the face images (see Figure 7(b)). Partial label learning problem also appears in crowdsourcing, where each instance may be given multiple labels by different annotators. However, some labels may be incorrect or biased due to differences in expertise or cultural background of different annotators, so it is necessary to find the most appropriate label for each instance from candidate labels (see Figure 7(c)).