arXiv subjects

Maruan Al-Shedivat

Publications and source records attributed to Maruan Al-Shedivat.

At least 19 recordsLinked to original sources

arXiv2026

On the Design Space of Discrete Diffusion Online Adaptation for Molecular Optimization

Molecular optimization often starts from a pretrained generative model that captures a broad prior over valid molecular structures. At test time, however, the goal is not to sample from this prior, but to use a limited oracle budget to shift generation toward task-specific high-reward molecules. We study this adaptation problem for discrete diffusion models. Each online round couples several choices. The loop must decide which candidates to evaluate, how rewards become model updates, which feedback to reuse, and how far to move beyond the pretrained prior. These choices have mostly been studied in isolation, leaving open whether they complement one another, become redundant, or interfere inside a full online adaptation loop. We conduct controlled studies across six small-molecule binding-affinity tasks and three protein-fitness tasks. We find that acquisition, reward shaping, and model debiasing provide complementary routes to higher reward, especially for small molecules. Replay further stabilizes learning, while validity penalties keep small-molecule exploration on the valid molecular manifold. Together, these findings point to a practical recipe for feedback-efficient molecular optimization: online fine-tuning with acquisition, reward shaping, debiasing, replay, and validity control. This recipe outperforms offline fine-tuning and inference-time search baselines under matched oracle-call budgets and GPU-hour accounting. The gains are largest when high-reward candidates require larger shifts from the pretrained prior.

cs.LG↗

arXiv2026

Few-step Cofolding with All-Atom Flow Maps

All-atom generative modeling of 3D biomolecular complexes has emerged as the dominant paradigm for predicting the structure of proteins and protein-ligand systems. Generating structures at the atomic level of fidelity, however, typically requires expensive iterative diffusion rollouts, making both conventional deployment and inference-time search techniques computationally costly. In this paper, we introduce the Denoiser Cofolding All-Atom Flowmap (DeCAF) framework for distilling state-of-the-art all-atom cofolding models into all-atom flow maps that produce high-quality samples in only a few inference steps. We build DeCAF on a denoiser-based formulation of flow maps with endpoint losses that naturally support SE(3) rigid alignment, which we show is critical for training accurate models. We further derive a simple change of variables that lets DeCAF operate in the σ-space noise schedule of EDM-style architectures, enabling direct distillation from pretrained cofolding diffusion models. Equipped with DeCAF's flowmap lookahead, we introduce a purpose-built inference-time framework that improves sampling through reward-guided search. Empirically, DeCAF-Boltz statistically improves over Boltz-1x in both accuracy (RMSD) and physical validity scores of protein-ligand poses at strict NFE budgets on the challenging Runs N' Poses, while also showing a more optimal Pareto frontier across all inference compute budgets on PoseBusters. Distilling the state-of-the-art Pearl cofolding model, DeCAF-Pearl outperforms diffusion-based cofolding models and matches its teacher on success rate while using 5x fewer NFEs. We release our code at https://github.com/genesistherapeutics/decaf.

cs.LG↗

arXiv2025

Triangle Multiplication Is All You Need For Biomolecular Structure Representations

AlphaFold has transformed protein structure prediction, but emerging applications such as virtual ligand screening, proteome-wide folding, and de novo binder design demand predictions at a massive scale, where runtime and memory costs become prohibitive. A major bottleneck lies in the Pairformer backbone of AlphaFold3-style models, which relies on computationally expensive triangular primitives-especially triangle attention-for pairwise reasoning. We introduce Pairmixer, a streamlined alternative that eliminates triangle attention while preserving higher-order geometric reasoning capabilities that are critical for structure prediction. Pairmixer substantially improves computational efficiency, matching state-of-the-art structure predictors across folding and docking benchmarks, delivering up to 4x faster inference on long sequences while reducing training cost by 34%. Its efficiency alleviates the computational burden of downstream applications such as modeling large protein complexes, high-throughput ligand and binder screening, and hallucination-based design. Within BoltzDesign, for example, Pairmixer delivers over 2x faster sampling and scales to sequences ~30% longer than the memory limits of Pairformer. Code is available at https://github.com/genesistherapeutics/pairmixer.

q-bio.QM↗

arXiv2025

Pearl: A Foundation Model for Placing Every Atom in the Right Location

Accurately predicting the three-dimensional structures of protein-ligand complexes remains a fundamental challenge in computational drug discovery that limits the pace and success of therapeutic design. Deep learning methods have recently shown strong potential as structural prediction tools, achieving promising accuracy across diverse biomolecular systems. However, their performance and utility are constrained by scarce experimental data, inefficient architectures, physically invalid poses, and the limited ability to exploit auxiliary information available at inference. To address these issues, we introduce Pearl (Placing Every Atom in the Right Location), a foundation model for protein-ligand cofolding at scale. Pearl addresses these challenges with three key innovations: (1) training recipes that include large-scale synthetic data to overcome data scarcity; (2) architectures that incorporate an SO(3)-equivariant diffusion module to inherently respect 3D rotational symmetries, improving generalization and sample efficiency, and (3) controllable inference, including a generalized multi-chain templating system supporting both protein and non-polymeric components as well as dual unconditional/conditional modes. Pearl establishes a new state-of-the-art performance in protein-ligand cofolding. On the key metric of generating accurate (RMSD < 2 Å) and physically valid poses, Pearl surpasses AlphaFold 3 and other open source baselines on the public Runs N' Poses and PoseBusters benchmarks, delivering 14.5% and 14.2% improvements, respectively, over the next best model. In the pocket-conditional cofolding regime, Pearl delivers $3.6\times$ improvement on a proprietary set of challenging, real-world drug targets at the more rigorous RMSD < 1 Å threshold. Finally, we demonstrate that model performance correlates directly with synthetic dataset size used in training.

cs.LG↗

arXiv2021

Knowledge-Aware Meta-learning for Low-Resource Text Classification

Meta-learning has achieved great success in leveraging the historical learned knowledge to facilitate the learning process of the new task. However, merely learning the knowledge from the historical tasks, adopted by current meta-learning algorithms, may not generalize well to testing tasks when they are not well-supported by training tasks. This paper studies a low-resource text classification problem and bridges the gap between meta-training and meta-testing tasks by leveraging the external knowledge bases. Specifically, we propose KGML to introduce additional representation for each sentence learned from the extracted sentence-specific knowledge graph. The extensive experiments on three datasets demonstrate the effectiveness of KGML under both supervised adaptation and unsupervised adaptation settings.

cs.CL↗

arXiv2021

A Field Guide to Federated Optimization

Federated learning and analytics are a distributed approach for collaboratively learning models (or statistics) from decentralized data, motivated by and designed for privacy protection. The distributed learning process can be formulated as solving federated optimization problems, which emphasize communication efficiency, data heterogeneity, compatibility with privacy and system requirements, and other constraints that are not primary considerations in other problem settings. This paper provides recommendations and guidelines on formulating, designing, evaluating and analyzing federated optimization algorithms through concrete examples and practical implementation, with a focus on conducting effective simulations to infer real-world performance. The goal of this work is not to survey the current literature, but to inspire researchers and practitioners to design federated learning algorithms that can be used in various practical applications.

cs.LG↗

arXiv2021

Federated Learning via Posterior Averaging: A New Perspective and Practical Algorithms

Federated learning is typically approached as an optimization problem, where the goal is to minimize a global loss function by distributing computation across client devices that possess local data and specify different parts of the global objective. We present an alternative perspective and formulate federated learning as a posterior inference problem, where the goal is to infer a global posterior distribution by having client devices each infer the posterior of their local data. While exact inference is often intractable, this perspective provides a principled way to search for global optima in federated settings. Further, starting with the analysis of federated quadratic objectives, we develop a computation- and communication-efficient approximate posterior inference algorithm -- federated posterior averaging (FedPA). Our algorithm uses MCMC for approximate inference of local posteriors on the clients and efficiently communicates their statistics to the server, where the latter uses them to refine a global estimate of the posterior mode. Finally, we show that FedPA generalizes federated averaging (FedAvg), can similarly benefit from adaptive optimizers, and yields state-of-the-art results on four realistic and challenging benchmarks, converging faster, to better optima.

cs.LG↗

arXiv2021

On Data Efficiency of Meta-learning

Meta-learning has enabled learning statistical models that can be quickly adapted to new prediction tasks. Motivated by use-cases in personalized federated learning, we study the often overlooked aspect of the modern meta-learning algorithms -- their data efficiency. To shed more light on which methods are more efficient, we use techniques from algorithmic stability to derive bounds on the transfer risk that have important practical implications, indicating how much supervision is needed and how it must be allocated for each method to attain the desired level of generalization. Further, we introduce a new simple framework for evaluating meta-learning methods under a limit on the available supervision, conduct an empirical study of MAML, Reptile, and Protonets, and demonstrate the differences in the behavior of these methods on few-shot and federated learning benchmarks. Finally, we propose active meta-learning, which incorporates active data selection into learning-to-learn, leading to better performance of all methods in the limited supervision regime.

cs.LG↗

arXiv2020

Regularizing Black-box Models for Improved Interpretability

Most of the work on interpretable machine learning has focused on designing either inherently interpretable models, which typically trade-off accuracy for interpretability, or post-hoc explanation systems, whose explanation quality can be unpredictable. Our method, ExpO, is a hybridization of these approaches that regularizes a model for explanation quality at training time. Importantly, these regularizers are differentiable, model agnostic, and require no domain knowledge to define. We demonstrate that post-hoc explanations for ExpO-regularized models have better explanation quality, as measured by the common fidelity and stability metrics. We verify that improving these metrics leads to significantly more useful explanations with a user study on a realistic task.

cs.LG↗

arXiv2020

Contextual Explanation Networks

Modern learning algorithms excel at producing accurate but complex models of the data. However, deploying such models in the real-world requires extra care: we must ensure their reliability, robustness, and absence of undesired biases. This motivates the development of models that are equally accurate but can be also easily inspected and assessed beyond their predictive performance. To this end, we introduce contextual explanation networks (CEN)---a class of architectures that learn to predict by generating and utilizing intermediate, simplified probabilistic models. Specifically, CENs generate parameters for intermediate graphical models which are further used for prediction and play the role of explanations. Contrary to the existing post-hoc model-explanation tools, CENs learn to predict and to explain simultaneously. Our approach offers two major advantages: (i) for each prediction valid, instance-specific explanation is generated with no computational overhead and (ii) prediction via explanation acts as a regularizer and boosts performance in data-scarce settings. We analyze the proposed framework theoretically and experimentally. Our results on image and text classification and survival analysis tasks demonstrate that CENs are not only competitive with the state-of-the-art methods but also offer additional insights behind each prediction, that can be valuable for decision support. We also show that while post-hoc methods may produce misleading explanations in certain cases, CENs are consistent and allow to detect such cases systematically.

cs.LG↗

arXiv2020

Learning from Imperfect Annotations

Many machine learning systems today are trained on large amounts of human-annotated data. Data annotation tasks that require a high level of competency make data acquisition expensive, while the resulting labels are often subjective, inconsistent, and may contain a variety of human biases. To improve the data quality, practitioners often need to collect multiple annotations per example and aggregate them before training models. Such a multi-stage approach results in redundant annotations and may often produce imperfect "ground truth" that may limit the potential of training accurate machine learning models. We propose a new end-to-end framework that enables us to: (i) merge the aggregation step with model training, thus allowing deep learning systems to learn to predict ground truth estimates directly from the available data, and (ii) model difficulties of examples and learn representations of the annotators that allow us to estimate and take into account their competencies. Our approach is general and has many applications, including training more accurate models on crowdsourced data, ensemble learning, as well as classifier accuracy estimation from unlabeled data. We conduct an extensive experimental evaluation of our method on 5 crowdsourcing datasets of varied difficulty and show accuracy gains of up to 25% over the current state-of-the-art approaches for aggregating annotations, as well as significant reductions in the required annotation redundancy.

cs.LG↗

arXiv2019

Regularizing Black-box Models for Improved Interpretability (HILL 2019 Version)

Most of the work on interpretable machine learning has focused on designing either inherently interpretable models, which typically trade-off accuracy for interpretability, or post-hoc explanation systems, which lack guarantees about their explanation quality. We propose an alternative to these approaches by directly regularizing a black-box model for interpretability at training time. Our approach explicitly connects three key aspects of interpretable machine learning: (i) the model's innate explainability, (ii) the explanation system used at test time, and (iii) the metrics that measure explanation quality. Our regularization results in substantial improvement in terms of the explanation fidelity and stability metrics across a range of datasets and black-box explanation systems while slightly improving accuracy. Further, if the resulting model is still not sufficiently interpretable, the weight of the regularization term can be adjusted to achieve the desired trade-off between accuracy and interpretability. Finally, we justify theoretically that the benefits of explanation-based regularization generalize to unseen points.

cs.LG↗

arXiv2019

Consistency by Agreement in Zero-shot Neural Machine Translation

Generalization and reliability of multilingual translation often highly depend on the amount of available parallel data for each language pair of interest. In this paper, we focus on zero-shot generalization---a challenging setup that tests models on translation directions they have not been optimized for at training time. To solve the problem, we (i) reformulate multilingual translation as probabilistic inference, (ii) define the notion of zero-shot consistency and show why standard training often results in models unsuitable for zero-shot tasks, and (iii) introduce a consistent agreement-based training method that encourages the model to produce equivalent translations of parallel sentences in auxiliary languages. We test our multilingual NMT models on multiple public zero-shot translation benchmarks (IWSLT17, UN corpus, Europarl) and show that agreement-based learning often results in 2-3 BLEU zero-shot improvement over strong baselines without any loss in performance on supervised translation directions.

cs.LG↗

arXiv2018

On the Complexity of Exploration in Goal-Driven Navigation

Building agents that can explore their environments intelligently is a challenging open problem. In this paper, we make a step towards understanding how a hierarchical design of the agent's policy can affect its exploration capabilities. First, we design EscapeRoom environments, where the agent must figure out how to navigate to the exit by accomplishing a number of intermediate tasks (\emph{subgoals}), such as finding keys or opening doors. Our environments are procedurally generated and vary in complexity, which can be controlled by the number of subgoals and relationships between them. Next, we propose to measure the complexity of each environment by constructing dependency graphs between the goals and analytically computing \emph{hitting times} of a random walk in the graph. We empirically evaluate Proximal Policy Optimization (PPO) with sparse and shaped rewards, a variation of policy sketches, and a hierarchical version of PPO (called HiPPO) akin to h-DQN. We show that analytically estimated \emph{hitting time} in goal dependency graphs is an informative metric of the environment complexity. We conjecture that the result should hold for environments other than navigation. Finally, we show that solving environments beyond certain level of complexity requires hierarchical approaches.

cs.LG↗

arXiv2018

Learning with Opponent-Learning Awareness

Multi-agent settings are quickly gathering importance in machine learning. This includes a plethora of recent work on deep multi-agent reinforcement learning, but also can be extended to hierarchical RL, generative adversarial networks and decentralised optimisation. In all these settings the presence of multiple learning agents renders the training problem non-stationary and often leads to unstable training or undesired final results. We present Learning with Opponent-Learning Awareness (LOLA), a method in which each agent shapes the anticipated learning of the other agents in the environment. The LOLA learning rule includes a term that accounts for the impact of one agent's policy on the anticipated parameter update of the other agents. Results show that the encounter of two LOLA agents leads to the emergence of tit-for-tat and therefore cooperation in the iterated prisoners' dilemma, while independent learning does not. In this domain, LOLA also receives higher payouts compared to a naive learner, and is robust against exploitation by higher order gradient-based methods. Applied to repeated matching pennies, LOLA agents converge to the Nash equilibrium. In a round robin tournament we show that LOLA agents successfully shape the learning of a range of multi-agent learning algorithms from literature, resulting in the highest average returns on the IPD. We also show that the LOLA update rule can be efficiently calculated using an extension of the policy gradient estimator, making the method suitable for model-free RL. The method thus scales to large parameter and input spaces and nonlinear function approximators. We apply LOLA to a grid world task with an embedded social dilemma using recurrent policies and opponent modelling. By explicitly considering the learning of the other agent, LOLA agents learn to cooperate out of self-interest. The code is at github.com/alshedivat/lola.

cs.AI↗

arXiv2018

DiCE: The Infinitely Differentiable Monte-Carlo Estimator

The score function estimator is widely used for estimating gradients of stochastic objectives in stochastic computation graphs (SCG), eg, in reinforcement learning and meta-learning. While deriving the first-order gradient estimators by differentiating a surrogate loss (SL) objective is computationally and conceptually simple, using the same approach for higher-order derivatives is more challenging. Firstly, analytically deriving and implementing such estimators is laborious and not compliant with automatic differentiation. Secondly, repeatedly applying SL to construct new objectives for each order derivative involves increasingly cumbersome graph manipulations. Lastly, to match the first-order gradient under differentiation, SL treats part of the cost as a fixed sample, which we show leads to missing and wrong terms for estimators of higher-order derivatives. To address all these shortcomings in a unified way, we introduce DiCE, which provides a single objective that can be differentiated repeatedly, generating correct estimators of derivatives of any order in SCGs. Unlike SL, DiCE relies on automatic differentiation for performing the requisite graph manipulations. We verify the correctness of DiCE both through a proof and numerical evaluation of the DiCE derivative estimates. We also use DiCE to propose and evaluate a novel approach for multi-agent learning. Our code is available at https://www.github.com/alshedivat/lola.

cs.LG↗

arXiv2018

Learning Policy Representations in Multiagent Systems

Modeling agent behavior is central to understanding the emergence of complex phenomena in multiagent systems. Prior work in agent modeling has largely been task-specific and driven by hand-engineering domain-specific prior knowledge. We propose a general learning framework for modeling agent behavior in any multiagent system using only a handful of interaction data. Our framework casts agent modeling as a representation learning problem. Consequently, we construct a novel objective inspired by imitation learning and agent identification and design an algorithm for unsupervised learning of representations of agent policies. We demonstrate empirically the utility of the proposed framework in (i) a challenging high-dimensional competitive environment for continuous control and (ii) a cooperative environment for communication, on supervised predictive tasks, unsupervised clustering, and policy optimization using deep reinforcement learning.

cs.MA↗

arXiv2018

Continuous Adaptation via Meta-Learning in Nonstationary and Competitive Environments

Ability to continuously learn and adapt from limited experience in nonstationary environments is an important milestone on the path towards general intelligence. In this paper, we cast the problem of continuous adaptation into the learning-to-learn framework. We develop a simple gradient-based meta-learning algorithm suitable for adaptation in dynamically changing and adversarial scenarios. Additionally, we design a new multi-agent competitive environment, RoboSumo, and define iterated adaptation games for testing various aspects of continuous adaptation strategies. We demonstrate that meta-learning enables significantly more efficient adaptation than reactive baselines in the few-shot regime. Our experiments with a population of agents that learn and compete suggest that meta-learners are the fittest.

cs.LG↗