Maruan Al-Shedivat

Genesis Research Team, Alejandro Dobles, Nina Jovic et al. · cmu

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.

Jakob Foerster, Gregory Farquhar, Maruan Al-Shedivat et al.

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.

Jakob N. Foerster, Richard Y. Chen, Maruan Al-Shedivat et al.

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.

Jeffrey Ouyang-Zhang, Pranav Murugan, Daniel J. Diaz et al. · cmu

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.

Huaxiu Yao, Yingxin Wu, Maruan Al-Shedivat et al.

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.

Jianyu Wang, Zachary Charles, Zheng Xu et al.

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.

Maruan Al-Shedivat, Liam Li, Eric Xing et al.

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.

Maruan Al-Shedivat, Jennifer Gillenwater, Eric Xing et al.

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.

Emmanouil Antonios Platanios, Maruan Al-Shedivat, Eric Xing et al.

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.

Gregory Plumb, Maruan Al-Shedivat, Eric Xing et al.

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.

Maruan Al-Shedivat, Ankur P. Parikh

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.

Gregory Plumb, Maruan Al-Shedivat, Angel Alexander Cabrera et al.

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.

Maruan Al-Shedivat, Lisa Lee, Ruslan Salakhutdinov et al.

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.

Aditya Grover, Maruan Al-Shedivat, Jayesh K. Gupta et al.

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.

Maruan Al-Shedivat, Avinava Dubey, Eric P. Xing

Accurate and transparent prediction of cancer survival times on the level of individual patients can inform and improve patient care and treatment practices. In this paper, we design a model that concurrently learns to accurately predict patient-specific survival distributions and to explain its predictions in terms of patient attributes such as clinical tests or assessments. Our model is flexible and based on a recurrent network, can handle various modalities of data including temporal measurements, and yet constructs and uses simple explanations in the form of patient- and time-specific linear regression. For analysis, we use two publicly available datasets and show that our networks outperform a number of baselines in prediction while providing a way to inspect the reasons behind each prediction.

Maruan Al-Shedivat, Avinava Dubey, Eric P. Xing

Linear approximations to the decision boundary of a complex model have become one of the most popular tools for interpreting predictions. In this paper, we study such linear explanations produced either post-hoc by a few recent methods or generated along with predictions with contextual explanation networks (CENs). We focus on two questions: (i) whether linear explanations are always consistent or can be misleading, and (ii) when integrated into the prediction process, whether and how explanations affect the performance of the model. Our analysis sheds more light on certain properties of explanations produced by different methods and suggests that learning models that explain and predict jointly is often advantageous.

Maruan Al-Shedivat, Trapit Bansal, Yuri Burda et al.

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.

Maruan Al-Shedivat, Avinava Dubey, Eric P. Xing

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.

Maruan Al-Shedivat, Andrew Gordon Wilson, Yunus Saatchi et al.

Many applications in speech, robotics, finance, and biology deal with sequential data, where ordering matters and recurrent structures are common. However, this structure cannot be easily captured by standard kernel functions. To model such structure, we propose expressive closed-form kernel functions for Gaussian processes. The resulting model, GP-LSTM, fully encapsulates the inductive biases of long short-term memory (LSTM) recurrent networks, while retaining the non-parametric probabilistic advantages of Gaussian processes. We learn the properties of the proposed kernels by optimizing the Gaussian process marginal likelihood using a new provably convergent semi-stochastic gradient procedure and exploit the structure of these kernels for scalable training and prediction. This approach provides a practical representation for Bayesian LSTMs. We demonstrate state-of-the-art performance on several benchmarks, and thoroughly investigate a consequential autonomous driving application, where the predictive uncertainties provided by GP-LSTM are uniquely valuable.

Kirthevasan Kandasamy, Maruan Al-Shedivat, Eric P. Xing

Recently, there has been a surge of interest in using spectral methods for estimating latent variable models. However, it is usually assumed that the distribution of the observations conditioned on the latent variables is either discrete or belongs to a parametric family. In this paper, we study the estimation of an $m$-state hidden Markov model (HMM) with only smoothness assumptions, such as Hölderian conditions, on the emission densities. By leveraging some recent advances in continuous linear algebra and numerical analysis, we develop a computationally efficient spectral algorithm for learning nonparametric HMMs. Our technique is based on computing an SVD on nonparametric estimates of density functions by viewing them as \emph{continuous matrices}. We derive sample complexity bounds via concentration results for nonparametric density estimation and novel perturbation theory results for continuous matrices. We implement our method using Chebyshev polynomial approximations. Our method is competitive with other baselines on synthetic and real problems and is also very computationally efficient.

Emre O. Neftci, Bruno U. Pedroni, Siddharth Joshi et al.

Recent studies have shown that synaptic unreliability is a robust and sufficient mechanism for inducing the stochasticity observed in cortex. Here, we introduce Synaptic Sampling Machines, a class of neural network models that uses synaptic stochasticity as a means to Monte Carlo sampling and unsupervised learning. Similar to the original formulation of Boltzmann machines, these models can be viewed as a stochastic counterpart of Hopfield networks, but where stochasticity is induced by a random mask over the connections. Synaptic stochasticity plays the dual role of an efficient mechanism for sampling, and a regularizer during learning akin to DropConnect. A local synaptic plasticity rule implementing an event-driven form of contrastive divergence enables the learning of generative models in an on-line fashion. Synaptic sampling machines perform equally well using discrete-timed artificial units (as in Hopfield networks) or continuous-timed leaky integrate & fire neurons. The learned representations are remarkably sparse and robust to reductions in bit precision and synapse pruning: removal of more than 75% of the weakest connections followed by cursory re-learning causes a negligible performance loss on benchmark classification tasks. The spiking neuron-based synaptic sampling machines outperform existing spike-based unsupervised learners, while potentially offering substantial advantages in terms of power and complexity, and are thus promising models for on-line learning in brain-inspired hardware.

Maruan Al-Shedivat, Emre Neftci, Gert Cauwenberghs

The goal of a generative model is to capture the distribution underlying the data, typically through latent variables. After training, these variables are often used as a new representation, more effective than the original features in a variety of learning tasks. However, the representations constructed by contemporary generative models are usually point-wise deterministic mappings from the original feature space. Thus, even with representations robust to class-specific transformations, statistically driven models trained on them would not be able to generalize when the labeled data is scarce. Inspired by the stochasticity of the synaptic connections in the brain, we introduce Energy-based Stochastic Ensembles. These ensembles can learn non-deterministic representations, i.e., mappings from the feature space to a family of distributions in the latent space. These mappings are encoded in a distribution over a (possibly infinite) collection of models. By conditionally sampling models from the ensemble, we obtain multiple representations for every input example and effectively augment the data. We propose an algorithm similar to contrastive divergence for training restricted Boltzmann stochastic ensembles. Finally, we demonstrate the concept of the stochastic representations on a synthetic dataset as well as test them in the one-shot learning scenario on MNIST.