A 5' UTR Language Model for Decoding Untranslated Regions of mRNA and Function Predictions

The 5' UTR, a regulatory region at the beginning of an mRNA molecule, plays a crucial role in regulating the translation process and impacts the protein expression level. Language models have showcased their effectiveness in decoding the functions of protein and genome sequences. Here, we introduced a language model for 5' UTR, which we refer to as the UTR-LM. The UTR-LM is pre-trained on endogenous 5' UTRs from multiple species and is further augmented with supervised information including secondary structure and minimum free energy. We fine-tuned the UTR-LM in a variety of downstream tasks. The model outperformed the best-known benchmark by up to 42% for predicting the Mean Ribosome Loading, and by up to 60% for predicting the Translation Efficiency and the mRNA Expression Level. The model also applies to identifying unannotated Internal Ribosome Entry Sites within the untranslated region and improves the AUPR from 0.37 to 0.52 compared to the best baseline. Further, we designed a library of 211 novel 5' UTRs with high predicted values of translation efficiency and evaluated them via a wet-lab assay. Experiment results confirmed that our top designs achieved a 32.5% increase in protein production level relative to well-established 5' UTR optimized for therapeutics.

Sample Complexity of Neural Policy Mirror Descent for Policy Optimization on Low-Dimensional Manifolds

Policy-based algorithms equipped with deep neural networks have achieved great success in solving high-dimensional policy optimization problems in reinforcement learning. However, current analyses cannot explain why they are resistant to the curse of dimensionality. In this work, we study the sample complexity of the neural policy mirror descent (NPMD) algorithm with convolutional neural networks (CNN) as function approximators. Motivated by the empirical observation that many high-dimensional environments have state spaces possessing low-dimensional structures, such as those taking images as states, we consider the state space to be a $d$-dimensional manifold embedded in the $D$-dimensional Euclidean space with intrinsic dimension $d\ll D$. We show that in each iteration of NPMD, both the value function and the policy can be well approximated by CNNs. The approximation errors are controlled by the size of the networks, and the smoothness of the previous networks can be inherited. As a result, by properly choosing the network size and hyperparameters, NPMD can find an $\epsilon$-optimal policy with $\widetilde{O}(\epsilon^{-\frac{d}{\alpha}-2})$ samples in expectation, where $\alpha\in(0,1]$ indicates the smoothness of environment. Compared to previous work, our result exhibits that NPMD can leverage the low-dimensional structure of state space to escape from the curse of dimensionality, providing an explanation for the efficacy of deep policy-based algorithms.

Deep Reinforcement Learning for Efficient and Fair Allocation of Health Care Resources

Scarcity of health care resources could result in the unavoidable consequence of rationing. For example, ventilators are often limited in supply, especially during public health emergencies or in resource-constrained health care settings, such as amid the pandemic of COVID-19. Currently, there is no universally accepted standard for health care resource allocation protocols, resulting in different governments prioritizing patients based on various criteria and heuristic-based protocols. In this study, we investigate the use of reinforcement learning for critical care resource allocation policy optimization to fairly and effectively ration resources. We propose a transformer-based deep Q-network to integrate the disease progression of individual patients and the interaction effects among patients during the critical care resource allocation. We aim to improve both fairness of allocation and overall patient outcomes. Our experiments demonstrate that our method significantly reduces excess deaths and achieves a more equitable distribution under different levels of ventilator shortage, when compared to existing severity-based and comorbidity-based methods in use by different governments. Our source code is included in the supplement and will be released on Github upon publication.

Aligning Agent Policy with Externalities: Reward Design via Bilevel RL

In reinforcement learning (RL), a reward function is often assumed at the outset of a policy optimization procedure. Learning in such a fixed reward paradigm in RL can neglect important policy optimization considerations, such as state space coverage and safety. Moreover, it can fail to encompass broader impacts in terms of social welfare, sustainability, or market stability, potentially leading to undesirable emergent behavior and potentially misaligned policy. To mathematically encapsulate the problem of aligning RL policy optimization with such externalities, we consider a bilevel optimization problem and connect it to a principal-agent framework, where the principal specifies the broader goals and constraints of the system at the upper level and the agent solves a Markov Decision Process (MDP) at the lower level. The upper-level deals with learning a suitable reward parametrization corresponding to the broader goals and the lower-level deals with learning the policy for the agent. We propose Principal driven Policy Alignment via Bilevel RL (PPA-BRL), which efficiently aligns the policy of the agent with the principal's goals. We explicitly analyzed the dependence of the principal's trajectory on the lower-level policy, prove the convergence of PPA-BRL to the stationary point of the problem. We illuminate the merits of this framework in view of alignment with several examples spanning energy-efficient manipulation tasks, social welfare-based tax design, and cost-effective robotic navigation.

Actions Speak What You Want: Provably Sample-Efficient Reinforcement Learning of the Quantal Stackelberg Equilibrium from Strategic Feedbacks

We study reinforcement learning (RL) for learning a Quantal Stackelberg Equilibrium (QSE) in an episodic Markov game with a leader-follower structure. In specific, at the outset of the game, the leader announces her policy to the follower and commits to it. The follower observes the leader's policy and, in turn, adopts a quantal response policy by solving an entropy-regularized policy optimization problem induced by leader's policy. The goal of the leader is to find her optimal policy, which yields the optimal expected total return, by interacting with the follower and learning from data. A key challenge of this problem is that the leader cannot observe the follower's reward, and needs to infer the follower's quantal response model from his actions against leader's policies. We propose sample-efficient algorithms for both the online and offline settings, in the context of function approximation. Our algorithms are based on (i) learning the quantal response model via maximum likelihood estimation and (ii) model-free or model-based RL for solving the leader's decision making problem, and we show that they achieve sublinear regret upper bounds. Moreover, we quantify the uncertainty of these estimators and leverage the uncertainty to implement optimistic and pessimistic algorithms for online and offline settings. Besides, when specialized to the linear and myopic setting, our algorithms are also computationally efficient. Our theoretical analysis features a novel performance-difference lemma which incorporates the error of quantal response model, which might be of independent interest.

Provable Benefits of Policy Learning from Human Preferences in Contextual Bandit Problems

A crucial task in decision-making problems is reward engineering. It is common in practice that no obvious choice of reward function exists. Thus, a popular approach is to introduce human feedback during training and leverage such feedback to learn a reward function. Among all policy learning methods that use human feedback, preference-based methods have demonstrated substantial success in recent empirical applications such as InstructGPT. In this work, we develop a theory that provably shows the benefits of preference-based methods in offline contextual bandits. In particular, we improve the modeling and suboptimality analysis for running policy learning methods on human-scored samples directly. Then, we compare it with the suboptimality guarantees of preference-based methods and show that preference-based methods enjoy lower suboptimality.

Reward-Directed Conditional Diffusion: Provable Distribution Estimation and Reward Improvement

We explore the methodology and theory of reward-directed generation via conditional diffusion models. Directed generation aims to generate samples with desired properties as measured by a reward function, which has broad applications in generative AI, reinforcement learning, and computational biology. We consider the common learning scenario where the data set consists of unlabeled data along with a smaller set of data with noisy reward labels. Our approach leverages a learned reward function on the smaller data set as a pseudolabeler. From a theoretical standpoint, we show that this directed generator can effectively learn and sample from the reward-conditioned data distribution. Additionally, our model is capable of recovering the latent subspace representation of data. Moreover, we establish that the model generates a new population that moves closer to a user-specified target reward value, where the optimality gap aligns with the off-policy bandit regret in the feature subspace. The improvement in rewards obtained is influenced by the interplay between the strength of the reward signal, the distribution shift, and the cost of off-support extrapolation. We provide empirical results to validate our theory and highlight the relationship between the strength of extrapolation and the quality of generated samples.

Sample-Efficient Learning of POMDPs with Multiple Observations In Hindsight

This paper studies the sample-efficiency of learning in Partially Observable Markov Decision Processes (POMDPs), a challenging problem in reinforcement learning that is known to be exponentially hard in the worst-case. Motivated by real-world settings such as loading in game playing, we propose an enhanced feedback model called ``multiple observations in hindsight'', where after each episode of interaction with the POMDP, the learner may collect multiple additional observations emitted from the encountered latent states, but may not observe the latent states themselves. We show that sample-efficient learning under this feedback model is possible for two new subclasses of POMDPs: \emph{multi-observation revealing POMDPs} and \emph{distinguishable POMDPs}. Both subclasses generalize and substantially relax \emph{revealing POMDPs} -- a widely studied subclass for which sample-efficient learning is possible under standard trajectory feedback. Notably, distinguishable POMDPs only require the emission distributions from different latent states to be \emph{different} instead of \emph{linearly independent} as required in revealing POMDPs.

Scaling In-Context Demonstrations with Structured Attention

The recent surge of large language models (LLMs) highlights their ability to perform in-context learning, i.e., "learning" to perform a task from a few demonstrations in the context without any parameter updates. However, their capabilities of in-context learning are limited by the model architecture: 1) the use of demonstrations is constrained by a maximum sentence length due to positional embeddings; 2) the quadratic complexity of attention hinders users from using more demonstrations efficiently; 3) LLMs are shown to be sensitive to the order of the demonstrations. In this work, we tackle these challenges by proposing a better architectural design for in-context learning. We propose SAICL (Structured Attention for In-Context Learning), which replaces the full-attention by a structured attention mechanism designed for in-context learning, and removes unnecessary dependencies between individual demonstrations, while making the model invariant to the permutation of demonstrations. We evaluate SAICL in a meta-training framework and show that SAICL achieves comparable or better performance than full attention while obtaining up to 3.4x inference speed-up. SAICL also consistently outperforms a strong Fusion-in-Decoder (FiD) baseline which processes each demonstration independently. Finally, thanks to its linear nature, we demonstrate that SAICL can easily scale to hundreds of demonstrations with continuous performance gains with scaling.

Nonparametric Classification on Low Dimensional Manifolds using Overparameterized Convolutional Residual Networks

Convolutional residual neural networks (ConvResNets), though overparameterized, can achieve remarkable prediction performance in practice, which cannot be well explained by conventional wisdom. To bridge this gap, we study the performance of ConvResNeXts, which cover ConvResNets as a special case, trained with weight decay from the perspective of nonparametric classification. Our analysis allows for infinitely many building blocks in ConvResNeXts, and shows that weight decay implicitly enforces sparsity on these blocks. Specifically, we consider a smooth target function supported on a low-dimensional manifold, then prove that ConvResNeXts can adapt to the function smoothness and low-dimensional structures and efficiently learn the function without suffering from the curse of dimensionality. Our findings partially justify the advantage of overparameterized ConvResNeXts over conventional machine learning models.