We resolve difficulties in training and sampling from a discrete generative model by learning a smoothed energy function, sampling from the smoothed data manifold with Langevin Markov chain Monte Carlo (MCMC), and projecting back to the true data manifold with one-step denoising. Our $\textit{Discrete Walk-Jump Sampling}$ formalism combines the contrastive divergence training of an energy-based model and improved sample quality of a score-based model, while simplifying training and sampling by requiring only a single noise level. We evaluate the robustness of our approach on generative modeling of antibody proteins and introduce the $\textit{distributional conformity score}$ to benchmark protein generative models. By optimizing and sampling from our models for the proposed distributional conformity score, 97-100\% of generated samples are successfully expressed and purified and 70\% of functional designs show equal or improved binding affinity compared to known functional antibodies on the first attempt in a single round of laboratory experiments. We also report the first demonstration of long-run fast-mixing MCMC chains where diverse antibody protein classes are visited in a single MCMC chain.

We introduce a generative model with an intrinsically interpretable layer---a concept bottleneck layer---that constrains the model to encode human-understandable concepts. The concept bottleneck layer partitions the generative model into three parts: the pre-concept bottleneck portion, the CB layer, and the post-concept bottleneck portion. To train CB generative models, we complement the traditional task-based loss function for training generative models with a concept loss and an orthogonality loss. The CB layer and these loss terms are model agnostic, which we demonstrate by applying the CB layer to three different families of generative models: generative adversarial networks, variational autoencoders, and diffusion models. On multiple datasets across different types of generative models, steering a generative model, with the CB layer, outperforms all baselines---in some cases, it is \textit{10 times} more effective. In addition, we show how the CB layer can be used to interpret the output of the generative model and debug the model during or post training.

Many scientific and industrial applications require the joint optimization of multiple, potentially competing objectives. Multi-objective Bayesian optimization (MOBO) is a sample-efficient framework for identifying Pareto-optimal solutions. At the heart of MOBO is the acquisition function, which determines the next candidate to evaluate by navigating the best compromises among the objectives. Acquisition functions that rely on integrating over the objective space scale poorly to a large number of objectives. In this paper, we show a natural connection between the non-dominated solutions and the highest multivariate rank, which coincides with the extreme level line of the joint cumulative distribution function (CDF). Motivated by this link, we propose the CDF indicator, a Pareto-compliant metric for evaluating the quality of approximate Pareto sets, that can complement the popular hypervolume indicator. We then introduce an acquisition function based on the CDF indicator, called BOtied. BOtied can be implemented efficiently with copulas, a statistical tool for modeling complex, high-dimensional distributions. Our experiments on a variety of synthetic and real-world experiments demonstrate that BOtied outperforms state-of-the-art MOBO algorithms while being computationally efficient for many objectives.

Multiple sequence alignments (MSAs) of proteins encode rich biological information and have been workhorses in bioinformatic methods for tasks like protein design and protein structure prediction for decades. Recent breakthroughs like AlphaFold2 that use transformers to attend directly over large quantities of raw MSAs have reaffirmed their importance. Generation of MSAs is highly computationally intensive, however, and no datasets comparable to those used to train AlphaFold2 have been made available to the research community, hindering progress in machine learning for proteins. To remedy this problem, we introduce OpenProteinSet, an open-source corpus of more than 16 million MSAs, associated structural homologs from the Protein Data Bank, and AlphaFold2 protein structure predictions. We have previously demonstrated the utility of OpenProteinSet by successfully retraining AlphaFold2 on it. We expect OpenProteinSet to be broadly useful as training and validation data for 1) diverse tasks focused on protein structure, function, and design and 2) large-scale multimodal machine learning research.

We propose a new score-based approach to generate 3D molecules represented as atomic densities on regular grids. First, we train a denoising neural network that learns to map from a smooth distribution of noisy molecules to the distribution of real molecules. Then, we follow the _neural empirical Bayes_ framework [Saremi and Hyvarinen, 2019] and generate molecules in two steps: (i) sample noisy density grids from a smooth distribution via underdamped Langevin Markov chain Monte Carlo, and (ii) recover the "clean" molecule by denoising the noisy grid with a single step. Our method, _VoxMol_, generates molecules in a fundamentally different way than the current state of the art (ie, diffusion models applied to atom point clouds). It differs in terms of the data representation, the noise model, the network architecture and the generative modeling algorithm. Our experiments show that VoxMol captures the distribution of drug-like molecules better than state of the art, while being faster to generate samples.

BACKGROUND: The ability to confidently predict health outcomes from gene expression would catalyze a revolution in molecular diagnostics. Yet, the goal of developing actionable, robust, and reproducible predictive signatures of phenotypes such as clinical outcome has not been attained in almost any disease area. Here, we report a comprehensive analysis spanning prediction tasks from ulcerative colitis, atopic dermatitis, diabetes, to many cancer subtypes for a total of 24 binary and multiclass prediction problems and 26 survival analysis tasks. We systematically investigate the influence of gene subsets, normalization methods and prediction algorithms. Crucially, we also explore the novel use of deep representation learning methods on large transcriptomics compendia, such as GTEx and TCGA, to boost the performance of state-of-the-art methods. The resources and findings in this work should serve as both an up-to-date reference on attainable performance, and as a benchmarking resource for further research. RESULTS: -regularized regression methods applied to centered log-ratio transformed transcript abundances provide the best predictive analyses overall. CONCLUSIONS: Transcriptomics-based phenotype prediction benefits from proper normalization techniques and state-of-the-art regularized regression approaches. In our view, breakthrough performance is likely contingent on factors which are independent of normalization and general modeling techniques; these factors might include reduction of systematic errors in sequencing data, incorporation of other data types such as single-cell sequencing and proteomics, and improved use of prior knowledge.