Recent work demonstrated a large ensemble of convolutional neural networks (CNNs) outperforms industry-standard approaches at annotating protein sequences that are far from the training data. These results highlight the potential of deep learning to significantly advance protein sequence annotation, but this particular system is not a practical tool for many biologists because of the computational burden of making predictions using a large ensemble. In this work, we fine-tune a transformer model that is pre-trained on millions of unlabeled natural protein sequences in order to reduce the system's compute burden at prediction time and improve accuracy. By switching from a CNN to the pre-trained transformer, we lift performance from 73.6% to 90.5% using a single model on a challenging clustering-based train-test split, where the ensemble of 59 CNNs achieved 89.0%. Through extensive stratified analysis of model performance, we provide evidence that the new model's predictions are trustworthy, even in cases known to be challenging for prior methods. Finally, we provide a case study of the biological insight enabled by this approach.

The use of black-box optimization for the design of new biological sequences is an emerging research area with potentially revolutionary impact. The cost and latency of wet-lab experiments requires methods that find good sequences in few experimental rounds of large batches of sequences — a setting that off-the-shelf black-box optimization methods are ill-equipped to handle. We find that the performance of existing methods varies drastically across optimization tasks, posing a significant obstacle to real-world applications. To improve robustness, we propose Population-Based Black-Box Optimization (P3BO), which generates batches of sequences by sampling from an ensemble of methods. The number of sequences sampled from any method is proportional to the quality of sequences it previously proposed, allowing P3BO to combine the strengths of individual methods while hedging against their innate brittleness. Adapting the hyper-parameters of each of the methods online using evolutionary optimization further improves performance. Through extensive experiments on in-silico optimization tasks, we show that P3BO outperforms any single method in its population, proposing higher quality sequences as well as more diverse batches. As such, P3BO and Adaptive-P3BO are a crucial step towards deploying ML to real-world sequence design.

Reparameterization of variational auto-encoders with continuous random variables is an effective method for reducing the variance of their gradient estimates. In the discrete case, one can perform reparametrization using the Gumbel-Max trick, but the resulting objective relies on an $\arg \max$ operation and is non-differentiable. In contrast to previous works which resort to \emph{softmax}-based relaxations, we propose to optimize it directly by applying the \emph{direct loss minimization} approach. Our proposal extends naturally to structured discrete latent variable models when evaluating the $\arg \max$ operation is tractable. We demonstrate empirically the effectiveness of the direct loss minimization technique in variational autoencoders with both unstructured and structured discrete latent variables.

Perturbation models are families of distributions induced from perturbations. They combine randomization of the parameters with maximization to draw unbiased samples. Unlike Gibbs’ distributions, a perturbation model defined on the basis of low order statistics still gives rise to high order dependencies. In this paper, we analyze, extend and seek to estimate such dependencies from data. In particular, we shift the modelling focus from the parameters of the Gibbs’ distribution used as a base model to the space of perturbations. We estimate dependent perturbations over the parameters using a hard-EM approach, cast in the form of inverse convex programs. Each inverse program confines the randomization to the parameter polytope responsible for generating the observed answer. We illustrate the method on several computer vision problems.