Machine learning optimization of candidate antibody yields highly diverse sub-nanomolar affinity antibody libraries.

Therapeutic antibodies are an important and rapidly growing drug modality. However, the design and discovery of early-stage antibody therapeutics remain a time and cost-intensive endeavor. Here we present an end-to-end Bayesian, language model-based method for designing large and diverse libraries of high-affinity single-chain variable fragments (scFvs) that are then empirically measured. In a head-to-head comparison with a directed evolution approach, we show that the best scFv generated from our method represents a 28.7-fold improvement in binding over the best scFv from the directed evolution. Additionally, 99% of designed scFvs in our most successful library are improvements over the initial candidate scFv. By comparing a library's predicted success to actual measurements, we demonstrate our method's ability to explore tradeoffs between library success and diversity. Results of our work highlight the significant impact machine learning models can have on scFv development. We expect our method to be broadly applicable and provide value to other protein engineering tasks.

Explaining COVID-19 outbreaks with reactive SEIRD models.

COVID-19 epidemics have varied dramatically in nature across the United States, where some counties have clear peaks in infections, and others have had a multitude of unpredictable and non-distinct peaks. Our lack of understanding of how the pandemic has evolved leads to increasing errors in our ability to predict the spread of the disease. This work seeks to explain this diversity in epidemic progressions by considering an extension to the compartmental SEIRD model. The model we propose uses a neural network to predict the infection rate as a function of both time and the disease's prevalence. We provide a methodology for fitting this model to available county-level data describing aggregate cases and deaths. Our method uses Expectation-Maximization to overcome the challenge of partial observability, due to the fact that the system's state is only partially reflected in available data. We fit a single model to data from multiple counties in the United States exhibiting different behavior. By simulating the model, we show that it can exhibit both single peak and multi-peak behavior, reproducing behavior observed in counties both in and out of the training set. We then compare the error of simulations from our model with a standard SEIRD model, and show that ours substantially reduces errors. We also use simulated data to compare our methodology for handling partial observability with a standard approach, showing that ours is significantly better at estimating the values of unobserved quantities.

Super-Resolution Community Detection for Layer-Aggregated Multilayer Networks.

Applied network science often involves preprocessing network data before applying a network-analysis method, and there is typically a theoretical disconnect between these steps. For example, it is common to aggregate time-varying network data into windows prior to analysis, and the trade-offs of this preprocessing are not well understood. Focusing on the problem of detecting small communities in multilayer networks, we study the effects of layer aggregation by developing random-matrix theory for modularity matrices associated with layer-aggregated networks with N nodes and L layers, which are drawn from an ensemble of Erdos-Rényi networks with communities planted in subsets of layers. We study phase transitions in which eigenvectors localize onto communities (allowing their detection) and which occur for a given community provided its size surpasses a detectability limit K* . When layers are aggregated via a summation, we obtain [Formula: see text], where T is the number of layers across which the community persists. Interestingly, if T is allowed to vary with L, then summation-based layer aggregation enhances small-community detection even if the community persists across a vanishing fraction of layers, provided that T/L decays more slowly than 𝒪(L-1/2). Moreover, we find that thresholding the summation can, in some cases, cause K* to decay exponentially, decreasing by orders of magnitude in a phenomenon we call super-resolution community detection. In other words, layer aggregation with thresholding is a nonlinear data filter enabling detection of communities that are otherwise too small to detect. Importantly, different thresholds generally enhance the detectability of communities having different properties, illustrating that community detection can be obscured if one analyzes network data using a single threshold.