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.

Probabilistic program inference in network-based epidemiological simulations.

Accurate epidemiological models require parameter estimates that account for mobility patterns and social network structure. We demonstrate the effectiveness of probabilistic programming for parameter inference in these models. We consider an agent-based simulation that represents mobility networks as degree-corrected stochastic block models, whose parameters we estimate from cell phone co-location data. We then use probabilistic program inference methods to approximate the distribution over disease transmission parameters conditioned on reported cases and deaths. Our experiments demonstrate that the resulting models improve the quality of fit in multiple geographies relative to baselines that do not model network topology.

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.

The social nestwork: tree structure determines nest placement in Kenyan weaverbird colonies.

Group living is a life history strategy employed by many organisms. This strategy is often difficult to study because the exact boundaries of a group can be unclear. Weaverbirds present an ideal model for the study of group living, because their colonies occupy a space with discrete boundaries: a single tree. We examined one aspect of group living. nest placement, in three Kenyan weaverbird species: the Black-capped Weaver (Pseudonigrita cabanisi), Grey-capped Weaver (P. arnaudi) and White-browed Sparrow Weaver (Ploceropasser mahali). We asked which environmental, biological, and/or abiotic factors influenced their nest arrangement and location in a given tree. We used machine learning to analyze measurements taken from 16 trees and 516 nests outside the breeding season at the Mpala Research Station in Laikipia Kenya, along with climate data for the area. We found that tree architecture, number of nests per tree, and nest-specific characteristics were the main variables driving nest placement. Our results suggest that different Kenyan weaverbird species have similar priorities driving the selection of where a nest is placed within a given tree. Our work illustrates the advantage of using machine learning techniques to investigate biological questions.