Abstract: Systems and methods are provided for sorting cells with distinct cell designs for characterizing a library of the cell designs. The present disclosure uses randomized sorting rules associated with bins and pseudo-random numbers to counts the cells with measured fluorescence values in one of the bins. A mean fluorescence value for a cell design group may be determined based on a ratio of cell counts of the cells associated with the cell design group across the bins. Unlike the traditional histogram-based sorting that use a mean fluorescence value of a bin, the disclosed technology determines mean fluorescence values of cell design groups for characterizing libraries of the cell design group. Use of the mean fluorescence values with unbiased “sort-seq” and a de-multiplexed sequencing using the mean fluorescence values enables characterizing libraries of cell designs with improved accuracy over traditional use of discrete histograms.

Abstract: Accurate function estimations and well-calibrated uncertainties are important for Bayesian optimization (BO). Most theoretical guarantees for BO are established for methods that model the objective function with a surrogate drawn from a Gaussian process (GP) prior. GP priors are poorly-suited for discrete, high-dimensional, combinatorial spaces, such as biopolymer sequences. Using a neural network (NN) as the surrogate function can obtain more accurate function estimates. Using a NN can allow arbitrarily complex models, removing the GP prior assumption, and enable easy pretraining, which is beneficial in the low-data BO regime. However, a fully-Bayesian treatment of uncertainty in NNs remains intractable, and existing approximate methods, like Monte Carlo dropout and variational inference, can highly miscalibrate uncertainty estimates.

Abstract: Humanizing proteins can be a laborious process, often involving trial and error or other non-systematic methods. To improve humanization, neural networks can be employed to generate new protein sequences having higher probabilities of being humanized. In an embodiment, a method includes evaluating the immunogenicity of a sampling of protein sequences. The method can include weighting the sampling of protein sequences from the generative model according to an estimated probability of a particular generated protein sequence having a deviation in immunogenicity than a particular percentile of immunogenicity of the sampling of protein sequences. The method can further include generating a protein sequence weighted sampling of protein sequences. The generated protein sequence representing a protein has an altered immunogenicity. Such a generated protein has a higher likelihood of being humanized.