Colin LaMont

Michael N. Pun, Andrew Ivanov, Quinn Bellamy et al.

Proteins play a central role in biology from immune recognition to brain activity. While major advances in machine learning have improved our ability to predict protein structure from sequence, determining protein function from structure remains a major challenge. Here, we introduce Holographic Convolutional Neural Network (H-CNN) for proteins, which is a physically motivated machine learning approach to model amino acid preferences in protein structures. H-CNN reflects physical interactions in a protein structure and recapitulates the functional information stored in evolutionary data. H-CNN accurately predicts the impact of mutations on protein function, including stability and binding of protein complexes. Our interpretable computational model for protein structure-function maps could guide design of novel proteins with desired function.

Jakub Otwinowski, Colin LaMont

Evolutionary algorithms, inspired by natural evolution, aim to optimize difficult objective functions without computing derivatives. Here we detail the relationship between population genetics and evolutionary optimization and formulate a new evolutionary algorithm. Optimization of a continuous objective function is analogous to searching for high fitness phenotypes on a fitness landscape. We summarize how natural selection moves a population along the non-euclidean gradient that is induced by the population on the fitness landscape (the natural gradient). Under normal approximations common in quantitative genetics, we show how selection is related to Newton's method in optimization. We find that intermediate selection is most informative of the fitness landscape. We describe the generation of new phenotypes and introduce an operator that recombines the whole population to generate variants that preserve normal statistics. Finally, we introduce a proof-of-principle algorithm that combines natural selection, our recombination operator, and an adaptive method to increase selection. Our algorithm is similar to covariance matrix adaptation and natural evolutionary strategies in optimization, and has similar performance. The algorithm is extremely simple in implementation with no matrix inversion or factorization, does not require storing a covariance matrix, and may form the basis of more general model-based optimization algorithms with natural gradient updates.

Colin H. LaMont, Paul A. Wiggins

In the information-based paradigm of inference, model selection is performed by selecting the candidate model with the best estimated predictive performance. The success of this approach depends on the accuracy of the estimate of the predictive complexity. In the large-sample-size limit of a regular model, the predictive performance is well estimated by the Akaike Information Criterion (AIC). However, this approximation can either significantly under or over-estimating the complexity in a wide range of important applications where models are either non-regular or finite-sample-size corrections are significant. We introduce an improved approximation for the complexity that is used to define a new information criterion: the Frequentist Information Criterion (QIC). QIC extends the applicability of information-based inference to the finite-sample-size regime of regular models and to singular models. We demonstrate the power and the comparative advantage of QIC in a number of example analyses.

Colin H. LaMont, Paul A. Wiggins

There are three principle paradigms of statistical inference: (i) Bayesian, (ii) information-based and (iii) frequentist inference. We describe an objective prior (the weighting or $w$-prior) which unifies objective Bayes and information-based inference. The $w$-prior is chosen to make the marginal probability an unbiased estimator of the predictive performance of the model. This definition has several other natural interpretations. From the perspective of the information content of the prior, the $w$-prior is both uniformly and maximally uninformative. The $w$-prior can also be understood to result in a uniform density of distinguishable models in parameter space. Finally we demonstrate the the $w$-prior is equivalent to the Akaike Information Criterion (AIC) for regular models in the asymptotic limit. The $w$-prior appears to be generically applicable to statistical inference and is free of {\it ad hoc} regularization. The mechanism for suppressing complexity is analogous to AIC: model complexity reduces model predictivity. We expect this new objective-Bayes approach to inference to be widely-applicable to machine-learning problems including singular models.

Paul A. Wiggins, Colin H. LaMont

Change-point analysis is a flexible and computationally tractable tool for the analysis of times series data from systems that transition between discrete states and whose observables are corrupted by noise. The change-point algorithm is used to identify the time indices (change points) at which the system transitions between these discrete states. We present a unified information-based approach to testing for the existence of change points. This new approach reconciles two previously disparate approaches to Change-Point Analysis (frequentist and information-based) for testing transitions between states. The resulting method is statistically principled, parameter and prior free and widely applicable to a wide range of change-point problems.