Determining the Number of Samples Required to Estimate Entropy in Natural Sequences

Calculating the Shannon entropy for symbolic sequences has been widely considered in many fields. For descriptive statistical problems such as estimating the N-gram entropy of English language text, a common approach is to use as much data as possible to obtain progressively more accurate estimates. However in some instances, only short sequences may be available. This gives rise to the question of how many samples are needed to compute entropy. In this paper, we examine this problem and propose a method for estimating the number of samples required to compute Shannon entropy for a set of ranked symbolic natural events. The result is developed using a modified Zipf-Mandelbrot law and the Dvoretzky-Kiefer-Wolfowitz inequality, and we propose an algorithm which yields an estimate for the minimum number of samples required to obtain an estimate of entropy with a given confidence level and degree of accuracy

Selection of sequence motifs and generative Hopfield-Potts models for protein familiesilies

Statistical models for families of evolutionary related proteins have recently gained interest: in particular pairwise Potts models, as those inferred by the Direct-Coupling Analysis, have been able to extract information about the three-dimensional structure of folded proteins, and about the effect of amino-acid substitutions in proteins. These models are typically requested to reproduce the one- and two-point statistics of the amino-acid usage in a protein family, {\em i.e.}~to capture the so-called residue conservation and covariation statistics of proteins of common evolutionary origin. Pairwise Potts models are the maximum-entropy models achieving this. While being successful, these models depend on huge numbers of {\em ad hoc} introduced parameters, which have to be estimated from finite amount of data and whose biophysical interpretation remains unclear. Here we propose an approach to parameter reduction, which is based on selecting collective sequence motifs. It naturally leads to the formulation of statistical sequence models in terms of Hopfield-Potts models. These models can be accurately inferred using a mapping to restricted Boltzmann machines and persistent contrastive divergence. We show that, when applied to protein data, even 20-40 patterns are sufficient to obtain statistically close-to-generative models. The Hopfield patterns form interpretable sequence motifs and may be used to clusterize amino-acid sequences into functional sub-families. However, the distributed collective nature of these motifs intrinsically limits the ability of Hopfield-Potts models in predicting contact maps, showing the necessity of developing models going beyond the Hopfield-Potts models discussed here.Comment: 26 pages, 16 figures, to app. in PR

Maximum entropy models for antibody diversity

Recognition of pathogens relies on families of proteins showing great diversity. Here we construct maximum entropy models of the sequence repertoire, building on recent experiments that provide a nearly exhaustive sampling of the IgM sequences in zebrafish. These models are based solely on pairwise correlations between residue positions, but correctly capture the higher order statistical properties of the repertoire. Exploiting the interpretation of these models as statistical physics problems, we make several predictions for the collective properties of the sequence ensemble: the distribution of sequences obeys Zipf's law, the repertoire decomposes into several clusters, and there is a massive restriction of diversity due to the correlations. These predictions are completely inconsistent with models in which amino acid substitutions are made independently at each site, and are in good agreement with the data. Our results suggest that antibody diversity is not limited by the sequences encoded in the genome, and may reflect rapid adaptation to antigenic challenges. This approach should be applicable to the study of the global properties of other protein families

Entropy-based parametric estimation of spike train statistics

We consider the evolution of a network of neurons, focusing on the asymptotic behavior of spikes dynamics instead of membrane potential dynamics. The spike response is not sought as a deterministic response in this context, but as a conditional probability : "Reading out the code" consists of inferring such a probability. This probability is computed from empirical raster plots, by using the framework of thermodynamic formalism in ergodic theory. This gives us a parametric statistical model where the probability has the form of a Gibbs distribution. In this respect, this approach generalizes the seminal and profound work of Schneidman and collaborators. A minimal presentation of the formalism is reviewed here, while a general algorithmic estimation method is proposed yielding fast convergent implementations. It is also made explicit how several spike observables (entropy, rate, synchronizations, correlations) are given in closed-form from the parametric estimation. This paradigm does not only allow us to estimate the spike statistics, given a design choice, but also to compare different models, thus answering comparative questions about the neural code such as : "are correlations (or time synchrony or a given set of spike patterns, ..) significant with respect to rate coding only ?" A numerical validation of the method is proposed and the perspectives regarding spike-train code analysis are also discussed.Comment: 37 pages, 8 figures, submitte

Nonlinear time-series analysis revisited

In 1980 and 1981, two pioneering papers laid the foundation for what became known as nonlinear time-series analysis: the analysis of observed data---typically univariate---via dynamical systems theory. Based on the concept of state-space reconstruction, this set of methods allows us to compute characteristic quantities such as Lyapunov exponents and fractal dimensions, to predict the future course of the time series, and even to reconstruct the equations of motion in some cases. In practice, however, there are a number of issues that restrict the power of this approach: whether the signal accurately and thoroughly samples the dynamics, for instance, and whether it contains noise. Moreover, the numerical algorithms that we use to instantiate these ideas are not perfect; they involve approximations, scale parameters, and finite-precision arithmetic, among other things. Even so, nonlinear time-series analysis has been used to great advantage on thousands of real and synthetic data sets from a wide variety of systems ranging from roulette wheels to lasers to the human heart. Even in cases where the data do not meet the mathematical or algorithmic requirements to assure full topological conjugacy, the results of nonlinear time-series analysis can be helpful in understanding, characterizing, and predicting dynamical systems

Approximations of Algorithmic and Structural Complexity Validate Cognitive-behavioural Experimental Results

We apply methods for estimating the algorithmic complexity of sequences to behavioural sequences of three landmark studies of animal behavior each of increasing sophistication, including foraging communication by ants, flight patterns of fruit flies, and tactical deception and competition strategies in rodents. In each case, we demonstrate that approximations of Logical Depth and Kolmogorv-Chaitin complexity capture and validate previously reported results, in contrast to other measures such as Shannon Entropy, compression or ad hoc. Our method is practically useful when dealing with short sequences, such as those often encountered in cognitive-behavioural research. Our analysis supports and reveals non-random behavior (LD and K complexity) in flies even in the absence of external stimuli, and confirms the "stochastic" behaviour of transgenic rats when faced that they cannot defeat by counter prediction. The method constitutes a formal approach for testing hypotheses about the mechanisms underlying animal behaviour.Comment: 28 pages, 7 figures and 2 table

Microbiome profiling by Illumina sequencing of combinatorial sequence-tagged PCR products

We developed a low-cost, high-throughput microbiome profiling method that uses combinatorial sequence tags attached to PCR primers that amplify the rRNA V6 region. Amplified PCR products are sequenced using an Illumina paired-end protocol to generate millions of overlapping reads. Combinatorial sequence tagging can be used to examine hundreds of samples with far fewer primers than is required when sequence tags are incorporated at only a single end. The number of reads generated permitted saturating or near-saturating analysis of samples of the vaginal microbiome. The large number of reads al- lowed an in-depth analysis of errors, and we found that PCR-induced errors composed the vast majority of non-organism derived species variants, an ob- servation that has significant implications for sequence clustering of similar high-throughput data. We show that the short reads are sufficient to assign organisms to the genus or species level in most cases. We suggest that this method will be useful for the deep sequencing of any short nucleotide region that is taxonomically informative; these include the V3, V5 regions of the bac- terial 16S rRNA genes and the eukaryotic V9 region that is gaining popularity for sampling protist diversity.Comment: 28 pages, 13 figure