Statistical evaluation of pairwise protein sequence comparison with the Bayesian bootstrap

Abstract

Motivation: Protein sequence comparison methods are routinely used to infer the intricate network of evolutionary relationships found within the rapidly growing library of protein sequences, and thereby to predict the structure and function of uncharacterized proteins. In the present study, we detail an improved statistical benchmark of pairwise protein sequence comparison algorithms. We use bootstrap resampling techniques to determine standard statistical errors and to estimate the confidence of our conclusions. We show that the underlying structure within benchmark databases causes Efron's standard, non-parametric bootstrap to be biased. Consequently, the standard bootstrap underpredicts average performance when used in the context of evaluating sequence comparison methods. We have developed, as an alternative, an unbiased statistical evaluation based on the Bayesian bootstrap, a resampling method operationally similar to the standard bootstrap. Results: We apply our analysis to the comparative study of amino acid substitution matrix families and find that using modern matrices results in a small, but statistically significant improvement in remote homology detection compared with the classic PAM and BLOSUM matrices. © The Author 2005. Published by Oxford University Press. All rights reserved.