A New Context Tree Inference Algorithm for Variable Length Markov Chain Model with Applications to Biological Sequence Analyses.

The statistical inference of high-order Markov chains (MCs) for biological sequences is vital for molecular sequence analyses but can be hindered by the high dimensionality of free parameters. In the seminal article by Bühlmann and Wyner, variable length Markov chain (VLMC) model was proposed to embed the full-order MC in a sparse structured context tree. In the key procedure of tree pruning of their proposed context algorithm, the word count-based statistic for each branch was defined and compared with a fixed cutoff threshold calculated from a common chi-square distribution to prune the branch of the context tree. In this study, we find that the word counts for each branch are highly intercorrelated, resulting in non-negligible effects on the distribution of the statistic of interest. We demonstrate that the inferred context tree based on the original context algorithm by Bühlmann and Wyner, which uses a fixed cutoff threshold based on a common chi-square distribution, can be systematically biased and error prone. We denote the original context algorithm as VLMC-Biased (VLMC-B). To solve this problem, we propose a new context tree inference algorithm using an adaptive tree-pruning scheme, termed VLMC-Consistent (VLMC-C). The VLMC-C is founded on the consistent branch-specific mixed chi-square distributions calculated based on asymptotic normal distribution of multiple word patterns. We validate our theoretical branch-specific asymptotic distribution using simulated data. We compare VLMC-C with VLMC-B on context tree inference using both simulated and real genome sequence data and demonstrate that VLMC-C outperforms VLMC-B for both context tree reconstruction accuracy and model compression capacity.