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Abstract MotivationK-mer-based methods are used ubiquitously in the field of computational biology. However, determining the optimal value of k for a specific application often remains heuristic. Simply reconstructing a new k-mer set with another k-mer size is computationally expensive, especially in metagenomic analysis where datasets are large. Here, we introduce a hashing-based technique that leverages a kind of bottom-m sketch as well as a k-mer ternary search tree (KTST) to obtain k-mer-based similarity estimates for a range of k values. By truncating k-mers stored in a pre-built KTST with a large k=kmax value, we can simultaneously obtain k-mer-based estimates for all k values up to kmax. This truncation approach circumvents the reconstruction of new k-mer sets when changing k values, making analysis more time and space-efficient. ResultsWe derived the theoretical expression of the bias factor due to truncation. And we showed that the biases are negligible in practice: when using a KTST to estimate the containment index between a RefSeq-based microbial reference database and simulated metagenome data for 10 values of k, the running time was close to 10× faster compared to a classic MinHash approach while using less than one-fifth the space to store the data structure. Availability and implementationA python implementation of this method, CMash, is available at https://github.com/dkoslicki/CMash. The reproduction of all experiments presented herein can be accessed via https://github.com/KoslickiLab/CMASH-reproducibles. Supplementary informationSupplementary data are available at Bioinformatics online. 

Abstract Metagenomic profiling, predicting the presence and relative abundances of microbes in a sample, is a critical first step in microbiome analysis. Alignment-based approaches are often considered accurate yet computationally infeasible. Here, we present a novel method, Metalign, that performs efficient and accurate alignment-based metagenomic profiling. We use a novel containment min hash approach to pre-filter the reference database prior to alignment and then process both uniquely aligned and multi-aligned reads to produce accurate abundance estimates. In performance evaluations on both real and simulated datasets, Metalign is the only method evaluated that maintained high performance and competitive running time across all datasets. 

Abstract Metagenomics studies leverage genomic reference databases to generate discoveries in basic science and translational research. However, current microbial studies use disparate reference databases that lack consistent standards of specimen inclusion, data preparation, taxon labelling and accessibility, hindering their quality and comprehensiveness, and calling for the establishment of recommendations for reference genome database assembly. Here, we analyze existing fungal and bacterial databases and discuss guidelines for the development of a master reference database that promises to improve the quality and quantity of omics research. 

When analyzing communities of microorganisms from their sequenced DNA, an important task is taxonomic profiling: enumerating the presence and relative abundance of all organisms, or merely of all taxa, contained in the sample. This task can be tackled via compressive-sensing-based approaches, which favor communities featuring the fewest organisms among those consistent with the observed DNA data. Despite their successes, these parsimonious approaches sometimes conflict with biological realism by overlooking organism similarities. Here, we leverage a recently developed notion of biological diversity that simultaneously accounts for organism similarities and retains the optimization strategy underlying compressive-sensing-based approaches. We demonstrate that minimizing biological diversity still produces sparse taxonomic profiles and we experimentally validate superiority to existing compressive-sensing-based approaches. Despite showing that the objective function is almost never convex and often concave, generally yielding NP-hard problems, we exhibit ways of representing organism similarities for which minimizing diversity can be performed via a sequence of linear programs guaranteed to decrease diversity. Better yet, when biological similarity is quantified by k-mer co-occurrence (a popular notion in bioinformatics), minimizing diversity actually reduces to one linear program that can utilize multiple k-mer sizes to enhance performance. In proof-of-concept experiments, we verify that the latter procedure can lead to significant gains when taxonomically profiling a metagenomic sample, both in terms of reconstruction accuracy and computational performance.