Isaac: ultra-fast whole-genome secondary analysis on Illumina sequencing platforms.

SUMMARY: An ultrafast DNA sequence aligner (Isaac Genome Alignment Software) that takes advantage of high-memory hardware (>48 GB) and variant caller (Isaac Variant Caller) have been developed. We demonstrate that our combined pipeline (Isaac) is four to five times faster than BWA + GATK on equivalent hardware, with comparable accuracy as measured by trio conflict rates and sensitivity. We further show that Isaac is effective in the detection of disease-causing variants and can easily/economically be run on commodity hardware. AVAILABILITY: Isaac has an open source license and can be obtained at https://github.com/sequencing.

Gene Vector Analysis (Geneva): a unified method to detect differentially-regulated gene sets and similar microarray experiments.

BACKGROUND: Microarray experiments measure changes in the expression of thousands of genes. The resulting lists of genes with changes in expression are then searched for biologically related sets using several divergent methods such as the Fisher Exact Test (as used in multiple GO enrichment tools), Parametric Analysis of Gene Expression (PAGE), Gene Set Enrichment Analysis (GSEA), and the connectivity map. RESULTS: We describe an analytical method (Geneva: Gene Vector Analysis) to relate genes to biological properties and to other similar experiments in a uniform way. This new method works on both gene sets and on gene lists/vectors as input queries, and can effectively query databases consisting of sets of biologically related sets, or of results from other microarray experiments. We also present an improvement to the null model estimate by using the empirical background distribution drawn from previous experiments. We validated Geneva by rediscovering a number of previous findings, and by finding significant relationships within microarrays in the GEO repository. CONCLUSION: Provided a reasonable corpus of previous experiments is available, this method is more accurate than the class label permutation model, especially for data sets with limited number of replicates. Geneva is, moreover, computationally faster because the background distributions can be precomputed. We also provide a standard evaluation data set based on 5 pairs of related experiments that should share similar functional relationships and 28 pairs of unrelated experiments from GEO. Discovering relationships amongst GEO data sets has implications for drug repositioning, and understanding relationships between diseases and drugs.

Clustering Molecular Dynamics Trajectories: 1. Characterizing the Performance of Different Clustering Algorithms.

Molecular dynamics simulation methods produce trajectories of atomic positions (and optionally velocities and energies) as a function of time and provide a representation of the sampling of a given molecule's energetically accessible conformational ensemble. As simulations on the 10-100 ns time scale become routine, with sampled configurations stored on the picosecond time scale, such trajectories contain large amounts of data. Data-mining techniques, like clustering, provide one means to group and make sense of the information in the trajectory. In this work, several clustering algorithms were implemented, compared, and utilized to understand MD trajectory data. The development of the algorithms into a freely available C code library, and their application to a simple test example of random (or systematically placed) points in a 2D plane (where the pairwise metric is the distance between points) provide a means to understand the relative performance. Eleven different clustering algorithms were developed, ranging from top-down splitting (hierarchical) and bottom-up aggregating (including single-linkage edge joining, centroid-linkage, average-linkage, complete-linkage, centripetal, and centripetal-complete) to various refinement (means, Bayesian, and self-organizing maps) and tree (COBWEB) algorithms. Systematic testing in the context of MD simulation of various DNA systems (including DNA single strands and the interaction of a minor groove binding drug DB226 with a DNA hairpin) allows a more direct assessment of the relative merits of the distinct clustering algorithms. Additionally, means to assess the relative performance and differences between the algorithms, to dynamically select the initial cluster count, and to achieve faster data mining by "sieved clustering" were evaluated. Overall, it was found that there is no one perfect "one size fits all" algorithm for clustering MD trajectories and that the results strongly depend on the choice of atoms for the pairwise comparison. Some algorithms tend to produce homogeneously sized clusters, whereas others have a tendency to produce singleton clusters. Issues related to the choice of a pairwise metric, clustering metrics, which atom selection is used for the comparison, and about the relative performance are discussed. Overall, the best performance was observed with the average-linkage, means, and SOM algorithms. If the cluster count is not known in advance, the hierarchical or average-linkage clustering algorithms are recommended. Although these algorithms perform well, it is important to be aware of the limitations or weaknesses of each algorithm, specifically the high sensitivity to outliers with hierarchical, the tendency to generate homogenously sized clusters with means, and the tendency to produce small or singleton clusters with average-linkage.