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1.  Optimally discriminative subnetwork markers predict response to chemotherapy 
Bioinformatics  2011;27(13):i205-i213.
Motivation: Molecular profiles of tumour samples have been widely and successfully used for classification problems. A number of algorithms have been proposed to predict classes of tumor samples based on expression profiles with relatively high performance. However, prediction of response to cancer treatment has proved to be more challenging and novel approaches with improved generalizability are still highly needed. Recent studies have clearly demonstrated the advantages of integrating protein–protein interaction (PPI) data with gene expression profiles for the development of subnetwork markers in classification problems.
Results: We describe a novel network-based classification algorithm (OptDis) using color coding technique to identify optimally discriminative subnetwork markers. Focusing on PPI networks, we apply our algorithm to drug response studies: we evaluate our algorithm using published cohorts of breast cancer patients treated with combination chemotherapy. We show that our OptDis method improves over previously published subnetwork methods and provides better and more stable performance compared with other subnetwork and single gene methods. We also show that our subnetwork method produces predictive markers that are more reproducible across independent cohorts and offer valuable insight into biological processes underlying response to therapy.
Availability: The implementation is available at: http://www.cs.sfu.ca/~pdao/personal/OptDis.html
Contact: cenk@cs.sfu.ca; alapuk@prostatecentre.com; ccollins@prostatecentre.com
doi:10.1093/bioinformatics/btr245
PMCID: PMC3117373  PMID: 21685072
2.  Inferring cancer subnetwork markers using density-constrained biclustering 
Bioinformatics  2010;26(18):i625-i631.
Motivation: Recent genomic studies have confirmed that cancer is of utmost phenotypical complexity, varying greatly in terms of subtypes and evolutionary stages. When classifying cancer tissue samples, subnetwork marker approaches have proven to be superior over single gene marker approaches, most importantly in cross-platform evaluation schemes. However, prior subnetwork-based approaches do not explicitly address the great phenotypical complexity of cancer.
Results: We explicitly address this and employ density-constrained biclustering to compute subnetwork markers, which reflect pathways being dysregulated in many, but not necessarily all samples under consideration. In breast cancer we achieve substantial improvements over all cross-platform applicable approaches when predicting TP53 mutation status in a well-established non-cross-platform setting. In colon cancer, we raise prediction accuracy in the most difficult instances from 87% to 93% for cancer versus non−cancer and from 83% to (astonishing) 92%, for with versus without liver metastasis, in well-established cross-platform evaluation schemes.
Availability: Software is available on request.
Contact: alexsch@math.berkeley.edu; ester@cs.sfu.ca
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btq393
PMCID: PMC2935415  PMID: 20823331
3.  Next-generation VariationHunter: combinatorial algorithms for transposon insertion discovery 
Bioinformatics  2010;26(12):i350-i357.
Recent years have witnessed an increase in research activity for the detection of structural variants (SVs) and their association to human disease. The advent of next-generation sequencing technologies make it possible to extend the scope of structural variation studies to a point previously unimaginable as exemplified by the 1000 Genomes Project. Although various computational methods have been described for the detection of SVs, no such algorithm is yet fully capable of discovering transposon insertions, a very important class of SVs to the study of human evolution and disease. In this article, we provide a complete and novel formulation to discover both loci and classes of transposons inserted into genomes sequenced with high-throughput sequencing technologies. In addition, we also present ‘conflict resolution’ improvements to our earlier combinatorial SV detection algorithm (VariationHunter) by taking the diploid nature of the human genome into consideration. We test our algorithms with simulated data from the Venter genome (HuRef) and are able to discover >85% of transposon insertion events with precision of >90%. We also demonstrate that our conflict resolution algorithm (denoted as VariationHunter-CR) outperforms current state of the art (such as original VariationHunter, BreakDancer and MoDIL) algorithms when tested on the genome of the Yoruba African individual (NA18507).
Availability: The implementation of algorithm is available at http://compbio.cs.sfu.ca/strvar.htm.
Contact: eee@gs.washington.edu; cenk@cs.sfu.ca
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btq216
PMCID: PMC2881400  PMID: 20529927
4.  PSORTb 3.0: improved protein subcellular localization prediction with refined localization subcategories and predictive capabilities for all prokaryotes 
Bioinformatics  2010;26(13):1608-1615.
Motivation: PSORTb has remained the most precise bacterial protein subcellular localization (SCL) predictor since it was first made available in 2003. However, the recall needs to be improved and no accurate SCL predictors yet make predictions for archaea, nor differentiate important localization subcategories, such as proteins targeted to a host cell or bacterial hyperstructures/organelles. Such improvements should preferably be encompassed in a freely available web-based predictor that can also be used as a standalone program.
Results: We developed PSORTb version 3.0 with improved recall, higher proteome-scale prediction coverage, and new refined localization subcategories. It is the first SCL predictor specifically geared for all prokaryotes, including archaea and bacteria with atypical membrane/cell wall topologies. It features an improved standalone program, with a new batch results delivery system complementing its web interface. We evaluated the most accurate SCL predictors using 5-fold cross validation plus we performed an independent proteomics analysis, showing that PSORTb 3.0 is the most accurate but can benefit from being complemented by Proteome Analyst predictions.
Availability: http://www.psort.org/psortb (download open source software or use the web interface).
Contact: psort-mail@sfu.ca
Supplementary Information: Supplementary data are availableat Bioinformatics online.
doi:10.1093/bioinformatics/btq249
PMCID: PMC2887053  PMID: 20472543
5.  Biomolecular network motif counting and discovery by color coding 
Bioinformatics  2008;24(13):i241-i249.
Protein–protein interaction (PPI) networks of many organisms share global topological features such as degree distribution, k-hop reachability, betweenness and closeness. Yet, some of these networks can differ significantly from the others in terms of local structures: e.g. the number of specific network motifs can vary significantly among PPI networks.
Counting the number of network motifs provides a major challenge to compare biomolecular networks. Recently developed algorithms have been able to count the number of induced occurrences of subgraphs with k≤ 7 vertices. Yet no practical algorithm exists for counting non-induced occurrences, or counting subgraphs with k≥ 8 vertices. Counting non-induced occurrences of network motifs is not only challenging but also quite desirable as available PPI networks include several false interactions and miss many others.
In this article, we show how to apply the ‘color coding’ technique for counting non-induced occurrences of subgraph topologies in the form of trees and bounded treewidth subgraphs. Our algorithm can count all occurrences of motif G′ with k vertices in a network G with n vertices in time polynomial with n, provided k=O(log n). We use our algorithm to obtain ‘treelet’ distributions for k≤ 10 of available PPI networks of unicellular organisms (Saccharomyces cerevisiae Escherichia coli and Helicobacter Pyloris), which are all quite similar, and a multicellular organism (Caenorhabditis elegans) which is significantly different. Furthermore, the treelet distribution of the unicellular organisms are similar to that obtained by the ‘duplication model’ but are quite different from that of the ‘preferential attachment model’. The treelet distribution is robust w.r.t. sparsification with bait/edge coverage of 70% but differences can be observed when bait/edge coverage drops to 50%.
Contact:cenk@cs.sfu.ca
doi:10.1093/bioinformatics/btn163
PMCID: PMC2718641  PMID: 18586721

Results 1-5 (5)