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1.  The multiscale backbone of the human phenotype network based on biological pathways 
BioData Mining  2014;7:1.
Background
Networks are commonly used to represent and analyze large and complex systems of interacting elements. In systems biology, human disease networks show interactions between disorders sharing common genetic background. We built pathway-based human phenotype network (PHPN) of over 800 physical attributes, diseases, and behavioral traits; based on about 2,300 genes and 1,200 biological pathways. Using GWAS phenotype-to-genes associations, and pathway data from Reactome, we connect human traits based on the common patterns of human biological pathways, detecting more pleiotropic effects, and expanding previous studies from a gene-centric approach to that of shared cell-processes.
Results
The resulting network has a heavily right-skewed degree distribution, placing it in the scale-free region of the network topologies spectrum. We extract the multi-scale information backbone of the PHPN based on the local densities of the network and discarding weak connection. Using a standard community detection algorithm, we construct phenotype modules of similar traits without applying expert biological knowledge. These modules can be assimilated to the disease classes. However, we are able to classify phenotypes according to shared biology, and not arbitrary disease classes. We present examples of expected clinical connections identified by PHPN as proof of principle.
Conclusions
We unveil a previously uncharacterized connection between phenotype modules and discuss potential mechanistic connections that are obvious only in retrospect. The PHPN shows tremendous potential to become a useful tool both in the unveiling of the diseases’ common biology, and in the elaboration of diagnosis and treatments.
doi:10.1186/1756-0381-7-1
PMCID: PMC3924922  PMID: 24460644
Diseasome; Phenotypes; GWAS; Network; Information theory; Biological pathways
2.  Genomic analyses with biofilter 2.0: knowledge driven filtering, annotation, and model development 
BioData Mining  2013;6:25.
Background
The ever-growing wealth of biological information available through multiple comprehensive database repositories can be leveraged for advanced analysis of data. We have now extensively revised and updated the multi-purpose software tool Biofilter that allows researchers to annotate and/or filter data as well as generate gene-gene interaction models based on existing biological knowledge. Biofilter now has the Library of Knowledge Integration (LOKI), for accessing and integrating existing comprehensive database information, including more flexibility for how ambiguity of gene identifiers are handled. We have also updated the way importance scores for interaction models are generated. In addition, Biofilter 2.0 now works with a range of types and formats of data, including single nucleotide polymorphism (SNP) identifiers, rare variant identifiers, base pair positions, gene symbols, genetic regions, and copy number variant (CNV) location information.
Results
Biofilter provides a convenient single interface for accessing multiple publicly available human genetic data sources that have been compiled in the supporting database of LOKI. Information within LOKI includes genomic locations of SNPs and genes, as well as known relationships among genes and proteins such as interaction pairs, pathways and ontological categories.
Via Biofilter 2.0 researchers can:
• Annotate genomic location or region based data, such as results from association studies, or CNV analyses, with relevant biological knowledge for deeper interpretation
• Filter genomic location or region based data on biological criteria, such as filtering a series SNPs to retain only SNPs present in specific genes within specific pathways of interest
• Generate Predictive Models for gene-gene, SNP-SNP, or CNV-CNV interactions based on biological information, with priority for models to be tested based on biological relevance, thus narrowing the search space and reducing multiple hypothesis-testing.
Conclusions
Biofilter is a software tool that provides a flexible way to use the ever-expanding expert biological knowledge that exists to direct filtering, annotation, and complex predictive model development for elucidating the etiology of complex phenotypic outcomes.
doi:10.1186/1756-0381-6-25
PMCID: PMC3917600  PMID: 24378202
Data mining; Bioinformatics; Expert knowledge; Modeling; Pathway analyses; Epistasis
3.  An association-adjusted consensus deleterious scheme to classify homozygous Mis-sense mutations for personal genome interpretation 
BioData Mining  2013;6:24.
Background
Personal genome analysis is now being considered for evaluation of disease risk in healthy individuals, utilizing both rare and common variants. Multiple scores have been developed to predict the deleteriousness of amino acid substitutions, using information on the allele frequencies, level of evolutionary conservation, and averaged structural evidence. However, agreement among these scores is limited and they likely over-estimate the fraction of the genome that is deleterious.
Method
This study proposes an integrative approach to identify a subset of homozygous non-synonymous single nucleotide polymorphisms (nsSNPs). An 8-level classification scheme is constructed from the presence/absence of deleterious predictions combined with evidence of association with disease or complex traits. Detailed literature searches and structural validations are then performed for a subset of homozygous 826 mis-sense mutations in 575 proteins found in the genomes of 12 healthy adults.
Results
Implementation of the Association-Adjusted Consensus Deleterious Scheme (AACDS) classifies 11% of all predicted highly deleterious homozygous variants as most likely to influence disease risk. The number of such variants per genome ranges from 0 to 8 with no significant difference between African and Caucasian Americans. Detailed analysis of mutations affecting the APOE, MTMR2, THSB1, CHIA, αMyHC, and AMY2A proteins shows how the protein structure is likely to be disrupted, even though the associated phenotypes have not been documented in the corresponding individuals.
Conclusions
The classification system for homozygous nsSNPs provides an opportunity to systematically rank nsSNPs based on suggestive evidence from annotations and sequence-based predictions. The ranking scheme, in-depth literature searches, and structural validations of highly prioritized mis-sense mutations compliment traditional sequence-based approaches and should have particular utility for the development of individualized health profiles. An online tool reporting the AACDS score for any variant is provided at the authors’ website.
doi:10.1186/1756-0381-6-24
PMCID: PMC3892026  PMID: 24365473
Homozygous variant; Non-synonymous single nucleotide polymorphism; Personal genome interpretation; Variant prioritization; Protein structure analysis
4.  ATHENA: Identifying interactions between different levels of genomic data associated with cancer clinical outcomes using grammatical evolution neural network 
BioData Mining  2013;6:23.
Background
Gene expression profiles have been broadly used in cancer research as a diagnostic or prognostic signature for the clinical outcome prediction such as stage, grade, metastatic status, recurrence, and patient survival, as well as to potentially improve patient management. However, emerging evidence shows that gene expression-based prediction varies between independent data sets. One possible explanation of this effect is that previous studies were focused on identifying genes with large main effects associated with clinical outcomes. Thus, non-linear interactions without large individual main effects would be missed. The other possible explanation is that gene expression as a single level of genomic data is insufficient to explain the clinical outcomes of interest since cancer can be dysregulated by multiple alterations through genome, epigenome, transcriptome, and proteome levels. In order to overcome the variability of diagnostic or prognostic predictors from gene expression alone and to increase its predictive power, we need to integrate multi-levels of genomic data and identify interactions between them associated with clinical outcomes.
Results
Here, we proposed an integrative framework for identifying interactions within/between multi-levels of genomic data associated with cancer clinical outcomes using the Grammatical Evolution Neural Networks (GENN). In order to demonstrate the validity of the proposed framework, ovarian cancer data from TCGA was used as a pilot task. We found not only interactions within a single genomic level but also interactions between multi-levels of genomic data associated with survival in ovarian cancer. Notably, the integration model from different levels of genomic data achieved 72.89% balanced accuracy and outperformed the top models with any single level of genomic data.
Conclusions
Understanding the underlying tumorigenesis and progression in ovarian cancer through the global view of interactions within/between different levels of genomic data is expected to provide guidance for improved prognostic biomarkers and individualized therapies.
doi:10.1186/1756-0381-6-23
PMCID: PMC3912499  PMID: 24359638
Integrative analysis; Multi-omics data; Grammatical evolution neural network; Ovarian cancer
5.  Big Data analysis on autopilot? 
BioData Mining  2013;6:22.
doi:10.1186/1756-0381-6-22
PMCID: PMC3878969  PMID: 24314297
6.  Graph representation of high-dimensional alpha-helical membrane protein data 
BioData Mining  2013;6:21.
Background
In genomics and proteomics, membrane protein analysis have shown that such analyses are very important to support the understanding of complex biological processes. In Genome-wide investigations of membrane proteins a large number of short, distinct sequence motifs has been revealed. Such motifs found so far support the understanding of the folded membrane protein in the membrane environment. They provide important information about functional or stabilizing properties. Recently several integrative approaches have been proposed to extract meaningful information out of the membrane environment. However, many information based approaches deliver results having deficits of visualisation outputs. Outgoing from high-throughput protein data analysis, these outputs play an important role in the evaluation of high-dimensional protein data, to establish a biological relationship and ultimately to provide useful information for research.
Results
We have evaluated different resulting graphs generated from statistical analysis of consecutive motifs in helical structures of the membrane environment. Our results show that representative motifs with high occurrence in all investigated protein families are responsible for the general importance in alpha-helical membrane structure formation. Further, motifs which often occur with others in their function as so called “hubs” lead to the assumption, that these motifs constitute as important components in helical structures within the membrane. Otherwise, consecutive motifs and hubs which show a high occurrence in certain families only can be classified as important for family-specific functional characteristics. Summarized, we are able to bridge our graphical results from high-throughput analysis of membrane proteins over networking with databases to a biological context.
Conclusions
Our results and the corresponding graphical visualisation support the understanding and interpretation of structure forming and functional motifs of membrane proteins. Our results are useful to interpret and refine results of common developed approaches. At last we show a simple way to visualise high-dimensional protein data in context to biological relevant information.
doi:10.1186/1756-0381-6-21
PMCID: PMC3879021  PMID: 24294896
Membrane proteins; Motifs; Graph; Architecture
7.  No-boundary thinking in bioinformatics research 
BioData Mining  2013;6:19.
Currently there are definitions from many agencies and research societies defining “bioinformatics” as deriving knowledge from computational analysis of large volumes of biological and biomedical data. Should this be the bioinformatics research focus? We will discuss this issue in this review article. We would like to promote the idea of supporting human-infrastructure (HI) with no-boundary thinking (NT) in bioinformatics (HINT).
doi:10.1186/1756-0381-6-19
PMCID: PMC3827872  PMID: 24192339
No-boundary thinking; Human infrastructure
8.  gff2sequence, a new user friendly tool for the generation of genomic sequences 
BioData Mining  2013;6:15.
Background
General Feature Format (GFF) files are used to store genome features such as genes, exons, introns, primary transcripts etc. Although many software packages (i.e. ab initio gene prediction programs) can annotate features by using such a standard, a small number of tools have been developed to extract the corresponding sequence information from the original genome. However the present tools do not execute either a quality control or a customizable filter of the annotated features is available.
Findings
gff2sequence is a program that extracts nucleotide/protein sequences from a genomic multifasta by using the information provided by a general feature format file. While a graphical user interface makes this software very easy to use, a C++ algorithm allows high performance together with low hardware demand. The software also allows the extraction of the genic portions such as the untranslated and the coding sequences. Moreover a highly customizable quality control pipeline can be used to deal with anomalous splicing sites, incorrect open reading frames and not canonical characters within the retrieved sequences.
Conclusions
gff2sequence is a user friendly program that allows the generation of highly customizable sequence datasets by processing a general feature format file. The presence of a wide range of quality filters makes this tool also suitable for refining the ab initio gene predictions.
doi:10.1186/1756-0381-6-15
PMCID: PMC3848729  PMID: 24020993
Gene annotation; General feature format; Sequence quality
9.  The central role of biological data mining in connecting diverse disciplines 
BioData Mining  2013;6:14.
doi:10.1186/1756-0381-6-14
PMCID: PMC3765075  PMID: 23937773
10.  Unraveling genomic variation from next generation sequencing data 
BioData Mining  2013;6:13.
Elucidating the content of a DNA sequence is critical to deeper understand and decode the genetic information for any biological system. As next generation sequencing (NGS) techniques have become cheaper and more advanced in throughput over time, great innovations and breakthrough conclusions have been generated in various biological areas. Few of these areas, which get shaped by the new technological advances, involve evolution of species, microbial mapping, population genetics, genome-wide association studies (GWAs), comparative genomics, variant analysis, gene expression, gene regulation, epigenetics and personalized medicine. While NGS techniques stand as key players in modern biological research, the analysis and the interpretation of the vast amount of data that gets produced is a not an easy or a trivial task and still remains a great challenge in the field of bioinformatics. Therefore, efficient tools to cope with information overload, tackle the high complexity and provide meaningful visualizations to make the knowledge extraction easier are essential. In this article, we briefly refer to the sequencing methodologies and the available equipment to serve these analyses and we describe the data formats of the files which get produced by them. We conclude with a thorough review of tools developed to efficiently store, analyze and visualize such data with emphasis in structural variation analysis and comparative genomics. We finally comment on their functionality, strengths and weaknesses and we discuss how future applications could further develop in this field.
doi:10.1186/1756-0381-6-13
PMCID: PMC3726446  PMID: 23885890
SNPs; SNVs; CNV; Structural variation; Sequencing; Genome browser; Visualization; Polymorphisms; Genome wide association studies
12.  MicroRNA-mediated regulation of target genes in several brain regions is correlated to both microRNA-targeting-specific promoter methylation and differential microRNA expression 
BioData Mining  2013;6:11.
Background
Public domain databases nowadays provide multiple layers of genome-wide data e.g., promoter methylation, mRNA expression, and miRNA expression and should enable integrative modeling of the mechanisms of regulation of gene expression. However, researches along this line were not frequently executed.
Results
Here, the public domain dataset of mRNA expression, microRNA (miRNA) expression and promoter methylation patterns in four regions, the frontal cortex, temporal cortex, pons and cerebellum, of human brain were sourced from the National Center for Biotechnology Informations gene expression omnibus, and reanalyzed computationally. A large number of miRNA-mediated regulation of target genes and miRNA-targeting-specific promoter methylation were identified in the six pairwise comparisons among the four brain regions. The miRNA-mediated regulation of target genes was found to be highly correlated with one or both of miRNA-targeting-specific promoter methylation and differential miRNA expression. Genes enriched for Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways that were related to brain function and/or development were found among the target genes of miRNAs whose differential expression patterns were highly correlated with the miRNA-mediated regulation of their target genes.
Conclusions
The combinatorial analysis of miRNA-mediated regulation of target genes, miRNA-targeting-specific promoter methylation and differential miRNA expression can help reveal the brain region-specific contributions of miRNAs to brain function and development.
doi:10.1186/1756-0381-6-11
PMCID: PMC3693885  PMID: 23725297
MicroRNA; Target gene regulation; Brain regions; Promoter methylation; Pathway analysis
13.  The limits of p-values for biological data mining 
BioData Mining  2013;6:10.
doi:10.1186/1756-0381-6-10
PMCID: PMC3668262  PMID: 23663551
14.  A robustness study of parametric and non-parametric tests in model-based multifactor dimensionality reduction for epistasis detection 
BioData Mining  2013;6:9.
Background
Applying a statistical method implies identifying underlying (model) assumptions and checking their validity in the particular context. One of these contexts is association modeling for epistasis detection. Here, depending on the technique used, violation of model assumptions may result in increased type I error, power loss, or biased parameter estimates. Remedial measures for violated underlying conditions or assumptions include data transformation or selecting a more relaxed modeling or testing strategy. Model-Based Multifactor Dimensionality Reduction (MB-MDR) for epistasis detection relies on association testing between a trait and a factor consisting of multilocus genotype information. For quantitative traits, the framework is essentially Analysis of Variance (ANOVA) that decomposes the variability in the trait amongst the different factors. In this study, we assess through simulations, the cumulative effect of deviations from normality and homoscedasticity on the overall performance of quantitative Model-Based Multifactor Dimensionality Reduction (MB-MDR) to detect 2-locus epistasis signals in the absence of main effects.
Methodology
Our simulation study focuses on pure epistasis models with varying degrees of genetic influence on a quantitative trait. Conditional on a multilocus genotype, we consider quantitative trait distributions that are normal, chi-square or Student’s t with constant or non-constant phenotypic variances. All data are analyzed with MB-MDR using the built-in Student’s t-test for association, as well as a novel MB-MDR implementation based on Welch’s t-test. Traits are either left untransformed or are transformed into new traits via logarithmic, standardization or rank-based transformations, prior to MB-MDR modeling.
Results
Our simulation results show that MB-MDR controls type I error and false positive rates irrespective of the association test considered. Empirically-based MB-MDR power estimates for MB-MDR with Welch’s t-tests are generally lower than those for MB-MDR with Student’s t-tests. Trait transformations involving ranks tend to lead to increased power compared to the other considered data transformations.
Conclusions
When performing MB-MDR screening for gene-gene interactions with quantitative traits, we recommend to first rank-transform traits to normality and then to apply MB-MDR modeling with Student’s t-tests as internal tests for association.
doi:10.1186/1756-0381-6-9
PMCID: PMC3668290  PMID: 23618370
Model-based multifactor dimensionality reduction; Epistasis; Model violations; Data transformation
15.  Prediction of Drosophila melanogaster gene function using Support Vector Machines 
BioData Mining  2013;6:8.
Background
While the genomes of hundreds of organisms have been sequenced and good approaches exist for finding protein encoding genes, an important remaining challenge is predicting the functions of the large fraction of genes for which there is no annotation. Large gene expression datasets from microarray experiments already exist and many of these can be used to help assign potential functions to these genes. We have applied Support Vector Machines (SVM), a sigmoid fitting function and a stratified cross‐validation approach to analyze a large microarray experiment dataset from Drosophila melanogaster in order to predict possible functions for previously un‐annotated genes. A total of approximately 5043 different genes, or about one‐third of the predicted genes in the D. melanogaster genome, are represented in the dataset and 1854 (or 37%) of these genes are un‐annotated.
Results
39 Gene Ontology Biological Process (GO‐BP) categories were found with precision value equal or larger than 0.75, when recall was fixed at the 0.4 level. For two of those categories, we have provided additional support for assigning given genes to the category by showing that the majority of transcripts for the genes belonging in a given category have a similar localization pattern during embryogenesis. Additionally, by assessing the predictions using a confidence score, we have been able to provide a putative GO‐BP term for 1422 previously un‐annotated genes or about 77% of the un‐annotated genes represented on the microarray and about 19% of all of the un‐annotated genes in the D. melanogaster genome.
Conclusions
Our study successfully employs a number of SVM classifiers, accompanied by detailed calibration and validation techniques, to generate a number of predictions for new annotations for D. melanogaster genes. The applied probabilistic analysis to SVM output improves the interpretability of the prediction results and the objectivity of the validation procedure.
doi:10.1186/1756-0381-6-8
PMCID: PMC3669044  PMID: 23547736
Gene ontology; Support Vector Machines; Drosophila melanogaster; Gene expression data; Gene function prediction
16.  Using Bayesian networks to discover relations between genes, environment, and disease 
BioData Mining  2013;6:6.
We review the applicability of Bayesian networks (BNs) for discovering relations between genes, environment, and disease. By translating probabilistic dependencies among variables into graphical models and vice versa, BNs provide a comprehensible and modular framework for representing complex systems. We first describe the Bayesian network approach and its applicability to understanding the genetic and environmental basis of disease. We then describe a variety of algorithms for learning the structure of a network from observational data. Because of their relevance to real-world applications, the topics of missing data and causal interpretation are emphasized. The BN approach is then exemplified through application to data from a population-based study of bladder cancer in New Hampshire, USA. For didactical purposes, we intentionally keep this example simple. When applied to complete data records, we find only minor differences in the performance and results of different algorithms. Subsequent incorporation of partial records through application of the EM algorithm gives us greater power to detect relations. Allowing for network structures that depart from a strict causal interpretation also enhances our ability to discover complex associations including gene-gene (epistasis) and gene-environment interactions. While BNs are already powerful tools for the genetic dissection of disease and generation of prognostic models, there remain some conceptual and computational challenges. These include the proper handling of continuous variables and unmeasured factors, the explicit incorporation of prior knowledge, and the evaluation and communication of the robustness of substantive conclusions to alternative assumptions and data manifestations.
doi:10.1186/1756-0381-6-6
PMCID: PMC3614442  PMID: 23514120
Structural learning; Belief networks; Genetic epidemiology; Bioinformatics; Complex traits; Arsenic; SNP
17.  Genetic variants and their interactions in disease risk prediction – machine learning and network perspectives 
BioData Mining  2013;6:5.
A central challenge in systems biology and medical genetics is to understand how interactions among genetic loci contribute to complex phenotypic traits and human diseases. While most studies have so far relied on statistical modeling and association testing procedures, machine learning and predictive modeling approaches are increasingly being applied to mining genotype-phenotype relationships, also among those associations that do not necessarily meet statistical significance at the level of individual variants, yet still contributing to the combined predictive power at the level of variant panels. Network-based analysis of genetic variants and their interaction partners is another emerging trend by which to explore how sub-network level features contribute to complex disease processes and related phenotypes. In this review, we describe the basic concepts and algorithms behind machine learning-based genetic feature selection approaches, their potential benefits and limitations in genome-wide setting, and how physical or genetic interaction networks could be used as a priori information for providing improved predictive power and mechanistic insights into the disease networks. These developments are geared toward explaining a part of the missing heritability, and when combined with individual genomic profiling, such systems medicine approaches may also provide a principled means for tailoring personalized treatment strategies in the future.
doi:10.1186/1756-0381-6-5
PMCID: PMC3606427  PMID: 23448398
18.  Multifactor dimensionality reduction reveals a three-locus epistatic interaction associated with susceptibility to pulmonary tuberculosis 
BioData Mining  2013;6:4.
Background
Identifying high-order genetics associations with non-additive (i.e. epistatic) effects in population-based studies of common human diseases is a computational challenge. Multifactor dimensionality reduction (MDR) is a machine learning method that was designed specifically for this problem. The goal of the present study was to apply MDR to mining high-order epistatic interactions in a population-based genetic study of tuberculosis (TB).
Results
The study used a previously published data set consisting of 19 candidate single-nucleotide polymorphisms (SNPs) in 321 pulmonary TB cases and 347 healthy controls from Guniea-Bissau in Africa. The ReliefF algorithm was applied first to generate a smaller set of the five most informative SNPs. MDR with 10-fold cross-validation was then applied to look at all possible combinations of two, three, four and five SNPs. The MDR model with the best testing accuracy (TA) consisted of SNPs rs2305619, rs187084, and rs11465421 (TA = 0.588) in PTX3, TLR9 and DC-Sign, respectively. A general 1000-fold permutation test of the null hypothesis of no association confirmed the statistical significance of the model (p = 0.008). An additional 1000-fold permutation test designed specifically to test the linear null hypothesis that the association effects are only additive confirmed the presence of non-additive (i.e. nonlinear) or epistatic effects (p = 0.013). An independent information-gain measure corroborated these results with a third-order epistatic interaction that was stronger than any lower-order associations.
Conclusions
We have identified statistically significant evidence for a three-way epistatic interaction that is associated with susceptibility to TB. This interaction is stronger than any previously described one-way or two-way associations. This study highlights the importance of using machine learning methods that are designed to embrace, rather than ignore, the complexity of common diseases such as TB. We recommend future studies of the genetics of TB take into account the possibility that high-order epistatic interactions might play an important role in disease susceptibility.
doi:10.1186/1756-0381-6-4
PMCID: PMC3618340  PMID: 23418869
Epistasis; Gene-gene interactions; Machine learning; Pulmonary tuberculosis
19.  Identification of SNPs associated with variola virus virulence 
BioData Mining  2013;6:3.
Background
Decades after the eradication of smallpox, its etiological agent, variola virus (VARV), remains a threat as a potential bioweapon. Outbreaks of smallpox around the time of the global eradication effort exhibited variable case fatality rates (CFRs), likely attributable in part to complex viral genetic determinants of smallpox virulence. We aimed to identify genome-wide single nucleotide polymorphisms associated with CFR. We evaluated unadjusted and outbreak geographic location-adjusted models of single SNPs and two- and three-way interactions between SNPs.
Findings
Using the data mining approach multifactor dimensionality reduction (MDR), we identified five VARV SNPs in models significantly associated with CFR. The top performing unadjusted model and adjusted models both revealed the same two-way gene-gene interaction. We discuss the biological plausibility of the influence of the SNPs identified these and other significant models on the strain-specific virulence of VARV.
Conclusions
We have identified genetic loci in the VARV genome that are statistically associated with VARV virulence as measured by CFR. While our ability to infer a causal relationship between the specific SNPs identified in our analysis and VARV virulence is limited, our results suggest that smallpox severity is in part associated with VARV strain variation and that VARV virulence may be determined by multiple genetic loci. This study represents the first application of MDR to the identification of pathogen gene-gene interactions for predicting infectious disease outbreak severity.
doi:10.1186/1756-0381-6-3
PMCID: PMC3599518  PMID: 23410064
Smallpox; Variola virus; Single nucleotide polymorphisms; Multifactor dimensionality reduction
20.  Identification of new biomarker candidates for glucocorticoid induced insulin resistance using literature mining 
BioData Mining  2013;6:2.
Background
Glucocorticoids are potent anti-inflammatory agents used for the treatment of diseases such as rheumatoid arthritis, asthma, inflammatory bowel disease and psoriasis. Unfortunately, usage is limited because of metabolic side-effects, e.g. insulin resistance, glucose intolerance and diabetes. To gain more insight into the mechanisms behind glucocorticoid induced insulin resistance, it is important to understand which genes play a role in the development of insulin resistance and which genes are affected by glucocorticoids.
Medline abstracts contain many studies about insulin resistance and the molecular effects of glucocorticoids and thus are a good resource to study these effects.
Results
We developed CoPubGene a method to automatically identify gene-disease associations in Medline abstracts. We used this method to create a literature network of genes related to insulin resistance and to evaluate the importance of the genes in this network for glucocorticoid induced metabolic side effects and anti-inflammatory processes.
With this approach we found several genes that already are considered markers of GC induced IR, such as phosphoenolpyruvate carboxykinase (PCK) and glucose-6-phosphatase, catalytic subunit (G6PC). In addition, we found genes involved in steroid synthesis that have not yet been recognized as mediators of GC induced IR.
Conclusions
With this approach we are able to construct a robust informative literature network of insulin resistance related genes that gave new insights to better understand the mechanisms behind GC induced IR. The method has been set up in a generic way so it can be applied to a wide variety of disease networks.
doi:10.1186/1756-0381-6-2
PMCID: PMC3577498  PMID: 23379763
Literature mining; Insulin resistance; Glucocorticoids; Gene networks
21.  Risk score modeling of multiple gene to gene interactions using aggregated-multifactor dimensionality reduction 
BioData Mining  2013;6:1.
Background
Multifactor Dimensionality Reduction (MDR) has been widely applied to detect gene-gene (GxG) interactions associated with complex diseases. Existing MDR methods summarize disease risk by a dichotomous predisposing model (high-risk/low-risk) from one optimal GxG interaction, which does not take the accumulated effects from multiple GxG interactions into account.
Results
We propose an Aggregated-Multifactor Dimensionality Reduction (A-MDR) method that exhaustively searches for and detects significant GxG interactions to generate an epistasis enriched gene network. An aggregated epistasis enriched risk score, which takes into account multiple GxG interactions simultaneously, replaces the dichotomous predisposing risk variable and provides higher resolution in the quantification of disease susceptibility. We evaluate this new A-MDR approach in a broad range of simulations. Also, we present the results of an application of the A-MDR method to a data set derived from Juvenile Idiopathic Arthritis patients treated with methotrexate (MTX) that revealed several GxG interactions in the folate pathway that were associated with treatment response. The epistasis enriched risk score that pooled information from 82 significant GxG interactions distinguished MTX responders from non-responders with 82% accuracy.
Conclusions
The proposed A-MDR is innovative in the MDR framework to investigate aggregated effects among GxG interactions. New measures (pOR, pRR and pChi) are proposed to detect multiple GxG interactions.
doi:10.1186/1756-0381-6-1
PMCID: PMC3560267  PMID: 23294634
A-MDR; Epistasis enriched risk score; Epistasis enriched gene network; pRR; pOR; pChi
22.  Multivariate methods and software for association mapping in dose‐response genome‐wide association studies 
BioData Mining  2012;5:21.
Background
The large sample sizes, freedom of ethical restrictions and ease of repeated measurements make cytotoxicity assays of immortalized lymphoblastoid cell lines a powerful new in vitro method in pharmacogenomics research. However, previous studies may have over‐simplified the complex differences in dose‐response profiles between genotypes, resulting in a loss of power.
Methods
The current study investigates four previously studied methods, plus one new method based on a multivariate analysis of variance (MANOVA) design. A simulation study was performed using differences in cancer drug response between genotypes for biologically meaningful loci. These loci also showed significance in separate genome‐wide association studies. This manuscript builds upon a previous study, where differences in dose‐response curves between genotypes were constructed using the hill slope equation.
Conclusion
Overall, MANOVA was found to be the most powerful method for detecting real signals, and was also the most robust method for detection using alternatives generated with the previous simulation study. This method is also attractive because test statistics follow their expected distributions under the null hypothesis for both simulated and real data. The success of this method inspired the creation of the software program MAGWAS. MAGWAS is a computationally efficient, user‐friendly, open source software tool that works on most platforms and performs GWASs for individuals having multivariate responses using standard file formats.
doi:10.1186/1756-0381-5-21
PMCID: PMC3661384  PMID: 23234571
Pharmacogenomics; Lymphoblastoid cell lines; Chemosensitivity; Chemotherapy; Temozolomide; Idarubicin; MANOVA; GWAS; Simulation study
23.  Application of a spatially-weighted Relief algorithm for ranking genetic predictors of disease 
BioData Mining  2012;5:20.
Background
Identification of genetic variants that are associated with disease is an important goal in elucidating the genetic causes of diseases. The genetic patterns that are associated with common diseases are complex and may involve multiple interacting genetic variants. The Relief family of algorithms is a powerful tool for efficiently identifying genetic variants that are associated with disease, even if the variants have nonlinear interactions without significant main effects. Many variations of Relief have been developed over the past two decades and several of them have been applied to single nucleotide polymorphism (SNP) data.
Results
We developed a new spatially weighted variation of Relief called Sigmoid Weighted ReliefF Star (SWRF*), and applied it to synthetic SNP data. When compared to ReliefF and SURF*, which are two algorithms that have been applied to SNP data for identifying interactions, SWRF* had significantly greater power. Furthermore, we developed a framework called the Modular Relief Framework (MoRF) that can be used to develop novel variations of the Relief algorithm, and we used MoRF to develop the SWRF* algorithm.
Conclusions
MoRF allows easy development of new Relief algorithms by specifying different interchangeable functions for the component terms. Using MORF, we developed a new Relief algorithm called SWRF* that had greater ability to identify interacting genetic variants in synthetic data compared to existing Relief algorithms.
doi:10.1186/1756-0381-5-20
PMCID: PMC3554553  PMID: 23198930
Feature selection; Relief; Single nucleotide polymorphisms; Genetic interactions; Epistasis
24.  Visualising associations between paired ‘omics’ data sets 
BioData Mining  2012;5:19.
Background
Each omics platform is now able to generate a large amount of data. Genomics, proteomics, metabolomics, interactomics are compiled at an ever increasing pace and now form a core part of the fundamental systems biology framework. Recently, several integrative approaches have been proposed to extract meaningful information. However, these approaches lack of visualisation outputs to fully unravel the complex associations between different biological entities.
Results
The multivariate statistical approaches ‘regularized Canonical Correlation Analysis’ and ‘sparse Partial Least Squares regression’ were recently developed to integrate two types of highly dimensional ‘omics’ data and to select relevant information. Using the results of these methods, we propose to revisit few graphical outputs to better understand the relationships between two ‘omics’ data and to better visualise the correlation structure between the different biological entities. These graphical outputs include Correlation Circle plots, Relevance Networks and Clustered Image Maps. We demonstrate the usefulness of such graphical outputs on several biological data sets and further assess their biological relevance using gene ontology analysis.
Conclusions
Such graphical outputs are undoubtedly useful to aid the interpretation of these promising integrative analysis tools and will certainly help in addressing fundamental biological questions and understanding systems as a whole.
Availability
The graphical tools described in this paper are implemented in the freely available R package mixOmics and in its associated web application.
doi:10.1186/1756-0381-5-19
PMCID: PMC3630015  PMID: 23148523
25.  Mining SOM expression portraits: feature selection and integrating concepts of molecular function 
BioData Mining  2012;5:18.
Background
Self organizing maps (SOM) enable the straightforward portraying of high-dimensional data of large sample collections in terms of sample-specific images. The analysis of their texture provides so-called spot-clusters of co-expressed genes which require subsequent significance filtering and functional interpretation. We address feature selection in terms of the gene ranking problem and the interpretation of the obtained spot-related lists using concepts of molecular function.
Results
Different expression scores based either on simple fold change-measures or on regularized Student’s t-statistics are applied to spot-related gene lists and compared with special emphasis on the error characteristics of microarray expression data. The spot-clusters are analyzed using different methods of gene set enrichment analysis with the focus on overexpression and/or overrepresentation of predefined sets of genes. Metagene-related overrepresentation of selected gene sets was mapped into the SOM images to assign gene function to different regions. Alternatively we estimated set-related overexpression profiles over all samples studied using a gene set enrichment score. It was also applied to the spot-clusters to generate lists of enriched gene sets. We used the tissue body index data set, a collection of expression data of human tissues as an illustrative example. We found that tissue related spots typically contain enriched populations of gene sets well corresponding to molecular processes in the respective tissues. In addition, we display special sets of housekeeping and of consistently weak and high expressed genes using SOM data filtering.
Conclusions
The presented methods allow the comprehensive downstream analysis of SOM-transformed expression data in terms of cluster-related gene lists and enriched gene sets for functional interpretation. SOM clustering implies the ability to define either new gene sets using selected SOM spots or to verify and/or to amend existing ones.
doi:10.1186/1756-0381-5-18
PMCID: PMC3599960  PMID: 23043905

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