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1.  Comparative analysis of methods for detecting interacting loci 
BMC Genomics  2011;12:344.
Background
Interactions among genetic loci are believed to play an important role in disease risk. While many methods have been proposed for detecting such interactions, their relative performance remains largely unclear, mainly because different data sources, detection performance criteria, and experimental protocols were used in the papers introducing these methods and in subsequent studies. Moreover, there have been very few studies strictly focused on comparison of existing methods. Given the importance of detecting gene-gene and gene-environment interactions, a rigorous, comprehensive comparison of performance and limitations of available interaction detection methods is warranted.
Results
We report a comparison of eight representative methods, of which seven were specifically designed to detect interactions among single nucleotide polymorphisms (SNPs), with the last a popular main-effect testing method used as a baseline for performance evaluation. The selected methods, multifactor dimensionality reduction (MDR), full interaction model (FIM), information gain (IG), Bayesian epistasis association mapping (BEAM), SNP harvester (SH), maximum entropy conditional probability modeling (MECPM), logistic regression with an interaction term (LRIT), and logistic regression (LR) were compared on a large number of simulated data sets, each, consistent with complex disease models, embedding multiple sets of interacting SNPs, under different interaction models. The assessment criteria included several relevant detection power measures, family-wise type I error rate, and computational complexity. There are several important results from this study. First, while some SNPs in interactions with strong effects are successfully detected, most of the methods miss many interacting SNPs at an acceptable rate of false positives. In this study, the best-performing method was MECPM. Second, the statistical significance assessment criteria, used by some of the methods to control the type I error rate, are quite conservative, thereby limiting their power and making it difficult to fairly compare them. Third, as expected, power varies for different models and as a function of penetrance, minor allele frequency, linkage disequilibrium and marginal effects. Fourth, the analytical relationships between power and these factors are derived, aiding in the interpretation of the study results. Fifth, for these methods the magnitude of the main effect influences the power of the tests. Sixth, most methods can detect some ground-truth SNPs but have modest power to detect the whole set of interacting SNPs.
Conclusion
This comparison study provides new insights into the strengths and limitations of current methods for detecting interacting loci. This study, along with freely available simulation tools we provide, should help support development of improved methods. The simulation tools are available at: http://code.google.com/p/simulation-tool-bmc-ms9169818735220977/downloads/list.
doi:10.1186/1471-2164-12-344
PMCID: PMC3161015  PMID: 21729295
2.  BACOM: in silico detection of genomic deletion types and correction of normal cell contamination in copy number data 
Bioinformatics  2011;27(11):1473-1480.
Motivation: Identification of somatic DNA copy number alterations (CNAs) and significant consensus events (SCEs) in cancer genomes is a main task in discovering potential cancer-driving genes such as oncogenes and tumor suppressors. The recent development of SNP array technology has facilitated studies on copy number changes at a genome-wide scale with high resolution. However, existing copy number analysis methods are oblivious to normal cell contamination and cannot distinguish between contributions of cancerous and normal cells to the measured copy number signals. This contamination could significantly confound downstream analysis of CNAs and affect the power to detect SCEs in clinical samples.
Results: We report here a statistically principled in silico approach, Bayesian Analysis of COpy number Mixtures (BACOM), to accurately estimate genomic deletion type and normal tissue contamination, and accordingly recover the true copy number profile in cancer cells. We tested the proposed method on two simulated datasets, two prostate cancer datasets and The Cancer Genome Atlas high-grade ovarian dataset, and obtained very promising results supported by the ground truth and biological plausibility. Moreover, based on a large number of comparative simulation studies, the proposed method gives significantly improved power to detect SCEs after in silico correction of normal tissue contamination. We develop a cross-platform open-source Java application that implements the whole pipeline of copy number analysis of heterogeneous cancer tissues including relevant processing steps. We also provide an R interface, bacomR, for running BACOM within the R environment, making it straightforward to include in existing data pipelines.
Availability: The cross-platform, stand-alone Java application, BACOM, the R interface, bacomR, all source code and the simulation data used in this article are freely available at authors' web site: http://www.cbil.ece.vt.edu/software.htm.
Contact: yuewang@vt.edu
Supplementary Information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btr183
PMCID: PMC3102226  PMID: 21498400
3.  DDN: a caBIG® analytical tool for differential network analysis 
Bioinformatics  2011;27(7):1036-1038.
Summary: Differential dependency network (DDN) is a caBIG® (cancer Biomedical Informatics Grid) analytical tool for detecting and visualizing statistically significant topological changes in transcriptional networks representing two biological conditions. Developed under caBIG® 's In Silico Research Centers of Excellence (ISRCE) Program, DDN enables differential network analysis and provides an alternative way for defining network biomarkers predictive of phenotypes. DDN also serves as a useful systems biology tool for users across biomedical research communities to infer how genetic, epigenetic or environment variables may affect biological networks and clinical phenotypes. Besides the standalone Java application, we have also developed a Cytoscape plug-in, CytoDDN, to integrate network analysis and visualization seamlessly.
Availability: The Java and MATLAB source code can be downloaded at the authors' web site http://www.cbil.ece.vt.edu/software.htm
Contact: yuewang@vt.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btr052
PMCID: PMC3065688  PMID: 21296752
4.  CAM-CM: a signal deconvolution tool for in vivo dynamic contrast-enhanced imaging of complex tissues 
Bioinformatics  2011;27(18):2607-2609.
Summary:In vivo dynamic contrast-enhanced imaging tools provide non-invasive methods for analyzing various functional changes associated with disease initiation, progression and responses to therapy. The quantitative application of these tools has been hindered by its inability to accurately resolve and characterize targeted tissues due to spatially mixed tissue heterogeneity. Convex Analysis of Mixtures – Compartment Modeling (CAM-CM) signal deconvolution tool has been developed to automatically identify pure-volume pixels located at the corners of the clustered pixel time series scatter simplex and subsequently estimate tissue-specific pharmacokinetic parameters. CAM-CM can dissect complex tissues into regions with differential tracer kinetics at pixel-wise resolution and provide a systems biology tool for defining imaging signatures predictive of phenotypes.
Availability: The MATLAB source code can be downloaded at the authors′ website www.cbil.ece.vt.edu/software.htm
Contact: yuewang@vt.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btr436
PMCID: PMC3167053  PMID: 21785131
5.  Simultaneous Analysis of All SNPs in Genome-Wide and Re-Sequencing Association Studies 
PLoS Genetics  2008;4(7):e1000130.
Testing one SNP at a time does not fully realise the potential of genome-wide association studies to identify multiple causal variants, which is a plausible scenario for many complex diseases. We show that simultaneous analysis of the entire set of SNPs from a genome-wide study to identify the subset that best predicts disease outcome is now feasible, thanks to developments in stochastic search methods. We used a Bayesian-inspired penalised maximum likelihood approach in which every SNP can be considered for additive, dominant, and recessive contributions to disease risk. Posterior mode estimates were obtained for regression coefficients that were each assigned a prior with a sharp mode at zero. A non-zero coefficient estimate was interpreted as corresponding to a significant SNP. We investigated two prior distributions and show that the normal-exponential-gamma prior leads to improved SNP selection in comparison with single-SNP tests. We also derived an explicit approximation for type-I error that avoids the need to use permutation procedures. As well as genome-wide analyses, our method is well-suited to fine mapping with very dense SNP sets obtained from re-sequencing and/or imputation. It can accommodate quantitative as well as case-control phenotypes, covariate adjustment, and can be extended to search for interactions. Here, we demonstrate the power and empirical type-I error of our approach using simulated case-control data sets of up to 500 K SNPs, a real genome-wide data set of 300 K SNPs, and a sequence-based dataset, each of which can be analysed in a few hours on a desktop workstation.
Author Summary
Tests of association with disease status are normally conducted one SNP at a time, ignoring the effects of all other genotyped SNPs. We developed a computationally efficient method to simultaneously analyse all SNPs, either in a genome-wide association (GWA) study, or a fine-mapping study based on re-sequencing and/or imputation. The method selects a subset of SNPs that best predicts disease status, while controlling the type-I error of the selected SNPs. This brings many advantages over standard single-SNP approaches, because the signal from a particular SNP can be more clearly assessed when other SNPs associated with disease status are already included in the model. Thus, in comparison with single-SNP analyses, power is increased and the false positive rate is reduced because of reduced residual variation. Localisation is also greatly improved. We demonstrate these advantages over the widely used single-SNP Armitage Trend Test using GWA simulation studies, a real GWA dataset, and a sequence-based fine-mapping simulation study.
doi:10.1371/journal.pgen.1000130
PMCID: PMC2464715  PMID: 18654633
6.  The Bayesian lasso for genome-wide association studies 
Bioinformatics  2010;27(4):516-523.
Motivation: Despite their success in identifying genes that affect complex disease or traits, current genome-wide association studies (GWASs) based on a single SNP analysis are too simple to elucidate a comprehensive picture of the genetic architecture of phenotypes. A simultaneous analysis of a large number of SNPs, although statistically challenging, especially with a small number of samples, is crucial for genetic modeling.
Method: We propose a two-stage procedure for multi-SNP modeling and analysis in GWASs, by first producing a ‘preconditioned’ response variable using a supervised principle component analysis and then formulating Bayesian lasso to select a subset of significant SNPs. The Bayesian lasso is implemented with a hierarchical model, in which scale mixtures of normal are used as prior distributions for the genetic effects and exponential priors are considered for their variances, and then solved by using the Markov chain Monte Carlo (MCMC) algorithm. Our approach obviates the choice of the lasso parameter by imposing a diffuse hyperprior on it and estimating it along with other parameters and is particularly powerful for selecting the most relevant SNPs for GWASs, where the number of predictors exceeds the number of observations.
Results: The new approach was examined through a simulation study. By using the approach to analyze a real dataset from the Framingham Heart Study, we detected several significant genes that are associated with body mass index (BMI). Our findings support the previous results about BMI-related SNPs and, meanwhile, gain new insights into the genetic control of this trait.
Availability: The computer code for the approach developed is available at Penn State Center for Statistical Genetics web site, http://statgen.psu.edu.
Contact: rwu@hes.hmc.psu.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btq688
PMCID: PMC3105480  PMID: 21156729
7.  Interaction among apoptosis-associated sequence variants and joint effects on aggressive prostate cancer 
BMC Medical Genomics  2012;5:11.
Background
Molecular and epidemiological evidence demonstrate that altered gene expression and single nucleotide polymorphisms in the apoptotic pathway are linked to many cancers. Yet, few studies emphasize the interaction of variant apoptotic genes and their joint modifying effects on prostate cancer (PCA) outcomes. An exhaustive assessment of all the possible two-, three- and four-way gene-gene interactions is computationally burdensome. This statistical conundrum stems from the prohibitive amount of data needed to account for multiple hypothesis testing.
Methods
To address this issue, we systematically prioritized and evaluated individual effects and complex interactions among 172 apoptotic SNPs in relation to PCA risk and aggressive disease (i.e., Gleason score ≥ 7 and tumor stages III/IV). Single and joint modifying effects on PCA outcomes among European-American men were analyzed using statistical epistasis networks coupled with multi-factor dimensionality reduction (SEN-guided MDR). The case-control study design included 1,175 incident PCA cases and 1,111 controls from the prostate, lung, colo-rectal, and ovarian (PLCO) cancer screening trial. Moreover, a subset analysis of PCA cases consisted of 688 aggressive and 488 non-aggressive PCA cases. SNP profiles were obtained using the NCI Cancer Genetic Markers of Susceptibility (CGEMS) data portal. Main effects were assessed using logistic regression (LR) models. Prior to modeling interactions, SEN was used to pre-process our genetic data. SEN used network science to reduce our analysis from > 36 million to < 13,000 SNP interactions. Interactions were visualized, evaluated, and validated using entropy-based MDR. All parametric and non-parametric models were adjusted for age, family history of PCA, and multiple hypothesis testing.
Results
Following LR modeling, eleven and thirteen sequence variants were associated with PCA risk and aggressive disease, respectively. However, none of these markers remained significant after we adjusted for multiple comparisons. Nevertheless, we detected a modest synergistic interaction between AKT3 rs2125230-PRKCQ rs571715 and disease aggressiveness using SEN-guided MDR (p = 0.011).
Conclusions
In summary, entropy-based SEN-guided MDR facilitated the logical prioritization and evaluation of apoptotic SNPs in relation to aggressive PCA. The suggestive interaction between AKT3-PRKCQ and aggressive PCA requires further validation using independent observational studies.
doi:10.1186/1755-8794-5-11
PMCID: PMC3355002  PMID: 22546513
Prostate cancer; Apoptosis; Single nucleotide polymorphisms; Gene-gene interactions; Multifactor dimensionality reduction (MDR); Statistical epistasis networks (SEN)
8.  PUGSVM: a caBIGTM analytical tool for multiclass gene selection and predictive classification 
Bioinformatics  2010;27(5):736-738.
Summary: Phenotypic Up-regulated Gene Support Vector Machine (PUGSVM) is a cancer Biomedical Informatics Grid (caBIG™) analytical tool for multiclass gene selection and classification. PUGSVM addresses the problem of imbalanced class separability, small sample size and high gene space dimensionality, where multiclass gene markers are defined by the union of one-versus-everyone phenotypic upregulated genes, and used by a well-matched one-versus-rest support vector machine. PUGSVM provides a simple yet more accurate strategy to identify statistically reproducible mechanistic marker genes for characterization of heterogeneous diseases.
Availability: http://www.cbil.ece.vt.edu/caBIG-PUGSVM.htm.
Contact: yuewang@vt.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btq721
PMCID: PMC3042183  PMID: 21186245
9.  Statistical Power of Model Selection Strategies for Genome-Wide Association Studies 
PLoS Genetics  2009;5(7):e1000582.
Genome-wide association studies (GWAS) aim to identify genetic variants related to diseases by examining the associations between phenotypes and hundreds of thousands of genotyped markers. Because many genes are potentially involved in common diseases and a large number of markers are analyzed, it is crucial to devise an effective strategy to identify truly associated variants that have individual and/or interactive effects, while controlling false positives at the desired level. Although a number of model selection methods have been proposed in the literature, including marginal search, exhaustive search, and forward search, their relative performance has only been evaluated through limited simulations due to the lack of an analytical approach to calculating the power of these methods. This article develops a novel statistical approach for power calculation, derives accurate formulas for the power of different model selection strategies, and then uses the formulas to evaluate and compare these strategies in genetic model spaces. In contrast to previous studies, our theoretical framework allows for random genotypes, correlations among test statistics, and a false-positive control based on GWAS practice. After the accuracy of our analytical results is validated through simulations, they are utilized to systematically evaluate and compare the performance of these strategies in a wide class of genetic models. For a specific genetic model, our results clearly reveal how different factors, such as effect size, allele frequency, and interaction, jointly affect the statistical power of each strategy. An example is provided for the application of our approach to empirical research. The statistical approach used in our derivations is general and can be employed to address the model selection problems in other random predictor settings. We have developed an R package markerSearchPower to implement our formulas, which can be downloaded from the Comprehensive R Archive Network (CRAN) or http://bioinformatics.med.yale.edu/group/.
Author Summary
Almost all published genome-wide association studies are based on single-marker analysis. Intuitively, joint consideration of multiple markers should be more informative when multiple genes and their interactions are involved in disease etiology. For example, an exhaustive search among models involving multiple markers and their interactions can identify certain gene–gene interactions that will be missed by single-marker analysis. However, an exhaustive search is difficult, or even impossible, to perform because of the computational requirements. Moreover, searching more models does not necessarily increase statistical power, because there may be an increased chance of finding false positive results when more models are explored. For power comparisons of different model selection methods, the published studies have relied on limited simulations due to the highly computationally intensive nature of such simulation studies. To enable researchers to compare different model search strategies without resorting to extensive simulations, we develop a novel analytical approach to evaluating the statistical power of these methods. Our results offer insights into how different parameters in a genetic model affect the statistical power of a given model selection strategy. We developed an R package to implement our results. This package can be used by researchers to compare and select an effective approach to detecting SNPs.
doi:10.1371/journal.pgen.1000582
PMCID: PMC2712761  PMID: 19649321
10.  TRM: A Powerful Two-stage Machine Learning Approach for Identifying SNP-SNP Interactions 
Annals of human genetics  2011;76(1):53-62.
SUMMARY
Studies have shown that interactions of single nucleotide polymorphism (SNP) may play an important role for understanding causes of complex disease. Machine learning approaches provide useful features to explore interactions more effectively and efficiently. We have proposed an integrated method that combines two machine learning methods - Random Forests (RF) and Multivariate Adaptive Regression Splines (MARS) - to identify a subset of important SNPs and detect interaction patterns. In this two-stage RF-MARS (TRM) approach, RF is first applied to detect a predictive subset of SNPs, and then MARS is used to identify the interaction patterns among the selected SNPs. We evaluated the TRM performances in four models: three causal models with one two-way interaction and one null model. RF variable selection was based on out-of-bag classification error rate (OOB) and variable important spectrum (IS). First, we compared the selection of important variable of RF and MARS. Our results support that RFOOB had better performance than MARS and RFIS in detecting important variables. We also evaluated the true positive rate and false positive rate of identifying interaction patterns in TRM and MARS. This study demonstrates that TRMOOB, which is RFOOB plus MARS, has combined the strengths of RF and MARS in identifying SNP-SNP interaction patterns in a scenario of 100 candidate SNPs. TRMOOB had greater true positive rate and lower false positive rate compared with MARS, particularly for searching interactions with a strong association with the outcome. Therefore the use of TRMOOB is favored for exploring SNP-SNP interactions in a large-scale genetic variation study.
doi:10.1111/j.1469-1809.2011.00692.x
PMCID: PMC3243917  PMID: 22150548
polymorphism; interaction; machine learning
11.  Genome-wide association analysis of seedling root development in maize (Zea mays L.) 
BMC Genomics  2015;16(1):47.
Background
Plants rely on the root system for anchorage to the ground and the acquisition and absorption of nutrients critical to sustaining productivity. A genome wide association analysis enables one to analyze allelic diversity of complex traits and identify superior alleles. 384 inbred lines from the Ames panel were genotyped with 681,257 single nucleotide polymorphism markers using Genotyping-by-Sequencing technology and 22 seedling root architecture traits were phenotyped.
Results
Utilizing both a general linear model and mixed linear model, a GWAS study was conducted identifying 268 marker trait associations (p ≤ 5.3×10-7). Analysis of significant SNP markers for multiple traits showed that several were located within gene models with some SNP markers localized within regions of previously identified root quantitative trait loci. Gene model GRMZM2G153722 located on chromosome 4 contained nine significant markers. This predicted gene is expressed in roots and shoots.
Conclusion
This study identifies putatively associated SNP markers associated with root traits at the seedling stage. Some SNPs were located within or near (<1 kb) gene models. These gene models identify possible candidate genes involved in root development at the seedling stage. These and respective linked or functional markers could be targets for breeders for marker assisted selection of seedling root traits.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1226-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s12864-015-1226-9
PMCID: PMC4326187  PMID: 25652714
Genome wide association study; Maize; Roots
12.  From phenotype to genotype: an association study of longitudinal phenotypic markers to Alzheimer's disease relevant SNPs 
Bioinformatics  2012;28(18):i619-i625.
Motivation: Imaging genetic studies typically focus on identifying single-nucleotide polymorphism (SNP) markers associated with imaging phenotypes. Few studies perform regression of SNP values on phenotypic measures for examining how the SNP values change when phenotypic measures are varied. This alternative approach may have a potential to help us discover important imaging genetic associations from a different perspective. In addition, the imaging markers are often measured over time, and this longitudinal profile may provide increased power for differentiating genotype groups. How to identify the longitudinal phenotypic markers associated to disease sensitive SNPs is an important and challenging research topic.
Results: Taking into account the temporal structure of the longitudinal imaging data and the interrelatedness among the SNPs, we propose a novel ‘task-correlated longitudinal sparse regression’ model to study the association between the phenotypic imaging markers and the genotypes encoded by SNPs. In our new association model, we extend the widely used ℓ2,1-norm for matrices to tensors to jointly select imaging markers that have common effects across all the regression tasks and time points, and meanwhile impose the trace-norm regularization onto the unfolded coefficient tensor to achieve low rank such that the interrelationship among SNPs can be addressed. The effectiveness of our method is demonstrated by both clearly improved prediction performance in empirical evaluations and a compact set of selected imaging predictors relevant to disease sensitive SNPs.
Availability: Software is publicly available at: http://ranger.uta.edu/%7eheng/Longitudinal/
Contact: heng@uta.edu or shenli@inpui.edu
doi:10.1093/bioinformatics/bts411
PMCID: PMC3436838  PMID: 22962490
13.  Associations and interactions between SNPs in the alcohol metabolizing genes and alcoholism phenotypes in European Americans 
Background
Alcohol abuse and dependence are major causes of morbidity and mortality worldwide, and have a strong familial component. Several linkage and association studies have identified chromosomal regions and/or genes that affect alcohol consumption, notably in genes involved in the two-stage pathway of alcohol metabolism.
Methods
Here, we use multiple regression models to test for associations and interactions between two alcohol related phenotypes and SNPs in 17 genes involved in alcohol metabolism in the U.S. Caucasian subset of the Collaborative Genetic Study of Nicotine Dependence (COGEND) participants.
Results
Several SNPs across six genes showed evidence for association with either maximum number of drinks consumed in a 24-hour period or DSM-IV symptom count. The strongest evidence for association was between rs1229984, a non-synonymous coding SNP in ADH1B, and DSM-IV symptom count (P = 0.0003). This SNP was also associated with maximum drinks (P = 0.0004). Each minor allele at this SNP predicts 45% fewer DSM-IV symptoms and 18% fewer max drinks. Another SNP in a splice site in ALDH1A1 (rs8187974) showed evidence for association with both phenotypes as well. Minor alleles at this SNP predict greater alcohol consumption. In addition, pairwise interactions were observed between SNPs in several genes (P = 0.00002).
Conclusions
We replicated the large effect of rs1229984 on alcohol behavior, and although not common (MAF = 4%), this polymorphism may be highly relevant from a public health perspective in European Americans. Another SNP, rs8187974, may also affect alcohol behavior but requires replication. Also, interactions between polymorphisms in genes involved in alcohol metabolism are likely determinants of the parameters that ultimately affect alcohol consumption.
doi:10.1111/j.1530-0277.2009.00904.x
PMCID: PMC2892966  PMID: 19298322
Alcoholism; Alcohol Metabolism; Genetic Association
14.  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
15.  Differential dependency network analysis to identify condition-specific topological changes in biological networks 
Bioinformatics  2008;25(4):526-532.
Motivation: Significant efforts have been made to acquire data under different conditions and to construct static networks that can explain various gene regulation mechanisms. However, gene regulatory networks are dynamic and condition-specific; under different conditions, networks exhibit different regulation patterns accompanied by different transcriptional network topologies. Thus, an investigation on the topological changes in transcriptional networks can facilitate the understanding of cell development or provide novel insights into the pathophysiology of certain diseases, and help identify the key genetic players that could serve as biomarkers or drug targets.
Results: Here, we report a differential dependency network (DDN) analysis to detect statistically significant topological changes in the transcriptional networks between two biological conditions. We propose a local dependency model to represent the local structures of a network by a set of conditional probabilities. We develop an efficient learning algorithm to learn the local dependency model using the Lasso technique. A permutation test is subsequently performed to estimate the statistical significance of each learned local structure. In testing on a simulation dataset, the proposed algorithm accurately detected all the genes with network topological changes. The method was then applied to the estrogen-dependent T-47D estrogen receptor-positive (ER+) breast cancer cell line datasets and human and mouse embryonic stem cell datasets. In both experiments using real microarray datasets, the proposed method produced biologically meaningful results. We expect DDN to emerge as an important bioinformatics tool in transcriptional network analyses. While we focus specifically on transcriptional networks, the DDN method we introduce here is generally applicable to other biological networks with similar characteristics.
Availability: The DDN MATLAB toolbox and experiment data are available at http://www.cbil.ece.vt.edu/software.htm.
Contact: yuewang@vt.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btn660
PMCID: PMC2642641  PMID: 19112081
16.  Multilevel support vector regression analysis to identify condition-specific regulatory networks 
Bioinformatics  2010;26(11):1416-1422.
Motivation: The identification of gene regulatory modules is an important yet challenging problem in computational biology. While many computational methods have been proposed to identify regulatory modules, their initial success is largely compromised by a high rate of false positives, especially when applied to human cancer studies. New strategies are needed for reliable regulatory module identification.
Results: We present a new approach, namely multilevel support vector regression (ml-SVR), to systematically identify condition-specific regulatory modules. The approach is built upon a multilevel analysis strategy designed for suppressing false positive predictions. With this strategy, a regulatory module becomes ever more significant as more relevant gene sets are formed at finer levels. At each level, a two-stage support vector regression (SVR) method is utilized to help reduce false positive predictions by integrating binding motif information and gene expression data; a significant analysis procedure is followed to assess the significance of each regulatory module. To evaluate the effectiveness of the proposed strategy, we first compared the ml-SVR approach with other existing methods on simulation data and yeast cell cycle data. The resulting performance shows that the ml-SVR approach outperforms other methods in the identification of both regulators and their target genes. We then applied our method to breast cancer cell line data to identify condition-specific regulatory modules associated with estrogen treatment. Experimental results show that our method can identify biologically meaningful regulatory modules related to estrogen signaling and action in breast cancer.
Availability and implementation: The ml-SVR MATLAB package can be downloaded at http://www.cbil.ece.vt.edu/software.htm
Contact: xuan@vt.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btq144
PMCID: PMC2872001  PMID: 20375112
17.  Phenotype forecasting with SNPs data through gene-based Bayesian networks 
BMC Bioinformatics  2009;10(Suppl 2):S7.
Background
Bayesian networks are powerful instruments to learn genetic models from association studies data. They are able to derive the existing correlation between genetic markers and phenotypic traits and, at the same time, to find the relationships between the markers themselves. However, learning Bayesian networks is often non-trivial due to the high number of variables to be taken into account in the model with respect to the instances of the dataset. Therefore, it becomes very interesting to use an abstraction of the variable space that suitably reduces its dimensionality without losing information. In this paper we present a new strategy to achieve this goal by mapping the SNPs related to the same gene to one meta-variable. In order to assign states to the meta-variables we employ an approach based on classification trees.
Results
We applied our approach to data coming from a genome-wide scan on 288 individuals affected by arterial hypertension and 271 nonagenarians without history of hypertension. After pre-processing, we focused on a subset of 24 SNPs. We compared the performance of the proposed approach with the Bayesian network learned with SNPs as variables and with the network learned with haplotypes as meta-variables. The results were obtained by running a hold-out experiment five times. The mean accuracy of the new method was 64.28%, while the mean accuracy of the SNPs network was 58.99% and the mean accuracy of the haplotype network was 54.57%.
Conclusion
The new approach presented in this paper is able to derive a gene-based predictive model based on SNPs data. Such model is more parsimonious than the one based on single SNPs, while preserving the capability of highlighting predictive SNPs configurations. The prediction performance of this approach was consistently superior to the SNP-based and the haplotype-based one in all the test sets of the evaluation procedure. The method can be then considered as an alternative way to analyze the data coming from association studies.
doi:10.1186/1471-2105-10-S2-S7
PMCID: PMC2646249  PMID: 19208195
18.  On the Use of Variance per Genotype as a Tool to Identify Quantitative Trait Interaction Effects: A Report from the Women's Genome Health Study 
PLoS Genetics  2010;6(6):e1000981.
Testing for genetic effects on mean values of a quantitative trait has been a very successful strategy. However, most studies to date have not explored genetic effects on the variance of quantitative traits as a relevant consequence of genetic variation. In this report, we demonstrate that, under plausible scenarios of genetic interaction, the variance of a quantitative trait is expected to differ among the three possible genotypes of a biallelic SNP. Leveraging this observation with Levene's test of equality of variance, we propose a novel method to prioritize SNPs for subsequent gene–gene and gene–environment testing. This method has the advantageous characteristic that the interacting covariate need not be known or measured for a SNP to be prioritized. Using simulations, we show that this method has increased power over exhaustive search under certain conditions. We further investigate the utility of variance per genotype by examining data from the Women's Genome Health Study. Using this dataset, we identify new interactions between the LEPR SNP rs12753193 and body mass index in the prediction of C-reactive protein levels, between the ICAM1 SNP rs1799969 and smoking in the prediction of soluble ICAM-1 levels, and between the PNPLA3 SNP rs738409 and body mass index in the prediction of soluble ICAM-1 levels. These results demonstrate the utility of our approach and provide novel genetic insight into the relationship among obesity, smoking, and inflammation.
Author Summary
Finding gene–gene and gene–environment interactions is a major challenge in genetics. In this report, we propose a novel method to help detect these interactions. This method works by first identifying a subset of genetic variants more likely to be involved in genetic interactions and then testing these variants for interaction effects. Using this method, we were able to identify three previously unknown genetic interactions. The first interaction involves a measure of body fat and a genetic variant of the LEPR gene in the prediction of C-reactive protein concentration, a marker of inflammation. The second interaction involves the same measure of body fat and a genetic variant of the PNPLA3 gene in the prediction of ICAM-1 levels, also a marker of inflammation. These results are significant because both LEPR and PNPLA3 are linked to the biological response to increased body fat, and inflammation itself is known to be increased in obesity and is thought to contribute to its adverse health effect. Finally, a third interaction was identified between a genetic variant of the ICAM1 gene and smoking in the prediction of ICAM-1 levels. The ICAM1 gene encodes ICAM-1 itself and smoking is known to be an important determinant of ICAM-1 concentrations.
doi:10.1371/journal.pgen.1000981
PMCID: PMC2887471  PMID: 20585554
19.  Analysis of genome-wide association study data using the protein knowledge base 
BMC Genetics  2011;12:98.
Background
Genome-wide association studies (GWAS) aim to identify causal variants and genes for complex disease by independently testing a large number of SNP markers for disease association. Although genes have been implicated in these studies, few utilise the multiple-hit model of complex disease to identify causal candidates. A major benefit of multi-locus comparison is that it compensates for some shortcomings of current statistical analyses that test the frequency of each SNP in isolation for the phenotype population versus control.
Results
Here we developed and benchmarked several protocols for GWAS data analysis using different in-silico gene prediction and prioritisation methodologies. We adopted a high sensitivity approach to the data, using less conservative statistical SNP associations. Multiple gene search spaces, either of fixed-widths or proximity-based, were generated around each SNP marker. We used the candidate disease gene prediction system Gentrepid to identify candidates based on shared biomolecular pathways or domain-based protein homology. Predictions were made either with phenotype-specific known disease genes as input; or without a priori knowledge, by exhaustive comparison of genes in distinct loci. Because Gentrepid uses biomolecular data to find interactions and common features between genes in distinct loci of the search spaces, it takes advantage of the multi-locus aspect of the data.
Conclusions
Results suggest testing multiple SNP-to-gene search spaces compensates for differences in phenotypes, populations and SNP platforms. Surprisingly, domain-based homology information was more informative when benchmarked against gene candidates reported by GWA studies compared to previously determined disease genes, possibly suggesting a larger contribution of gene homologs to complex diseases than Mendelian diseases.
doi:10.1186/1471-2156-12-98
PMCID: PMC3261104  PMID: 22077927
20.  A single nucleotide polymorphism tags variation in the arylamine N-acetyltransferase 2 phenotype in populations of European background 
Pharmacogenetics and genomics  2011;21(4):231-236.
Objective
The arylamine N-acetyltransferase 2 (NAT2) slow acetylation phenotype is an established risk factor for urinary bladder cancer. We previously reported on this risk association using NAT2 phenotypic categories inferred from NAT2 haplotypes based on 7 single nucleotide polymorphisms (SNPs) in a study in Spain. In a subsequent genome-wide scan, we have identified a single common tag SNP (rs1495741) located in the 3′ end of NAT2 that is also associated with bladder cancer risk. The aim of this report is to evaluate the agreement between the common tag SNP and the 7-SNP NAT2 inferred phenotype.
Methods
The agreement between the 7-SNP NAT2 inferred phenotype and the tag SNP, rs1495741, was initially assessed in 2,174 subjects from the Spanish Bladder Cancer Study (SBCS), and confirmed in a subset of subjects from the Main and Vermont component the New England Bladder Cancer Study (NEBCS). We also investigated the association of rs1495741 genotypes with NAT2 catalytic activity in cryopreserved hepatocytes from 154 individuals of European background.
Results
We observed very strong agreement between rs1495741 and the 7-SNP inferred NAT2 phenotype: sensitivity and specificity for the NAT2 slow phenotype was 99% and 95%, respectively. Our findings were replicated in an independent population from the United States. Estimates for the association between NAT2 slow phenotype and bladder cancer risk in the SBCS and its interaction with cigarette smoking were comparable for the 7-SNP inferred NAT2 phenotype and rs1495741. In addition, rs1495741 genotypes were strongly related to NAT2 activity measured in hepatocytes (P<0.0001).
Conclusion
A novel NAT2 tag SNP (rs1495741) predicts with high accuracy the 7- SNP inferred NAT2 phenotype, and thus can be used as a sole marker in pharmacogenetic or epidemiological studies of populations of European background. These findings illustrate the utility of tag SNPs, often employed in genome-wide association studies (GWAS), to identify novel phenotypic markers. Further studies are required to determine the functional implications of this novel SNP and the structure and evolution of the haplotype on which it resides.
doi:10.1097/FPC.0b013e32833e1b54
PMCID: PMC3003749  PMID: 20739907
21.  Lower-Order Effects Adjustment in Quantitative Traits Model-Based Multifactor Dimensionality Reduction 
PLoS ONE  2012;7(1):e29594.
Identifying gene-gene interactions or gene-environment interactions in studies of human complex diseases remains a big challenge in genetic epidemiology. An additional challenge, often forgotten, is to account for important lower-order genetic effects. These may hamper the identification of genuine epistasis. If lower-order genetic effects contribute to the genetic variance of a trait, identified statistical interactions may simply be due to a signal boost of these effects. In this study, we restrict attention to quantitative traits and bi-allelic SNPs as genetic markers. Moreover, our interaction study focuses on 2-way SNP-SNP interactions. Via simulations, we assess the performance of different corrective measures for lower-order genetic effects in Model-Based Multifactor Dimensionality Reduction epistasis detection, using additive and co-dominant coding schemes. Performance is evaluated in terms of power and familywise error rate. Our simulations indicate that empirical power estimates are reduced with correction of lower-order effects, likewise familywise error rates. Easy-to-use automatic SNP selection procedures, SNP selection based on “top” findings, or SNP selection based on p-value criterion for interesting main effects result in reduced power but also almost zero false positive rates. Always accounting for main effects in the SNP-SNP pair under investigation during Model-Based Multifactor Dimensionality Reduction analysis adequately controls false positive epistasis findings. This is particularly true when adopting a co-dominant corrective coding scheme. In conclusion, automatic search procedures to identify lower-order effects to correct for during epistasis screening should be avoided. The same is true for procedures that adjust for lower-order effects prior to Model-Based Multifactor Dimensionality Reduction and involve using residuals as the new trait. We advocate using “on-the-fly” lower-order effects adjusting when screening for SNP-SNP interactions using Model-Based Multifactor Dimensionality Reduction analysis.
doi:10.1371/journal.pone.0029594
PMCID: PMC3252336  PMID: 22242176
22.  GWIS - model-free, fast and exhaustive search for epistatic interactions in case-control GWAS 
BMC Genomics  2013;14(Suppl 3):S10.
Background
It has been hypothesized that multivariate analysis and systematic detection of epistatic interactions between explanatory genotyping variables may help resolve the problem of "missing heritability" currently observed in genome-wide association studies (GWAS). However, even the simplest bivariate analysis is still held back by significant statistical and computational challenges that are often addressed by reducing the set of analysed markers. Theoretically, it has been shown that combinations of loci may exist that show weak or no effects individually, but show significant (even complete) explanatory power over phenotype when combined. Reducing the set of analysed SNPs before bivariate analysis could easily omit such critical loci.
Results
We have developed an exhaustive bivariate GWAS analysis methodology that yields a manageable subset of candidate marker pairs for subsequent analysis using other, often more computationally expensive techniques. Our model-free filtering approach is based on classification using ROC curve analysis, an alternative to much slower regression-based modelling techniques. Exhaustive analysis of studies containing approximately 450,000 SNPs and 5,000 samples requires only 2 hours using a desktop CPU or 13 minutes using a GPU (Graphics Processing Unit). We validate our methodology with analysis of simulated datasets as well as the seven Wellcome Trust Case-Control Consortium datasets that represent a wide range of real life GWAS challenges. We have identified SNP pairs that have considerably stronger association with disease than their individual component SNPs that often show negligible effect univariately. When compared against previously reported results in the literature, our methods re-detect most significant SNP-pairs and additionally detect many pairs absent from the literature that show strong association with disease. The high overlap suggests that our fast analysis could substitute for some slower alternatives.
Conclusions
We demonstrate that the proposed methodology is robust, fast and capable of exhaustive search for epistatic interactions using a standard desktop computer. First, our implementation is significantly faster than timings for comparable algorithms reported in the literature, especially as our method allows simultaneous use of multiple statistical filters with low computing time overhead. Second, for some diseases, we have identified hundreds of SNP pairs that pass formal multiple test (Bonferroni) correction and could form a rich source of hypotheses for follow-up analysis.
Availability
A web-based version of the software used for this analysis is available at http://bioinformatics.research.nicta.com.au/gwis.
doi:10.1186/1471-2164-14-S3-S10
PMCID: PMC3665501  PMID: 23819779
23.  Predicting Adaptive Phenotypes From Multilocus Genotypes in Sitka Spruce (Picea sitchensis) Using Random Forest 
G3: Genes|Genomes|Genetics  2012;2(9):1085-1093.
Climate is the primary driver of the distribution of tree species worldwide, and the potential for adaptive evolution will be an important factor determining the response of forests to anthropogenic climate change. Although association mapping has the potential to improve our understanding of the genomic underpinnings of climatically relevant traits, the utility of adaptive polymorphisms uncovered by such studies would be greatly enhanced by the development of integrated models that account for the phenotypic effects of multiple single-nucleotide polymorphisms (SNPs) and their interactions simultaneously. We previously reported the results of association mapping in the widespread conifer Sitka spruce (Picea sitchensis). In the current study we used the recursive partitioning algorithm ‘Random Forest’ to identify optimized combinations of SNPs to predict adaptive phenotypes. After adjusting for population structure, we were able to explain 37% and 30% of the phenotypic variation, respectively, in two locally adaptive traits—autumn budset timing and cold hardiness. For each trait, the leading five SNPs captured much of the phenotypic variation. To determine the role of epistasis in shaping these phenotypes, we also used a novel approach to quantify the strength and direction of pairwise interactions between SNPs and found such interactions to be common. Our results demonstrate the power of Random Forest to identify subsets of markers that are most important to climatic adaptation, and suggest that interactions among these loci may be widespread.
doi:10.1534/g3.112.002733
PMCID: PMC3429923  PMID: 22973546
Random Forest; adaptation; association mapping; epistasis; phenology; cold hardiness; GenPred; shared data resources
24.  GVCBLUP: a computer package for genomic prediction and variance component estimation of additive and dominance effects 
BMC Bioinformatics  2014;15(1):270.
Background
Dominance effect may play an important role in genetic variation of complex traits. Full featured and easy-to-use computing tools for genomic prediction and variance component estimation of additive and dominance effects using genome-wide single nucleotide polymorphism (SNP) markers are necessary to understand dominance contribution to a complex trait and to utilize dominance for selecting individuals with favorable genetic potential.
Results
The GVCBLUP package is a shared memory parallel computing tool for genomic prediction and variance component estimation of additive and dominance effects using genome-wide SNP markers. This package currently has three main programs (GREML_CE, GREML_QM, and GCORRMX) and a graphical user interface (GUI) that integrates the three main programs with an existing program for the graphical viewing of SNP additive and dominance effects (GVCeasy). The GREML_CE and GREML_QM programs offer complementary computing advantages with identical results for genomic prediction of breeding values, dominance deviations and genotypic values, and for genomic estimation of additive and dominance variances and heritabilities using a combination of expectation-maximization (EM) algorithm and average information restricted maximum likelihood (AI-REML) algorithm. GREML_CE is designed for large numbers of SNP markers and GREML_QM for large numbers of individuals. Test results showed that GREML_CE could analyze 50,000 individuals with 400 K SNP markers and GREML_QM could analyze 100,000 individuals with 50K SNP markers. GCORRMX calculates genomic additive and dominance relationship matrices using SNP markers. GVCeasy is the GUI for GVCBLUP integrated with an existing software tool for the graphical viewing of SNP effects and a function for editing the parameter files for the three main programs.
Conclusion
The GVCBLUP package is a powerful and versatile computing tool for assessing the type and magnitude of genetic effects affecting a phenotype by estimating whole-genome additive and dominance heritabilities, for genomic prediction of breeding values, dominance deviations and genotypic values, for calculating genomic relationships, and for research and education in genomic prediction and estimation.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2105-15-270) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2105-15-270
PMCID: PMC4133608  PMID: 25107495
GVCBLUP; Genomic selection; Variance component; Heritability; BLUP
25.  Genomic prediction of breeding values using previously estimated SNP variances 
Background
Genomic prediction requires estimation of variances of effects of single nucleotide polymorphisms (SNPs), which is computationally demanding, and uses these variances for prediction. We have developed models with separate estimation of SNP variances, which can be applied infrequently, and genomic prediction, which can be applied routinely.
Methods
SNP variances were estimated with Bayes Stochastic Search Variable Selection (BSSVS) and BayesC. Genome-enhanced breeding values (GEBV) were estimated with RR-BLUP (ridge regression best linear unbiased prediction), using either variances obtained from BSSVS (BLUP-SSVS) or BayesC (BLUP-C), or assuming equal variances for each SNP. Datasets used to estimate SNP variances comprised (1) all animals, (2) 50% random animals (RAN50), (3) 50% best animals (TOP50), or (4) 50% worst animals (BOT50). Traits analysed were protein yield, udder depth, somatic cell score, interval between first and last insemination, direct longevity, and longevity including information from predictors.
Results
BLUP-SSVS and BLUP-C yielded similar GEBV as the equivalent Bayesian models that simultaneously estimated SNP variances. Reliabilities of these GEBV were consistently higher than from RR-BLUP, although only significantly for direct longevity. Across scenarios that used data subsets to estimate GEBV, observed reliabilities were generally higher for TOP50 than for RAN50, and much higher than for BOT50. Reliabilities of TOP50 were higher because the training data contained more ancestors of selection candidates. Using estimated SNP variances based on random or non-random subsets of the data, while using all data to estimate GEBV, did not affect reliabilities of the BLUP models. A convergence criterion of 10−8 instead of 10−10 for BLUP models yielded similar GEBV, while the required number of iterations decreased by 71 to 90%. Including a separate polygenic effect consistently improved reliabilities of the GEBV, but also substantially increased the required number of iterations to reach convergence with RR-BLUP. SNP variances converged faster for BayesC than for BSSVS.
Conclusions
Combining Bayesian variable selection models to re-estimate SNP variances and BLUP models that use those SNP variances, yields GEBV that are similar to those from full Bayesian models. Moreover, these combined models yield predictions with higher reliability and less bias than the commonly used RR-BLUP model.
Electronic supplementary material
The online version of this article (doi:10.1186/s12711-014-0052-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s12711-014-0052-x
PMCID: PMC4176585

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