11712321
HAPLORE: a program for haplotype reconstruction in general pedigrees without recombination
MOTIVATION
Haplotype reconstruction is an essential step in genetic linkage and association studies. Although many methods have been developed to estimate haplotype frequencies and reconstruct haplotypes for a sample of unrelated individuals, haplotype reconstruction in large pedigrees with a large number of genetic markers remains a challenging problem.


METHODS
We have developed an efficient computer program, HAPLORE (HAPLOtype REconstruction), to identify all haplotype sets that are compatible with the observed genotypes in a pedigree for tightly linked genetic markers. HAPLORE consists of three steps that can serve different needs in applications. In the first step, a set of logic rules is used to reduce the number of compatible haplotypes of each individual in the pedigree as much as possible. After this step, the haplotypes of all individuals in the pedigree can be completely or partially determined. These logic rules are applicable to completely linked markers and they can be used to impute missing data and check genotyping errors. In the second step, a haplotype-elimination algorithm similar to the genotype-elimination algorithms used in linkage analysis is applied to delete incompatible haplotypes derived from the first step. All superfluous haplotypes of the pedigree members will be excluded after this step. In the third step, the expectation-maximization (EM) algorithm combined with the partition and ligation technique is used to estimate haplotype frequencies based on the inferred haplotype configurations through the first two steps. Only compatible haplotype configurations with haplotypes having frequencies greater than a threshold are retained.


RESULTS
We test the effectiveness and the efficiency of HAPLORE using both simulated and real datasets. Our results show that, the rule-based algorithm is very efficient for completely genotyped pedigree. In this case, almost all of the families have one unique haplotype configuration. In the presence of missing data, the number of compatible haplotypes can be substantially reduced by HAPLORE, and the program will provide all possible haplotype configurations of a pedigree under different circumstances, if such multiple configurations exist. These inferred haplotype configurations, as well as the haplotype frequencies estimated by the EM algorithm, can be used in genetic linkage and association studies.


AVAILABILITY
The program can be downloaded from http://bioinformatics.med.yale.edu.
2217384
A semiparametric approach for marker gene selection based on gene expression data
MOTIVATION
Identification of differentially expressed genes is a major issue in gene expression data analysis and selection of marker genes is critical in tumor classification using gene expression data. In this paper, we propose a semiparametric two-sample test to identify both differentially expressed genes and select marker genes for sample classification.


RESULTS
A simulation study shows that the proposed method is more robust and powerful than the methods, generally used such as t-tests and non-parametric rank-sum tests, when the sample size is small. Cross-validation shows that the sample classification based on genes selected using this semiparametric method has lower misclassification rates.


CONTACT
hongyu.zhao@yale.edu.
7867544
A statistical method for identifying differential gene-gene co-expression patterns
MOTIVATION
To understand cancer etiology, it is important to explore molecular changes in cellular processes from normal state to cancerous state. Because genes interact with each other during cellular processes, carcinogenesis related genes may form differential co-expression patterns with other genes in different cell states. In this study, we develop a statistical method for identifying differential gene-gene co-expression patterns in different cell states.


RESULTS
For efficient pattern recognition, we extend the traditional F-statistic and obtain an Expected Conditional F-statistic (ECF-statistic), which incorporates statistical information of location and correlation. We also propose a statistical method for data transformation. Our approach is applied to a microarray gene expression dataset for prostate cancer study. For a gene of interest, our method can select other genes that have differential gene-gene co-expression patterns with this gene in different cell states. The 10 most frequently selected genes, include hepsin, GSTP1 and AMACR, which have recently been proposed to be associated with prostate carcinogenesis. However, genes GSTP1 and AMACR cannot be identified by studying differential gene expression alone. By using tumor suppressor genes TP53, PTEN and RB1, we identify seven genes that also include hepsin, GSTP1 and AMACR. We show that genes associated with cancer may have differential gene-gene expression patterns with many other genes in different cell states. By discovering such patterns, we may be able to identify carcinogenesis related genes.
10817560
Information assessment on predicting protein-protein interactions
BackgroundIdentifying protein-protein interactions is fundamental for understanding the molecular machinery of the cell. Proteome-wide studies of protein-protein interactions are of significant value, but the high-throughput experimental technologies suffer from high rates of both false positive and false negative predictions. In addition to high-throughput experimental data, many diverse types of genomic data can help predict protein-protein interactions, such as mRNA expression, localization, essentiality, and functional annotation. Evaluations of the information contributions from different evidences help to establish more parsimonious models with comparable or better prediction accuracy, and to obtain biological insights of the relationships between protein-protein interactions and other genomic information.ResultsOur assessment is based on the genomic features used in a Bayesian network approach to predict protein-protein interactions genome-wide in yeast. In the special case, when one does not have any missing information about any of the features, our analysis shows that there is a larger information contribution from the functional-classification than from expression correlations or essentiality. We also show that in this case alternative models, such as logistic regression and random forest, may be more effective than Bayesian networks for predicting interactions.ConclusionsIn the restricted problem posed by the complete-information subset, we identified that the MIPS and Gene Ontology (GO) functional similarity datasets as the dominating information contributors for predicting the protein-protein interactions under the framework proposed by Jansen et al. Random forests based on the MIPS and GO information alone can give highly accurate classifications. In this particular subset of complete information, adding other genomic data does little for improving predictions. We also found that the data discretizations used in the Bayesian methods decreased classification performance.
11367648
Inferring protein-protein interactions through high-throughput interaction data from diverse organisms
MOTIVATION
Identifying protein-protein interactions is critical for understanding cellular processes. Because protein domains represent binding modules and are responsible for the interactions between proteins, computational approaches have been proposed to predict protein interactions at the domain level. The fact that protein domains are likely evolutionarily conserved allows us to pool information from data across multiple organisms for the inference of domain-domain and protein-protein interaction probabilities.


RESULTS
We use a likelihood approach to estimating domain-domain interaction probabilities by integrating large-scale protein interaction data from three organisms, Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster. The estimated domain-domain interaction probabilities are then used to predict protein-protein interactions in S.cerevisiae. Based on a thorough comparison of sensitivity and specificity, Gene Ontology term enrichment and gene expression profiles, we have demonstrated that it may be far more informative to predict protein-protein interactions from diverse organisms than from a single organism.


AVAILABILITY
The program for computing the protein-protein interaction probabilities and supplementary material are available at http://bioinformatics.med.yale.edu/interaction.
18920027
A computational approach for ordering signal transduction pathway components from genomics and proteomics Data
BackgroundSignal transduction is one of the most important biological processes by which cells convert an external signal into a response. Novel computational approaches to mapping proteins onto signaling pathways are needed to fully take advantage of the rapid accumulation of genomic and proteomics information. However, despite their importance, research on signaling pathways reconstruction utilizing large-scale genomics and proteomics information has been limited.ResultsWe have developed an approach for predicting the order of signaling pathway components, assuming all the components on the pathways are known. Our method is built on a score function that integrates protein-protein interaction data and microarray gene expression data. Compared to the individual datasets, either protein interactions or gene transcript abundance measurements, the integrated approach leads to better identification of the order of the pathway components.ConclusionsAs demonstrated in our study on the yeast MAPK signaling pathways, the integration analysis of high-throughput genomics and proteomics data can be a powerful means to infer the order of pathway components, enabling the transformation from molecular data into knowledge of cellular mechanisms.
8780756
A Modular k-Nearest Neighbor Classification Method for Massively Parallel Text Categorization
This paper presents a Min-Max modular k-nearest neighbor (M3-k-NN) classification method for massively parallel text categorization. The basic idea behind the method is to decompose a large-scale text categorization problem into a number of smaller two-class subproblems and combine all of the individual modular k-NN classifiers trained on the smaller two-class subproblems into an M3-k-NN classifier. Our experiments in text categorization demonstrate that M3-k-NN is much faster than conventional k-NN, and meanwhile the classification accuracy of M3-k-NN is slightly better than that of the conventional k-NN. In practical, M3-k-NN has intimate relationship with high order k-NN algorithm; therefore, in theoretical sense, the reliability of M3-k-NN has been supported to some extend.
9567759
A hybrid heuristic for DAG scheduling on heterogeneous systems
Summary form only given. This paper is motivated by the observation that different methods to compute the weights of nodes and edges when scheduling DAGs onto heterogeneous machines may lead to significant variations in the generated schedule. To minimize such variations, we present a novel heuristic for DAG scheduling, which is based upon solving a series of independent task scheduling problems. A novel heuristic for the latter problem is also included. Both heuristics compare favourably with other related heuristics.
16473944
Analysis of Fault Tolerance of a Combining Classifier
This paper mainly analyses the fault tolerant capability of a combining classifier that uses a K-voting strategy for integrating binary classifiers. From the point view of fault tolerance, we discuss the influence of the failure of binary classifiers on the final output of the combining classifier, and present a theoretical analysis of combination performance under three fault models. The results provide a theoretical base for fault detection of the combining classifier.
1139392
Pathway analysis using random forests classification and regression
MOTIVATION
Although numerous methods have been developed to better capture biological information from microarray data, commonly used single gene-based methods neglect interactions among genes and leave room for other novel approaches. For example, most classification and regression methods for microarray data are based on the whole set of genes and have not made use of pathway information. Pathway-based analysis in microarray studies may lead to more informative and relevant knowledge for biological researchers.


RESULTS
In this paper, we describe a pathway-based classification and regression method using Random Forests to analyze gene expression data. The proposed methods allow researchers to rank important pathways from externally available databases, discover important genes, find pathway-based outlying cases and make full use of a continuous outcome variable in the regression setting. We also compared Random Forests with other machine learning methods using several datasets and found that Random Forests classification error rates were either the lowest or the second-lowest. By combining pathway information and novel statistical methods, this procedure represents a promising computational strategy in dissecting pathways and can provide biological insight into the study of microarray data.


AVAILABILITY
Source code written in R is available from http://bioinformatics.med.yale.edu/pathway-analysis/rf.htm.
12416682
Handling multiple testing while interpreting microarrays with the Gene Ontology Database
BackgroundThe development of software tools that analyze microarray data in the context of genetic knowledgebases is being pursued by multiple research groups using different methods. A common problem for many of these tools is how to correct for multiple statistical testing since simple corrections are overly conservative and more sophisticated corrections are currently impractical. A careful study of the nature of the distribution one would expect by chance, such as by a simulation study, may be able to guide the development of an appropriate correction that is not overly time consuming computationally.ResultsWe present the results from a preliminary study of the distribution one would expect for analyzing sets of genes extracted from Drosophila, S. cerevisiae, Wormbase, and Gramene databases using the Gene Ontology Database.ConclusionsWe found that the estimated distribution is not regular and is not predictable outside of a particular set of genes. Permutation-based simulations may be necessary to determine the confidence in results of such analyses.