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Omics data usually have ultra-high dimension (p) and small sample size (n). Standard support vector machines (SVMs), which minimize the L 2 norm for the primal variables, only lead to sparse solutions for the dual variables. L 1 based SVMs, directly minimizing the L 1 norm, have been used for feature selection with omics data. However, most current methods directly solve the primal formulations of the problem, which are not computationally scalable. The computational complexity increases with the number of features. In addition, L 1 norm is known to be asymptotically biased and not consistent for feature selection. In this paper, we develop an efficient method for sparse support vector machines with L 0 norm approximation. The proposed method approximates the L 0 minimization through solving a series of L 2 optimization problems, which can be formulated with dual variables. It finds the optimal solution for p primal variables through estimating n dual variables, which is more efficient as long as the sample size is small. L 0 approximation leads to sparsity in both dual and primal variables, and can be used for both feature and sample selections. The proposed method identifies much less number of features and achieves similar performances in simulations. We apply the proposed method to feature selections with metagenomic sequencing and gene expression data. It can identify biologically important genes and taxa efficiently., (Copyright © 2019 Elsevier B.V. All rights reserved.)

For the diagnosis and outcome prediction of gastric cancer (GC), machine learning methods based on whole slide pathological images (WSIs) have shown promising performance and reduced the cost of manual analysis. Nevertheless, accurate prediction of GC outcome may rely on multiple modalities with complementary information, particularly gene expression data. Thus, there is a need to develop multimodal learning methods to enhance prediction performance. In this paper, we collect a dataset from Ruijin Hospital and propose a multimodal learning method for GC diagnosis and outcome prediction, called GaCaMML, which is featured by a cross-modal attention mechanism and Per-Slide training scheme. Additionally, we perform feature attribution analysis via integrated gradient (IG) to identify important input features. The proposed method improves prediction accuracy over the single-modal learning method on three tasks, i.e., survival prediction (by 4.9% on C-index), pathological stage classification (by 11.6% on accuracy), and lymph node classification (by 12.0% on accuracy). Especially, the Per-Slide strategy addresses the issue of a high WSI-to-patient ratio and leads to much better results compared with the Per-Person training scheme. For the interpretable analysis, we find that although WSIs dominate the prediction for most samples, there is still a substantial portion of samples whose prediction highly relies on gene expression information. This study demonstrates the great potential of multimodal learning in GC-related prediction tasks and investigates the contribution of WSIs and gene expression, respectively, which not only shows how the model makes a decision but also provides insights into the association between macroscopic pathological phenotypes and microscopic molecular features. [Display omitted] • GaCaMML outperforms the single-modal learning method across three tasks on accuracy. • Per-Slide strategy enhances prediction results by optimizing WSI-to-patient ratio. • WSI features prevail in gastric cancer outcome prediction for most samples. • Certain genes like MMPs and TP53 significantly impact prediction results. [ABSTRACT FROM AUTHOR]

Objective: Both supervised methods and unsupervised methods have been widely used to solve the tumor classification problem based on gene expression profiles. This paper introduces a semi-supervised graph-based method for tumor classification. Feature extraction plays a key role in tumor classification based on gene expression profiles, and can greatly improve the performance of a classifier. In this paper we propose a novel multi-step dimensionality reduction method for extracting tumor-related features., Methods and Materials: First the Wilcoxon rank-sum test is used for gene selection. Then gene ranking and discrete cosine transform are combined with principal component analysis for feature extraction. Finally, the performance is evaluated by semi-supervised learning algorithms., Results: To show the validity of the proposed method, we apply it to classify four tumor datasets involving various human normal and tumor tissue samples. The experimental results show that the proposed method is efficient and feasible. Compared with other methods, our method can achieve relatively higher prediction accuracy. Particularly, it is found that semi-supervised method is superior to support vector machines in classification performance., Conclusions: The proposed approach can effectively improve the performance of tumor classification based on gene expression profiles. This work is a meaningful attempt to explore and apply multi-step dimensionality reduction and semi-supervised learning methods in the field of tumor classification. Considering the high classification accuracy, there should be much room for the application of multi-step dimensionality reduction and semi-supervised learning methods to perform tumor classification., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Objective: Recently, much research has been proposed using nature inspired algorithms to perform complex machine learning tasks. Ant colony optimization (ACO) is one such algorithm based on swarm intelligence and is derived from a model inspired by the collective foraging behavior of ants. Taking advantage of the ACO in traits such as self-organization and robustness, this paper investigates ant-based algorithms for gene expression data clustering and associative classification., Methods and Material: An ant-based clustering (Ant-C) and an ant-based association rule mining (Ant-ARM) algorithms are proposed for gene expression data analysis. The proposed algorithms make use of the natural behavior of ants such as cooperation and adaptation to allow for a flexible robust search for a good candidate solution., Results: Ant-C has been tested on the three datasets selected from the Stanford Genomic Resource Database and achieved relatively high accuracy compared to other classical clustering methods. Ant-ARM has been tested on the acute lymphoblastic leukemia (ALL)/acute myeloid leukemia (AML) dataset and generated about 30 classification rules with high accuracy., Conclusions: Ant-C can generate optimal number of clusters without incorporating any other algorithms such as K-means or agglomerative hierarchical clustering. For associative classification, while a few of the well-known algorithms such as Apriori, FP-growth and Magnum Opus are unable to mine any association rules from the ALL/AML dataset within a reasonable period of time, Ant-ARM is able to extract associative classification rules.

Background and Motivation: DNA microarray technology has made it possible to determine the expression levels of thousands of genes in parallel under multiple experimental conditions. Genome-wide analyses using DNA microarrays make a great contribution to the exploration of the dynamic state of genetic networks, and further lead to the development of new disease diagnosis technologies. An important step in the analysis of gene expression data is to classify genes with similar expression patterns into the same groups. To this end, hierarchical clustering algorithms have been widely used. Major advantages of hierarchical clustering algorithms are that investigators do not need to specify the number of clusters in advance and results are presented visually in the form of a dendrogram. However, since traditional hierarchical clustering methods simply provide results on the statistical characteristics of expression data, biological interpretations of the resulting clusters are not easy, and it requires laborious tasks to unveil hidden biological processes regulated by members in the clusters. Therefore, it has been a very difficult routine for experts., Objective: Here, we propose a novel algorithm in which cluster boundaries are determined by referring to functional annotations stored in genome databases., Materials and Methods: The algorithm first performs hierarchical clustering of gene expression profiles. Then, the cluster boundaries are determined by the Variance Inflation Factor among the Gene Function Vectors, which represents distributions of gene functions in each cluster. Our algorithm automatically specifies a cutoff that leads to functionally independent agglomerations of genes on the dendrogram derived from similarities among gene expression patterns. Finally, each cluster is annotated according to dominant gene functions within the respective cluster., Results and Conclusions: In this paper, we apply our algorithm to two gene expression datasets related to cell cycle and cold stress response in budding yeast Saccharomyces cerevisiae. As a result, we show that the algorithm enables us to recognize cluster boundaries characterizing fundamental biological processes such as the Early G1, Late G1, S, G2 and M phases in cell cycles, and also provides novel annotation information that has not been obtained by traditional hierarchical clustering methods. In addition, using formal cluster validity indices, high validity of our algorithm is verified by the comparison through other popular clustering algorithms, K-means, self-organizing map and AutoClass.

Objective: Acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood, representing nearly one third of all pediatric cancers. Currently, the treatment of pediatric ALL is centered on tailoring the intensity of the therapy applied to a patient's risk of relapse, which is linked to the type of leukemia the patient has. Hence, accurate and correct diagnosis of the various leukemia subtypes becomes an important first step in the treatment process. Recently, gene expression profiling using DNA microarrays has been shown to be a viable and accurate diagnostic tool to identify the known prognostically important ALL subtypes. Thus, there is currently a huge interest in developing autonomous classification systems for cancer diagnosis using gene expression data. This is to achieve an unbiased analysis of the data and also partly to handle the large amount of genetic information extracted from the DNA microarrays., Methodology: Generally, existing medical decision support systems (DSS) for cancer classification and diagnosis are based on traditional statistical methods such as Bayesian decision theory and machine learning models such as neural networks (NN) and support vector machine (SVM). Though high accuracies have been reported for these systems, they fall short on certain critical areas. These included (a) being able to present the extracted knowledge and explain the computed solutions to the users; (b) having a logical deduction process that is similar and intuitive to the human reasoning process; and (c) flexible enough to incorporate new knowledge without running the risk of eroding old but valid information. On the other hand, a neural fuzzy system, which is synthesized to emulate the human ability to learn and reason in the presence of imprecise and incomplete information, has the ability to overcome the above-mentioned shortcomings. However, existing neural fuzzy systems have their own limitations when used in the design and implementation of DSS. Hence, this paper proposed the use of a novel neural fuzzy system: the generic self-organising fuzzy neural network (GenSoFNN) with truth-value restriction (TVR) fuzzy inference, as a fuzzy DSS (denoted as GenSo-FDSS) for the classification of ALL subtypes using gene expression data., Results and Conclusion: The performance of the GenSo-FDSS system is encouraging when benchmarked against those of NN, SVM and the K-nearest neighbor (K-NN) classifier. On average, a classification rate of above 90% has been achieved using the GenSo-FDSS system.

Omics data usually have ultra-high dimension (p) and small sample size (n). Standard support vector machines (SVMs), which minimize the L2 norm for the primal variables, only lead to sparse solutions for the dual variables. L1 based SVMs, directly minimizing the L1 norm, have been used for feature selection with omics data. However, most current methods directly solve the primal formulations of the problem, which are not computationally scalable. The computational complexity increases with the number of features. In addition, L1 norm is known to be asymptotically biased and not consistent for feature selection. In this paper, we develop an efficient method for sparse support vector machines with L0 norm approximation. The proposed method approximates the L0 minimization through solving a series of L2 optimization problems, which can be formulated with dual variables. It finds the optimal solution for p primal variables through estimating n dual variables, which is more efficient as long as the sample size is small. L0 approximation leads to sparsity in both dual and primal variables, and can be used for both feature and sample selections. The proposed method identifies much less number of features and achieves similar performances in simulations. We apply the proposed method to feature selections with metagenomic sequencing and gene expression data. It can identify biologically important genes and taxa efficiently. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Accurate cancer prognosis prediction is critical to cancer treatment. There have been many prognosis models based on clinical markers, but few of them are satisfied in clinical applications. And with the development of microarray technologies, cancer researchers have discovered many genes as new markers from the gene expression data and have further developed powerful prognosis models based on these so-called genetic biomarkers. However, the application of such biomarkers still suffers from some problems. The first one is there are a great number of genes and a few samples in the gene expression data so that it is difficult to select a unified gene set to establish a stable classifier for prognosis. The second one is that, due to the experimental and technical reasons, there are existing noises and redundancies in gene expression data, which may lead to building a prognosis predictor with poor performance. The last but not the least one is the microarray experiments are so expensive currently that it is hard to obtain abundant samples. Therefore, it is practical to develop prognosis methods mainly based on conventional clinical markers in real cancer treatment applications. This paper aims to establish an accurate classification model for cancer prognosis, in order to make full use of the invaluable information in clinical data, especially which is usually ignored by most of the existing methods when they aim for high prediction accuracies. Methods: First, this paper gives the formal description of general classification problem, and presents a novel mixture classification model to make full use of the invaluable information in clinical data, which is similar to the traditional ensemble classification models except for putting strict constraints on the construction of mapping functions to avoid voting process. Then, a two-layer instance of the proposed model, named as MRS (Mixture of Rough set and Support vector machine), is constructed by integrating rough set and support vector machine (SVM) classification methods, in which, the rough set classifier acts as the first layer to identify some singular samples in data, and the SVM classifier acts as the second layer to classify the remaining samples. Finally, MRS is used to make prognosis prediction on two open breast cancer datasets. One dataset, denoted as BRC-1 hereafter, is a high quality, publicly available dataset of 97 breast cancer tumors of node-negative patients. The other, denoted as BRC-2 hereafter, uses baseline human primary breast tumor data from LBL breast cancer cell collection containing 174 samples. Results: We have done two experiments on BRC-1 and BRC-2, respectively. In the first experiment, the BRC-1 dataset is divided into train set with 78 patients (34 ones belonging to poor prognosis group and 44 ones belonging to good prognosis group) and test set with 19 patients (12 ones belonging to poor prognosis group and 7 ones belonging to good prognosis). After trained on the train set, the MRS can correctly classify all the 12 patients with poor prognosis, and 6 of 7 patients with good prognosis in the test set. The results are better than previous researches, even better than the 70-gene based biomarkers. And in the second experiment, we construct the classifiers using BRC-2 dataset, and compare MRS with other representative methods in Weka software by 5-fold cross-validation, and comparison results show that MRS has higher prediction accuracy than those methods. Conclusions: The proposed mixture classification model can easily integrate methods with different characteristics. It can overcome the shortcomings of traditional voting-based ensemble models and thus can make full use of the information in clinical data. The experimental results illustrate that our implemented MRS classifier can predict the breast cancer prognosis more accurately than previous prognostic methods. [Copyright &y& Elsevier]

The inference of Gene Regulatory Networks (GRNs) using gene expression data in order to detect the basic cellular processes is a key issue in biological systems. Inferring GRN correctly requires inferring predictor set accurately. In this paper, a fast and accurate predictor set inference framework which linearly combines some inference methods is proposed. The purpose of the combination of various methods is to increase the accuracy of inferred GRN. The proposed framework offers a linear weighted combination of Pearson Correlation Coefficient (PCC) and two different feature selection approaches, namely: Information Gain (IG) and ReliefF. In order to set the appropriate weights, Genetic Algorithm (GA) is used. Similarity measure is considered as fitness function to guide GA. At the end, based on the obtained weights, the best predictor set of GRN using three aforementioned inference methods is selected and the network topology is formed. Due to the huge volume of gene expression data, GRN inference algorithms should infer GRN at a reasonable runtime. Hence, a novel criterion is provided to evaluate GRNs based on runtime and accuracy. The simulation results using biological data indicate that the proposed framework is fast and more reliable compared to other recent methods [1-7]. [ABSTRACT FROM AUTHOR]

Objective: High-throughput technologies have generated an unprecedented amount of high-dimensional gene expression data. Algorithmic approaches could be extremely useful to distill information and derive compact interpretable representations of the statistical patterns present in the data. This paper proposes a mining approach to extract an informative representation of gene expression profiles based on a generative model called the Counting Grid (CG).Method: Using the CG model, gene expression values are arranged on a discrete grid, learned in a way that "similar" co-expression patterns are arranged in close proximity, thus resulting in an intuitive visualization of the dataset. More than this, the model permits to identify the genes that distinguish between classes (e.g. different types of cancer). Finally, each sample can be characterized with a discriminative signature - extracted from the model - that can be effectively employed for classification.Results: A thorough evaluation on several gene expression datasets demonstrate the suitability of the proposed approach from a twofold perspective: numerically, we reached state-of-the-art classification accuracies on 5 datasets out of 7, and similar results when the approach is tested in a gene selection setting (with a stability always above 0.87); clinically, by confirming that many of the genes highlighted by the model as significant play also a key role for cancer biology.Conclusion: The proposed framework can be successfully exploited to meaningfully visualize the samples; detect medically relevant genes; properly classify samples. [ABSTRACT FROM AUTHOR]

Summary: Objective: The desirable property of tools used to investigate biological data is easy to understand models and predictive decisions. Decision trees are particularly promising in this regard due to their comprehensible nature that resembles the hierarchical process of human decision making. However, existing algorithms for learning decision trees have tendency to underfit gene expression data. The main aim of this work is to improve the performance and stability of decision trees with only a small increase in their complexity. Methods: We propose a multi-test decision tree (MTDT); our main contribution is the application of several univariate tests in each non-terminal node of the decision tree. We also search for alternative, lower-ranked features in order to obtain more stable and reliable predictions. Results: Experimental validation was performed on several real-life gene expression datasets. Comparison results with eight classifiers show that MTDT has a statistically significantly higher accuracy than popular decision tree classifiers, and it was highly competitive with ensemble learning algorithms. The proposed solution managed to outperform its baseline algorithm on 14 datasets by an average 6%. A study performed on one of the datasets showed that the discovered genes used in the MTDT classification model are supported by biological evidence in the literature. Conclusion: This paper introduces a new type of decision tree which is more suitable for solving biological problems. MTDTs are relatively easy to analyze and much more powerful in modeling high dimensional microarray data than their popular counterparts. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Modelling the associations from high-throughput experimental molecular data has provided unprecedented insights into biological pathways and signalling mechanisms. Graphical models and networks have especially proven to be useful abstractions in this regard. Ad hoc thresholds are often used in conjunction with structure learning algorithms to determine significant associations. The present study overcomes this limitation by proposing a statistically motivated approach for identifying significant associations in a network. Methods and materials: A new method that identifies significant associations in graphical models by estimating the threshold minimising the L 1 norm between the cumulative distribution function (CDF) of the observed edge confidences and those of its asymptotic counterpart is proposed. The effectiveness of the proposed method is demonstrated on popular synthetic data sets as well as publicly available experimental molecular data corresponding to gene and protein expression profiles. Results: The improved performance of the proposed approach is demonstrated across the synthetic data sets using sensitivity, specificity and accuracy as performance metrics. The results are also demonstrated across varying sample sizes and three different structure learning algorithms with widely varying assumptions. In all cases, the proposed approach has specificity and accuracy close to 1, while sensitivity increases linearly in the logarithm of the sample size. The estimated threshold systematically outperforms common ad hoc ones in terms of sensitivity while maintaining comparable levels of specificity and accuracy. Networks from experimental data sets are reconstructed accurately with respect to the results from the original papers. Conclusion: Current studies use structure learning algorithms in conjunction with ad hoc thresholds for identifying significant associations in graphical abstractions of biological pathways and signalling mechanisms. Such an ad hoc choice can have pronounced effect on attributing biological significance to the associations in the resulting network and possible downstream analysis. The statistically motivated approach presented in this study has been shown to outperform ad hoc thresholds and is expected to alleviate spurious conclusions of significant associations in such graphical abstractions. [Copyright &y& Elsevier]

Abstract: Objective: Re-construction of a genetic regulatory network from a given time-series gene expression data is an important research topic in systems biology. One of the main difficulties in building a genetic regulatory network lies in the fact that practical data set has a huge number of genes vs. a small number of sampling time points. In this paper, we propose a new linear regression model that may overcome this difficulty for uncovering the regulatory relationship in a genetic network. Methods: The proposed multiple regression model makes use of the scale-free property of a real biological network. In particular, a filter is constructed by using this scale-free property and some appropriate statistical tests to remove redundant interactions among the genes. A model is then constructed by minimizing the gap between the observed and the predicted data. Results: Numerical examples based on yeast gene expression data are given to demonstrate that the proposed model fits the practical data very well. Some interesting properties of the genes and the underlying network are also observed. Conclusions: In conclusion, we propose a new multiple regression model based on the scale-free property of real biological network for genetic regulatory network inference. Numerical results using yeast cell cycle gene expression dataset show the effectiveness of our method. We expect that the proposed method can be widely used for genetic network inference using high-throughput gene expression data from various species for systems biology discovery. [Copyright &y& Elsevier]

Summary: Objective: Nonnegative matrix factorization (NMF) has been proven to be a powerful clustering method. Recently Cichocki and coauthors have proposed a family of new algorithms based on the -divergence for NMF. However, it is an open problem to choose an optimal . Methods and materials: In this paper, we tested such NMF variant with different values on clustering cancer gene expression data for optimal selection experimentally with 11 datasets. Results and conclusion: Our experimental results show that and 2 are two special optimal cases for real applications. [Copyright &y& Elsevier]

Summary: Objective: Gene Ontology (GO) has become a routine resource for functional analysis of gene lists. Although a number of tools have been provided to identify enriched GO terms in one or two gene lists, two technical challenges remain. First, how to handle multiple hypothesis testing in the analysis given that the tests are heavily correlated; second, how to identify GO terms that are enriched in a gene cluster, as compared to multiple other gene clusters. We provide a statistical procedure to rigorously treat these problems and offer a software tool for applying GO to the analysis of gene clusters. Methods: We previously introduced a statistical procedure that handles hypothesis testing in a two-group comparison scenario. In this paper we extend the two-group comparison procedure into a general procedure that enables the analysis of any number of gene lists/clusters. This new procedure enables identification of GO terms enriched in any gene cluster, while it controls for multiple hypothesis testing. This procedure is implemented into a user-friendly analysis tool: GoSurfer. The current version of GoSurfer takes one or several gene lists as input, and it identifies the GO terms that are enriched in any of the input gene lists. GoSurfer estimates a conservative false discovery rate (FDR) for every GO term. The FDR estimation procedure in GoSurfer has two advantages: it does not rely on independence assumption, and it does not assume all the hypotheses are null hypothesis (complete null). Thus GoSurfer''s FDR estimates are mildly conservative rather than overly conservative. Results: We implemented the new procedure for GO analysis in multiple gene clusters into the GoSurfer software. We provide three examples on using GoSurfer to analyze time course gene expression data sets on the differentiation of embryonic stem cells. In the example of analysis of multiple gene clusters, we first used a typical clustering algorithm and identified five gene clusters, representing up-regulation, down-regulation and other patterns in the differentiation time course. Taking all the five gene clusters as input data, GoSurfer reports “cell adhesion” and “muscle contraction” as significant GO terms for the up-regulated cluster, “amino acids metabolism” as a significant GO term for the down-regulated gene cluster, and GoSurfer reports a number of GO terms related to RNA processing and RNA transport as significant terms to a cluster that is up-regulated in both early and late time points. This may suggest that genes for RNA processing and genes for RNA transport are coregulated in the differentiation process of embryonic stem cells. Conclusion: The GoSurfer software is provided to analyze multiple gene clusters and identify GO terms that are enriched in any gene cluster. Gosurfer is available at: www.gosurfer.org. [Copyright &y& Elsevier]

Summary: Objective:: To improve the performance of gene extraction for cancer diagnosis by recursive feature elimination with support vector machines (RFE-SVMs): A cancer diagnosis by using the DNA microarray data faces many challenges the most serious one being the presence of thousands of genes and only several dozens (at the best) of patient''s samples. Thus, making any kind of classification in high-dimensional spaces from a limited number of data is both an extremely difficult and a prone to an error procedure. The improved RFE-SVMs is introduced and used here for an elimination of less relevant genes and just for a reduction of the overall number of genes used in a medical diagnostic. Methods:: The paper shows why and how the, usually neglected, penalty parameter C and some standard data preprocessing techniques (normalizing and scaling) influence classification results and the gene selection of RFE-SVMs. The gene selected by RFE-SVMs is compared with eight other gene selection algorithms implemented in the Rankgene software to investigate whether there is any consensus among the algorithms, so the scope of finding the right set of genes can be reduced. Results:: The improved RFE-SVMs is applied on the two benchmarking colon and lymphoma cancer data sets with various C parameters and different standard preprocessing techniques. Here, decreasing C leads to the smaller diagnosis error in comparisons to other known methods applied to the benchmarking data sets. With an appropriate parameter C and with a proper preprocessing procedure, the reduction in a diagnosis error is as high as 36%. Conclusions:: The results suggest that with a properly chosen parameter C, the extracted genes and the constructed classifier will ensure less overfitting of the training data leading to an increased accuracy in selecting relevant genes. Finally, comparison in gene ranking obtained by different algorithms shows that there is a significant consensus among the various algorithms as to which set of genes is relevant. [Copyright &y& Elsevier]

Summary: Objective:: The gene promoter region controls transcriptional initiation of a gene, which is the most important step in gene regulation. In-silico detection of promoter region in genomic sequences has a number of applications in gene discovery and understanding gene expression regulation. However, computational prediction of eukaryotic poly-II promoters has remained a difficult task. This paper introduces a novel statistical technique for detecting promoter regions in long genomic sequences. Method:: A number of existing techniques analyze the occurrence frequencies of oligonucleotides in promoter sequences as compared to other genomic regions. In contrast, the present work studies the positional densities of oligonucleotides in promoter sequences. The analysis does not require any non-promoter sequence dataset or any model of the background oligonucleotide content of the genome. The statistical model learnt from a dataset of promoter sequences automatically recognizes a number of transcription factor binding sites simultaneously with their occurrence positions relative to the transcription start site. Based on this model, a continuous naïve Bayes classifier is developed for the detection of human promoters and transcription start sites in genomic sequences. Results:: The present study extends the scope of statistical models in general promoter modeling and prediction. Promoter sequence features learnt by the model correlate well with known biological facts. Results of human transcription start site prediction compare favorably with existing 2nd generation promoter prediction tools. [Copyright &y& Elsevier]

Genome-wide transcription profiling is a powerful technique for studying the enormous complexity of cellular states. Moreover, when applied to disease tissue it may reveal quantitative and qualitative alterations in gene expression that give information on the context or underlying basis for the disease and may provide a new diagnostic approach. However, the data obtained from high-density microarrays is highly complex and poses considerable challenges in data mining. The data requires care in both pre-processing and the application of data mining techniques.This paper addresses the problem of dealing with microarray data that come from two known classes (Alzheimer and normal). We have applied three separate techniques to discover genes associated with Alzheimer disease (AD). The 67 genes identified in this study included a total of 17 genes that are already known to be associated with Alzheimer’s or other neurological diseases. This is higher than any of the previously published Alzheimer’s studies. Twenty known genes, not previously associated with the disease, have been identified as well as 30 uncharacterized expressed sequence tags (ESTs). Given the success in identifying genes already associated with AD, we can have some confidence in the involvement of the latter genes and ESTs.From these studies we can attempt to define therapeutic strategies that would prevent the loss of specific components of neuronal function in susceptible patients or be in a position to stimulate the replacement of lost cellular function in damaged neurons.Although our study is based on a relatively small number of patients (four AD and five normal), we think our approach sets the stage for a major step in using gene expression data for disease modeling (i.e. classification and diagnosis). It can also contribute to the future of gene function identification, pathology, toxicogenomics, and pharmacogenomics. [Copyright &y& Elsevier]

The main topic of this paper is modeling the expected value of experimentation (EVE) for discovering causal pathways in gene expression data. By experimentation we mean both interventions (e.g., a gene knockout experiment) and observations (e.g., passively observing the expression level of a “wild-type” gene). We introduce a system called GEEVE (causal discovery in Gene Expression data using Expected Value of Experimentation), which implements expected value of experimentation in discovering causal pathways using gene expression data. GEEVE provides the following assistance, which is intended to help biologists in their quest to discover gene-regulation pathways:In recommending which experiments to perform (and how many times to repeat them) the EVE approach considers the biologist’s preferences for which genes to focus the discovery process. Also, since exact EVE calculations are exponential in time, GEEVE incorporates approximation methods. GEEVE is able to combine data from knockout experiments with data from wild-type experiments to suggest additional experiments to perform and then to analyze the results of those microarray experimental results. It models the possibility that unmeasured (latent) variables may be responsible for some of the statistical associations among the expression levels of the genes under study.To evaluate the GEEVE system, we used a gene expression simulator to generate data from specified models of gene regulation. The results show that the GEEVE system gives better results than two recently published approaches (1) in learning the generating models of gene regulation and (2) in recommending experiments to perform. [Copyright &y& Elsevier]