The Genome Conformation As an Integrator of Multi-Omic Data: The Example of Damage Spreading in Cancer.

Publicly available multi-omic databases, in particular if associated with medical annotations, are rich resources with the potential to lead a rapid transition from high-throughput molecular biology experiments to better clinical outcomes for patients. In this work, we propose a model for multi-omic data integration (i.e., genetic variations, gene expression, genome conformation, and epigenetic patterns), which exploits a multi-layer network approach to analyse, visualize, and obtain insights from such biological information, in order to use achieved results at a macroscopic level. Using this representation, we can describe how driver and passenger mutations accumulate during the development of diseases providing, for example, a tool able to characterize the evolution of cancer. Indeed, our test case concerns the MCF-7 breast cancer cell line, before and after the stimulation with estrogen, since many datasets are available for this case study. In particular, the integration of data about cancer mutations, gene functional annotations, genome conformation, epigenetic patterns, gene expression, and metabolic pathways in our multi-layer representation will allow a better interpretation of the mechanisms behind a complex disease such as cancer. Thanks to this multi-layer approach, we focus on the interplay of chromatin conformation and cancer mutations in different pathways, such as metabolic processes, that are very important for tumor development. Working on this model, a variance analysis can be implemented to identify normal variations within each omics and to characterize, by contrast, variations that can be accounted to pathological samples compared to normal ones. This integrative model can be used to identify novel biomarkers and to provide innovative omic-based guidelines for treating many diseases, improving the efficacy of decision trees currently used in clinic

Multi-test Decision Tree and its Application to Microarray Data Classification

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 $6$ percent. 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

A Multi-Gene Genetic Programming Application for Predicting Students Failure at School

Several efforts to predict student failure rate (SFR) at school accurately still remains a core problem area faced by many in the educational sector. The procedure for forecasting SFR are rigid and most often times require data scaling or conversion into binary form such as is the case of the logistic model which may lead to lose of information and effect size attenuation. Also, the high number of factors, incomplete and unbalanced dataset, and black boxing issues as in Artificial Neural Networks and Fuzzy logic systems exposes the need for more efficient tools. Currently the application of Genetic Programming (GP) holds great promises and has produced tremendous positive results in different sectors. In this regard, this study developed GPSFARPS, a software application to provide a robust solution to the prediction of SFR using an evolutionary algorithm known as multi-gene genetic programming. The approach is validated by feeding a testing data set to the evolved GP models. Result obtained from GPSFARPS simulations show its unique ability to evolve a suitable failure rate expression with a fast convergence at 30 generations from a maximum specified generation of 500. The multi-gene system was also able to minimize the evolved model expression and accurately predict student failure rate using a subset of the original expressionComment: 14 pages, 9 figures, Journal paper. arXiv admin note: text overlap with arXiv:1403.0623 by other author

Building Gene Expression Profile Classifiers with a Simple and Efficient Rejection Option in R

Background: The collection of gene expression profiles from DNA microarrays and their analysis with pattern recognition algorithms is a powerful technology applied to several biological problems. Common pattern recognition systems classify samples assigning them to a set of known classes. However, in a clinical diagnostics setup, novel and unknown classes (new pathologies) may appear and one must be able to reject those samples that do not fit the trained model. The problem of implementing a rejection option in a multi-class classifier has not been widely addressed in the statistical literature. Gene expression profiles represent a critical case study since they suffer from the curse of dimensionality problem that negatively reflects on the reliability of both traditional rejection models and also more recent approaches such as one-class classifiers. Results: This paper presents a set of empirical decision rules that can be used to implement a rejection option in a set of multi-class classifiers widely used for the analysis of gene expression profiles. In particular, we focus on the classifiers implemented in the R Language and Environment for Statistical Computing (R for short in the remaining of this paper). The main contribution of the proposed rules is their simplicity, which enables an easy integration with available data analysis environments. Since in the definition of a rejection model tuning of the involved parameters is often a complex and delicate task, in this paper we exploit an evolutionary strategy to automate this process. This allows the final user to maximize the rejection accuracy with minimum manual intervention. Conclusions: This paper shows how the use of simple decision rules can be used to help the use of complex machine learning algorithms in real experimental setups. The proposed approach is almost completely automated and therefore a good candidate for being integrated in data analysis flows in labs where the machine learning expertise required to tune traditional classifiers might not be availabl

Automatic programming methodologies for electronic hardware fault monitoring

This paper presents three variants of Genetic Programming (GP) approaches for intelligent online performance monitoring of electronic circuits and systems. Reliability modeling of electronic circuits can be best performed by the Stressor - susceptibility interaction model. A circuit or a system is considered to be failed once the stressor has exceeded the susceptibility limits. For on-line prediction, validated stressor vectors may be obtained by direct measurements or sensors, which after pre-processing and standardization are fed into the GP models. Empirical results are compared with artificial neural networks trained using backpropagation algorithm and classification and regression trees. The performance of the proposed method is evaluated by comparing the experiment results with the actual failure model values. The developed model reveals that GP could play an important role for future fault monitoring systems.This research was supported by the International Joint Research Grant of the IITA (Institute of Information Technology Assessment) foreign professor invitation program of the MIC (Ministry of Information and Communication), Korea

Machine learning techniques to discover genes with potential prognosis role in Alzheimer’s disease using different biological sources

Alzheimer’s disease is a complex progressive neurodegenerative brain disorder, being its prevalence ex pected to rise over the next decades. Unconventional strategies for elucidating the genetic mechanisms are necessary due to its polygenic nature. In this work, the input information sources are five: a public DNA microarray that measures expression levels of control and patient samples, repositories of known genes associated to Alzheimer’s disease, additional data, Gene Ontology and finally, a literature review or expert knowledge to validate the results. As methodology to identify genes highly related to this disease, we present the integration of three machine learning techniques: particularly, we have used decision trees, quantitative association rules and hierarchical cluster to analyze Alzheimer’s disease gene expres sion profiles to identify genes highly linked to this neurodegenerative disease, through changes in their expression levels between control and patient samples. We propose an ensemble of decision trees and quantitative association rules to find the most suitable configurations of the multi-objective evolutionary algorithm GarNet, in order to overcome the complex parametrization intrinsic to this type of algorithms. To fulfill this goal, GarNet has been executed using multiple configuration settings and the well-known C4.5 has been used to find the minimum accuracy to be satisfied. Then, GarNet is rerun to identify de pendencies between genes and their expression levels, so we are able to distinguish between healthy individuals and Alzheimer’s patients using the configurations that overcome the minimum threshold of accuracy defined by C4.5 algorithm. Finally, a hierarchical cluster analysis has been used to validate the obtained gene-Alzheimer’s Disease associations provided by GarNet. The results have shown that the ob tained rules were able to successfully characterize the underlying information, grouping relevant genes for Alzheimer Disease. The genes reported by our approach provided two well defined groups that per fectly divided the samples between healthy and Alzheimer’s Disease patients. To prove the relevance of the obtained results, a statistical test and gene expression fold-change were used. Furthermore, this rel evance has been summarized in a volcano plot, showing two clearly separated and significant groups of genes that are up or down-regulated in Alzheimer’s Disease patients. A biological knowledge integration phase was performed based on the information fusion of systematic literature review, enrichment Gene Ontology terms for the described genes found in the hippocampus of patients. Finally, a validation phase with additional data and a permutation test is carried out, being the results consistent with previous studies.Ministerio de Ciencia y Tecnología TIN2011-28956-C02-02Ministerio de Ciencia y Tecnología TIN2014-55894-C2-1-RJunta de Andalucía P11-TIC-752

Identification of an Efficient Gene Expression Panel for Glioblastoma Classification.

We present here a novel genetic algorithm-based random forest (GARF) modeling technique that enables a reduction in the complexity of large gene disease signatures to highly accurate, greatly simplified gene panels. When applied to 803 glioblastoma multiforme samples, this method allowed the 840-gene Verhaak et al. gene panel (the standard in the field) to be reduced to a 48-gene classifier, while retaining 90.91% classification accuracy, and outperforming the best available alternative methods. Additionally, using this approach we produced a 32-gene panel which allows for better consistency between RNA-seq and microarray-based classifications, improving cross-platform classification retention from 69.67% to 86.07%. A webpage producing these classifications is available at http://simplegbm.semel.ucla.edu

Predicting gene expression in the human malaria parasite Plasmodium falciparum using histone modification, nucleosome positioning, and 3D localization features.

Empirical evidence suggests that the malaria parasite Plasmodium falciparum employs a broad range of mechanisms to regulate gene transcription throughout the organism's complex life cycle. To better understand this regulatory machinery, we assembled a rich collection of genomic and epigenomic data sets, including information about transcription factor (TF) binding motifs, patterns of covalent histone modifications, nucleosome occupancy, GC content, and global 3D genome architecture. We used these data to train machine learning models to discriminate between high-expression and low-expression genes, focusing on three distinct stages of the red blood cell phase of the Plasmodium life cycle. Our results highlight the importance of histone modifications and 3D chromatin architecture in Plasmodium transcriptional regulation and suggest that AP2 transcription factors may play a limited regulatory role, perhaps operating in conjunction with epigenetic factors

Modelling and trading the Greek stock market with gene expression and genetic programing algorithms

This paper presents an application of the gene expression programming (GEP) and integrated genetic programming (GP) algorithms to the modelling of ASE 20 Greek index. GEP and GP are robust evolutionary algorithms that evolve computer programs in the form of mathematical expressions, decision trees or logical expressions. The results indicate that GEP and GP produce significant trading performance when applied to ASE 20 and outperform the well-known existing methods. The trading performance of the derived models is further enhanced by applying a leverage filter

Refining interaction search through signed iterative Random Forests

Advances in supervised learning have enabled accurate prediction in biological systems governed by complex interactions among biomolecules. However, state-of-the-art predictive algorithms are typically black-boxes, learning statistical interactions that are difficult to translate into testable hypotheses. The iterative Random Forest algorithm took a step towards bridging this gap by providing a computationally tractable procedure to identify the stable, high-order feature interactions that drive the predictive accuracy of Random Forests (RF). Here we refine the interactions identified by iRF to explicitly map responses as a function of interacting features. Our method, signed iRF, describes subsets of rules that frequently occur on RF decision paths. We refer to these rule subsets as signed interactions. Signed interactions share not only the same set of interacting features but also exhibit similar thresholding behavior, and thus describe a consistent functional relationship between interacting features and responses. We describe stable and predictive importance metrics to rank signed interactions. For each SPIM, we define null importance metrics that characterize its expected behavior under known structure. We evaluate our proposed approach in biologically inspired simulations and two case studies: predicting enhancer activity and spatial gene expression patterns. In the case of enhancer activity, s-iRF recovers one of the few experimentally validated high-order interactions and suggests novel enhancer elements where this interaction may be active. In the case of spatial gene expression patterns, s-iRF recovers all 11 reported links in the gap gene network. By refining the process of interaction recovery, our approach has the potential to guide mechanistic inquiry into systems whose scale and complexity is beyond human comprehension