Spectral analysis of gene expression profiles using gene networks

Microarrays have become extremely useful for analysing genetic phenomena, but establishing a relation between microarray analysis results (typically a list of genes) and their biological significance is often difficult. Currently, the standard approach is to map a posteriori the results onto gene networks to elucidate the functions perturbed at the level of pathways. However, integrating a priori knowledge of the gene networks could help in the statistical analysis of gene expression data and in their biological interpretation. Here we propose a method to integrate a priori the knowledge of a gene network in the analysis of gene expression data. The approach is based on the spectral decomposition of gene expression profiles with respect to the eigenfunctions of the graph, resulting in an attenuation of the high-frequency components of the expression profiles with respect to the topology of the graph. We show how to derive unsupervised and supervised classification algorithms of expression profiles, resulting in classifiers with biological relevance. We applied the method to the analysis of a set of expression profiles from irradiated and non-irradiated yeast strains. It performed at least as well as the usual classification but provides much more biologically relevant results and allows a direct biological interpretation

Computational Models for Transplant Biomarker Discovery.

Translational medicine offers a rich promise for improved diagnostics and drug discovery for biomedical research in the field of transplantation, where continued unmet diagnostic and therapeutic needs persist. Current advent of genomics and proteomics profiling called "omics" provides new resources to develop novel biomarkers for clinical routine. Establishing such a marker system heavily depends on appropriate applications of computational algorithms and software, which are basically based on mathematical theories and models. Understanding these theories would help to apply appropriate algorithms to ensure biomarker systems successful. Here, we review the key advances in theories and mathematical models relevant to transplant biomarker developments. Advantages and limitations inherent inside these models are discussed. The principles of key -computational approaches for selecting efficiently the best subset of biomarkers from high--dimensional omics data are highlighted. Prediction models are also introduced, and the integration of multi-microarray data is also discussed. Appreciating these key advances would help to accelerate the development of clinically reliable biomarker systems

The influence of feature selection methods on accuracy, stability and interpretability of molecular signatures

Motivation: Biomarker discovery from high-dimensional data is a crucial problem with enormous applications in biology and medicine. It is also extremely challenging from a statistical viewpoint, but surprisingly few studies have investigated the relative strengths and weaknesses of the plethora of existing feature selection methods. Methods: We compare 32 feature selection methods on 4 public gene expression datasets for breast cancer prognosis, in terms of predictive performance, stability and functional interpretability of the signatures they produce. Results: We observe that the feature selection method has a significant influence on the accuracy, stability and interpretability of signatures. Simple filter methods generally outperform more complex embedded or wrapper methods, and ensemble feature selection has generally no positive effect. Overall a simple Student's t-test seems to provide the best results. Availability: Code and data are publicly available at http://cbio.ensmp.fr/~ahaury/

Using machine learning to support better and intelligent visualisation for genomic data

Massive amounts of genomic data are created for the advent of Next Generation Sequencing technologies. Great technological advances in methods of characterising the human diseases, including genetic and environmental factors, make it a great opportunity to understand the diseases and to find new diagnoses and treatments. Translating medical data becomes more and more rich and challenging. Visualisation can greatly aid the processing and integration of complex data. Genomic data visual analytics is rapidly evolving alongside with advances in high-throughput technologies such as Artificial Intelligence (AI), and Virtual Reality (VR). Personalised medicine requires new genomic visualisation tools, which can efficiently extract knowledge from the genomic data effectively and speed up expert decisions about the best treatment of an individual patient’s needs. However, meaningful visual analysis of such large genomic data remains a serious challenge. Visualising these complex genomic data requires not only simply plotting of data but should also lead to better decisions. Machine learning has the ability to make prediction and aid in decision-making. Machine learning and visualisation are both effective ways to deal with big data, but they focus on different purposes. Machine learning applies statistical learning techniques to automatically identify patterns in data to make highly accurate prediction, while visualisation can leverage the human perceptual system to interpret and uncover hidden patterns in big data. Clinicians, experts and researchers intend to use both visualisation and machine learning to analyse their complex genomic data, but it is a serious challenge for them to understand and trust machine learning models in the serious medical industry. The main goal of this thesis is to study the feasibility of intelligent and interactive visualisation which combined with machine learning algorithms for medical data analysis. A prototype has also been developed to illustrate the concept that visualising genomics data from childhood cancers in meaningful and dynamic ways could lead to better decisions. Machine learning algorithms are used and illustrated during visualising the cancer genomic data in order to provide highly accurate predictions. This research could open a new and exciting path to discovery for disease diagnostics and therapies

How to understand the cell by breaking it: network analysis of gene perturbation screens

Modern high-throughput gene perturbation screens are key technologies at the forefront of genetic research. Combined with rich phenotypic descriptors they enable researchers to observe detailed cellular reactions to experimental perturbations on a genome-wide scale. This review surveys the current state-of-the-art in analyzing perturbation screens from a network point of view. We describe approaches to make the step from the parts list to the wiring diagram by using phenotypes for network inference and integrating them with complementary data sources. The first part of the review describes methods to analyze one- or low-dimensional phenotypes like viability or reporter activity; the second part concentrates on high-dimensional phenotypes showing global changes in cell morphology, transcriptome or proteome.Comment: Review based on ISMB 2009 tutorial; after two rounds of revisio

Microarray Data Mining and Gene Regulatory Network Analysis

The novel molecular biological technology, microarray, makes it feasible to obtain quantitative measurements of expression of thousands of genes present in a biological sample simultaneously. Genome-wide expression data generated from this technology are promising to uncover the implicit, previously unknown biological knowledge. In this study, several problems about microarray data mining techniques were investigated, including feature(gene) selection, classifier genes identification, generation of reference genetic interaction network for non-model organisms and gene regulatory network reconstruction using time-series gene expression data. The limitations of most of the existing computational models employed to infer gene regulatory network lie in that they either suffer from low accuracy or computational complexity. To overcome such limitations, the following strategies were proposed to integrate bioinformatics data mining techniques with existing GRN inference algorithms, which enables the discovery of novel biological knowledge. An integrated statistical and machine learning (ISML) pipeline was developed for feature selection and classifier genes identification to solve the challenges of the curse of dimensionality problem as well as the huge search space. Using the selected classifier genes as seeds, a scale-up technique is applied to search through major databases of genetic interaction networks, metabolic pathways, etc. By curating relevant genes and blasting genomic sequences of non-model organisms against well-studied genetic model organisms, a reference gene regulatory network for less-studied organisms was built and used both as prior knowledge and model validation for GRN reconstructions. Networks of gene interactions were inferred using a Dynamic Bayesian Network (DBN) approach and were analyzed for elucidating the dynamics caused by perturbations. Our proposed pipelines were applied to investigate molecular mechanisms for chemical-induced reversible neurotoxicity