Stable Feature Selection for Biomarker Discovery

Feature selection techniques have been used as the workhorse in biomarker discovery applications for a long time. Surprisingly, the stability of feature selection with respect to sampling variations has long been under-considered. It is only until recently that this issue has received more and more attention. In this article, we review existing stable feature selection methods for biomarker discovery using a generic hierarchal framework. We have two objectives: (1) providing an overview on this new yet fast growing topic for a convenient reference; (2) categorizing existing methods under an expandable framework for future research and development

The ubiquitous interleukin-6: a time for reappraisal

Interleukin-6 (IL-6) is a multifunctional cytokine regulating humoral and cellular responses and playing a central role in inflammation and tissue injury. Its effects are mediated through interaction with its receptor complex, IL-6Rβ (also known as gp130). It plays an important role in the pathogenesis of coronary artery disease and large quantities of IL-6 are found in human atherosclerotic plaques. IL-6 levels positively correlate with higher all-cause mortality, unstable angina, left ventricular dysfunction, propensity to diabetes and its complications, hypertension, obesity and several types of cancer. IL-6 levels augmentation demonstrates a remarkable parallel with another biomarkers reflecting harmful processes, like tumor necrosis factor alpha, interleukins 8 and 18, YKL-40, C reactive protein and resistin. Due to these facts, IL-6 was classified as a noxious interleukin. Nonetheless, there are several facts that challenge this usually accepted point of view. Since IL-6 has also anti-inflammatory activity, it seems reasonable to assume that favorable aspects exist. These aspects are two: 1. protection against bacterial infections, inactivating proinflammatory mediators, mitigating the course of septic shock and inducing the production of cortisol; and 2. influence on insulin sensitivity during exercise; this aspect is even more important. During exercise IL-6 is synthesized and released by muscles, with enhanced insulin action immediately at early recovery. Skeletal muscle may be considered as an endocrine organ; contracting muscles produce IL-6 and release it into the blood exerting its effects on other organs. The increase in circulating levels of IL-6 after exercise is consistent and proportional to exercise duration, intensity, muscle mass involved and endurance capacity. Thus, the fascinating possibility that the plenteous beneficial health effects of exercise could be ultimately mediated by IL-6 merits further elucidation. Interleukins were termed "good" or "bad", probably due to a tendency to see things in black and white, with no gray area in between. Calling IL-6 "a molecule with both beneficial and destructive potentials" would be a more equitable approach. In the literary creatures of Dr. Jekyll and Mr. Hyde, a good and an evil personality are found in the same individual. IL-6 playing the role of Dr. Jekyll is emerging; the time for IL-6 reappraisal is coming

An optimized protocol for microarray validation by quantitative PCR using amplified amino allyl labeled RNA

<p>Abstract</p> <p>Background</p> <p>Validation of microarrays data by quantitative real-time PCR (qPCR) is often limited by the low amount of available RNA. This raised the possibility to perform validation experiments on the amplified amino allyl labeled RNA (AA-aRNA) leftover from microarrays. To test this possibility, we used an ongoing study of our laboratory aiming at identifying new biomarkers of graft rejection by the transcriptomic analysis of blood cells from brain-dead organ donors.</p> <p>Results</p> <p>qPCR for ACTB performed on AA-aRNA from 15 donors provided Cq values 8 cycles higher than when original RNA was used (P < 0.001), suggesting a strong inhibition of qPCR performed on AA-aRNA. When expression levels of 5 other genes were measured in AA-aRNA generated from a universal reference RNA, qPCR sensitivity and efficiency were decreased. This prevented the quantification of one low-abundant gene, which was readily quantified in un-amplified and un-labeled RNA. To overcome this limitation, we modified the reverse transcription (RT) protocol that generates cDNA from AA-aRNA as follows: addition of a denaturation step and 2-min incubation at room temperature to improve random primers annealing, a transcription initiation step to improve RT, and a final treatment with RNase H to degrade remaining RNA. Tested on universal reference AA-aRNA, these modifications provided a gain of 3.4 Cq (average from 5 genes, P < 0.001) and an increase of qPCR efficiency (from -1.96 to -2.88; P = 0.02). They also allowed for the detection of a low-abundant gene that was previously undetectable. Tested on AA-aRNA from 15 brain-dead organ donors, RT optimization provided a gain of 2.7 cycles (average from 7 genes, P = 0.004). Finally, qPCR results significantly correlated with microarrays.</p> <p>Conclusion</p> <p>We present here an optimized RT protocol for validation of microarrays by qPCR from AA-aRNA. This is particularly valuable in experiments where limited amount of RNA is available.</p

AlexSys: a knowledge-based expert system for multiple sequence alignment construction and analysis

Multiple sequence alignment (MSA) is a cornerstone of modern molecular biology and represents a unique means of investigating the patterns of conservation and diversity in complex biological systems. Many different algorithms have been developed to construct MSAs, but previous studies have shown that no single aligner consistently outperforms the rest. This has led to the development of a number of ‘meta-methods’ that systematically run several aligners and merge the output into one single solution. Although these methods generally produce more accurate alignments, they are inefficient because all the aligners need to be run first and the choice of the best solution is made a posteriori. Here, we describe the development of a new expert system, AlexSys, for the multiple alignment of protein sequences. AlexSys incorporates an intelligent inference engine to automatically select an appropriate aligner a priori, depending only on the nature of the input sequences. The inference engine was trained on a large set of reference multiple alignments, using a novel machine learning approach. Applying AlexSys to a test set of 178 alignments, we show that the expert system represents a good compromise between alignment quality and running time, making it suitable for high throughput projects. AlexSys is freely available from http://alnitak.u-strasbg.fr/∼aniba/alexsys

Coordinated modular functionality and prognostic potential of a heart failure biomarker-driven interaction network

<p>Abstract</p> <p>Background</p> <p>The identification of potentially relevant biomarkers and a deeper understanding of molecular mechanisms related to heart failure (HF) development can be enhanced by the implementation of biological network-based analyses. To support these efforts, here we report a global network of protein-protein interactions (PPIs) relevant to HF, which was characterized through integrative bioinformatic analyses of multiple sources of "omic" information.</p> <p>Results</p> <p>We found that the structural and functional architecture of this PPI network is highly modular. These network modules can be assigned to specialized processes, specific cellular regions and their functional roles tend to partially overlap. Our results suggest that HF biomarkers may be defined as key coordinators of intra- and inter-module communication. Putative biomarkers can, in general, be distinguished as "information traffic" mediators within this network. The top high traffic proteins are encoded by genes that are not highly differentially expressed across HF and non-HF patients. Nevertheless, we present evidence that the integration of expression patterns from high traffic genes may support accurate prediction of HF. We quantitatively demonstrate that intra- and inter-module functional activity may be controlled by a family of transcription factors known to be associated with the prevention of hypertrophy.</p> <p>Conclusion</p> <p>The systems-driven analysis reported here provides the basis for the identification of potentially novel biomarkers and understanding HF-related mechanisms in a more comprehensive and integrated way.</p

Nutrigenómica

Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências FarmacêuticasNuma sociedade cada vez mais preocupada com a saúde, a nutrição tem desempenhado um papel muito importante, não só com a causa da doença, mas também como uma forma de prevenção da doença. Isto ocorre porque os nutrientes são capazes de interagir com os mecanismos moleculares do organismo e assim, modificar as funções fisiológicas. A nutrigenómica (o estudo dos nutrientes na expressão dos genes) pode assim ser explorada de duas formas: os alimentos podem influenciar a atividade dos genes, e os genes podem influenciar a necessidade de certos nutrientes. Isto proporciona uma compreensão genética de como os componentes da dieta comum poderão afetar o equilíbrio entre a saúde e a doença, alterando desta forma a expressão e ou estrutura da composição genética de um individuo. Apesar de os indivíduos serem diferentes uns dos outros, o genoma é 99,9% semelhante entre eles. Esta diferença de 0.1% representa variações visíveis como a cor do cabelo, pele e olhos e diferenças mais subtis, como o aumento de predisposição para desenvolver doenças crónicas e a necessidade de determinados nutrientes e compostos bioativos. As várias mudanças nos hábitos alimentares e estilo de vida que surgem no dia-a-dia das pessoas podem assim estar relacionadas com o aparecimento de doenças influenciadas pela alimentação. Assim, lições de Nutrigenómica mostram a importância de consciencializar as pessoas para a importância da nutrição no estado de saúde de cada ser humano individual. No presente trabalho, pretende-se transmitir ao leitor uma visão compreensível mas ampla e detalhada de como a nutrigenómica é importante e quais as vantagens de usar esta ferramenta de estudo. In an increasingly health-conscious society, nutrition has played a very important role not only as the cause of disease but also as a way of disease prevention. This occurs because nutrients are able to interact with the organism’s molecular mechanisms and thereby modify physiological functions Nutrigenomics (the study of the influence of nutrients in gene expression) can thus be explored in two ways: food can influence the activity of genes and; genes can influence the need for certain nutrients. This provides an understanding of how the genetic components of common diets may affect the balance between health and disease, thereby altering the expression or structure and the genetic makeup of an individual. Despite being different from each other individual, the Human Genome is 99,9 % similar between individuals. This 0.1 % difference accounts for visible variations such in hair, skin and eye color and more subtle differences such as the increased predisposition to develop chronic diseases and the need for certain nutrients and bioactive compounds. The various changes in eating habits and lifestyle that arise in the day-to-day life of people can thus be related to the onset of diet-related disorders. Thus, lessons from Nutrigenomics indicate the importance of making people aware of the relevance of nutrition in the health status of every individual human being. The present work, aims at providing the reader with a comprehensive but broad and detailed view of how nutrigenomics is important and what are the advantages of using this study tool

Nutrigenómica

Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências FarmacêuticasNuma sociedade cada vez mais preocupada com a saúde, a nutrição tem desempenhado um papel muito importante, não só com a causa da doença, mas também como uma forma de prevenção da doença. Isto ocorre porque os nutrientes são capazes de interagir com os mecanismos moleculares do organismo e assim, modificar as funções fisiológicas. A nutrigenómica (o estudo dos nutrientes na expressão dos genes) pode assim ser explorada de duas formas: os alimentos podem influenciar a atividade dos genes, e os genes podem influenciar a necessidade de certos nutrientes. Isto proporciona uma compreensão genética de como os componentes da dieta comum poderão afetar o equilíbrio entre a saúde e a doença, alterando desta forma a expressão e ou estrutura da composição genética de um individuo. Apesar de os indivíduos serem diferentes uns dos outros, o genoma é 99,9% semelhante entre eles. Esta diferença de 0.1% representa variações visíveis como a cor do cabelo, pele e olhos e diferenças mais subtis, como o aumento de predisposição para desenvolver doenças crónicas e a necessidade de determinados nutrientes e compostos bioativos. As várias mudanças nos hábitos alimentares e estilo de vida que surgem no dia-a-dia das pessoas podem assim estar relacionadas com o aparecimento de doenças influenciadas pela alimentação. Assim, lições de Nutrigenómica mostram a importância de consciencializar as pessoas para a importância da nutrição no estado de saúde de cada ser humano individual. No presente trabalho, pretende-se transmitir ao leitor uma visão compreensível mas ampla e detalhada de como a nutrigenómica é importante e quais as vantagens de usar esta ferramenta de estudo. In an increasingly health-conscious society, nutrition has played a very important role not only as the cause of disease but also as a way of disease prevention. This occurs because nutrients are able to interact with the organism’s molecular mechanisms and thereby modify physiological functions Nutrigenomics (the study of the influence of nutrients in gene expression) can thus be explored in two ways: food can influence the activity of genes and; genes can influence the need for certain nutrients. This provides an understanding of how the genetic components of common diets may affect the balance between health and disease, thereby altering the expression or structure and the genetic makeup of an individual. Despite being different from each other individual, the Human Genome is 99,9 % similar between individuals. This 0.1 % difference accounts for visible variations such in hair, skin and eye color and more subtle differences such as the increased predisposition to develop chronic diseases and the need for certain nutrients and bioactive compounds. The various changes in eating habits and lifestyle that arise in the day-to-day life of people can thus be related to the onset of diet-related disorders. Thus, lessons from Nutrigenomics indicate the importance of making people aware of the relevance of nutrition in the health status of every individual human being. The present work, aims at providing the reader with a comprehensive but broad and detailed view of how nutrigenomics is important and what are the advantages of using this study tool