Feature Selection and Dimensionality Reduction in Genomics and Proteomics

International audienceFinding reliable, meaningful patterns in data with high numbers of attributes can be extremely difficult. Feature selection helps us to decide what attributes or combination of attributes are most important for finding these patterns. In this chapter, we study feature selection methods for building classification models from high-throughput genomic (microarray) and proteomic (mass spectrometry) data sets. Thousands of feature candidates must be analyzed, compared and combined in such data sets. We describe the basics of four different approaches used for feature selection and illustrate their effects on an MS cancer proteomic data set. The closing discussion provides assistance in performing an analysis in high-dimensional genomic and proteomic data

Late Quaternary climatic changes revealed by luminescence dating, mineral magnetism and diffuse reflectance spectroscopy of river terrace palaeosols: a new form of geoproxy data for the southern African interior

AbstractThe nature, spatial patterns and forcing mechanisms of Quaternary climatic changes across southern Africa remain unresolved and contentious, principally due to the scarcity of continuous and robustly-dated proxy records. We present what we interpret to be a broadly continuous record of late Quaternary climatic change based on optically stimulated luminescence (OSL) dating, and mineral magnetic and diffuse reflectance spectroscopy (DRS) analyses of stacked palaeosols within an overbank alluvial succession along the Modder River, central South Africa. The OSL ages indicate that alluvial sedimentation occurred at a fairly steady rate, averaging ∼0.15 mm/yr from at least 44 ka until ∼0.83 ka. This suggests that the palaeosols are accretionary, having formed contemporaneously with sedimentation. Climate is identified as the key soil-forming factor controlling the intensity of pedogenesis and is reflected in the changing concentration of pedogenic ferrimagnetic minerals (magnetite/maghemite) of single domain and superparamagnetic dimensions, and by variations in the amount of hematite compared to goethite. These data indicate that the climate was generally dry (rainfall ∼200–400 mm/yr) from ∼46 to 32 ka, except for a brief peak in humidity at ∼42 ka. There was then a period of greater humidity (rainfall ∼400–600 mm/yr) from ∼32 to 28 ka, possibly reflecting enhanced moisture supply from the Atlantic Ocean associated with the equatorward migration and intensification of westerly storm tracks. Although the precise mechanism remains unresolved, this climatic change may have been linked to an obliquity minimum at ∼29 ka. After ∼28 ka, the climate became progressively cooler and drier, especially between ∼18 and 15.5 ka when rainfall was as low as ∼100–200 mm/yr. Temperatures and rainfall then increased from ∼15.5 ka onwards, with the latter possibly linked to rising sea-surface temperatures in the SW Indian Ocean and enhanced moisture supply from easterly circulation. At ∼0.83 ka, a time corresponding with part of the Medieval Climatic Anomaly (MCA, ∼900–1300 AD), rainfall reached ∼600–700 mm/yr and was higher than at present (∼400–500 mm/yr). Fluvial landforms have previously been overlooked as a source of palaeoenvironmental information in southern Africa, but this study clearly demonstrates the potential to extract robust palaeoenvironmental data from alluvial-palaeosol successions in the arid to semi-arid interior where other forms of proxy record are scarce

Comparison of paired quartz OSL and feldspar post-IR IRSL dose distributions in poorly bleached fluvial sediments from South Africa

AbstractA comparative study using quartz optically stimulated luminescence (OSL) and feldspar post-infrared infrared stimulated luminescence (post-IR IRSL) was undertaken on Quaternary fluvial sediments from an unnamed tributary of the Moopetsi River in South Africa. The aim is to assess whether the post-IR IRSL signal can be used to date incompletely bleached sediments. Several post-IR IRSL signals using varying stimulation and preheat temperatures were investigated; of these the post-IR IRSL225 signal was deemed most appropriate for dating because it bleached most rapidly. The feldspar post-IR IRSL225 equivalent dose (De) values from this site are consistently larger than those from quartz OSL, probably due to differences in the bleaching characteristics of the two signals. Additionally, the post-IR IRSL225 De values within a sample showed less variation in precision than the quartz De data, possibly due to greater averaging between grains in the feldspar small aliquots. The agreement between ages based on the OSL and post-IR IRSL225 signals was better for younger samples (<20 ka) than for older ones (>50 ka); the cause of this variation is unclear

Targeted genomic analysis reveals widespread autoimmune disease association with regulatory variants in the TNF superfamily cytokine signalling network.

BACKGROUND: Tumour necrosis factor (TNF) superfamily cytokines and their receptors regulate diverse immune system functions through a common set of signalling pathways. Genetic variants in and expression of individual TNF superfamily cytokines, receptors and signalling proteins have been associated with autoimmune and inflammatory diseases, but their interconnected biology has been largely unexplored. METHODS: We took a hypothesis-driven approach using available genome-wide datasets to identify genetic variants regulating gene expression in the TNF superfamily cytokine signalling network and the association of these variants with autoimmune and autoinflammatory disease. Using paired gene expression and genetic data, we identified genetic variants associated with gene expression, expression quantitative trait loci (eQTLs), in four peripheral blood cell subsets. We then examined whether eQTLs were dependent on gene expression level or the presence of active enhancer chromatin marks. Using these eQTLs as genetic markers of the TNF superfamily signalling network, we performed targeted gene set association analysis in eight autoimmune and autoinflammatory disease genome-wide association studies. RESULTS: Comparison of TNF superfamily network gene expression and regulatory variants across four leucocyte subsets revealed patterns that differed between cell types. eQTLs for genes in this network were not dependent on absolute gene expression levels and were not enriched for chromatin marks of active enhancers. By examining autoimmune disease risk variants among our eQTLs, we found that risk alleles can be associated with either increased or decreased expression of co-stimulatory TNF superfamily cytokines, receptors or downstream signalling molecules. Gene set disease association analysis revealed that eQTLs for genes in the TNF superfamily pathway were associated with six of the eight autoimmune and autoinflammatory diseases examined, demonstrating associations beyond single genome-wide significant hits. CONCLUSIONS: This systematic analysis of the influence of regulatory genetic variants in the TNF superfamily network reveals widespread and diverse roles for these cytokines in susceptibility to a number of immune-mediated diseases.The Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Library of Medicine of the US National Institutes of Health (Intramural Research Program) , Wellcome Trust (080327/Z/06/Z, 087007/Z/08/Z, 094227/Z/10/Z, Clinical PhD Programme, 079895, 076113 and 085475) , Medical Research Council (G0400929) , National Institute for Health Research , National Institutes of Health (Oxford-Cambridge Scholars Program) , Istanbul University Research Fund and UK Behcet’s Syndrome Society.This is the final version of the article. It first appeared from BioMed Central via http://dx.doi.org/10.1186/s13073-016-0329-

Reduced monocyte and macrophage TNFSF15/TL1A expression is associated with susceptibility to inflammatory bowel disease.

Chronic inflammation in inflammatory bowel disease (IBD) results from a breakdown of intestinal immune homeostasis and compromise of the intestinal barrier. Genome-wide association studies have identified over 200 genetic loci associated with risk for IBD, but the functional mechanisms of most of these genetic variants remain unknown. Polymorphisms at the TNFSF15 locus, which encodes the TNF superfamily cytokine commonly known as TL1A, are associated with susceptibility to IBD in multiple ethnic groups. In a wide variety of murine models of inflammation including models of IBD, TNFSF15 promotes immunopathology by signaling through its receptor DR3. Such evidence has led to the hypothesis that expression of this lymphocyte costimulatory cytokine increases risk for IBD. In contrast, here we show that the IBD-risk haplotype at TNFSF15 is associated with decreased expression of the gene by peripheral blood monocytes in both healthy volunteers and IBD patients. This association persists under various stimulation conditions at both the RNA and protein levels and is maintained after macrophage differentiation. Utilizing a "recall-by-genotype" bioresource for allele-specific expression measurements in a functional fine-mapping assay, we localize the polymorphism controlling TNFSF15 expression to the regulatory region upstream of the gene. Through a T cell costimulation assay, we demonstrate that genetically regulated TNFSF15 has functional relevance. These findings indicate that genetically enhanced expression of TNFSF15 in specific cell types may confer protection against the development of IBD

Comparison of gene expression microarray data with count-based RNA measurements informs microarray interpretation.

BACKGROUND: Although numerous investigations have compared gene expression microarray platforms, preprocessing methods and batch correction algorithms using constructed spike-in or dilution datasets, there remains a paucity of studies examining the properties of microarray data using diverse biological samples. Most microarray experiments seek to identify subtle differences between samples with variable background noise, a scenario poorly represented by constructed datasets. Thus, microarray users lack important information regarding the complexities introduced in real-world experimental settings. The recent development of a multiplexed, digital technology for nucleic acid measurement enables counting of individual RNA molecules without amplification and, for the first time, permits such a study. RESULTS: Using a set of human leukocyte subset RNA samples, we compared previously acquired microarray expression values with RNA molecule counts determined by the nCounter Analysis System (NanoString Technologies) in selected genes. We found that gene measurements across samples correlated well between the two platforms, particularly for high-variance genes, while genes deemed unexpressed by the nCounter generally had both low expression and low variance on the microarray. Confirming previous findings from spike-in and dilution datasets, this "gold-standard" comparison demonstrated signal compression that varied dramatically by expression level and, to a lesser extent, by dataset. Most importantly, examination of three different cell types revealed that noise levels differed across tissues. CONCLUSIONS: Microarray measurements generally correlate with relative RNA molecule counts within optimal ranges but suffer from expression-dependent accuracy bias and precision that varies across datasets. We urge microarray users to consider expression-level effects in signal interpretation and to evaluate noise properties in each dataset independently

A systematic review of optical coherence tomography findings in adults with mild traumatic brain injury

Mild traumatic brain injury (mTBI) is common with many patients suffering disabling long-term sequelae, with visual symptoms frequently reported. There are no objective biomarkers of mTBI that are routinely used in clinical practice. Optical coherence tomography (OCT) has been used in mTBI research, as it enables visualisation of the neuroretina, allowing measurement of the retinal nerve fibre layer and ganglion cell layer. This systematic review aims to appraise the available literature and assess whether there are significant changes within the retinal nerve fibre layer and ganglion cell layer in subjects after mTBI. A systematic review was carried out in accordance with PRISMA guidelines and registered with PROSPERO (Number: CRD42022360498). Four databases were searched for relevant literature published from inception until 1 September 2022. Abstracts and full texts were screened by three independent reviewers. Initial screening of databases yielded 341 publications, of these, three fulfilled all the criteria for inclusion. All three studies showed thinning of the retinal nerve fibre layer, whereas there were no significant changes in the ganglion cell layer. This systematic review demonstrated that thinning of the retinal nerve fibre layer (but not of the ganglion cell layer) is associated with mTBI. It provides preliminary evidence for the use of the retinal nerve fibre layer as a potential biomarker of damage to the visual system in mTBI. Further prospective longitudinal studies ensuring uniform diagnosis and accurate phenotyping of mTBI are needed to understand the effects on the visual system and potential of OCT as a prognostic biomarker

Response to Questions in the First White Paper, \u27Modernizing the Communications Act\u27

The House Energy and Commerce Committee has begun a process to review and update the Communications Act of 1934, last revised in any material way in 1996. As the Committee begins the review process, this paper responds to questions posed by the Committee that all relate, in fundamental ways, to the question: What should a modern Communications Act look like? The Response advocates a clean slate approach under which the regulatory silos that characterize the current statute would be eliminated, along with almost all of the ubiquitous \u27public interest\u27 delegation of authority found throughout the Communications Act. The replacement regime would have at its core a new competition-based standard that, except in limited circumstances, would require that the FCC\u27s regulatory activities be tied to findings of consumer harm resulting from lack of sufficient competition. The FCC\u27s authority to adopt broad anticipatory rules on an ex ante basis would be substantially circumscribed, and the agency would be required to rely more heavily than is presently the case on ex post adjudication of individual complaints alleging specific abuses of market power and consumer harm. Some aspects of the FCC\u27s current jurisdiction, such as privacy and data security regulation, might be transferred to the FTC in light of the FTC\u27s institutional competence in these areas

Response to Questions in the First White Paper, \u27Modernizing the Communications Act\u27

The House Energy and Commerce Committee has begun a process to review and update the Communications Act of 1934, last revised in any material way in 1996. As the Committee begins the review process, this paper responds to questions posed by the Committee that all relate, in fundamental ways, to the question: What should a modern Communications Act look like? The Response advocates a clean slate approach under which the regulatory silos that characterize the current statute would be eliminated, along with almost all of the ubiquitous \u27public interest\u27 delegation of authority found throughout the Communications Act. The replacement regime would have at its core a new competition-based standard that, except in limited circumstances, would require that the FCC\u27s regulatory activities be tied to findings of consumer harm resulting from lack of sufficient competition. The FCC\u27s authority to adopt broad anticipatory rules on an ex ante basis would be substantially circumscribed, and the agency would be required to rely more heavily than is presently the case on ex post adjudication of individual complaints alleging specific abuses of market power and consumer harm. Some aspects of the FCC\u27s current jurisdiction, such as privacy and data security regulation, might be transferred to the FTC in light of the FTC\u27s institutional competence in these areas

Insight into Genotype-Phenotype Associations through eQTL Mapping in Multiple Cell Types in Health and Immune-Mediated Disease

Genome-wide association studies (GWAS) have transformed our understanding of the genetics of complex traits such as autoimmune diseases, but how risk variants contribute to pathogenesis remains largely unknown. Identifying genetic variants that affect gene expression (expression quantitative trait loci, or eQTLs) is crucial to addressing this. eQTLs vary between tissues and following in vitro cellular activation, but have not been examined in the context of human inflammatory diseases. We performed eQTL mapping in five primary immune cell types from patients with active inflammatory bowel disease (n = 91), anti-neutrophil cytoplasmic antibody-associated vasculitis (n = 46) and healthy controls (n = 43), revealing eQTLs present only in the context of active inflammatory disease. Moreover, we show that following treatment a proportion of these eQTLs disappear. Through joint analysis of expression data from multiple cell types, we reveal that previous estimates of eQTL immune cell-type specificity are likely to have been exaggerated. Finally, by analysing gene expression data from multiple cell types, we find eQTLs not previously identified by database mining at 34 inflammatory bowel disease-associated loci. In summary, this parallel eQTL analysis in multiple leucocyte subsets from patients with active disease provides new insights into the genetic basis of immune-mediated diseases.This research was funded by a Wellcome Trust Clinical PhD Programme Fellowship (JEP), the NIH-Oxford-Cambridge Scholars Program (ACR), Wellcome Trust Grant 083650/Z/07/Z and MRC Grant MR/L19027/1 (KGCS), and the National Institute for Health Research Cambridge Biomedical Research Centre. KGCS is a National Institute for Health Research Senior Investigator. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript