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Sökning: WFRF:(Holmes Elaine)

  • Resultat 1-10 av 26
  • [1]23Nästa
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  • Birney, Ewan, et al. (författare)
  • Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project
  • 2007
  • Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 447:7146, s. 799-816
  • Tidskriftsartikel (refereegranskat)abstract
    • We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.
  • Brindle, Joanne T, et al. (författare)
  • Rapid and Nonivasive Diagnosis of the Presence and Severity of Coronary Heart Disease Using 1H-NMR-Based Metabonomics
  • 2002
  • Ingår i: Nature Medicine. ; 8, s. 1439-45
  • Tidskriftsartikel (refereegranskat)abstract
    • Although a wide range of risk factors for coronary heart disease have been identified from population studies, these measures, singly or in combination, are insufficiently powerful to provide a reliable, noninvasive diagnosis of the presence of coronary heart disease. Here we show that pattern-recognition techniques applied to proton nuclear magnetic resonance (1H-NMR) spectra of human serum can correctly diagnose not only the presence, but also the severity, of coronary heart disease. Application of supervised partial least squares-discriminant analysis to orthogonal signal-corrected data sets allows >90% of subjects with stenosis of all three major coronary vessels to be distinguished from subjects with angiographically normal coronary arteries, with a specificity of >90%. Our studies show for the first time a technique capable of providing an accurate, noninvasive and rapid diagnosis of coronary heart disease that can be used clinically, either in population screening or to allow effective targeting of treatments such as statins.
  • Craddock, Nick, et al. (författare)
  • Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls
  • 2010
  • Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 464:7289, s. 713-720
  • Tidskriftsartikel (refereegranskat)abstract
    • Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed,19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated similar to 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
  • Grafton, Ben, et al. (författare)
  • Confusing procedures with process when appraising the impact of cognitive bias modification on emotional vulnerability
  • 2017
  • Ingår i: British Journal of Psychiatry. - : CAMBRIDGE UNIV PRESS. - 0007-1250 .- 1472-1465. ; 211:5, s. 266-271
  • Tidskriftsartikel (refereegranskat)abstract
    • If meta-analysis is to provide valuable answers, then it is critical to ensure clarify about the questions being asked. Here, we distinguish two important questions concerning cognitive bias modification research that are not differentiated in the meta-analysis recently published by Cristea et al (2015) in this journal: (1) do the varying procedures that investigators have employed with the intention of modifying cognitive bias, on average, significantly impact emotional vulnerability?; and (2) does the process of successfully modifying cognitive bias, on average, significantly impact emotional vulnerability? We reanalyse the data from Cristea et al to address this latter question. Our new analyses demonstrate that successfully modifying cognitive bias does significantly alter emotional vulnerability. We revisit Cristea et al's conclusions in light of these findings.
  • Jonsson, Pär, et al. (författare)
  • Extraction, interpretation and validation of information for comparing samples in metabolic LC/MS data sets
  • 2005
  • Ingår i: The Analyst. - 0003-2654 .- 1364-5528. ; 130:5, s. 701-707
  • Tidskriftsartikel (populärvet., debatt m.m.)abstract
    • LC/MS is an analytical technique that, due to its high sensitivity, has become increasingly popular for the generation of metabolic signatures in biological samples and for the building of metabolic data bases. However, to be able to create robust and interpretable ( transparent) multivariate models for the comparison of many samples, the data must fulfil certain specific criteria: (i) that each sample is characterized by the same number of variables, (ii) that each of these variables is represented across all observations, and (iii) that a variable in one sample has the same biological meaning or represents the same metabolite in all other samples. In addition, the obtained models must have the ability to make predictions of, e. g. related and independent samples characterized accordingly to the model samples. This method involves the construction of a representative data set, including automatic peak detection, alignment, setting of retention time windows, summing in the chromatographic dimension and data compression by means of alternating regression, where the relevant metabolic variation is retained for further modelling using multivariate analysis. This approach has the advantage of allowing the comparison of large numbers of samples based on their LC/MS metabolic profiles, but also of creating a means for the interpretation of the investigated biological system. This includes finding relevant systematic patterns among samples, identifying influential variables, verifying the findings in the raw data, and finally using the models for predictions. The presented strategy was here applied to a population study using urine samples from two cohorts, Shanxi (People's Republic of China) and Honolulu ( USA). The results showed that the evaluation of the extracted information data using partial least square discriminant analysis (PLS-DA) provided a robust, predictive and transparent model for the metabolic differences between the two populations. The presented findings suggest that this is a general approach for data handling, analysis, and evaluation of large metabolic LC/MS data sets.
  • Nicholson, George, et al. (författare)
  • A genome-wide metabolic QTL analysis in Europeans implicates two loci shaped by recent positive selection
  • 2011
  • Ingår i: PLoS genetics. - 1553-7404. ; 7:9, s. e1002270-
  • Tidskriftsartikel (refereegranskat)abstract
    • We have performed a metabolite quantitative trait locus (mQTL) study of the 1H nuclear magnetic resonance spectroscopy (1H NMR) metabolome in humans, building on recent targeted knowledge of genetic drivers of metabolic regulation. Urine and plasma samples were collected from two cohorts of individuals of European descent, with one cohort comprised of female twins donating samples longitudinally. Sample metabolite concentrations were quantified by 1H NMR and tested for association with genome-wide single-nucleotide polymorphisms (SNPs). Four metabolites' concentrations exhibited significant, replicable association with SNP variation (8.6×10−11<p<2.8×10−23). Three of these—trimethylamine, 3-amino-isobutyrate, and an N-acetylated compound—were measured in urine. The other—dimethylamine—was measured in plasma. Trimethylamine and dimethylamine mapped to a single genetic region (hence we report a total of three implicated genomic regions). Two of the three hit regions lie within haplotype blocks (at 2p13.1 and 10q24.2) that carry the genetic signature of strong, recent, positive selection in European populations. Genes NAT8 and PYROXD2, both with relatively uncharacterized functional roles, are good candidates for mediating the corresponding mQTL associations. The study's longitudinal twin design allowed detailed variance-components analysis of the sources of population variation in metabolite levels. The mQTLs explained 40%–64% of biological population variation in the corresponding metabolites' concentrations. These effect sizes are stronger than those reported in a recent, targeted mQTL study of metabolites in serum using the targeted-metabolomics Biocrates platform. By re-analysing our plasma samples using the Biocrates platform, we replicated the mQTL findings of the previous study and discovered a previously uncharacterized yet substantial familial component of variation in metabolite levels in addition to the heritability contribution from the corresponding mQTL effects.
  • Antti, Henrik, et al. (författare)
  • Statistical experimental design and partial least squares regression analysis of biofluid metabonomic NMR and clinical chemistry data for screening of adverse drug effects
  • 2004
  • Ingår i: Chemometrics and Intelligent Laboratory Systems. ; 73:1, s. 139-49
  • Tidskriftsartikel (refereegranskat)abstract
    • Metabonomic analysis is increasingly recognised as a powerful approach for delineating the integrated metabolic changes in biofluids and tissues due to toxicity, disease processes or genetic modification in whole animal systems. When dealing with complex biological data sets, as generated within metabonomics, as well as related fields such as genomics and proteomics, reliability and significance of identified biomarkers associated with specific states related to toxicity or disease are crucial in order to gain detailed and relevant interpretations of the metabolic fluxes in the studied systems. Since various physiological factors, such as diet, state of health, age, diurnal cycles, stress, genetic drift, and strain differences, affect the metabolic composition of biological matrices, it is of great importance to create statistically reliable decision tools for distinguishing between physiological and pathological responses in animal models. In the screening for new biomarkers or patterns of pathological dysfunction, methods providing statistically valid measures of effect-related changes will become increasingly important as the data within areas such as genomics, proteomics and metabonomics continues to grow in size and complexity. 1H NMR spectroscopy and mass spectrometry are the principal analytical platforms used to derive the data and, because extensively large data sets are required, as much consideration has to be given to optimum design of experiments (DoE) as for subsequent data analysis. Thus, statistical experimental design combined with partial least squares (PLS) regression is proposed as an efficient approach for undertaking metabonomic studies and for analysis of the results. The method was applied to data from a liver toxicology study in the rat using hydrazine as a model toxin. 1D projections of 2D J-resolved (J-RES) 1H NMR spectra and the corresponding clinical chemistry parameters of blood serum samples from control and dosed rats (30 and 90 mg/kg) collected at 48 and 168 h post dose were analysed. Confidence intervals for the PLS regression coefficients were used to create a statistical means for screening of biomarkers in the two combined data blocks (NMR and clinical chemistry data). PLS analysis was also used to reveal the correlation pattern between the two blocks of data as well as the within the two blocks according to dose, time and the interaction dose×time.
  • Azmi, Jahanara, et al. (författare)
  • Metabolic trajectory characterisation of xenobiotic-induced hepatotoxic lesions using statistical batch processing of NMR data : Nicholson Jeremy K., Holmes Elaine
  • 2002
  • Ingår i: Analyst. ; 127, s. 271-6
  • Tidskriftsartikel (refereegranskat)abstract
    • Multivariate statistical batch processing (BP) analysis of 1H NMR urine spectra was employed to establish time-dependent metabolic variations in animals treated with the model hepatotoxin, -naphthylisothiocyanate (ANIT). ANIT (100 mg kg-1) was administered orally to rats (n = 5) and urine samples were collected from dosed and matching control rats at time-points up to 168 h post-dose. Urine samples were measured via1H NMR spectroscopy and partial least squares (PLS) based batch processing analysis was used to interpret the spectral data, treating each rat as an individual batch comprising a series of timed urine samples. A model defining the mean urine profile over the 7 day study period was established, together with model confidence limits (±3 standard deviation), for the control group. Samples obtained from ANIT treated animals were evaluated using the control model. Time-dependent deviations from the control model were evident in all ANIT treated animals consisting of glycosuria, bile aciduria, an initial decrease in taurine levels followed by taurinuria and a reduction of tricarboxylic acid cycle intermediate excretion. BP provided an efficient means of visualising the biochemical response to ANIT in terms of both inter-animal variation and net variation in metabolite excretion profiles. BP also allowed multivariate statistical limits for normality to be established and provided a template for defining the sequence of time-dependent metabolic consequences of toxicity in NMR based metabonomic studies.
  • Blaise, Benjamin J., et al. (författare)
  • Statistical analysis in metabolic phenotyping
  • 2021
  • Ingår i: Nature Protocols. - : Nature Publishing Group. - 1754-2189 .- 1750-2799. ; 16:9, s. 4299-4326
  • Forskningsöversikt (refereegranskat)abstract
    • Metabolic phenotyping is an important tool in translational biomedical research. The advanced analytical technologies commonly used for phenotyping, including mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy, generate complex data requiring tailored statistical analysis methods. Detailed protocols have been published for data acquisition by liquid NMR, solid-state NMR, ultra-performance liquid chromatography (LC-)MS and gas chromatography (GC-)MS on biofluids or tissues and their preprocessing. Here we propose an efficient protocol (guidelines and software) for statistical analysis of metabolic data generated by these methods. Code for all steps is provided, and no prior coding skill is necessary. We offer efficient solutions for the different steps required within the complete phenotyping data analytics workflow: scaling, normalization, outlier detection, multivariate analysis to explore and model study-related effects, selection of candidate biomarkers, validation, multiple testing correction and performance evaluation of statistical models. We also provide a statistical power calculation algorithm and safeguards to ensure robust and meaningful experimental designs that deliver reliable results. We exemplify the protocol with a two-group classification study and data from an epidemiological cohort; however, the protocol can be easily modified to cover a wider range of experimental designs or incorporate different modeling approaches. This protocol describes a minimal set of analyses needed to rigorously investigate typical datasets encountered in metabolic phenotyping.
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  • Resultat 1-10 av 26
  • [1]23Nästa
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