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Brief Bioinform ; 2019 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-31220206


Recent advances in sequencing, mass spectrometry and cytometry technologies have enabled researchers to collect large-scale omics data from the same set of biological samples. The joint analysis of multiple omics offers the opportunity to uncover coordinated cellular processes acting across different omic layers. In this work, we present a thorough comparison of a selection of recent integrative clustering approaches, including Bayesian (BCC and MDI) and matrix factorization approaches (iCluster, moCluster, JIVE and iNMF). Based on simulations, the methods were evaluated on their sensitivity and their ability to recover both the correct number of clusters and the simulated clustering at the common and data-specific levels. Standard non-integrative approaches were also included to quantify the added value of integrative methods. For most matrix factorization methods and one Bayesian approach (BCC), the shared and specific structures were successfully recovered with high and moderate accuracy, respectively. An opposite behavior was observed on non-integrative approaches, i.e. high performances on specific structures only. Finally, we applied the methods on the Cancer Genome Atlas breast cancer data set to check whether results based on experimental data were consistent with those obtained in the simulations.

Nat Commun ; 10(1): 1893, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015461


Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from -183 to 178 grams per 10% increase in methylation (PBonferroni < 1.06 x 10-7). In additional analyses in 7,278 participants, <1.3% of birthweight-associated differential methylation is also observed in childhood and adolescence, but not adulthood. Birthweight-related CpGs overlap with some Bonferroni-significant CpGs that were previously reported to be related to maternal smoking (55/914, p = 6.12 x 10-74) and BMI in pregnancy (3/914, p = 1.13x10-3), but not with those related to folate levels in pregnancy. Whether the associations that we observe are causal or explained by confounding or fetal growth influencing DNA methylation (i.e. reverse causality) requires further research.

Peso ao Nascer/genética , DNA/metabolismo , Epigênese Genética , Genoma Humano , Adolescente , Adulto , Índice de Massa Corporal , Criança , Ilhas de CpG , DNA/genética , Metilação de DNA , Feminino , Desenvolvimento Fetal/genética , Feto , Ácido Fólico/sangue , Estudo de Associação Genômica Ampla , Humanos , Recém-Nascido , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Fumar/efeitos adversos , Fumar/sangue , Fumar/genética
Artigo em Inglês | MEDLINE | ID: mdl-30791383


A high body mass (BMI) index has repeatedly been associated with non-atopic asthma, but the biological mechanism linking obesity to asthma is still poorly understood. We aimed to test the hypothesis that inflammation and/or innate immunity plays a role in the obesity-asthma link. DNA methylome was measured in blood samples of 61 non-atopic participants with asthma and 146 non-atopic participants without asthma (non-smokers for at least 10 years) taking part in the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA) study. Modification by DNA methylation of the association of BMI or BMI change over 10 years with adult-onset asthma was examined at each CpG site and differentially methylated region. Pathway enrichment tests were conducted for genes in a priori curated inflammatory pathways and the NLRP3-IL1B-IL17 axis. The latter was chosen on the basis of previous work in mice. Inflammatory pathways including glucocorticoid/PPAR signaling (p = 0.0023), MAPK signaling (p = 0.013), NF-κB signaling (p = 0.031), and PI3K/AKT signaling (p = 0.031) were enriched for the effect modification of BMI, while NLRP3-IL1B-IL17 axis was enriched for the effect modification of BMI change over 10 years (p = 0.046). DNA methylation measured in peripheral blood is consistent with inflammation as a link between BMI and adult-onset asthma and with the NLRP3-IL1B-IL17 axis as a link between BMI change over 10 years and adult-onset asthma in non-atopic participants.

Asma/genética , Índice de Massa Corporal , Metilação de DNA , Inflamação/metabolismo , Adulto , Animais , Estudos de Coortes , Feminino , Humanos , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , NF-kappa B/metabolismo , Obesidade/complicações , PPAR gama/metabolismo
Clin Epigenetics ; 10: 38, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29588806


Background: Methylation measures quantified by microarray techniques can be affected by systematic variation due to the technical processing of samples, which may compromise the accuracy of the measurement process and contribute to bias the estimate of the association under investigation. The quantification of the contribution of the systematic source of variation is challenging in datasets characterized by hundreds of thousands of features.In this study, we introduce a method previously developed for the analysis of metabolomics data to evaluate the performance of existing normalizing techniques to correct for unwanted variation. Illumina Infinium HumanMethylation450K was used to acquire methylation levels in over 421,000 CpG sites for 902 study participants of a case-control study on breast cancer nested within the EPIC cohort. The principal component partial R-square (PC-PR2) analysis was used to identify and quantify the variability attributable to potential systematic sources of variation. Three correcting techniques, namely ComBat, surrogate variables analysis (SVA) and a linear regression model to compute residuals were applied. The impact of each correcting method on the association between smoking status and DNA methylation levels was evaluated, and results were compared with findings from a large meta-analysis. Results: A sizeable proportion of systematic variability due to variables expressing 'batch' and 'sample position' within 'chip' was identified, with values of the partial R2 statistics equal to 9.5 and 11.4% of total variation, respectively. After application of ComBat or the residuals' methods, the contribution was 1.3 and 0.2%, respectively. The SVA technique resulted in a reduced variability due to 'batch' (1.3%) and 'sample position' (0.6%), and in a diminished variability attributable to 'chip' within a batch (0.9%). After ComBat or the residuals' corrections, a larger number of significant sites (k = 600 and k = 427, respectively) were associated to smoking status than the SVA correction (k = 96). Conclusions: The three correction methods removed systematic variation in DNA methylation data, as assessed by the PC-PR2, which lent itself as a useful tool to explore variability in large dimension data. SVA produced more conservative findings than ComBat in the association between smoking and DNA methylation.