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We report a case of an active-duty diver who developed severe decompression sickness with concomitant patent foramen ovale that was successfully closed contrary to standard guideline recommendations. This case should prompt evaluation of the role of cardiac screening in occupational divers, including tactical athletes, relative to recreational divers.
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Doença da Descompressão , Mergulho , Forame Oval Patente , Humanos , Doença da Descompressão/complicações , Doença da Descompressão/diagnóstico por imagem , Mergulho/efeitos adversos , Forame Oval Patente/complicações , Forame Oval Patente/diagnóstico por imagem , Masculino , Adulto , Militares , Programas de Rastreamento/métodos , Programas de Rastreamento/normasRESUMO
Chronic kidney disease (CKD) impacts about 1 in 7 adults in the United States, but African Americans (AAs) carry a disproportionately higher burden of disease. Epigenetic modifications, such as DNA methylation at cytosine-phosphate-guanine (CpG) sites, have been linked to kidney function and may have clinical utility in predicting the risk of CKD. Given the dynamic relationship between the epigenome, environment, and disease, AAs may be especially sensitive to environment-driven methylation alterations. Moreover, risk models incorporating CpG methylation have been shown to predict disease across multiple racial groups. In this study, we developed a methylation risk score (MRS) for CKD in cohorts of AAs. We selected nine CpG sites that were previously reported to be associated with estimated glomerular filtration rate (eGFR) in epigenome-wide association studies to construct a MRS in the Hypertension Genetic Epidemiology Network (HyperGEN). In logistic mixed models, the MRS was significantly associated with prevalent CKD and was robust to multiple sensitivity analyses, including CKD risk factors. There was modest replication in validation cohorts. In summary, we demonstrated that an eGFR-based CpG score is an independent predictor of prevalent CKD, suggesting that MRS should be further investigated for clinical utility in evaluating CKD risk and progression.
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Ilhas de CpG , Metilação de DNA , Taxa de Filtração Glomerular , Insuficiência Renal Crônica , Humanos , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/epidemiologia , Masculino , Feminino , Pessoa de Meia-Idade , Fatores de Risco , Negro ou Afro-Americano/genética , Idoso , Estudo de Associação Genômica Ampla , Epigênese Genética , Adulto , Predisposição Genética para DoençaRESUMO
The World Health Organization identified vitamin A deficiency (VAD) as a major public health issue in low-income communities and developing countries, while additional studies have shown dietary VAD leads to various lung pathologies. Once believed to be sterile, research now shows that transient microbial communities exist within healthy lungs and are often dysregulated in patients suffering from malnourishment, respiratory infections, and disease. The inability to parse vitamin A-mediated mechanisms from other metabolic mechanisms in humans with pathogenic endotypes, as well as the lack of data investigating how VAD affects the lung microbiome, remains a significant gap in the field. To address this unmet need, we compared molecular, metatranscriptomic, and morphometric data to identify how dietary VAD affects the lung as well as the lung microbiome. Our research shows structural and functional alterations in host-microbe-diet interactions in VAD lungs compared to vitamin A-sufficient (VAS) lungs; these changes are associated with epithelial remodeling, a breakdown in mucociliary clearance, microbial imbalance, and altered microbial colonization patterns after 8 weeks of vitamin A deficient diet. These findings confirm vitamin A is critical for lung homeostasis and provide mechanistic insights that could be valuable for the prevention of respiratory infections and disease.
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Despite two decades of research on silver nanoparticle (AgNP) toxicity, a safe threshold for exposure has not yet been established, albeit being critically needed for risk assessment and regulatory decision-making. Traditionally, a point-of-departure (PoD) value is derived from dose response of apical endpoints in animal studies using either the no-observed-adverse-effect level (NOAEL) approach, or benchmark dose (BMD) modeling. To develop new approach methodologies (NAMs) to inform human risk assessment of AgNPs, we conducted a concentration response modeling of the transcriptomic changes in hepatocytes derived from human induced pluripotent stem cells (iPSCs) after being exposed to a wide range concentration (0.01-25 µg/ml) of AgNPs for 24 h. A plausible transcriptomic PoD of 0.21 µg/ml was derived for a pathway related to the mode-of-action (MOA) of AgNPs, and a more conservative PoD of 0.10 µg/ml for a gene ontology (GO) term not apparently associated with the MOA of AgNPs. A reference dose (RfD) could be calculated from either of the PoDs as a safe threshold for AgNP exposure. The current study illustrates the usefulness of in vitro transcriptomic concentration response study using human cells as a NAM for toxicity study of chemicals that lack adequate toxicity data to inform human risk assessment.
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Relação Dose-Resposta a Droga , Hepatócitos , Células-Tronco Pluripotentes Induzidas , Nanopartículas Metálicas , Prata , Transcriptoma , Humanos , Prata/toxicidade , Nanopartículas Metálicas/toxicidade , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Medição de Risco , Nível de Efeito Adverso não Observado , Doença Hepática Induzida por Substâncias e Drogas/genética , Benchmarking , Células Cultivadas , Perfilação da Expressão Gênica/métodosRESUMO
BACKGROUND: Blood-based transcriptional gene signatures for tuberculosis (TB) have been developed with potential use to diagnose disease. However, an unresolved issue is whether gene set enrichment analysis of the signature transcripts alone is sufficient for prediction and differentiation or whether it is necessary to use the original model created when the signature was derived. Intra-method comparison is complicated by the unavailability of original training data and missing details about the original trained model. To facilitate the utilization of these signatures in TB research, comparisons between gene set scoring methods cross-data validation of original model implementations are needed. METHODS: We compared the performance of 19 TB gene signatures across 24 transcriptomic datasets using both rrebuilt original models and gene set scoring methods. Existing gene set scoring methods, including ssGSEA, GSVA, PLAGE, Singscore, and Zscore, were used as alternative approaches to obtain the profile scores. The area under the ROC curve (AUC) value was computed to measure performance. Correlation analysis and Wilcoxon paired tests were used to compare the performance of enrichment methods with the original models. RESULTS: For many signatures, the predictions from gene set scoring methods were highly correlated and statistically equivalent to the results given by the original models. In some cases, PLAGE outperformed the original models when considering signatures' weighted mean AUC values and the AUC results within individual studies. CONCLUSION: Gene set enrichment scoring of existing gene sets can distinguish patients with active TB disease from other clinical conditions with equivalent or improved accuracy compared to the original methods and models. These data justify using gene set scoring methods of published TB gene signatures for predicting TB risk and treatment outcomes, especially when original models are difficult to apply or implement.
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Perfilação da Expressão Gênica , Tuberculose , Humanos , Tuberculose/diagnóstico , Tuberculose/genética , Tuberculose/microbiologia , Perfilação da Expressão Gênica/métodos , Mycobacterium tuberculosis/genética , Transcriptoma , Curva ROC , Reprodutibilidade dos TestesRESUMO
Using data from the nationally representative Millennium Cohort Study, this study examined the association between age of starting and weekly hours in formal childcare between birth and 5 years with internalising and externalising behaviour trajectories from ages 5 to 14 years in England (N = 6194 children). Associations were analysed using multilevel general linear regression models, with adjustment for socio-economic position, maternal mental health, demographics, and child temperament. Later entry was associated with more internalising behaviours at age 14 years. Children who spent > 40 h per week in childcare between birth and 3 years displayed more externalising behaviour at 5 years than children who did not attend childcare. Controlling for socio-economic position and parental mental health attenuated findings.
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Opioid use disorder is heritable, yet its genetic etiology is largely unknown. Analysis of addiction model traits in rodents (e.g., opioid behavioral sensitivity and withdrawal) can facilitate genetic and mechanistic discovery. C57BL/6J and C57BL/6NJ substrains have extremely limited genetic diversity, yet can show reliable phenotypic diversity which together, can facilitate gene discovery. The C57BL/6NJ substrain was less sensitive to oxycodone (OXY)-induced locomotor activity compared to the C57BL/6J substrain. Quantitative trait locus (QTL) mapping in an F2 cross identified a distal chromosome 1 QTL explaining 7-12% of the variance in OXY locomotor sensitivity and anxiety-like withdrawal in the elevated plus maze. We identified a second QTL for withdrawal on chromosome 5 near the candidate gene Gabra2 (alpha-2 subunit of GABA-A receptor) explaining 9% of the variance. Next, we generated recombinant lines from an F2 founder spanning the distal chromosome 1 locus (163-181 Mb), captured the QTL for OXY sensitivity and withdrawal, and fine-mapped a 2.45-Mb region (170.16-172.61 Mb). There were five striatal cis-eQTL transcripts in this region (Pcp4l1, Ncstn, Atp1a2, Kcnj9, Igsf9), two of which were confirmed at the protein level (KCNJ9, ATP1A2). Kcnj9, a.k.a., GIRK3, codes for a potassium channel that is a major effector of mu opioid receptor signaling. Atp1a2 codes for a subunit of a Na+/K+ ATPase enzyme that regulates neuronal excitability and shows adaptations following chronic opioid administration. To summarize, we identified genetic sources of opioid behavioral differences in C57BL/6 substrains, two of the most widely and often interchangeably used substrains in opioid addiction research.
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Background: Intradural, extramedullary capillary hemangiomas of the cauda equina are exceedingly rare malformations arising from the endothelial cells of the nervous system vasculature. Roughly 20 cases have been reported in the literature, with the youngest and only pediatric case being in a 17-year-old patient. We report the youngest case of intradural extramedullary capillary hemangioma of the cauda equina in a 14-year-old patient. Case Description: A 14-year-old female presented with two-month history of low back pain with bilateral leg pain and numbness. Magnetic resonance imaging (MRI) revealed an L2 well-defined homogenous contrast-enhancing intradural, extramedullary mass causing severe spinal canal stenosis. Patient underwent laminoplasty for resection of an intradural tumor. Intraoperative hemostasis was readily achieved via early identification and coagulation of the predominate feeding vessel. Postoperatively, the patient awoke with no deficits and resolved leg pain. A 3-month postoperative MRI revealed no tumor recurrence and fully healed lamina. Conclusions: Given the benign nature, the operative goal is complete excision of the tumor without damage to surrounding neural structures. Postoperatively the goal is relief of pain and improvement in neurologic function. To our knowledge we report the first case in which laminoplasty is utilized for the treatment of this pathology in a pediatric patient. Evidence for laminoplasty in this patient population is sparse and future studies are still needed. In any case, reconstruction of the surgical site in a manner that returns the patient's normal anatomy should be strongly considered especially in younger patients.
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Bulk-tissue molecular quantitative trait loci (QTLs) have been the starting point for interpreting disease-associated variants, and context-specific QTLs show particular relevance for disease. Here, we present the results of mapping interaction QTLs (iQTLs) for cell type, age, and other phenotypic variables in multi-omic, longitudinal data from the blood of individuals of diverse ancestries. By modeling the interaction between genotype and estimated cell-type proportions, we demonstrate that cell-type iQTLs could be considered as proxies for cell-type-specific QTL effects, particularly for the most abundant cell type in the tissue. The interpretation of age iQTLs, however, warrants caution because the moderation effect of age on the genotype and molecular phenotype association could be mediated by changes in cell-type composition. Finally, we show that cell-type iQTLs contribute to cell-type-specific enrichment of diseases that, in combination with additional functional data, could guide future functional studies. Overall, this study highlights the use of iQTLs to gain insights into the context specificity of regulatory effects.
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Regulação da Expressão Gênica , Locos de Características Quantitativas , Humanos , Locos de Características Quantitativas/genética , Genótipo , FenótipoRESUMO
AIM: To examine trends in all body mass index (BMI) groups in children from 1936 to 2011. METHODS: We included 197 694 girls and 201 276 boys from the Copenhagen School Health Records Register, born between 1930 and 1996, with longitudinal weight and height measurements (6-14 years). Using International Obesity Task Force criteria, BMI was classified as underweight, normal-weight, overweight and obesity. Sex- and age-specific prevalences were calculated. RESULTS: From the 1930s, the prevalence of underweight was stable until a small increase occurred from 1950 to 1970s, and thereafter it declined into the early 2000s. Using 7-year-olds as an example, underweight changed from 10% to 7% in girls and from 9% to 6% in boys during the study period. The prevalence of overweight plateaued from 1950 to 1970s and then steeply increased from 1970s onwards and in 1990-2000s 15% girls and 11% boys at 7 years had overweight. The prevalence of obesity particularly increased from 1980s onwards and in 1990-2000s 5% girls and 4% boys at 7 years had obesity. These trends slightly differed by age. CONCLUSION: Among Danish schoolchildren, the prevalence of underweight was greater than overweight until the 1980s and greater than obesity throughout the period. Thus, monitoring the prevalence of childhood underweight remains an important public health issue.
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Sobrepeso , Magreza , Masculino , Criança , Feminino , Humanos , Índice de Massa Corporal , Magreza/epidemiologia , Sobrepeso/epidemiologia , Obesidade/epidemiologia , Prevalência , Dinamarca/epidemiologiaRESUMO
Environmental metabolomics has emerged as a promising technique in the field of biomonitoring and as an indicator of aquatic ecosystem health. In the Milwaukee Estuary (Wisconsin, USA), previous studies have used a nontargeted metabolomic approach to distinguish between zebra mussels (Dreissena polymorpha) collected from sites of varying contamination. To further elucidate the potential effects of contaminants on bivalve health in the Milwaukee Estuary, the present study adopted a caging approach to study the metabolome of quagga mussels (Dreissena bugensis rostriformis) deployed in six sites of varying contamination for 2, 5, or 55 days. Caged mussels were co-deployed with two types of passive sampler (polar organic chemical integrative samplers and semipermeable membrane devices) and data loggers. In conjunction, in situ quagga mussels were collected from the four sites studied previously and analyzed for residues of contaminants and metabolomics using a targeted approach. For the caging study, temporal differences in the metabolomic response were observed with few significant changes observed after 2 and 5 days, but larger differences (up to 97 significantly different metabolites) to the metabolome in all sites after 55 days. A suite of metabolic pathways were altered, including biosynthesis and metabolism of amino acids, and upmodulation of phospholipids at all sites, suggesting a potential biological influence such as gametogenesis. In the caging study, average temperatures appeared to have a greater effect on the metabolome than contaminants, despite a large concentration gradient in polycyclic aromatic hydrocarbons residues measured in passive samplers and mussel tissue. Conversely, significant differences between the metabolome of mussels collected in situ from all three contaminated sites and the offshore reference site were observed. Overall, these findings highlight the importance of contextualizing the effects of environmental conditions and reproductive processes on the metabolome of model organisms to facilitate the wider use of this technique for biomonitoring and environmental health assessments. Environ Toxicol Chem 2024;43:307-323. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
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Bivalves , Dreissena , Animais , Dreissena/fisiologia , Ecossistema , Estuários , WisconsinRESUMO
PURPOSE: Prior studies indicate that the physiologic response to stress can affect gene expression. We evaluated differential gene expression in breast cancers collected from Black women with high versus low exposure to psychosocial stressors. METHODS: We analyzed tumor RNA sequencing data from 417 Black Women's Health Study breast cancer cases with data on early life trauma and neighborhood disadvantage. We conducted age-adjusted differential gene expression analyses and pathway analyses. We also evaluated Conserved Transcriptional Response to Adversity (CTRA) contrast scores, relative fractions of immune cell types, T cell exhaustion, and adrenergic signaling. Analyses were run separately for estrogen receptor positive (ER+; n = 299) and ER- (n = 118) cases. RESULTS: Among ER+ cases, the top differentially expressed pathways by stress exposure were related to RNA and protein metabolism. Among ER- cases, they were related to developmental biology, signal transduction, metabolism, and the immune system. Targeted analyses indicated greater immune pathway enrichment with stress exposure for ER- cases, and possible relevance of adrenergic signaling for ER+ cases. CTRA contrast scores did not differ by stress exposure, but in analyses of the CTRA components, ER- breast cancer cases with high neighborhood disadvantage had higher pro-inflammatory gene expression (p = 0.039) and higher antibody gene expression (p = 0.006) compared to those with low neighborhood disadvantage. CONCLUSION: There are multiple pathways through which psychosocial stress exposure may influence breast tumor biology. Given the present findings on inflammation and immune response in ER- tumors, further research to identify stress-induced changes in the etiology and progression of ER- breast cancer is warranted.
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Neoplasias da Mama , Feminino , Humanos , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Receptores de Estrogênio/metabolismo , Saúde da Mulher , Adrenérgicos , Expressão GênicaRESUMO
Bivalves serve as an ideal ecological indicator; hence, their use by the NOAA Mussel Watch Program to monitor environmental health. This study aimed to expand the baseline knowledge of using metabolic end points in environmental monitoring by investigating the dreissenid mussel metabolome in the field. Dreissenids were caged at four locations along the Maumee River for 30 days. The mussel metabolome was measured using nuclear magnetic resonance spectroscopy, and mussel tissue chemical contaminants were analyzed using gas or liquid chromatography coupled with mass spectrometry. All Maumee River sites had a distinct mussel metabolome compared to the reference site and revealed changes in the energy metabolism and amino acids. Data also highlighted the importance of considering seasonality or handling effects on the metabolome at the time of sampling. The furthest upstream site presented a specific mussel tissue chemical signature of pesticides (atrazine and metolachlor), while a downstream site, located at Toledo's wastewater treatment plant, was characterized by polycyclic aromatic hydrocarbons and other organic contaminants. Further research into the dreissenid mussel's natural metabolic cycle and metabolic response to specific anthropogenic stressors is necessary before successful implementation of metabolomics in a biomonitoring program.
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Bivalves , Poluentes Químicos da Água , Animais , Lagos , Bivalves/química , Bivalves/metabolismo , Metabolômica , Monitoramento Ambiental/métodos , Metaboloma , Poluentes Químicos da Água/análiseRESUMO
Introduction: Associative connections have previously been identified between nasopharyngeal infections and infant mortality. The nasopharyngeal microbiome may potentially influence the severity of these infections. Methods: We conducted an analysis of a longitudinal prospective cohort study of 1,981 infants who underwent nasopharyngeal sampling from 1 week through 14 weeks of age at 2-3-week intervals. In all, 27 microbiome samples from 9 of the infants in the cohort who developed fatal acute febrile illness (fAFI) were analyzed in pooled comparisons with 69 samples from 10 healthy comparator infants. We completed 16S rRNA amplicon gene sequencing all infant NP samples and characterized the maturation of the infant NP microbiome among the fAFI(+) and fAFI(-) infant cohorts. Results: Beta diversity measures of fAFI(-) infants were markedly higher than those of fAFI(+) infants. The fAFI(+) infant NP microbiome was marked by higher abundances of Escherichia, Pseudomonas, Leuconostoc, and Weissella, with low relative presence of Alkalibacterium, Dolosigranulum, Moraxella, and Streptococcus. Conclusions: Our results suggest that nasopharyngeal microbiome dysbiosis precedes fAFI in young infants. Early dysbiosis, involving microbes such as Escherichia, may play a role in the causal pathway leading to fAFI or could be a marker of other pathogenic forces that directly lead to fAFI.
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Despite the prognostic value of arterial stiffness (AS) and pulsatile hemodynamics (PH) for cardiovascular morbidity and mortality, epigenetic modifications that contribute to AS/PH remain unknown. To gain a better understanding of the link between epigenetics (DNA methylation) and AS/PH, we examined the relationship of eight measures of AS/PH with CpG sites and co-methylated regions using multi-ancestry participants from Trans-Omics for Precision Medicine (TOPMed) Multi-Ethnic Study of Atherosclerosis (MESA) with sample sizes ranging from 438 to 874. Epigenome-wide association analysis identified one genome-wide significant CpG (cg20711926-CYP1B1) associated with aortic augmentation index (AIx). Follow-up analyses, including gene set enrichment analysis, expression quantitative trait methylation analysis, and functional enrichment analysis on differentially methylated positions and regions, further prioritized three CpGs and their annotated genes (cg23800023-ETS1, cg08426368-TGFB3, and cg17350632-HLA-DPB1) for AIx. Among these, ETS1 and TGFB3 have been previously prioritized as candidate genes. Furthermore, both ETS1 and HLA-DPB1 have significant tissue correlations between Whole Blood and Aorta in GTEx, which suggests ETS1 and HLA-DPB1 could be potential biomarkers in understanding pathophysiology of AS/PH. Overall, our findings support the possible role of epigenetic regulation via DNA methylation of specific genes associated with AIx as well as identifying potential targets for regulation of AS/PH.
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Aterosclerose , Epigênese Genética , Humanos , Epigenoma , Fator de Crescimento Transformador beta3/genética , Medicina de Precisão , Estudo de Associação Genômica Ampla , Metilação de DNA , Ilhas de CpG/genética , Aterosclerose/genéticaRESUMO
Each human genome has tens of thousands of rare genetic variants; however, identifying impactful rare variants remains a major challenge. We demonstrate how use of personal multi-omics can enable identification of impactful rare variants by using the Multi-Ethnic Study of Atherosclerosis, which included several hundred individuals, with whole-genome sequencing, transcriptomes, methylomes, and proteomes collected across two time points, 10 years apart. We evaluated each multi-omics phenotype's ability to separately and jointly inform functional rare variation. By combining expression and protein data, we observed rare stop variants 62 times and rare frameshift variants 216 times as frequently as controls, compared to 13-27 times as frequently for expression or protein effects alone. We extended a Bayesian hierarchical model, "Watershed," to prioritize specific rare variants underlying multi-omics signals across the regulatory cascade. With this approach, we identified rare variants that exhibited large effect sizes on multiple complex traits including height, schizophrenia, and Alzheimer's disease.
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Blood lipid traits are treatable and heritable risk factors for heart disease, a leading cause of mortality worldwide. Although genome-wide association studies (GWAS) have discovered hundreds of variants associated with lipids in humans, most of the causal mechanisms of lipids remain unknown. To better understand the biological processes underlying lipid metabolism, we investigated the associations of plasma protein levels with total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL), and low-density lipoprotein cholesterol (LDL) in blood. We trained protein prediction models based on samples in the Multi-Ethnic Study of Atherosclerosis (MESA) and applied them to conduct proteome-wide association studies (PWAS) for lipids using the Global Lipids Genetics Consortium (GLGC) data. Of the 749 proteins tested, 42 were significantly associated with at least one lipid trait. Furthermore, we performed transcriptome-wide association studies (TWAS) for lipids using 9,714 gene expression prediction models trained on samples from peripheral blood mononuclear cells (PBMCs) in MESA and 49 tissues in the Genotype-Tissue Expression (GTEx) project. We found that although PWAS and TWAS can show different directions of associations in an individual gene, 40 out of 49 tissues showed a positive correlation between PWAS and TWAS signed p-values across all the genes, which suggests a high-level consistency between proteome-lipid associations and transcriptome-lipid associations.
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Most experiments studying bacterial microbiomes rely on the PCR amplification of all or part of the gene for the 16S rRNA subunit, which serves as a biomarker for identifying and quantifying the various taxa present in a microbiome sample. Several computational methods exist for analyzing 16S amplicon sequencing. However, the most-used bioinformatics tools cannot produce high quality genus-level or species-level taxonomic calls and may underestimate the potential accuracy of these calls. We used 16S sequencing data from mock bacterial communities to evaluate the sensitivity and specificity of several bioinformatics pipelines and genomic reference libraries used for microbiome analyses, concentrating on measuring the accuracy of species-level taxonomic assignments of 16S amplicon reads. We evaluated the tools DADA2, QIIME 2, Mothur, PathoScope 2, and Kraken 2 in conjunction with reference libraries from Greengenes, SILVA, Kraken 2, and RefSeq. Profiling tools were compared using publicly available mock community data from several sources, comprising 136 samples with varied species richness and evenness, several different amplified regions within the 16S rRNA gene, and both DNA spike-ins and cDNA from collections of plated cells. PathoScope 2 and Kraken 2, both tools designed for whole-genome metagenomics, outperformed DADA2, QIIME 2 using the DADA2 plugin, and Mothur, which are theoretically specialized for 16S analyses. Evaluations of reference libraries identified the SILVA and RefSeq/Kraken 2 Standard libraries as superior in accuracy compared to Greengenes. These findings support PathoScope and Kraken 2 as fully capable, competitive options for genus- and species-level 16S amplicon sequencing data analysis, whole genome sequencing, and metagenomics data tools.
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Cercozoários , Microbiota , Poliarterite Nodosa , Humanos , Metagenômica , RNA Ribossômico 16S/genética , Metagenoma , Placas ÓsseasRESUMO
Multi-omics datasets are becoming more common, necessitating better integration methods to realize their revolutionary potential. Here, we introduce multi-set correlation and factor analysis (MCFA), an unsupervised integration method tailored to the unique challenges of high-dimensional genomics data that enables fast inference of shared and private factors. We used MCFA to integrate methylation markers, protein expression, RNA expression, and metabolite levels in 614 diverse samples from the Trans-Omics for Precision Medicine/Multi-Ethnic Study of Atherosclerosis multi-omics pilot. Samples cluster strongly by ancestry in the shared space, even in the absence of genetic information, while private spaces frequently capture dataset-specific technical variation. Finally, we integrated genetic data by conducting a genome-wide association study (GWAS) of our inferred factors, observing that several factors are enriched for GWAS hits and trans-expression quantitative trait loci. Two of these factors appear to be related to metabolic disease. Our study provides a foundation and framework for further integrative analysis of ever larger multi-modal genomic datasets.