Biology subjects

Baccarelli, A. A.

Publications and source records attributed to Baccarelli, A. A..

5 recordsLinked to original sources

bioRxiv2025

CoxMDS: Multiple Data Splitting for High-dimensional Mediation Analysis with Survival Outcomes in Epigenome-wide Studies

Causal mediation analysis investigates whether the effect of an exposure on an outcome operates through intermediate variables known as mediators. Although progress has been made in high-dimensional mediation analysis, current methods do not reliably control the false discovery rate (FDR) in finite samples, especially when mediators are moderately to highly correlated or follow non-Gaussian distributions. These challenges frequently arise in DNA methylation studies. We introduce CoxMDS, a multiple data splitting method that uses Cox proportional hazards models to identify putative causal mediators for survival outcomes. CoxMDS ensures finite-sample FDR control even in the presence of correlated or non-Gaussian mediators. Through simulations, CoxMDS is shown to maintain FDR control and achieve higher statistical power compared with existing approaches. In applications to DNA methylation data with survival outcomes, CoxMDS identified eight CpG sites in The Cancer Genome Atlas (TCGA) that are consistent with the hypothesis that DNA methylation may mediate the effect of smoking on lung cancer survival, and two CpG sites in the Alzheimers Disease Neuroimaging Initiative (ADNI) that are consistent with the hypothesis that DNA methylation may mediate the effect of smoking on time to Alzheimers disease conversion.

bioinformatics↗

bioRxiv2022

Epigenome-wide meta-analysis of BMI in nine population-based cohorts: examining the utility of methylation as a biomarker of BMI

This study sought to examine the association between DNA methylation and body mass index (BMI) and the potential utility of these cytosine-phosphate-guanine (CpG) sites in predicting metabolic health. We pooled summary statistics from six trans-ethnic EWAS of BMI representing nine cohorts (n=17058), replicated these findings in the Womens Health Initiative (WHI, n=4822) and developed an epigenetic prediction score of BMI. In the pooled EWAS, 1265 CpG sites were associated with BMI (p<1E-7), and 1238 replicated in the WHI (FDR < 0.05). We performed several stratified analyses to examine whether these associations differed between individuals of European descent and individuals of African descent. We found five CpG sites had a significant interaction with BMI by race/ethnicity. To examine the utility of the significant CpG sites in predicting BMI, we used elastic net regression to predict log normalized BMI in the WHI (80% training/20% testing). This model found 397 sites could explain 32% of the variance in BMI in the WHI test set. Individuals whose methylome-predicted BMI overestimated their BMI (high epigenetic BMI) had significantly higher glucose and triglycerides, and lower HDL-cholesterol and LDL-cholesterol compared to accurately predicted BMI. Individuals whose methylome-predicted BMI underestimated their BMI (low epigenetic BMI) had significantly higher HDL-cholesterol and lower glucose and triglycerides. This study identified 553 previously identified and 685 novel CpG sites associated with BMI. Participants with high epigenetic BMI had poorer metabolic health suggesting that the overestimation may be driven in part by cardiometabolic derangements characteristic of metabolic syndrome.

genetics↗

bioRxiv2022

Novel modification of Luminex assay for characterization of extracellular vesicle populations in biofluids.

Most approaches to extracellular vesicle (EV) characterization focus on EV size or density. However, such approaches provide few clues regarding EV origin, molecular composition, and function. New methods to characterize the EV surface proteins may aid our understanding of their origin, physiological roles, and biomarker potential. Recently developed immunoassays for intact EVs based on ELISA, NanoView, SIMOA and MesoScale platforms are highly sensitive, but have limited multiplexing capabilities, whereas MACSPlex FACS enables the detection of multiple EV surface proteins, but requires significant quantities of purified EVs, which limits its adoption. Here, we describe a novel Luminex-based immunoassay, which combines multiplexing capabilities with high sensitivity and, importantly, bypasses the enrichment and purification steps that require larger sample volumes. We demonstrate the methods specificity for detecting EV surface proteins using multiple EV depletion techniques, EVs of specific cellular origin isolated from culture media, and by co-localization with established EV surface markers. Using this novel approach, we elucidate differences in the tetraspanin profiles of the EVs carrying erythrocyte and neuron markers. Using size exclusion chromatography, we show that plasma EVs of putative neuronal and tissue macrophage origin are eluted in fractions distinct from those derived from erythrocytes, or from their respective cultured cells. In conclusion, our novel multiplexed assay differentiates between EVs from erythrocytes, macrophages, and neurons, and offers a new means for capture, classification, and profiling of EVs from diverse sources.

cell biology↗

bioRxiv2018

An epigenetic biomarker of aging for lifespan and healthspan

Identifying reliable biomarkers of aging is a major goal in geroscience. While the first generation of epigenetic biomarkers of aging were developed using chronological age as a surrogate for biological age, we hypothesized that incorporation of composite clinical measures of phenotypic age that capture differences in lifespan and healthspan may identify novel CpGs and facilitate the development of a more powerful epigenetic biomarker of aging. Using a innovative two-step process, we develop a new epigenetic biomarker of aging, DNAm PhenoAge, that strongly outperforms previous measures in regards to predictions for a variety of aging outcomes, including all-cause mortality, cancers, healthspan, physical functioning, and Alzheimers disease. While this biomarker was developed using data from whole blood, it correlates strongly with age in every tissue and cell tested. Based on an in-depth transcriptional analysis in sorted cells, we find that increased epigenetic, relative to chronological age, is associated increased activation of pro-inflammatory and interferon pathways, and decreased activation of transcriptional/translational machinery, DNA damage response, and mitochondrial signatures. Overall, this single epigenetic biomarker of aging is able to capture risks for an array of diverse outcomes across multiple tissues and cells, and provide insight into important pathways in aging.

epidemiology↗

bioRxiv2017

GWAS of epigenetic ageing rates in blood reveals a critical role for TERT

DNA methylation age is an accurate biomarker of chronological age and predicts lifespan, but its underlying molecular mechanisms are unknown. In this genome-wide association study of 9,907 individuals, we found gene variants mapping to five loci associated with intrinsic epigenetic age acceleration (IEAA) and gene variants in 3 loci associated extrinsic epigenetic age acceleration (EEAA). Mendelian randomization analysis suggested causal influences of menarche and menopause on IEAA and lipid levels on IEAA and EEAA. Variants associated with longer leukocyte telomere length (LTL) in the telomerase reverse transcriptase gene (TERT) locus at 5p15.33 confer higher IEAA (P<2.7x10-11). Causal modelling indicates TERT-specific and independent effects on LTL and IEAA. Experimental hTERT expression in primary human fibroblasts engenders a linear increase in DNA methylation age with cell population doubling number. Together, these findings indicate a critical role for hTERT in regulating the DNA methylation clock, in addition to its established role of compensating for cell replication-dependent telomere shortening.

genetics↗