Accurate age prediction from blood using a small set of DNA methylation sites and a cohort-based machine learning algorithm

Varshavsky, Miri; Harari, Gil; Glaser, Benjamin; Dor, Yuval; Shemer, Ruth; Kaplan, Tommy

doi:10.1016/j.crmeth.2023.100567

Cited by 14 publications

(5 citation statements)

References 76 publications

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“…1g). Across “aging CpGs” reported by Varshavsky et al in 2023 15 , we again found correlations that were larger in magnitude than those observed for aging transcripts, and more consistent across cohorts. Thus, age-associated DNAm data are considerably more replicable across cohorts than transcriptomic data.…”

Section: Resultssupporting

confidence: 78%

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Integrative epigenetics and transcriptomics identify aging genes in human blood

Moqri,

Poganik,

Herzog

et al. 2024

Preprint

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Recent epigenome-wide studies have identified a large number of genomic regions that consistently exhibit changes in their methylation status with aging across diverse populations, but the functional consequences of these changes are largely unknown. On the other hand, transcriptomic changes are more easily interpreted than epigenetic alterations, but previously identified age-related gene expression changes have shown limited replicability across populations. Here, we develop an approach that leverages high-resolution multi-omic data for an integrative analysis of epigenetic and transcriptomic age-related changes and identify genomic regions associated with both epigenetic and transcriptomic age-dependent changes in blood. Our results show that these “multi-omic aging genes” in blood are enriched for adaptive immune functions, replicate more robustly across diverse populations and are more strongly associated with aging-related outcomes compared to the genes identified using epigenetic or transcriptomic data alone. These multi-omic aging genes may serve as targets for epigenetic editing to facilitate cellular rejuvenation.

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Section: Resultssupporting

confidence: 78%

“…As expected, DNAm levels at “aging CpGs” 15 exhibited consistent age-dependent changes, with slightly stronger correlations for the MGB cohort compared to other cohorts (Fig. 3b).…”

Section: Resultssupporting

confidence: 77%

Integrative epigenetics and transcriptomics identify aging genes in human blood

Moqri,

Poganik,

Herzog

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…It is well established that human aging is associated with characteristic changes in DNA methylation throughout the genome [ 41 – 43 ]. To estimate the size of this effect in our markers, we fit linear regression models between age and DNA methylation level (Additional file 1 : Fig.…”

Section: Resultsmentioning

confidence: 99%

Discovery and technical validation of high-performance methylated DNA markers for the detection of cervical lesions at risk of malignant progression in low- and middle-income countries

Fackler,

Pleas,

et al. 2024

Clin Epigenet

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Background Cervical cancer remains a leading cause of death, particularly in developing countries. WHO screening guidelines recommend human papilloma virus (HPV) detection as a means to identify women at risk of developing cervical cancer. While HPV testing identifies those at risk, it does not specifically distinguish individuals with neoplasia. We investigated whether a quantitative molecular test that measures methylated DNA markers could identify high-risk lesions in the cervix with accuracy. Results Marker discovery was performed in TCGA-CESC Infinium Methylation 450 K Array database and verified in three other public datasets. The panel was technically validated using Quantitative Multiplex-Methylation-Specific PCR in tissue sections (N = 252) and cervical smears (N = 244) from the USA, South Africa, and Vietnam. The gene panel consisted of FMN2, EDNRB, ZNF671, TBXT, and MOS. Cervical tissue samples from all three countries showed highly significant differential methylation in squamous cell carcinoma (SCC) with a sensitivity of 100% [95% CI 74.12–100.00], and specificity of 91% [95% CI 62.26–99.53] to 96% [95% CI 79.01–99.78], and receiver operating characteristic area under the curve (ROC AUC) = 1.000 [95% CI 1.00–1.00] compared to benign cervical tissue, and cervical intraepithelial neoplasia 2/3 with sensitivity of 55% [95% CI 37.77–70.84] to 89% [95% CI 67.20–98.03], specificity of 93% [95% CI 84.07–97.38] to 96% [95% CI 79.01–99.78], and a ROC AUC ranging from 0.793 [95% CI 0.68–0.89] to 0.99 [95% CI 0.97–1.00] compared to CIN1. In cervical smears, the marker panel detected SCC with a sensitivity of 87% [95% CI 77.45–92.69], specificity 95% [95% CI 88.64–98.18], and ROC AUC = 0.925 [95% CI 0.878–0.974] compared to normal, and high-grade squamous intraepithelial lesion (HSIL) at a sensitivity of 70% (95% CI 58.11–80.44), specificity of 94% (95% CI 88.30–97.40), and ROC AUC = 0.884 (95% CI 0.822–0.945) compared to low-grade intraepithelial lesion (LSIL)/normal in an analysis of pooled data from the three countries. Similar to HPV-positive, HPV-negative cervical carcinomas were frequently hypermethylated for these markers. Conclusions This 5-marker panel detected SCC and HSIL in cervical smears with a high level of sensitivity and specificity. Molecular tests with the ability to rapidly detect high-risk HSIL will lead to timely treatment for those in need and prevent unnecessary procedures in women with low-risk lesions throughout the world. Validation of these markers in prospectively collected cervical smear cells followed by the development of a hypermethylated marker-based cervical cancer detection test is warranted.

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“…Correlation of age to methylation. It is well established that human aging is associated with characteristic changes in DNA methylation throughout the genome [32][33][34]. To estimate the size of this effect in our markers, we t linear regression models between age and DNA methylation level (Additional le 1: Fig.…”

Section: Association Between Methylation Of the Ve Cpg Markers And Ge...mentioning

confidence: 99%

High-performance methylated DNA markers for the detection of cervical lesions at risk of malignant progression in low- and middle-income countries

Fackler,

Pleas,

et al. 2023

Preprint

View full text Add to dashboard Cite

Background Cervical cancer remains a leading cause of death, particularly in developing countries. WHO screening guidelines recommend Human Papilloma Virus (HPV) detection as a means to identify women at risk of developing cervical cancer. While HPV testing identifies those at risk, it does not specifically recognize individuals with neoplasia. We investigated whether a molecular test that quantitatively measures methylated DNA markers could identify high-risk lesions in the cervix with accuracy. Results Marker discovery was performed in TCGA-CESC Infinium Methylation 450K Array database, and the selected 5-gene panel was verified in three other public datasets. The panel was technically validated using Quantitative Multiplex-Methylation Specific PCR (QM-MSP) in tissue sections (N = 293) and cervical smears (N = 244) from the U. S., S. Africa, and Vietnam. The gene panel consisted of FMN2, EDNRB, ZNF671, TBXT, and MOS. Cervical tissue samples from U.S., South Africa, and Vietnam showed highly significant differential methylation in squamous cell carcinoma (SCC) with 100% sensitivity, 91–93% specificity, and a Receiver Operating Characteristic Area under the curve (ROC AUC) = 1.000 [CI 1.000 to 1.000], and cervical intraepithelial neoplasia 2/3 (CIN2/3) with 55–100% sensitivity, 91–96% specificity, and a ROC AUC ranging from 0.793 [CI 0.681 to 0.905] to 1.000 [CI 1.000 to 1.000] compared to normal. In cervical smears, the marker panel detected SCC at 87% sensitivity, 95% specificity, and ROC AUC = 0.925 [CI 0.878 to 0.974], and high-grade intraepithelial lesion (HSIL) at 74% sensitivity, 95% specificity, and a ROC AUC = 0.907 [CI 0.851 to 0.964] in an analysis of pooled data from the three countries. Similar to HPV-positive, HPV-negative cervical carcinomas were frequently hypermethylated for these markers. Conclusions This 5-marker panel detected SCC and CIN2/3 in cervical smears with a high level of sensitivity and specificity. Molecular tests with the ability to rapidly detect high-risk CIN3 + lesions will lead to timely treatment for those in need while preventing unnecessary procedures in women with low-risk lesions throughout the world. Validation of these markers in prospectively collected cervical smear cells followed by the development of a hypermethylated marker-based cervical cancer detection test is warranted.

show abstract

Accurate age prediction from blood using a small set of DNA methylation sites and a cohort-based machine learning algorithm

Cited by 14 publications

References 76 publications

Integrative epigenetics and transcriptomics identify aging genes in human blood

Integrative epigenetics and transcriptomics identify aging genes in human blood

Discovery and technical validation of high-performance methylated DNA markers for the detection of cervical lesions at risk of malignant progression in low- and middle-income countries

High-performance methylated DNA markers for the detection of cervical lesions at risk of malignant progression in low- and middle-income countries

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