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A Deep Survival EWAS approach estimating risk profile based on pre-diagnostic DNA methylation: An application to breast cancer time to diagnosis

Previous studies for cancer biomarker discovery based on pre-diagnostic blood DNA methylation (DNAm) profiles, either ignore the explicit modeling of the Time To Diagnosis (TTD), or provide inconsistent results. This lack of consistency is likely due to the limitations of standard EWAS approaches, t...

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Autores principales: Massi, Michela Carlotta, Dominoni, Lorenzo, Ieva, Francesca, Fiorito, Giovanni
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9536632/
https://www.ncbi.nlm.nih.gov/pubmed/36155971
http://dx.doi.org/10.1371/journal.pcbi.1009959
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author Massi, Michela Carlotta
Dominoni, Lorenzo
Ieva, Francesca
Fiorito, Giovanni
author_facet Massi, Michela Carlotta
Dominoni, Lorenzo
Ieva, Francesca
Fiorito, Giovanni
author_sort Massi, Michela Carlotta
collection PubMed
description Previous studies for cancer biomarker discovery based on pre-diagnostic blood DNA methylation (DNAm) profiles, either ignore the explicit modeling of the Time To Diagnosis (TTD), or provide inconsistent results. This lack of consistency is likely due to the limitations of standard EWAS approaches, that model the effect of DNAm at CpG sites on TTD independently. In this work, we aim to identify blood DNAm profiles associated with TTD, with the aim to improve the reliability of the results, as well as their biological meaningfulness. We argue that a global approach to estimate CpG sites effect profile should capture the complex (potentially non-linear) relationships interplaying between sites. To prove our concept, we develop a new Deep Learning-based approach assessing the relevance of individual CpG Islands (i.e., assigning a weight to each site) in determining TTD while modeling their combined effect in a survival analysis scenario. The algorithm combines a tailored sampling procedure with DNAm sites agglomeration, deep non-linear survival modeling and SHapley Additive exPlanations (SHAP) values estimation to aid robustness of the derived effects profile. The proposed approach deals with the common complexities arising from epidemiological studies, such as small sample size, noise, and low signal-to-noise ratio of blood-derived DNAm. We apply our approach to a prospective case-control study on breast cancer nested in the EPIC Italy cohort and we perform weighted gene-set enrichment analyses to demonstrate the biological meaningfulness of the obtained results. We compared the results of Deep Survival EWAS with those of a traditional EWAS approach, demonstrating that our method performs better than the standard approach in identifying biologically relevant pathways.
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spelling pubmed-95366322022-10-07 A Deep Survival EWAS approach estimating risk profile based on pre-diagnostic DNA methylation: An application to breast cancer time to diagnosis Massi, Michela Carlotta Dominoni, Lorenzo Ieva, Francesca Fiorito, Giovanni PLoS Comput Biol Research Article Previous studies for cancer biomarker discovery based on pre-diagnostic blood DNA methylation (DNAm) profiles, either ignore the explicit modeling of the Time To Diagnosis (TTD), or provide inconsistent results. This lack of consistency is likely due to the limitations of standard EWAS approaches, that model the effect of DNAm at CpG sites on TTD independently. In this work, we aim to identify blood DNAm profiles associated with TTD, with the aim to improve the reliability of the results, as well as their biological meaningfulness. We argue that a global approach to estimate CpG sites effect profile should capture the complex (potentially non-linear) relationships interplaying between sites. To prove our concept, we develop a new Deep Learning-based approach assessing the relevance of individual CpG Islands (i.e., assigning a weight to each site) in determining TTD while modeling their combined effect in a survival analysis scenario. The algorithm combines a tailored sampling procedure with DNAm sites agglomeration, deep non-linear survival modeling and SHapley Additive exPlanations (SHAP) values estimation to aid robustness of the derived effects profile. The proposed approach deals with the common complexities arising from epidemiological studies, such as small sample size, noise, and low signal-to-noise ratio of blood-derived DNAm. We apply our approach to a prospective case-control study on breast cancer nested in the EPIC Italy cohort and we perform weighted gene-set enrichment analyses to demonstrate the biological meaningfulness of the obtained results. We compared the results of Deep Survival EWAS with those of a traditional EWAS approach, demonstrating that our method performs better than the standard approach in identifying biologically relevant pathways. Public Library of Science 2022-09-26 /pmc/articles/PMC9536632/ /pubmed/36155971 http://dx.doi.org/10.1371/journal.pcbi.1009959 Text en © 2022 Massi et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Massi, Michela Carlotta
Dominoni, Lorenzo
Ieva, Francesca
Fiorito, Giovanni
A Deep Survival EWAS approach estimating risk profile based on pre-diagnostic DNA methylation: An application to breast cancer time to diagnosis
title A Deep Survival EWAS approach estimating risk profile based on pre-diagnostic DNA methylation: An application to breast cancer time to diagnosis
title_full A Deep Survival EWAS approach estimating risk profile based on pre-diagnostic DNA methylation: An application to breast cancer time to diagnosis
title_fullStr A Deep Survival EWAS approach estimating risk profile based on pre-diagnostic DNA methylation: An application to breast cancer time to diagnosis
title_full_unstemmed A Deep Survival EWAS approach estimating risk profile based on pre-diagnostic DNA methylation: An application to breast cancer time to diagnosis
title_short A Deep Survival EWAS approach estimating risk profile based on pre-diagnostic DNA methylation: An application to breast cancer time to diagnosis
title_sort deep survival ewas approach estimating risk profile based on pre-diagnostic dna methylation: an application to breast cancer time to diagnosis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9536632/
https://www.ncbi.nlm.nih.gov/pubmed/36155971
http://dx.doi.org/10.1371/journal.pcbi.1009959
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