Assessment of aberrant DNA methylation two years after paediatric critical illness: a pre-planned secondary analysis of the international PEPaNIC trial
Critically ill children requiring intensive care suffer from impaired physical/neurocognitive development 2 y later, partially preventable by omitting early use of parenteral nutrition (early-PN) in the paediatric intensive-care-unit (PICU). Altered methylation of DNA from peripheral blood during PI...
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| creator | Coppens, Grégoire Vanhorebeek, Ilse Verlinden, Ines Derese, Inge Wouters, Pieter J Joosten, Koen F. Verbruggen, Sascha C. Güiza, Fabian Van den Berghe, Greet |
| description | Critically ill children requiring intensive care suffer from impaired physical/neurocognitive development 2 y later, partially preventable by omitting early use of parenteral nutrition (early-PN) in the paediatric intensive-care-unit (PICU). Altered methylation of DNA from peripheral blood during PICU-stay provided a molecular basis hereof. Whether DNA-methylation of former PICU patients, assessed 2 y after critical illness, is different from that of healthy children remained unknown. In a pre-planned secondary analysis of the PEPaNIC-RCT (clinicaltrials.gov-NCT01536275) 2-year follow-up, we assessed buccal-mucosal DNA-methylation (Infinium-HumanMethylation-EPIC-BeadChip) of former PICU-patients (N = 406 early-PN; N = 414 late-PN) and matched healthy children (N = 392). CpG-sites differentially methylated between groups were identified with multivariable linear regression and differentially methylated DNA-regions via clustering of differentially methylated CpG-sites using kernel-estimates. Analyses were adjusted for technical variation and baseline risk factors, and corrected for multiple testing (false-discovery-rate |
| doi_str_mv | 10.1080/15592294.2022.2146966 |
| format | Article |
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Altered methylation of DNA from peripheral blood during PICU-stay provided a molecular basis hereof. Whether DNA-methylation of former PICU patients, assessed 2 y after critical illness, is different from that of healthy children remained unknown. In a pre-planned secondary analysis of the PEPaNIC-RCT (clinicaltrials.gov-NCT01536275) 2-year follow-up, we assessed buccal-mucosal DNA-methylation (Infinium-HumanMethylation-EPIC-BeadChip) of former PICU-patients (N = 406 early-PN; N = 414 late-PN) and matched healthy children (N = 392). CpG-sites differentially methylated between groups were identified with multivariable linear regression and differentially methylated DNA-regions via clustering of differentially methylated CpG-sites using kernel-estimates. Analyses were adjusted for technical variation and baseline risk factors, and corrected for multiple testing (false-discovery-rate <0.05). Differentially methylated genes were functionally annotated (KEGG-pathway database), and allocated to three classes depending on involvement in physical/neurocognitive development, critical illness and intensive medical care, or pre-PICU-admission disorders. As compared with matched healthy children, former PICU-patients showed significantly different DNA-methylation at 4047 CpG-sites (2186 genes) and 494 DNA-regions (468 genes), with most CpG-sites being hypomethylated (90.3%) and with an average absolute 2% effect-size, irrespective of timing of PN initiation. Of the differentially methylated KEGG-pathways, 41.2% were related to physical/neurocognitive development, 32.8% to critical illness and intensive medical care and 26.0% to pre-PICU-admission disorders. Two years after critical illness in children, buccal-mucosal DNA showed abnormal methylation of CpG-sites and DNA-regions located in pathways known to be important for physical/neurocognitive development.</description><identifier>ISSN: 1559-2294</identifier><identifier>EISSN: 1559-2308</identifier><identifier>DOI: 10.1080/15592294.2022.2146966</identifier><identifier>PMID: 36384393</identifier><language>eng</language><publisher>United States: Taylor & Francis</publisher><subject>Child ; children ; Critical illness ; Critical Illness - therapy ; Development ; DNA Methylation ; epigenetic ; growth ; Humans ; Intensive Care Units, Pediatric ; neurocognitive development ; nutrition ; parenteral nutrition ; Parenteral Nutrition - adverse effects ; PICU ; Research Paper ; Risk Factors</subject><ispartof>Epigenetics, 2023-12, Vol.18 (1), p.2146966-2146966</ispartof><rights>2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. 2023</rights><rights>2023 The Author(s). 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Altered methylation of DNA from peripheral blood during PICU-stay provided a molecular basis hereof. Whether DNA-methylation of former PICU patients, assessed 2 y after critical illness, is different from that of healthy children remained unknown. In a pre-planned secondary analysis of the PEPaNIC-RCT (clinicaltrials.gov-NCT01536275) 2-year follow-up, we assessed buccal-mucosal DNA-methylation (Infinium-HumanMethylation-EPIC-BeadChip) of former PICU-patients (N = 406 early-PN; N = 414 late-PN) and matched healthy children (N = 392). CpG-sites differentially methylated between groups were identified with multivariable linear regression and differentially methylated DNA-regions via clustering of differentially methylated CpG-sites using kernel-estimates. Analyses were adjusted for technical variation and baseline risk factors, and corrected for multiple testing (false-discovery-rate <0.05). Differentially methylated genes were functionally annotated (KEGG-pathway database), and allocated to three classes depending on involvement in physical/neurocognitive development, critical illness and intensive medical care, or pre-PICU-admission disorders. As compared with matched healthy children, former PICU-patients showed significantly different DNA-methylation at 4047 CpG-sites (2186 genes) and 494 DNA-regions (468 genes), with most CpG-sites being hypomethylated (90.3%) and with an average absolute 2% effect-size, irrespective of timing of PN initiation. Of the differentially methylated KEGG-pathways, 41.2% were related to physical/neurocognitive development, 32.8% to critical illness and intensive medical care and 26.0% to pre-PICU-admission disorders. Two years after critical illness in children, buccal-mucosal DNA showed abnormal methylation of CpG-sites and DNA-regions located in pathways known to be important for physical/neurocognitive development.</description><subject>Child</subject><subject>children</subject><subject>Critical illness</subject><subject>Critical Illness - therapy</subject><subject>Development</subject><subject>DNA Methylation</subject><subject>epigenetic</subject><subject>growth</subject><subject>Humans</subject><subject>Intensive Care Units, Pediatric</subject><subject>neurocognitive development</subject><subject>nutrition</subject><subject>parenteral nutrition</subject><subject>Parenteral Nutrition - adverse effects</subject><subject>PICU</subject><subject>Research Paper</subject><subject>Risk Factors</subject><issn>1559-2294</issn><issn>1559-2308</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>0YH</sourceid><sourceid>EIF</sourceid><sourceid>DOA</sourceid><recordid>eNp9kstuEzEUhkcIREvhEUBesknwfcYsEFEoEKkqXcDaOmN7GlceO9jTVnkSXhenSSq6YeWj4_9856K_ad4SPCe4wx-IEIpSxecUUzqnhEsl5bPmdJefUYa758e4ik6aV6XcYMyZVOplc8Ik6zhT7LT5syjFlTK6OKE0IOhdzlDjL5cLNLppvQ0w-RTRdJ_Q1kEuCIbJZbQBZz1M2Rtksp-8gYB8CLGyPiJAm-xmmwAxOouKMylayFsEEcK2-LLrNK0d8rGi4kODWn51fgWXqyWqUAivmxcDhOLeHN6z5tfX85_L77OLH99Wy8XFzAjGpxnHvDeK8Fa01gyUd1i4nrbcdLQnVAjLLeFcGmGVGHgPXErJeyUIUZ0lzLKzZrXn2gQ3epP9WAfVCbx-SKR8rSHX9YLTdDBO0G5oneLcStIxSVorBbeCYCx3rE971ua2H5019aYZwhPo05_o1_o63WmlOixpWwHvD4Ccft-6MunRF-NCPaRLt0VXScslqztUqdhLTU6lZDc8tiFY7wyijwbRO4Pog0Fq3bt_Z3ysOjqiCj7vBT4OKY9wn3KweoJtSHmo1jC-aPb_Hn8BLjXMgw</recordid><startdate>20231231</startdate><enddate>20231231</enddate><creator>Coppens, Grégoire</creator><creator>Vanhorebeek, Ilse</creator><creator>Verlinden, Ines</creator><creator>Derese, Inge</creator><creator>Wouters, Pieter J</creator><creator>Joosten, Koen F.</creator><creator>Verbruggen, Sascha C.</creator><creator>Güiza, Fabian</creator><creator>Van den Berghe, Greet</creator><general>Taylor & Francis</general><general>Taylor & Francis Group</general><scope>0YH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-0504-2475</orcidid><orcidid>https://orcid.org/0000-0001-6705-5063</orcidid><orcidid>https://orcid.org/0000-0002-5261-5192</orcidid><orcidid>https://orcid.org/0000-0002-5320-1362</orcidid><orcidid>https://orcid.org/0000-0001-7026-0957</orcidid><orcidid>https://orcid.org/0000-0001-7637-3549</orcidid><orcidid>https://orcid.org/0000-0003-4866-9865</orcidid></search><sort><creationdate>20231231</creationdate><title>Assessment of aberrant DNA methylation two years after paediatric critical illness: a pre-planned secondary analysis of the international PEPaNIC trial</title><author>Coppens, Grégoire ; Vanhorebeek, Ilse ; Verlinden, Ines ; Derese, Inge ; Wouters, Pieter J ; Joosten, Koen F. ; Verbruggen, Sascha C. ; Güiza, Fabian ; Van den Berghe, Greet</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c534t-404bc914757dcf24805eb274c82b1255d4d1446c5d95f4ba46664b951198d13d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Child</topic><topic>children</topic><topic>Critical illness</topic><topic>Critical Illness - therapy</topic><topic>Development</topic><topic>DNA Methylation</topic><topic>epigenetic</topic><topic>growth</topic><topic>Humans</topic><topic>Intensive Care Units, Pediatric</topic><topic>neurocognitive development</topic><topic>nutrition</topic><topic>parenteral nutrition</topic><topic>Parenteral Nutrition - adverse effects</topic><topic>PICU</topic><topic>Research Paper</topic><topic>Risk Factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Coppens, Grégoire</creatorcontrib><creatorcontrib>Vanhorebeek, Ilse</creatorcontrib><creatorcontrib>Verlinden, Ines</creatorcontrib><creatorcontrib>Derese, Inge</creatorcontrib><creatorcontrib>Wouters, Pieter J</creatorcontrib><creatorcontrib>Joosten, Koen F.</creatorcontrib><creatorcontrib>Verbruggen, Sascha C.</creatorcontrib><creatorcontrib>Güiza, Fabian</creatorcontrib><creatorcontrib>Van den Berghe, Greet</creatorcontrib><collection>Taylor & Francis Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>Epigenetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Coppens, Grégoire</au><au>Vanhorebeek, Ilse</au><au>Verlinden, Ines</au><au>Derese, Inge</au><au>Wouters, Pieter J</au><au>Joosten, Koen F.</au><au>Verbruggen, Sascha C.</au><au>Güiza, Fabian</au><au>Van den Berghe, Greet</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Assessment of aberrant DNA methylation two years after paediatric critical illness: a pre-planned secondary analysis of the international PEPaNIC trial</atitle><jtitle>Epigenetics</jtitle><addtitle>Epigenetics</addtitle><date>2023-12-31</date><risdate>2023</risdate><volume>18</volume><issue>1</issue><spage>2146966</spage><epage>2146966</epage><pages>2146966-2146966</pages><issn>1559-2294</issn><eissn>1559-2308</eissn><abstract>Critically ill children requiring intensive care suffer from impaired physical/neurocognitive development 2 y later, partially preventable by omitting early use of parenteral nutrition (early-PN) in the paediatric intensive-care-unit (PICU). Altered methylation of DNA from peripheral blood during PICU-stay provided a molecular basis hereof. Whether DNA-methylation of former PICU patients, assessed 2 y after critical illness, is different from that of healthy children remained unknown. In a pre-planned secondary analysis of the PEPaNIC-RCT (clinicaltrials.gov-NCT01536275) 2-year follow-up, we assessed buccal-mucosal DNA-methylation (Infinium-HumanMethylation-EPIC-BeadChip) of former PICU-patients (N = 406 early-PN; N = 414 late-PN) and matched healthy children (N = 392). CpG-sites differentially methylated between groups were identified with multivariable linear regression and differentially methylated DNA-regions via clustering of differentially methylated CpG-sites using kernel-estimates. Analyses were adjusted for technical variation and baseline risk factors, and corrected for multiple testing (false-discovery-rate <0.05). Differentially methylated genes were functionally annotated (KEGG-pathway database), and allocated to three classes depending on involvement in physical/neurocognitive development, critical illness and intensive medical care, or pre-PICU-admission disorders. As compared with matched healthy children, former PICU-patients showed significantly different DNA-methylation at 4047 CpG-sites (2186 genes) and 494 DNA-regions (468 genes), with most CpG-sites being hypomethylated (90.3%) and with an average absolute 2% effect-size, irrespective of timing of PN initiation. Of the differentially methylated KEGG-pathways, 41.2% were related to physical/neurocognitive development, 32.8% to critical illness and intensive medical care and 26.0% to pre-PICU-admission disorders. 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| subjects | Child children Critical illness Critical Illness - therapy Development DNA Methylation epigenetic growth Humans Intensive Care Units, Pediatric neurocognitive development nutrition parenteral nutrition Parenteral Nutrition - adverse effects PICU Research Paper Risk Factors |
| title | Assessment of aberrant DNA methylation two years after paediatric critical illness: a pre-planned secondary analysis of the international PEPaNIC trial |
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