Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Mar;9(3):253-265.
doi: 10.2217/epi-2016-0145. Epub 2017 Feb 21.

Misclassified exposure in epigenetic mediation analyses. Does DNA methylation mediate effects of smoking on birthweight?

Linda Valeri  1   2 , Sarah L Reese  3 , Shanshan Zhao  3 , Christian M Page  4 , Wenche Nystad  4 , Brent A Coull  5 , Stephanie J London  3
Affiliations

Misclassified exposure in epigenetic mediation analyses. Does DNA methylation mediate effects of smoking on birthweight?

Linda Valeri et al. Epigenomics. 2017 Mar.

Abstract

Aims: Assessing whether epigenetic alterations mediate associations between environmental exposures and health outcomes is increasingly popular. We investigate the impact of exposure misclassification in such investigations.

Materials & methods: We quantify bias and false-positive rates due to exposure misclassification in mediation analysis and assess the performance of the simulation extrapolation method (SIMEX). We evaluate whether DNA-methylation mediates smoking-birth weight relationship in the Norwegian Mother and Child Study birth cohort.

Results: Ignoring exposure misclassification increases type I error in mediation analysis. The direct effect is underestimated and, when the mediator is a biomarker of the exposure, as is true for smoking, the indirect effect is overestimated.

Conclusion: Misclassification correction plus cautious interpretation are recommended for mediation analyses in the presence of exposure misclassification.

Keywords: DNA methylation; mediation analysis; misclassification.

PubMed Disclaimer

Conflict of interest statement

Financial & competing interests disclosure

This work was supported in part by the Intramural Research Program of NIH, National Institute of Environmental Health Sciences (NIEHS). The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health and the Ministry of Education and Research, NIH/NIEHS (contract number N01-ES-75558 and ZO1 ES-49019), NIH/NINDS (grant number 1 UO1 NS 047537-01) and the Norwegian Research Council/FUGE (grant number 151918/S10), and the present project by the Norwegian Research Council/BIOBANK (grant no 221097). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Figures

<b>Figure 1.</b>
Figure 1.
(A) Directed acyclic graph for average causal effect of sustained smoking during pregnancy (A) on birth weight (Y) (TE = formula imagefrom Equation 1); (B) Directed acyclic graph for direct of sustained smoking during pregnancy (A) on birth weight (Y) and indirect effect of sustained smoking during pregnancy (A) on birth weight (Y) through DNA-methylation (M) (NDE = θ1 from Equation 3, NIE = formula image) (C) denotes a vector of confounders.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

  • Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight.
    Küpers LK, Monnereau C, Sharp GC, Yousefi P, Salas LA, Ghantous A, Page CM, Reese SE, Wilcox AJ, Czamara D, Starling AP, Novoloaca A, Lent S, Roy R, Hoyo C, Breton CV, Allard C, Just AC, Bakulski KM, Holloway JW, Everson TM, Xu CJ, Huang RC, van der Plaat DA, Wielscher M, Merid SK, Ullemar V, Rezwan FI, Lahti J, van Dongen J, Langie SAS, Richardson TG, Magnus MC, Nohr EA, Xu Z, Duijts L, Zhao S, Zhang W, Plusquin M, DeMeo DL, Solomon O, Heimovaara JH, Jima DD, Gao L, Bustamante M, Perron P, Wright RO, Hertz-Picciotto I, Zhang H, Karagas MR, Gehring U, Marsit CJ, Beilin LJ, Vonk JM, Jarvelin MR, Bergström A, Örtqvist AK, Ewart S, Villa PM, Moore SE, Willemsen G, Standaert ARL, Håberg SE, Sørensen TIA, Taylor JA, Räikkönen K, Yang IV, Kechris K, Nawrot TS, Silver MJ, Gong YY, Richiardi L, Kogevinas M, Litonjua AA, Eskenazi B, Huen K, Mbarek H, Maguire RL, Dwyer T, Vrijheid M, Bouchard L, Baccarelli AA, Croen LA, Karmaus W, Anderson D, de Vries M, Sebert S, Kere J, Karlsson R, Arshad SH, Hämäläinen E, Routledge MN, Boomsma DI, Feinberg AP, Newschaffer CJ, Govarts E, Moisse M, Fallin MD, Melén E, Prentice AM, Kajantie E, Almqvist C, Oken E, Dabelea D, Boezen HM, Melton PE, Wright RJ, … See abstract for full author list ➔ Küpers LK, et al. Nat Commun. 2019 Apr 23;10(1):1893. doi: 10.1038/s41467-019-09671-3. Nat Commun. 2019. PMID: 31015461 Free PMC article.
  • Cohort Profile: Pregnancy And Childhood Epigenetics (PACE) Consortium.
    Felix JF, Joubert BR, Baccarelli AA, Sharp GC, Almqvist C, Annesi-Maesano I, Arshad H, Baïz N, Bakermans-Kranenburg MJ, Bakulski KM, Binder EB, Bouchard L, Breton CV, Brunekreef B, Brunst KJ, Burchard EG, Bustamante M, Chatzi L, Cheng Munthe-Kaas M, Corpeleijn E, Czamara D, Dabelea D, Davey Smith G, De Boever P, Duijts L, Dwyer T, Eng C, Eskenazi B, Everson TM, Falahi F, Fallin MD, Farchi S, Fernandez MF, Gao L, Gaunt TR, Ghantous A, Gillman MW, Gonseth S, Grote V, Gruzieva O, Håberg SE, Herceg Z, Hivert MF, Holland N, Holloway JW, Hoyo C, Hu D, Huang RC, Huen K, Järvelin MR, Jima DD, Just AC, Karagas MR, Karlsson R, Karmaus W, Kechris KJ, Kere J, Kogevinas M, Koletzko B, Koppelman GH, Küpers LK, Ladd-Acosta C, Lahti J, Lambrechts N, Langie SAS, Lie RT, Liu AH, Magnus MC, Magnus P, Maguire RL, Marsit CJ, McArdle W, Melén E, Melton P, Murphy SK, Nawrot TS, Nisticò L, Nohr EA, Nordlund B, Nystad W, Oh SS, Oken E, Page CM, Perron P, Pershagen G, Pizzi C, Plusquin M, Raikkonen K, Reese SE, Reischl E, Richiardi L, Ring S, Roy RP, Rzehak P, Schoeters G, Schwartz DA, Sebert S, Snieder H, Sørensen TIA, Starling AP, Sunyer J, Taylor JA, Tiemeier H, Ullemar V, Vafeiadi M, Van Ijzendoorn MH,… See abstract for full author list ➔ Felix JF, et al. Int J Epidemiol. 2018 Feb 1;47(1):22-23u. doi: 10.1093/ije/dyx190. Int J Epidemiol. 2018. PMID: 29025028 Free PMC article. No abstract available.
  • Epigenetic biomarkers and preterm birth.
    Park B, Khanam R, Vinayachandran V, Baqui AH, London SJ, Biswal S. Park B, et al. Environ Epigenet. 2020 Jun 14;6(1):dvaa005. doi: 10.1093/eep/dvaa005. eCollection 2020 Jan. Environ Epigenet. 2020. PMID: 32551139 Free PMC article. Review.
  • Exploring the genetic basis of human population differences in DNA methylation and their causal impact on immune gene regulation.
    Husquin LT, Rotival M, Fagny M, Quach H, Zidane N, McEwen LM, MacIsaac JL, Kobor MS, Aschard H, Patin E, Quintana-Murci L. Husquin LT, et al. Genome Biol. 2018 Dec 18;19(1):222. doi: 10.1186/s13059-018-1601-3. Genome Biol. 2018. PMID: 30563547 Free PMC article.
  • DNA methylation as a potential mediator of the association between prenatal tobacco and alcohol exposure and child neurodevelopment in a South African birth cohort.
    Abrishamcar S, Chen J, Feil D, Kilanowski A, Koen N, Vanker A, Wedderburn CJ, Donald KA, Zar HJ, Stein DJ, Hüls A. Abrishamcar S, et al. Transl Psychiatry. 2022 Sep 30;12(1):418. doi: 10.1038/s41398-022-02195-3. Transl Psychiatry. 2022. PMID: 36180424 Free PMC article.
See all "Cited by" articles

References

    1. Joehanes R, Just AC, Marioni RE, et al. Epigenetic signatures of cigarette smoking. Circ. Cardiovasc. Genet. 2016;9(5):436–447. - PMC - PubMed
    1. Joubert BR, Felix JF, Yousefi P, et al. DNA methylation in newborns and maternal smoking in pregnancy: genome-wide consortium meta-analysis. Am. J. Hum Genet. 2016;98(4):680–696. - PMC - PubMed

    2. • The large-scale meta-analysis across many birth cohorts identifies numerous replicable loci involved in response to maternal smoking in pregnancy with persistence into later childhood.

    1. Reese SE, Zhao S, Wu MC, et al. DNA methylation score as a biomarker in newborns for sustained maternal smoking during pregnancy. Environ. Health Perspect. 2016 Epub ahead of print. - PMC - PubMed

    2. •• Develops a biomarker in newborns of sustained maternal smoking during pregnancy using CpGs differentially methylated in relation to this exposure in the Norwegian Mother and Child Cohort Study.

    1. Zhang Y, Yang R, Burwinkel B, Breitling LP, Brenner H. F2RL3 methylation as a biomarker of current and lifetime smoking exposures. Environ. Health Perspect. 2014;122(2):131. - PMC - PubMed
    1. Zhang Y, Schottker B, Florath I, et al. Smoking-associated DNA methylation biomarkers and their predictive value for all-cause and cardiovascular mortality. Environ. Health Perspect. 2016;124(1):67–74. - PMC - PubMed

Publication types

LinkOut - more resources