scholarly journals A structured approach to evaluating life course hypotheses: Moving beyond analyses of exposed versus unexposed in the omics context

2019 ◽  
Author(s):  
Yiwen Zhu ◽  
Andrew J. Simpkin ◽  
Matthew J. Suderman ◽  
Alexandre A. Lussier ◽  
Esther Walton ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Life Course ◽  
Childhood Abuse ◽  
Statistical Power ◽  
Time Dependent ◽  
Genome Wide ◽  
The Life Course ◽  
Inference Tests ◽  
Selective Inference ◽  
Empirical Analyses

AbstractBackgroundLife course epidemiology provides a framework for studying the effects of time-varying exposures on health outcomes. The structured life course modeling approach (SLCMA) is a theory-driven analytic method that empirically compares multiple prespecified life course hypotheses characterizing time-dependent exposure-outcome relationships to determine which theory best fits the observed data. However, the statistical properties of inference methods used with the SLCMA have not been investigated with high-dimensional omics outcomes.MethodsWe performed simulations and empirical analyses to evaluate the performance of the SLCMA when applied to genome-wide DNA methylation (DNAm). In the simulations, we compared five statistical inference tests used by SLCMA (n=700). For each, we assessed the familywise error rate (FWER), statistical power, and confidence interval coverage to determine whether inference based on these tests was valid in the presence of substantial multiple testing and small effect sizes, two hallmark challenges of inference from omics data. In the empirical analyses, we applied the SLCMA to evaluate the time-dependent relationship of childhood abuse with genome-wide DNAm (n=703).ResultsIn the simulations, selective inference and max-|t|-test performed best: both controlled FWER and yielded moderate statistical power. Empirical analyses using SLCMA revealed time-dependent effects of childhood abuse on DNA methylation.ConclusionsOur findings show that SLCMA, applied and interpreted appropriately, can be used in the omics setting to examine time-dependent effects underlying exposure-outcome elationships over the life course. We provide recommendations for applying the SLCMA in high-throughput settings, which we hope will encourage researchers to move beyond analyses of exposed versus unexposed.Key messagesThe structured life course modeling approach (SLCMA) is an effective approach to directly compare life course theories and can be scaled-up in the omics context to examine nuanced relationships between environmental exposures over the life course and biological processes.Of the five statistical inference tests assessed in simulations, we recommend the selective inference method and max-|t|-test for post-selection inference in omics applications of the SLCMA.In an empirical example, we revealed time-dependent effects of childhood abuse on DNA methylation using the SLCMA, with improvement in statistical power when accounting for covariates by applying the Frisch-Waugh-Lovell (FWL) theorem.Researchers should assess p-values in parallel with effects sizes and confidence intervals, as triangulating multiple forms of statistical evidence can strengthen inferences and point to new directions for replication.

scholarly journals A Structured Approach to Evaluating Life Course Hypotheses: Moving Beyond Analyses of Exposed Versus Unexposed in the Omics Context

2020 ◽  
Author(s):  
Yiwen Zhu ◽  
Andrew J Simpkin ◽  
Matthew J Suderman ◽  
Alexandre A Lussier ◽  
Esther Walton ◽  
...  
Keyword(s):  
Life Course ◽  
Childhood Abuse ◽  
Error Rate ◽  
Multiple Testing ◽  
Statistical Power ◽  
Time Dependent ◽  
Family Wise Error Rate ◽  
Genome Wide ◽  
Inference Tests ◽  
Empirical Analyses

Abstract The structured life course modeling approach (SLCMA) is a theory-driven analytic method that empirically compares multiple prespecified life course hypotheses characterizing time-dependent exposure-outcome relationships to determine which theory best fits the observed data. In this study, we performed simulations and empirical analyses to evaluate the performance of the SLCMA when applied to genome-wide DNA methylation (DNAm). Using simulations, we compared five statistical inference tests used with SLCMA (n=700), assessing the family-wise error rate, statistical power, and confidence interval coverage to determine whether inference based on these tests was valid in the presence of substantial multiple testing and small effects, two hallmark challenges of inference from omics data. In the empirical analyses, we evaluated the time-dependent relationship of childhood abuse with genome-wide DNAm (n=703). In simulations, selective inference and max-|t|-test performed best: both controlled family-wise error rate and yielded moderate statistical power. Empirical analyses using SLCMA revealed time-dependent effects of childhood abuse on DNAm. Our findings show that SLCMA, applied and interpreted appropriately, can be used in high-throughput settings to examine time-dependent effects underlying exposure-outcome relationships over the life course. We provide recommendations for applying the SLCMA in omics settings and encourage researchers to move beyond analyses of exposed versus unexposed.

scholarly journals A Faith to Move Mountains? Childhood Abuse, Religious Change, and Mental Health at Midlife

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 461-461
Author(s):  
Laura Upenieks
Keyword(s):  
Mental Health ◽  
Life Course ◽  
Childhood Abuse ◽  
Childhood Maltreatment ◽  
Well Being ◽  
The United States ◽  
Religious Attendance ◽  
Three Dimensions ◽  
Religious Importance ◽  
The Life Course

Abstract Of all the various forms of adversity experienced during childhood, childhood maltreatment (emotional and physical abuse) is shown to have the largest impacts on mental health and well-being. Yet we still have a limited understanding of why some victims of early maltreatment suffer immense mental health consequences later on in the life course, while others are able to cushion the blow of these early insults. Using two waves of data from the National Survey of Midlife Development in the United States (MIDUS), this study considers change in religiosity as a buffer across three dimensions for victims of childhood abuse: religious importance, attendance, and the specific act of seeking comfort through religion. Results suggest that increases in religious comfort during adulthood are positively associated with adult mental health for victims of abuse, while decreases in religious comfort over time were associated with worse mental health. Changes in religious attendance and religious importance were not significant associated with mental health for victims of abuse. Taken together, my results show that the stress-moderating effects of religion for victims of childhood maltreatment are contingent on the stability or increases or decreases in religiosity over the life course, which has been overlooked in previous work.

Making Sense of Heterogeneity in the Influence of Childhood Abuse, Mental Health, and Drug Use on Women’s Offending Pathways

2018 ◽  
Vol 45 (10) ◽  
pp. 1565-1587 ◽  
Author(s):  
Lisa Broidy ◽  
Jason Payne ◽  
Alex R. Piquero
Keyword(s):  
Drug Use ◽  
Life Course ◽  
Childhood Abuse ◽  
Internalizing Symptoms ◽  
Age Of Onset ◽  
Making Sense ◽  
Pathways Model ◽  
Female Offending ◽  
Using Data ◽  
The Life Course

Building from the developmental and life course literature and the feminist pathways literature, we aim to detail when and how exposure to abuse in childhood shapes female offending trajectories. Using data from 470 female offenders in Australia, our analyses assess whether internalizing symptoms and drug use help explain the link between early abuse and later offending among females. We then examine whether these links are most acute for females who onset early and evidence chronic involvement in offending. In support of the feminist pathways model, we find evidence for a pathway from early abuse to internalizing symptoms to drug use and then offending. In addition, and in line with the life course literature, we also find important differences in how these risks unfold across women, depending particularly on age of onset and offending chronicity. We reflect on the implications of our findings for theory and intervention with respect to female offending.

Domestic Violence and the Victim/Offender Overlap Across the Life Course

2017 ◽  
Vol 62 (9) ◽  
pp. 2801-2816 ◽  
Author(s):  
Amaia Iratzoqui
Keyword(s):  
Domestic Violence ◽  
Life Course ◽  
Childhood Abuse ◽  
Add Health ◽  
Intimate Partner ◽  
Health Data ◽  
Criminal Justice Policy ◽  
Violence Perpetration ◽  
Current Article ◽  
The Life Course

The current article examined the overlap of domestic violence across the life course, connecting childhood abuse and adolescent dating victimization to adult intimate partner victimization, and the connection between these behaviors and adult domestic violence perpetration against partners and children. Using three waves of Add Health data, the study found that childhood and adolescent domestic victimization were directly and indirectly linked to adult intimate partner victimization and that domestic violence perpetration also played a role. These findings indicate that offending must be accounted for in tracking patterns of victimization over the life course and that the overlap must more directly be reconciled in current criminal justice policy.

scholarly journals Associations between indicators of socioeconomic position and DNA methylation: A systematic review

2021 ◽  
Author(s):  
Janine K. Cerutti ◽  
Alexandre A. Lussier ◽  
Yiwen Zhu ◽  
Jiaxuan Liu ◽  
Erin C. Dunn
Keyword(s):  
Systematic Review ◽  
Dna Methylation ◽  
Life Course ◽  
Socioeconomic Position ◽  
Prenatal Development ◽  
Future Research ◽  
Socioeconomic Environment ◽  
The Life Course ◽  
Study Designs

AbstractSocioeconomic position (SEP) is a major determinant of health across the life course. Yet, little is known about the biological mechanisms explaining this relationship. One possible explanation is through an epigenetic process called DNA methylation (DNAm), wherein the socioeconomic environment causes no alteration in the DNA sequence but modifies gene activity, gene expression, and therefore long-term health. To understand the evidence supporting a potential SEP-DNAm link, we performed a systematic review of published empirical findings on the association between SEP (from prenatal development to adulthood) and DNAm measured across the life course, with an eye toward evaluating how the timing, duration, and type of SEP exposure influenced DNAm. Across the 37 studies we identified, there was some evidence for the effect of SEP timing and duration on DNAm, with early-life SEP and persistently low SEP being particularly strong indicators of DNAm. Different indicators of SEP also had some unique associations with DNAm profiles, suggesting that SEP is not a singular concept, but rather that different aspects of the socioeconomic environment can shift DNAm patterns through distinct pathways. These differences with respect to SEP timing, duration, and type were notable because they were detected even among heterogenous study designs. Overall, findings from this review underscore the importance of analyzing SEP timing, duration, and type, given the complex relationship between SEP and DNAm across the lifespan. To guide future research, we highlight current limitations in the literature and propose recommendations for overcoming some of these challenges.

scholarly journals A pooling-based approach to mapping genetic variants associated with DNA methylation

2015 ◽  
Author(s):  
Irene Miriam Kaplow ◽  
Julia L MacIsaac ◽  
Sarah M Mah ◽  
Lisa M McEwen ◽  
Michael S Kobor ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Genetic Variants ◽  
Statistical Power ◽  
Epigenetic Modification ◽  
Chromatin Accessibility ◽  
Ctcf Binding ◽  
Sequencing Data ◽  
Individual Level ◽  
Novel Approach ◽  
Genome Wide

DNA methylation is an epigenetic modification that plays a key role in gene regulation. Previous studies have investigated its genetic basis by mapping genetic variants that are associated with DNA methylation at specific sites, but these have been limited to microarrays that cover less than 2% of the genome and cannot account for allele-specific methylation (ASM). Other studies have performed whole-genome bisulfite sequencing on a few individuals, but these lack statistical power to identify variants associated with DNA methylation. We present a novel approach in which bisulfite-treated DNA from many individuals is sequenced together in a single pool, resulting in a truly genome-wide map of DNA methylation. Compared to methods that do not account for ASM, our approach increases statistical power to detect associations while sharply reducing cost, effort, and experimental variability. As a proof of concept, we generated deep sequencing data from a pool of 60 human cell lines; we evaluated almost twice as many CpGs as the largest microarray studies and identified over 2,000 genetic variants associated with DNA methylation. We found that these variants are highly enriched for associations with chromatin accessibility and CTCF binding but are less likely to be associated with traits indirectly linked to DNA, such as gene expression and disease phenotypes. In summary, our approach allows genome-wide mapping of genetic variants associated with DNA methylation in any tissue of any species, without the need for individual-level genotype or methylation data.

scholarly journals DNA methylation and brain structure and function across the life course: A systematic review

2020 ◽  
Vol 113 ◽  
pp. 133-156 ◽  
Author(s):  
Emily N.W. Wheater ◽  
David Q. Stoye ◽  
Simon R. Cox ◽  
Joanna M. Wardlaw ◽  
Amanda J. Drake ◽  
...  
Keyword(s):  
Systematic Review ◽  
Dna Methylation ◽  
Life Course ◽  
Brain Structure ◽  
Structure And Function ◽  
Brain Structure And Function ◽  
And Function ◽  
The Life Course

scholarly journals Exploring the relation between socioeconomic position and DNA methylation in a European population

2020 ◽  
Vol 30 (Supplement_5) ◽  
Author(s):  
D Petrovic ◽  
C Carmeli ◽  
B Bodinier ◽  
M Chadeau-Hyam ◽  
G Ehret ◽  
...  
Keyword(s):  
Life Course ◽  
Socioeconomic Position ◽  
Disease Risk ◽  
Premature Death ◽  
Population Based ◽  
European Population ◽  
Differential Methylation ◽  
Genome Wide ◽  
Cardiometabolic Disorders ◽  
The Life Course

Abstract Background Previous investigations have reported that adverse socioeconomic circumstances across the life-course lead to the alteration of major biological processes, eventually resulting in a higher disease risk and premature death. In particular, a low life-course socioeconomic position (SEP) has been associated with a modified epigenetic signature of loci involved in inflammation, the physiological response to stress, and other regulatory processes. Methods In this study, we investigated the association between nine indicators of SEP across the life-course and the differential methylation of 451'000 genome-wide CpG markers, using data from 690 adults included in a Swiss population-based study. We further examined the interrelations between the SEP-related CpGs, and the biological pathways in which the identified markers are involved. Results Three SEP indicators in adulthood were associated the differential methylation of 161 genome-wide CpG markers, whereby 156 CpGs were less methylated in people with low versus high SEP. Among the identified CpGs, a substantial proportion of markers were no longer associated with SEP upon accounting for health behaviors and cardiometabolic disorders. In addition, the identified CpGs were found to be involved in immune, inflammatory, and cancer-related processes. Conclusions Our results support the hypothesis that adverse socioeconomic circumstances may lead to the dysregulation of inflammatory processes, eventually resulting in the occurrence of serious chronic conditions such as atherosclerosis, diabetes, or cancer. Key messages Socioeconomic position is a major determinant of health-related outcomes. Epigenetic modifications may constitute a biological mechanism through which socioeconomic circumstances affect health.

scholarly journals Associations between indicators of socioeconomic position and DNA methylation: a scoping review

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Janine Cerutti ◽  
Alexandre A. Lussier ◽  
Yiwen Zhu ◽  
Jiaxuan Liu ◽  
Erin C. Dunn
Keyword(s):  
Dna Methylation ◽  
Life Course ◽  
Scoping Review ◽  
Socioeconomic Position ◽  
Prenatal Development ◽  
Future Research ◽  
Socioeconomic Environment ◽  
The Life Course ◽  
The Relationship ◽  
Epigenetic Processes

Abstract Background Socioeconomic position (SEP) is a major determinant of health across the life course. Yet, little is known about the biological mechanisms explaining this relationship. One possibility widely pursued in the scientific literature is that SEP becomes biologically embedded through epigenetic processes such as DNA methylation (DNAm), wherein the socioeconomic environment causes no alteration in the DNA sequence but modifies gene activity in ways that shape health. Methods To understand the evidence supporting a potential SEP-DNAm link, we performed a scoping review of published empirical findings on the association between SEP assessed from prenatal development to adulthood and DNAm measured across the life course, with an emphasis on exploring how the developmental timing, duration, and type of SEP exposure influenced DNAm. Results Across the 37 identified studies, we found that: (1) SEP-related DNAm signatures varied across the timing, duration, and type of SEP indicator; (2) however, longitudinal studies examining repeated SEP and DNAm measures are generally lacking; and (3) prior studies are conceptually and methodologically diverse, limiting the interpretability of findings across studies with respect to these three SEP features. Conclusions Given the complex relationship between SEP and DNAm across the lifespan, these findings underscore the importance of analyzing SEP features, including timing, duration, and type. To guide future research, we highlight additional research gaps and propose four recommendations to further unravel the relationship between SEP and DNAm.

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