The relationship between type, timing and duration of exposure to adverse childhood experiences and adolescent self-harm and depression: findings from three UK prospective population-based cohorts.

BACKGROUND: Adverse childhood experiences (ACEs) are well-established risk factors for self-harm and depression. However, despite their high comorbidity, there has been little focus on the impact of developmental timing and the duration of exposure to ACEs on co-occurring self-harm and depression. METHODS: Data were utilised from over 22,000 children and adolescents participating in three UK cohorts, followed up longitudinally for 14-18 years: the Avon Longitudinal Study of Parents and Children (ALSPAC), the Millennium Cohort Study (MCS) and the Environmental Risk (E-Risk) Longitudinal Twin Study. Multinomial logistic regression models estimated associations between each ACE type and a four-category outcome: no self-harm or depression, self-harm alone, depression alone and self-harm with co-occurring depression. A structured life course modelling approach was used to examine whether the accumulation (duration) of exposure to each ACE, or a critical period (timing of ACEs) had the strongest effects on self-harm and depression in adolescence. RESULTS: The majority of ACEs were associated with co-occurring self-harm and depression, with consistent findings across cohorts. The importance of timing and duration of ACEs differed across ACEs and across cohorts. For parental mental health problems, longer duration of exposure was strongly associated with co-occurring self-harm and depression in both ALSPAC (adjusted OR: 1.18, 95% CI: 1.10-1.25) and MCS (1.18, 1.11-1.26) cohorts. For other ACEs in ALSPAC, exposure in middle childhood was most strongly associated with co-occurring self-harm and depression, and ACE occurrence in early childhood and adolescence was more important in the MCS. CONCLUSIONS: Efforts to mitigate the impact of ACEs should start in early life with continued support throughout childhood, to prevent long-term exposure to ACEs contributing to risk of self-harm and depression in adolescence.

How well do parents identify their child's baby teeth? Engagement and accuracy of parent-reported information on a tooth checklist survey.

OBJECTIVES: Naturally exfoliated primary teeth are being increasingly collected in child development studies. Most of these odontological collections and tooth biobanks use parent-reported information from questionnaires or tooth checklists to collect data on offspring teeth. To the best of the authors' knowledge, no studies have assessed parental engagement in tooth checklists, nor parental accuracy in identifying their child's baby tooth. This study aimed to evaluate these dimensions by analysing data from the about this tooth checklist returned with donated primary teeth in a natural experimental study called STRONG (the Stories Teeth Record of Newborn Growth). METHODS: Parental self-reported information were analysed on checklists returned with 825 primary teeth belonging to 199 children. The percentage of blank answers was calculated for each question. The accuracy of parents-reported tooth identification was evaluated by comparing parental ratings to researchers' ratings. Reliability of researchers' tooth identification was first evaluated by calculating intra-observer and inter-observer agreements, as well as Cohen's Kappa values. The percentage of accuracy of parents' tooth identification (relative to researcher's) was then calculated, and logistic regressions were used to evaluate if time elapsed between when exfoliation occurred and the checklist was completed associated with parental accuracy in tooth identification. RESULTS: Parents returned 98.4% of the checklists and completed 74.9% to 97.7% of the questions. Excellent reliability was demonstrated for researchers' intra- and inter-rater tooth identification (agreement percentages >90%; Cohen's Kappa values >.83). Moderate accuracy of parents-reported tooth identifications was found, with parents correctly identifying 49.5% of the donated tooth. Better parental accuracies were highlighted for partial identifications (87.1% of correct jaw, 75.6% of correct tooth type, and 65.8% of correct lateralization). Logistic regressions showed the odds of correct parental identifications decreased on average by 1.8% every 30 days of distance between tooth exfoliation and checklist completion. CONCLUSIONS: While parental engagement is high, parents-reported tooth identifications have moderate accuracy, which decreases over time. High accuracy is however found for partial identifications. Parent-reported information on the accompanying questionnaire of naturally exfoliated primary teeth collection or tooth biobanks, even when filled in a long time after exfoliation took place, should be encouraged. However, expert identifications of teeth should remain best practice.

Ambulance clinicians implementing evidence-based practice: mind the gap! Attitudes, perceptions and experiences of student paramedics.

Background: Evidence-based practice (EBP) represents the conscientious and judicious use of the best contemporaneous evidence in partnership with patient values and clinical expertise to guide healthcare professionals. As a result, EBP is a recommended component of undergraduate education and considered fundamental for improving patient outcomes. EBP principles have thus become deeply rooted in higher education curricula, but only in recent years has this begun to permeate the world of paramedic practice. Despite this paradigm, the impact of EBP may be limited because ambulance clinicians may struggle with implementation, as a variety of barriers influence translation and application. Methods: A survey study aimed to gain insight into the epistemological and metacognitive barriers impacting student experience in order to help improve teaching and learning practices. Results: A sample of 64 students, across two different undergraduate paramedic science programmes, were recruited. Of these, 70% of BSc (Hons) students versus 33% of DipHE students agreed to some extent or greater that EBP represented minimal benefit in real-world practice due to Trust policy and the guidelines set out by the Joint Royal Colleges Ambulance Liaison Committee (Welch's t = 2.571, df = 26, p = 0.016 two-sided). Furthermore, 25% felt standard operating procedures negatively impacted their ability to implement EBP, and 39% reported their EBP learning had improved their ability to implement improved levels of patient care. Conclusion: A disparity between theoretical learning and EBP implementation was identified. EBP may not dovetail with standard operating procedure within UK ambulance Trusts, resulting in confusion among student paramedics as to the true worth of EBP.

Sensitive Periods for the Effect of Child Maltreatment on Psychopathology Symptoms in Adolescence.

Introduction: Child maltreatment is among the strongest risk factors for mental disorders. However, little is known about whether there are ages when children may be especially vulnerable to its effects. We sought to identify potential sensitive periods when exposure to the 2 most common types of maltreatment (neglect and harsh physical discipline) had a particularly detrimental effect on youth mental health. Methods: Data came from the Future of Families and Child Wellbeing Study (FFCWS), a birth cohort oversampled from "fragile families" (n = 3,474). Maltreatment was assessed at 3, 5, and 9 years of age using an adapted version of the Parent-Child Conflict Tactics Scales (CTS-PC). Using least angle regression, we examined the relationship between repeated measures of exposure to maltreatment on psychopathology symptoms at age 15 years (Child Behavior Checklist; CBCL/6-18). For comparison, we evaluated the strength of evidence to support the existence of sensitive periods in relation to an accumulation of risk model. Results: We identified sensitive periods for harsh physical discipline, whereby psychopathology symptom scores were highest among girls exposed at age 9 years (r2 = 0.67 internalizing symptoms; r2 = 1% externalizing symptoms) and among boys exposed at age 5 years (r2 = 0.41%). However, for neglect, the accumulation of risk model explained more variability in psychopathology symptoms for both boys and girls. Conclusion: Child maltreatment may have differential effects based on the child's sex, type of exposure, and the age at which it occurs. These findings provide additional evidence for clinicians assessing the benefits and drawbacks of screening efforts and point toward possible mechanisms driving increased vulnerability to psychopathology.

Sensitive periods for exposure to indoor air pollutants and psychosocial factors in association with symptoms of psychopathology at school-age in a South African birth cohort.

Background: Gestation and the first few months of life are important periods for brain development. During these periods, exposure to environmental toxicants and psychosocial stressors are particularly harmful and may impact brain development. Specifically, exposure to indoor air pollutants (IAP) and psychosocial factors (PF) during these sensitive periods has been shown to predict childhood psychopathology. Objectives: This study aims to investigate sensitive periods for the individual and joint effects of IAP and PF on childhood psychopathology at 6.5 years. Methods: We analyzed data from the Drakenstein Child Health Study (N=599), a South African birth cohort. Exposure to IAP and PF was measured during the second trimester of pregnancy and 4 months postpartum. The outcome of childhood psychopathology was assessed at 6.5 years old using the Childhood Behavior Checklist (CBCL). We investigated individual effects of either pre-or postnatal exposure to IAP and PF on CBCL scores using adjusted linear regression models, and joint effects of these exposures using quantile g-computation and self-organizing maps (SOM). To identify possible sensitive periods, we used a structured life course modeling approach (SLCMA) as well as exposure mixture methods (quantile g-computation and SOM). Results: Prenatal exposure to IAP or PFs, as well as the total prenatal mixture assessed using quantile g-computation, were associated with increased psychopathology. SLCMA and SOM models also indicated that the prenatal period is a sensitive period for IAP exposure on childhood psychopathology. Depression and alcohol were associated in both the pre-and postnatal period, while CO was associated with the postnatal period. Discussion: Pregnancy may be a sensitive period for the effect of indoor air pollution on childhood psychopathology. Exposure to maternal depression and alcohol in both periods was also associated with psychopathology. Determining sensitive periods of exposure is vital to ensure effective interventions to reduce childhood psychopathology.

Association between the timing of childhood adversity and epigenetic patterns across childhood and adolescence: findings from the Avon Longitudinal Study of Parents and Children (ALSPAC) prospective cohort.

BACKGROUND: Childhood adversity is a potent determinant of health across development and is associated with altered DNA methylation signatures, which might be more common in children exposed during sensitive periods in development. However, it remains unclear whether adversity has persistent epigenetic associations across childhood and adolescence. We aimed to examine the relationship between time-varying adversity (defined through sensitive period, accumulation of risk, and recency life course hypotheses) and genome-wide DNA methylation, measured three times from birth to adolescence, using data from a prospective, longitudinal cohort study. METHODS: We first investigated the relationship between the timing of exposure to childhood adversity between birth and 11 years and blood DNA methylation at age 15 years in the Avon Longitudinal Study of Parents and Children (ALSPAC) prospective cohort study. Our analytic sample included ALSPAC participants with DNA methylation data and complete childhood adversity data between birth and 11 years. We analysed seven types of adversity (caregiver physical or emotional abuse, sexual or physical abuse [by anyone], maternal psychopathology, one-adult households, family instability, financial hardship, and neighbourhood disadvantage) reported by mothers five to eight times between birth and 11 years. We used the structured life course modelling approach (SLCMA) to identify time-varying associations between childhood adversity and adolescent DNA methylation. Top loci were identified using an R2 threshold of 0·035 (ie, ≥3·5% of DNA methylation variance explained by adversity). We attempted to replicate these associations using data from the Raine Study and Future of Families and Child Wellbeing Study (FFCWS). We also assessed the persistence of adversity-DNA methylation associations we previously identified from age 7 blood DNA methylation into adolescence and the influence of adversity on DNA methylation trajectories from ages 0-15 years. FINDINGS: Of 13 988 children in the ALSPAC cohort, 609-665 children (311-337 [50-51%] boys and 298-332 [49-50%] girls) had complete data available for at least one of the seven childhood adversities and DNA methylation at 15 years. Exposure to adversity was associated with differences in DNA methylation at 15 years for 41 loci (R2 ≥0·035). Sensitive periods were the most often selected life course hypothesis by the SLCMA. 20 (49%) of 41 loci were associated with adversities occurring between age 3 and 5 years. Exposure to one-adult households was associated with differences in DNA methylation at 20 [49%] of 41 loci, exposure to financial hardship was associated with changes at nine (22%) loci, and physical or sexual abuse was associated with changes at four (10%) loci. We replicated the direction of associations for 18 (90%) of 20 loci associated with exposure to one-adult household using adolescent blood DNA methylation from the Raine Study and 18 (64%) of 28 loci using saliva DNA methylation from the FFCWS. The directions of effects for 11 one-adult household loci were replicated in both cohorts. Differences in DNA methylation at 15 years were not present at 7 years and differences identified at 7 years were no longer apparent by 15 years. We also identified six distinct DNA methylation trajectories from these patterns of stability and persistence. INTERPRETATION: These findings highlight the time-varying effect of childhood adversity on DNA methylation profiles across development, which might link exposure to adversity to potential adverse health outcomes in children and adolescents. If replicated, these epigenetic signatures could ultimately serve as biological indicators or early warning signs of initiated disease processes, helping identify people at greater risk for the adverse health consequences of childhood adversity. FUNDING: Canadian Institutes of Health Research, Cohort and Longitudinal Studies Enhancement Resources, EU's Horizon 2020, US National Institute of Mental Health.

Incorporating interactions into structured life course modelling approaches: A simulation study and applied example of the role of access to green space and socioeconomic position on cardiometabolic health.

Background: Structured life course modelling approaches (SLCMA) have been developed to understand how exposures across the lifespan relate to later health, but have primarily been restricted to single exposures. As multiple exposures can jointly impact health, here we: i) demonstrate how to extend SLCMA to include exposure interactions; ii) conduct a simulation study investigating the performance of these methods; and iii) apply these methods to explore associations of access to green space, and its interaction with socioeconomic position, with child cardiometabolic health. Methods: We used three methods, all based on lasso regression, to select the most plausible life course model: visual inspection, information criteria and cross-validation. The simulation study assessed the ability of these approaches to detect the correct interaction term, while varying parameters which may impact power (e.g., interaction magnitude, sample size, exposure collinearity). Methods were then applied to data from a UK birth cohort. Results: There were trade-offs between false negatives and false positives in detecting the true interaction term for different model selection methods. Larger sample size, lower exposure collinearity, centering exposures, continuous outcomes and a larger interaction effect all increased power. In our applied example we found little-to-no association between access to green space, or its interaction with socioeconomic position, and child cardiometabolic outcomes. Conclusions: Incorporating interactions between multiple exposures is an important extension to SLCMA. The choice of method depends on the researchers' assessment of the risks of under- vs over-fitting. These results also provide guidance for improving power to detect interactions using these methods.

Socioeconomic changes predict genome-wide DNA methylation in childhood.

Childhood socioeconomic position (SEP) is a major determinant of health and well-being across the entire life course. To effectively prevent and reduce health risks related to SEP, it is critical to better understand when and under what circumstances socioeconomic adversity shapes biological processes. DNA methylation (DNAm) is one such mechanism for how early life adversity 'gets under the skin'. In this study, we evaluated the dynamic relationship between SEP and DNAm across childhood using data from 946 mother-child pairs in the Avon Longitudinal Study of Parents and Children. We assessed six SEP indicators spanning financial, occupational and residential domains during very early childhood (ages 0-2), early childhood (ages 3-5) and middle childhood (ages 6-7). Epigenome-wide DNAm was measured at 412 956 cytosine-guanines (CpGs) from peripheral blood at age 7. Using an innovative two-stage structured life-course modeling approach, we tested three life-course hypotheses for how SEP shapes DNAm profiles-accumulation, sensitive period and mobility. We showed that changes in the socioeconomic environment were associated with the greatest differences in DNAm, and that middle childhood may be a potential sensitive period when socioeconomic instability is especially important in shaping DNAm. Top SEP-related DNAm CpGs were overrepresented in genes involved in pathways important for neural development, immune function and metabolic processes. Our findings highlight the importance of socioeconomic stability during childhood and if replicated, may emphasize the need for public programs to help children and families experiencing socioeconomic instability and other forms of socioeconomic adversity.

Testing lifecourse theories characterising associations between maternal depression and offspring depression in emerging adulthood: the Avon Longitudinal Study of Parents and Children.

BACKGROUND: Maternal depression is a major determinant of offspring mental health. Yet, little is understood about how the duration and timing of maternal depression shapes youth risk for depressive symptoms, which if understood could inform when best to intervene. This study aimed to determine how the timing and duration of maternal depression was related to offspring depression in emerging adulthood, and if these associations varied by sex. METHODS: We analysed data from the Avon Longitudinal Study of Parents and Children (a prenatal cohort in the Avon area of England, 1991-2003), n = 3,301. We applied the structured lifecourse modelling approach to maternal depression (assessed at 13 points from prenatal period to adolescence) and emerging adult depressive symptoms (age 21). Lifecourse models assessed were accumulation (sum of timepoints when maternal depression was reported), sensitive periods (each period assessed as one during which maternal depression has a stronger effect) and instability (frequent fluctuations in maternal depression). RESULTS: Female adolescents (n = 2,132) had higher SMFQ scores (mean = 6.15, SD = 5.90) than males (n = 1,169, mean = 4.87, SD = 4.82). Maternal depression was most common in the infancy period (21.2% males; 21.4% females). For males, accumulation was the most appropriate lifecourse model; for each additional period of maternal depression, depressive symptoms in emerging adulthood increased by 0.11 (95% CI: 0.07, 0.15, one-sided p value ≤ .001). For females, exposure to maternal depression was associated with increasing depressive symptoms in emerging adulthood, with the largest effect in mid-childhood (increase of 0.27 units, 95% CI 0.03-0.50, p = .015 for difference between mid-childhood and other time-periods) and a smaller, equal effect at all other time-periods (increase of 0.07 units per time-period, 95% CI: 0.03-0.12, p = .002). CONCLUSIONS: This study highlights the importance of ongoing maternal depression for the development of depression in offspring through to emerging adulthood. Because long-term exposure to maternal depression was particularly important, early interventions are warranted.

Examining the epigenetic mechanisms of childhood adversity and sensitive periods: A gene set-based approach.

BACKGROUND: Sensitive periods are developmental stages of heightened plasticity when life experiences, including exposure to childhood adversity, have the potential to exert more lasting impacts. Epigenetic mechanisms, including DNA methylation (DNAm), may provide a pathway through which adversity induces long-term biological changes. DNAm shifts may be more likely to occur during sensitive periods, especially within genes that regulate the timing of sensitive periods. Here, we investigated the possibility that childhood adversity during specific life stages is associated with DNAm changes in genes known to regulate the timing and duration of sensitive periods. METHODS: Genome-wide DNAm profiles came from the Avon Longitudinal Study of Parents and Children (n = 785). We first used principal component analysis (PCA) to summarize DNAm variation across 530 CpG sites mapped to the promoters of 58 genes previously-identified as regulating sensitive periods. Gene-level DNAm summaries were calculated for genes regulating sensitive period opening (ngenes = 15), closing (ngenes = 36), and expression (ngenes = 8). We then performed linear discriminant analysis (LDA) to test associations between seven types of parent-reported, time-varying measures of exposure to childhood adversity and DNAm principal components. To our knowledge, this is the first time LDA has been applied to analyze functionally grouped DNAm data to characterize associations between an environmental exposure and epigenetic differences. RESULTS: Suggestive evidence emerged for associations between sexual or physical abuse as well as financial hardship during middle childhood, and DNAm of genetic pathways regulating sensitive period opening and expression. However, no statistically significant associations were identified after multiple testing correction. CONCLUSIONS: Our gene set-based method combining PCA and LDA complements epigenome-wide approaches. Although our results were largely null, these findings provide a proof-of-concept for studying time-varying exposures and gene- or pathway-level epigenetic modifications.

Statistical Modeling of Sensitive Period Effects Using the Structured Life Course Modeling Approach (SLCMA).

Sensitive periods are times during development when life experiences can have a greater impact on outcomes than at other periods during the life course. However, a dearth of sophisticated methods for studying time-dependent exposure-outcome relationships means that sensitive periods are often overlooked in research studies in favor of more simplistic and easier-to-use hypotheses such as ever being exposed, or the effect of an exposure accumulated over time. The structured life course modeling approach (SLCMA; pronounced "slick-mah") allows researchers to model complex life course hypotheses, such as sensitive periods, to determine which hypothesis best explains the amount of variation between a repeated exposure and an outcome. The SLCMA makes use of the least angle regression (LARS) variable selection technique, a type of least absolute shrinkage and selection operator (LASSO) estimation procedure, to yield a parsimonious model for the exposure-outcome relationship of interest. The results of the LARS procedure are complemented with a post-selection inference method, called selective inference, which provides unbiased effect estimates, confidence intervals, and p-values for the final explanatory model. In this chapter, we provide a brief overview of the genesis of this sensitive period modeling approach and provide a didactic step-by-step user's guide to implement the SLCMA in sensitive- period research. R code to complete the SLCMA is available on our GitHub page at: https://github.com/thedunnlab/SLCMA-pipeline .

Updates to data versions and analytic methods influence the reproducibility of results from epigenome-wide association studies.

Biomedical research has grown increasingly cooperative through the sharing of consortia-level epigenetic data. Since consortia preprocess data prior to distribution, new processing pipelines can lead to different versions of the same dataset. Similarly, analytic frameworks evolve to incorporate cutting-edge methods and best practices. However, it remains unknown how different data and analytic versions alter the results of epigenome-wide analyses, which could influence the replicability of epigenetic associations. Thus, we assessed the impact of these changes using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. We analysed DNA methylation from two data versions, processed using separate preprocessing and analytic pipelines, examining associations between seven childhood adversities or prenatal smoking exposure and DNA methylation at age 7. We performed two sets of analyses: (1) epigenome-wide association studies (EWAS); (2) Structured Life Course Modelling Approach (SLCMA), a two-stage method that models time-dependent effects. SLCMA results were also compared across two analytic versions. Data version changes impacted both EWAS and SLCMA analyses, yielding different associations at conventional p-value thresholds. However, the magnitude and direction of associations was generally consistent between data versions, regardless of p-values. Differences were especially apparent in analyses of childhood adversity, while smoking associations were more consistent using significance thresholds. SLCMA analytic versions similarly altered top associations, but time-dependent effects remained concordant. Alterations to data and analytic versions influenced the results of epigenome-wide analyses. Our findings highlight that magnitude and direction are better measures for replication and stability than p-value thresholds.

Exposure to early childhood maltreatment and its effect over time on social cognition.

Social cognitive deficits can have many negative consequences, spanning social withdrawal to psychopathology. Prior work has shown that child maltreatment may associate with poorer social cognitive skills in later life. However, no studies have examined this association from early childhood into adolescence. Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 4,438), we examined the association between maltreatment (caregiver physical or emotional abuse; sexual or physical abuse), assessed repeatedly (every 1-3 years) from birth to age 9, and social cognitive skills at ages 7.5, 10.5, and 14 years. We evaluated the role of both the developmental timing (defined by age at exposure) and accumulation of maltreatment (defined as the number of occasions exposed) using a least angle regression variable selection procedure, followed by structural equation modeling. Among females, accumulation of maltreatment explained the most variation in social cognitive skills. For males, no significant associations were found. These findings underscore the importance of early intervention to minimize the accumulation of maltreatment and showcase the importance of prospective studies to understand the development of social cognition over time.

2008 financial crisis versus 2020 economic fallout: how COVID-19 might influence fertility treatment and live births.

RESEARCH QUESTION: The economic and reproductive medicine response to the coronavirus disease 2019 (COVID-19) pandemic in the USA has reduced the affordability and accessibility of fertility care. What is the impact of the 2008 financial recession and the COVID-19 recession on fertility treatments and cumulative live births? DESIGN: The study examined annual US natality, Centers for Disease Control and Prevention IVF cycle activity and live birth data from 1999 to 2018 encompassing 3,286,349 treatment cycles, to estimate the age-stratified reduction in IVF cycles undertaken after the 2008 financial recession, with forward quantitative modelling of IVF cycle activity and cumulative live births for 2020 to 2023. RESULTS: The financial recession of 2008 caused a 4-year plateau in fertility treatments with a predicted 53,026 (95% confidence interval [CI] 49,581 to 56,471) fewer IVF cycles and 16,872 (95% CI 16,713 to 17,031) fewer live births. A similar scale of economic recession would cause 67,386 (95% CI 61,686 to 73,086) fewer IVF cycles between 2020 and 2023, with women younger than 35 years overall undertaking 22,504 (95% CI 14,320 to 30,690) fewer cycles, compared with 4445 (95% CI 3144 to 5749) fewer cycles in women over the age of 40 years. This equates to overall 25,143 (95% CI 22,408 to 27,877) fewer predicted live births from IVF, of which only 490 (95% CI 381 to 601) are anticipated to occur in women over the age of 40 years. CONCLUSIONS: The COVID-19 recession could have a profound impact on US IVF live birth rates in young women, further aggravating pre-existing declines in total fertility rates.

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

The structured life-course modeling approach (SLCMA) is a theory-driven analytical 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 genomewide DNA methylation (DNAm). Using simulations (n = 700), we compared 5 statistical inference tests used with SLCMA, assessing the familywise 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-2 hallmark challenges of inference from -omics data. In the empirical analyses (n = 703), we evaluated the time-dependent relationship between childhood abuse and genomewide DNAm. In simulations, selective inference and the max-|t|-test performed best: Both controlled the familywise 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 individuals.

The mental health effects of pet death during childhood: is it better to have loved and lost than never to have loved at all?

Pet ownership is common. Growing evidence suggests children form deep emotional attachments to their pets. Yet, little is known about children's emotional reactions to a pet's death. The goal of this study was to describe the relationship between experiences of pet death and risk of childhood psychopathology and determine if it was "better to have loved and lost than never to have loved at all". Data came from the Avon Longitudinal Study of Parents and Children, a UK-based prospective birth cohort (n = 6260). Children were characterized based on their exposure to pet ownership and pet death from birth to age 7 (never loved; loved without loss; loved with loss). Psychopathology symptoms at age 8 were compared across groups using multivariable linear regression. Psychopathology symptoms were higher among children who had loved with loss compared to those who had loved without loss (ß = 0.35, p = 0.013; 95% CI = 0.07, 0.63), even after adjustment for other adversities. This group effect was more pronounced in males than in females. There was no difference in psychopathology symptoms between children who had loved with loss and those who had never loved (ß = 0.20, p = 0.31, 95% CI = -0.18-0.58). The developmental timing, recency, or accumulation of pet death was unassociated with psychopathology symptoms. Pet death may be traumatic for children and associated with subsequent mental health difficulties. Where childhood pet ownership and pet bereavement is concerned, Tennyson's pronouncement may not apply to children's grief responses: it may not be "better to have loved and lost than never to have loved at all".

Population implications of cessation of IVF during the COVID-19 pandemic.

RESEARCH QUESTION: Discontinuation of IVF cycles has been part of the radical transformation of healthcare provision to enable reallocation of staff and resources to deal with the COVID-19 pandemic. This study sought to estimate the impact of cessation of treatment on individual prognosis and US population live birth rates. DESIGN: Data from 271,438 ovarian stimulation UK IVF cycles was used to model the effect of age as a continuous, yet non-linear, function on cumulative live birth rate. This model was recalibrated to cumulative live birth rates reported for the 135,673 stimulation cycles undertaken in the USA in 2016, with live birth follow-up to October 2018. The effect of a 1-month, 3-month and 6-month shutdown in IVF treatment was calculated as the effect of the equivalent increase in a woman's age, stratified by age group. RESULTS: The average reduction in cumulative live birth rate would be 0.3% (95% confidence interval [CI] 0.3-0.3), 0.8% (95% CI 0.8-0.8) and 1.6% (95% CI 1.6-1.6) for 1-month, 3-month and 6-month shutdowns. This corresponds to a reduction of 369 (95% CI 360-378), 1098 (95% CI 1071-1123) and 2166 (95% CI 2116-2216) live births in the cohort, respectively. Th e greatest contribution to this reduction was from older mothers. CONCLUSIONS: The study demonstrated that the discontinuation of fertility treatment for even 1 month in the USA could result in 369 fewer women having a live birth, due to the increase in patients' age during the shutdown. As a result of reductions in cumulative live birth rate, more cycles may be required to overcome infertility at individual and population levels.

Adversity exposure during sensitive periods predicts accelerated epigenetic aging in children.

OBJECTIVES: Exposure to adversity has been linked to accelerated biological aging, which in turn has been shown to predict numerous physical and mental health problems. In recent years, measures of DNA methylation-based epigenetic age--known as "epigenetic clocks"--have been used to estimate accelerated epigenetic aging. Although a small number of studies have found an effect of adversity exposure on epigenetic age in children, none have investigated if there are "sensitive periods" when adversity is most impactful. METHODS: Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 973), we tested the prospective association between repeated measures of childhood exposure to seven types of adversity on epigenetic age assessed at age 7.5 using the Horvath and Hannum epigenetic clocks. With a Least Angle Regression variable selection procedure, we evaluated potential sensitive period effects. RESULTS: We found that exposure to abuse, financial hardship, or neighborhood disadvantage during sensitive periods in early and middle childhood best explained variability in the deviation of Hannum-based epigenetic age from chronological age, even after considering the role of adversity accumulation and recency. Secondary sex-stratified analyses identified particularly strong sensitive period effects. These effects were undetected in analyses comparing children "exposed" versus "unexposed" to adversity. We did not identify any associations between adversity and epigenetic age using the Horvath epigenetic clock. CONCLUSIONS: Our results suggest that adversity may alter methylation processes in ways that either directly or indirectly perturb normal cellular aging and that these effects may be heightened during specific life stages.