Guide to Decomposition of Causal Effects Into Mediation, Interaction, and Direct Effects: Case Study on Aerobic Exercise and Parkinson Disease.

Mediation analysis can be applied in medical research with the aim of understanding the pathways that operate between an exposure and its effects on an outcome. This method can help to improve our understanding of pathophysiologic mechanisms and may guide the choice of potential treatment strategies. Traditional mediation analysis decomposes the total effect of an intervention on the outcome into 2 effects: (1) an indirect effect, from exposure using a mediator to the outcome, and (2) a direct effect, directly from exposure to outcome. A limitation of this method is that it assumes no interaction between the exposure and the mediator, which can either lead to an over- or underestimation of clinically relevant effects. The "4-way decomposition" method has the advantage of overcoming this limitation. Specifically, the total effect of an exposure on the outcome is decomposed into 4 elements: (1) reference interaction (interaction only), (2) mediated interaction (mediation and interaction), (3) the pure indirect effect (mediation but not interaction), and (4) the direct effect (no mediation and no interaction). We provide a guide to select the most appropriate method to investigate and decompose any causal effect given the research question at hand. We explain the application of the 4-way decomposition and illustrate this with a real-world example of how aerobic exercise may influence motor function in persons with Parkinson disease.

Counterfactual Mediation Analysis with a Latent Class Exposure.

Latent classes are a useful tool in developmental research, however there are challenges associated with embedding them within a counterfactual mediation model. We develop and test a new method "updated pseudo class draws (uPCD)" to examine the association between a latent class exposure and distal outcome that could easily be extended to allow the use of any counterfactual mediation method. UPCD extends an existing group of methods (based on pseudo class draws) that assume that the true values of the latent class variable are missing, and need to be multiply imputed using class membership probabilities. We simulate data based on the Avon Longitudinal Study of Parents and Children, examine performance for existing techniques to relate a latent class exposure to a distal outcome ("one-step," "bias-adjusted three-step," "modal class assignment," "non-inclusive pseudo class draws," and "inclusive pseudo class draws") and compare bias in parameter estimates and their precision to uPCD when estimating counterfactual mediation effects. We found that uPCD shows minimal bias when estimating counterfactual mediation effects across all levels of entropy. UPCD performs similarly to recommended methods (one-step and bias-adjusted three-step), but provides greater flexibility and scope for incorporating the latent grouping within any commonly-used counterfactual mediation approach.

Childhood Adversity and Incident Psychotic Experiences in Early Adulthood: Cognitive and Psychopathological Mediators.

BACKGROUND AND HYPOTHESIS: Childhood adversity is often described as a potential cause of incident psychotic experiences, but the underlying mechanisms are not well understood. We aimed to examine the mediating role of cognitive and psychopathological factors in the relation between childhood adversity and incident psychotic experiences in early adulthood. STUDY DESIGN: We analyzed data from the Avon Longitudinal Study of Parents and Children, a large population-based cohort study. Childhood adversity was measured prospectively from birth to age 11 years, mediators (anxiety, depression, external locus of control [LoC], negative symptoms) were assessed at approximately 16 years of age, and incident psychotic experiences were assessed at ages 18 and 24 years. Mediation was examined via the counterfactual g-computation formula. STUDY RESULTS: In total, 7% of participants had incident suspected or definite psychotic experiences in early adulthood. Childhood adversity was related to more incident psychotic experiences (ORadjusted = 1.34, 95% CI = 1.21; 1.49), and this association was partially mediated via all mediators examined (proportion mediated: 19.9%). In separate analyses for each mediator, anxiety, depression, external LoC, and negative symptoms were all found to mediate the link between adversity and incident psychotic experiences. Accounting for potential confounders did not modify our results. CONCLUSIONS: Our study shows that cognitive biases as well as mood symptomatology may be on the causal pathway between early-life adversity and the development of psychotic experiences. Future studies should determine which mediating factors are most easily modifiable and most likely to reduce the risk of developing psychotic experiences.

Adverse childhood experiences and crime outcomes in early adulthood: A multi-method approach in a Brazilian birth cohort.

This study aimed to investigate alternative approaches to a cumulative risk score in the relationship between adverse childhood experiences (ACEs) and crime. Using data from the 1993 Pelotas (Brazil) Birth Cohort (n = 3236), we measured 12 ACEs up to 15 years, and past-year violent and non-violent crime at 22 years. We used four analytical approaches: single adversities, cumulative risk, latent class analysis, and network analysis. When examined individually, physical abuse, emotional abuse, and domestic violence were associated with both crime outcomes, whereas maternal mental illness and discrimination were associated with violent crime only, and parental divorce and poverty with non-violent crime only. There was a cumulative effect of ACEs on crime. The class with child maltreatment and household challenges was associated with both crime outcomes; exposure to household challenges and social risks was associated with violent crime only. In network models, crime showed conditional associations with physical abuse, maternal mental illness, and parental divorce. Although cumulative ACEs did associate with crime, some individual and combinations of ACEs showed particularly strong and robust effects, which were not captured by the cumulative score. Many ACEs are closely connected and/or cluster together, and the usefulness of the ACE score needs to be further evaluated.

Pathways from maternal depression to child resilience: Socioeconomic, family, and individual factors in the 2004 Pelotas (Brazil) birth cohort.

Background: The negative impacts of maternal depression on child mental health outcomes are well-documented. However, some children show adaptive functioning following exposure to maternal depression, demonstrating resilience. In a large birth cohort from Brazil, a middle-income country, we examined direct and indirect pathways, considering socioeconomic, family, and individual factors, contributing to the development of resilience. Methods: Using data from the 2004 Pelotas Birth Cohort (N = 4231), we restricted the sample to those exposed to maternal depression up to age 6 years (depression present at ≥2 out of 5 assessment waves; n = 1132; 50% boys). Resilience was defined as scoring below or equal to the mean of the unexposed group on all four problem subscales of the parent-report Strengths and Difficulties Questionnaire at age 11 years. We examined pathways from socioeconomic status (SES; measured at birth) to resilience via cognitive stimulation (CS) (at 24 and 48 months) and Intelligence quotient (IQ) (at 6 years), and from CS to resilience via IQ, using counterfactual mediation. Results: A minority of children exposed to maternal depression showed resilience (12.4%). There was evidence of indirect pathways from SES to resilience via CS (odds ratio (OR) = 1.76, 95% confidence interval (CI) 1.02-3.38) and IQ (OR = 1.19, 95% CI 1.01-1.42), such that higher SES was associated with resilience via both higher levels of CS and higher IQ, which, in turn, were each positively associated with resilience. Furthermore, there was evidence of a direct (OR = 1.86, 95% CI 1.01-3.76) and total effect (OR = 1.94, 95% CI 1.05-3.89) of CS on resilience, even after controlling for SES. However, these effects varied depending on how persistent and severe depression was defined. Conclusions: These findings suggest that CS in early childhood may represent a modifiable protective factor for children exposed to maternal depression and a promising intervention target to promote child resilience in the context of maternal depression exposure.

The association of alcohol dependence and consumption during adolescence with depression in young adulthood, in England: a prospective cohort study.

BACKGROUND: The role of alcohol use in the development of depression is unclear. We aimed to investigate whether alcohol dependence, but not high frequency or quantity of consumption, during adolescence increased the risk of depression in young adulthood. METHODS: In this prospective cohort study, we included adolescents who were born to women recruited to the Avon Longitudinal Study of Parents and Children in Avon, UK, with delivery dates between April 1, 1991, and Dec 31, 1992. Alcohol dependence and consumption were measured at about age 16 years, 18 years, 19 years, 21 years, and 23 years using the self-reported Alcohol Use Disorders Identification Test, and at about age 18 years, 21 years, and 23 years using items corresponding to DSM-IV symptoms. The primary outcome was depression at age 24 years, assessed using the Clinical Interview Schedule Revised. Analyses were probit regressions between growth factors for alcohol dependence and consumption and depression, before and after adjustments for confounders: sex, housing tenure, maternal education, maternal depressive symptoms, parents' alcohol use, conduct problems at age 4 years, being bullied from age 12-16 years, and frequency of smoking cigarettes or cannabis. Adolescents were included in analyses if they had data from at least one timepoint for alcohol use and confounders. FINDINGS: We included 3902 adolescents (2264 [58·0%] female; 1638 [42·0%] male) in our analysis, and 3727 (96·7%) of 3853 participants with data on ethnicity were White. After adjustments, we found a positive association between alcohol dependence at 18 years of age (latent intercept) and depression at 24 years of age (probit coefficient 0·13 [95% CI 0·02 to 0·25]; p=0·019), but no association between rate of change (linear slope) and depression (0·10 [-0·82 to 1·01]; p=0·84). There was no evidence of an association between alcohol consumption and depression (latent intercept probit coefficient -0·01 [-0·06 to 0·03]; p=0·60; linear slope 0·01 [-0·40 to 0·42]; p=0·96) after adjustments. INTERPRETATION: Psychosocial or behavioural interventions that reduce the risk of alcohol dependence during adolescence could contribute to preventing depression in young adulthood. FUNDING: UK Medical Research Council and Alcohol Research UK (grant number MR/L022206/1).

Stratification of adolescents across mental phenomena emphasizes the importance of transdiagnostic distress: a replication in two general population cohorts.

Characterizing patterns of mental phenomena in epidemiological studies of adolescents can provide insight into the latent organization of psychiatric disorders. This avoids the biases of chronicity and selection inherent in clinical samples, guides models of shared aetiology within psychiatric disorders and informs the development and implementation of interventions. We applied Gaussian mixture modelling to measures of mental phenomena from two general population cohorts: the Avon Longitudinal Study of Parents and Children (ALSPAC, n = 3018) and the Neuroscience in Psychiatry Network (NSPN, n = 2023). We defined classes according to their patterns of both positive (e.g. wellbeing and self-esteem) and negative (e.g. depression, anxiety, and psychotic experiences) phenomena. Subsequently, we characterized classes by considering the distribution of diagnoses and sex split across classes. Four well-separated classes were identified within each cohort. Classes primarily differed by overall severity of transdiagnostic distress rather than particular patterns of phenomena akin to diagnoses. Further, as overall severity of distress increased, so did within-class variability, the proportion of individuals with operational psychiatric diagnoses. These results suggest that classes of mental phenomena in the general population of adolescents may not be the same as those found in clinical samples. Classes differentiated only by overall severity support the existence of a general, transdiagnostic mental distress factor and have important implications for intervention.

Emotional dysregulation in childhood and disordered eating and self-harm in adolescence: prospective associations and mediating pathways.

BACKGROUND: Emotional dysregulation may be a risk factor for disordered eating and self-harm in young people, but few prospective studies have assessed these associations long-term, or considered potential mediators. We examined prospective relationships between childhood emotional dysregulation and disordered eating and self-harm in adolescence; and social cognition, emotional recognition, and being bullied as mediators. METHODS: We analysed Avon Longitudinal Study of Parents and Children data on 3,453 males and 3,481 females. We examined associations between emotional dysregulation at 7 years and any disordered eating and any self-harm at 16 years with probit regression models. We also assessed whether social cognition (7 years), emotional recognition (8 years) and bullying victimisation (11 years) mediated these relationships. RESULTS: Emotional dysregulation at age 7 years was associated with disordered eating [fully adjusted probit B (95% CI) = 0.082 (0.029, 0.134)] and self-harm [fully adjusted probit B (95% CI) = 0.093 (0.036, 0.150)] at age 16 years. There was no evidence of sex interactions or difference in effects between self-harm and disordered eating. Mediation models found social cognition was a key pathway to disordered eating (females 51.2%; males 27.0% of total effect) and self-harm (females 15.7%; males 10.8% of total effect). Bullying victimisation was an important pathway to disordered eating (females 17.1%; males 10.0% of total effect), but only to self-harm in females (15.7% of total effect). Indirect effects were stronger for disordered eating than self-harm. CONCLUSIONS: In males and females, emotional dysregulation in early childhood is associated with disordered eating and self-harm in adolescence and may be a useful target for prevention and treatment. Mediating pathways appeared to differ by sex and outcome, but social cognition was a key mediating pathway for both disordered eating and self-harm.

Childhood Trauma As a Mediator of the Association Between Autistic Traits and Psychotic Experiences: Evidence From the Avon Longitudinal Study of Parents and Children Cohort.

BACKGROUND: Little is known on whether associations between childhood autistic traits and psychotic experiences persist into adulthood and whether genetic confounding and childhood trauma influence them. Here we investigate the associations between childhood autistic traits and psychotic experiences until young adulthood and assess the influence of schizophrenia polygenic risk and childhood traumatic experiences, using the Avon Longitudinal Study of Parents and Children (ALSPAC) population-based birth cohort. STUDY DESIGN: We used a measure of broad autistic traits (autism factor mean score), and four dichotomised measures of autistic traits capturing social communication difficulties (age 7), repetitive behaviours (age 5), sociability (age 3), and pragmatic language (age 9). Psychotic experiences were assessed at ages 18 and 24 using the semi-structured Psychosis-Like Symptoms interview (PLIKSi). Traumatic experiences between ages 5 and 11 were assessed with questionnaires and interviews administered to children and parents at multiple ages. STUDY RESULTS: Broad autistic traits, as well as social communication difficulties, were associated with psychotic experiences that were distressing and/or frequent until age 24 (autism factor mean score, n = 3707: OR 1.19, 95%CI 1.01-1.39; social communication difficulties, n = 3384: OR 1.54, 95%CI 0.97-2.45). Childhood trauma mediated a substantial proportion of the identified associations (~28% and 36% respectively, maximum n = 3577). Schizophrenia polygenic risk did not appear to confound the associations. Multiple imputation analyses (maximum n = 13 105) yielded comparable results. CONCLUSIONS: Childhood trauma may be an important, potentially modifiable pathway between autistic features and later onset of psychotic psychopathology.

Maternal postnatal depressive symptoms and offspring emotional and behavioral development at age 7 years in a U.K. birth cohort: The role of paternal involvement.

There is considerable variability in developmental outcomes of children whose mothers experience depression. Few longitudinal studies have examined contributions of paternal involvement in the association between maternal postnatal depression (PND) and offspring development. We examined pathways from maternal PND at 8 weeks (Edinburgh Postnatal Depression Scale; total score) to offspring emotional and behavioral development at 7 years (Strengths and Difficulties Questionnaire; total score) through behavioral, affective, and cognitive dimensions of paternal involvement in a U.K.-based birth cohort (Avon Longitudinal Study of Parents and Children; n = 3,434). Analyses were adjusted for baseline confounders and paternal PND (Edinburgh Postnatal Depression Scale; total score) as an intermediate confounder. Maternal PND was strongly associated with offspring development, but this association was not mediated by the combination of all indirect pathways through various dimensions of paternal involvement. Only father-child conflict emerged as a risk factor for adverse offspring development and as a mediator in the association between maternal PND and offspring development (albeit the effect size was small). If found causal, interventions that reduce father-child conflict may reduce the risk of adverse development in offspring of mothers with PND. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Associations between childhood trauma and childhood psychiatric disorders in Brazil: a population-based, prospective birth cohort study.

BACKGROUND: Childhood trauma is a proposed transdiagnostic risk factor for psychopathology, but epidemiological evidence from low-income and middle-income countries (LMICs) is scarce. We investigated associations between trauma and child psychiatric disorders in a birth cohort in Brazil. METHODS: The 2004 Pelotas Birth Cohort is an ongoing, population-based, prospective birth cohort, including all hospital births occurring between Jan 1 and Dec 31, 2004, in the city of Pelotas, Brazil. When the children were aged 6 and 11 years, trained psychologists administered the Development and Well-Being Assessment clinical interview to caregivers to assess current child psychiatric disorders (anxiety disorders, mood disorders, ADHD and hyperactivity disorders, and conduct and oppositional disorders), and lifetime trauma exposure (ie, experiencing or witnessing life-threatening events) including interpersonal and non-interpersonal events. Analyses used multiple imputation and logistic regression models. OUTCOMES: Of 4263 live births, 4231 children were included in the study sample, and 4229 (2195 [51·9%] boys and 2034 [48·1%] girls; 2581 [61·7%] with White mothers and 1600 [38·3%] with Black or mixed race mothers) were included in the imputed analyses. 1154 (34·3%) of 3367 children with complete data at age 11 years had been exposed to trauma by that age. After adjusting for confounders, at age 6 years, trauma was associated with increased odds of anxiety disorders (adjusted odds ratio 1·79 [95% CI 1·33-2·42]) and any psychiatric disorder (1·59 [1·22-2·06]), and at age 11 years, with any psychiatric disorder (1·45 [1·17-1·79]) and all four specific diagnostic classes of anxiety disorders (1·47 [1·04-2·09]), mood disorders (1·66 [1·08-2·55]), ADHD and hyperactivity disorders (1·47 [1·01-2·13]), and conduct and oppositional disorders (1·76 [1·19-2·61]). Interpersonal trauma and non-interpersonal trauma were each associated with increased odds of multiple psychiatric disorders, even when adjusting for their co-occurrence. INTERPRETATION: A considerable mental health burden associated with childhood trauma is already evident by middle childhood in this sample from Brazil. Evidence-based efforts to reduce the incidence of childhood trauma in Brazil and address its consequences are urgently needed. FUNDING: Children's Pastorate, WHO, National Support Program for Centres of Excellence, Brazilian National Research Council, Brazilian Ministry of Health, São Paulo Research Foundation, University of Bath, Wellcome Trust. TRANSLATION: For the Portuguese translation of the abstract see Supplementary Materials section.

Mental health resilience in offspring of depressed parents: a systematic literature review protocol.

BACKGROUND: Parental depression is associated with a range of mental health conditions and other difficulties in the offspring. Nevertheless, some offspring exposed to parental depression do not develop mental health problems, indicating the presence of protective factors that may buffer parental depression-related risk effects. However, evidence of protective factors that might explain good sustained mental health in offspring of depressed parents is limited and systematic synthesis of these factors is still needed. Therefore, as far as we are aware, this will be the first systematic review that will identify parent, family, child, social, and lifestyle factors associated with mental health resilience in offspring of depressed parents, examine evidence for sex-, developmental stage-, and outcome-specific factors and define mental health resilience in the parental depression context. METHODS: This protocol has been developed according to the PRISMA-P guidelines. Electronic searches will be performed for articles published up to 2022 in PsycINFO, Embase, MEDLINE, Web of Science Core Collection, and Cochrane Library. Two reviewers will independently screen titles/abstracts and full-texts against eligibility criteria, extract the data, and assess the overall quality of evidence. Both observational and RCT studies will be eligible for inclusion if they report offspring mental health resilience/outcome and depressive symptoms or depressive disorder in at least one of the parents/caregivers. Risk of bias will be assessed using The Joanna Briggs Institute (JBI) critical appraisal checklists and The Revised Cochrane risk of bias tool for randomised trials (RoB 2). It is expected that studies will be heterogeneous; therefore, meta-analysis will not be attempted. Studies will be systematically retrieved and collated using numerical, graphical, tabular, and narrative summaries and grouped by their design, scope, or overall quality. Further sub-group analyses will be performed to examine sex-, developmental stage-, and outcome-specific protective factors. DISCUSSION: The proposed systematic review will be the first to summarise and critically assess quality and strength of evidence of protective factors associated with mental health resilience in offspring of depressed parents. Directions and effect sizes of the protective factors will be discussed as well as differences between the studies, their limitations, and research gaps and future directions. Strengths and limitations of the proposed systematic review will be also discussed. The proposed systematic review findings are expected to help better understand mental health resilience and identify targets for evidence-based prevention and intervention strategies for those in need. SYSTEMATIC REVIEW REGISTRATION: A previous version of this systematic review protocol has been registered in the International Prospective Register of Systematic Reviews (PROSPERO) database ( www.crd.york.ac.uk/PROSPERO , CRD42021229955).

The Protective Effect of Neighbourhood Collective Efficacy On Family Violence and Youth Antisocial Behaviour in Two South Korean Prospective Longitudinal Cohorts.

Neighbourhood collective efficacy has been proposed as a protective factor against family violence and youth antisocial behaviour. However, little is known about its impact on parent and child behaviour in non-Western countries. Using data from two population-based prospective cohorts from South Korea, including primary school students aged 10-12 years (N = 2844) and secondary school students aged 15-17 years (N = 3449), we examined the interplay between collective efficacy, family violence, and youth antisocial behaviour, and whether effects vary by SES. In a first series of models, in both samples, higher levels of collective efficacy were associated with lower levels of family violence, whereas higher levels of family violence were associated with higher levels of youth antisocial behaviour. There was no direct effect of collective efficacy on youth antisocial behaviour; however, there was an indirect effect via family violence. Although these effects were more pronounced in low SES children, there was no evidence of moderation by SES. In a second series of models, in primary school students, collective efficacy was not associated with youth antisocial behaviour. However, there was a direct effect of collective efficacy on family violence, even after adjusting for youth antisocial behaviour. Again, there was no evidence of moderation by SES. In secondary school students, the pattern of results was less consistent, however, again, suggesting more pronounced effects of collective efficacy in low SES children. The findings suggest that collective efficacy may influence family violence more directly, whereas youth antisocial behaviour may be affected more indirectly through the family environment.

How does childhood maltreatment influence cardiovascular disease? A sequential causal mediation analysis.

BACKGROUND: Childhood maltreatment has been consistently associated with cardiovascular disease (CVD). However, the mechanisms of this relationship are not yet fully understood. We explored the relative contribution of anxiety/depression, smoking, body mass index (BMI) and inflammation (C-reactive protein, CRP) to the association between childhood maltreatment and CVD in men and women aged 40-69 years in the UK. METHODS: We used data from 40 596 men and 59 511 women from UK Biobank. To estimate the indirect effects of childhood maltreatment (physical, sexual and emotional abuse, and emotional and physical neglect) on incident CVD via each of the mediators, we applied a sequential mediation approach. RESULTS: All forms of maltreatment were associated with increased CVD risk [hazard ratios (HRs) ranging from 1.09 to 1.27]. Together, anxiety/depression, smoking, BMI and inflammation (indexed by CRP) mediated 26-90% of the association between childhood maltreatment and CVD, and the contribution of these mediators differed by type of maltreatment and sex. Anxiety/depression mediated the largest proportion of the association of sexual abuse, emotional abuse and emotional neglect with CVD (accounting for 16-43% of the total effect), especially in women. In men, BMI contributed the most to the indirect effect of associations of physical abuse and physical neglect with CVD; in women, anxiety/depression and BMI had similar contributions. CONCLUSIONS: These findings add to the understanding of how childhood maltreatment affects CVD risk and identify modifiable mediating factors that could potentially reduce the burden of CVD in people exposed to maltreatment in early life.

Examining pathways between genetic liability for schizophrenia and patterns of tobacco and cannabis use in adolescence.

BACKGROUND: It is not clear to what extent associations between schizophrenia, cannabis use and cigarette use are due to a shared genetic etiology. We, therefore, examined whether schizophrenia genetic risk associates with longitudinal patterns of cigarette and cannabis use in adolescence and mediating pathways for any association to inform potential reduction strategies. METHODS: Associations between schizophrenia polygenic scores and longitudinal latent classes of cigarette and cannabis use from ages 14 to 19 years were investigated in up to 3925 individuals in the Avon Longitudinal Study of Parents and Children. Mediation models were estimated to assess the potential mediating effects of a range of cognitive, emotional, and behavioral phenotypes. RESULTS: The schizophrenia polygenic score, based on single nucleotide polymorphisms meeting a training-set p threshold of 0.05, was associated with late-onset cannabis use (OR = 1.23; 95% CI = 1.08,1.41), but not with cigarette or early-onset cannabis use classes. This association was not mediated through lower IQ, victimization, emotional difficulties, antisocial behavior, impulsivity, or poorer social relationships during childhood. Sensitivity analyses adjusting for genetic liability to cannabis or cigarette use, using polygenic scores excluding the CHRNA5-A3-B4 gene cluster, or basing scores on a 0.5 training-set p threshold, provided results consistent with our main analyses. CONCLUSIONS: Our study provides evidence that genetic risk for schizophrenia is associated with patterns of cannabis use during adolescence. Investigation of pathways other than the cognitive, emotional, and behavioral phenotypes examined here is required to identify modifiable targets to reduce the public health burden of cannabis use in the population.

PTSD as a mediator of the relationship between trauma and psychotic experiences.

BACKGROUND: Traumatic experiences are associated with a higher risk of psychotic illnesses, but little is known about potentially modifiable mechanisms underlying this relationship. This study aims to examine whether post-traumatic stress disorder (PTSD) symptoms mediate the relationship between trauma and psychotic experiences (PEs). METHODS: We used data from the Avon Longitudinal Study of Parents and Children to examine whether: PTSD symptoms mediate the relationships between (a) childhood trauma and adolescent PEs (study of adolescent PEs; n = 2952), and (b) childhood/adolescent trauma and PEs in early adulthood (study of adult PEs; n = 2492). We examined associations between variables using logistic regression, and mediation using the parametric g-computation formula. RESULTS: Exposure to trauma was associated with increased odds of PEs (adolescent PEs: ORadjusted 1.48, 95% CI 1.23-1.78; adult PEs: ORadjusted 1.57, 95% CI 1.25-1.98) and PTSD symptoms (adolescent PTSD: ORadjusted 1.59, 95% CI 1.31-1.93; adult PTSD: ORadjusted 1.50, 95% CI 1.36-1.65). The association between PTSD symptoms and PE was stronger in adolescence (ORadjusted 4.63, 95% CI 2.34-9.17) than in adulthood (ORadjusted 1.62, 95% CI 0.80-3.25). There was some evidence that PTSD symptoms mediated the relationship between childhood trauma and adolescent PEs (proportion mediated 14%), though evidence of mediation was weaker for adult PEs (proportion mediated 8%). CONCLUSIONS: These findings are consistent with the hypothesis that PTSD symptoms partly mediate the association between trauma exposure and PEs. Targeting PTSD symptoms might help prevent the onset of psychotic outcomes.

Harsh parenting and child conduct and emotional problems: parent- and child-effects in the 2004 Pelotas Birth Cohort.

In high-income countries, links between harsh and abusive parenting and child conduct and emotional problems are well-documented. However, less is known about these relationships in low- and middle-income countries, where harsh parenting may be more widely accepted and higher rates of conduct or emotional problems may exist which could influence the strength of these associations. We sought to investigate these relationships in a large population-based, prospective longitudinal study from Brazil, which also allowed us to test for sex differences. Using data from the 2004 Pelotas Birth Cohort Study (N = 4231) at ages 6 and 11 years, we applied cross-lagged path analysis to examine the relationships between harsh parenting (Conflict Tactics Scale Parent-Child version), and child conduct and emotional problems (Strengths and Difficulties Questionnaire). We found reciprocal relationships between harsh parenting and child conduct problems, with harsh parenting at age 6 predicting child conduct problems at age 11, and vice versa, even after adjusting for initial levels of conduct problems and harsh parenting, respectively. For child emotional problems, only unidirectional effects were found, with harsh parenting at age 6 predicting child emotional problems at age 11, after adjusting for initial levels of emotional problems, but not vice versa. No significant sex differences were observed in these relationships. These observations based on a middle-income country birth cohort highlight the potential universality of detrimental effects of harsh parenting on child conduct and emotional problems and affirm the importance of addressing parent- and child-effects in preventive and treatment interventions, especially those targeting conduct problems.

Maternal adverse childhood experiences (ACEs) and their associations with intimate partner violence and child maltreatment: Results from a Brazilian birth cohort.

Adverse childhood experiences (ACEs) have been found to predict many negative life outcomes. However, very little evidence exists on Intimate Partner Violence (IPV) and Child Maltreatment (CM). We investigated the impact of maternal ACEs on IPV and CM in three different: cumulative risk, individual adversities and particular groupings of ACEs. The 2015 Pelotas Birth Cohort, Southern Brazil, has followed a population-based sample mothers and children repeatedly until children were aged 4 years, when mothers provided data on ACEs, and current IPV and CM. ACEs were examined in three different ways: (i) as a cumulative risk score; (ii) individual adversities; and (iii) patterns of ACEs (Latent Class Analysis: LCA). One quarter (25.4%) of mothers reported having 5+ ACEs in childhood. Compared to mothers with no ACEs, those who reported 5+ ACEs, had 4.9 (95%CI 3.5; 6.7) times the risk of experiencing IPV and 3.8 (95%CI 2.5; 5.6) times the risk of reporting child maltreatment. LCA results also highlighted the major influence of multiple ACEs on later IPV and CM. However, individual ACEs related to violence (exposure to abuse or domestic violence) showed some specificity for both later IPV and CM, over and above the influence of cumulative childhood adversity. This is the first large study to demonstrate a strong link between maternal ACEs and both IPV and CM. Cumulative ACE exposure and some specificity in effects of childhood violence are important for later IPV and CM. Integrated prevention is essential for reducing the intergenerational transmission of adversity and violence.

Mendelian randomisation for mediation analysis: current methods and challenges for implementation.

Mediation analysis seeks to explain the pathway(s) through which an exposure affects an outcome. Traditional, non-instrumental variable methods for mediation analysis experience a number of methodological difficulties, including bias due to confounding between an exposure, mediator and outcome and measurement error. Mendelian randomisation (MR) can be used to improve causal inference for mediation analysis. We describe two approaches that can be used for estimating mediation analysis with MR: multivariable MR (MVMR) and two-step MR. We outline the approaches and provide code to demonstrate how they can be used in mediation analysis. We review issues that can affect analyses, including confounding, measurement error, weak instrument bias, interactions between exposures and mediators and analysis of multiple mediators. Description of the methods is supplemented by simulated and real data examples. Although MR relies on large sample sizes and strong assumptions, such as having strong instruments and no horizontally pleiotropic pathways, our simulations demonstrate that these methods are unaffected by confounders of the exposure or mediator and the outcome and non-differential measurement error of the exposure or mediator. Both MVMR and two-step MR can be implemented in both individual-level MR and summary data MR. MR mediation methods require different assumptions to be made, compared with non-instrumental variable mediation methods. Where these assumptions are more plausible, MR can be used to improve causal inference in mediation analysis.