Cross-direct effects in settings with two mediators.

When multiple mediators are present, there are additional effects that may be of interest beyond the well-known natural (NDE) and controlled direct effects (CDE). These effects cross the type of control on the mediators, setting one to a constant level and one to its natural level, which differs across subjects. We introduce five such estimands for the cross-CDE and -NDE when two mediators are measured. We consider both the scenario where one mediator is influenced by the other, referred to as sequential mediators, and the scenario where the mediators do not influence each other. Such estimands may be of interest in immunology, as we discuss in relation to measured immunological responses to SARS-CoV-2 vaccination. We provide identifying expressions for the estimands in observational settings where there is no residual confounding, and where intervention, outcome, and mediators are of arbitrary type. We further provide tight symbolic bounds for the estimands in randomized settings where there may be residual confounding of the outcome and mediator relationship and all measured variables are binary.

Rethinking causal assumptions about maternal BMI, gestational weight gain, and adverse pregnancy outcomes.

BACKGROUND: The aim of this study was to evaluate commonly assumed causal relationships between body mass index (BMI), gestational weight gain (GWG), and adverse pregnancy outcomes, which have formed the basis of guidelines and interventions aimed at limiting GWG in women with overweight or obesity. We explored relationships between maternal BMI, total GWG (as a continuous variable and as 'excessive' GWG), and pregnancy outcomes (including infant birthweight measures and caesarean birth). METHODS: Analysis of individual participant data (IPD) from the i-WIP (International Weight Management in Pregnancy) Collaboration, from randomised trials of diet and/or physical activity interventions during pregnancy reporting GWG and maternal and neonatal outcomes. Women randomised to the control arm of 20 eligible randomised trials (4370 of 8908 participants) from the i-WIP dataset of 36 randomised trials (total 12,240 women). The main research questions were to characterise the relationship between maternal BMI and (a) total GWG, (b) the risk of 'excessive' GWG (using the Institute of Medicine's guidelines), and (c) adverse pregnancy outcomes as mediated via GWG versus other pathways to determine the extent to which the observed effect of maternal BMI on pregnancy outcomes is mediated via GWG. We utilised generalised linear models and regression-based mediation analyses within an IPD meta-analysis framework. RESULTS: Mean GWG decreased linearly as maternal BMI increased; however, the risk of 'excessive' GWG increased markedly at BMI category thresholds (i.e. between the normal and overweight BMI category threshold and between the overweight and obese BMI category threshold). Increasing maternal BMI was associated with increased risk of all pregnancy outcomes assessed; however, there was no evidence that this effect was mediated via effects on GWG. CONCLUSIONS: There is evidence of a meaningful relationship between maternal BMI and GWG and between maternal BMI and adverse pregnancy outcomes. There is no evidence that the effect of maternal BMI on outcomes is via an effect on GWG. Our analyses also cast doubt on the existence of a relationship between 'excessive' GWG and adverse pregnancy outcomes. Our findings challenge the practice of actively managing GWG throughout pregnancy.

Editorial: Thinking outside the box - enhancing causal models of neurodevelopmental disorders.

Neurodevelopmental disorders are best conceptualised as the result of multiple risk factors, which accumulate and determine the likelihood of reaching the threshold for fulfilling agreed diagnostic criteria. This multiple-risk framework allows the inclusion of research findings focusing on single disorders, while highlighting the need for extending and specifying existing causal models. Such specifications need to address at least three challenges: First, causal models need to account for the heterogeneity of symptoms within neurodevelopmental disorders, the dissociations between disorders, and also the high comorbidity rates observed between them. Second, causal models need to take into account the fact that associations between risk factors and psychopathology may be developmentally conditioned and are likely to change over time. Third, causal models need to incorporate a better understanding of the causal pathways between neurobiological risk factors and their interaction with environmental risk factors. Several articles in the present issue address these challenges, by assessing the interplay between neurobiological and environmental risk factors, and their impact on psychopathology, and by investigating how this relationship changes over time.

Causal relationships between atopic dermatitis and psychiatric disorders: a bidirectional two-sample Mendelian randomization study.

BACKGROUND: Observational studies have suggested the potential associations between atopic dermatitis (AD) and psychiatric disorders. However, the causal relationship between them remains uncertain. This study aimed to evaluate the potential bidirectional causal relationship between AD and psychiatric disorders, including autism spectrum disorder (ASD), major depressive disorder (MDD), attention deficit hyperactivity disorder (ADHD), bipolar disorder (BD), anorexia nervosa (AN), Tourette syndrome (TS), schizophrenia, and anxiety. METHODS: Bidirectional two-sample Mendelian randomization (MR) was employed to elucidate the causality between AD and psychiatric disorders, using summary statistics from the most comprehensive genome-wide association studies conducted on AD (Ncases = 60,653, Ncontrols = 804,329). Psychiatric disorders were derived from the Psychiatric Genomics Consortium and were independent of AD data sources. The MR analysis entailed the implementation of multiple methods, including the inverse variance weighted method, MR-Egger regression method, weighted median method, simple mode method, and weighted mode method. RESULTS: Bidirectional two-sample MR analysis uncovered significant causal associations between AD and severe psychiatric disorders. Specifically, liability to AD was associated with increased risk of ADHD (OR = 1.116; 95% CI: [1.009, 1.234]; P = 0.033) and ASD (OR = 1.131; 95% CI: [1.023, 1.251]; P = 0.016). Additionally, evidence suggested that liability to ADHD (OR = 1.112; 95% CI: [1.094, 1.130]; P = 9.20e-40), liability to AN (OR = 1.1; 95% CI: [1.068, 1.134]; P = 4.45e-10) and liability to BD (OR = 1.067; 95% CI: [1.009, 1.128]; P = 0.023) were associated with an increased risk of AD. Only the causal association between AD and ASD was independent of the reverse effect bias. These causal associations were robust and not affected by biases of heterogeneity and horizontal pleiotropy. CONCLUSIONS: Our study emphasizes the significant causal association between AD and an increased risk of ASD, and also identifying BD and AN as risk factors for AD.

Mendelian Randomization Analysis Reveals a Complex Genetic Interplay among Atopic Dermatitis, Asthma, and Gastroesophageal Reflux Disease.

Rationale: Gastroesophageal reflux disease (GERD) is commonly associated with atopic disorders, but cause-effect relationships remain unclear. Objectives: We applied Mendelian randomization analysis to explore whether GERD is causally related to atopic disorders of the lung (asthma) and/or skin (atopic dermatitis [AD]). Methods: We conducted two-sample bidirectional Mendelian randomization to infer the magnitude and direction of causality between asthma and GERD, using summary statistics from the largest genome-wide association studies conducted on asthma (Ncases = 56,167) and GERD (Ncases = 71,522). In addition, we generated instrumental variables for AD from the latest population-level genome-wide association study meta-analysis (Ncases = 22,474) and assessed their fidelity and confidence of predicting the likely causal pathway(s) leading to asthma and/or GERD. Measurements and Main Results: Applying three different methods, each method revealed similar magnitude of causal estimates that were directionally consistent across the sensitivity analyses. Using an inverse variance-weighted method, the largest effect size was detected for asthma predisposition to AD (odds ratio [OR], 1.46; 95% confidence interval [CI], 1.34-1.59), followed by AD to asthma (OR, 1.34; 95% CI, 1.24-1.45). A significant association was detected for genetically determined asthma on risk of GERD (OR, 1.06; 95% CI, 1.03-1.09) but not genetically determined AD on GERD. In contrast, GERD equally increased risks of asthma (OR, 1.21; 95% CI, 1.09-1.35) and AD (OR, 1.21; 95% CI, 1.07-1.37). Conclusions: This study uncovers previously unrecognized causal pathways that have clinical implications in European-ancestry populations: 1) asthma is a causal risk for AD, and 2) the predisposition to AD, including asthma, can arise from specific pathogenic mechanisms manifested by GERD.

Considering the role of speech processing in cleft-related speech sound disorders: Implications for causal pathways and classification systems.

BACKGROUND: Classification systems in healthcare support shared understanding of conditions for clinical communication, service monitoring and development, and research. Children born with cleft palate with or without cleft lip (CP+/-L) are at high risk of developing cleft-related speech sound disorder (SSD). The way cleft-related SSD is represented and described in SSD classification systems varies. Reflecting on the potential causal pathways for different cleft-related speech features, including the role of speech processing skills, may inform how cleft-related SSD is represented in classification systems. AIM & APPROACH: To explore and reflect on how cleft-related SSD is represented in current SSD classification systems in the context of considering how speech processing skills and other factors may be involved in causal pathways of cleft speech characteristics (CSCs). MAIN CONTRIBUTION: Variation in the representation of cleft-related SSD in classification systems is described. Potential causal pathways for passive cleft- related speech features and different active CSCs are explored. The factors involved in the development and/or persistence of different active CSCs may vary. Some factors may be specific to children born with CP+/-L, but if speech processing skills are also involved, this is an overlap with other SSD subtypes. Current evidence regarding relationships between different speech processing skills and active CSCs is limited. Implications for the representation of cleft-related SSD in SSD classification systems are discussed. CONCLUSION: There are different categories of cleft-related speech features which are essential to understand and identify in children with cleft-related SSD to ensure appropriate management. Representation of these feature categories in classification systems could support understanding of speech in this population. Speech processing skills could be involved in the development and/or persistence of different active CSCs in individual children. Reflection and discussion on how cleft-related SSD is represented in classification systems in relation to other SSD subtypes may inform future iterations of these systems. Further work is needed to understand factors influencing the development and/or persistence of active CSCs, including speech processing skills. WHAT THIS PAPER ADDS: What is already known on the subject Cleft-related speech sound disorder (SSD) is commonly described as being of known origin. The features of cleft-related SSD have been described extensively and several authors have also examined factors which may contribute to speech development and outcomes in children born with cleft palate +/- lip. There is limited evidence regarding the role of speech processing in the development and persistence of cleft-related SSD. What this study adds This paper reflects on how cleft-related SSD is represented in SSD classification systems in relation to key feature categories of cleft-related SSD and possible causal pathways for passive features and active cleft speech characteristics (CSCs). The role of cognitive speech processing skills is specifically considered alongside other factors that may contribute to the development of active CSCs. What are the clinical implications of this work? Causal pathways for different features of cleft-related SSD may vary, particularly between passive and active features, abut also between different active CSCs. Speech and language therapists (SLTs) need to differentially diagnose passive speech features and active CSCs. Consideration of the role of different speech processing skills and interactions with other potentially influencing factors in relation to active CSCs may inform clinical hypotheses and speech and language therapy (SLT) intervention. Representing key features of cleft-related SSD in classification systems may support understanding of cleft-related SSD in relation to other SSD subtypes.

Is association of preterm birth with cognitive-neurophysiological impairments and ADHD symptoms consistent with a causal inference or due to familial confounds?

BACKGROUND: Preterm birth is associated with an increased risk for cognitive-neurophysiological impairments and attention-deficit/hyperactivity disorder (ADHD). Whether the associations are due to the preterm birth insult per se, or due to other risk factors that characterise families with preterm-born children, is largely unknown. METHODS: We employed a within-sibling comparison design, using cognitive-performance and event-related potential (ERP) measures from 104 preterm-born adolescents and 104 of their term-born siblings. Analyses focused on ADHD symptoms and cognitive and ERP measures from a cued continuous performance test, an arrow flanker task and a reaction time task. RESULTS: Within-sibling analyses showed that preterm birth was significantly associated with increased ADHD symptoms (ß = 0.32, p = 0.01, 95% CI 0.05 to 0.58) and specific cognitive-ERP impairments, such as IQ (ß = -0.20, p = 0.02, 95% CI -0.40 to -0.01), preparation-vigilance measures and measures of error processing (ranging from ß = 0.71, -0.35). There was a negligible within-sibling association between preterm birth with executive control measures of inhibition (NoGo-P3, ß = -0.07, p = 0.45, 95% CI -0.33 to 0.15) or verbal working memory (digit span backward, ß = -0.05, p = 0.63, 95% CI -0.30 to 0.18). CONCLUSIONS: Our results suggest that the relationship between preterm birth with ADHD symptoms and specific cognitive-neurophysiological impairments (IQ, preparation-vigilance and error processing) is independent of family-level risk and consistent with a causal inference. In contrast, our results suggest that previously observed associations between preterm birth with executive control processes of inhibition and working memory are instead linked to background characteristics of families with a preterm-born child rather than preterm birth insult per se. These findings suggest that interventions need to target both preterm-birth specific and family-level risk factors.

The impact of social disadvantage in moderate-to-severe chronic kidney disease: an equity-focused systematic review.

It is unclear whether a social gradient in health outcomes exists for people with moderate-to-severe chronic kidney disease (CKD). We critically review the literature for evidence of social gradients in health and investigate the 'suitability' of statistical analyses in the primary studies. In this equity-focused systematic review among adults with moderate-to-severe CKD, factors of disadvantage included gender, race/ethnicity, religion, education, socio-economic status or social capital, occupation and place of residence. Outcomes included access to healthcare, kidney disease progression, cardiovascular events, all-cause mortality and suitability of analyses. Twenty-four studies in the pre-dialysis population and 34 in the dialysis population representing 8.9 million people from 10 countries were included. In methodologically suitable studies among pre-dialysis patients, a significant social gradient was observed in access to healthcare for those with no health insurance and no home ownership. Low income and no home ownership were associated with higher cardiovascular event rates and higher mortality [HR 1.94, 95% confidence interval (CI) 1.27-2.98; HR 1.28, 95% CI 1.04-1.58], respectively. In methodologically suitable studies among dialysis patients, females, ethnic minorities, those with low education, no health insurance, low occupational level or no home ownership were significantly less likely to access cardiovascular healthcare than their more advantaged dialysis counterparts. Low education level and geographic remoteness were associated with higher cardiovascular event rates and higher mortality (HR 1.54, 95% CI 1.01-2.35; HR 1.21, 95% CI 1.08-1.37), respectively. Socially disadvantaged pre-dialysis and dialysis patients experience poorer access to specialist cardiovascular health services, and higher rates of cardiovascular events and mortality than their more advantaged counterparts.

Ambient and at-the-ear occupational noise exposure and serum lipid levels.

OBJECTIVES: Occupational and residential noise exposure has been related to increased risk of cardiovascular disease. Alteration of serum lipid levels has been proposed as a possible causal pathway. The objective of this study was to investigate the relation between ambient and at-the-ear occupational noise exposure and serum levels of total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, and triglycerides when accounting for well-established predictors of lipid levels. METHODS: This cross-sectional study included 424 industrial workers and 84 financial workers to obtain contrast in noise exposure levels. They provided a serum sample and wore portable dosimeters that every 5-s recorded ambient noise exposure levels during a 24-h period. We extracted measurements obtained during work and calculated the full-shift mean ambient noise level. For 331 workers who kept a diary on the use of a hearing protection device (HPD), we subtracted 10 dB from every noise recording obtained during HPD use and estimated the mean full-shift noise exposure level at the ear. RESULTS: Mean ambient noise level was 79.9 dB (A) [range 55.0-98.9] and the mean estimated level at the ear 77.8 dB (A) [range 55.0-94.2]. Ambient and at-the-ear noise levels were strongly associated with increasing levels of triglycerides, cholesterol-HDL ratio, and decreasing levels of HDL-cholesterol, but only in unadjusted analyses that did not account for HPD use and other risk factors. CONCLUSION: No associations between ambient or at-the-ear occupational noise exposure and serum lipid levels were observed. This indicates that a causal pathway between occupational and residential noise exposure and cardiovascular disease does not include alteration of lipid levels.

Annual research review: Rare genotypes and childhood psychopathology--uncovering diverse developmental mechanisms of ADHD risk.

BACKGROUND: Through the increased availability and sophistication of genetic testing, it is now possible to identify causal diagnoses in a growing proportion of children with neurodevelopmental disorders. In addition to developmental delay and intellectual disability, many genetic disorders are associated with high risks of psychopathology, which curtail the wellbeing of affected individuals and their families. Beyond the identification of significant clinical needs, understanding the diverse pathways from rare genetic mutations to cognitive dysfunction and emotional-behavioural disturbance has theoretical and practical utility. METHODS: We overview (based on a strategic search of the literature) the state-of-the-art on causal mechanisms leading to one of the most common childhood behavioural diagnoses - attention deficit hyperactivity disorder (ADHD) - in the context of specific genetic disorders. We focus on new insights emerging from the mapping of causal pathways from identified genetic differences to neuronal biology, brain abnormalities, cognitive processing differences and ultimately behavioural symptoms of ADHD. FINDINGS: First, ADHD research in the context of rare genotypes highlights the complexity of multilevel mechanisms contributing to psychopathology risk. Second, comparisons between genetic disorders associated with similar psychopathology risks can elucidate convergent or distinct mechanisms at each level of analysis, which may inform therapeutic interventions and prognosis. Third, genetic disorders provide an unparalleled opportunity to observe dynamic developmental interactions between neurocognitive risk and behavioural symptoms. Fourth, variation in expression of psychopathology risk within each genetic disorder points to putative moderating and protective factors within the genome and the environment. CONCLUSION: A common imperative emerging within psychopathology research is the need to investigate mechanistically how developmental trajectories converge or diverge between and within genotype-defined groups. Crucially, as genetic predispositions modify interaction dynamics from the outset, longitudinal research is required to understand the multi-level developmental processes that mediate symptom evolution.

Causal mediation analysis with multiple mediators.

In diverse fields of empirical research-including many in the biological sciences-attempts are made to decompose the effect of an exposure on an outcome into its effects via a number of different pathways. For example, we may wish to separate the effect of heavy alcohol consumption on systolic blood pressure (SBP) into effects via body mass index (BMI), via gamma-glutamyl transpeptidase (GGT), and via other pathways. Much progress has been made, mainly due to contributions from the field of causal inference, in understanding the precise nature of statistical estimands that capture such intuitive effects, the assumptions under which they can be identified, and statistical methods for doing so. These contributions have focused almost entirely on settings with a single mediator, or a set of mediators considered en bloc; in many applications, however, researchers attempt a much more ambitious decomposition into numerous path-specific effects through many mediators. In this article, we give counterfactual definitions of such path-specific estimands in settings with multiple mediators, when earlier mediators may affect later ones, showing that there are many ways in which decomposition can be done. We discuss the strong assumptions under which the effects are identified, suggesting a sensitivity analysis approach when a particular subset of the assumptions cannot be justified. These ideas are illustrated using data on alcohol consumption, SBP, BMI, and GGT from the Izhevsk Family Study. We aim to bridge the gap from "single mediator theory" to "multiple mediator practice," highlighting the ambitious nature of this endeavor and giving practical suggestions on how to proceed.

Biomarker- versus drug-driven tumor growth inhibition models: an equivalence analysis.

The mathematical modeling of tumor xenograft experiments following the dosing of antitumor drugs has received much attention in the last decade. Biomarker data can further provide useful insights on the pathological processes and be used for translational purposes in the early clinical development. Therefore, it is of particular interest the development of integrated pharmacokinetic-pharmacodynamic (PK-PD) models encompassing drug, biomarker and tumor-size data. This paper investigates the reciprocal consistency of three types of models: drug-to-tumor, such as established drug-driven tumor growth inhibition (TGI) models, drug-to-biomarker, e.g. indirect response models, and biomarker-to-tumor, e.g. the more recent biomarker-driven TGI models. In particular, this paper derives a mathematical relationship that guarantees the steady-state equivalence of the cascade of drug-to-biomarker and biomarker-to-tumor models with a drug-to-tumor TGI model. Using the Simeoni TGI model as a reference, conditions for steady-state equivalence are worked out and used to derive a new biomarker-driven model. Simulated and real data are used to show that in realistic cases the steady-state equivalence extends also to transient responses. The possibility of predicting the drug-to-tumor potency of a new candidate drug based only on biomarker response is discussed.

Evaluating Research for Development: Innovation to Navigate Complexity.

Large publicly funded programmes of research continue to receive increased investment as interventions aiming to produce impact for the world's poorest and most marginalized populations. At this intersection of research and development, research is expected to contribute to complex processes of societal change. Embracing a co-produced view of impact as emerging along uncertain causal pathways often without predefined outcomes calls for innovation in the use of complexity-aware approaches to evaluation. The papers in this special issue present rich experiences of authors working across sectors and geographies, employing methodological innovation and navigating power as they reconcile tensions. They illustrate the challenges with (i) evaluating performance to meet accountability demands while fostering learning for adaptation; (ii) evaluating prospective theories of change while capturing emergent change; (iii) evaluating internal relational dimensions while measuring external development outcomes; (iv) evaluating across scales: from measuring local level end impact to understanding contributions to systems level change. Taken as a whole, the issue illustrates how the research for development evaluation field is maturing through the experiences of a growing and diverse group of researchers and evaluators as they shift from using narrow accountability instruments to appreciating emergent causal pathways within research for development.

Les grands programmes de recherche financés par des fonds publics continuent de recevoir des investissements accrus en tant qu'interventions visant à produire un impact pour les populations les plus pauvres et les plus marginalisées dans le monde. À cette intersection entre la recherche et le développement, la recherche devrait contribuer aux processus complexes de changement sociétal. Pour adopter une vision coconstruite de l'impact comme phénomène émergeant au fil de liens de causalité incertains, bien souvent sans résultats prédéfinis, il faut innover en utilisant des approches d'évaluation sensibles à la complexité. Les articles de ce numéro spécial présentent de riches expériences d'auteurs travaillant dans différents secteurs et zones géographiques, employant l'innovation méthodologique et le pouvoir de navigation tout en réconciliant les tensions. Ils illustrent les défis lorsqu'il s'agit (i) d'évaluer des performances pour répondre aux exigences de redevabilité tout en favorisant l'apprentissage pour l'adaptation; (ii) d'évaluer les théories prospectives du changement tout en saisissant le changement émergent; (iii) d'évaluer les dimensions relationnelles internes tout en mesurant les résultats de développement externes; (iv) d'évaluer à différentes échelles: de la mesure de l'impact final au niveau local à la compréhension des contributions au changement au niveau des systèmes. Pris dans son ensemble, ce numéro illustre la façon dont l'évaluation de la recherche pour le développement mûrit à travers les expériences d'un groupe toujours plus important et divers de chercheurs et d'évaluateurs qui abandonnent des outils de redevabilité étriqués afin d'apprécier les liens de causalité émergents au sein de la recherche pour le développement.

Occupational and environmental noise exposure during pregnancy and rare health outcomes of offspring: a scoping review focusing on congenital anomalies and perinatal mortality.

As environmental and occupational noise can be health hazards, recent studies have investigated the effects of noise exposure during pregnancy. Despite biological plausibility and animal studies supporting an association, studies focusing on congenital anomalies and perinatal mortality as outcomes of noise exposure are still scarce. We performed a scoping review to collect, summarise, and discuss the existing scientific research about the relationships between noise exposure during pregnancy and congenital anomalies and/or perinatal mortality. We searched electronic databases for papers published between 1970 and March 2021. We included 16 studies (seven on congenital anomalies, three on perinatal mortality, and two on both congenital anomalies and perinatal mortality). We assessed four studies on congenital hearing dysfunction as the definition of congenital anomalies includes functional anomalies. We found few studies on this topic and no studies on the combined effects of occupational and environmental noise exposures. Evidence suggests a small increase in the risk of congenital anomalies in relation to occupational and to a lesser extent environmental noise exposure. In addition, few studies investigated perinatal mortality and the ones that did, used different outcome definitions, so no conclusions could be made. However, a recent big cross-sectional study demonstrated an association between road traffic noise and stillbirth. A few studies suggest a possible association between congenital hearing dysfunction and occupational noise exposure during pregnancy. Future studies with larger samples, better exposure assessments, and better statistical modelling strategies are needed to investigate these relationships further.

Instrumental variables for implementation science: exploring context-dependent causal pathways between implementation strategies and evidence-based interventions.

BACKGROUND: The impact of both implementation strategies (IS) and evidence-based interventions (EBI) can vary across contexts, and a better understanding of how and why this occurs presents fundamental but challenging questions that implementation science as a field will need to grapple with. We use causal epidemiologic methods to explore the mechanisms of why sharp distinctions between implementation strategies (IS) and efficacy of an evidence-based intervention (EBI) may fail to recognize that the effect of an EBI can be deeply intertwined and dependent on the context of the IS leading to its uptake. METHODS: We explore the use of instrumental variable (IV) analyses as a critical tool for implementation science methods to isolate three relevant quantities within the same intervention context when exposure to an implementation strategy is random: (1) the effect of an IS on implementation outcomes (e.g., uptake), (2) effect of EBI uptake on patient outcomes, and (3) overall effectiveness of the IS (i.e., ~ implementation*efficacy). We discuss the mechanisms by which an implementation strategy can alter the context, and therefore effect, of an EBI using the underlying IV assumptions. We illustrate these concepts using examples of the implementation of new ART initiation guidelines in Zambia and community-based masking programs in Bangladesh. RESULTS: Causal questions relevant to implementation science are answered at each stage of an IV analysis. The first stage assesses the effect of the IS (e.g., new guidelines) on EBI uptake (e.g., same-day treatment initiation). The second stage leverages the IS as an IV to estimate the complier average causal effect (CACE) of the EBI on patient outcomes (e.g., effect of same-day treatment initiation on viral suppression). The underlying assumptions of CACE formalize that the causal effect of EBI may differ in the context of a different IS because (1) the mechanisms by which individuals uptake an intervention may differ and (2) the subgroup of individuals who take up an EBI may differ. IV methods thus provide a conceptual framework for how IS and EBIs are linked and that the IS itself needs to be considered a critical contextual determinant. Moreover, it also provides rigorous methodologic tools to isolate the effect of an IS, EBI, and combined effect of the IS and EBI. DISCUSSION: Leveraging IV methods when exposure to an implementation strategy is random helps to conceptualize the context-dependent nature of implementation strategies, EBIs, and patient outcomes. IV methods formalize that the causal effect of an EBI may be specific to the context of the implementation strategy used to promote uptake. This integration of implementation science concepts and theory with rigorous causal epidemiologic methods yields novel insights and provides important tools for exploring the next generation of questions related to mechanisms and context in implementation science.

Risk and protective factors for children's psychopathology in the context of domestic violence - A study using nationally representative longitudinal survey data.

BACKGROUND: Little is known about the causal pathways through which domestic violence affects children's internalising, externalising and prosocial behaviours over time, and the role that risk and protective factors play in mediating and moderating direct effects. OBJECTIVE: We explored how different risk and protective factors affect children's psychopathology in the context of domestic violence. We focused on the mother and child bond and explored if this moderates or mediates the effect of domestic violence on children's internalising, externalising and prosocial behaviours. PARTICIPANTS AND SETTING: A prospective longitudinal nationally representative study of children in Scotland aged 6 to 13 years (N:2554). METHODS: Multivariate logit models, moderation and mediation analysis. RESULTS: Domestic violence exposure predicted higher internalising and externalising behaviours and lower prosocial skills (e.g. OR2.17, 95%CI 1.15-4.08 for externalising symptoms). Children with a strong mother-child bond had lower odds of internalising and externalising symptoms, and were more likely to manifest prosocial skills (OR4.14, 95%CI 3.09-5.55). We found evidence that the mother-child relationship both moderated and mediated the effect that domestic violence exposure had on children's internalising, externalising and prosocial scores. The mediation effect was strongest for prosocial behaviours, and strongest in cases where the abuse was less intense. CONCLUSIONS: We show how domestic violence directly and indirectly affects children, via the mother-child relationship. We propose a model which could explain how the mother-child bond both mediates and moderates the effect of domestic violence on children's psychopathology. Our findings suggest mothers need support to in turn support children in the context of domestic violence.

Inter-relationships of risk factors and pathways associated with all-cause mortality in patients with chronic schizophrenia.

Introduction: Of all psychiatric disorders, schizophrenia is associated with the highest risk of all-cause mortality. This study aimed to investigate independent risk factors for all-cause mortality in patients with chronic schizophrenia. In addition, the possible causal inter-relationships among these independent risk factors and all-cause mortality were also explored. Methods: We conducted an analysis of 1,126 patients with chronic schizophrenia from our psychiatric department from April 2003 to August 2022, and retrospectively reviewed their medical records. The study endpoint was all-cause mortality. Baseline clinical characteristics including sociodemographic data, biochemical data, lifestyle factors, comorbidities and antipsychotic treatment were examined with Cox proportional hazards analysis. Results: The all-cause mortality rate was 3.9% (44 patients). Multivariate Cox regression analysis revealed that several factors were independently associated with all-cause mortality, including diabetes mellitus (DM), hypertension, heart failure, gastroesophageal reflux disease (GERD), peptic ulcer disease, ileus, underweight, fasting glucose, triglycerides, albumin, and hemoglobin. Structural equation modeling (SEM) analysis revealed that several factors had statistically significant direct effects on all-cause mortality. Heart failure, hypertension, underweight, age at onset, and ileus showed positive direct effects, while albumin and hemoglobin demonstrated negative direct effects. In addition, several factors had indirect effects on all-cause mortality. GERD indirectly affected all-cause mortality through ileus, and peptic ulcer disease had indirect effects through albumin and ileus. Ileus, underweight, DM, and hypertension also exhibited indirect effects through various pathways involving albumin, hemoglobin, and heart failure. Overall, the final model, which included these factors, explained 13% of the variability in all-cause mortality. Discussion: These results collectively suggest that the presence of DM, hypertension, heart failure, GERD, peptic ulcer disease, ileus, and underweight, along with lower levels of albumin or hemoglobin, were independently associated with all-cause mortality. The SEM analysis further revealed potential causal pathways and inter-relationships among these risk factors contributing to all-cause mortality in patients with chronic schizophrenia.

Developing an implementation research logic model: using a multiple case study design to establish a worked exemplar.

BACKGROUND: Implementation science frameworks explore, interpret, and evaluate different components of the implementation process. By using a program logic approach, implementation frameworks with different purposes can be combined to detail complex interactions. The Implementation Research Logic Model (IRLM) facilitates the development of causal pathways and mechanisms that enable implementation. Critical elements of the IRLM vary across different study designs, and its applicability to synthesizing findings across settings is also under-explored. The dual purpose of this study is to develop an IRLM from an implementation research study that used case study methodology and to demonstrate the utility of the IRLM to synthesize findings across case sites. METHOD: The method used in the exemplar project and the alignment of the IRLM to case study methodology are described. Cases were purposely selected using replication logic and represent organizations that have embedded exercise in routine care for people with cancer or mental illness. Four data sources were selected: semi-structured interviews with purposely selected staff, organizational document review, observations, and a survey using the Program Sustainability Assessment Tool (PSAT). Framework analysis was used, and an IRLM was produced at each case site. Similar elements within the individual IRLM were identified, extracted, and re-produced to synthesize findings across sites and represent the generalized, cross-case findings. RESULTS: The IRLM was embedded within multiple stages of the study, including data collection, analysis, and reporting transparency. Between 33-44 determinants and 36-44 implementation strategies were identified at sites that informed individual IRLMs. An example of generalized findings describing "intervention adaptability" demonstrated similarities in determinant detail and mechanisms of implementation strategies across sites. However, different strategies were applied to address similar determinants. Dependent and bi-directional relationships operated along the causal pathway that influenced implementation outcomes. CONCLUSIONS: Case study methods help address implementation research priorities, including developing causal pathways and mechanisms. Embedding the IRLM within the case study approach provided structure and added to the transparency and replicability of the study. Identifying the similar elements across sites helped synthesize findings and give a general explanation of the implementation process. Detailing the methods provides an example for replication that can build generalizable knowledge in implementation research.

Modern slavery and labor exploitation during the COVID-19 pandemic: a conceptual model.

BACKGROUND: Modern slavery is a complex global health problem that includes forced labor exploitation. An ecological systems perspective is needed to understand how contextual upstream and midstream factors contribute to labor exploitation, and how disruptive societal challenges, such as infectious disease pandemics, may exacerbate established pathways leading to exploitation. Accumulation of familial and societal risk factors likely heightens vulnerability; for instance, economic precarity for an individual interacts with poor livelihood options and lack of social welfare supports increasing their likelihood of accepting exploitative labor. However, few frameworks exist that account for the accumulation of and interdependence between risk factors at different levels and across contexts. OBJECTIVE: Using an ecological systems framework, we review literature on the pathways leading to labor exploitation, with the aim of developing a conceptual model grounded in existing research. Next, we discuss how pathways in this conceptual model are likely exacerbated by the COVID-19 pandemic. This conceptual model can guide future research to detect modifiable factors and strategic points of intervention. METHODS: A critical review of research articles and gray literature was performed with a primary focus on sub-Saharan Africa. The review utilized various scholarly databases to identify perspectives from multiple disciplines and to more fully account for complex processes linked to labor exploitation. RESULTS: A conceptual model of these pathways was developed that emphasizes established determinants and risk factors for labor exploitation in sub-Saharan Africa. The model highlights how the COVID-19 pandemic may have exacerbated these pathways. CONCLUSIONS: Future studies should carefully examine the direct and indirect pathways, accumulation of and interactions between factors, and specific external and personal stressors. Interdisciplinary research on multilevel interventions is needed to guide solutions to prevent the persistent problem of labor exploitation.

Social causation or social selection? The longitudinal interrelationship between poverty and depressive symptoms in China.

RATIONALE: To our knowledge, no prior studies have investigated these bidirectional pathways between poverty and depressive symptoms to identify potential mechanisms. OBJECTIVE: This study aimed to investigate the interrelationship between poverty and depressive symptoms by examining two causal theories: social causation, which claims that the condition of poverty causes mental health disorders, and social selection, which suggests that those with poor mental health are more likely to drift into poverty. METHOD: We obtained data from 17,250 adults aged 45 years or above from the China Health and Retirement Longitudinal Studies, first conducted in 2011-2012. Participants were tracked for 4 years, with baseline measurements taken as well as two 2-year follow-up visits. Structural equation models were used to examine the pathways in two directions at baseline, 2-year follow-up and 4-year follow-up. RESULTS: We found significant total effects and indirect effects of poverty on depressive symptoms at baseline, which were mediated through deterioration of household living conditions, decrease in social participation, and decline in life satisfaction. In the opposite direction, depressive symptoms directly led individuals to drift into poverty at baseline and at follow-up. CONCLUSIONS: This study suggested that social causation and social selection may operate concurrently. Proactive interventions, especially ones focusing on modifiable protective factors that our findings identified as mediators in the link between poverty and depression, are urgently needed to break the vicious cycle of poverty and depression and create a virtuous cycle of increasing returns.