A Causal Mediation Approach to Account for Interaction of Treatment and Intercurrent Events: Using Hypothetical Strategy.

Hypothetical strategy is a common strategy for handling intercurrent events (IEs). No current guideline or study considers treatment-IE interaction to target the estimand in any one IE-handling strategy. Based on the hypothetical strategy, we aimed to (1) assess the performance of three estimators with different considerations for the treatment-IE interaction in a simulation and (2) compare the estimation of these estimators in a real trial. Simulation data were generalized based on realistic clinical trials of Alzheimer's disease. The estimand of interest was the effect of treatment with no IE occurring under the hypothetical strategy. Three estimators, namely, G-estimation with and without interaction and IE-ignored estimation, were compared in scenarios where the treatment-IE interaction effect was set as -50% to 50% of the main effect. Bias was the key performance measure. The real case was derived from a randomized trial of methadone maintenance treatment. Only G-estimation with interaction exhibited unbiased estimations regardless of the existence, direction or magnitude of the treatment-IE interaction in those scenarios. Neglecting the interaction and ignoring the IE would introduce a bias as large as 0.093 and 0.241 (true value, -1.561) if the interaction effect existed. In the real case, compared with G-estimation with interaction, G-estimation without interaction and IE-ignored estimation increased the estimand of interest by 33.55% and 34.36%, respectively. This study highlights the importance of considering treatment-IE interaction in the estimand framework. In practice, it would be better to include the interaction in the estimator by default.

A unified web cloud computing platform MiMedSurv for microbiome causal mediation analysis with survival responses.

In human microbiome studies, mediation analysis has recently been spotlighted as a practical and powerful analytic tool to survey the causal roles of the microbiome as a mediator to explain the observed relationships between a medical treatment/environmental exposure and a human disease. We also note that, in a clinical research, investigators often trace disease progression sequentially in time; as such, time-to-event (e.g., time-to-disease, time-to-cure) responses, known as survival responses, are prevalent as a surrogate variable for human health or disease. In this paper, we introduce a web cloud computing platform, named as microbiome mediation analysis with survival responses (MiMedSurv), for comprehensive microbiome mediation analysis with survival responses on user-friendly web environments. MiMedSurv is an extension of our prior web cloud computing platform, named as microbiome mediation analysis (MiMed), for survival responses. The two main features that are well-distinguished are as follows. First, MiMedSurv conducts some baseline exploratory non-mediational survival analysis, not involving microbiome, to survey the disparity in survival response between medical treatments/environmental exposures. Then, MiMedSurv identifies the mediating roles of the microbiome in various aspects: (i) as a microbial ecosystem using ecological indices (e.g., alpha and beta diversity indices) and (ii) as individual microbial taxa in various hierarchies (e.g., phyla, classes, orders, families, genera, species). To illustrate its use, we survey the mediating roles of the gut microbiome between antibiotic treatment and time-to-type 1 diabetes. MiMedSurv is freely available on our web server ( http://mimedsurv.micloud.kr ).

Dexmedetomidine administration is associated with improved outcomes in critically ill patients with acute myocardial infarction partly through its anti-inflammatory activity.

Background: Dexmedetomidine (DEX) is a commonly used sedative in the intensive care unit and has demonstrated cardioprotective properties against ischemia-reperfusion injury in preclinical studies. However, the protective effects of early treatment of DEX in patients with acute myocardial infarction (AMI) and its underlying mechanism are still not fully understood. This study aims to investigate the association between early DEX treatment and in-hospital mortality in patients with AMI, and to explore the potential mediating role of white blood cell (WBC) reduction in this relationship. Methods: A retrospective cohort analysis was conducted using the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Patients with AMI were divided into the DEX and non-DEX group, based on whether they received DEX treatment in the early stage of hospitalization. The primary outcome measured was in-hospital mortality. The study evaluated the association between DEX use and in-hospital mortality using the Kaplan-Meier (KM) method and Cox proportional hazards model. Additionally, 1:1 propensity score matching (PSM) was conducted to validate the results. Furthermore, causal mediation analysis (CMA) was utilized to explore potential causal pathways mediated by WBC reduction between early DEX use and the primary outcome. Results: This study analyzed data from 2,781 patients, with 355 in the DEX group and 2,426 in the non-DEX group. KM survival analysis revealed a significantly lower in-hospital mortality rate in the DEX group compared to the non-DEX group. After adjusting for multiple confounding factors, the Cox regression model demonstrated a significant positive impact of DEX on the risk of in-hospital mortality in patients with AMI, with hazard ratios (HR) of 0.50 (95% confidence interval (CI): 0.35-0.71, p < 0.0001). PSM analysis confirmed these results, showing HR of 0.49 (95% CI: 0.31-0.77, p = 0.0022). Additionally, CMA indicated that 13.7% (95% CI: 1.8%-46.9%, p = 0.022) of the beneficial effect of DEX on reducing in-hospital mortality in patients with AMI was mediated by the reduction in WBC. Conclusion: The treatment of DEX was associated with a lower risk of in-hospital mortality in patients with AMI, potentially due to its anti-inflammatory properties.

Prevention of Heart Failure in Hypertension-the Role of Coronary Heart Disease Events Treated With Versus Without Revascularization: The ALLHAT Study.

In modern clinical practice, less than half of patients with new-onset heart failure (HF) undergo ischemic evaluation and only a minority undergo revascularization. We aimed to assess the proportion of the effect of hypertension (antihypertensive treatment) on incident HF to be eliminated by prevention of coronary heart disease (CHD) event treated with or without revascularization, considering possible treatment-mediator interaction. The causal mediation analysis of Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) included 42,418 participants (age 66.9 ± 7.7, 35.6% black, 53.2% men). A new CHD event (myocardial infarction or angina) that occurred after randomization but before the incident HF outcome was the mediator. Incident symptomatic congestive HF (CHF) and hospitalized/fatal HF (HHF) were the primary and secondary outcomes, respectively. Logistic regression (for mediator) and Cox proportional hazards regression (for outcome) were adjusted for demographics, cardiovascular disease history, and risk factors. During a median 4.5-year follow-up, 2,785 patients developed CHF, including 2,216 HHF events. Participants who developed CHD events had twice the higher incidence rate of CHF than CHD-free (28.5 vs 13.9 events/1,000 person-years). The proportion of reference interaction indicating direct harm because of a CHD event for lisinopril (234% for CHF, 355% for HHF) and amlodipine (244% for CHF, 468% for HHF) was greater than for chlortalidone (143% for CHF, 269% for HHF). In patients with revascularized CHD events, chlortalidone and amlodipine eliminated 21% to 24% and lisinopril eliminated -45% of HHF. Antihypertensive treatment could not eliminate harm from CHD events treated without revascularization. In conclusion, the antihypertensive drugs (chlortalidone, lisinopril, and amlodipine) prevent HF not principally by preventing CHD events but by way of other pathways. HF is moderated but not mediated by CHD events. Revascularization of CHD events is paramount for HF prevention.

Co-residence with children as a mediator between widowhood and loneliness in older adults.

BACKGROUND: Loneliness in older adults, exacerbated by widowhood, is a significant public health concern. While widowhood can lead to changes in living arrangements, its impact on loneliness may vary across cultural contexts. In Western societies, widowhood often results in older adults living alone, which can intensify feelings of loneliness. However, in China, the cultural norm of filial piety and multigenerational households may lead to different outcomes. As few studies have explored this connection over time, this research seeks to bridge this gap using data from older Chinese adults. METHODS: Using 16 years of data from the Chinese Longitudinal Healthy Longevity Survey, which covers 21,986 individuals aged 65-104 years, we conducted causal mediation analysis to test if changes in living arrangements (i.e., living alone versus with children) serve as a mediator between widowhood and loneliness. The potential variation in this mediation effect by gender and age was also evaluated. RESULTS: Spousal loss was associated with an increase in loneliness. However, living with adult children post-loss reduced this emotional strain compared to living alone. The mediating influence of living arrangements was notably stronger for women than men and intensified with age in long term. In the short term, the mediating impact of living arrangements is significantly greater, particularly for older adults under 80 years old. CONCLUSION: Alterations in living arrangements play a pivotal role in mediating the effects of widowhood on loneliness among China's older adults. Encouraging co-residence with adult children post-spousal loss, especially for older women and the eldest age groups, might mitigate social isolation. These insights both deepen our theoretical understanding and suggest interventions to enhance the well-being of widowed older adults.

Causal Effects of Competing Obstetrical Interventions: Mediators of Placental Abruption and Perinatal Mortality.

Placental abruption, the premature placental separation, confers increased perinatal mortality risk with preterm delivery as an important pathway through which the risk appears mediated. While pregnancies complicated by abruption are often delivered through an obstetrical intervention, many deliver spontaneously. We examined the contributions of clinician-initiated (PTDIND) and spontaneous (PTDSPT) preterm delivery at <37 weeks as competing causal mediators of the abruption-perinatal mortality association. Using the Consortium for Safe Labor (2002-2008) data (n = 203,990; 1.6% with abruption), we applied a potential outcomes-based mediation analysis to decompose the total effect into direct and mediator-specific indirect effects through PTDIND and PTDSPT. Each mediated effect describes the reduction in the counterfactual mortality risk if that preterm delivery subtype was shifted from its distribution under abruption to without abruption. The total effect risk ratio (RR) of abruption on perinatal mortality was 5.4 (95% confidence interval [CI] 4.6, 6.3). The indirect effect RRs for PTDIND and PTDSPT were 1.5 (95% CI: 1.4, 1.6) and 1.5 (95% CI: 1.5, 1.6), respectively; these corresponded to mediated proportions of 25% each. These findings underscore that spontaneous and clinician-initiated preterm deliveries each play essential roles in shaping perinatal mortality risks associated with placental abruption.

The association between rs6859 in NECTIN2 gene and Alzheimer's disease is partly mediated by pTau.

Introduction: Emerging evidence suggests a connection between vulnerability to infections and Alzheimer's disease (AD). The nectin cell adhesion molecule 2 (NECTIN2) gene coding for a membrane component of adherens junctions is involved in response to infections, and its single nucleotide polymorphism (SNP) rs6859 was significantly associated with AD risk in several human cohorts. It is unclear, however, how exactly rs6859 influences the development of AD pathology. The aggregation of hyperphosphorylated tau protein (pTau) is a key pathological feature of neurodegeneration in AD, which may be induced by infections, among other factors, and potentially influenced by genes involved in both AD and vulnerability to infections, such as NECTIN2. Materials and methods: We conducted a causal mediation analysis (CMA) on a sample of 708 participants in the Alzheimer's disease Neuroimaging Initiative (ADNI). The relationship between rs6859 and Alzheimer's disease (AD), with AD (yes/no) as the outcome and pTau-181 levels in the cerebrospinal fluid (CSF) acting as a mediator in this association, was assessed. Adjusted estimates from the probit and linear regression models were used in the CMA model, where an additive model considered an increase in dosage of the rs6859 A allele (AD risk factor). Results: The increase in dose of allele A of the SNP rs6859 resulted in about 0.144 increase per standard deviation (SD) of pTau-181 (95% CI: 0.041, 0.248, p < 0.01). When included together in the probit model, the change in A allele dose and each standard deviation change in pTau-181 predicted 6.84% and 9.79% higher probabilities for AD, respectively. In the CMA, the proportion of the average mediated effect was 17.05% and was higher for the risk allele homozygotes (AA), at 19.40% (95% CI: 6.20%, 43.00%, p < 0.01). The sensitivity analysis confirmed the evidence of a robust mediation effect. Conclusion: This study reported a new potential causal relationship between pTau-181 and AD. We found that the association between rs6859 in the NECTIN2 gene and AD is partly mediated by pTau-181 levels in CSF. The rest of this association may be mediated by other factors. Our finding sheds light on the complex interplay between genetic susceptibility, protein aggregation, and neurodegeneration in AD. Further research, using other biomarkers, is needed to uncover the remaining mechanisms of the association between the NECTIN2 gene and AD.

GFR decline predicts total mortality and mediates the effect of tryptophan metabolism on death risk in type 2 diabetes.

CONTEXT: The independent role of glomerular filtration rate (GFR) decline in shaping the risk of mortality in people with type 2 diabetes has only been partially addressed. OBJECTIVE: The objective of the study was twofold: i) to investigate the association between all-cause mortality and eGFR changes over time; ii) to understand whether renal dysfunction mediates the effect of tryptophan metabolism on death risk. DESIGN: Prospective study with an average follow-up of 14.8 years. SETTING: Research Hospital. PATIENTS: The aggregate Gargano Mortality Study included 962 patients with type 2 diabetes who had at least three eGFR recordings and at least 1.5 years of follow-up. INTERVENTIONS: This was an observational study, with no intervention. MAIN OUTCOME MEASURES: Rate of all-cause mortality. RESULTS: Age and sex adjusted annual incident rate of mortality was 2.75 events per 100 person-years. The median annual rate of decline of eGFR was 1.3 ml/min per 1.73 m2 per year (range -3.7; 7.8). The decline of kidney function was strongly and independently associated with the risk of death. Serum kynurenine-to-tryptophan ratio (KTR) was associated with both eGFR decline and all-cause mortality. Causal mediation analysis showed that 24.3% of the association between KTR and mortality was mediated by eGFR decline. CONCLUSIONS: In patients with type 2 diabetes, eGFR decline is independently associated with the risk of all-cause mortality and mediates a significant proportion of the association between tryptophan metabolism and death.

The Effect of Sodium Glucose Cotransporter-2 Inhibitors on Hemoglobin A1c Variability and Acute Kidney Injury: A Causal Mediation Analysis.

PURPOSE: The role of lower hemoglobin A1c (HbA1c) variability in the effect of sodium glucose cotransporter-2 inhibitors (SGLT2i) on acute kidney injury (AKI) remains unclear. We compared AKI risk between SGLT2i and dipeptidyl peptidase 4 inhibitors (DPP4i) initiators. Additionally, we aimed to explore the extent to which SGLT2i's influence on AKI risk is mediated by reducing long-term HbA1c variability. METHODS: Using 2018-2022 year data in Yinzhou Regional Health Care Database, we included adult, type 2 diabetes patients who were new users of SGLT2i or DPP4i. The effect of SGLT2i versus DPP4i on AKI, HbA1c variability, and AKI through HbA1c variability was compared using inverse probability of treatment weighted Cox proportional hazards models, median regression models, and causal mediation analysis. RESULTS: With a median follow-up of 1.76 years, 19 717 adults (for SGLT2i, n = 6008; for DPP4i, n = 13 709) with type 2 diabetes were included. The adjusted hazard ratio for SGLT2i versus DPP4i was 0.79 (95% confidence interval [CI] 0.64-0.98) for AKI. The adjusted differences in median HbA1c variability score (HVS) and HbA1c reduction were -16.67% (95% CI: -27.71% to -5.62%) and -1.98% (95% CI: -14.34% to 10.38%), respectively. Furthermore, lower AKI risk associated with SGLT2i was moderately mediated (22.77%) through HVS. The results remained consistent across various subgroups and sensitivity analyses. CONCLUSIONS: Compared to DPP4i, lower AKI risk associated with SGLT2i is moderately mediated through HbA1c variability. These findings enhance our understanding of the effect of SGLT2i on AKI and underscore the importance of considering HbA1c variability in diabetes treatment and management.

Prognostic implications of thyroid hormones in acute aortic dissection: mediating roles of renal function and coagulation.

Background: Thyroid hormones significantly influence cardiovascular pathophysiology, yet their prognostic role in acute aortic dissection (AAD) remains inadequately explored. This study assesses the prognostic value of thyroid hormone levels in AAD, focusing on the mediating roles of renal function and coagulation. Methods: We included 964 AAD patients in this retrospective cohort study. Utilizing logistic regression, restricted cubic splines, and causal mediation analysis, we investigated the association between thyroid hormones and in-hospital mortality and major adverse cardiovascular events (MACEs). Results: In AAD patients overall, an increase of one standard deviation in FT4 levels was associated with a 31.9% increased risk of MACEs (OR 1.319; 95% CI 1.098-1.584) and a 36.1% increase in in-hospital mortality (OR 1.361; 95% CI 1.095-1.690). Conversely, a higher FT3/FT4 ratio was correlated with a 20.2% reduction in risk of MACEs (OR 0.798; 95% CI 0.637-0.999). This correlation was statistically significant predominantly in Type A AAD, while it did not hold statistical significance in Type B AAD. Key renal and coagulation biomarkers, including blood urea nitrogen, creatinine, cystatin C, prothrombin time ratio, prothrombin time, and prothrombin time international normalized ratio, were identified as significant mediators in the interplay between thyroid hormones and MACEs. The FT3/FT4 ratio exerted its prognostic influence primarily through the mediation of renal functions and coagulation, while FT4 levels predominantly impacted outcomes via a partial mediation effect on coagulation. Conclusion: FT4 levels and the FT3/FT4 ratio are crucial prognostic biomarkers in AAD patients. Renal function and coagulation mediate the association between the thyroid hormones and MACEs.

Gut Microbiome-Driven metabolites influence skin pigmentation in TYRP1 mutant Oujiang Color Common Carp.

The gut microbiome plays a key role in regulating the gut-skin axis, and host genetics partially influence this regulation. The study investigated the role of gut microbiota and host genetics in the gut-skin axis, focusing on the unusual "coffee-like" color phenotype observed in TYRP1 mutant Oujiang Color Common Carp. We employed comparative high-throughput omics data from wild-type and mutant fish to quantify the influence of both genetics and gut microbes on skin transcriptomic expression and blood metabolites. We found 525 differential metabolites (DMs) and 45 distinct gut microbial genera in TYRP1 mutant fish compared to wild type. Interaction and causal mediation analyses revealed a complex interplay. The TYRP1 mutation likely triggers an inflammatory pathway involving Acinetobacter bacteria, Leukotrience-C4 and Spermine. This inflammatory response appears to be counterbalanced by an anti-inflammatory cardiovascular genetic network. The net effect is the upregulation of COMT, PLG, C2, C3, F10, TDO2, MHC1, and SERPINF2, leading to unusual coffee-like coloration. This study highlights the intricate interplay between gut microbiota, host genetics, and metabolic pathways in shaping complex phenotypes.

Elevated maternal serum bile acids level, hypertensive disorders of pregnancy and adverse fetal outcomes: a cohort study of 117,789 pregnant women in China.

BACKGROUND: Elevated maternal serum total bile acids (sTBA) level during pregnancy was associated with adverse fetal outcomes. Women with elevated sTBA could complicate with hepatic dysfunction or vascular disorders (hypertensive disorders of pregnancy, HDP), which aggravated adverse fetal outcomes. However, the relationships among sTBA level, hepatic dysfunction, HDP and adverse fetal outcomes were still illusive. OBJECTIVE: We aimed to explore whether hepatic dysfunction or vascular disorders (HDP) mediated the associations between elevated sTBA level and adverse fetal outcomes. METHODS: A large retrospective cohort study encompassing 117,789 Chinese pregnant women with singleton delivery between Jan 2014 and Dec 2022 was conducted. Causal mediation analysis was applied to assess the mediating role of hepatic dysfunction (alanine transaminase > 40 U/L) or HDP in explaining the relationship between high maternal sTBA level (≥10 µmol/L) and adverse fetal outcomes, including low birth weight (LBW), small for gestational age (SGA), and preterm birth (PTB). RESULTS: sTBA level were positively associated with LBW (adjusted odds ratio (aOR) = 1.40; [95 % confidence interval (CI): 1.24-1.59]), SGA (aOR=1.31; [95 % CI: 1.18-1.46]), and PTB (aOR=1.27; [95 % CI: 1.15-1.41]), respectively. The estimated proportions of the total associations mediated by HDP were 47 % [95 % CI: 31 %-63 %] for LBW, 24 % [95 % CI: 13 %-35 %] for SGA, and 34 % [95 % CI: 19 %-49 %] for PTB, excepting the direct effects of high sTBA level. The contribution of hepatic dysfunction as a mediator was weaker on the association between high sTBA level on fetal outcomes, as the proportions mediated and 95 % CI were 16 % [4 %-29 %], 4 % [-6%-14 %], 32 % [15 %-50 %] for LBW, SGA, and PTB, respectively. Moreover, the mediating effect of hepatic dysfunction was nearly eliminated after excluding cases of HDP in the sensitivity analysis. CONCLUSIONS: The substantial mediating effects through HDP highlighted its significant role in adverse fetal outcomes associated with elevated sTBA level. The findings also provoked new insights into understanding the mechanism and developing clinical management strategies (i.e. vascular protection) for adverse fetal outcomes associated with elevated sTBA level.

Decomposition analysis to assess intervention strategies for reducing health-related exposure disparities in Michigan public drinking water systems.

OBJECTIVE: Contamination in U.S. public drinking water systems (PWS) is estimated to cause millions of illnesses and billions of dollars in medical expenditures annually. Few prior studies have explored intervention strategies, including environmental enforcement, to reduce estimated health-related exposure disparities (exposure disparity) in PWS, which are driven partially by socioeconomic status (SES), racism, and PWS characteristics. METHOD: This study used a longitudinal measurement method to estimate the annual health-related exposure level (health level) of each PWS in Michigan, based on data from the Enforcement and Compliance Online (ECHO) and U.S. Census Bureau databases. Using a decomposition model with four strategies, we analyzed how eliminating disparities in SES, proportion minority, environmental enforcement, and PWS characteristics across communities would affect adjusted exposure disparities. RESULTS: This study found that adjusted race- and poverty-based exposure disparities have existed since the 1980s but might have decreased in the last one or two decades. PWS characteristics strongly impacted the crude and adjusted exposure disparity. Environmental enforcement, although less effective in minority-concentrated communities, reduced the adjusted race-based exposure disparity by 10%-20% in the 1980s, 8% in the 1990s, and 0.012% in the 2010s. Equalizing the poverty rate distribution reduced the adjusted race-based exposure disparity by 0.72% in the 1980s and 6.8% in the 2010s. However, equalizing racial and ethnic composition distribution increased the adjusted poverty-based exposure disparity in the 2000s. CONCLUSION: These findings indicate that economically disadvantaged or minority-concentrated communities in Michigan disproportionately suffer from poorer PWS quality. Enhanced environmental enforcement, increased household income, PWS investment, and other actions are needed to address these exposure disparities effectively.

Delirium Mediated the Association Between a History of Falls and Short-Term Mortality Risk in Critically Ill Ischemic Stroke Patients.

Patients with ischemic stroke have an increased propensity to fall, resulting in significant physical and psychological distress. This study examined the association between falls in the 3 months prior to intensive care unit (ICU) admission and mortality within 28 days among 2950 adult ICU patients diagnosed with ischemic stroke from 2008 to 2019, focusing on the potential mediating role of delirium. The primary outcomes were short-term mortality (28, 60, and 90 days) and the risk of delirium. Each patient was followed for at least 1 year. Delirium was primarily assessed using the Confusion Assessment Method for the ICU and by reviewing nursing notes. Group differences between patients with and without a history of falls were compared using the Wilcoxon rank-sum test or the chi-squared test. Cox proportional risk or logistic regression models were used to explore the association between fall history and outcomes, and causal mediation analysis was performed. Results showed that patients with a recent fall history had a significantly increased risk of 28-day (hazard ratio [HR]: 1.62, 95% confidence interval [CI]: 1.35-1.94), 60-day (HR: 1.67, 95% CI: 1.42-1.98), and 90-day mortality (HR: 1.66, 95% CI: 1.41-1.95), as well as an increased risk of delirium (odds ratio: 2.00, 95% CI: 1.66-2.42). Delirium significantly mediated the association between fall history and 28-day mortality (total effect: HR: 1.77, 95% CI: 1.45-2.16; natural indirect effect: HR: 1.12, 95% CI: 1.05-1.21; proportion mediated: 24.6%). These findings suggest that ischemic stroke patients with a recent fall have an increased risk of short-term mortality, partly mediated by delirium. Strategies aimed at preventing delirium may potentially improve prognosis in this patient population.

Mediation by parent health literacy and behaviour of socioeconomic inequality in child overweight.

BACKGROUND: Socioeconomic inequalities contribute to childhood overweight. Identifying mediators could help reduce these inequalities. OBJECTIVE: We assessed to what extent and how parental health literacy and health behaviours mediate the relationship between parental socioeconomic status and childhood overweight. METHODS: Data were taken from the multigenerational prospective Dutch Lifelines Cohort Study. We included 6683 children, baseline age 9.8 years (SD = 2.6), with an average follow-up of 36.2 months (SD = 9.3). Overweight was defined using age- and sex-specific cut-offs. Three indicators of socioeconomic status were included: education, income and occupation. We assessed the mediating role of parental health literacy and health behaviours (smoking, diet, physical activity and alcohol) using causal mediation. RESULTS: Four additional years of education and an SD-increase in both income and occupation decreased the odds of childhood overweight by 42%, 12% and 20%, respectively. Only parental smoking independently mediated the relationship of both education (6.6%) and occupation (5.7%) with overweight. Parental health behaviours jointly explained 8.4% (education), 19.4% (income) and 9.8% (occupation) per relationship. Lastly, adding parental health literacy explained 10.8% (education), 27.4% (income) and 13.3% (occupation) of these relationships. CONCLUSIONS: We found large socioeconomic inequalities in childhood overweight. Remarkably, parental smoking was a key mediator. Therefore, prevention targeting smoking may reduce socioeconomic inequalities in childhood overweight.

The association between rs6859 in NECTIN2 gene and Alzheimer's disease is partly mediated by pTau.

Introduction: Emerging evidence suggests a connection between vulnerability to infections and Alzheimer's disease (AD). The nectin cell adhesion molecule 2 (NECTIN2) gene coding for a membrane component of adherens junctions is involved in response to infection, and its single nucleotide polymorphism (SNP) rs6859 was significantly associated with AD risk in several human cohorts. It is unclear, however, how exactly rs6859 influences the development of AD pathology. The aggregation of hyperphosphorylated tau protein (pTau) is a key pathological feature of neurodegeneration in AD, which may be induced by infections, among other factors, and potentially influenced by genes involved in both AD and vulnerability to infections, such as NECTIN2. Materials and methods: We conducted a causal mediation analysis (CMA) on a sample of 708 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI). The relationship between rs6859 and Alzheimer's disease (AD), with AD (yes/no) as the outcome and pTau-181 levels in the cerebrospinal fluid (CSF) acting as a mediator in this association, was assessed. Adjusted estimates from the probit and linear regression models were used in the CMA model, where an additive model considered an increase in dosage of the rs6859 A allele (AD risk factor). Results: The increase in dose of allele A of the SNP rs6859 resulted in about 0.144 increase per standard deviation (SD) of pTau-181 (95% CI: 0.041, 0.248, p<0.01). When included together in the probit model, the change in A allele dose and each standard deviation change in pTau-181 predicted 6.84% and 9.79% higher probabilities for AD, respectively. In the CMA, the proportion of the average mediated effect was 17.05% and was higher for the risk allele homozygotes (AA), at 19.40% (95% CI: 6.20%, 43.00%, p<0.01). The sensitivity analysis confirmed the evidence of a robust mediation effect. Conclusion: This study reported a new causal relationship between pTau-181 and AD. We found that the association between rs6859 in the NECTIN2 gene and AD is partly mediated by pTau-181 levels in CSF. The rest of this association may be mediated by other factors. Further research, using other biomarkers, is needed to uncover the remaining mechanisms of the association between the NECTIN2 gene and AD.

Biological Age, Chronological Age, and Survival in Pulmonary Fibrosis: A Causal Mediation Analysis.

Rationale: Accelerated biological aging has been implicated in the development of interstitial lung disease (ILD) and other diseases of aging but remains poorly understood. Objectives: To identify plasma proteins that mediate the relationship between chronological age and survival association in patients with ILD. Methods: Causal mediation analysis was performed to identify plasma proteins that mediated the chronological age-survival relationship in an idiopathic pulmonary fibrosis discovery cohort. Proteins mediating this relationship after adjustment for false discovery were advanced for testing in an independent ILD validation cohort and explored in a chronic obstructive pulmonary disease cohort. A proteomic-based measure of biological age was constructed and survival analysis performed, assessing the impact of biological age and peripheral blood telomere length on the chronological age-survival relationship. Measurements and Main Results: Twenty-two proteins mediated the chronological age-survival relationship after adjustment for false discovery in the idiopathic pulmonary fibrosis discovery cohort (n = 874), with 19 remaining significant mediators of this relationship in the ILD validation cohort (n = 983) and one mediating this relationship in the chronic obstructive pulmonary disease cohort. Latent transforming growth factor-ß binding protein 2 and ectodysplasin A2 receptor showed the strongest mediation across cohorts. A proteomic measure of biological age completely attenuated the chronological age-survival association and better discriminated survival than chronological age. Results were robust to adjustment for peripheral blood telomere length, which did not mediate the chronological age-survival relationship. Conclusions: Molecular measures of aging completely mediate the relationship between chronological age and survival, suggesting that chronological age has no direct effect on ILD survival.

Do health literacy, physical health and past rehabilitation utilization explain educational differences in the subjective need for medical rehabilitation? Results of the lidA cohort study.

BACKGROUND: Medical rehabilitation can be helpful for maintaining workers' health and work ability. Its contribution to longer working lives is of high economic relevance in aging populations. In Germany, individuals must apply for rehabilitative measures themselves. Therefore, the subjective need for rehabilitation (SNR) is a prerequisite for rehabilitation access. A low education level is associated with poor health, lower health literacy and more frequent utilization of health services. In the present study, we investigated whether lower educational levels are also associated with a greater SNR and whether health literacy, past rehabilitation utilization and physical health play a mediating role in this path in older employees. METHODS: 3,130 socially insured older employees (born in 1959 or 1965) who participated in the German prospective lidA (leben in der Arbeit) cohort-study in 2011, 2014 and 2018 were included. A causal mediation analysis with an inverse odds weighting approach was performed with the SNR as the dependent variable; educational level as the independent variable; and health, health literacy and past rehabilitation utilization as the mediating variables. Sociodemographic variables were adjusted for. RESULTS: The SNR was significantly greater in subjects with a low education level, poor physical health, inadequate health literacy and those who had utilized rehabilitation in the past. For health literacy, past rehabilitation utilization and physical health, a significant partial mediating effect on the SNR was found for employees with low compared to those with high education levels. However, the combined mediating effect of all the mediators was lower than the sum of their individual effects. Among those with medium or high education levels, none of the variables constituted a significant mediator. CONCLUSIONS: The path between a low education level and a high SNR is mediated by inadequate health literacy, past rehabilitation utilization and poor physical health; these factors do not act independently of each other. Promoting health education may lower the SNR by improving physical health and health literacy. While improving physical health is beneficial for individuals, improved health literacy can be economically advantageous for the health system by reducing inappropriate expectations of rehabilitation benefits and subsequent applications for rehabilitation.

Multi-omic integration reveals alterations in nasal mucosal biology that mediate air pollutant effects on allergic rhinitis.

BACKGROUND: Allergic rhinitis is a common inflammatory condition of the nasal mucosa that imposes a considerable health burden. Air pollution has been observed to increase the risk of developing allergic rhinitis. We addressed the hypotheses that early life exposure to air toxics is associated with developing allergic rhinitis, and that these effects are mediated by DNA methylation and gene expression in the nasal mucosa. METHODS: In a case-control cohort of 505 participants, we geocoded participants' early life exposure to air toxics using data from the US Environmental Protection Agency, assessed physician diagnosis of allergic rhinitis by questionnaire, and collected nasal brushings for whole-genome DNA methylation and transcriptome profiling. We then performed a series of analyses including differential expression, Mendelian randomization, and causal mediation analyses to characterize relationships between early life air toxics, nasal DNA methylation, nasal gene expression, and allergic rhinitis. RESULTS: Among the 505 participants, 275 had allergic rhinitis. The mean age of the participants was 16.4 years (standard deviation = 9.5 years). Early life exposure to air toxics such as acrylic acid, phosphine, antimony compounds, and benzyl chloride was associated with developing allergic rhinitis. These air toxics exerted their effects by altering the nasal DNA methylation and nasal gene expression levels of genes involved in respiratory ciliary function, mast cell activation, pro-inflammatory TGF-ß1 signaling, and the regulation of myeloid immune cell function. CONCLUSIONS: Our results expand the range of air pollutants implicated in allergic rhinitis and shed light on their underlying biological mechanisms in nasal mucosa.

Family concerns and relationship problems in anxious pregnant women and their associations with postnatal functional disability in Pakistan.

OBJECTIVE: Expanding on existing research suggesting that strategies to reduce prenatal anxiety can decrease functional disability (e.g., difficulties in performing everyday activities and social participation), we examined if this effect varied by type of anxiety-producing problem (i.e., having family concerns and relationship problems versus other problems) reported during pregnancy. Further, we explored if perceived social support mediated this relationship. METHODS: We used longitudinal data on 310 anxious Pakistani women who received any psychosocial intervention sessions as part of a program that was based on Cognitive Behavioral Therapy. The Psychological Outcome Profiles (PSYCHLOPS) was used to assess whether women had 'family concerns and relationship problems' or 'other problems.' The WHO Disability Assessment Schedule 2.0 assessed functional disability at six-weeks after delivery. Lack of support was measured using a 12-item Multi-dimensional Scale of Perceived Social Support. We employed linear regression to examine associations between types of problems reported during pregnancy and postnatal functional disability. Causal mediation analysis was used to assess whether postnatal social support mediated this relationship. RESULTS: Of anxious pregnant women, 34% reported family concerns or relationship problems as primary problems in pregnancy. They were more likely to report higher functional disability at six-weeks after delivery than women who reported other problems (adjusted B = 2.40, 95% CI: 0.83-3.97). Lack of overall social support (Estimateindirect = 0.69, 95% CI: 0.04-1.38) and lack of support from friends (Estimateindirect = 0.62, 95% CI: 0.01-1.29) significantly mediated the relationship. CONCLUSIONS: Findings suggest that complementing pre- and post-natal care with support programs and services that address family concerns and relationship problems, as well as enhancing social support is important to functional disability.