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.

Epidemiologic studies have reported the relationships between perfluoroalkyl substances (PFASs) and breast cancer incidence, yet the underlying mechanisms are not well understood. This study aimed to elucidate the mediation role of mitochondrial DNA copy number (mtDNAcn) in the relationships between PFASs exposure and breast cancer risk. We conducted a case-cohort study within the Dongfeng-Tongji cohort, involving 226 incident breast cancer cases and a random sub-cohort (n = 990). Their plasma concentrations of six PFASs [including perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroheptanoic acid (PFHpA), perfluorooctane sulfonic acid (PFOS) and perfluorohexane sulfonic acid (PFHxS)], and peripheral blood levels of mtDNAcn, were detected at baseline by using ultraperformance liquid chromatography-tandem mass spectrometry and quantitative real-time PCR, respectively. Linear regression and Barlow-weighted Cox models were employed separately to assess the relationships of mtDNAcn with PFASs and breast cancer risk. Mediation analysis was further conducted to quantify the mediating effects of mtDNAcn on PFAS-breast cancer relationships. We observed increased blood mtDNAcn levels among participants with the highest PFNA and PFHpA exposure [Q4 vs. Q1, β(95%CI) = 0.092(0.022, 0.162) and 0.091(0.022, 0.160), respectively], while no significant associations were observed of PFOA, PFDA, PFOS, or PFHxS with mtDNAcn. Compared to participants within the lowest quartile subgroup of mtDNAcn, those with the highest mtDNAcn levels exhibited a significantly increased risk of breast cancer and postmenopausal breast cancer [Q4 vs. Q1, HR(95%CI) = 3.34(1.80, 6.20) and 3.71(1.89, 7.31)]. Furthermore, mtDNAcn could mediate 14.6 % of the PFHpA-breast cancer relationship [Indirect effect, HR(95%CI) = 1.02(1.00, 1.05)]. Our study unveiled the relationships of PFNA and the short-chain PFHpA with mtDNAcn and the mediation role of mtDNAcn in the PFHpA-breast cancer association. These findings provided insights into the potential biological mechanisms linking PFASs to breast cancer risk.

BACKGROUND: In the causal mediation analysis framework, several parametric regression-based approaches have been introduced in past years for decomposing the total effect of an exposure on a binary outcome into a direct effect and an indirect effect through a target mediator. In this context, a well-known strategy involves specifying a logistic model for the outcome and invoking the rare outcome assumption (ROA) to simplify estimation. Recently, exact estimators for natural direct and indirect effects have been introduced to circumvent the challenges prompted by the ROA. As for the approximate approaches relying on the ROA, these exact approaches cannot be used as is on case-control data where the sampling mechanism depends on the outcome.
METHODS: Considering a continuous or a binary mediator, we empirically compare the approximate and exact approaches using simulated data under various case-control scenarios. An illustration of these approaches on case-control data is provided, where the natural mediation effects of long-term use of oral contraceptives on ovarian cancer, with lifetime number of ovulatory cycles as the mediator, are estimated.
RESULTS: In the simulations, we found few differences between the performances of the approximate and exact approaches when the outcome was rare, both marginally and conditionally on variables. However, the performance of the approximate approaches degraded as the prevalence of the outcome increased in at least one stratum of variables. Differences in behavior were also observed among the approximate approaches. In the data analysis, all studied approaches were in agreement with respect to the natural direct and indirect effects estimates.
CONCLUSIONS: In the case where a violation of the ROA applies or is expected, approximate mediation approaches should be avoided or used with caution, and exact estimators favored.

We investigated the causal impact of conflict-related violence on individual mental health and its potential pathways in Colombia. Using data from before and after the 2016 peace accord between the Colombian government and the Revolutionary Armed Forces of Colombia (FARC), we adopted a difference-in-differences empirical design combined with instrumental variables estimation. We also used formal mediation analysis to investigate a possible mediating role of alcohol consumption in the relationship between conflict exposure and mental health. Our results did not support the hypothesis that changes in exposure to conflict violence after the peace accord causally led to any changes in individual mental health. We were unable to identify a statistically significant mediating effect of alcohol consumption in the relationship between exposure to conflict violence and mental health.

With reference to a stratified case-control (CC) procedure based on a binary variable of primary interest, we derive the expression of the distortion induced by the sampling design on the parameters of the logistic model of a secondary variable. This is particularly relevant when performing mediation analysis (possibly in a causal framework) with stratified case-control (SCC) data in settings where both the outcome and the mediator are binary. Despite being designed for parametric identification, our strategy is general and can be used also in a nonparametric context. With reference to parametric estimation, we derive the maximum likelihood (ML) estimator and the M-estimator of the joint outcome-mediator parameter vector. We then conduct a simulation study focusing on the main causal mediation quantities (i.e., natural effects) and comparing M- and ML estimation to existing methods, based on weighting. As an illustrative example, we reanalyze a German CC data set in order to investigate whether the effect of reduced immunocompetency on listeriosis onset is mediated by the intake of gastric acid suppressors.

Vaccine effectiveness (VE) studies consolidate knowledge of real-world effectiveness in different contexts. However, methodological issues may undermine their conclusions: to assess the VE against COVID-19 within the Italian population, a specific threat to validity is related to the consequences of divergent compliance to the Green Pass policy.
To address this challenge we conducted a test negative case-control (TNCC) study and multiple sensitivity analysis among residents aged ≥ 12 in Friuli Venezia Giulia Region (FVG), North-east Italy, from February 1, 2021 to March 31, 2022. Information regarding 211,437 cases of COVID-19 infection and 845,748 matched controls was obtained from the regional computerized health database. The investigation considered: COVID-19 infection, hospitalization, and death. Multiple conditional logistic regressions adjusted for covariates were performed and VE was estimated as (1-OR COVID-19vaccinated vs. unvaccinated)x100. Mediation analyses were carried out to offset potential collider variables, particularly, the number of swabs performed after the introduction of pandemic restrictions.
Full-cycle VE against infection decreased from 96% (95% CI: 96, 97) in the Alpha period to 43% (95% CI: 42, 45) in the Omicron period. Booster dose raised the protection in Omicron period to 67% (95% CI: 66, 67). Against the evasive Omicron variant, the protection of the booster dose was 87% (95% CI: 83, 90) for hospitalization and 90% (95% CI: 82, 95) for death. The number of swabs performed was included as a covariate in the adjustments, and the mediation analysis confirmed that it was a strong mediator between vaccination and COVID-19-related outcomes.
The study suggests that, under similar TNCC settings, mediation analysis and adjustment for number of diagnostic tests should be included, as an effective approach to the challenge of differential testing behavior that may determine substantial selection bias. This correction allowed us to align with results from other studies that show how full-cycle VE against infection was initially high but decreased over time by variant circulation, counterbalanced by booster dose that raised protection across variants and outcome severity.

Although numerous evidences suggest that zinc may have a beneficial impact on preventing and treating diabetes, findings from the population studies are inconclusive. To address this gap, we conducted a nested case-control study, employing restricted cubic splines and a conditional logistic regression model to explore the association between serum zinc levels and the risk of diabetes. We also assessed potential effect modifications through stratified analyses and examined the mediating effects of metabolic indicators using a multiclass mediation effect model. We measured baseline serum zinc concentrations using Inductively Coupled Plasma Mass Spectrometry in a cohort of 2156 participants, including 1078 individuals with diabetes and 1078 matched controls. Our findings revealed a 51 % increased risk of diabetes when comparing the highest quartile (Q4) to the lowest quartile (Q1) of serum zinc levels (Odds Ratio [95 % Confidence Interval]: 1.51 [1.09, 2.09]). There was a positive linear dose-response relationship between serum zinc and diabetes risk (P overall ≤0.01, P nonlinear = 0.20). Effect modifications were evident between serum zinc and factors such as educational attainment, body mass index, alcohol index, family history of diabetes, history of hypertension, coronary heart disease, and stroke, all of which influenced the risk of diabetes (all P-interaction <0.05). Moreover, our study identified significant indirect effects of triglycerides levels on diabetes risk for participants in the third (Q3) and fourth (Q4) quartiles of serum zinc, with mediation proportions of 19.23 % and 19.28 %, respectively. A significant indirect effect of alanine aminotransferase on diabetes risk was found for those in the Q4 of serum zinc, with a mediation proportion of 12.05 %. Considering these findings, it is advisable to conduct testing for serum zinc level and exercise caution when considering zinc supplementation. Furthermore, our results emphasized the necessity for additional validation through large-sample prospective population studies and experimental research.

UNASSIGNED: No known published empirical study in the social work literature has investigated goal-related feedback seeking\'s direct or indirect impact on human service case managers. Consequently, this field survey study sought to fill this gap in the extant literature using two different samples of county-based human service case managers across the state of New York.
UNASSIGNED: Four hundred and sixty-three public assistance and 349 child welfare case managers were surveyed in order to test goal-related feedback seeking\'s main and receiving goal-related feedback\'s mediating effect on internal work motivation.
UNASSIGNED: Data from each sample confirmed both types of effects.
UNASSIGNED: As the first to uncover these two sets of findings, this field survey study makes a unique contribution to the social work and feedback seeking literatures.

BACKGROUND: Ingested alcohol is predominantly oxidized to acetaldehyde by alcohol dehydrogenase 1B (ADH1B), and acetaldehyde is further oxidized to acetate mainly by aldehyde dehydrogenase 2 (ALDH2). Although alcohol consumption is a convincing risk factor for oesophageal cancer, the role of ADH1B rs1229984 (His48Arg), the single-nucleotide polymorphism associated with slow alcohol metabolism, in oesophageal cancer development is unclear. Because this single-nucleotide polymorphism is associated with both increased risk of oesophageal cancer and drinking intensity, its association with oesophageal cancer might operate either through a direct pathway independently of drinking intensity, via an indirect pathway mediated by drinking intensity, or both.
METHODS: To disentangle these different pathways, we applied a mediation analysis to an oesophageal cancer case-control study (600 cases and 865 controls) by defining the ADH1B Arg allele and alcohol consumption as exposure and mediator, respectively, and decomposed the total-effect odds ratio of the ADH1B Arg allele into direct- and indirect-effect odds ratio.
RESULTS: The ADH1B Arg allele was associated with oesophageal cancer risk through pathways other than change in drinking intensity (direct-effect odds ratio, 2.03; 95% confidence interval, 1.41-2.92), in addition to the indirect pathway mediated by drinking intensity (indirect-effect odds ratio, 1.27; 95% confidence interval, 1.05-1.53). Further analyses by stratifying genotypes of ALDH2 rs671 (Glu504Lys), the functional single-nucleotide polymorphism that strongly attenuates the enzymatic activity, showed significant direct-effect odds ratio within each stratum.
CONCLUSIONS: These results indicate that ADH1B Arg allele contributes to oesophageal cancer risk by slowing alcohol breakdown, in addition to its effect on the amount of alcohol consumed.

This study investigates how health literacy (HL) and trust in health information affected COVID-19 vaccine hesitancy among Chinese Hong Kong adults. A cross-sectional study was conducted in August 2022. A total of 401 participants completed the study. Participants completed a newly developed Hong Kong HL scale and self-reported their trust levels in health information from different resources. The proportions of early uptake of the first dose and booster dose of COVID-19 vaccine were 69.1% and 71.8%, respectively. The risk of delaying the first dose was higher among participants with inadequate functional HL (OR = 0.58, p = 0.015), adequate levels of two subdomains of critical HL (OR = 1.82, p = 0.013; OR = 1.91, p < 0.01), and low-level trust in health information from the government (OR = 0.57, p = 0.019). Respondents with adequate interactive HL (OR = 0.52, p = 0.014) and inadequate level of one subdomain of critical HL (OR =1.71, p = 0.039) were more likely to delay the booster dose. This negative association between critical HL and vaccination was suppressed by trust in health information from the government. This study shows that HL and trust in health information from the government are associated with COVID-19 vaccine hesitancy. Efforts should be directed at providing tailored communication strategies with regard to people\'s HL and increasing public confidence in health authorities to decrease vaccine hesitancy.