High-throughput technologies have made high-dimensional settings increasingly common, providing opportunities for the development of high-dimensional mediation methods. We aimed to provide useful guidance for researchers using high-dimensional mediation analysis and ideas for biostatisticians to develop it by summarizing and discussing recent advances in high-dimensional mediation analysis. The method still faces many challenges when extended single and multiple mediation analyses to high-dimensional settings. The development of high-dimensional mediation methods attempts to address these issues, such as screening true mediators, estimating mediation effects by variable selection, reducing the mediation dimension to resolve correlations between variables, and utilizing composite null hypothesis testing to test them. Although these problems regarding high-dimensional mediation have been solved to some extent, some challenges remain. First, the correlation between mediators are rarely considered when the variables are selected for mediation. Second, downscaling without incorporating prior biological knowledge makes the results difficult to interpret. In addition, a method of sensitivity analysis for the strict sequential ignorability assumption in high-dimensional mediation analysis is still lacking. An analyst needs to consider the applicability of each method when utilizing them, while a biostatistician could consider extensions and improvements in the methodology.

Nonsurgical interventions are recommended for osteoarthritis (OA). However, how interventions change pain and physical function is unclear. Therefore, the objectives of this scoping review were to 1) identify what potential mediators of nonsurgical interventions on pain and physical function have been evaluated and 2) summarize the findings according to intervention, joint, and outcome.
We searched Medline, Embase, CINAHL, Cochrane Central Register of Controlled Trials, and Scopus databases. Studies were included if they conducted a mediation analysis on a randomized controlled trial evaluating a nonsurgical intervention on OA of any joint. Outcomes were pain and physical function.
Nine knee OA studies, evaluating diet plus exercise, exercise, unloading shoes, high-expectation communication during acupuncture, and telephone-based weight loss plus exercise were identified. Except for weight loss and self-efficacy, putative mediators (knee muscle perfusion/extensor strength/adduction moment, systemic inflammatory biomarkers, physical activity, dietary intake, and pain beliefs) were evaluated by single studies. Ten mediators partially mediated intervention (diet plus exercise, exercise, high-expectation communication) effects on pain and physical function. Eight mediators were common to pain and function (reduced weight, increased knee extensor strength, and increased self-efficacy). Constant knee flexor muscle perfusion partially mediated exercise effects on pain, and knee pain relief partially mediated exercise effects on function.
In knee OA, some evidence suggests that the benefits of 1) diet and exercise are mediated through changes in body weight, systemic inflammation, and self-efficacy; 2) exercise is mediated through changes in knee muscle strength and self-efficacy; and 3) high-expectation communication style is mediated through changes in self-efficacy.

Psychologically based interventions aim to improve pain-related functioning by targeting pain-related fears, cognitions and behaviors. Mediation and moderation analyses permit further examination of the effect of treatment on an outcome. This systematic review and meta-analysis aims to synthetize the evidence of specific mediators and moderators (i.e., treatment targets) of psychologically based treatment effects on pain and disability. A total of 28 mediation and 11 moderation analyses were included. Thirteen mediation studies were included in a meta-analysis, and the rest was narratively synthetized. Reductions in pain-related fear (indirect effect [IE]: -0.07; 95% confidence interval [CI]: -0.11, -0.04) and catastrophizing (IE: -0.07; 95%CI: -0.14, -0.00), as well as increases in self-efficacy (IE: -0.07; 95%CI: -0.11, -0.04), mediated effects of cognitive behavioral therapy on disability but not on pain intensity, when compared to control treatments. Enhancing pain acceptance (IE: -0.17; 95%CI: -0.31, -0.03) and psychological flexibility (IE: -0.30; 95%CI: -0.41, -0.18) mediated acceptance and commitment therapy effects on disability. The narrative synthesis showed conflicting evidence, which did not support a robust moderated effect for any of the examined constructs. Overall, the methodological quality regarding mediation was low, and some key pitfalls are highlighted alongside recommendations to provide a platform for future research.

DNA methylation alterations have been widely studied as mediators of environmentally induced disease risks. With new advances in technique, epigenome-wide DNA methylation data (EWAS) have become the new standard for epigenetic studies in human populations. However, to date most epigenetic studies of mediation effects only involve selected (gene-specific) candidate methylation markers. There is an urgent need for appropriate analytical methods for EWAS mediation analysis. In this chapter, we provide an overview of recent advances on high-dimensional mediation analysis, with application to two DNA methylation data.

Chocolate is a rich dietary source of various bioactive flavonoid compounds. Despite being one of the most popular foods worldwide, the association between chocolate consumption and long-term mortality remains unclear. The objective of this study is to determine the associations between chocolate consumption and long-term overall and cause-specific mortality, to evaluate dose-response and potential mediators, and to conduct an updated meta-analysis based on prospective cohort studies. We performed a prospective analysis in the Alpha-Tocopherol, Beta-Carotene cancer prevention (ATBC) Study with a total of 27,111 men who were recruited between 1985 and 1988 and followed through 2015. Exposure data of daily chocolate consumption was obtained from validated baseline food frequency questionnaire. Hazard ratios (HRs) and 30-year absolute risk differences (ARDs) including 95% confidence intervals (CI) for overall and cause-specific mortality were estimated using multivariable-adjusted Cox proportional hazards regression models. An updated meta-analysis of cohort studies was also conducted. During 482,807 person-years of follow-up, a total of 22,064 men died. The multivariable analyses showed a statistically significant inverse association between chocolate consumption and risk of overall mortality, with HRs of 0.91, 0.89, 0.89, and 0.88 for the increasing categories 2-5 as compared with those in the lowest category (Ptrend < 0.0001, and P for nonlinearity < 0.0001). We observed significantly lower mortality from cardiovascular disease (CVD), heart disease and cancer, representing 13%, 16% and 12% risk reductions for the highest compared to lowest chocolate category, respectively (all Ptrend ≤ 0.002; all P for nonlinearity < 0.0001). The inverse associations of chocolate consumption with risk of overall, CVD and heart disease mortality were generally consistent across cohort subgroups (e.g., body mass index and serum cholesterol). Mediation analysis showed that 4.3% of the inverse association of chocolate and overall mortality was mediated through reducing blood pressure. Within the updated meta-analysis of cohort studies (21 risk estimates, 908,390 participants and 65,407 events), greater consumption of chocolate (per 5 g/day) was associated with a lower risk of CVD incidence and mortality (pooled relative risk = 0.98, P value < 0.001; P for nonlinearity < 0.001). The predefined subgroup analyses generally revealed consistent inverse chocolate-CVD risk associations. In this prospective study, calorie-balanced greater consumption of chocolate was inversely associated with lower overall, CVD, heart disease and cancer mortality. The systematic review and meta-analysis provide support for the inverse chocolate-CVD association. Our findings may provide evidence to partially allay concerns regarding adverse health outcomes from low-to-moderate chocolate consumption.

Statistics plays a key role in many areas of modern society, including technology, social and behavior studies, economics, and the sciences. Statistics anxiety (SA) has a detrimental impact on academic experiences in university populations, although the mediating factors remain underexplored. We conducted the first systematic review and meta-analysis focused on SA in university students in the context of statistical performance, individual differences in statistical learning, self-perceptions regarding the statistics course and instructor, and sociodemographic factors. Searches were carried out in the PsycINFO, PubMed, Scielo, and Web of Science databases according to our preregistration. Forty studies were selected for systematic review. Seventeen were included in a series of six meta-analyses concerning academic achievement, attitudes, self-perception, procrastination, and gender. The findings reveal learning strategies, procrastination, self-efficacy, and self-awareness as predictors of SA. However, the impact of sociodemographic data in these moderators is still uncharted. We conclude with a critical appraisal of the selected studies and present future directions for research in SA.

Mediation analysis is a common statistical method used to investigate mechanisms of health exposure and interventions. The reporting quality of mediation studies used in randomised controlled trials has been considered heterogeneous and incomplete. The reporting quality of mediation analysis in observational studies is unknown. We conducted a systematic review to describe the reporting standards of recently published observational studies that used mediation analysis to understand the mechanism of health exposures. We searched for studies published between June 2017 and June 2019 indexed in EMBASE, MEDLINE and PsycINFO. Two reviewers screened articles and selected a random sample of 50 eligible studies for inclusion. We included studies across 13 healthcare fields and ten different health conditions. Most studies (74%) collected data on healthy individuals to assess their risk of developing a health disorder. Psychosocial and behavioural factors (self-control, self-esteem, alcohol consumption, pain) were the most prevalent exposures (n = 30, 60%), outcomes (n = 23, 46%) and mediators (n = 29, 58%). Most studies used a cross-sectional design (64%, n = 32), and a few studies reported sample size calculations (4%, n = 8). In 20% (n = 10) of the studies, adjustment for confounders was reported. Only 10% (n = 5) of studies reported the assumptions underlying the mediation analysis, and 14% (n = 7) of studies conducted some sensitivity analysis to assess the degree which unmeasured confounders would affect the estimate of the mediation effect. Mediation analysis is a common method used to investigate mechanisms in prevention research. The reporting of mediation analysis in observational studies is incomplete and may impact reproducibility, evidence synthesis and implementation.

Mediation analysis methodology underwent many advancements throughout the years, with the most recent and important advancement being the development of causal mediation analysis based on the counterfactual framework. However, a previous review showed that for experimental studies the uptake of causal mediation analysis remains low. The aim of this paper is to review the methodological characteristics of mediation analyses performed in observational epidemiologic studies published between 2015 and 2019 and to provide recommendations for the application of mediation analysis in future studies.
We searched the MEDLINE and EMBASE databases for observational epidemiologic studies published between 2015 and 2019 in which mediation analysis was applied as one of the primary analysis methods. Information was extracted on the characteristics of the mediation model and the applied mediation analysis method.
We included 174 studies, most of which applied traditional mediation analysis methods (n = 123, 70.7%). Causal mediation analysis was not often used to analyze more complicated mediation models, such as multiple mediator models. Most studies adjusted their analyses for measured confounders, but did not perform sensitivity analyses for unmeasured confounders and did not assess the presence of an exposure-mediator interaction.
To ensure a causal interpretation of the effect estimates in the mediation model, we recommend that researchers use causal mediation analysis and assess the plausibility of the causal assumptions. The uptake of causal mediation analysis can be enhanced through tutorial papers that demonstrate the application of causal mediation analysis, and through the development of software packages that facilitate the causal mediation analysis of relatively complicated mediation models.

DNA methylation (DNAm) is one of the most studied epigenetic modifications. DNAm has emerged as a key biological mechanism and biomarkers to test associations between environmental exposure and outcomes in epidemiological studies. Although previous studies have focused on associations between DNAm and either exposure/outcomes, it is useful to test for mediation of the association between exposure and outcome by DNAm. The purpose of this scoping review is to introduce the methodological essence of statistical mediation analysis and to examine emerging epidemiological research applying mediation analyses. We conducted this scoping review for published peer-reviewed journals on this topic using online databases (PubMed, Scopus, Cochrane, and CINAHL) ending in December 2020. We extracted a total of 219 articles by initial screening. After reviewing titles, abstracts, and full texts, a total of 69 articles were eligible for this review. The breakdown of studies assigned to each category was 13 for smoking (18.8%), 8 for dietary intake and famine (11.6%), 6 for other lifestyle factors (8.7%), 8 for clinical endpoints (11.6%), 22 for environmental chemical exposures (31.9%), 2 for socioeconomic status (SES) (2.9%), and 10 for genetic factors and race (14.5%). In this review, we provide an exposure-wide summary for the mediation analysis using DNAm levels. However, we found heterogenous methods and interpretations in mediation analysis with typical issues such as different cell compositions and tissue-specificity. Further accumulation of evidence with diverse exposures, populations and with rigorous methodology will be expected to provide further insight in the role of DNAm in disease susceptibility.

BACKGROUND: Anti-transcriptional intermediary factor 1 gamma (TIF1γ) antibody is a marker for predicting cancer association in patients with dermatomyositis (DM). The overall survival rate in DM patients with cancer was reported to be considerably worse than that in DM patients without cancer. However, the treatment for cancer-associated DM remains controversial, because the treatment priority between surgical resection for the tumor and internal treatments, including glucocorticoids, immunosuppressive agents, and intravenous immune globulin, has not been established.
METHODS: We report the case of a 57-year-old Japanese man diagnosed with anti-TIF1γ antibody-positive DM associated with ascending colon cancer. His clinical symptoms included facial and brachial edema, muscle weakness, dysphagia, myalgia, and rash. Physical examination revealed periorbital edema and Gottron\'s papules over his knuckles with brachial edema, and tenderness and weakness of the proximal limb muscles. The findings of hyperintense muscles in T2-weighted sequences of brachial contrast-enhanced magnetic resonance imaging and the infiltration of lymphocytic cells and CD4-positive lymphocytes from muscle biopsy were compatible with the diagnostic criteria for dermatomyositis. Anti-TIF1γ antibody was positive by immunoprecipitation assay. He first started internal treatment including intravenous immunoglobulin, steroid pulse, prednisolone, and azathioprine, followed by surgical resection for the tumor because of the elevation of creatine kinase and progression of dysphagia. However, clinical symptoms did not improve, and the patient died 6 months later.
CONCLUSIONS: We faced difficulties in determining the treatment priority between surgical resection and internal treatment for our case; therefore, this case would be educational for readers. We searched PubMed to identify English-language case reports of anti-TIF1γ antibody-positive dermatomyositis with malignancy and found 21 reported cases. We herein review and summarize previously reported cases of anti-TIF1γ antibody-positive DM with malignancy. Cancer screening is essential in patients with anti-TIF1γ antibody-positive dermatomyositis because it is associated with a high prevalence of malignancies. Our review revealed that initial surgical treatment should be recommended for better prognosis if the general condition allows.