Table 1.
General description of epidemiological studies that were eligible for the systematic review
| References | Country, population, and sample size of studya | Directed acyclic graph (DAG) included? | Specific mediation hypothesis specified? | Exposure | Primary outcome | Mediator | Confoundersb |
|---|---|---|---|---|---|---|---|
| Randomized controlled trials | |||||||
| D’Amelio et al. [27] | Italy Non-diabetic women with postmenopausal osteoporosis (n = 46) |
No | Biologic mechanisms discussed | All treated with calcium 1200 mg/day and cholecalciferol 800 UI/day Randomized to with PTH 1–84 100 μg/day subcutaneous Or Without PTH 1–84 100 μg/day subcutaneous (binary) |
Glucose metabolism, (continuous, log scale) | Total osteocalcin (OC) undercarboxylated (uOC) (continuous) |
Biomarkers that were unbalanced between the two treatment groups at baseline including uOC and serum tartrate resistant acid phosphatase 5B (TRAP5b) |
| Freeman et al. [28] | England Patients with persecutory delusions from 6 mental health sites (n = 59) |
No | Guided by cognitive model of persecutory delusions |
Randomized to street exposure in areas of relative deprivation during busy mid-day Or A neutral control condition which included sitting in a room watching mildly humorous television clips for 10 min (binary) |
(1) State Paranoia using six visual analog scales (VAS) (2) State social paranoia scale (3) Schizotypal Symptoms Inventory—Paranoia (continuous) |
Voices
Hallucinations VAS Distress VAS Affective Anxiety VAS Depression VAS Brief core schema scales (BCSS) Self-focus Threat anticipation Interpretation bias (continuous) Reasoning measures Jumping to conclusions Possibility of being mistaken Alternative explanations Hypothetical contradiction (binary) Probability of being mistaken (continuous) |
Baseline measures of paranoia, all of the mediators considered, and center |
| Cohort studies | |||||||
| Banack et al. [26] | United States Nationally representative noninstitutionalized Sample of adults aged 20 to 80 years in the U.S. (1988–2004) (n = 7212) |
Yes | Guided by previous research | Obesity defined as body mass index ≥30 kg/m2 vs. 18.5–29.9 kg/m2(binary) | All-cause mortality with follow-up through 2006 (binary) | Self-reported acute cardiac event (e.g. stroke or myocardial infarction) (binary) | Age, gender, race, education, smoking status, and cardiorespiratory fitness |
| Jackson et al. [29] | New Jersey and Pennsylvania, United States Older adults dually enrolled in medicare and pharmacy assistance programs; “new users” (n = 26,197) |
No | Mediators selected based on previous literature | New user of first generation antipsychotic versus new user of second generation antipsychotic (binary) | Mortality with 180 days (binary) | Medical events stroke, ventricular arrhythmia, acute myocardial infarction, venous thromboembolism, pneumonia, bacterial infection (besides pneumonia), and hip fracture) (binary) | 70 different demographic characteristics, health service utilization and medication usage, co-existing medical and psychiatric illness, and indicators of functional impairment |
| Kositsawat et al. [30] | Memphis, Tennessee and Pittsburgh, Pennsylvania, United States Black and white medicare eligible—community dwelling adults aged 70–79 years without diabetes at year 2 of the study (n = 2193) |
No | Rationale not clear | Serum vitamin D levels (25-hydroxyvitamin D) <20 ng/mL (binary) | A1c level ≥6.5 % at year 4 (binary) | Diabetes status at year 4 (binary) | Confounders considered in mediation analysis not reported |
| Louwies et al. [31] | Belgium Working nurses aged between 22 and 59 years without cardiovascular diseases and diabetes (n = 55) |
No | Guided by previous literature | Subchronic black carbon exposure (continuous) | Diastolic blood pressure Systolic blood pressure (continuous ) |
Retinal microcirculation (continuous) | Age, sex, body mass index, smoking, use of anti-hypertensive medication, γ-GT, A1c, distance to major road, clinic, and average weekly temperature |
| Lu et al. [32] | United States Adults free of coronary heart disease who participated in 9 National Heart, Lung, and Blood Institute funded cohort studies with body mass index ≥ 20 kg/m2 (1954–2001) (n = 58,322 for metabolic risk factors; n = 19,572 for fibrinogen analysis) |
Yes | Biologic mechanisms discussed | Body mass index (categories ≥30 kg/m2, 25–<30 kg/m2, 20–25 kg/m2) (categorical and continuous) |
First fatal or non-fatal occurrence of ischemic heart disease, acute myocardial infarction, or angina pectoris (binary) |
Explored in data combined from nine cohort studies
Systolic blood pressure, total serum cholesterol, glucose Explored in data combined from three cohort studies Fibrinogen, high-sensitive C-reactive protein (continuous) |
Age, sex, smoking, race/ethnicity, socioeconomic status, alcohol intake, physical activity, and dietary intake |
| Mendola et al. [33] | United States Singleton newborns with ≥23 weeks of gestation (n = 210,610) |
Yes | Biologic mechanisms discussed | Preeclampsia (binary) | Ten neonatal outcomes (binary) | Preterm birth (binary) | Study site, maternal age, maternal race/ethnicity, insurance status, marital status, parity, pre-pregnancy body mass index, and chronic diseases during pregnancy |
| Messerlian et al. [34] | Montreal, Canada Women aging 20–45 years without preexisting medical conditions potentially associated with both infertility and preterm birth and primary analysis was restricted to singleton pregnancies (n = 18,147) |
Yes | Noted that the biologic mechanisms are unclear | Reason for infertility (ovulatory, endo-tubal, male factor, uterine abnormalities, unexplained, unspecified) (categorical) | Preterm birth categorized as <32, <35, <37, ≥37 weeks) (ordinal) | Any type of Infertility treatment (binary) |
Maternal age, parity, education, smoking, and alcohol or substance use during pregnancy, and body mass index |
| Raghavan et al. [35] | Framingham, Massachusetts, United States Participants without type 2 diabetes who had whole-genome, common variant genotyping and were followed for a median of 13 years at exam 5 (n = 2361) |
Yes | Informed by the literature | Parental history of diabetes—none, one or two parents (ordinal) | Incident type 2 diabetes in offspring (binary) |
Metabolic
corrected insulin response, HOMA-IR, metabolic syndrome, components score Genetic genetic risk score Lifestyle diabetogenic, diet score, physical activity index (continuous) |
Age, sex and genetic risk score (for models not focused on genetic mediators) |
| Case control studies | |||||||
| Rao et al. [36] | Karnataka, India Source population from which cases and controls were drawn included adults who were either patients or visitors at 4 major cancer hospitals (n = 452) |
Yes | Yes, critical period model guided the DAG construction | Early life socioeconomic disadvantage (low/high) |
Cases
Diagnosed with oral and/or oropharyngeal cancer (ICD-10 codes C00-C10). Controls Visitors or those seeking medical care for medical conditions not related to tobacco or alcohol (binary) |
Smoking, chewing quid and/or tobacco, alcohol (binary) | Age, sex, adult socioeconomic measures and paternal alcohol drinking |
| Song et al. [37] | United States Source population from which cases and controls were drawn included postmenopausal women at 40 clinical centers (n = 3049) |
Yes | Mediators selected based on previous literature | Low birth weight (ordinal) |
Cases
Self-reported first-time use of medication for diabetes during the follow-up periods Controls For each incident case, controls were selected at random from women who remained free from cardiovascular diseases and/or diabetes at the diagnosed time in the case patient (binary) |
Biomarkers of insulin resistance, leptin and its receptor, sex steroid hormones and their binding protein, inflammation, endothelial function, cellular ageing and blood pressure (continuous) |
Two sets of confounders were considered: (1) Before birth: race/ethnicity and family history of diabetes (2) After birth: age, smoking, alcohol consumption, physical exercise, dietary fiber intake, dietary glycaemic load, and BMI |
| Xie et al. [38] | Shanghai, China Pre-pubertal and early pre-pubertal boys aged 8-15 years old (n = 167) |
No | Yes, biologic mechanisms discussed | Total phthalates (continuous) |
Cases Diagnosis if constitutional delay of growth and puberty defined by bone age <1.75 years than chronological age Controls age and Tanner stage (1 or 2) matched (binary) |
Serum testosterone level (continuous) | Age and body mass index |
γ-GT gamma glutamyl transferase; HOMA-IR homeostatic model assessment for insulin resistance; ICD international classification of diseases; PTH parathyroid hormone
aOverall sample size of the study
bConfounders included in the causal mediation analysis
cThe results of mediation analysis were graphically presented