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Table 1 General description of epidemiological studies that were eligible for the systematic review

From: Implementation and reporting of causal mediation analysis in 2015: a systematic review in epidemiological studies

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

  1. γ-GT gamma glutamyl transferase; HOMA-IR homeostatic model assessment for insulin resistance; ICD international classification of diseases; PTH parathyroid hormone
  2. aOverall sample size of the study
  3. bConfounders included in the causal mediation analysis
  4. cThe results of mediation analysis were graphically presented