Table 4.

Pathway enrichment tests ($p$-values) for transportation noise and air pollution exposures based on curated CpGs reported for selected cross-systemic outcomes.

Exposure	CRP	Metabolic syndrome	Lipids	FG/HbA1c	Insulin	WC	BMI	Blood pressure	eGFR	CAR	Allostatic load
N (CpGs)	256	10	14	9	158	168	893	20	296	7	1,626
Aircraft Lden	0.0038	0.5915	0.6326	0.4545	0.6630	0.2925	0.0007	0.1020	0.0015	0.9096	0.0004
Railway Lden	0.3163	0.4943	0.9533	0.5778	0.6284	0.3001	0.9023	0.6773	0.0562	0.0229	0.0871
Road traffic Lden	0.0395	0.2434	0.9969	0.3879	0.3461	0.5361	0.0008	0.2858	0.0031	0.8013	0.0004
${\mathrm{NO}}_2$	0.2117	0.1237	0.7831	0.5733	0.3697	0.6873	0.8818	0.5355	0.0058	0.9728	0.0510
${\mathrm{PM}}_{2.5}$	0.0004	0.4517	0.1263	0.0947	0.3451	0.0004	0.0004	0.3759	0.0004	0.3814	0.0004

Note: Lipids includes triglycerides, high-, low- and very low-density lipoprotein cholesterol. Insulin includes measures of insulin secretion and resistance. WC also includes central obesity and adiposity. BMI also includes general obesity. Blood pressure includes systolic and diastolic blood pressure. eGFR also includes impaired renal function. CAR includes acceleration and deceleration capacity. Allostatic load combines all the phenotypes. Pathway enrichment $p$-values derived from Weighted Kolmogorov-Smirnov method using the absolute values of test statistics from multiexposure epigenome-wide association studies (EWAS), and comparing the EWAS-derived CpGs mapped to each pathway to the empirical null distribution derived by 10,000 permutation samples. The overall procedure included permutation-based multiple testing correction. EWAS was done using linear mixed-effects models, with random intercept at the level of participant, and adjusted for age; sex; educational level; area; neighborhood socioeconomic status; greenness index; smoking status; smoking pack-years; exposure to passive smoke; consumption of fruits, vegetables, and alcohol; nested study; asthma status; noise truncation indicators; survey; and leukocyte composition. In a preliminary step, DNA methylation $\mathrm{\beta }$-values were regressed on the Illumina control probe-derived first 30 principal components to correct for correlation structures and technical bias, and residuals of these regressions covering 430,477 CpGs were used as the technical bias-corrected methylation level at the CpG sites. Extreme values of the residuals (lying beyond three times the interquartile range below the first quartile and above the third quartile at each CpG site) were replaced with their corresponding detection threshold value (“modified winsorization”). The “winsorized” data were then used as the dependent variables in the EWAS. BMI, body mass index; CAR, cardiac autonomic response; CpG, Cytosine-phosphate-Guanine; CRP, C-reactive proteins; eGFR, estimated glomerular filtration rate; FG, fasting glucose; HbA1c, glycated hemoglobin; Lden, day-evening-night noise level; ${\mathrm{NO}}_2$, nitrogen dioxide; ${\mathrm{PM}}_{2.5}$, particulate matter $<2.5\text{\hspace{0.17em}microns}$ in diameter; WC, waist circumference.