Using Cg05575921 methylation to predict lung cancer risk: a potentially bias-free precision epigenetics approach

Figures & data

Table 1. Clinical and demographic characteristics of NLST subjects by gender; count or mean (SD).

Var	Male	Female
N	1820	1261
Age	61.80 (5.01)	61.26 (4.83)
Race
White	1691	1190
African Am.	73	46
Asian	22	9
Other	34	16
Ethnicity
Hispanic	42	16
Education
8th Grade or less	37	9
9–11th	87	63
HS Graduate or GED	337	344
Post HS training	242	157
Some College	403	313
Bachelor’s Degree	349	175
Graduate School	327	170
Other	38	30
Marital Status
Never married	94	69
Married	1341	669
Divorced, separated or widowed	381	517
Other	4	6
BMI	28.29 (4.69)	27.38 (5.57)
Personal Hx Cancer	23	82
Family Hx Cancer	417	304
COPD	118	103
Current Smoker
N	840	654
Cg05575921 (%)	46.05 (14.05)	49.33 (13.77)
Former Smoker
N	980	607
Years quit	7.51 (5.12)	6.90 (4.73)
Cg05575921 (%)	65.58 (12.57)	69.21 (11.06)
Cigs per day	29.10 (11.28)	26.50 (9.84)
Pack year consumption	58.46 (24.51)	51.61 (19.75)
Screening status
T0-T2 cancer	57	29
Post screen cancer	26	23
Nodules, no cancer	533	397
No nodules, no cancer	1204	812

Figure 1. The relationship between cg05575921 methylation and smoking intensity (cigarettes per day) in currently smoking subjects with males at top (N = 840, trend p = 0.012, adj R-sq = 0.009, deviance explained = 1.162%) and females at bottom (N = 654, trend p = 0.084, adj R-sq = 0.007, deviance explained = 1.140%).

Figure 2. The relationship between cg05575921 methylation and pack year consumption in currently smoking subjects with males at top (N = 840, trend p < .001, adj R-sq = 0.039, deviance explained = 4.786%), and females at bottom (N = 654, trend p = 0.002, adj R-sq = 0.017, deviance explained = 2.017%).

Figure 3. The relationship between cg05575921 methylation and years of smoking cessation in subjects who have reported quitting smoking (N = 1535, trend p < .001, adj R-sq = 0.164, deviance explained = 16.741%).

Table 2. Survival model selection results.

Model	Vars	M	AIC	dAIC	AICwt	LL	Rank
1	Cg055	7	1545.5	6.1	0.029	−765.7	3
2	PY	7	1546.2	6.9	0.020	−766.1	4
3	Status	7	1554.4	15.0	<.001	−770.2	8
4	Demos	22	1567.8	28.4	<.001	−761.9	14
5	Cg055, PY	8	1539.4	0.0	0.613	−761.7	1
6	Cg055, Status	8	1546.4	7.0	0.019	−765.2	5
7	Cg055, Demos	23	1560.6	21.2	<.001	−757.3	12
8	PY, Status	8	1546.9	7.5	0.015	−765.4	6
9	PY, Demos	23	1559.3	19.9	<.001	−756.6	10
10	Status, Demos	23	1568.9	29.5	<.001	−761.4	15
11	Cg055, PY, Status	9	1540.8	1.4	0.303	−761.4	2
12	Cg055, PY, Demos	24	1553.1	13.7	<.001	−752.6	7
13	Cg055, Status, Demos	24	1561.4	22.0	<.001	−756.7	13
14	PY, Status, Demos	24	1560.2	20.8	<.001	−756.1	11
15	Cg055, PY, Status, Demos	25	1554.4	15.0	<.001	−752.2	9

Note. Spline knots for log(year) = −3.60, −0.59, 0.78, 1.35, 1.94

Table 3. Parameter estimates for best model.

Effect	Est	SE	Z	L95%	U95%	exp(Est)
gamma0	−7.814	1.121	−6.972	−10.011	−5.618	0.000
gamma1	0.976	0.198	4.939	0.589	1.363	2.653
gamma2	0.135	0.052	2.622	0.034	0.236	1.145
gamma3	−0.458	0.218	−2.097	−0.886	−0.030	0.633
gamma4	0.496	0.286	1.734	−0.065	1.057	1.642
Age	0.076	0.017	4.527	0.043	0.109	1.079
Cg05575921	−0.016	0.005	−2.990	−0.026	−0.005	0.984
PY	0.009	0.003	3.055	0.003	0.015	1.009

Note. Age was in every model; M = number of parameters; LL = log-likelihood; Rank of 1 = best.

Figure 4. The time-varying AUC (95% CIs) for the top five fitting models (in order of AIC fit, Model 5, 11, 1, 2, 6; see Table 2). The times were the quantiles of the event times (in years) .

Figure 5. Cumulative hazard (95% confidence ribbons) as a function of year on study, pack years consumption (PY), and Cg05575921. Values for the latter two are set at the 25th and 75th percentiles, and age is set to the mean of the sample. Curves are estimated based on the best fitting survival model (Table 3) .

Data availability statement

The genome-wide data included in this manuscript were prepared with funding from the United States National Institutes of Health (NIH). They are not yet publicly available.