NDN and CD1A are novel prognostic methylation markers in patients with head and neck squamous carcinomas

BMC Cancer

Table 4 Stratified Cox Proportional Hazards Analysis comparing overall survival time (OST) and recurrence/persistence free time (RPFT) by gene methylation

			Multivariable cox model	Stratified cox proportional hazards model
	Gene methylation^a	N^b	Multivariable HR (95 % CI)^c,d	Stratified model among HPV + ^c,e	Stratified model among HPV-^c,e	p-value^f
OST	CCNA1	341	1.13 (0.81, 1.59)	0.62 (0.25, 1.52)	1.25 (0.86, 1.81)	0.16
	NDN	346	2.35 (1.40, 3.94) **	3.12 (0.95, 10.21)	2.22 (1.25, 3.92)*	0.61
	CD1A	342	1.31 (1.01, 1.71)*	3.34 (1.88, 5.93)**	1.13 (0.84, 1.51)	0.001**
	DCC	344	1.30 (0.95, 1.78)	1.45 (0.59, 3.60)	1.28 (0.91, 1.79)	0.79
	p16	343	1.11 (0.93, 1.32)	0.76 (0.48, 1.19)	1.17 (0.97, 1.42)	0.08
	GADD45	340	0.88 (0.66, 1.17)	0.80 (0.43, 1.50)	0.91 (0.66, 1.25)	0.73
RPFT	CCNA1	334	0.81 (0.57, 1.14)	0.31 (0.13, 0.74)*	0.96 (0.66, 1.42)	0.02*
	NDN	339	1.86 (1.12, 3.07)*	2.08 (0.70, 6.19)	1.77 (1.00, 3.13)	0.79
	CD1A	335	1.24 (0.95, 1.62)	2.06 (1.21, 3.49)*	1.07 (0.79, 1.46)	0.04*
	DCC	337	1.32 (0.96, 1.83)	0.97 (0.40, 2.34)	1.37 (0.97, 1.94)	0.47
	p16	336	1.00 (0.84, 1.19)	0.91 (0.57, 1.46)	1.00 (0.84, 1.20)	0.72
	GADD45	333	1.12 (0.87, 1.46)	0.84 (0.49, 1.42)	1.23 (0.91, 1.66)	0.22

Each row represents the hazard ratios in the multivariable or stratified Cox Proportional Hazards model for each gene. The top panel lists all overall survival time models and the bottom panel lists all recurrence/persistence-free survival time models. ^aAll genes log-transformed to better fit the linear functional relationship between predictor and outcome ^bn number of subjects in models ^cAll methylation measurements standardized to interquartile ranges. HRs are interpreted as comparison between those with methylation in the 25th percentile compared to those with methylation in the 75th percentile ^dMultivariable HR calculated from a multivariable Cox Proportional Hazards model after controlling for: age, HPV status, disease site, stage, and comorbidity score in the OST model and age, HPV status, disease site and stage in the RPFT model. ^eMultivariable HR (95 % CI) calculated from a stratified multivariable Cox Proportional Hazards model to allow for differing baseline hazard functions for HPV+ and HPV- groups. These models include an interaction of HPV status and gene methylation. Hazards listed for each HPV group in the stratified models calculated from this interaction term. Stratified OST models control for: age, disease site, stage, and comorbidity score and stratified RPFT models control for: age, disease site and stage. ^fp-value for interaction term. *p-value < 0.05; **significance at the Bonferroni-adjusted p-value < 0.004

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