Table 4.

Association between male sex and cancer risk before and after adjustment for height, by anatomic site, Vitamin and Lifestyle (VITAL) cohort (n = 65 038)*

Cancer site	Model 1 Age and race adjusted†	Model 1A Age and race adjusted‡	Model 2 Age, race, and height adjusted§	Model 3 Age and covariable adjusted||	Model 4 Age, covariable, and height adjusted§,||
All shared-site cancers (n = 3466)¶, #
β (95% CI), male vs female	0.44 (0.37 to 0.51)	0.43 (0.34 to 0.51)	0.29 (0.19 to 0.40)	0.33 (0.19 to 0.47)	0.18 (0.01 to 0.34)
% reduction (95% CI); P value, in β vs model 1 or 1A**			33.8 (10.2 to 57.3); P = .005	23.1 (−9.4 to 55.5); P = .16	59.2 (19.9 to 98.5); P = .003
% reduction (95% CI); P value, in β vs model 3**					47.0 (−4.1 to 98.0); P = .07
HR (95% CI); P value, male vs female††	1.55 (1.45 to 1.66); P < .001	1.54 (1.41 to 1.67); P < .001	1.34 (1.21 to 1.48); P < .001	1.39 (1.21 to 1.60); P < .001	1.19 (1.01 to 1.41); P = .04
Gastrointestinal tract (n = 940)‡‡
β (95% CI), male vs female	0.33 (0.20 to 0.46)	0.29 (0.13 to 0.45)	0.25 (0.06 to 0.45)	0.16 (−0.10 to 0.39)	0.08 (−0.24 to 0.39)
% reduction (95% CI); P value, in β vs model 1 or 1A**			23.0 (−37.1 to 83.1); P = .45	45.5 (−43.7 to 134.7) P = .32	73.8 (−35.7 to 183.3) P = .19
% reduction (95% CI); P value, in β vs model 3**					51.9 (−149.1 to 252.9) to P = .61
HR (95% CI); P value, male vs female††	1.39 (1.22 to 1.58); P < .001	1.34 (1.14 to 1.57); P < .001	1.29 (1.06 to 1.56); P = .01	1.17 (0.90 to 1.52); P = .23	1.08 (0.79 to 1.48); P = .64
Colon and rectum (n = 491)
β (95% CI), male vs female	0.16 (−0.02 to 0.34)	0.18 (−0.05 to 0.40)	0.03 (−0.23 to 0.30)	0.25 (−0.11 to 0.60)	0.21 (−0.23 to 0.65)
% reduction (95% CI); P value, in β vs model 1 or 1A**			78.6 (−90.3 to 247.5); P = .36	<0; P = .70	<0; P = .89
% reduction (95% CI); P value, in β vs model 3**					15.7 (−160.6 to 192.0); P = .86
HR (95% CI); P value, male vs female††	1.17 (0.98 to 1.40); P = .08	1.20 (0.95 to 1.50); P = .12	1.04 (0.79 to 1.35); P = .80	1.28 (0.90 to 1.83); P = .17	1.23 (0.80 to 1.91); P = .35
Pancreas (n = 164)
β (95% CI), male vs female	0.17 (−0.14 to 0.47)	0.08 (−0.30 to 0.46)	−0.15 (−0.62 to 0.31)	−0.43 (−1.05 to 0.19)	−0.67 (−1.42 to 0.09)
% reduction (95% CI); P value, in β vs model 1 or 1A**			192.8 (−88.2 to 473.8); P = .18	NA; P = .10	NA; P = .05
% reduction (95% CI); P value, in β vs model 3**					<0; P = .54
HR (95% CI); P value, male vs female††	1.18 (0.87 to1.60); P = .29	1.08 (0.74 to 1.58); P = .68	0.86 (0.54 to 1.37); P = .52	0.65 (0.35 to 1.21); P = .17	0.51 (0.24 to 1.09); P = .08
Lung (n = 743)§§
β (95% CI), male vs female	0.36 (0.21 to 0.50)	0.29 (0.11 to 0.48)	0.36 (0.13 to 0.58)	0.03 (−0.21 to 0.27)	−0.01 (−0.32 to 0.31)
% reduction (95% CI); P value, in β vs model 1 or 1A**			1.1 (−60.6 to 62.8); P = .97	90.0 (7.9 to 172.2) to P = .03	102.7 (−5.7 to 211.2); P = .06
% reduction (95% CI); P value, in β vs model 3**					NA; P = .82
HR (95% CI); P value, male vs female††	1.43 (1.24 to 1.66); P < .001	1.34 (1.11 to 1.61); P = .002	1.43 (1.14 to 1.78); P = .002	1.03 (0.81 to 1.31); P = .81	0.99 (0.72 to 1.36); P = .96
Urinary system (n = 338)||||
β (95% CI), male vs female	0.97 (0.73 to 1.20)	0.87 (0.58 to 1.16)	0.56 (0.21 to 0.91)	0.70 (0.34 to 1.06)	0.39 (−0.10 to 0.87)
% reduction (95% CI); P value, in β vs model 1 or 1A**			42.0 (5.5 to 78.5); P = .02	19.0 (−22.8 to 60.9); P = .37	55.5 (−0.1 to 111.1); P = .05
% reduction (95% CI); P value, in β vs model 3**					45.0 (−23.7 to 113.7); P = .20
HR (95% CI); P value, male vs female††	2.63 (2.08 to 3.33); P < .001	2.38 (1.78 to 3.18); P < .001	1.75 (1.23 to 2.49); P = .002	2.02 (1.40 to 2.90); P < .001	1.47 (0.91 to 2.38); P = .12
Kidney (n = 191)
β (95% CI), male vs female	0.67 (0.37 to 0.97)	0.50 (0.14 to 0.86)	0.06 (−0.39 to 0.51)	0.46 (−0.01 to 0.92)	−0.04 (−0.65 to 0.57)
% reduction (95% CI); P value, in β vs model 1 or 1A**			90.9 (23.8 to 158.0); P = .008	9.3 (−83.2 to 101.9); P = .84	108.1 (−13.6 to 229.9); P = .08
% reduction (95% CI); P value, in β vs model 3**					109.0 (−25.3 to 243.2); P = .11
HR (95% CI); P value, male vs female††	1.95 (1.45 to 2.63); P < .001	1.66 (1.15 to 2.38); P = .006	1.06 (0.68 to 1.67); P = .79	1.58 (0.99 to 2.52); P = .06	0.96 (0.52 to 1.77); P = .90
Bladder (n = 123)
β (95% CI), male vs female	1.74 (1.26 to 2.22)	1.72 (1.11 to 2.33)	1.78 (1.11 to 2.46)	1.37 (0.66 to 2.07)	1.55 (0.66 to 2.45)
% reduction (95% CI); P value, in β vs model 1 or 1A**			<0; P = .91	20.5 (−20.6 to 61.5); P = .33	9.4 (−42.9 to 61.8); P = .72
% reduction (95% CI); P value, in β vs model 3**					< ; P = .68
HR (95% CI); P value, male vs female††	5.70 (3.53 to 9.20); P < .001	5.56 (3.03 to 10.23); P < .001	5.94 (3.03 to 11.64); P < .001	3.91 (1.94 to 7.91); P < .001	4.73 (1.93 to 11.62); P < .001
Melanoma (n = 349)¶¶
β (95% CI), male vs female	0.59 (0.38 to 0.81)	0.68 (0.41 to 0.94)	0.25 (−0.08 to 0.58)	0.77 (0.43 to 1.11)	0.32 (−0.13 to 0.77)
% reduction (95% CI); P value, in β vs model 1 or 1A**			57.3 (1.8 to 112.9); P = .04)	<0; P = .61	52.7 (−13.8 to 119.1); P = .12
% reduction (95% CI); P value, in β vs model 3**					58.2 (−0.5 to 116.9); P = .05
HR (95% CI); P value, male vs female††	1.81 (1.46 to 2.25); P < .001	1.97 (1.51 to 2.57); P < .001	1.29 (0.93 to 1.79); P = .13	2.16 (1.53 to 3.04); P < .001	1.38 (0.88 to 2.16); P = .16
Thyroid (n = 95)##
β (95% CI), male vs female	−1.09 (−1.56 to −0.62)	−0.99 (−1.52 to −0.47)	−1.13 (−1.81 to −0.45)	−1.27 (−2.01 to −0.52)	−1.33 (−2.24 to −0.43)
% reduction (95% CI); P value, in β vs model 1 or 1A**			<0; P = .90	<0; P = .47	<0; P = .46
% reduction (95% CI); P value, in β vs model 3**					<0; P = .89
HR (95% CI); P value, male vs female††	0.34 (0.21 to 0.54); P < .001	0.37 (0.22 to 0.62); P < .001	0.32 (0.16 to 0.63); P = .001	0.28 (0.13 to 0.59); P = .001	0.26 (0.11 to 0.65); P = .004
Hematologic malignancies (n = 693)***
β (95% CI), male vs female	0.49 (0.34 to 0.64)	0.49 (0.47 to 0.51)	0.25 (0.02 to 0.48)	0.53 (0.28 to 0.78)	0.34 (0.01 to 0.67)
% reduction (95% CI); P value, in β vs model 1 or 1A**			49.6 (2.4 to 96.8); P = .04	<0; P = .73	30.5 (−36.9 to 97.8); P = .38
% reduction (95% CI); P value, in β vs model 3**					36.2 (−25.5 to 98.0); P = .25
HR (95% CI); P value, male vs female††	1.63 (1.40 to 1.90); P < .001	1.63 (1.34 to 1.97); P < .001	1.28 (1.02 to 1.61); P = .04	1.70 (1.32 to 2.18); P < .001	1.40 (1.01 to 1.95); P = .04
Myeloid neoplasms (n = 169)
β (95% CI), male vs female	0.73 (0.42−1.05)	0.70 (0.30 to 1.09)	0.37 (−0.11 to 0.84)	0.69 (0.18 to 1.20)	0.34 (−0.32 to 1.01)
% reduction (95% CI); P value, in β vs model 1 or 1A**			50.2 (−14.8 to 115.2); P = .13	1.0 (−71.9 to 73.9); P = .98	50.6 (−44.6 to 145.8); P = .30
% reduction (95% CI); P value, in β vs model 3**					50.1 (−46.1 to 146.2); P = .31
HR (95% CI); P value, male vs female††	2.08 (1.51 to 2.86); P < .001	2.01 (1.35 to 2.99); P < .001	1.44 (0.89 to 2.32); P = .13	1.99 (1.20 to 3.31); P = .008	1.41 (0.73 to 2.74); P = .31
CLL/SLL (n = 112)
β (95% CI), male vs female	0.55 (0.16 to 0.93)	0.72 (0.20 to 1.23)	0.46 (−0.12 to 1.04)	0.78 (0.12 to 1.44)	0.74 (−0.13 to 1.60)
% reduction (95% CI); P value, in β vs model 1 or 1A**			15.6 (−91.2 to 122.4); P = .77	<0; P = .85	<0; P = .96
% reduction (95% CI); P value, in β vs model 3**					5.4 (−105.7 to 116.5); P = .92
HR (95% CI); P value, male vs female††	1.73 (1.18 to 2.53); P = .005	2.05 (1.23 to 3.41); P = .006	1.58 (0.89 to 2.83); P = .12	2.18 (1.13 to 4.22); P = .02	2.09 (0.88 to 4.96); P = .10
B-cell neoplasms other than CLL/SLL or plasma cell disorders (n = 264)
β (95% CI), male vs female	0.40 (0.15 to 0.64)	0.37 (0.07 to 0.68)	0.05 (−0.32 to 0.43)	0.41 (0.00 to 0.81)	0.11 (−0.42 to 0.64)
% reduction (95% CI); P value, in β vs model 1 or 1A**			86.5 (−6.9 to 179.8); P = .07	<0; P = .87	70.4 (−71.3 to 212.2); P = .33
% reduction (95% CI); P value, in β vs model 3**					72.9 (−57.0 to 202.8); P = .27
HR (95% CI); P value, male vs female††	1.49 (1.17 to 1.90); P = .001	1.45 (1.07 to 1.97); P = .016	1.06 (0.73 to 1.53); P = .78	1.50 (1.00 to 2.25); P = .05	1.12 (0.66 to 1.89); P = .68

* CI = confidence interval; CLL/SLL = chronic lymphocytic leukemia/small lymphocytic leukemia; HR = hazard ratio; NA: percent change in β from model 1, 1A, or 3 not calculated when β in model 1, 1A, or 3 was small (0–0.08).

† White, black, Hispanic, Asian/Pacific Islander, other race.

‡ All models 1A restricted to participants with complete data on all covariables in multivariable regression models (n = 45 726 in cohort; n = 2332 cases).

§ All models 2 and 4 were adjusted for height and height-squared.

|| All models 3 and 4 were adjusted for age, race, education (≤high school graduate, some college, ≥college graduate), marital status (never married, married/cohabitating, separated/divorced, widowed), body mass index (<25, 25–25.9, ≥30kg/m²), physical activity (none and tertiles of MET-hours/week), pack-years of smoking (continuous), pack-years squared (continuous), years smoked (continuous), alcohol at age 45 (none, <1, 1–2, ≥2 drinks/day), fruit and vegetable consumption (without potatoes; continuous), red meat consumption (continuous), energy intake (continuous), 10-year use of low-dose aspirin, regular-strength aspirin, or nonaspirin nonsteroidal anti-inflammatory drugs (as separate terms; nonuser, low use [<4 days/week or <4 years], high use [≥4 days/week for ≥4 years]), and self-rated health (excellent, very good, good, fair, poor). Alcohol intake at age 45 was included because it was a better predictor of total cancer incidence in this cohort than alcohol intake at baseline. Smoking was adjusted for by inclusion of three variables—pack-years, pack-years squared, and years smoked—because these three variables all contributed statistically significantly to lung cancer risk in this cohort. Models 3 and 4 are based on participants with complete data on all covariables (n = 45 726 in cohort; n = 2332 cases).

¶ Includes cancers of the gastrointestinal tract, lung, urinary system, head and neck, connective tissue, brain, and endocrine system, as well as melanoma and hematologic malignancies. Models 3 and 4 for shared-site cancers additionally adjusted for family history of colon cancer, lung cancer, hematologic malignancies, pancreatic cancer, melanoma, or bladder cancer (as separate terms; yes/no); sigmoidoscopy in the past 10 years (yes/no), years of estrogen therapy (never, 1–4, 4.1–9, >9), years of combined hormone therapy (never, 1–4, 4.1–9, >9), 10-year use of acetaminophen (nonuser, low use [<4 days/week or <4 years], high use [≥4 days/week for ≥4 years]), diabetes (yes/no), pancreatitis (yes/no), high blood pressure medication use (yes/no), kidney disease (yes/no), chronic obstructive pulmonary disease (yes/no), fatigue (yes/no), rheumatoid arthritis (yes/no), freckles at 10–20 years (yes/no), three or more sunburns at 10–20 years (yes/no), red/blond hair at 10–20 years (yes/no), reaction to 1 hour in strong sunlight (severe sunburn/blisters, painful sunburn/peeling, mild burn/tan, tan/no sunburn, don’t know), personal history of nonmelanoma skin cancer (yes/no), and history of mole biopsy (yes/no).

# Major categories do not add up to 3466 cases because of exclusion of cancer sites with less than 100 cases.

** Percent reduction in β is based on model 2 vs model 1, model 3 vs model 1A, model 4 vs model 1A, and model 4 vs model 3. Note that this “proportion” is not bounded by 0 and 1. A less than 0% reduction in β means that after adjustment for explanatory factors, the sex difference became greater than before adjustment. A greater than 100% reduction in β means that after adjustment for mediators, women are at greater risk than men. Two-sided P-values are provided for the hypothesis that the βs for sex in the models with and without height were equal (see Methods section for details).

†† Two-sided P values are provided for the association between male sex and cancer risk.

‡‡ Besides cancers of colon/rectum and pancreas, contains cancers of esophagus, stomach, liver, small intestines, anus and anal canal, gall bladder, biliary tract, and other or ill-defined digestive organs. Models 3 and 4 for cancers of the gastrointestinal tract additionally adjusted for family history of colon cancer or pancreatic cancer (as separate terms; yes/no); sigmoidoscopy in the past 10 years (yes/no), years of estrogen therapy (never, 1–4, 4.1–9, >9), years of combined hormone therapy (never, 1–4, 4.1–9, >9), diabetes (yes/no), and pancreatitis (yes/no).

§§ Models 3 and 4 for lung cancer additionally adjusted for family history of lung cancer (yes/no) and chronic obstructive pulmonary disease (yes/no).

|||| Besides cancers of kidney and bladder, contains cancers of renal pelvis, ureter, and other/unspecified urinary organs. Models 3 and 4 for urinary cancers additionally adjusted for family history of bladder cancer (yes/no), high blood pressure medication use (yes/no), and kidney disease (yes/no).

¶¶ Models 3 and 4 for melanoma additionally adjusted for family history of melanoma (yes/no), freckles at 10–20 years (yes/no), three or more sunburns at 10–20 years (yes/no), red/blond hair at 10–20 years (yes/no), reaction to 1 hour in strong sunlight (severe sunburn/blisters, painful sunburn/peeling, mild burn/tan, tan/no sunburn, don’t know), personal history of nonmelanoma skin cancer (yes/no), and history of mole biopsy (yes/no).

## Models 3 and 4 for thyroid cancer additionally adjusted for years of estrogen therapy (never, 1–4, 4.1–9, >9) and years of combined hormone therapy (never, 1–4, 4.1–9, >9).

*** Models 3 and 4 for hematologic malignancies additionally adjusted for: family history of hematologic malignancies (yes/no), 10-year use of acetaminophen (nonuser, low use [<4 days/week or <4 years], high use [≥4 days/week for ≥4 years]), fatigue (yes/no), and rheumatoid arthritis (yes/no).