Symptoms of Sleep Disordered Breathing and Risk of Cancer: A Prospective Cohort Study

SYMPTOMS OF SDB AND RISK OF CANCER: A PROSPECTIVE COHORT STUDY http://dx.doi.org/10.5665/sleep.3030 Symptoms of Sleep Disordered Brething nd Risk of Cncer: A Prospective Cohort Study Anne Sofie Christensen, BSc 1,2 ; Alice Clrk, MSc 1,2 ; Pul Slo, PhD 3,4 ; Peter Nymnn, PhD 5 ; Peter Lnge, DMSc 1,6,7 ; Ev Prescott, DMSc 6,8 ; Nj Hulvej Rod, PhD 1,2 1 Deprtment of Public Helth, University of Copenhgen, Copenhgen, Denmrk; 2 Copenhgen Stress Reserch Center, Copenhgen, Denmrk; 3 Finnish Institute of Occuptionl Helth, Helsinki, Finlnd; 4 Deprtment of Psychology, University of Turku, Finlnd; 5 Privte Prctice, Copenhgen, Denmrk; 6 The Copenhgen City Hert Study, Frederiksberg Hospitl, Copenhgen, Denmrk; 7 Section of Respirtory Medicine, Hvidovre Hospitl, Copenhgen, Denmrk; 8 Deprtment of Crdiology, Bispebjerg University Hospitl, Copenhgen, Denmrk Study Objectives: Sleep disordered brething (SDB) hs been ssocited with oxidtive stress, inflmmtion, nd ltered hormonl levels, ll of which could ffect the risk of cncer. The im of the study is to exmine if symptoms of SDB including snoring, brething cesstions, nd dytime sleepiness ffect the incidence of totl cncer nd subtypes of cncer. Design: Prospective cohort study. Setting: The third wve (1991-1993) of the Copenhgen City Hert Study. Prticipnts: There were 8,783 men nd women in whom cncer hd not been previously dignosed. Mesurements nd Results: Prticipnts nswered questions bout snoring nd brething cesstions in 1991-1993, wheres informtion bout dytime sleepiness bsed on the Epworth Sleepiness Scle ws collected in subset of the prticipnts (n = 5,894) in 1998. First-time incidence of cncer ws followed until December 2009 in ntionwide cncer register. We found no overll ssocition between symptoms of SDB nd incident cncer. Yet, in the smll group with high dytime sleepiness, we observed surprisingly higher cncer incidence (hzrd rtio = 4.09; 95% CI 1.58-10.55) in persons younger thn 50 yers. We lso found higher risk of virus/immune-relted cncers (2.73; 1.27-5.91) nd lcohol-relted cncers (4.92; 1.45-16.76) mong persons with dytime sleepiness. More SDB symptoms were ssocited with higher risk of smoking-relted cncers (P trend : 0.04). Aprt from these findings there were no cler ssocitions between symptoms of sleep disordered brething nd cncer subtypes. Conclusion: We found very limited evidence of reltionship between symptoms of sleep disordered brething nd incidence of cncer. Keywords: Cncer, cohort study, dytime sleepiness, impired sleep, sleep disordered brething Cittion: Christensen AS; Clrk A; Slo P; Nymnn P; Lnge P; Prescott E; Rod NH. Symptoms of sleep disordered brething nd risk of cncer: prospective cohort study. SLEEP 2013;36(10):1429-1435. INTRODUCTION Sleep disordered brething (SDB) is prevlent condition in modern society, estimted to ffect 24% of men nd 9% of women. 1 SDB refers to rnge of sleep disorders chrcterized by brething cesstions during sleep, often ccompnied by snoring. 2 Most often the interruption of ventiltion is cused by prtil or complete closure of the upper irwy, lso known s obstructive sleep pne. 3 Such interruptions will cuse decresed blood oxygen sturtion nd sleep frgmenttion, which in mny instnces will led to dytime sleepiness. 4 SDB hs been ssocited with reduced qulity of life 5 nd higher risk of crdiometbolic disorders nd ll-cuse mortlity in number of studies, 6-8 but studies ssessing the reltionship between SDB nd cncer re few. 9-12 Experimentl nd observtionl studies hve shown tht sleep impirment is ssocited with severl fctors relted to cncer initition nd promotion such s inflmmtion, 13,14 oxidtive stress, 15,16 hormonl levels, 17-19 nd ltertions of the A commentry on this rticle ppers in this issue on pge 1409. Submitted for publiction November, 2012 Submitted in finl revised form Februry, 2013 Accepted for publiction Mrch, 2013 Address correspondence to: Nj Hulvej Rod, PhD, Deprtment of Public Helth, University of Copenhgen, Øster Frimgsgde 5, Postbox 2099, 1014 Copenhgen K, Denmrk; Tel: +45 3532 6735; Fx: +45 3535 1181; E-mil: nhuro@sund.ku.dk immune system. 20-22 Moreover, intermittent hypoxi, similr to tht experienced by ptients with SDB, hs been shown to enhnce cncer progression in mice. 9,10 In humns, SDB hs recently been ssocited with cncer mortlity in prospective cohort study. 12 The uthors found tht prticipnts with severe SDB hd n lmost five times higher risk of cncer deth thn those free of SDB. Cncer mortlity ws used s the outcome mesure in this study nd it ws therefore not possible to distinguish between the etiologic nd prognostic role of SDB. Tht SDB my lso be relevnt for cncer etiology ws recently emphsized by prospective study, 11 in which they found tht severity of SDB, bsed on the pne-hypopne index nd percentge of the nighttime spent with SO 2 less thn 90%, ws ssocited with higher risk of incident cncer. This study included 4,910 ptients investigted for suspected obstructive sleep pne who were followed up for medin of 4.5 yers, during which only 261 received dignosis of cncer, mking it difficult to distinguish between cncer subtypes with different etiology. In contrst, the current study is popultion bsed, hs longer follow-up, nd ddresses subtypes of cncer in ddition to totl cncer incidence. We hypothesize tht SDB my ffect cncer incidence through biologicl nd probbly lso behviorl pthwys. The objective of the current study is to determine the reltionship between symptoms of SDB including snoring, brething cesstions nd dytime sleepiness, nd risk of ll incident cncers s well s subtypes of cncer including lcohol-, smoking-, virus/ immune-, nd hormone-relted cncers in lrge prospective cohort study of 8,783 men nd women. SLEEP, Vol. 36, No. 10, 2013 1429 SDB nd Cncer Risk Christensen et l

METHODS Study Popultion The Copenhgen City Hert Study (CCHS) is Dnish longitudinl cohort study initited in 1976. An ge-strtified smple of 19,698 men nd women ge 20 to 93 yers ws drwn from the Centrl Popultion Registry nd invited to prticipte in the study. Of these, 14,223 individuls (72%) ttended the first exmintion in 1976-1978. A physicl exmintion ws performed nd the prticipnts completed comprehensive questionnire regrding vrious risk fctors. In the yers 1981-1983, 1991-1993, nd 2001-2003 the study popultion ws expnded nd dditionl study ssessments were performed for both new nd continuing study prticipnts. A totl of 10,135 persons prticipted in the third wve (1991-1993) of the study (response proportion: 61%) in which questionnire informtion on snoring nd brething cesstions ws collected. The third wve ws used s the bseline for the current study. Most of the prticipnts were Cucsin. All prticipnts gve written informed consent. More detiled description of the CCHS cn be found elsewhere. 23 Prticipnts in whom cncer ws previously dignosed t bseline (n = 730) or with invlid dtes of outcome were excluded (n = 2). Also excluded were prticipnts with missing informtion on ny of the covrites: eductionl ttinment (n = 113), smoking (n = 43), physicl ctivity (n = 47), lcohol consumption (n = 75), mritl sttus (n = 12), or body mss index (BMI; weight (kg)/height (m) 2 ) (n = 330). There were 4,860 women nd 3,923 men (8,783 in totl) who were eligible for the nlyses of snoring nd brething cesstions. In Jnury 1998, between wves, questionnire focusing on dytime sleepiness ws sent to the 9,118 persons still live from the third wve of the CCHS. 24 Of those invited, 6,794 persons returned the questionnire (response proportion: 75%). The yer 1998 ws used s the bseline for nlyses focusing on dytime sleepiness. Prticipnts in whom cncer ws dignosed (n = 688) or who hd missing informtion on covrites (n = 212) in the 1991-1993 CCHS questionnire were excluded gin, leving 3,288 women nd 2,606 men (5,894 in totl) eligible for the dytime sleepiness nlyses. Symptoms of SDB We ddressed three symptoms of SDB: snoring, brething cesstions during sleep, nd dytime sleepiness. Informtion on snoring nd brething cesstions were ssessed by the following two questions: Hve you or your prtner noticed tht you re snoring during sleep? nd: Hve you or your prtner noticed tht you hold your breth for long time ( stop brething ) during sleep?, with four possible responses: Seldom/never, Sometimes, Often/lwys, or I do not know. Dytime sleepiness ws mesured by the Epworth Sleepiness Scle (ESS), which is vlidted eight-item scle developed to mesure dytime sleepiness. 25 The items relte to the probbility (0 = never, 1 = slight, 2 = moderte, 3 = high) of dozing in eight situtions from everydy life. The eight scores re summed to obtin single score in the rnge of 0-24. The ESS scores were split into the following ctegories for our nlyses: 0-4, 5-9 (reference group), 10-15, nd 16-24. The ctegoriztion nd the choice of reference group ws bsed on previous reports tht the norml rnge is between 0-10, 25,26 combined with the finding tht very low score my indicte insomni 25 nd the fct tht scores 16 were exclusively found in ptients with moderte or severe SDB in one study. 25 Finlly, we combined snoring, brething cesstions, nd dytime sleepiness into one composite mesure of number of SDB symptoms. Points were obtined when reporting snoring sometimes or often/lwys, brething cesstions sometimes or often/lwys, nd scoring 10 on the ESS, yielding score rnging from 0 to 3. Two nd three symptoms were combined into one ctegory for the sttisticl nlyses, s only 84 prticipnts experienced ll three symptoms. Prticipnts who nswered I do not know to the questions bout snoring or brething cesstions nd prticipnts with missing informtion on ny of the symptoms of SDB were not included in these nlyses. Therefore only 3,647 men nd women were eligible for nlyses with number of SDB symptoms. Covrites Covrites included sex, ge, BMI (< 25, 25-29, 30), lcohol consumption (< 1, 1-7, 8-14, 15-21, 22+ drinks/week), smoking (never-smoker, ex-smoker, smoker of 1-14 g/dy, smoker of 15-24 g/dy, nd smoker of more thn 24 g/dy), eductionl ttinment (< 8, 8-10, 11 yers), physicl ctivity in leisure time (sedentry or very light ctivity, 2-4 h of light ctivity per w, more thn 4 h of light ctivity or 2-4 h of highlevel ctivity, nd more thn 4 h of high-level ctivity per week), mritl sttus (mrried/cohbitting, unmrried, seprted/ divorced, widowed), lung function (mesured by spirometry t bseline nd expressed s forced expirtory volume in 1 sec in percent of the predicted vlue), menopuse (yes/no) nd use of postmenopusl hormone therpy (yes/no). All covrites were mesured t bseline in 1991-1993. Follow-up Prticipnts were followed from the dte of the third exmintion until the dte of the first dignosis of cncer (n = 1,985), deth (n = 2,137), emigrtion out of Denmrk (n = 105), or end of follow-up on December 31, 2009 (n = 4,556). Thus, fewer thn 2% were lost to follow-up. Incidence of cncer nd deths were identified through linkge to ntionwide hospitl dischrge nd deth registries, nd the min outcomes of interest were ll incident cncers, s well s smokingrelted cncers (Interntionl Clssifiction of Diseses [ICD] 7-codes 140, 141, 143-149, 150, 157, 160-162, 180, 181 nd [ICD] 10-codes C0-C6.9, C9-C15.9, C25-C25.9, C30-C34.9, C38.4, C45, C46.2, C64-C68.9), lcohol-relted cncers (ICD7-codes 141, 143-146, 148-150, 155, 161 nd ICD10- codes C1-C6.9, C9-C15.9, C22-C24.9, C32-C32.9, C46.2), virus/immune-relted cncers (ICD7-codes 155, 171, 191, 200-202, 204 nd ICD10-codes C22-C24.9, C44-C44.9, C46, C53-C53.9, C82-C85.9, C91-C96.9), nd hormone-relted cncers (ICD7-codes 170, 172, 175, 177 nd ICD10-codes C50-C50.9, C54-C54.9, C56-C57.4, C61-C61.9). These re min subtypes of cncer nd it is worth noting tht some cncers will not fit into ny ctegory, wheres others fit into more thn SLEEP, Vol. 36, No. 10, 2013 1430 SDB nd Cncer Risk Christensen et l

Tble 1 Bseline chrcteristics of the 8,783 prticipnts from the third wve of the Copenhgen City Hert Study Totl popultion 1998 popultion Number of SDB symptoms b (n = 3,647) (n = 8,783) (n = 5,894) 0 (n = 1,218) 1 (n = 1,759) 2-3 (n = 670) Number of cncer cses (%) 1,985 (23) 1,097 (19) 171 (14) 350 (20) 131 (20) Men ge t bseline (SD) 57 (15.3) 55 (15.0) 50 (17) 54 (14) 55 (13) Men BMI (SD) 26 (4.4) 25 (4.2) 24 (4) 26 (4) 27 (4) Women, n (%) 4,860 (55) 3,288 (56) 784 (64) 877 (50) 219 (33) Schooling < 8 yers, n (%) 2,945 (34) 1,763 (30) 230 (19) 470 (27) 227 (34) Physiclly inctive, n (%) 1,056 (12) 584 (10) 80 (7) 146 (8) 85 (13) Living without prtner, n (%) 3,759 (43) 2,352 (40) 441 (36) 404 (23) 147 (22) High lcohol intke, n (%) 1,373 (16) 897 (15) 142 (12) 305 (17) 135 (20) Current smoker, n (%) 4,293 (49) 2,733 (46) 450 (37) 868 (49) 364 (54) The Dnish drinking limits in the 1990s were 14 drinks/week for women nd 21 drinks/week for men. b Prticipnts who nswered do not know to the questions bout snoring or brething cesstions nd prticipnts with missing informtion on ny of the symptoms of SDB were not included in the nlyses with number of SDB symptoms. Therefore only 3,647 men nd women were eligible for these nlyses. BMI, body mss index; SD, stndrd devition; SDB, sleep disordered brething. one, e.g., smoking- nd lcohol-relted cncers. The cncers were included in ll the ctegories tht they fit into. Sttisticl Anlysis We used the Cox proportionl hzrds model to ssess the reltionship between symptoms of SDB nd cncer incidence. Age ws included s the underlying time vrible, which llowed for thorough djustment for ge. Due to similrity of effects in the initil sex-specific nlyses the nlyses were combined for women nd men nd sex strtum vrible ws included to llow the bseline hzrd to differ by sex. Initilly, we estimted the ge-djusted hzrd rtios (HR) nd their 95% confidence intervls (95% CI) for incidence of totl cncer s well s subtypes of cncer in seprte models including snoring, brething cesstions, dytime sleepiness, nd number of SDB symptoms, respectively. We tested the ssumption of proportionl hzrds nd it ws not met for the reltionship between dytime sleepiness nd totl cncer, mening tht there ws n interction between dytime sleepiness nd ge s ge ws the underlying time vrible. This nlysis ws therefore split into two ge bnds (younger thn 50 yers nd 50 yers or older), in which the ssumption ws met. Multivrite models were fitted to djust for potentil confounding from bseline covrites. Potentil confounders were identified bsed on prior knowledge nd the method of Directed Acyclic Grphs 27 nd included ge, sex, BMI, mritl sttus, eductionl ttinment, physicl ctivity level, lcohol consumption, nd smoking. These confounders were included in ll multivrite nlyses. Additionl djustment for lung function ws performed in the smoking-relted cncer nlyses, 28,29 wheres menopusl sttus nd postmenopusl hormone therpy use ws included in the nlyses of hormone-relted cncers. 30-32 In sensitivity nlyses, we excluded the first 2 yers of follow-up to prevent reverse custion (e.g., yet undignosed cncer cusing dytime sleepiness). We lso performed secondry nlyses restricted to mrried/cohbitting prticipnts (n = 5,024), s we were concerned tht those who did not hve prtner might not be wre of their snoring or brething cesstions. RESULTS Bseline Chrcteristics At bseline, the 8,783 prticipnts hd men ge of 57 yers (rnge 21-93 yers), 4,860 were women (55%) nd 3,923 were men. Cncer ws dignosed in totl of 1,985 prticipnts during n verge follow-up time of 13 yers. The most frequent cncers were virus/immune-relted cncers (n = 559), followed by smoking-relted cncers (n = 490), hormonerelted cncers (n = 455) nd lcohol-relted cncers (n = 120). Bseline chrcteristics re shown in Tble 1. Almost two in three prticipnts (61%) experienced t lest one symptom of SDB. Snoring ws the most prevlent symptom (59%), followed by dytime sleepiness defined s n ESS score 10 (11%) nd brething cesstions (9%). Those with symptoms of SDB were older, hd higher BMI, nd were more likely to be men, hve low eduction, be physiclly inctive, live with prtner, drink bove the Dnish sensible drinking limits (> 21 drinks/week for men nd > 14 drinks/week for women), nd be current smokers compred to prticipnts with no symptoms. The 1998 popultion (n = 5,894) differed only in minor wys from the min popultion (n = 8,783) on these bseline vribles. When compring those with nd without prtner, those who did not hve prtner were much more likely to nswer I do not know to the questions bout snoring nd brething cesstions, wheres the responses to the ESS were similr in the two groups. Symptoms of SDB nd Totl Cncer Risk There were no cler ssocitions between snoring, brething cesstions, or the totl number of SDB symptoms nd totl cncer incidence (Tbles 2 nd 3). However, high levels of dytime sleepiness (ESS score of 16-24) were ssocited with higher cncer risk mong younger (younger thn 50 yers) (HR = 4.09, 95% CI 1.58-10.55), but not older prticipnts (0.87; 0.41-1.85). Nevertheless, there were no signs of doseresponse reltionship between the severity of dytime sleepiness nd the risk of totl cncer, nd the higher risk observed mong the younger prticipnts ws only bsed on five cncer cses. SLEEP, Vol. 36, No. 10, 2013 1431 SDB nd Cncer Risk Christensen et l

Tble 2 Risk of totl cncer ssocited with snoring nd brething cesstions mong the 8,783 Dnish men nd women from the third wve of the Copenhgen City Hert Study Age-djusted HR (95% CI) Multiple djusted HR (95% CI) b Totl cncer Number of cses IR / 10,000 yers Overll popultion (n = 8,783) 1,985 175 Snoring (n = 8,767) Seldom/rrely (n = 2,334) 436 138 1 (ref) 1 (ref) Sometimes (n = 3,713) 874 180 1.03 (0.92;1.16) 0.99 (0.88;1.11) Often/lwys (n = 1,429) 351 190 1.09 (0.95;1.26) 1.04 (0.90;1.21) Do not know (n = 1,291) 317 215 1.03 (0.89;1.20) 0.99 (0.85;1.16) Brething cesstions (n = 8,760) Seldom/rrely (n = 4,643) 992 161 1 (ref) 1 (ref) Sometimes (n = 663) 152 179 0.99 (0.83;1.18) 0.96 (0.80;1.14) Often/lwys (n = 103) 23 180 1.06 (0.70;1.61) 1.07 (0.70;1.62) Do not know (n = 3,351) 809 193 1.05 (0.95;1.15) 1.03 (0.93;1.14) The totl number of cncer cses ws 1,985, but becuse of missing vlues, the number of cses does not dd up to the totl. b Adjusted for ge, BMI, tobcco consumption, lcohol consumption, yers of schooling, physicl ctivity, mritl sttus. CI, confidence intervl; HR, hzrd rtio; IR, incidence rte. Tble 3 Risk of totl cncer ssocited with dytime sleepiness nd number of SDB symptoms mong the 5,894 Dnish men nd women from the third wve of the Copenhgen City Hert Study who lso responded in 1998 Age-djusted HR (95% CI) Multiple djusted HR (95% CI) b Totl cncer Number of cses IR / 10,000 yers 1998 popultion (n = 5,894) 1,097 191 Dytime sleepiness (ESS score) (n = 5,814) < 50 yers of ge (n = 2,008) (n = 2,003) 0-4 (n = 755) 61 72 1.00 (0.72;1.41) 0.97 (0.69;1.36) 5-9 (n = 1,005) 77 68 1 (ref) 1 (ref) 10-15 (n = 228) 17 66 0.98 (0.58;1.65) 0.99 (0.58;1.68) 16-24 (n = 15) 5 317 3.83 (1.53;9.56) 4.09 (1.58;10.55) 50 yers of ge (n = 3,886) (n = 3,811) 0-4 (n = 1,971) 497 281 1.07 (0.93;1.23) 1.03 (0.90;1.18) 5-9 (n = 1,457) 342 259 1 (ref) 1 (ref) 10-15 (n = 347) 83 274 1.12 (0.88;1.42) 1.10 (0.87;1.40) 16-24 (n = 36) 7 217 0.85 (0.40;1.80) 0.87 (0.41;1.85) Number of SDB symptoms c (n = 3,647) 0 (n = 1,218) 171 136 1 (ref) 1 (ref) 1 (n = 1,759) 350 202 1.22 (1.01;1.47) 1.18 (0.98;1.43) 2-3 (n = 670) 131 201 1.17 (0.92;1.48) 1.13 (0.89;1.44) P trend 0.14 0.27 The totl number of cncer cses ws 1,097 in the 1998 popultion, but becuse of missing vlues, the number of cses does not dd up to the totl. b Adjusted for ge, body mss index, tobcco consumption, lcohol consumption, yers of schooling, physicl ctivity, mritl sttus. c Symptoms include snoring (sometimes or often/lwys), brething cesstions (sometimes or often/lwys) nd ESS score 10. CI, confidence intervl; ESS, Epworth Sleepiness Scle; HR, hzrd rtio; IR, incidence rte; SDB, sleep disordered brething. The 1998 popultion consisted of 2,008 individuls below the ge of 50 yers nd 3,886 of 50 yers nd bove. Of those, 2,003 nd 3,811 individuls, respectively, reported vlid informtion on the ESS. Symptoms of SDB nd Risk of Cncer Subtypes The incidence of lcohol-relted cncers ws not ssocited with snoring, brething cesstions, or the number of SDB symptoms (Tbles 4 nd 5). Dytime sleepiness, however, with n ESS score in the rnge 16-24, ws ssocited with mrkedly higher risk of lcohol-relted cncers (HR = 4.92, 95% CI 1.45-16.76), lthough with no exposure-dependent effect. Adjusting for lcohol intke continuously only chnged the results mrginlly (results not shown). Smoking-relted cncers were not relted to snoring, brething cesstions, or dytime sleepiness (Tbles 4 nd 5). However, n exposure-dependent ssocition between number SLEEP, Vol. 36, No. 10, 2013 1432 SDB nd Cncer Risk Christensen et l

Tble 4 Risk of different subtypes of cncer ssocited with snoring nd brething cesstions mong the 8,783 Dnish men nd women from the third wve of the Copenhgen City Hert Study Alcohol-relted Smoking-relted Virus/immune-relted Hormone-relted N HR (95% CI) N HR (95% CI) b N HR (95% CI) N HR (95% CI) Number of cses 120 490 559 455 Snoring (n = 8,767 c ) Seldom/rrely 18 1 (ref) 78 1 (ref) 134 1 (ref) 125 1 (ref) Sometimes 50 1.09 (0.63;1.87) 212 1.10 (0.85;1.43) 243 1.01 (0.81;1.25) 200 0.83 (0.66;1.04) Often/lwys 30 1.25 (0.69;2.29) 100 1.18 (0.87;1.61) 91 1.07 (0.81;1.42) 72 0.85 (0.63;1.14) Do not know 22 1.59 (0.83;3.06) 88 1.24 (0.90;1.70) 89 1.04 (0.79;1.39) 58 0.60 (0.44;0.84) Brething cesstions (n = 8,760 c ) Seldom/rrely 56 1 (ref) 210 1 (ref) 306 1 (ref) 234 1 (ref) Sometimes 6 0.46 (0.20;1.07) 50 1.10 (0.81;1.51) 30 0.72 (0.49;1.05) 30 0.94 (0.64;1.38) Often/lwys 1 0.52 (0.07;3.78) 5 0.79 (0.32;1.92) 4 0.71 (0.26;1.92) 5 1.22 (0.50;2.97) Do not know 57 1.32 (0.89;1.94) 213 1.16 (0.94;1.42) 216 0.96 (0.79;1.15) 185 0.96 (0.79;1.18) Adjusted for ge, body mss index, tobcco consumption, lcohol consumption, yers of schooling, physicl ctivity, mritl sttus. b Adjusted for ge, body mss index, tobcco consumption, lcohol consumption, yers of schooling, physicl ctivity, mritl sttus, lung function. c Prticipnts with missing on lung function were excluded from the smoking-relted nlyses, hence the popultion ws smller in these: snoring (n = 8,761), brething cesstions (n = 8,664). dj, djusted; CI, confidence intervl; HR, hzrd rtio. Tble 5 Risk of different subtypes of cncer ssocited with dytime sleepiness nd number of SDB symptoms mong the 5,894 Dnish men nd women from the third wve of the Copenhgen City Hert Study who lso responded in 1998 Alcohol-relted Smoking-relted Virus/immune-relted Hormone-relted N HR (95% CI) N HR (95% CI) b N HR (95% CI) N HR (95% CI) Number of cses 61 257 324 259 Dytime sleepiness (ESS score) (n = 5,814 c ) 0-4 (n = 2,726) 27 0.90 (0.52;1.56) 125 0.94 (0.71;1.23) 163 1.07 (0.84;1.36) 136 1.05 (0.81;1.36) 5-9 (n = 2,462) 26 1 (ref) 94 1 (ref) 121 1 (ref) 101 1 (ref) 10-15 (n = 575) 4 0.70 (0.24;2.00) 28 1.34 (0.88;2.05) 31 1.17 (0.78;1.73) 21 0.92 (0.57;1.47) 16-24 (n = 51) 3 4.92 (1.45;16.76) 2 1.02 (0.25;4.18) 7 2.73 (1.27;5.91) 1 0.49 (0.07;3.51) Number of SDB symptoms d (n = 3,647 c ) 0 4 1 (ref) 25 1 (ref) 57 1 (ref) 47 1 (ref) 1 16 1.51 (0.49;4.66) 73 1.44 (0.90;2.29) 109 1.25 (0.89;1.74) 87 1.10 (0.76;1.59) 2-3 9 1.61 (0.47;5.53) 42 1.73 (1.03;2.91) 35 1.13 (0.72;1.76) 25 0.82 (0.49;1.36) P trend 0.49 0.04 0.46 0.55 Adjusted for ge, body mss index, tobcco consumption, lcohol consumption, yers of schooling, physicl ctivity, mritl sttus. b Adjusted for ge, body mss index, tobcco consumption, lcohol consumption, yers of schooling, physicl ctivity, mritl sttus, lung function. c Prticipnts with missing on lung function were excluded from the smoking-relted nlyses, hence, the popultion ws smller in these: dytime sleepiness (n = 5,774), symptoms (n = 3,616). d Symptoms include snoring (sometimes or often/lwys), brething cesstions (sometimes or often/lwys) nd ESS score 10. dj, djusted; CI, confidence intervl; ESS, Epworth Sleepiness Scle; HR, hzrd rtio; SDB, sleep disordered brething. of SDB symptoms nd smoking-relted cncers ppered when these mesures were summed (P trend : 0.04). Virus/immune-relted cncers were ssocited with dytime sleepiness, with prticipnts who hd n ESS score in the rnge 16-24 experiencing higher risk of these cncers (HR = 2.73, 95% CI 1.27-5.91). None of the dditionl mesures were relted to the incidence of virus/immune-relted cncers (Tbles 4 nd 5). The risk of hormone-relted cncers ws in generl not relted to snoring, brething cesstions, nor dytime sleepiness, lthough prticipnts who nswered I do not know to the question bout snoring hd lower risk (Tbles 4 nd 5). Adjustment for menopusl sttus nd use of hormone replcement therpy mong women only mrginlly ffected the estimtes (results not shown). The totl number of SDB symptoms ws not ssocited with the incidence of hormone-relted cncers. Anlyses restricted to prticipnts who were mrried or who hd cohbitting prtner t bseline (n = 5,024) showed results quite similr to the min nlyses (results not shown). Excluding the first 2 yers of follow-up only mrginlly ltered SLEEP, Vol. 36, No. 10, 2013 1433 SDB nd Cncer Risk Christensen et l

the results, with some ssocitions becoming slightly stronger (results not shown). DISCUSSION In this lrge study, with severl mesures of SDB symptoms nd register-bsed informtion on cncer incidence, we found very limited evidence of n ssocition between symptoms of SDB nd incidence of cncer. Yet, in the smll group with high dytime sleepiness (ESS 16), we observed surprisingly high cncer incidence. Dytime sleepiness ws relted to higher risk of totl cncer mong prticipnts younger thn 50 yers, nd to higher incidence of lcohol- nd virus/immune-relted cncers. However, these ssocitions must be interpreted cutiously becuse they were bsed on very few cses nd no dose-response reltion ws evident. Aprt from these findings, dose-response ssocition between the risk of smoking-relted cncers nd the number of SDB symptoms ws lso observed. The findings of the current study do not convincingly support n ssocition between symptoms of SDB nd cncer incidence, lthough we did observe some ssocitions between symptoms of SDB nd different cncer subtypes. Cmpos-Rodriguez et l. 11 reported more consistent ssocitions between mesures of SDB nd cncer incidence, lthough the ssocition seemed to be limited to men nd ptients younger thn 65 yers. These differences in results might be due to differences in ptient nd popultion smples. But it could lso be due to the different mesures of SDB, where Cmpos-Rodriguez et l. used the pne-hypopne index nd percentge of nighttime spent with SO 2 less thn 90% compred to the self-reported mesures SDB symptoms in the current study. In fct, the vlue of self-reported SDB symptoms s surrogtes for SDB cn be questioned. 33 Although dytime sleepiness mesured by the ESS hs previously been shown to discriminte well between persons with nd without SDB nd to correlte with the severity of SDB mesured by polysomnogrphy, 25 it is likely to be ffected by misclssifiction. A review evluting screening questionnires for SDB found tht symptom-bsed instruments hd men sensitivity nd specificity of 77% nd 53%, respectively, in nonptient popultion. 33 This exposure misclssifiction my hve bised our results towrd null, nd it is likely tht more consistent nd stronger ssocitions between SDB nd cncer incidence would hve been found, if more vlid mesure of SDB hd been vilble. We supplemented the ESS with snoring nd brething cesstions in composite mesure of SDB symptoms to increse the specificity, but when interpreting the results one should be wre tht the included symptoms of SDB re not identicl to SDB. Nieto et l. 12 found cler dose-response reltion between severity of SDB nd cncer mortlity (P trend : 0.005), nd n lmost five times higher risk of cncer deth mong prticipnts with severe SDB compred with those free of SDB. The mgnitude of these results mde us wonder if SDB is more importnt prognostic thn etiologic fctor for cncer, mening tht the incidence of cncer is not necessrily incresed in ptients with SDB, but tht they my hve worse prognosis compred with people without SDB. We therefore performed seprte nlysis with totl cncer mortlity s outcome nd found slightly stronger effect of the number of SDB symptoms on cncer mortlity compred with cncer incidence (dt not shown). Although the ssocition ws not of such mgnitude s reported by Nieto et l., 12 this might indicte tht SDB is stronger prognostic thn etiologic fctor in cncer. Further studies re needed to ddress this issue. Other possible cuses of impired sleep such s short sleep durtion (< 6 h) nd night shift work hve lso previously been linked to higher risk of overll cncer nd hormone-relted cncers, respectively. 34,35 These previous results on hormonerelted cncer re in contrst to our results of no ssocitions between symptoms of SDB nd hormone-relted cncers. To our knowledge, this is the first study to ddress cncer subtypes in reltion to SDB. Investigtions into the differences in effects of SDB on different cncer subtypes re therefore needed. In the current study, ge ws found to modify the ssocition between dytime sleepiness nd totl cncer risk, possibly indicting tht SDB my hve worse consequences in the young nd middle-ged compred with the older prticipnts. This is in line with the study by Cmpos-Rodriguez et l., 11 who likewise reported SDB to more strongly ffect cncer incidence in the younger ge group (younger thn 65 yers). We observed higher risk of lcohol-relted cncers ssocited with dytime sleepiness, which is likely due to residul confounding from lcohol misuse. It is possible tht prticipnts with high lcohol consumption obtin higher scores on the ESS due to their high consumption rther thn due to SDB. The ssocition between number of SDB symptoms nd smoking-relted cncers hs t lest three possible explntions. One is tht the SDB nd the ccompnying dytime sleepiness my increse the prticipnts cigrette consumption, hence lso heightening the rte of smoking-relted cncers. Residul confounding by smoking is second explntion, s smoking is n estblished risk fctor for SDB. 36 Third, the finding could be due to chnce. The risk of virus/immune cncers ws higher in the presence of dytime sleepiness. Immune suppression represents plusible explntion for this ssocition. Sleep hs been shown to support immune defense, nd sleep deprivtion hs therefore been ssocited with reduction of nturl immune responses in experimentl studies. 20,21 Such ltertions of the immune system might increse the risk of virus/immune-relted cncers s the immune system is involved in the defense ginst these cncers. 37 Strengths nd Limittions To the best of our knowledge, this is the first study to lso ddress cncer subtypes, when investigting the ssocition between SDB nd cncer incidence. The prospective design of the current study ensured temporlity between the symptoms of SDB nd cncer incidence, nd the lrge smple size llowed us to ddress cncer subtypes seprtely. The third wve of the CCHS included informtion on importnt socioeconomic, demogrphic nd, lifestyle fctors, llowing for thorough djustment for confounding. Linkge of civil registry numbers to ntionwide cncer register enbled identifiction of firsttime hospitl dmission for cncer nd llowed for nerly complete long-term follow-up. Prticipnts without prtner more often did not know if they snored or hd brething cesstions during sleep, nd smller proportion reported SDB symptoms compred with those who hd prtner. This rised the concern tht the mount of snoring nd brething cesstions ws underestimted mong those SLEEP, Vol. 36, No. 10, 2013 1434 SDB nd Cncer Risk Christensen et l

without prtner. However, when the nlyses were restricted to prticipnts who hd prtner, we found results quite similr to the min nlyses. In summry, the current study did not convincingly support our hypothesis tht SDB ffects the incidence of cncer. The results were essentilly negtive nd the few ssocitions observed were most often bsed on very few cses. Misclssifiction of exposure due to self-report of SDB my, however, hve bised our results in the null direction. The higher risk of virus/ immune-relted cncers mong persons with dytime sleepiness my reflect n effect of SDB on this cncer subtype, with ltertions of the immune system s plusible pthwy. Experimentl studies to ddress more directly the ssocitions between SDB nd the function of the immune system re needed to support this hypothesis. Further, future prospective studies will benefit from ddressing cncer subtypes in ddition to totl cncer. ACKNOWLEDGMENTS The uthors thnk the stff nd the prticipnts of the Copenhgen City Hert Study. 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