31.05.

2013

Disturbed Sleep among COPD Patients is Longitudinally Associated with Mortality and Adverse COPD Outcomes

Disturbed Sleep among COPD Patients is Longitudinally Associated with Mortality and Adverse COPD Outcomes
Theodore A. Omachi, MD, MBA, Paul D. Blanc, MD, MSPH, [...], and Patricia P. Katz, PhD

Abstract
Objective
T o in v est ig a t e t h e cr oss-sect ion a l a ssocia t ion bet w een COPD sev er it y a n d dist u r bed sleep a n d t h e lon g it u din a l a ssocia t ion bet w een dist u r bed sleep a n d poor h ea lt h ou t com es.

Methods
9 8 a du lt s w it h spir om et r ica lly -con fir m ed COPD w er e r ecr u it ed t h r ou g h popu la t ion -ba sed, r a n dom dig it t eleph on e dia lin g . Sleep dist u r ba n ce w a s ev a lu a t ed u sin g a 4 -it em sca le a ssessin g in som n ia sy m pt om s a s: difficu lt y fa llin g a sleep, n oct u r n a l a w a k en in g , m or n in g t ir edn ess, a n d sleep du r a t ion a dequ a cy . COPD sev er it y w a s qu a n t ified by : FEV 1 a n d COPD Sev er it y Scor e, w h ich in cor por a t es COPD sy m pt om s, r equ ir em en t for COPD m edica t ion s a n d ox y g en , a n d h ospit a l-ba sed u t iliza t ion . Su bject s w er e a ssessed on e y ea r a ft er ba selin e t o det er m in e lon g it u din a l COPD ex a cer ba t ion s a n d em er g en cy u t iliza t ion a n d w er e follow ed for a m edia n 2 .4 y ea r s t o a ssess a ll-ca u se m or t a lit y .

Results
Sleep dist u r ba n ce w a s cr oss-sect ion a lly a ssocia t ed w it h cou g h , dy spn ea , a n d COPD Sev er it y Scor e bu t n ot FEV 1. In m u lt iv a r ia ble log ist ic r eg r ession , con t r ollin g for sociodem og r a ph ics a n d body -m a ss in dex , sleep dist u r ba n ce lon g it u din a lly pr edict ed bot h in ciden t COPD ex a cer ba t ion s (OR=4 .7 ; p=0 .0 1 8 ) a n d r espir a t or y -r ela t ed em er g en cy u t iliza t ion (OR=1 1 .5 ; p=0 .0 0 4 ). In Cox pr opor t ion a l h a za r ds a n a ly sis, con t r ollin g for t h e sa m e cov a r ia t es, sleep dist u r ba n ce pr edict ed poor er su r v iv a l (HR=5 .0 ; p=0 .0 1 3 ). For a ll ou t com es, t h ese r ela t ion sh ips per sist ed a ft er a lso con t r ollin g for ba selin e FEV 1 a n d COPD Sev er it y Scor e.

Conclusions
Dist u r bed sleep is cr oss-sect ion a lly a ssocia t ed w it h w or se COPD a n d is lon g it u din a lly pr edict iv e of COPD ex a cer ba t ion s, em er g en cy h ea lt h ca r e u t iliza t ion , a n d m or t a lit y .
Key words: ch r on ic

obst r u ct iv e pu lm on a r y disea se, cog n it iv e per for m a n ce, in som n ia , m or t a lit y ,

ou t com es

INTRODUCTION
Sleep qu a lit y is lik ely t o be pa r t icu la r ly im por t a n t in t h e set t in g of a ch r on ic, sy m pt om a t ic, a n d pr og r essiv e disea se su ch a s ch r on ic obst r u ct iv e pu lm on a r y disea se (COPD). COPD m a y lea d t o w or se sleep qu a lit y a n d in som n ia by v ir t u e of r espir a t or y sy m pt om s, su ch a s n oct u r n a l cou g h a n d dy spn ea . Mor eov er , poor sleep qu a lit y cou ld con t r ibu t e t o poor COPD-r ela t ed ou t com es su ch a s ex a cer ba t ion s or ev en m or t a lit y r isk . Su ch a dv er se effect s cou ld oper a t e t h r ou g h v a r iou s pa t h w a y s. Poor sleep qu a lit y cou ld lea d t o im pa ir ed cog n it ion , t h u s im pa ir in g COPD self-m a n a g em en t beh a v ior s [1 2 ]. A lt er n a t iv ely , poor sleep qu a lit y m a y im pa ir im m u n e fu n ct ion , con t r ibu t in g t o t h e lik elih ood or sev er it y of COPD ex a cer ba t ion s [3 4 ]. Poor sleep qu a lit y m a y a ct in w a y s t h a t depen d on t h e pr esen ce of u n der ly in g COPD, w h ich u n der scor es t h e n eed t o st u dy sleep dist u r ba n ce specifica lly in COPD popu la t ion s. In a r ecen t r ev iew of sleep a bn or m a lit ies in COPD, Kr a ch m a n a n d collea g u es con clu de t h a t it is
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Disturbed Sleep among COPD Patients is Longitudinally Associated with Mortality and Adverse COPD Outcomes

u n k n ow n w h et h er t h er e is a r ela t ion sh ip bet w een sleep qu a lit y a n d disea se sev er it y in COPD [5 ]. T h ey fu r t h er m or e n ot e t h a t it h a s y et t o be det er m in ed w h et h er poor sleep qu a lit y in pa t ien t s w it h COPD h a s a n effect on n eu r ocog n it ion [5 ]. T h is k n ow ledg e g a p m a y r eflect t h e cr oss-sect ion a l n a t u r e of t h e lim it ed st u dies t h a t h a v e dem on st r a t ed a lin k bet w een r espir a t or y sy m pt om s a n d sleep com pla in t s in COPD pa t ien t s [6 7 ]. In deed, t h er e h a s been a dea r t h of lon g it u din a l st u dies ex a m in in g t h e con sequ en ces of dist u r bed sleep in COPD, especia lly w it h r espect t o t h e ou t com e of m or t a lit y . In t h is a n a ly sis, w e sou g h t t o a ddr ess t h ese g a ps in t h e pu blish ed lit er a t u r e. Fir st , w e w ish ed t o con fir m t h e a n t icipa t ed a ssocia t ion bet w een in som n ia sy m pt om s a n d COPD sy m pt om s a n d sev er it y , sin ce su ch a cr oss-sect ion a l r ela t ion sh ip pr ov ides biolog ica l coh er en ce t o a n y sleep-r ela t ed a dv er se effect s w e m ig h t obser v e lon g er -t er m . Nex t , w e ex a m in ed w h et h er sleep dist u r ba n ce pr edict ed a dv er se ou t com es, in clu din g : COPD ex a cer ba t ion s, em er g en cy h ea lt h ser v ices u t iliza t ion , a n d ov er a ll su r v iv a l. W e a lso w ish ed t o in v est ig a t e w h et h er su ch a n a ssocia t ion w it h sleep dist u r ba n ce, if pr esen t , m ig h t be ex pla in ed solely by COPD sev er it y a n d w h et h er cog n it iv e dy sfu n ct ion , depr ession , or a n x iet y m ig h t m edia t e pa r t of t h e r ela t ion sh ip bet w een dist u r bed sleep a n d poor ou t com es. W e con du ct ed ou r st u dy on a n on -g oin g popu la t ion -ba sed lon g it u din a l COPD coh or t , u t ilizin g su ch da t a a s COPD sev er it y a n d lu n g fu n ct ion a ssessm en t s, st r u ct u r ed cog n it iv e fu n ct ion ev a lu a t ion s, a n d lon g it u din a l h ea lt h ca r e u t iliza t ion in for m a t ion , w it h lin k a g e t o m or t a lit y da t a .

METHODS
Overview
In 9 8 su bject s fr om a popu la t ion -ba sed st u dy w it h spir om et r ica lly -con fir m ed COPD, w e a dm in ist er ed st r u ct u r ed t eleph on e in t er v iew s a n d, t o obt a in m ea su r em en t s of cog n it iv e a n d lu n g fu n ct ion , w e con du ct ed su bject h om e v isit s. Sleep dist u r ba n ce w a s ev a lu a t ed u sin g fou r su r v ey it em s w h ich a ssessed in som n ia sy m pt om s. Disea se sev er it y w a s qu a n t ified w it h t h e COPD Sev er it y Scor e ba sed on in t er v iew r espon ses. Lu n g fu n ct ion w a s m ea su r ed spir om et r ica lly . Cog n it iv e fu n ct ion w a s a ssessed u sin g dir ect ly a dm in ist er ed v a lida t ed object iv e t est s of m em or y a n d ex ecu t iv e fu n ct ion du r in g su bject h om e v isit s. Depr essiv e a n d a n x iet y sy m pt om s w er e m ea su r ed du r in g st r u ct u r ed in t er v iew s u sin g v a lida t ed sca les. Su bject s w er e r e-a ssessed t h r ou g h st r u ct u r ed in t er v iew s on e y ea r a ft er ba selin e t o a scer t a in COPD ex a cer ba t ion s a n d r espir a t or y -r ela t ed h ospit a liza t ion s or em er g en cy depa r t m en t (ED) v isit s. Su bject s w er e follow ed for t h e ou t com e of a llca u se m or t a lit y , w h ich w a s det er m in ed by lin k a g e t o pu blica lly a v a ila ble da t a ba ses. A ll st u dy pr ocedu r es w er e a ppr ov ed by t h e Un iv er sit y of Ca lifor n ia Sa n Fr a n cisco Com m it t ee on Hu m a n Resea r ch .

Study Population
T h is st u dy w a s con du ct ed on t h e UCSF COPD coh or t , a n on g oin g popu la t ion -ba sed, lon g it u din a l st u dy of U.S. a du lt s, r a n g in g bet w een a g es 5 6 a n d 7 7 a t t h e t im e of ou r ba selin e a ssessm en t [8 ]. Resea r ch su bject s w er e in it ia lly iden t ified fr om t h r ou g h ou t t h e U.S. by r a n dom -dig it t eleph on e dia lin g . Su bject s w er e in clu ded in lon g it u din a l follow -u p if t h ey r epor t ed bein g dia g n osed by a ph y sicia n w it h a n a ir w a y disea se. In 2 0 0 6 a n d 2 0 0 7 , pa r t icipa n t s w h o liv ed in Nor t h er n Ca lifor n ia , a n d w er e t h u s log ist ica lly a ccessible t o in v est ig a t or s, w er e a sk ed t o pa r t icipa t e in a sin g le h om e v isit closely follow in g a st r u ct u r ed t eleph on e in t er v iew . In t h e h om e v isit , r esea r ch per son n el con du ct ed spir om et r y a n d cog n it iv e fu n ct ion m ea su r es on r esea r ch su bject s. Of t h e 3 2 6 g eog r a ph ica lly elig ible in div idu a ls fr om t h e la r g er coh or t , 2 5 1 (7 7 %) su ccessfu lly pa r t icipa t ed in a h om e v isit . Fr om t h ese 2 5 1 su bject s, w e iden t ified 9 8 su bject s w h o m et cr it er ia for COPD: FEV 1/FV C r a t io<0 .7 a n d a self-r epor t ed ph y sicia n s dia g n osis of COPD, em ph y sem a , or ch r on ic br on ch it is.

Measurements
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Disturbed Sleep among COPD Patients is Longitudinally Associated with Mortality and Adverse COPD Outcomes

Sleep Disturbance W e m ea su r ed sleep dist u r ba n ce u sin g fou r it em s con sist en t w it h m a jor cr it er ia for in som n ia a n d dr a w n fr om t h e Medica l Ou t com es St u dy sleep ba t t er y : (1 ) difficu lt fa llin g a sleep, (2 ) n oct u r n a l a w a k en in g , (3 ) m or n in g t ir edn ess, a n d (4 ) per ceiv ed sleep du r a t ion a dequ a cy [9 1 2 ]. It em s fr om t h e Medica l Ou t com es St u dy sleep ba t t er y su g g est iv e of sleep-disor der ed br ea t h in g , su ch a s m or n in g h ea da ch e a n d sn or in g , w er e ex clu ded beca u se t h e biolog ic pa t h w a y s in v olv ed in sleepdisor der ed br ea t h in g m a y be dist in ct fr om t h ose oper a t in g in in som n ia [9 1 0 ]. For ea ch of t h e fou r it em s, r espon ses a r e elicit ed con for m in g t o fiv e r espon se opt ion s, scor ed 0 t o 4 : n on e of t h e t im e, a lit t le of t h e t im e, som e of t h e t im e, m ost of t h e t im e, a ll of t h e t im e. T ot a l sleep dist u r ba n ce scor es for t h e fou r it em s cou ld t h er efor e r a n g e fr om 0 t o 1 6 , w it h h ig h er scor es in dica t in g g r ea t er in som n ia , w h ich w e dich ot om ized a t a cu t -off: scor e <8 vs scor e 8 . Ou r r a t ion a le for t h is cu t -poin t w a s t h a t is cor r espon ds t o a r espon se of som e of t h e t im e a v er a g ed ov er a ll fou r it em s (i.e. cor r espon ds t o a n a v er a g e scor e of 2 ou t of 4 ). T h is dich ot om iza t ion is a lso con sist en t w it h t h a t u sed in a la r g e It a lia n st u dy of sleep dist u r ba n ce in obst r u ct iv e lu n g disea se, w h ich u t ilized a com pa r a ble 1 6 -poin t sca le of in som n ia sy m pt om s [1 3 ]. Beca u se t h e fou r it em s u t ilized r epr esen t a su bset of t h e lon g er MOS sca le, w e w ish ed t o ev a lu a t e it s per for m a n ce ch a r a ct er ist ics a s pa r t of t h is a n a ly sis. A s det a iled below , w e t h er efor e ev a lu a t ed it s in t er n a l con sist en cy , r espon se dist r ibu t ion , a n d con cu r r en t v a lidit y . COPD Symptom and Severity W e con du ct ed spir om et r y , a ccor din g t o A m er ica n T h or a cic Societ y g u idelin es,[1 4 ] u sin g t h e Ea sy On e Fr on t lin e spir om et er (n dd Medica l T ech n olog ies, Ch elm sfor d, MA ) [1 5 1 6 ]. Ba sed on spir om et r ic r esu lt s, COPD w a s st a g ed by Globa l Obst r u ct iv e Lu n g Disea se cr it er ia [1 7 ]. By in clu sion cr it er ia , a ll su bject s h a d Globa l Obst r u ct iv e Lu n g Disea se (GOLD) st a g e 1 . Ox y g en sa t u r a t ion w a s a ssessed on r oom a ir du r in g h om e v isit s w it h st a n da r d pu lse ox im et r y , w it h t h e st u dy pa r t icipa n t sit t in g a t r est . W e a lso a ssessed COPD sev er it y u sin g t h e pr ev iou sly -v a lida t ed COPD Sev er it y Scor e, w h ich is ba sed on r espon ses t o su r v ey it em s t h a t com pr ise 5 dom a in s of sev er it y : dy spn ea , COPD-r ela t ed r equ ir em en t for sy st em ic cor t icost er oids a n d a n t ibiot ics, r eg u la r COPD m edica t ion u sa g e, pr ior COPD-r ela t ed h ospit a liza t ion s a n d in t u ba t ion s, a n d h om e ox y g en u se [1 8 ]. Scor es ca n r a n g e fr om 0 3 5 , w it h h ig h er scor es r epr esen t in g m or e sev er e COPD. T h e COPD Sev er it y Scor e dem on st r a t es bot h con cu r r en t a n d pr edict iv e v a lidit y a s a m ea su r e of COPD sev er it y , in clu din g a pr ospect iv e a ssocia t ion w it h COPD ex a cer ba t ion s a n d h ospit a liza t ion s t h a t is in depen den t of it s a ssocia t ion w it h ex er cise ca pa cit y a n d lu n g fu n ct ion [1 8 2 1 ]. COPD sy m pt om s w er e a ssessed a s bot h dy spn ea a n d cou g h du r in g ba selin e st r u ct u r ed in t er v iew s. T h e dy spn ea sca le u t ilized is a 0 7 poin t sca le w h ich in clu ded bot h it em s fr om t h e Medica l Resea r ch Cou n cil (MRC) Dy spn ea Sca le a s w ell a s t h e n u m ber of da y s or n ig h t s of dy spn ea sy m pt om s ov er t h e pr ior 2 w eek s. Su bject s w er e ca t eg or ized a s h a v in g cou g h sy m pt om s if t h ey v er ified eit h er da ily cou g h in g a t t a ck s or cou g h in g u p ph leg m fr om t h eir ch est or lu n g for m or e t h a n 3 m on t h s a y ea r for ea ch of t h e pa st 2 y ea r s, t h e la t t er bein g con sist en t w it h MRC cr it er ia for ch r on ic br on ch it is [2 2 ]. Psychological and Health Status Measurements Depr essiv e sy m pt om s w er e obt a in ed u sin g t h e 1 5 -it em sh or t for m Ger ia t r ic Depr ession Sca le (GDS). T h e GDS h a s been v a lida t ed bot h in n on -g er ia t r ic popu la t ion s g en er a lly a s w ell a s specifica lly in y ou n g er a du lt s w it h obst r u ct iv e lu n g disea se [2 3 2 6 ]. A n x iet y w a s a ssessed u sin g t h e a n x iet y por t ion of t h e Hospit a l A n x iet y a n d Depr ession (HA D) sca le [2 7 2 8 ]. W e u t ilized on ly t h e a n x iet y por t ion of t h is sca le beca u se t h e GDS is felt t o be a bet t er v a lida t ed m ea su r e of depr essiv e sy m pt om s in COPD t h a n t h e HA D. Ph y sica l a n d m en t a l h ea lt h st a t u s w er e m ea su r ed u sin g t h e Sh or t -For m (SF)-1 2 Ph y sica l Com pon en t Su m m a r y (PCS) a n d Men t a l Com pon en t Su m m a r y (MCS) scor es [2 9 ]. T h e SF-1 2 PCS a n d MCS a r e der iv ed fr om t h e Medica l Ou t com es St u dy SF-3 6 in st r u m en t , w h ich h a s been ex t en siv ely v a lida t ed in t h e g en er a l popu la t ion a n d a m on g a du lt s w it h COPD [3 0 ]. Hig h er scor es r eflect bet t er h ea lt h st a t u s.

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Disturbed Sleep among COPD Patients is Longitudinally Associated with Mortality and Adverse COPD Outcomes

Cognitive Status Du r in g t h e h om e v isit , ex a m in er s a ssessed su bject s cog n it iv e fu n ct ion u sin g t est s of bot h ex ecu t iv e fu n ct ion a n d m em or y . Beca u se of t h e com plex it y of ex ecu t iv e fu n ct ion , w e u t ilized t h r ee sepa r a t e t est s: t h e St r oop Color W or d In t er fer en ce t est , t h e Delis Ka pla n Ex ecu t iv e Fu n ct ion Sy st em (DKEFS) T r a il Ma k in g Set Sh ift in g Con dit ion t est , a n d t h e Ph on em ic V er ba l Flu en cy t est , a ll of w h ich a r e w ell-est a blish ed dir ect m ea su r em en t s of ex ecu t iv e fu n ct ion [3 2 3 6 ]. Lea r n in g a n d episodic m em or y w a s a ssessed u sin g t h e r ev ised Hopk in s V er ba l Lea r n in g T est (HV LT ), w h ich is essen t ia lly t h e n u m ber it em s fr om a 1 2 -it em w or d list r eca lled 2 0 m in u t es a ft er im m edia t e-r eca ll lea r n in g t r ia ls [3 7 ]. T h e r esu lt s of a ll cog n it iv e fu n ct ion m ea su r es w er e st a n da r dized (i.e., con v er t ed t o z-scor es), w h er e a z-scor e=0 is t h e popu la t ion m ea n of h ea lt h y a g e-m a t ch ed r efer en t s a n d a z-scor e=1 is on e st a n da r d dev ia t ion below t h is popu la t ion m ea n [3 6 3 9 ]. Covariates A g e, g en der , m a r it a l st a t u s, self-iden t ified r a ce (cla ssified a s n on -La t in o w h it e vs ot h er ), a n d edu ca t ion a l a t t a in m en t w er e a ssessed a s pa r t of t h e t eleph on e in t er v iew . Body m a ss in dex (BMI) w a s ca lcu la t ed fr om h eig h t a n d w eig h t m ea su r ed in t h e h om e v isit a n d ca t eg or ized a s u n der w eig h t (<1 8 .5 ), n or m a l (1 8 .5 u p t o 2 5 ), ov er w eig h t (2 5 .0 u p t o 3 0 ), a n d obese (3 0 ) u sin g st a n da r d cla ssifica t ion s [4 0 ]. Health Outcomes: COPD Exacerbations and Emergency Utilization Su bject s w er e a ssessed on e y ea r a ft er ba selin e t o ev a lu a t e t h e lon g it u din a l a ssocia t ion of ba selin e sleep dist u r ba n ce w it h bot h COPD ex a cer ba t ion s a n d r espir a t or y -r ela t ed em er g en cy u t iliza t ion (h ospit a liza t ion s or ED v isit s). For t h is lon g it u din a l a n a ly sis, 1 8 of t h e 9 8 su bject s w er e u n a v a ila ble for follow -u p in t er v iew , du e in pa r t t o su bject dea t h s (see below ). T h u s, t h is por t ion of t h e a n a ly sis w a s r est r ict ed t o t h e 8 0 su bject s a v a ila ble for r ea ssessm en t . T o r edu ce possible bia s fr om loss t o follow -u p, w e in cor por a t ed pr oba bilit y -of-a t t r it ion w eig h t in g s in t o ou r a n a ly ses for t h ese ou t com es, a s descr ibed below in st a t ist ica l a n a ly sis sect ion . Con sist en t w it h pr ev iou sly pr oposed g u idelin es, su bject s w er e ca t eg or ized a s h a v in g h a d a COPD ex a cer ba t ion if t h ey r epor t ed t h e pr escr ipt ion a n d u sa g e of n ew or a ddit ion a l sy st em ic cor t icost er oids du e t o w or sen in g r espir a t or y sy m pt om s [4 1 ]. Hospit a liza t ion s a n d ED v isit s w er e ca t eg or ized a s r espir a t or y -r ela t ed if su bject s iden t ified t h e pr im a r y ca u se of su ch u t iliza t ion t o be du e t o w or sen in g r espir a t or y st a t u s. For log ist ic r eg r ession a n a ly ses, COPD ex a cer ba t ion s a n d em er g en cy u t iliza t ion w er e dich ot om ized a s 1 ev en t vs n on e. All-Cause Mortality For t h e ou t com e of m or t a lit y , su bject s w er e follow ed t h r ou g h 1 2 /3 1 /2 0 0 8 , a m edia n follow -u p per iod of 2 .4 y ea r s (2 5 th 7 5 th in t er qu a r t ile r a n g e: 1 .4 2 .5 y ea r s). Min im u m follow -u p a m on g su r v iv in g su bject s w a s 1 .2 y ea r s. Beca u se w e ev a lu a t ed t h e lon g it u din a l a ssocia t ion bet w een dist u r bed sleep a n d r isk of a ll-ca u se m or t a lit y u sin g pr opor t ion a l h a za r ds a n a ly sis, t h is r equ ir ed n ot on ly con fir m a t ion of v it a l st a t u s bu t a lso da t e of dea t h . W e a ssessed v it a l st a t u s t h r ou g h 1 2 /3 1 /2 0 0 8 , n ot la t er , t o lea v e a dequ a t e t im e for r esea r ch su bject s t o be r eg ist er ed in pu blic da t a ba ses in t h e ev en t of t h eir dea t h . T h r ou g h con t a ct w it h t h e r esea r ch su bject s h ou seh old or fa m ily m em ber s, ou r r esea r ch per son n el w er e in for m ed of t h e dea t h of 1 2 of ou r 9 8 r esea r ch su bject s, a n d w e w er e a ble t o con fir m t h e da t e of dea t h u sin g t h e Socia l Secu r it y A dm in ist r a t ion in dex for 1 1 ou t of t h ose 1 2 su bject s. W e w er e u n a ble t o con fir m v it a l st a t u s for t h e 1 2 th su bject a n d so om it t ed t h is su bject fr om a n a ly sis; t h e r esu lt s of ou r a n a ly sis w er e n ot su bst a n t iv ely a ffect ed in sen sit iv it y a n a ly ses in w h ich w e eit h er a ssu m ed t h a t t h e 1 2 th su bject h a d died, u sin g a n est im a t ed dea t h da t e ba sed on con t a ct w it h fa m ily m em ber s, or a ssu m ed t h a t t h e 1 2 th su bject h a d n ot died (da t a n ot sh ow n ). W e w er e a ble t o con fir m t h a t t h e r em a in in g 8 6 su bject s w er e a liv e a s of 1 2 /3 1 /2 0 0 8 t h r ou g h dir ect con t a ct w it h t h ose su bject s (n =7 3 ), con t a ct w it h h ou seh old or fa m ily m em ber s (n =9 ), or qu er ies of t h e A ccu r in t da t a ba se of Lex is Nex is (n =4 ). T h ese 8 6 su bject s w er e a lso n ot list ed a s decea sed in t h e Socia l Secu r it y A dm in ist r a t ion da t a ba se.

Statistical Analysis
Internal Consistency and Concurrent Validity of Sleep Scale Items W e u t ilized Cr on ba ch s a lph a a n a ly sis t o ex a m in e t h e in t er n a l con sist en cy of t h e 4 -it em sleep sca le. Sin ce psy ch olog ica l fa ct or s a n d ov er a ll ph y sica l
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a n d m en t a l h ea lt h st a t u s a r e t h eor et ica lly r elev a n t con st r u ct s t o in som n ia sy m pt om s [4 2 4 4 ], w e ex a m in ed t h e cr oss-sect ion a l cor r ela t ion bet w een t h e 4 -it em sleep dist u r ba n ce sca le a n d depr essiv e sy m pt om s, a n x iet y sy m pt om s, a n d t h e SF-1 2 PCS a n d MCS u sin g Pea r son pr odu ct -m om en t cor r ela t ion s. Cross-Sectional Associations A ll m u lt iv a r ia ble a n a ly ses con t r olled for a g e, g en der , r a ce, m a r it a l st a t u s, edu ca t ion a l a t t a in m en t a n d BMI. W e u sed m u lt iv a r ia ble log ist ic r eg r ession a n a ly sis t o est im a t e t h e cr oss-sect ion a l a ssocia t ion bet w een sleep dist u r ba n ce a n d t h e v a r iou s m ea su r es of COPD sy m pt om s a n d sev er it y (Fig u r e 1 : Pathway #1 ). In ea ch of fiv e dist in ct a n a ly ses, t h e pr esen ce or a bsen ce of sleep dist u r ba n ce w a s t h e depen den t (ou t com e) in a m u lt iv a r ia ble a n a ly sis, a n d a sin g le m ea su r em en t of COPD sy m pt om s or sev er it y w a s t h e in depen den t (pr edict or ) of in t er est : (1 ) cou g h sy m pt om s, (2 ) dy spn ea , (3 ) COPD Sev er it y Scor e, (4 ) r est in g ox y g en sa t u r a t ion , (5 ) FEV 1.
Fi gur e 1 The study addr essed questi ons of c r oss-sec ti onal assoc i ati ons (Pathw ay s #1 and #2), questi ons of l ongi tudi nal assoc i ati ons (Pathw ay #3), and questi ons of c ogni ti v e def i c i ts or psy c hol ogi c al f ac tor s as potenti al medi ator s i n l ongi tudi nal assoc i ati ons (Pathw ay ...

In ou r a n a ly sis of cog n it iv e fu n ct ion , w e u t ilized m u lt iv a r ia ble lin ea r r eg r ession t o det er m in e t h e a ssocia t ion bet w een sleep dist u r ba n ce a n d ea ch m ea su r e of cog n it iv e fu n ct ion , ex pr essed a s a g ea dju st ed z-scor es (Fig u r e 1 : Pathway #2 ). T h a t is, ea ch of fou r cog n it iv e fu n ct ion v a r ia bles w a s t est ed a s a depen den t v a r ia ble in it s ow n m u lt iv a r ia ble lin ea r r eg r ession in w h ich sleep dist u r ba n ce w a s t h e in depen den t v a r ia ble of in t er est . Longitudinal Analyses Lon g it u din a l a n a ly ses ex a m in ed t h e pr edict iv e a ssocia t ion bet w een dist u r bed sleep a n d poor ou t com es (Fig u r e 1 : Pathway #3 ). Mu lt iv a r ia ble log ist ic r eg r ession a n a ly ses w er e u t ilized t o est im a t e t h e a ssocia t ion bet w een dist u r bed sleep a t ba selin e a n d t h e lik elih ood, ov er t h e en su in g 1 2 m on t h s, of (1 ) COPD ex a cer ba t ion s or , in a sepa r a t e m odel, (2 ) r espir a t or y -r ela t ed em er g en cy u t iliza t ion . Lon g it u din a l a n a ly ses a lso ex a m in ed t h e pr edict iv e a ssocia t ion bet w een dist u r bed sleep a t ba selin e a n d su bsequ en t a ll-ca u se m or t a lit y , occu r r in g ov er t h e per iod fr om ba selin e a ssessm en t u p t o t h e en d of t h e a ssessm en t per iod on 1 2 /3 1 /2 0 0 8 . For t h is a n a ly sis, w e u t ilized m u lt iv a r ia ble Cox pr opor t ion a l h a za r ds r eg r ession m odels (su r v iv a l a n a ly sis) t o det er m in e t h e lon g it u din a l a ssocia t ion bet w een ba selin e dist u r bed sleep a n d t im e u n t il su bsequ en t a ll-ca u se m or t a lit y ; per son t im e w a s cen sor ed for en d of t h e st u dy per iod w it h ou t m or t a lit y . In a ll lon g it u din a l a n a ly ses, w e con t r olled for t h e sa m e pot en t ia lly con fou n din g cov a r ia t es (sociodem og r a ph ics + BMI) a s in ou r cr oss-sect ion a l a n a ly ses. How ev er , in a ddit ion t o con t r ollin g for pot en t ia lly con fou n din g sociodem og r a ph ic cov a r ia t es a n d BMI (Model 1 ), w e a lso t est ed lon g it u din a l m odels in w h ich w e con t r olled for FEV 1 (Model 2 ), a n d FEV 1 + COPD Sev er it y Scor e (Model 3 ). T h e pu r pose of Model 2 a n d Model 3 w a s t o det er m in e w h et h er dist u r bed sleep w a s r ela t ed t o poor ou t com es in depen den t of t h e k n ow n a ssocia t ion bet w een FEV 1/COPD sev er it y a n d poor ou t com es. T h a t is, if t h e pa t h w a y is su ch t h a t COPD sev er it y ca u ses dist u r bed sleep, does su ch dist u r bed sleep con t in u e t o pr edict poor ou t com es a ft er t h e r ole COPD sev er it y is t a k en in t o a ccou n t ? In lon g it u din a l ou t com es a n a ly ses, w e a lso con du ct ed a m edia t ion a n a ly sis in w h ich w e ex a m in ed w h et h er poor cog n it iv e fu n ct ion , depr ession , or a n x iet y m ig h t m edia t e t h e r ela t ion sh ip bet w een dist u r bed sleep a n d poor ou t com es (Fig u r e 1 : Pathway #4) [4 5 ]. For ex a m ple, if dist u r bed sleep is r ela t ed t o poor cog n it iv e fu n ct ion , a n d dist u r bed sleep is a lso a ssocia t ed w it h poor ou t com es, does t h e a ssocia t ion bet w een dist u r bed sleep a n d poor ou t com es per sist a ft er con t r ollin g for su ch poor cog n it iv e fu n ct ion ? If n ot , t h is w ou ld su g g est t h a t poor cog n it iv e fu n ct ion is m edia t in g t h e r ela t ion sh ip bet w een dist u r bed sleep a n d poor ou t com es. In t h ese a n a ly ses, w e con t r olled, in t u r n , for cog n it iv e dy sfu n ct ion , depr essiv e sy m pt om s, or a n x iet y sy m pt om s, in a ddit ion t o sociodem og r a ph ic fa ct or s, BMI, FEV 1, a n d t h e COPD Sev er it y Scor e. Of t h e cog n it iv e dy sfu n ct ion m ea su r es, on ly m em or y im pa ir m en t w a s a ssocia t ed w it h dist u r bed sleep a n d, t h er efor e, m em or y
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im pa ir m en t w a s t h e on ly cog n it iv e dy sfu n ct ion m ea su r e t est ed in t h is m edia t ion a n a ly sis (a lon g w it h depr essiv e a n d a n x iet y sy m pt om s). T o ex a m in e w h et h er dist u r bed sleep a t ba selin e m ig h t m or e st r on g ly be a ssocia t ed w it h poor ou t com es a m on g su bject s w it h m or e a dv a n ced COPD a s com pa r ed t o less a dv a n ced COPD, w e con du ct ed a n ex plor a t or y secon da r y a n a ly sis in w h ich w e dich ot om ized ou r sa m ple in t o su bject s w it h m or e a dv a n ced COPD (GOLD st a g es 3 a n d 4 ; n =4 2 ) vs less a dv a n ced COPD (GOLD st a g es 1 a n d 2 ; n =5 6 ). In ea ch of t h ese t w o su b-g r ou ps, w e t h en r epea t ed log ist ic a n d Cox r eg r ession a n a ly ses. W e con du ct ed t h is a n a ly sis a s a u n iv a r ia t e a n a ly sis, in clu din g sleep dist u r ba n ce a s t h e on ly in depen den t (pr edict or ) v a r ia ble, beca u se t h e sm a ller sa m ple size pr oh ibit ed t h e in clu sion of m u lt iple in depen den t cov a r ia t es. For a ll a n a ly ses of t h e ou t com es of COPD ex a cer ba t ion s a n d r espir a t or y -r ela t ed em er g en cy u t iliza t ion , w e a pplied pr oba bilit y -of-a t t r it ion w eig h t s t o t a k e losses t o follow -u p in t o a ccou n t ; pr oba bilit y -of-a t t r it ion w eig h t s h a v e been sh ow n t o r edu ce bia s fr om n on -r espon se in lon g it u din a l coh or t st u dies [4 6 4 8 ]. In ou r st u dy , pr oba bilit y -of a t t r it ion w eig h t s w er e dev eloped u sin g t h e k ey sociodem og r a ph ic fa ct or s of st u dy in t er est a s w ell a s FEV 1, COPD Sev er it y Scor e, a n d sleep dist u r ba n ce a t ba selin e [4 6 4 8 ]. T h u s, w e dev eloped a m u lt iv a r ia t e log ist ic r eg r ession m odel t o det er m in e t h e pr oba bilit y of follow -u p a n d t h en w eig h t ed su bject s ba sed on t h eir lik elih ood of follow u p su ch t h a t t h ose w h o a r e less lik ely t o r e-in t er v iew w er e w eig h t ed m or e h ea v ily . A ll a n a ly ses u sed St a t a /SE v er sion 9 .2 (St a t a Cor p; Colleg e St a t ion , T X ). For a ll m u lt iv a r ia ble log ist ic r eg r ession m odels, t h e Hosm er -Lem esh ow t est dem on st r a t ed a dequ a t e g oodn ess-of-fit (p>0 .2 0 for a ll m odels) [4 9 ]. For su r v iv a l a n a ly ses, t h e pr opor t ion a l h a za r ds a ssu m pt ion w a s v er ified by obt a in in g sca led Sch oen feld r esidu a ls (p >0 .2 0 for a ll Cox m odels).

RESULTS
Subject Characteristics
Ba selin e su bject ch a r a ct er ist ics a r e pr esen t ed in T a ble 1 . A m on g 9 8 st u dy pa r t icipa n t s, t h e m ea n a g e w a s 6 7 .6 y ea r s (SD=5 .4 ), 5 6 % of pa t ien t s w er e w om en , a n d 8 5 % w h er e w h it e, n on -La t in o. T h er e w a s a br oa d r a n g e of BMI ca t eg or iza t ion s: 6 % u n der w eig h t , 3 2 % n or m a l w eig h t , 3 4 % ov er w eig h t , a n d 2 9 % obese or m or bidly obese. T h e deg r ee of COPD w a s m oder a t ely a dv a n ced, w it h a m ea n FEV 1 % pr edict ed of 5 4 % (SD=2 2 %). St a g ed by GOLD cr it er ia , w h er e h ig h er st a g e r epr esen t s m or e a dv a n ced COPD, 1 5 % of su bject s w er e St a g e 1 ; 4 2 % St a g e 2 ; 3 0 % St a g e 3 , a n d 1 3 % St a g e 4 .
Tab l e 1 Basel i ne c har ac ter i sti c s of 98 sub jec ts w i th COPD

Internal Consistency and Concurrent Validity of Sleep Scale Items

Ov er a ll, 2 4 .5 % of su bject s (n =2 4 ) m a n ifest ed dist u r bed sleep ba sed on t h e sleep sca le it em s. T h e Cr on ba ch s a lph a for t h e fou r sleep sca le it em s w a s 0 .7 1 , in dica t iv e of a dequ a t e in t er n a l con sist en cy . A t ba selin e, dist u r bed sleep on t h e fou r -it em sleep sca le w a s cor r ela t ed cr oss-sect ion a lly a n d in t h e a n t icipa t ed dir ect ion s w it h g r ea t er depr essiv e sy m pt om s (r =0 .4 1 ; p<0 .0 0 1 ) a n d g r ea t er a n x iet y sy m pt om s (r =0 .3 2 ; p=0 .0 0 1 ). Fu r t h er m or e, poor er sleep qu a lit y on t h e sleep sca le cor r ela t ed w it h w or se ov er a ll ph y sica l h ea lt h st a t u s (r =0 .3 1 ; p=0 .0 0 2 ) a n d m en t a l h ea lt h st a t u s (r =0 .2 1 ; p=0 .0 4 ).
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Association of Disturbed Sleep with COPD Symptoms and Severity

A s pr esen t ed in T a ble 2 , pa t ien t s w it h cou g h sy m pt om s (ju st ov er h a lf of t h e g r ou p) h a d t h r ee-fold g r ea t er lik elih ood of dist u r bed sleep (odds r a t io [OR]=3 .3 , 9 5 % con fiden ce in t er v a l [CI] = 1 .1 9 .7 ; p=0 .0 3 4 ). T h e deg r ee of dy spn ea a lso w a s a ssocia t ed w it h a h ig h er lik elih ood of dist u r bed sleep (OR=1 .4 per 1 poin t in cr em en t in dy spn ea sca le; 9 5 % CI 1 .1 1 .7 ; p = 0 .0 0 4 ). Gr ea t er COPD sev er it y , a s m ea su r ed by COPD Sev er it y Scor e, w a s a ssocia t ed w it h g r ea t er lik elih ood of sleep dist u r ba n ce (OR=1 .9 per SD in cr em en t in scor e; 9 5 % CI 1 .1 3 .2 ; p=0 .0 1 5 ). T h e lik elih ood of sleep dist u r ba n ce in pa t ien t s w it h h y pox em ia (ox y g en sa t u r a t ion a t r est 9 2 %) w a s in cr ea sed bu t n ot st a t ist ica lly sig n ifica n t ly (OR=2 .2 ; 9 5 % CI 0 .7 6 .5 ; p=0 .1 8 ). FEV 1 w a s n ot r ela t ed t o sleep dist u r ba n ce (OR=0 .9 7 ; 9 5 % CI 0 .4 2 .2 ; p=0 .9 4 ).

Tab l e 2 Cr oss-sec ti onal assoc i ati on of di stur b ed sl eep w i th COPD sy mptoms and sev er i ty among 98 COPD sub jec ts

Cognitive Function
Sleep dist u r ba n ce w a s a ssocia t ed w it h in cr em en t a lly w or se HV LT m em or y t est scor es (differ en ce in Z-scor e=0 .6 2 ; 9 5 % CI 1 .1 3 t o 0 .1 1 ; p=0 .0 1 8 ), bu t w a s n ot sig n ifica n t ly a ssocia t ed w it h in cr em en t a l differ en ces in a n y of t h e t h r ee t est s of ex ecu t iv e fu n ct ion (T a ble 3 ).

Tab l e 3 A ssoc i ati on b etw een sl eep di stur b anc e and c ogni ti v e dy sf unc ti on among 98 sub jec ts w i th COPD*

Longitudinal Analyses: Association between Sleep Disturbance and Health Outcomes

Sleep dist u r ba n ce pr edict ed bot h COPD ex a cer ba t ion s (OR=4 .7 ; 9 5 % CI 1 .3 1 7 ; p=0 .0 1 8 ) a n d r espir a t or y -r ela t ed em er g en cy u t iliza t ion (OR=1 1 .5 ; 9 5 % CI 2 .1 6 2 ; p=0 .0 0 4 ) ov er t h e en su in g y ea r (T a ble 4 ). In m u lt iv a r ia ble Cox pr opor t ion a l h a za r ds a n a ly sis ov er a m edia n of 2 .4 y ea r s, sleep dist u r ba n ce w a s a ssocia t ed w it h fiv e-fold in cr ea sed h a za r d of poor er su r v iv a l (h a za r d r a t io [HR]=5 .0 ; 9 5 % CI 1 .4 1 8 ; p=0 .0 1 3 ). W h en con t r ollin g for FEV 1 or FEV 1 a n d COPD Sev er it y Scor e, in a ddit ion t o sociodem og r a ph ic fa ct or s a n d BMI, sleep dist u r ba n ce r em a in ed lon g it u din a lly a ssocia t ed w it h ea ch of t h e t h r ee lon g it u din a l ou t com es ex a m in ed.
Tab l e 4 Longi tudi nal A nal y ses: Mul ti v ar i ab l e anal y ses of the assoc i ati on b etw een sl eep di stur b anc e at b asel i ne and sub sequent heal th outc omes

Mediation Analyses
In t h ese a n a ly ses, w e con t r olled a lt er n a t ely for m em or y im pa ir m en t , depr essiv e sy m pt om s, a n d a n x iet y sy m pt om s. A ddin g t h e HV LT m em or y t est t o m u lt iv a r ia ble m odels, sleep dist u r ba n ce m a in t a in ed it s pr edict iv e a ssocia t ion w it h ea ch of t h e t h r ee lon g it u din a l ou t com es a n d t h e poin t est im a t es did n ot declin e (T a ble 5 ), t h u s fa ilin g t o pr ov ide ev iden ce t h a t poor m em or y m edia t ed t h e r ela t ion sh ip bet w een sleep dist u r ba n ce a n d poor ou t com es [4 5 ]. W h en con t r ollin g for depr essiv e or a n x iet y sy m pt om s, sleep dist u r ba n ce w a s st ill pr edict iv e of dea t h a n d COPD-r ela t ed em er g en cy
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u t iliza t ion a t t h e 9 5 % con fiden ce lev el, bu t con fiden ce in t er v a ls in clu ded n o a ssocia t ion for t h e ou t com e of COPD ex a cer ba t ion s (T a ble 5 ). W h en a ddin g depr essiv e or a n x iet y sy m pt om s t o m u lt iv a r ia ble m odelin g , t h e poin t est im a t e for t h e a ssocia t ion bet w een sleep dist u r ba n ce a n d poor ou t com es a lso declin ed m odest ly for a ll lon g it u din a l ou t com es.

Tab l e 5 Medi ati on A nal y ses: Pr edi c ti v e assoc i ati on b etw een sl eep di stur b anc e and poor outc omes af ter c ontr ol l i ng f or memor y i mpai r ment, depr essi v e sy mptoms, or anx i ety sy mptoms

Secondary Analysis: Longitudinal Associations by GOLD Stage

A s sh ow n in T a ble 6 , sleep dist u r ba n ce a t ba selin e pr edict ed r espir a t or y -r ela t ed em er g en cy u t iliza t ion a n d m or t a lit y a m on g su bject s w it h m or e a dv a n ced COPD, bu t t h is r ela t ion sh ip w a s n ot st a t ist ica lly sig n ifica n t a m on g su bject s w it h less a dv a n ced COPD. T h e pr esen ce of sleep dist u r ba n ce a t ba selin e per fect ly pr edict ed a t lea st on e su bsequ en t ex a cer ba t ion a m on g su bject s w it h COPD GOLD st a g es 3 t o 4 , a n d t h u s t h e OR for t h e lon g it u din a l a ssocia t ion bet w een dist u r bed sleep a n d COPD ex a cer ba t ion s in t h is su b-g r ou p w a s u n defin ed.
Tab l e 6 Sec ondar y A nal y si s: A ssoc i ati on b etw een sl eep di stur b anc e at b asel i ne and sub sequent heal th outc omes, b y COPD GOLD stage

DISCUSSION
In t h is popu la t ion -ba sed, lon g it u din a l st u dy of per son s w it h COPD, w e fou n d t h a t dist u r bed sleep is pr edict iv e of ex a cer ba t ion s, r espir a t or y -r ela t ed em er g en cy u t iliza t ion , a n d a ll-ca u se m or t a lit y . T h is lon g it u din a l r ela t ion sh ip per sist ed ev en a ft er con t r ollin g for bot h FEV 1 a n d COPD Sev er it y Scor e, su g g est in g t h a t dist u r bed sleep is pla y in g a n in depen den t r ole a s a r isk fa ct or for poor ou t com es in COPD, r a t h er t h a n sim ply bein g a m a r k er of w or se disea se. A lt h ou g h sleep dist u r ba n ce w a s n ot r ela t ed t o FEV 1, ou r fin din g s dem on st r a t ed a n a ssocia t ion bet w een sleep dist u r ba n ce a n d bot h r espir a t or y sy m pt om s a n d COPD Sev er it y Scor e, in dica t in g t h a t sleep dist u r ba n ce is, on ba la n ce, a ssocia t ed w it h sev er it y of disea se in COPD. T h e la ck of a r ela t ion sh ip bet w een sleep qu a lit y a n d FEV 1 t h a t w e obser v ed is con sist en t w it h t h e fin din g s of Klin k a n d collea g u es [6 ]. A lt h ou g h per h a ps su r pr isin g , a n d t h er efor e im por t a n t t h a t t h e w or k of Klin k a n d collea g u es be r eplica t ed, w e n ot e t h a t t h e cor r ela t ion bet w een dy spn ea a n d FEV 1 is oft en low [5 0 ]. Reg a r dless, t h e COPD Sev er it y Scor e, a lt h ou g h m odest ly cor r ela t ed w it h FEV 1, is a st r on g pr edict or of poor ou t com es in COPD, a n d h ig h er COPD Sev er it y Scor es w er e a ssocia t ed w it h g r ea t er lik elih ood of dist u r bed sleep [1 8 2 1 ]. T h u s, by v ir t u e of a n effect -r espon se r ela t ion sh ip, ou r fin din g s su g g est t h a t COPD m a y in fa ct be con t r ibu t in g t o dist u r bed sleep, w h ich w ou ld pot en t ia lly low er on es t h r esh old, in t h e clin ic, for su spect in g sleep dist u r ba n ce in COPD pa t ien t s. Ou r fin din g s, h ow ev er , a lso su ppor t a bi-dir ect ion a lit y t o t h e r ela t ion sh ip bet w een dist u r bed sleep a n d disea se sev er it y in COPD. T h a t is, COPD sy m pt om s su ch a s cou g h a n d dy spn ea m a y be, in pa r t , r espon sible for poor sleep qu a lit y , y et dist u r bed sleep m a y in t u r n con t r ibu t e t o COPD ex a cer ba t ion s a n d g r ea t er COPD sev er it y . T h e fa ct t h a t dist u r bed sleep w a s lon g it u din a lly pr edict iv e of poor COPD-r ela t ed ou t com es, ev en a ft er r ig or ou sly con t r ollin g for COPD sev er it y w it h bot h FEV 1 a n d COPD Sev er it y Scor e in m u lt iv a r ia t e m odels, su ppor t s t h is con cept . T h is w ou ld be con sist en t w it h sleep dist u r ba n ce bein g pa r t of a v iciou s cir cle, w h er eby COPD con t r ibu t es t o poor sleep, w h ich in t u r n con t r ibu t es t o w or se COPD.
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Hy pot h et ica lly , if t h er e w er e a n in t er a ct ion bet w een COPD a n d dist u r bed sleep, w e m ig h t ex pect t h a t sleep dist u r ba n ce w ou ld pla ce su bject s w it h m or e a dv a n ced COPD a t h ig h er r isk of a dv er se ou t com es. Ou r sa m ple size lim it ed a r obu st a n a ly sis of t h is qu est ion , bu t t h e h ig h er est im a t es for m or t a lit y a n d r espir a t or y -r ela t ed em er g en cy u t iliza t ion a ssocia t ed w it h sleep dist u r ba n ce a t ba selin e, com pa r in g su bject s w it h GOLD st a g es 3 4 t o su bject s w it h GOLD st a g es 1 2 , w ou ld be con sist en t w it h su ch a n in t er a ct ion . How ev er , a su bst a n t ia lly la r g er sa m ple size a dequ a t e t o st a t ist ica lly ex a m in e a n in t er a ct ion effect w ou ld be n ecessa r y t o con clu siv ely est a blish su ch a fin din g . T h er e a r e sev er a l t h eor et ica l m ech a n ism s by w h ich sleep dist u r ba n ce cou ld con t r ibu t e t o w or sen in g COPD. It is t h ou g h t t h a t dist u r bed sleep, in g en er a l popu la t ion s, m a y a ffect m em or y , lea r n in g , a n d a bst r a ct pr oblem solv in g [5 1 5 3 ]. It is a lso k n ow n t h a t v er ba l m em or y im pa ir m en t in COPD pa t ien t s is a ssocia t ed w it h poor a dh er en ce t o m edica t ion s [1 , 5 1 ]. A lt er n a t iv ely , poor sleep qu a lit y is a lso k n ow n t o a ffect im m u n e fu n ct ion , a n d poor im m u n it y m a y be pa r t icu la r ly h a r m fu l for pa t ien t s w it h COPD in w h om in fect iou s et iolog ies m a y pr ecipit a t e COPD ex a cer ba t ion s [3 4 ]. Fin a lly , a lt h ou g h w e a t t em pt ed t o m ea su r e in som n ia sy m pt om s r a t h er t h a n sleep-disor der ed br ea t h in g sy m pt om s, it is possible t h a t n oct u r n a l h y pox em ia or ot h er n oct u r n a l r espir a t or y fa ct or s m a y h a v e con t r ibu t ed t o t h e obser v ed fin din g s. In ou r m odelin g , w e t est ed w h et h er poor ou t com es m ig h t h a v e r esu lt ed fr om cog n it iv e dy sfu n ct ion , depr ession , or a n x iet y r ela t ed t o sleep dist u r ba n ce. A lt h ou g h sleep dist u r ba n ce w a s in deed cr osssect ion a lly a ssocia t ed w it h poor m em or y , t h is did n ot a ppea r t o ex pla in t h e r isk for poor er ou t com es. A s ex pect ed, sleep dist u r ba n ce w a s cr oss-sect ion a lly a ssocia t ed w it h depr essiv e a n d a n x iet y sy m pt om s. T h is st u dy ca n n ot r esolv e w h et h er su ch psy ch olog ica l fa ct or s w er e t h e r esu lt or t h e ca u se of in som n ia sy m pt om s; pr ior r esea r ch , h ow ev er , h a s sh ow n t h a t in som n ia sy m pt om s do st r on g ly pr edict t h e su bsequ en t dev elopm en t of depr ession [4 3 ]. Reg a r dless, t h e cen t r a l obser v a t ion r em a in s t h a t sleep dist u r ba n ce pr edict ed dea t h a n d COPD-r ela t ed em er g en cy u t iliza t ion ev en a ft er con t r ollin g for depr essiv e or a n x iet y sy m pt om s, su g g est in g t h a t t h ese psy ch olog ica l fa ct or s do n ot en t ir ely ex pla in t h e r ole of sleep dist u r ba n ce. T h is st u dy h a s im por t a n t lim it a t ion s. T h e la ck of object iv e sleep-r ela t ed da t a , su ch a s t h a t obt a in ed fr om poly som n og r a ph y , does n ot per m it u s t o m or e fu lly u n der st a n d t h e et iolog y of t h e sleep dist u r ba n ce w e ch a r a ct er ized; for ex a m ple, w h et h er it is r ela t ed, a t lea st in pa r t , t o sleep-dist u r bed br ea t h in g or h y pox em ia . It is cer t a in ly possible t h a t dist u r bed sleep, a s a ssessed in ou r st u dy , w a s a m a n ifest a t ion of n oct u r n a l h y pox em ia . Secon d, a lt h ou g h t h e Medica l Ou t com es St u dy sleep sca le h a s been psy ch om et r ica lly v a lida t ed in a v a r iet y of popu la t ion s, a n d w e con du ct ed ou r ow n a n a ly sis of per for m a n ce ch a r a ct er ist ics, t h is sleep qu est ion n a ir e h a s n ot been v a lida t ed a g a in st object iv e m ea su r es of sleep qu a lit y su ch a s poly som n og r a ph y da t a . Non et h eless, t h ese qu est ion s h a v e st r on g fa ce v a lidit y by v ir t u e of t h eir con sist en cy w it h m a jor cr it er ia u sed for in som n ia . T h ir d, t h e w ide con fiden ce in t er v a ls in ou r lon g it u din a l a n a ly ses, especia lly for t h e ou t com es of COPD ex a cer ba t ion s a n d em er g en cy u t iliza t ion , lim it ou r a bilit y t o a ccu r a t ely est im a t e t h e a ct u a l m a g n it u de of t h e a ssocia t ion bet w een sleep dist u r ba n ce a n d poor ou t com es, a lt h ou g h t h e fa ct t h a t t h e con fiden ce in t er v a ls ex clu ded u n it y len ds cr eden ce t o t h e pr esen ce of a n a ssocia t ion bet w een sleep dist u r ba n ce a n d poor ou t com es in t h e dir ect ion obser v ed. Nex t , w e m ea su r ed lu n g fu n ct ion spir om et r ica lly bu t beca u se of t h e popu la t ion -ba sed n a t u r e of r ecr u it m en t w it h in -h om e a ssessm en t s, a ddit ion a l m ea su r es of pu lm on a r y fu n ct ion w er e n ot fea sible. W e w er e u n a ble t o det er m in e, t h er efor e, w h et h er pu lm on a r y im pa ir m en t s su ch a s a ir -t r a ppin g or r edu ced diffu sin g ca pa cit y m ig h t be a ssocia t ed w it h sleep dist u r ba n ce. Loss t o follow -u p for t h e ou t com es of COPD ex a cer ba t ion s a n d em er g en cy u t iliza t ion is a n a ddit ion a l lim it a t ion . W e a t t em pt ed t o com pen sa t e for pot en t ia l bia ses by u t ilizin g pr oba bilit y -of-a t t r it ion m odels, bu t less a t t r it ion w ou ld h a v e pr ov ided g r ea t er con fiden ce in t h ese r esu lt s. Non et h eless, it is r ea ssu r in g t h a t t h e m or t a lit y a n a ly sis r eflect ed sim ila r r esu lt s, sin ce t h is a n a ly sis did n ot r equ ir e
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su bject r ea ssessm en t a n d t h er efor e w a s n ot su bject t o follow -u p loss. A lso, t h e ex a cer ba t ion a n d u t iliza t ion ou t com es w er e det er m in ed by self-r epor t , a lbeit a t su bject follow -u p. Object iv e con fir m a t ion m ig h t h a v e pr ov ided m or e a ccu r a t e m ea su r em en t , bu t t h e a ppr oa ch of self-r epor t h a s been sh ow n t o be v a lid a n d r ea son a bly a ccu r a t e, especia lly for em er g en cy u t iliza t ion ser v ices [5 4 5 6 ]. A lt h ou g h t h er e is som e ev iden ce t h a t older a du lt s m a y t en d t o u n der -r epor t u t iliza t ion [5 5 ], u n der -r epor t in g w ou ld t en d t o dim in ish a n y obser v ed a ssocia t ion s w it h sleep dist u r ba n ce, a n d t h u s be a con ser v a t iv e bia s (t h a t is, bia sin g t ow a r d t h e n u ll). Fu r t h er m or e, it is a g a in r ea ssu r in g t h a t t h e m or t a lit y ou t com e, w h ich w a s con fir m ed t h r ou g h da t a ba se qu er ies, y ielded r esu lt s sim ila r t o t h e self-r epor t ed ou t com es. Ou r st u dy u n der scor es t h e pot en t ia l im por t a n ce of sleep qu a lit y in COPD. Sleep qu a lit y w a s a ssessed u sin g it em s w h ich elicit ed sy m pt om s r eflect in g m a jor cr it er ia for in som n ia , a n d dist u r bed sleep a s su ch pr edict ed poor er lon g it u din a l ou t com es in COPD, ev en a ft er con t r ollin g for COPD sev er it y . In t er v en t ion a l t r ia ls t h a t specifica lly t a r g et in som n ia sy m pt om s, eit h er by v ir t u e of COPD con t r ol focu sed specifica lly on n oct u r n a l sy m pt om s or beh a v ior a l t h er a pies t a r g et ed a t im pr ov ed sleep h y g ien e a n d sleep qu a lit y , w ou ld a ppea r w a r r a n t ed. A lt h ou g h fu r t h er in v est ig a t ion s a r e n eeded t o bet t er delin ea t e t h e ca u sa l pa t h w a y s a ccou n t in g for t h e pot en t a dv er se r isk s w e obser v ed, t h is st u dy su ppor t s t h e con clu sion t h a t dist u r bed sleep, a ssessed in t er m s of in som n ia sy m pt om s, is a pot en t ia l con t r ibu t or t o poor ou t com es in COPD.

Acknowledgments
F unding: Dr .

Om a ch i w a s su ppor t ed by K2 3 HL1 0 2 1 5 9 -0 1 fr om t h e Na t ion a l Hea r t , Lu n g , a n d Blood

In st it u t e, Na t ion a l In st it u t es of Hea lt h . Dr . Ka t z, Dr . Bla n c a n d r ecr u it m en t of t h e UCSF COPD coh or t w er e su ppor t ed by R0 1 HL0 6 7 4 3 8 fr om t h e Na t ion a l Hea r t , Lu n g , a n d Blood In st it u t e, Na t ion a l In st it u t es of Hea lt h .

ABBREVIATIONS
BMI COPD DKEFS ED HR HV LT FEV 1 FV C GOLD MRC OR SD body m a ss in dex ch r on ic obst r u ct iv e pu lm on a r y disea se Delis Ka pla n Ex ecu t iv e Fu n ct ion Sy st em

em er g en cy depa r t m en t h a za r d r a t io Hopk in s V er ba l Lea r n in g T est for ced ex pir a t or y v olu m e in 1 secon d for ced v it a l ca pa cit y Globa l Obst r u ct iv e Lu n g Disea se Medica l Resea r ch Cou n cil odds r a t io st a n da r d dev ia t ion

Footnotes
No authors have any conflicts of interest to disclose Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Article information
Sleep Med. Author manuscript; available in PMC 2013 May 1. Published in final edited form as:
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Sleep Med. 2012 May; 13(5): 476483. Published online 2012 March 18. doi: 10.1016/j.sleep.2011.12.007 PMCID: PMC3336048 NIHMSID: NIHMS366229 Theodore A. Omachi, MD, MBA,1,* Paul D. Blanc, MD, MSPH,2 David M. Claman, MD,1 Hubert Chen, MD, MPH,1 Edward H. Yelin, PhD,3,4 Laura Julian, PhD,4 and Patricia P. Katz, PhD3
1 Division 2 Division 3 Institute 4 Division

of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of California San Francisco of Occupational and Environmental Medicine, Department of Medicine, University of California, San Francisco for Health Policy Studies, University of California, San Francisco of Rheumatology, Department of Medicine, University of California, San Francisco

Theodore A. Omachi: omachi/at/ucsf.edu; Paul D. Blanc: paul.blanc/at/ucsf.edu; David M. Claman: david.claman/at/ucsf.edu; Hubert Chen: hubert.chen/at/ucsf.edu; Edward H. Yelin: ed.yelin/at/ucsf.edu; Laura Julian: laura.julian/at/ucsf.edu; Patricia P. Katz: patti.katz/at/ucsf.edu
* Corresponding

Author: Theodore A. Omachi, MD, MBA, University of California, San Francisco, Sleep Disorders Center, 2330 Post Street, #420, San

Francisco, CA 94115, Phone: 415-476-8058, Fax: 415-885-3650, Email: omachi/at/ucsf.edu Copyright notice and Disclaimer Publisher's Disclaimer The publisher's final edited version of this article is available at Sleep Med

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