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KauppilaJH, e al. BMJ Open 2019;9:e024094. doi:10.1136/bmjopen-2018-024094
Open access
Finnish Na ional Esophago-Gas ic
Cance Coho (FINEGO) o s udying
ou comes a e oesophageal and gas ic
cance su ge y: a p o ocol o a
e ospec i e, popula ion-based,
na ionwide coho s udy in Finland
Joonas H Kauppila,1,2 Pasi Oh onen,3 Tuomo J Ka unen,4 A o Kokkola,5
Simo Laine,6 Tuomo Ran anen,7 A i Ris imäki,8 Ja i V Räsänen,9 Juha Saa nio,3
Ee o Sih o,10 Vesa Toikkanen,11 Tuula Ty äinen12
To ci e: KauppilaJH, Oh onenP,
Ka unenTJ, e al. Finnish
Na ional Esophago-Gas ic
Cance Coho (FINEGO) o
s udying ou comes a e
oesophageal and gas ic
cance su ge y: a p o ocol o
a e ospec i e, popula ion-
based, na ionwide coho
s udy in Finland. BMJ Open
2019;9:e024094. doi:10.1136/
bmjopen-2018-024094
►P epublica ion his o y and
addi ional ma e ial o his
pape a e a ailable online. To
iew hese iles, please isi
he jou nal online (h p:// dx. doi.
o g/ 10. 1136/ bmjopen- 2018-
024094).
Recei ed 9 May 2018
Re ised 10 Oc obe 2018
Accep ed 16 No embe 2018
Fo numbe ed a ilia ions see
end o a icle.
Co espondence o
D Joonas HKauppila;
joonas. kauppila@ oulu. i
P o ocol
© Au ho (s) (o hei
employe (s)) 2019. Re-use
pe mi ed unde CC BY-NC. No
comme cial e-use. See igh s
and pe missions. Published by
BMJ.
Abs AC
In oduc ion Su ge y o oesophageal and gas ic
cance s is associa ed wi h high mo bidi y, mo ali y and
poo quali y o li e pos ope a i ely. The Finnish Na ional
Esophago-Gas ic Cance Coho has been es ablished
wi h he aim o iden i ying ac o s ha could con ibu e o
imp o ed ou comes in oesophago-gas ic cance .
Me hods and analysis All pa ien s wi h oesophageal and
gas ic cance diagnosed in Finland be ween 1987 and
2015 will be iden i ied om he Finnish na ional egis ies.
The Finnish Cance Regis y and Finnish Pa ien Regis y
will be used o iden i y pa ien s ha ul il he inclusion
c i e ia o he s udy: (1) diagnosis o oesophageal, gas o-
oesophageal junc ion, o gas ic cance , (2) any su gical
ea men o he diagnosed cance and (3) age o 18
o o e a he ime o diagnosis. Clinical a iables and
complica ion in o ma ion will be e ie ed in ex ensi e da a
collec ion om he medical eco ds o he ele an Finnish
hospi als and comple e ollow-up o i al s a us om
S a is ics Finland. P ima y endpoin is o e all all-cause
mo ali y and seconda y endpoin s include complica ions,
eope a ions, medica ion use and sick lea es. Sub-s udies
will be implemen ed wi hin he coho o in es iga e
speci ic popula ions unde going oesophageal and gas ic
cance su ge y. The ini ial es ima ed sample size is 1800
pa ien s wi h su gically ea ed oesophageal cance and
7500 pa ien s wi h su gically ea ed gas ic cance .
E hics and dissemina ion The s udy has been app o ed
by he E hical Commi ee in No he n Os obo hnia, Finland
and The Na ional Ins i u e o Heal h and Wel a e, Finland.
S udy indings will be dissemina ed ia p esen a ions a
con e ences and publica ions in pee - e iewed jou nals.
In oduC Ion
Gas ic cance is he hi d, and oesophageal
cance he six h, leading cause o cance
dea h wo ldwide.1 The incidence o oesoph-
ageal adenoca cinoma is inc easing, while
ha o oesophageal squamous cell ca cinoma
and gas ic cance is dec easing in Finland,2
simila o o he Wes e n coun ies.3 The inci-
dence o gas ic cance is slowly dec easing in
majo i y o he coun ies ac oss he globe.4
Howe e , bo h cance s a e cha ac e ised by
poo su i al e en a e cu a i ely in ended
su ge y5–8 and a ‘ ex book ou come’ may
be achie ed in less han hal o he pa ien s
unde going oesophago-gas ic cance
su ge y.9 S udies on sick lea es,10 o pos op-
e a i e use o opioids as an ou come a e
oesophageal and gas ic cance su ge y a e
lacking, while hese a e impo an ou comes
o he pa ien s. I has been shown ha sick
lea es a ec o example job e en ion in
pa ien s wi h cance .11
Randomised ials in oesophageal and
gas ic cance ha e p o ided quali y
s eng hs and limi a ions o his s udy
►The main s eng h o he s udy is he popula-
ion-based design wi h comple e and accu a e as-
ce ainmen and ollow-up o all pa ien s diagnosed
wi h oesophageal o gas ic cance in Finland, coun-
e ac ing selec ion bias.
►The inclusion o mul iple po en ial con ounding ac-
o s om he egis ies and pa ien eco ds allows
accu a e analysis o a a ie y o exposu es and end
poin s.
►The sample size will la ge enough o enable obus
su i al and eg ession analyses in smalle sub-
g oups o pa ien s.
►The main limi a ions o he s udy a e he exclusion
o pa ien s no unde going su ge y and in o ma ion
lag o up o 2 yea s.
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Open access
e idence ha neoadju an —and adju an he apies
inc ease su i al12–15 and ha minimally in asi e su gical
app oaches educe, o a leas do no inc ease compli-
ca ions.16 17 Despi e hei good in e nal alidi y and lack
o bias, andomised con olled s udies in gene al ha e
limi ed ex e nal alidi y and applicabili y o gene al popu-
la ion, and hus need o be complemen ed by quali y
obse a ional s udies o eliably assess he e ec s o imple-
men a ion o ial esul s in o p ac ice.18 Addi ionally,
obse a ional s udies can p o ide e idence on ques ions
ha ha e no , o canno , be e alua ed in andomised
ials.18
In Finland, high-quali y egis y da a on hese cance s
is eadily a ailable.19 Despi e he good a ailabili y, he
exposu e and ou come da a in he egis ies a e no
de ailed enough o su gical esea ch. Because o small
popula ion (5.5 million) spa sely popula ing Finland,
he hospi als a e many, and he single-cen e coho s
con aining de ailed in o ma ion a e small, no neces-
sa ily gene alisable and ha e po en ial selec ion bias.
The e a e no p e ious coo dina ed na ionwide popula-
ion-based esea ch e o s wi h de ailed clinical da a on
oesophago-gas ic cance in Finland. To o e come hese
challenges, an ex ensi e e ospec i e na ionwide da a
collec ion om he pa ien medical eco ds is needed.
The Finnish Na ional Esophago-Gas ic Cance Coho
(FINEGO) was es ablished as a esea che -led e o o
coo dina e his e ospec i e da abase.
objec i es
The speci ic objec i es o he FINEGO a e:
►To es ablish impo an baseline da a on na ional and
egional ends and changes o e ime in oesophageal
and gas ic cance su ge y, pos ope a i e mo bidi y
and long- e m ou comes in Finland.
►To in es iga e associa ions be ween su geon and
hospi al olume and pos ope a i e mo bidi y and
mo ali y in oesophago-gas ic cance s.
►To assess he ele ance o clinical cha ac e is ics,
modi iable isk ac o s, such as p eope a i e eeding,
su gical app oach, ype o neoadju an ea men ,
o me hod o analgesia in ela ion o mo ali y and
mo bidi y ou comes, as well as cance su i o ship,
such as pos ope a i e medica ion use in oesopha-
go-gas ic cance .
►To in es iga e whe he his ological assessmen could
be used o p edic ion o p ognosis in oesophageal
and gas ic cance .
ME hods
A mul icen e FINEGO-collabo a i e has been es ablished
o conduc la ge-scale epidemiological, clinical and clini-
copa hological s udies in oesophago-gas ic cance s. The
collabo a i e includes one o wo senio consul an s uppe
gas oin es inal o ho acic su geons as he local p incipal
in es iga o s (PIs) om all academic cen es conduc ing
oesophageal and gas ic cance su ge y in Finland, as
well as senio consul an oesophago-gas ic pa hologis s
and bios a is icians. The pa icipa ing esea che s will
sign he needed p o essional con iden iali y consen s
o be allowed access o pa ien da a ob ained om he
egis ies.
s udy design
This s udy is a popula ion-based, na ionwide, e ospec i e
coho s udy in Finland. The ini ial s udy pe iod is om
1 Janua y 1987 o 31 Decembe 2015, wi h ollow-up un il
31 Decembe 2016. The s udy pe iod will be expanded
e e y 5 yea s o keep he coho upda ed o he mos
ecen da a.
Inclusion and exclusion c i e ia
The pa ien s ul illing he ollowing inclusion c i e ia a e
included in he s udy:
1. P ima y cance o epi helial o igin in he oesophagus,
he gas o-oesophageal junc ion o he s omach.
2. Pa ien ecei es su gical ea men o he cance , in-
cluding cu a i e, pallia i e, escue su ge y ha is, su -
ge y a e cu a i e chemo adia ion, o endoscopic cu-
a i e su ge y, such as endoscopic mucosal esec ion
and endoscopic submucosal dissec ion.
3. Age a leas o o e 18 yea s du ing he ime o
diagnosis.
Iden i ica ion o he s udy pa icipan s
The immu able, 11-digi pe sonal iden i ica ion numbe
assigned o each esiden in he coun y allows eliable
iden i ica ion and combining he egis y da a wi h
pa ien eco ds.20 The pa ien s will be iden i ied h ough
he Finnish Cance Regis y, and he Finnish Pa ien
Regis y by sea ching hese egis ies o cance diag-
noses (online supplemen a y able 1) and ope a ion
s a us and ope a ions codes (online supplemen a y able
2). The iden i ica ion h ough bo h egis ies is done o
ensu e nea 100% comple eness on oesophago-gas ic
cance diagnosis. The pa ien s unde going oesophageal
o gas ic cance su ge y will be iden i ied using he ope -
a ions codes in he Finnish Pa ien Regis y. The Finnish
Pa ien Regis y will p o ide he hospi al names and ope -
a ion da es, based on which he ele an pa ien eco ds
will be e ie ed om he a chi es o he hospi als in all
21 hospi al dis ic s in Finland.
da a collec ion
Regis y da a will be collec ed om The Finnish Cance
Regis y, The Finnish Pa ien Regis y, The Popula ion Regis e
Cen e, S a is ics Finland and The Social Insu ance Ins i u ion
(Kela)- egis y ( able 1). The quali y o da a in hese egis-
ies is known o be e y high21–24 and epo ing o he
egis ies is manda o y by he Finnish Law. These egis y
da a include he iden i ying in o ma ion, he a iables
ela ed o he socio-economy, and will be used o calcu-
la e he well- alida ed Cha lson’s Como bidi y Index
(online supplemen a y able 3)25 and annual hospi al
olumes. All egis y da a-de i ed a iables a e calcula ed
by a bios a is ician. The pa ien eco ds o he included
pa ien s iden i ied om he egis ies will be sc u inised by
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KauppilaJH, e al. BMJ Open 2019;9:e024094. doi:10.1136/bmjopen-2018-024094
Open access
he s udy nu ses and he in es iga o s using s anda dised
o ms o clinical a iables, including pa ien cha ac e is-
ics and su geon, ou come and complica ion in o ma ion
( able 1 and online supplemen a y ex 1). The clinical
a iables ha e been decided on by he in es iga o s in
he FINEGO g oup. Key a iables, such as hose om he
ope a ions cha s will be ex ac ed by one o he in es iga-
o s, while he nu se ex ac s in o ma ion no conside ed
p one o e o s, such as adminis a i e da a and labo a o y
esul s. All eco ds and he co esponding da a collec ion
o ms will be scanned and sa ed o la e use. The his o-
logical samples will be collec ed om he biobanks. These
o iginal, p ospec i ely collec ed diagnos ic slides om
he p eope a i e gas oscopy and he su gical specimen
will be sough om he biobanks’ a chi es o he s udy
pa ien s. The sample slides a e e ie ed acco ding o he
biobank policies, and scanned and digi ised in o a pic u e
o m o assessmen and e iew o he his ological pa am-
e e s and neoadju an ea men esponse ( able 1).
The iden i ying in o ma ion o he selec ed pa ien s
om each hospi al dis ic will be p o ided o he espec-
i e PIs and adminis a i e pe sonnel o ob aining he
pa ien eco ds da a om he heal hca e en i ies’ a chi es.
The ob ained egis y da a, medical and heal h eco ds
da a, as well as he digi ised his ological samples, will
be en e ed in o he s udy da abase and pseudonymised
using s udy iden i ie s a e he comple ion o he da a
collec ion. The ha d copies o some o he s udy da a will
be kep in a sa e deposi on he p emises o Uni e si y o
Oulu. The iden i ica ion a iables om he egis ies will
be kep in an enc yp ed and passwo d-p o ec ed ile wi h
limi ed access g an ed o only he main bios a is ician and
he PI o he p ojec . The pseudonymised coho wi hou
iden i ying in o ma ion is a ailable o he membe s o
he collabo a i e o sub-s udies wi hin he amewo k
speci ied below.
da a managemen and analysis plan
The da a managemen and analyses in his s udy will be
supe ised and conduc ed by an expe bios a is ician
(PO). A e inishing he da a collec ion, a coho p o ile
will be published. Fo he coho p o ile, numbe o new
yea ly cance cases and he yea ly numbe o ope a ed
cance s will be calcula ed based on he egis y da a.
The baseline cha ac e is ics, ha is, numbe o pa ien s
in each g oup o selec ed a iables will be epo ed in
ables. O e all all-cause mo ali y will be epo ed o
each cance ype based on he li e able me hod26 and
depic ed using Kaplan-Meie cu es.
Each o he sub-s udies will be planned in he collabo-
a i e wi h a de ailed a p io i s udy p o ocol desc ibing
he a ionale, aims, hypo hesis and s a is ical analysis plan
including app op ia e me hods, po en ial con ounding
and biases o he pa icula esea ch ques ion, as well as
he bios a is ician in ol ed in he analysis.
da a quali y assessmen
The da a quali y in he egis ies will be checked h ough
compa ing he collec ed clinical da a agains he da a,
namely ype o su ge y and umou s age ob ained om
he egis ies. In e nal audi , whe e a andom sample
Table 1 Da a sou ces and da ase in o ma ion
Da a sou ce Va iables
The Finnish Cance
Regis y
Pe sonal iden i ica ion numbe
(age, sex)
Diagnosis numbe
Da e o cance diagnosis
Tumou s age
The Finnish Pa ien
Regis y
Pe sonal iden i ica ion numbe
(age, sex)
Hospi al admissions da a
►Admi ing hospi al
►Da es o admission and
discha ge
►Diagnosis codes
►Ope a ions codes
The Popula ion Regis e
Cen e
Ma i al s a us
S a is ics Finland Educa ion le el
Da e o dea h
Causes o dea h
TheSocial Insu ance
Ins i u ion(Kela) egis y
Dispensed d ugs
►Type (Ana omical The apeu ic
Chemical (ATC)-code)
►Da e dispensed
►Amoun o dispensed d ug
Sick lea e (s a da e, end da e)
Pension in o ma ion (s a da e)
Pa ien eco ds Tumou s age in o ma ion
Anaes hesia in o ma ion
►Type o anaes hesia
►ASA classi ica ion*
Su ge y in o ma ion
►Type o su ge y
►Su geon olume
►Bleeding
►Ope a ion du a ion
Complica ions
►Acco ding o he
Esophagec omy
Complica ions Consensus
G oup
►Cla ien-Dindo classi ica ion
Oncological ea men
►Neoadju an and adju an
ea men
►T ea men modali y
►Complica ions
Pa hology
►Tumou loca ion and s age
►Lymph node yield and
esec ion adicali y
Hospi al and in ensi e ca e uni
s ay
Biobanks Scans o o iginal diagnos ic
slides
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4KauppilaJH, e al. BMJ Open 2019;9:e024094. doi:10.1136/bmjopen-2018-024094
Open access
o he pa ien eco ds o 50 pa ien s wi h oesophageal
cance and 50 pa ien s wi h gas ic cance will be e- e-
iewed by ano he in es iga o , and he di e ences
be ween he wo assessmen s will be checked agains he
o iginal da a collec ion. I he e a e signs o di icul ies in
he assessmen o ce ain a iables o sys ema ic e o s,
hese a iables will be audi ed in mo e de ail. As o now,
no ex e nal audi is planned, bu all s udy p o ocols, da a
iles, s a is ical syn ax used o ob ain he esul s and he
end-p oduc will be kep o u he po en ial audi s.
sample size
One o he main s eng hs is he la ge sample size o
he s udy. I is es ima ed ha a leas 6000 oesophageal
and 25 000 pa ien s wi h gas ic cance will be ound in
sc eening du ing he s udy pe iod. O hese pa ien s, es i-
ma ed 30% ha e been ope a ed o hei cance , yielding
es ima es o 1800 oesophageal and 7500 pa ien s wi h
gas ic cance o he s udy.
Wi h 1800 pa ien s wi h oesophageal cance , he es i-
ma ed powe would be >80% o eliably de ec weak
associa ions (HR =1.15), gi en an equal dis ibu ion o
pa ien s in he exposu e g oups. Wi h 7500 pa ien s wi h
gas ic cance , he powe would be >80 o de ec an associ-
a ion a he le el HR=1.07.
Pe missions and egis a ion
Rele an local pe missions and egis a ions a e ob ained
by he collabo a i e om all he 21 hospi al dis ic s,
namely he Lapland Hospi al dis ic , Länsi-Pohja Hospi al
Dis ic , Kainuun Social and Heal h Ca e Join Au ho i y,
The Hospi al dis ic o No he n Os obo hnia, Soi e,
The Hospi al Dis ic o Sou h Os obo hnia, Pi kanmaa
Hospi al Dis ic , Kan a-Häme Hospi al Dis ic , Vaasa
Hospi al Dis ic , Sa akun a Hospi al Dis ic , Hospi al
Dis ic o Sou hwes Finland, Ålands hälso- och sjuk å d,
Join Au ho i y o he Helsinki and Uusimaa Hospi al
Dis ic , Päijä -Häme Hospi al Dis ic , Kymenlaakso
Social and Heal h Se ices Ca e, Sou h Ka elia Social
and Heal h Ca e Dis ic (Ekso e), No h Ka elia Cen al
Hospi al and Honkalampi Cen e, Eas Sa o Hospi al
Dis ic , Sou h Sa o Social and Heal h Se ices, Kuopio
Uni e si y Hospi al Dis ic and The Cen al Finland
Hospi al Dis ic , as well as he ele an Biobanks, namely
Au ia Biobank, Helsinki Biobank, Biobank o Eas e n
Finland, Cen al Finland Biobank, No he n Finland
Biobank Bo ealis and Finnish Clinical Biobank Tampe e.
Indi idual in o med consen will no be sough om
he pa ien s whose da a a e used in his obse a ional
s udy. Ob aining he in o med consen has been wai ed
by he Finnish law. The s udy will be conduc ed in acco -
dance wi h he Decla a ion o Helsinki.
Pa ien and public in ol emen
Pa ien s o public we e no in ol ed in he de elopmen
o he esea ch ques ion and s udy design o conduc ing
he p esen s udy.
dIsCussIon
Oesophageal and gas ic cance s ha e poo p ognosis,
e en a e cu a i e su ge y.5 6 The p esen popula-
ion-based, na ionwide e ospec i e coho s udy will
p o ide in o ma ion on he ecen ime ends in he
ea men o oesophageal and gas ic cance and iden i y
new, and e i y p e iously iden i ied, modi iable ac o s
ela ed o mo bidi y, mo ali y and su i o ship a e
oesophageal and gas ic cance su ge y.
The s eng hs o he FINEGO-coho include i s popu-
la ion-based design wi h comple e and accu a e asce -
ainmen and ollow-up o all pa ien s diagnosed wi h
oesophageal o gas ic cance in Finland, coun e ac ing
selec ion bias. The combined use o egis y and pa ien
eco ds da a educes in o ma ion bias. The inclusion o
mul iple po en ial con ounding ac o s om he egis ies
and pa ien eco ds allows accu a e analysis o a a ie y
o exposu es and end poin s. The sample size will la ge
enough o enable obus su i al and eg ession analyses
in smalle sub-g oups o pa ien s. Compa ed wi h some
global collabo a i es, such as he Wo ldwide Esophageal
Cance Collabo a ion27 o Esophagec omy Complica ions
Consensus G oup,28 he FINEGO can con ibu e o he
scien i ic communi y by p oducing esul s in a eal-li e
se ing including all pa ien s ope a ed o oesophageal
and gas ic cance s in he coun y, while he collabo a-
i es ypically include a sample o pa ien s ope a ed in
high- olume cen es. Fu he mo e, he abo e-men ioned
collabo a i es include only oesophageal cance , while
he p esen s udy includes bo h oesophageal and gas ic
cance .
The e a e also limi a ions in he p esen s udy. The
e ospec i e s udy design is po en ially weake in da a
quali y, compa ed wi h a p ospec i e s udy. Howe e , he
e ospec i e design enables ob aining a la ge numbe
o pa ien s mo e quickly han a p ospec i e da a collec-
ion, and he da a quali y in he egis ies he coho is
based on is known o be e y high, and he manually
collec ed pa ien eco ds da a will be igo ously checked
and alida ed o quali y. Fu he mo e, a na ional quali y
egis y o hese pa ien s is going o be es ablished, and
he p ospec i e clinical da a collec ed in ha quali y
egis y can be la e used in he upda es o he FINE-
GO-coho o po en ially imp o e he quali y o he mo e
ecen da a. All pa ien s no unde going su ge y will be
excluded, because examining he pa ien eco ds o
all he pa ien s would inc ease he numbe o in ol ed
heal hca e en i ies signi ican ly o o e 250, educing
he easibili y o he da a collec ion. Pa ien s unde going
cu a i ely in ended o pallia i e chemo he apy and/o
adio he apy will be excluded, educing he possibili ies
o s udy pa ien s wi h dissemina ed disease o no eligible
o any ype o su ge y. The coho is planned o be
upda ed e e y 5 yea s, and he e is a lag o up o 2 yea s,
including quali y checks and con ols, be o e he egis y
da a is made a ailable o esea ch, p e en ing he s udy
g oup om ge ing he mos ecen da a o analysis
e en du ing he coho upda es. Howe e , his lag will
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KauppilaJH, e al. BMJ Open 2019;9:e024094. doi:10.1136/bmjopen-2018-024094
Open access
no educe he ela i e sample size conside ably and he
e ec on ollow-up in pe son-yea s is minimal due o high
mo ali y a es o he cance s. Fu he mo e, he e a e
some a iables, including smoking his o y and alcohol
use, ha a e no eco ded in he egis ies and canno be
eliably e ie ed om he pa ien eco ds, as hey a e no
ou inely eco ded by he heal hca e pe sonnel in a s uc-
u ed way. Howe e , he da a quali y and missing da a will
be me iculously checked be o e unning he sub-s udies,
and he missing da a will be aken in o accoun by using
mul iple impu a ion me hods in he analyses o educe
bias om missing da a.
Taken oge he , his popula ion-based, na ionwide
e ospec i e coho s udy will p o ide new e idence
ega ding a ious unanswe ed ques ions in oesophageal
and gas ic cance su ge y by combining epidemiolog-
ical and clinical da a, as well as complemen andomised
clinical ials by assessing hei indings in an unselec ed
popula ion.
Au ho a ilia ions
1Cance and T ansla ional Medicine Resea ch Uni , Uni e si y o Oulu and Oulu
Uni e si y Hospi al, Oulu, Finland
2Uppe Gas oin es inal Su ge y, Depa men o Molecula Medicine and Su ge y,
Ka olinska Ins i u e and Ka olinska Uni e si y Hospi al, S ockholm, Sweden
3Depa men o Su ge y, Oulu Uni e si y Hospi al, Oulu, Finland
4Depa men o Pa hology, Oulu Uni e si y Hospi al and Uni e si y o Oulu, Oulu,
Finland
5Depa men o Su ge y, Uni e si y o Helsinki and Helsinki Uni e si y Hospi al,
Helsinki, Finland
6The Di ision o Diges i e Su ge y and U ology, Tu ku Uni e si y Hospi al, Tu ku,
Finland
7Depa men o Su ge y, Uni e si y o Eas e n Finland and Kuopio Uni e si y
Hospi al, Kuopio, Finland
8Depa men o Pa hology and HUSLAB, Uni e si y o Helsinki and Helsinki
Uni e si y Hospi al, Helsinki, Finland
9Depa men o Gene al Tho acic and Oesophageal Su ge y, Hea and Lung Cen e,
Uni e si y o Helsinki and Helsinki Uni e si y Hospi al, Helsinki, Finland
10Depa men o Su ge y, Cen al Finland Cen al Hospi al, Jy askyla, Finland
11Depa men o Ca dio ho acic Su ge y, Hea Cen e , Tampe e Uni e si y Hospi al
and Uni e si y o Tampe e, Tampe e, Tampe e, Finland
12Depa men o Gas oen e ology and Alimen a y T ac Su ge y, Tampe e Uni e si y
Hospi al, Tampe e, Finland
Con ibu o s JHK de eloped he s udy idea, concep and design, ini ia ed he
collabo a i e p ojec , de eloped da a collec ion ools, ob ained pe missions and
unding and d a ed he s udy p o ocol. PO was in ol ed in he s a is ical design,
made subs an ial e isions o he p o ocol and was in ol ed in he o iginal
concep , s udy design and implemen a ion. TJK was in ol ed in design and
implemen a ion o he s udy, and e ised he p o ocol. AK was in ol ed in design
and implemen a ion o he s udy, and e ised he p o ocol. SL was in ol ed in
design and implemen a ion o he s udy, and e ised he p o ocol. TR was in ol ed
in design and implemen a ion o he s udy, and e ised he p o ocol. AR was
in ol ed in design and implemen a ion o he s udy, and e ised he p o ocol. JVR
was in ol ed in design and implemen a ion o he s udy, and e ised he p o ocol.
JS was in ol ed in design and implemen a ion o he s udy, and e ised he
p o ocol. ES was in ol ed in design and implemen a ion o he s udy, and e ised
he p o ocol. VT was in ol ed in design and implemen a ion o he s udy, and
e ised he p o ocol. TT was in ol ed in design and implemen a ion o he s udy,
and e ised he p o ocol. JHK is he gua an o .
Funding This wo k is suppo ed by esea ch g an s om he Sig id Jusélius
Founda ion (Sig id Juséliuksen Sää iö), The Finnish Cance Founda ion
(Syöpäsää iö) and O ion Resea ch Founda ion (O ionin Tu kimussää iö). The
unding sou ces ha e no ole in he design and conduc o he s udy; collec ion,
managemen , analysis and in e p e a ion o he da a; p epa a ion, e iew,
o app o al o he manusc ip ; o decision o submi he s udy p o ocol o
publica ion.
Compe ing in e es s None decla ed.
Pa ien consen o publica ion No equi ed.
E hics app o al The E hical Commi ee in No he n Os h obo nia; The Na ional
Ins i u e o Heal h and Wel a e; S a is ics Finland and he O ice o he Da a
P o ec ion Ombudsman.
P o enance and pee e iew No commissioned; ex e nally pee e iewed.
open access This is an open access a icle dis ibu ed in acco dance wi h he
C ea i e Commons A ibu ion Non Comme cial (CC BY-NC 4.0) license, which
pe mi s o he s o dis ibu e, emix, adap , build upon his wo k non-comme cially,
and license hei de i a i e wo ks on di e en e ms, p o ided he o iginal wo k is
p ope ly ci ed, app op ia e c edi is gi en, any changes made indica ed, and he use
is non-comme cial. See: h p:// c ea i ecommons. o g/ licenses/ by- nc/ 4. 0/.
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Open access
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