In e ne In e en ions 34 (2023) 100640
A ailable online 22 June 2023
2214-7829/© 2023 The Au ho (s). Published by Else ie B.V. This is an open access a icle unde he CC BY-NC-ND license (h p://c ea i ecommons.o g/licenses/by-
nc-nd/4.0/).
E ec i eness o a uni e sal pe sonalized in e en ion o he p e en ion o
anxie y diso de s: P o ocol o a andomized con olled ial ( he
p e ANS p ojec )
P. Mo eno-Pe al
a
,
b
,
c
,
*
, A. Rod íguez-Mo ej´
on
a
,
b
,
c
, J.A. Bell´
on
a
,
b
,
d
,
e
,
**
, C. Ga cía-Hu´
e cano
a
,
C. Ma ínez-Vispo
, H. Campos-Paino
a
,
b
, S. Gal´
an
a
,
b
, S. Reyes-Ma ín
a
, N. S´
anchez Aguade o
g
,
M. Rangel-Hen iques
h
, E. Mo ico
i
, S. Conejo-Ce ´
on
a
,
b
a
Biomedical Resea ch Ins i u e o Malaga (IBIMA Pla a o ma BIONAND), C. Se e o Ochoa, 35, 29590 M´
alaga, Spain
b
Ch onici y, P ima y Ca e and Heal h P omo ion Resea ch Ne wo k (RICAPSS), ISCIII, G an Via de les Co s Ca alanes, 587, `
a ic, 08007 Ba celona, Spain
c
Depa men o Pe sonali y, E alua ion and Psychological T ea men , Uni e si y o M´
alaga (UMA), C/ D . O iz Ramos, 12; 29010 M´
alaga, Spain
d
‘El Palo’ Heal h Cen e, Se icio Andaluz de Salud (SAS), A . Sal ado Allende, 159, 29018 M´
alaga, Spain
e
Depa men o Public Heal h and Psychia y, Facul y o Medicine, Uni e si y o M´
alaga (UMA), Campus de Tea inos, Bl d. Louis Pas eu , 32, 29010 M´
alaga, Spain
Depa men o Clinical Psychology and Psychobiology, Uni e si y o San iago de Compos ela (USC), Campus Vida, Calle Xos´
e Ma ía Su´
a ez Nú˜
nez, s/n, 15782 San iago
de Compos ela, Spain
g
Depa men o Nu sing and Physio he apy, Uni e si y o Salamanca (USAL), Campus Miguel de Unamuno, C. Donan es de Sang e, s/n, 37007 Salamanca, Spain
h
Facul y o Psychology and Educa ion Science, Uni e si y o Po o, R. Al edo Allen, 4200-135 Po o, Po ugal
i
Depa men o Psychology, Uni e si y Loyola Andalucía, A . de las Uni e sidades, s/n, 41704 Dos He manas, Se illa, Spain
ARTICLE INFO
Keywo ds
Anxie y diso de s
P e en ion
In e ne -based in e en ions, Mobile-based in-
e en ions, RCT
ABSTRACT
Backg ound: To da e, all p e en i e anxie y diso de s in e en ions a e one- i -all and none o hem a e based on
indi idual le el and isk p o ile. The aim o his p ojec is o design, de elop and e alua e an online pe sonalized
in e en ion based on a isk algo i hm o he uni e sal p e en ion o anxie y diso de s in he gene al popula ion.
Me hods: A andomized con olled ial (RCT) wi h wo pa allel a ms (p e ANS s usual ca e) and 1-yea ollow-
up including 2000 pa icipan s wi hou anxie y diso de s om Spain and Po ugal will be conduc ed.
The p e ANS in e en ion will be sel -guided and can be implemen ed om he p e ANS web o om he
pa icipan s' Sma phone ( h ough an App). The p e ANS in e en ion will ha e di e en in ensi ies depending
on he isk le el o he popula ion, e alua ed om he isk algo i hm o anxie y: p edic A. Bo h low and
mode a e-high isk pa icipan s will ecei e in o ma ion on hei le el and p o ile ( isk ac o s) o anxie y dis-
o de s, will ha e access o s ess managemen ools and psychoeduca ional in o ma ion pe iodically. In addi ion,
pa icipan s wi h a mode a e-high isk o anxie y diso de s will also ha e access o cogni i e-beha io al aining
(p oblem-sol ing, decision-making, communica ion skills, and wo king wi h hough s). The con ol g oup will
no ecei e any in e en ion, bu hey will ill ou he same ques ionnai es as he in e en ion g oup.
Assessmen s will be comple ed a baseline, 6 and 12-mon h ollow-up. The p ima y ou come is he cumula i e
incidence o anxie y diso de s. Seconda y ou comes include dep essi e and anxie y symp oms, isk p obabili y o
anxie y diso de s (p edic A algo i hm) and dep ession (p edic D algo i hm), imp o emen in physical and
men al quali y o li e, and accep abili y and sa is ac ion wi h he in e en ion. In addi ion, cos -e ec i eness and
cos -u ili y analyses will also be ca ied ou om wo pe spec i es, socie al and heal h sys em, and analyses o
media o s and mode a o s will also be pe o med.
* Co espondence o: P. Mo eno-Pe al, Depa amen o de Pe sonalidad, E aluaci´
on y T a amien o Psicol´
ogico, Facul ad de Psicología y Logopedia, Uni e sidad de
M´
alaga (UMA), Ampliaci´
on del Campus de Tea inos, c/ D . O iz Ramos 12, 29010 M´
alaga, Spain.
** Co espondence o: J.A. Bell´
on, Depa amen o de Salud Pública y Psiquia ía, Facul ad de Medicina, Uni e sidad de M´
alaga (UMA), Campus de Tea inos, c/
Bule a Louis Pas eu , 32, 29071 M´
alaga, Spain.
E-mail add esses: [email p o ec ed] (P. Mo eno-Pe al), [email p o ec ed] (J.A. Bell´
on).
Con en s lis s a ailable a ScienceDi ec
In e ne In e en ions
jou nal homepage: www.else ie .com/loca e/in en
h ps://doi.o g/10.1016/j.in en .2023.100640
Recei ed 13 Ma ch 2023; Recei ed in e ised o m 2 June 2023; Accep ed 19 June 2023
In e ne In e en ions 34 (2023) 100640
2
Discussion: To he bes o ou knowledge, p e ANS s udy will be he i s o e alua e he e ec i eness and cos -
e ec i eness o a pe sonalized online in e en ion based on a isk p edic i e algo i hm o he uni e sal p e-
en ion o anxie y diso de s.
T ial egis a ion: ClinicalT ials.go : NCT05682365.
1. In oduc ion
1.1. Anxie y as public heal h issue
Cu en ly, a ound 300 million people su e om anxie y diso de s
wo ldwide (GBD, 2020) and in Spain hey a ec abou 2.8 million
people (Ha o e al., 2006). Recen s udies indica e ha since he onse o
he COVID-19 pandemic, he occu ence o dep ession and anxie y dis-
o de s has mul iplied (Luo e al., 2020). Du ing he decade 2007–2017,
he anxie y diso de s bu den (yea s li ed wi h disabili y) inc eased by
12.4 % and 13.6 % o women and men, espec i ely, anking eigh h
(women) and hi een h (men) in he wo ld (GBD, 2018). In addi ion o
he bu den o disease, anxie y diso de s a e associa ed wi h high eco-
nomic cos s. In he yea 2010, o al cos s s emming om anxie y dis-
o de s in Eu ope we e es ima ed a
€
74,380 million, 62.2 % o which
we e heal hca e cos s, 0.2 % we e di ec non-medical cos s, and 37.6 %
we e indi ec cos s (sick lea e and dec ease in p oduc i i y wo k)
(Olesen e al., 2012). In Spain anxie y diso de s a e es ima ed a
€
10,365
million annually, o which
€
4300 million a e due o di ec heal hca e
cos s,
€
150 million o di ec non-heal hca e cos s and
€
5914 o indi ec
cos s (Pa ´
es-Badell e al., 2014).
1.2. Need o p e en anxie y diso de s
Al hough he e a e easonably e ec i e ea men s o anxie y dis-
o de s (Cuijpe s e al., 2014; S´
anchez-Meca e al., 2010), no all a ec ed
people ecei e adequa e ea men (Fe n´
andez e al., 2007) due o
accessibili y di icul ies, e o s in diagnosis, incomple e e ec i eness o
ea men s, and lack o adhe ence. In de eloped coun ies, despi e he
ac ha ea men s o anxie y diso de s ha e inc eased subs an ially in
he las decade, he anxie y p e alence has no dec eased (Jo m e al.,
2017). This is pa ly because he incidence o new cases o anxie y dis-
o de s is e y high compa ed o he p e alence (p e en i e gap). E en in
he hypo he ical case ha all exis ing cases o anxie y diso de s would
be ea ed app op ia ely, new cases could be a oided h ough p ima y
p e en ion a he han ea men . Following his line, he Eu opean
Commission es ablished he p e en ion o men al diso de s as one o i s
main p io i ies (Fio illo e al., 2013).
1.3. In e na ional esea ch s a egies o p e en anxie y diso de s
(e ec i eness and cos -e ec i eness)
A me a-analysis ca ied ou in 2017 showed ha psychological and
psychoeduca ional in e en ions a e e ec i e in p e en ing he onse o
new cases o anxie y diso de s, al hough he e ec size was small
(Mo eno-Pe al e al., 2017). Howe e , om a public heal h poin o
iew, e en hough such e ec i eness was small, he gene aliza ion o
p e en i e in e en ions o anxie y diso de s o la ge popula ions could
ha e a ele an impac on imp o ing heal h, quali y o li e and cos s.
This gene aliza ion o scalabili y would be easible h ough in o ma ion
and communica ion echnologies (ICTs). In addi ion, he e is signi ican
oom o imp o emen in he ield o psychological in e en ions o
p e en anxie y diso de s. This e ec i eness o p e en i e in e en ions
could be op imized h ough he s udy o media o s and mode a o s
(Mo eno-Pe al e al., 2020a; Mo eno-Pe al e al., 2020b). Rega ding he
cos -e ec i eness o psychological in e en ions o p e en anxie y
diso de s, we conduc ed a sys ema ic e iew o ial-based economic
e alua ions, and we concluded ha he e idence on he cos -
e ec i eness o hese in e en ions is e y limi ed, since no i m con-
clusions can be d awn on he cos -e ec i eness o he psychological
in e en ions o he p e en ion o anxie y diso de s (Mo eno-Pe al
e al., in p ess).
1.4. P edic ing u u e episodes o anxie y: he p edic A algo i hm
An algo i hm o p edic ing he onse o anxie y diso de s a 12
mon hs, called he p edic A isk algo i hm (Mo eno-Pe al e al., 2014b)
was alida ed on 3564 p ima y ca e pa ien s wi hou anxie y om 6
Spanish egions, and i s calib a ion and disc iminan alidi y we e e y
good (C-index 0.80). The inal model o he p edic A isk algo i hm was
composed o 8 isk ac o s (sex, age, physical and men al quali y o li e,
dissa is ac ion wi h paid and unpaid wo k, inancial di icul ies, medi-
ca ion o anxie y, dep ession o s ess). P e iously, a isk algo i hm o
p edic anxie y diso de s a 6 and 24 mon hs in Eu opean popula ion
was de eloped and alida ed (King e al., 2011), which sha ed 6 isk
ac o s wi h he Spanish one. In addi ion o hese algo i hms, we had
p e iously de eloped a Spanish algo i hm o p edic ing he onse o
majo dep essi e episodes a 12 mon hs, called p edic D (Bell´
on e al.,
2011). The inal model o he p edic D isk algo i hm was composed o
11 isk ac o s. The wo Spanish algo i hms o anxie y and dep ession
p edic ion sha e 6 isk ac o s. In e ening on hese sha ed ac o s could
educe he isk o onse o bo h diso de s, dep ession and anxie y. This is
in line wi h p omising ansdiagnos ic app oaches ha inc ease he
po en ial each and impac o psychological p e en ion p og ams
(Ba low e al., 2016).
1.5. In o ma ion and communica ion echnologies (ICTs) in heal h
In Eu ope, 85 % o ci izens used he in e ne in 2019 (Eu opean
Commission, 2020). The In e ne o e s easy and inexpensi e access o
p og ams ha ea o p e en men al diso de s. I is anonymous,
ea men can be ob ained a any ime, by se ing he indi idual's own
pace, and i s use and adhe ence can be easily moni o ed. Fu he mo e, i
enables scaling o la ge popula ions, once he in e en ions a e shown o
be e ec i e.
M-Heal h has been de ined as he medical and public heal h p ac-
ices implemen ed in mobile de ices such as sma phones, pa ien
moni o ing de ices, pe sonal digi al assis an s and o he wi eless de-
ices (WHO, 2011). Sma phones a e pe sonal, po able, connec ed
and people end o ca y hem wi h hemsel es all he ime, so hey a e
in eg a ed in o daily li e. This means ha heal h messages and m-
Heal h p og ams can be p oac i ely o e ed o people in an app op ia e
way o e ime. In Eu ope he sma phone pene a ion is abo e 85 %
and inc easing (Di endia, 2020). Special men ion should be made o
he impac o he co ona i us hese mon hs on sma phone usage.
Du ing he COVID-19 pandemic, he ime o use o mobile applica ions
g ew by 6 % in Eu ope. The e o e, heal h in e en ions ca ied ou on
sma phones ha e g ea po en ial o de elopmen , implemen a ion
and scalabili y. Howe e , he e is e y limi ed e idence ha p e en-
i e heal h p og ams based on sma phones a e e ec i e and ensu ing
use s' adhe ence is c i ical (Ma colino e al., 2018; Vodopi ec-Jamsek
e al., 2012).
Engagemen in psychological in e en ions based on ICTs is gene -
ally poo . The a es o a i ion a e high and da a o ull comple ion
show a wide ange (Eysenbach, 2005; McDonald e al., 2020).
P. Mo eno-Pe al e al.
In e ne In e en ions 34 (2023) 100640
3
1.6. In e ne - and mobile-based in e en ions (IMIs) o he managemen
o anxie y
The me a-analyses o he in e ne -based in e en ions in men al
heal h ha e been shown o be as e ec i e as he ace- o- ace ea men s
and supe io o he con ol g oups (And ews e al., 2010; Ba ak e al.,
2008; Lina don e al., 2019). Rega ding he p e en ion o men al heal h
diso de s, se e al sys ema ic e iews and me a-analyses o in e ne -
based in e en ions ha e been published, showing posi i e esul s
(Deady e al., 2017; Rigabe e al., 2020; Sande e al., 2016; S a on
e al., 2017). Howe e , when we look a p e en i e heal h p og ams
based on sma phones he e is e y limi ed e idence on hei e ec-
i eness (Ma colino e al., 2018; Vodopi ec-Jamsek e al., 2012).
Speci ically, in ela ion o anxie y diso de s, a me a-analysis
concluded ha online in e en ions had a posi i e, al hough small, e -
ec on educing anxie y symp oms in he gene al popula ion; howe e ,
he adhe ence was low, he e we e only a ew ials o p e en anxie y
diso de s and mos o hese p e en i e ials included popula ion wi h
anxie y diso de s a he beginning o he s udy (Deady e al., 2017). The
Beacon 2.0 websi e o he ‘Na ional Ins i u e o Men al Heal h Resea ch
a he Aus alian Na ional Uni e si y’ has egis e ed 40 websi es ha
o e ea men o p e en ion o anxie y diso de s (Beacon 2.0, n.d.-a, n.
d.-b, n.d.-c, n.d.-d), among which he in e en ions based on cogni i e-
beha io al he apy (CBT) a e he mos used. In mos o hese s udies, he
p og ams ha e been e alua ed o ea anxie y diso de s and e y ew
we e e alua ed o p e en hem. Fu he mo e, he p e en i e ials
included pa icipan s wi h anxie y diso de s a he beginning o he
s udy, making i di icul o sepa a e ea men o p e en ion. In 2017, a
me a-analysis on he p e en ion o anxie y diso de s (Mo eno-Pe al
e al., 2017), only included 4 IMI's wi h a small e ec size and p esen ing
adhe ence p oblems.
1.7. Pe sonalized p e en ion o anxie y and dep ession
Mos o he ime, pe sonalized medicine is ela ed o he iden i ica-
ion o gene ic and molecula ac o s o apply indi idualized ea men s.
This ype o pe sonalized medicine is also applicable o men al illnesses
in he case o he choice o an idep essan s and an ipsycho ics. Howe e ,
in he con ex o p e en ion o men al heal h diso de s, speci ically
anxie y diso de s and dep ession, he clinician's objec i e is o o e a
ange o e ec i e in e en ion op ions aking in o accoun he di e en
ulne abili ies and isk ac o s o pa ien s (Cuijpe s, 2009). This ype o
p e en ion was called pe sonalized p e en ion (Cuijpe s, 2009; Golub-
ni schaja e al., 2012). Ou isk algo i hms (Bell´
on e al., 2011; Mo eno-
Pe al e al., 2014b) include indi idual in o ma ion on bo h isk le els
(p obabili y o isk) and he isk ac o s p o ile o bo h anxie y diso de s
and dep ession. In he case o dep ession and based on he dep ession
isk algo i hm, we designed an inno a i e pe sonalized in e en ion,
p edic D-CCRT (Bell´
on e al., 2013), o p e en his diso de in p ima y
ca e. The in e en ion consis ed o amily doc o s p o iding hei pa-
ien s wi h in o ma ion abou hei le el and isk p o ile o su e ing
dep ession in he nex yea . This in e en ion was es ed in a andom-
ized con olled ial (RCT) wi h 3326 p ima y ca e consul an s. The
p edic D-CCRT in e en ion, compa ed o usual ca e, educed he inci-
dence o dep ession by 21 % (Bell´
on e al., 2016) and anxie y diso de s
by 23 % (Mo eno-Pe al e al., 2021) and was also cos -e ec i e
(Fe n´
andez e al., 2018). Fo anxie y diso de s, he e idence in
pe sonalized p e en ion is much mo e limi ed. Un il now, isk algo-
i hms ha e no been used o es ablish di e en in ensi ies o in-
e en ions in ela ion o he isk le el o anxie y diso de s o he
popula ion. In e en ions o p e en anxie y diso de s ha e been
designed so ha all use s wo k wi h a s anda dized in e en ion (Mo -
eno-Pe al e al., 2017).
1.8. The gaps ha need o be co e ed
Taking in o accoun he s a e o he a desc ibed abo e:
1. The e is signi ican oom o imp o emen in he ield o he e ec-
i eness o psychological in e en ions in gene al, and IMIs in
pa icula , o he p e en ion o anxie y diso de s.
2. The e is e y limi ed e idence on he e ec i eness o IMIs, especially
based on sma phones, o he p e en ion o anxie y diso de s, gi en
he sca ce numbe o ials.
3. IMIs ha e adhe ence p oblems. Adhe ence in he eal-wo d is poo
and i is s ill a challenge o imp o e he adhe ence o IMIs in men al
heal h.
4. The e is e y limi ed e idence on he cos -e ec i eness o p e en i e
in e en ions o anxie y diso de s, and his e idence in IMIs is
almos non-exis en . To inco po a e a new heal h echnology,
decision-make s need e idence on i s cos -e ec i eness.
5. Un il now, in e en ions o p e en anxie y diso de s ha e been
designed as a one- i s-all solu ion. None o he in e en ions de el-
oped o p e en anxie y diso de s ha e been pe sonalized acco ding
o he anxie y diso de s le el and isk p o ile. The po en ial o p o-
duce e ec i e, adhe en and ans e able-scalable in e en ions e-
lies on he quali y o he design ( ailo ed and pe sonalized, co e ing
people's mo i a ions and suppo ing use s in decision making), he
e alua ion, and he dissemina ion p ocess. Howe e , none o he
in e en ions ook in o accoun he le el o isk o es ablish di e en
in ensi ies o in e en ions and he p o ile o isk o de eloping
pe sonalized in e en ions in he gene al popula ion.
6. Li le is known abou he media o s and mode a o s o in e en ions
o p e en anxie y diso de s, and especially in IMIs. This knowledge
would help op imize in e en ions and inc ease hei e ec i eness.
In conclusion, i is necessa y o design and e alua e anxie y diso de s
p e en ion in e en ions wi h highe e ec i eness, accep abili y, and
adhe ence compa ed o exis ing ones. An inno a i e and p omising
p oposal would include a pe sonalized app oach based on he p edic A
isk algo i hm, in ol ing he whole gene al popula ion, wi h mul iple
componen s acco ding he le el o isk, ha has e idence o i s e ec-
i eness, based on ICTs, and comple ely sel -guided.
1.9. Objec i es
The gene al objec i e o he p e ANS s udy is o design, de elop and
e alua e a pe sonalized online in e en ion o p e en he onse o
anxie y diso de s, based on an algo i hm o calcula e he isk o su e ing
om anxie y diso de s in he nea u u e (p edic A-algo i hm).
The speci ic aims a e:
1. To design and de elop a new pe sonalized online in e en ion
(p e ANS) based on p edic A isk algo i hm o p e en anxie y
diso de s.
2. To e alua e he e ec i eness o he p e ANS in e en ion in p e-
en ing he onse o anxie y diso de s as compa ed o a usual ca e
g oup.
3. To e alua e he e ec i eness o p e ANS in e en ion in educing
anxie y and dep ession symp oms, and he isk le el o anxie y dis-
o de s and dep ession as compa ed o a usual ca e g oup.
4. To e alua e he e ec i eness o p e ANS in e en ion in imp o ing
men al and physical quali y o li e.
5. To e alua e he adhe ence and usabili y o p e ANS in e en ion.
6. To e alua e he pa icipan s' accep abili y and sa is ac ion on he
p e ANS in e en ion.
7. To e alua e he cos -e ec i eness and cos -u ili y o he p e ANS o
p e en anxie y diso de s as compa ed o a usual ca e g oup.
8. To p o ide e idence on he mode a o s and media o s o p e ANS
in e en ion.
P. Mo eno-Pe al e al.
In e ne In e en ions 34 (2023) 100640
4
2. Me hod
2.1. Design
The p e ANS s udy is s uc u ed in h ee phases. In he i s phase,
he p e ANS in e en ion/ ool was designed and de eloped by clini-
cians (psychologis s, psychia is s, amily doc o s) and echnical p o-
essionals ( elecommunica ions and compu e enginee s). In he second
phase, a quali a i e assessmen is being conduc ed o unde s and he
ba ie s and enable s o he be a e sion o he p e ANS ool. Sugges-
ions o imp o emen will be collec ed and implemen ed be o e he
main ial begins. In he hi d phase, a andomized-con olled ial
(RCT) wi h wo pa allel a ms and one yea ollow-up will be conduc ed.
In his ial, he p e ANS in e en ion will be compa ed wi h usual ca e.
P ima y and seconda y ou comes will be assessed a baseline (T0), 6-
mon h (T6) and 12-mon h (T12) ollow-up.
This clinical ial has been app o ed by E hics and Resea ch Regional
Commi ee o Malaga and E hics Commi ee o Facul y o Psychology
and Educa ion Science o he Uni e si y o Po o (FPCEUP). This s udy
will be epo ed in acco dance wi h he S anda d P o ocol I ems: Rec-
ommenda ions o In e en ional T ials (SPIRIT; Chan e al., 2013), he
Consolida ed S anda ds o Repo ing T ials 2018 S a emen o Social
and Psychological In e en ions (CONSORT-SPI; Mon gome y e al.,
2018) as well as he guidelines o execu ing and epo ing in e ne
in e en ion esea ch (Eysenbach, 2013). This s udy was egis e ed on
Clinical T ials (NCT05682365) on Janua y 12, 2023, be o e he i s
pa icipan en olmen .
2.2. Pa icipan s & p ocedu e
The s udy will be conduc ed in subjec s o he gene al popula ion
esiding in Spain and Po ugal. Pa icipan s will be ec ui ed using a
dissemina ion campaign on he media (newspape s, he In e ne , social
ne wo ks, Google Adds, e c.), heal h cen e s, uni e si ies and on he
p e ANS websi e i sel , which will summon he popula ion o pa ici-
pa e. Some o he key messages ha he dissemina ion campaign will use
o a ac he a en ion o candida es o inclusion in he s udy include:
‘How may I p e en anxie y p oblems? Pa icipa e in he p e ANS s udy
o ee! All you need is access o he In e ne ’; ‘Ha e you e e pa ici-
pa ed in a scien i ic s udy? Take pa in he p e ANS s udy. I 's ee!
Pa icipa e om you mobile phone’ ‘Do you wan o p e en anxie y?’
I you a e in e es ed in pa icipa ing, isi he p e ANS ec ui men
websi e o u he in o ma ion abou he s udy. P ospec i e pa icipan s
will be in i ed o isi he p e ANS ec ui men websi e o u he in-
o ma ion abou he s udy. Those who sign in o med consen will be
in i ed o comple e he sc eening ques ionnai e.
The inclusion c i e ia will include: 1) being 18 yea s o olde , and 2)
ha ing a compu e , sma phone, o able o pe sonal use connec ed o
he in e ne du ing he s udy yea . Pa icipan s will be excluded i hey:
1) e use o sign in o med consen ; 2) eside ou side Spain o Po ugal;
3) epo ha ing a se ious men al diso de (psychosis, bipola , addic-
ions, e c.); 4) ha e a e minal illness; 5) ha e cogni i e impai men
(demen ia); 6) ha e di icul y unde s anding Spanish o Po uguese; 7)
a e pa icipa ing in a esea ch s udy o in ol ed in a psychological
in e en ion o dep ession o anxie y; o 8) ha e expe ienced clinically
ele an anxie y symp oms in he las wo weeks acco ding o he
Gene al Anxie y Diso de -7 ques ionnai e (GAD-7; Ga cía-Campayo
e al., 2010) wi h a sco e equal o o highe han 10 poin s a he
beginning o he s udy. The GAD-7 (sco e ≤9), o a p e alence o
anxie y diso de s o 15–20 %, has a Nega i e P edic i e Value (NPV) o
99 % (1 % alse nega i es) (Spi ze e al., 2006). P ospec i e pa icipan s
who ob ain a sco e o ≥10 poin s will be con ac ed i hey p o ide hei
elephone numbe , and diagnosis o anxie y diso de s is con i med based
on CIDI in e iew, in which case hey will be de ini i ely excluded and
sugges ed o isi a heal h p o essional.
2.3. Randomized alloca ion and masking
Those p ospec i e pa icipan s who mee all he inclusion c i e ia
wi hou mee ing any exclusion c i e ia will be assigned by he p e ANS
websi e au oma ically and andomly o one o he wo g oups (p e ANS
in e en ion o con ol) wi h a 1:1 a io wi h a block o andom sizes
ha a e no disclosed o ensu e concealmen . In bo h g oups, pa ici-
pan s will c ea e pe sonal passwo ds ha hey can use om he pe sonal
a ea o he websi e o by downloading an app.
The pa icipan s will no be blind o he in e en ion, which is he
mos common in ials ha e alua e psychological and psychosocial
in e en ions (Bou on e al., 2008). Howe e , in e iewe s ( esea ch
assis an s who assess ou comes) will be blind o he pa icipan s´s a us
(con ol o in e en ion g oup) and hose who pe o m s a is ical ana-
lyses will also be blind o he in e en ion and con ol codes.
2.4. In e en ion
The p e ANS is a pe sonalized online in e en ion o p e en ing
anxie y diso de s, based on a alida ed isk algo i hm o p edic anxie y
diso de s (p edic A; Mo eno-Pe al e al., 2014b), which will be used
h ough a mobile phone applica ion (App) as he main use 's in e ace o
a use - iendly websi e. The p e ANS in e en ion will be sel -guided
and mul i-componen (Fig. 1), including e idence-based psychological
and psychoeduca ional in o ma ion and exe cises o p e en ing he
eme gence o anxie y symp oms (Ho mann and G´
omez, 2017; Mo eno-
Pe al e al., 2017; Mo eno-Pe al e al., 2020a).
The i s s ep o be aken by he pa icipan s in he in e en ion
g oup will be o comple e a se ies o ques ionnai es o assess he le el o
isk o su e ing anxie y diso de s in he nex yea (p edic A algo i hm).
A e his, pa icipan s will be p o ided wi h a simple bu de ailed epo
wi h he esul s o hese ques ionnai es one by one and in o ma ion
abou hei p obabili y o su e ing anxie y diso de s in he nex yea .
A e he pa icipan s ha e ecei ed hei epo s, he ool will clas-
si y hem as: a) low isk (p obabili y o su e ing anxie y diso de s ≤7
%), b) mode a e-high isk (p obabili y o su e ing anxie y diso de s
abo e 7 %). This classi ica ion is based on he da a ob ained in he s udy
o he p edic A algo i hm (Mo eno-Pe al e al., 2014b). The 50 h
pe cen ile o he sco es on he p obabili y o isk o su e ing om
anxie y diso de s has been used as a h eshold o ank he pa icipan s as
low e sus mode a e-high isk. Depending on his classi ica ion, he
in e en ion will be milde (low isk) o mo e in ense (mode a e-high
isk) in i s he apeu ic wo k:
a) Low isk o anxie y diso de s: The sys em will p o ide in o ma ion
on he le el and isk p o ile o de elop anxie y diso de s and he
de ailed epo on ecommenda ions o ac ion based on isk ac o s.
The in o ma ion and ecommenda ions will be di ec ed owa d he
impo ance and ad an ages o ha ing his low p obabili y and he
pa icipan will be encou aged o con inue wi h hose ac i i ies o
habi s ha he/she ca ies ou in his/he li e ha yield ha low isk,
iden i ying and expanding p e en i e/p o ec i e ac o s. On he
o he hand, he ool will p o ide weekly psychoeduca ional in o -
ma ion in he o m o ideos, audios, quizzes and ex s based on
cogni i e-beha io al biblio he apy (emo ional well-being, s ess,
sel -ca e, e c.). In addi ion, i will be o e ed a se ies o echniques
based on he p inciples o mind ulness o lea n o s op a imes ha
equi e i , lea n o ake b ea hs and lea n o elax. These echniques
ha e been shown o be e ec i e in managing anxie y (Ho mann and
G´
omez, 2017).
b) Mode a e-high isk o anxie y diso de s: Pa icipan s classi ied a his
le el, in addi ion o all he he apeu ic componen s included in he
low- isk p o ile, will be p o ided wi h a cogni i e-beha io al
aining, which will consis o wo king on speci ic aspec s ha a e
a he o igin o anxie y diso de s. This aining consis s o wo king on
he ollowing modules:
P. Mo eno-Pe al e al.
In e ne In e en ions 34 (2023) 100640
5
•P oblem sol ing module ins uc s o apply p oblem-sol ing
s a egies. Pa icipan s will lea n e ec i e s a egies o sol ing
p oblems and u ning p oblems in o objec i es; hen, hey will
apply hem o hei own p oblems. Finally, a e iew will be pe -
o med o he wo k done.
•Communica ion skills module. Pa icipan s will be ins uc ed
ega ding o he good communica ion p inciples add essing com-
ponen s o asse i eness, empa hy and ac i e lis ening.
•Decision making module ins uc s o apply se e al s eps based on
decision making s a egies. T aining in ol es p o iding guidance
abou use ul s a egies o making decisions and seeking al e na-
i es. We will also help pa icipan s make decisions abou hei
own p oblems. In his module, pa icipan s a e encou aged o use
he s a egies lea ned in a eal con ex .
•Wo king wi h hough s module aims o educe au oma ic nega-
i e hough s and wo ies. This aining ins uc s o iden i y and
analyze au oma ic nega i e hough s and u n hem in o posi i e
hough s. Conce ning o wo ies, he goal is o analyze he wo ies
anking hem by ele ance and p io i y and educe hem h ough
elaxing exe cises, mind ulness, psychoeduca ion and moni o ing.
Rega dless o he le el o isk, he p e ANS in e en ion will o e
pe sonalized in o ma ion on he balance be ween isk and p o ec i e
ac o s. In o ma ion on he isk le el, isk ac o s, p o ec i e ac o s and
ecommenda ions will be ansmi ed a baseline and a 6 mon hs o
ollow-up. All inpu s will be e-assessed a 6 mon hs. I any pa icipan
who was a low isk a baseline we e o inc ease hei isk p obabili y o
he mode a e-high le el a he 6-mon h ollow-up, hey would be p o-
posed o ca y ou he componen s o he mos in ensi e in e en ion
indica ed o his le el o isk.
2.4.1. The con ol g oup
Pa icipan s in bo h g oups will con inue o ecei e heal h ca e om
hei usual p o ide s, and he pa icipan s a con ol g oup will comple e
he same ques ionnai es epea edly o e ime, also ecei ing he same
no i ica ions o ill hem ou and in he same ag eed sequence. Howe e ,
hey will ecei e no in e en ion, no pe sonaliza ion, and no in o ma-
ion on he le el o isk and isk ac o s. I p e ANS in e en ion is
e ec i e, he pa icipan s in he con ol g oup will ha e access o all he
con en s o p e ANS in e en ion once he s udy has been comple ed.
2.5. Po en ial isk o he pa icipan s
Based on ou p e ious s udies, he pa icipa ion o pa ien s in he
ial does no inc ease he isk o ha m o he pa ien s (Bell´
on e al.,
2016). I he sys em de ec s (du ing ec ui men and/o ollow-up) high
le els o anxie y symp oms and/o mode a e-se e e dep ession o a high
isk o suicide, pa icipan s om bo h a ms will be in o med o his and
will ecei e sugges ions o ac ion h ough messages. Suicidal idea ion
will be sc eened using one ques ion om PHQ-9. Pa icipa ion does no
imply making isi s o he heal hca e sys em bu , du ing ec ui men
and ollow-up, a ained eam membe will p o ide suppo h ough
email o elephone du ing o ice hou s o any ype o doub s o eques s,
echnical suppo (e.g., di icul ies o download he App) o o he ypes
o in o ma ion (e.g., con iden iali y gua an ee ques ions), ha he pa -
icipan s may demand du ing he s udy. In addi ion, he appea ance o
seconda y e ec s and incon eniences de i ed om he p e en i e
in e en ion will be e alua ed by means o a message sen by he App o
websi e e e y 3 mon hs wi h he op ion o ee ex esponse.
2.6. Adhe ence and s a egies o ial e en ion
A moni o ing and suppo plan o each pa icipan will be es ab-
lished, o e ing eedback on his/he pe o mance in he in e en ion and
i s esul s h ough a sys em o poin s/awa ds, wi h he aim o inc easing
use adhe ence and sa is ac ion o he p e en ion p og am.
In o de o imp o e ial e en ion, he ool will send a eminde o
he pa icipan s o comple e he ollow-up ques ionnai es e e y 6
mon hs. In addi ion, a esea ch assis an will con ac pa icipan s when
he ollowing si ua ions happen: 1) pa icipan s do no comple e ques-
ionnai e a baseline, 2) pa icipan s ha e no used he App (which
means hey ha e no ca ied ou any ac i i y), and 3) pa icipan s ha e
no comple ed a ollow-up ques ionnai e. The pu pose o his call will be
o encou age hem o comple e he ques ionnai es o use he app and o
check ha pa icipan s do no ha e any echnical p oblems wi h he app
ha p e en /hinde hem om using i .
Fig. 1. p e ANS in e en ion.
P. Mo eno-Pe al e al.

In e ne In e en ions 34 (2023) 100640
6
2.7. Powe and sample size calcula ion
We assume ha he pa icipan s o his s udy will ha e some eason
o being in e es ed in he p e en ion o anxie y diso de s, which in-
ol es a highe isk o ha ing an anxie y diso de han andom subjec s
o he gene al popula ion. We expec ed ha he incidence o anxie y
diso de s in he con ol g oup would be simila o ha in p ima y ca e
pa ien s. The e o e, o calcula e sample size, he incidence o anxie y
diso de s in he con ol g oup was assumed o be he one epo ed in he
p edic A s udy (Mo eno-Pe al e al., 2014b), which algo i hm was
de eloped based on a coho o p ima y ca e pa ien s. Mo e speci ically,
we assumed an incidence o anxie y diso de s o 14 % o he con ol
g oup and 8.4 % o he in e en ion g oup. Rega ding he p e en i e
ac ion (di e ence =30 %), his was assumed conside ing p e ious
s udies o anxie y p e en ion o all ypes o popula ions (Mo eno-Pe al
e al., 2017; Mo eno-Pe al e al., 2021). Al hough he andom assign-
men will be done indi idually, we canno ule ou he exis ence o
in aclus e co ela ion be ween pa icipan s o he same ci y; and since
we do no ha e empi ical da a on i s magni ude, in p inciple we will
assume a ho =0.025. I we assume an alpha e o o 5 %, a powe o 80
%, and a wo- ailed p, we will need 745 indi iduals o each g oup, ha
is, 1.490 indi iduals in o al. Assuming ha 30 % o subjec s will
wi hd aw om he s udy, we should inc ease he sample size o 250
pa icipan s pe g oup. Ou goal will be o ec ui 2000 subjec s o he
p e ANS s udy (Fig. 2). These calcula ions assume an a e age numbe o
pa icipan s pe ci y o 50 and ha he clus e dis ibu ion will be ho-
mogeneous (coe icien o a ia ion <0.23) (Eld idge e al., 2006).
2.8. Ou comes
Ou p ima y ou come will be he cumula i e incidence o any anxi-
e y diso de s acco ding o DSM-V (panic diso de , ago aphobic, gene -
alized anxie y diso de o social anxie y diso de ) du ing 12 mon hs o
ollow-up assessed h ough he sec ion o anxie y diso de s o he
Composi e In e na ional Diagnos ic In e iew a 6 and 12 mon hs ollow
(CIDI; WHO, 1997). I will be conside ed as an anxie y diagnosis i he
pa icipan p esen s any anxie y diso de du ing he whole ollow-up
pe iod. As seconda y ou comes, we will use measu emen s o men al
and physical quali y o li e using he 12-i em Sho Fo m (SF-12; Jen-
kinson e al., 1997), dep essi e symp oma ology (PHQ-9; K oenke e al.,
2001), anxious symp oma ology (GAD-7; Spi ze e al., 2006), p oba-
bili y o onse o anxie y diso de s and majo dep ession a 12 mon hs
Rec ui ing h ough online pla o m
Exclusion c i e ia:
No in o med consen
Diagnosis o anxie y diso de s by CIDI o pa icipan s
wi h GAD-7 ≥10
Age unde 18 yea s
Inabili y o unde s and o speak Spanish o Po uguese
Se e e men al diso de
Cogni i e impai men
Te minal illness
Do no ha e a sma phone o compu e a home
Being in ol ed in any psychological in e en ion o
dep ession o anxie y
Online sel - epo
CSRI [ elephone call]
Follow-up assessmen
(T6)
Comple e Baseline
assessmen (T0)
Assessmen online o
eligibili y
In e en ion g oup
(p e ANS)
Randomisa ion alloca ion o
pa icipan s
Con ol g oup
(TAU)
Online sel - epo
CSRI
CIDI elephone call
u-MARS
Follow-up assessmen
(T12)
Comple e Baseline
assessmen (T0)
Follow-up assessmen
(T6)
Follow-up assessmen
(T12)
Online sel - epo
CSRI
CIDI elephone call
u-MARS
Fig. 2. Flowcha o he p e ANS s udy.
CIDI: Composi e In e na ional Diagnos ic In e iew; GAD-7: Gene alized Anxie y Diso de -7; CSRI: Clien Se ice Receip In en o y; u-MARS: Use Ve sion o he
Mobile Applica ion Ra ing Scale.
P. Mo eno-Pe al e al.
In e ne In e en ions 34 (2023) 100640
7
(p edic A and p edic D isk algo i hm; Mo eno-Pe al e al., 2014b;
Bell´
on e al., 2011), social suppo (DUKE; Bell´
on e al., 1996), cogni i e
change as a media o o he in e en ion (assessed by he hough s
wo ked on he p og am) and subg oup analysis (acco ding o age, sex,
educa ion le el, anxie y and dep ession symp oms and le el o isk o
anxie y diso de s and dep ession). All hese a iables will be e alua ed
a baseline, 6- and 12-mon hs ollow-up, excep he incidence o anxie y
diso de s, which will be e alua ed a 6 and 12 mon hs. In addi ion, cos -
e ec i eness and cos -u ili y es ima es will be pe o med.
2.9. Va iables and measu emen s
Online sel -comple ed ques ionnai es and ques ions include:
- The Pa ien Heal h Ques ionnai e (PHQ-9; K oenke e al., 2001)
consis s o 9 i ems assessing he p esence o dep essi e symp oms
p esen in he pas 2 weeks. Each i em has a se e i y index anging
om 0 o 3 (0=“no a all”, 1 =“se e al days”, 2=“mo e han hal o
he days” and 3=“almos e e y day”). The PHQ-9 shows good psy-
chome ic p ope ies in Spain and Po ugal (G´
omez-G´
omez e al.,
2022; Fe ei a e al., 2019).
- The se en-i em Gene alized Anxie y Diso de ques ionnai e (GAD-7;
Spi ze e al., 2006) which comp ises 7 i ems measu ing symp oms
and se e i y o anxie y based on he DSM-V diagnos ic c i e ia o
GAD. The GAD-7 is also an e ec i e sc eene o o he ela ed-
anxie y diso de s (K oenke e al., 2010). The sco e anges om
0 o 21; highe sco es indica e g ea e se e i y o symp oms. The
Spanish and Po uguese e sion o GAD-7 has shown good me ic
p ope ies (Ga cía-Campayo e al., 2010; Sousa e al., 2015).
- The Spanish p edic A (Mo eno-Pe al e al., 2014a) and p edic D
(Bell´
on e al., 2011) isk algo i hms calcula e he indi idual p oba-
bili y o he onse o anxie y diso de s and majo dep ession in he
nex 12 mon hs. These p edic i e isk algo i hms we e p e iously
alida ed and con ain he ollowing p edic o s:
o Spanish p o ince.
o Age.
o Sex.
o Educa ional le el (beyond seconda y educa ion, seconda y edu-
ca ion, p ima y educa ion and incomple e p ima y educa ion/
illi e a e).
o Quali y o li e using he 12-i em Sho Fo m (SF-12; Jenkinson
e al., 1997). This ques ionnai e consis s o wo componen s, one
ela ed o physical heal h and ano he ela ed o men al heal h.
Sco es ange om 0 o 100; highe sco es indica e be e heal h-
ela ed quali y o li e. The SF-12 has been alida ed in he Span-
ish and Po uguese popula ion and has demons a ed adequa e
le els o eliabili y and alidi y.
o Con ols, demands and ewa ds o unpaid and paid wo k using an
adap ed 7-i em e sion o he Job Con en Ins umen (Ka asek
and Theo ell, 1990). This ques ionnai e consis s o ques ions abou
di icul ies o unpaid and paid wo k, he equency wi h which
help is pe cei ed and sa is ac ion wi h he wo k pe o med. The
esul is classi ied in o 3 ca ego ies (sa is ied, dissa is ied and e y
dissa is ied) by he sum o he 7 i ems. The ques ionnai e has
shown good psychome ic p ope ies in Spain (Bell´
on e al., 2013)
and Po ugal (Boas and Ce quei a, 2017).
o Economic di icul ies using a 4-Like - ype esponse op ion i em
anging om 1 (li ing com o ably) o 4 ( inding i e y di icul ).
o Sa is ac ion wi h li ing oge he a home using a 5-Like - ype
esponse op ion i em anging om 1 ( e y dissa is ied) o 5
( e y sa is ied).
o P esence o se ious p oblems in amily membe s o close pe sons
using 4 di e en dicho omous esponse i ems (yes/no) on se ious
physical, psychological o subs ance misuse p oblems and any
se ious disabili y.
o Childhood expe iences o physical abuse using a 5-Like - ype
esponse i em anging om 1 (ne e ) o 5 ( equen ly).
o Li e ime dep ession using he i s 2 ques ions included in he CIDI
(WHO, 1997) on li e ime low mood.
o Use o medica ion o anxie y, dep ession o s ess in he p e ious
6 mon hs by means o a dicho omous esponse i em (yes/no).
- Two ques ions o he Spanish e sion o he DUKE-UNC-11 ins u-
men o e alua e he pe cei ed unc ional social suppo e e ed o
a ec i e social suppo and con iden ial social suppo (Bell´
on e al.,
1996). This ques ionnai e has been also alida ed in Po uguese
popula ion (Ma ins e al., 2022).
- O he sociodemog aphic a iables (ques ions abou gende , sexual
o ien a ion and iden i y) will be also collec ed.
A elephone call will be made based on pa icipan 's a ailabili y.
This in e iew will be conduc ed by ained in e iewe s blind o
pa icipan assignmen and will include:
o Anxie y diso de s sec ion o he CIDI (WHO, 1997). The CIDI is a
s uc u ed psychia ic in e iew ha was designed and e alua ed
by he WHO and has shown excellen e idence o in e iew al-
idi y in di e en cul u es and popula ions. The pu pose o his
in e iew is asce aining diagnoses based on DSM c i e ia. This
in e iew will be adminis e ed a 6- and 12-mon hs ollow-up;
also, o he pa icipan s wi h a sco e o 10 poin s o mo e a
baseline.
o The use o heal hca e esou ces will be e alua ed by means o he
Clien Se ice Receip In en o y (CSRI) ha collec s in o ma ion
on he use o se ices, psycho opic d ugs, sick lea e and loss o
p oduc i i y (Vazquez-Ba que o e al., 1997). This in en o y will
be adminis e ed a baseline, 6- and 12-mon hs ollow-up.
o Quali y Adjus ed Li e Yea s (QALYs) will be measu ed using he
i e-dimensional Eu oQol ques ionnai e (EQ-5D; He dman e al.,
2001; Badia e al., 1998; Badia e al., 1999; Fe ei a e al., 2013).
This is a widely used measu e o gene al heal h and quali y o li e
which includes i e domains add essing mobili y, pe sonal ca e,
usual ac i i ies, pain/discom o and anxie y/ dep ession. In
addi ion, i includes a isual analog scale (VAS) g aded om 0 ( he
wo s heal h s a us) o 100 ( he bes heal h s a us). Spanish and
Po uguese a i s will be used o es ima e he u ili y o heal h
s a es desc ibed by he pa icipan s. This ques ionnai e will be
adminis e ed a baseline, 6- and 12-mon hs ollow-up.
o Accep abili y and sa is ac ion wi h he in e en ion will be
measu ed using The Use Ve sion o he Mobile Applica ion Ra ing
Scale (u-MARS; Ma in Payo e al., 2019; Oli ei a e al., 2022). The
u-MARS scale consis s o 26 i ems assessing app quali y, each o
which is sco ed om 1 (‘poo ’) o 5 (‘excellen ’), excep i ems
13–16, which also include a “no applicable” op ion, and he las
poin , which includes an open-ended ques ion. Highe sco es a e
equi alen o highe App quali y. This ques ionnai e will be
adminis e ed a 6- and 12-mon hs ollow-up.
Fo an o e iew o ins umen s a sc eening, baseline (T0) and
ollow-up assessmen s (T6-T12), see Table 1.
2.10. S a is ical analysis
Ou p ima y analysis will be he absolu e isk di e ence in he cu-
mula i e incidence o any anxie y diso de s a 12 mon hs ollow-up, a
p io i adjus ed o isk o anxie y diso de s a baseline. Al hough he
andom assignmen will be done indi idually, he in aclus e co ela-
ion coe icien will be calcula ed (pa icipan s nes ed in p o inces). We
will use mul ile el logis ic eg ession i he co ela ion be ween pa ic-
ipan s nes ed in p o inces is ele an . The “p o ince” a iable will be
included as a andom componen . The “g oup” a iable will be used as a
ixed componen o he model (independen a iable), whe eas su e ing
om anxie y diso de s du ing ollow up will be used as he dependen
a iable. The incidence o anxie y diso de s will be es ima ed using
P. Mo eno-Pe al e al.
In e ne In e en ions 34 (2023) 100640
8
STATA command `ma gins'. In he seconda y analyses, mul ile el linea
eg essions including as andom componen s ime and p o ince a i-
ables, and as ixed componen s he a iables g oup, ime, he in e ac ion
g oup * ime and he espec i e measu emen s o he dependen a i-
ables a baseline will be used. We will calcula e s anda dized mean
di e ences using he ma gins in STATA. All analysis will be conduc ed
wi h STATA and will be based on he in en ion- o- ea p inciple,
analyzing all pa icipan s acco ding o hei andomized ea men and
including all hem in he analyses. We will use mul iple impu a ions (MI)
o dealing wi h missing da a unde a missing-a - andom amewo k.
The ollowing sensi i i y analyses will be ca ied ou : 1) o he p ima y
and seconda y analyses adjus ing o he p obabili y o isk o anxie y a
he baseline and hose o he co a ia es ha could ha e indica ions o an
imbalance be ween he a ms o he ial; 2) pe o ming comple e case
analysis and adjus ing o in e se p obabili y weigh ing (IPW) (He n´
an
e al., 2004) o minimize a i ion bias du ing ollow-up. We will e al-
ua e some mode a o s (coun y, age, sex, educa ional le el, physical and
men al quali y o li e, and anxie y isk le el) and a media o (cogni i e
change) using mul ile el s uc u al equa ion models o desc ibe he
causal chain as sugges ed by K aeme (2014).
2.10.1. Economic e alua ion
We will calcula e he inc emen al cos -e ec i eness a ios (ICERs)
o he p ima y and seconda y economic e alua ions using GLM models
(Glick e al., 2007). In he p ima y analysis (cos -u ili y), we will use he
di e ence in quali y adjus ed li e yea s (QALYs) be ween he p e ANS
in e en ion compa ed o he con ol g oup. In he seconda y analysis
(cos -e ec i eness), we will use he di e ence in he numbe o di-
agnoses o anxie y be ween he wo a ms. The mean QALYs pe pa ien
will be calcula ed om he EQ-5D-5L (EQ-5D-5L, 2019), using o icial
a i s a ailable o es ima e pa icipan s' u ili y weigh s. We will
conside wo sepa a e cos pe spec i es, om socie y and om he
heal h sys em. Heal h ca e cos s will be calcula ed by mul iplying he
numbe o heal h se ice uni s (consul a ions, hospi al days, e c.) by
hei s anda d cos lis ed in he o icial da ase s a ailable. Cos s o
medica ion will be calcula ed by mul iplying he cos pe daily dose
(a ailable om na ional o mula ies) by he numbe o p esc ip ion
days. Indi ec cos s will include he cos s o absen eeism and p e-
sen eeism. Cos s o p oduc i i y loss will be calcula ed by mul iplying
he ime missed due o absence om wo k (absen eeism) plus ime los
due o educed p oduc i i y while a wo k (p esen eeism) by he mini-
mum wage. Con idence in e als and cos -e ec i eness accep abili y
planes and cu es (CEACs) will be gene a ed wi h boo s ap o each
impu ed da a ile, a ying he alues o he a ailabili y o pay om 0 o
€
100,000. Sensi i i y analyses will be ca ied ou by modi ying uni
p ices, using he a e age wage ins ead o he minimum wage.
3. Discussion
The p e ANS s udy will p o ide new in o ma ion abou he e ec-
i eness and cos -e ec i eness o an inno a i e and pe sonalized online
in e en ion based on a isk p edic ion algo i hm o he uni e sal
p e en ion o anxie y diso de s.
This s udy is cha ac e ized by se e al s eng hs. Un il now, in-
e en ions o p e en anxie y diso de s ha e been designed so ha all
use s wo k on a s anda dized in e en ion; p e ANS will adap he
he apeu ic con en o each pe son. Acco ding o he le el o isk o he
pa icipan s, di e en kinds o in e en ions will be o e ed. I is well
known ha online sel -guided in e en ions ha e adhe ence p oblems,
making i di icul o use s o comple e hei p og ams. By gi ing pa -
icipan s pe sonalized in e en ions as p e ANS o e s, we expec o
imp o e he adhe ence igu es. In addi ion, he ool will e o i he
sys em wi h in o ma ion on he in e en ion implemen a ion, wi h he
aim o achie ing op imal use's adhe ence o he p e en ion p og am.
This pe sonalized app oach, in addi ion o inc easing he e ec i eness o
he in e en ions conduc ed un il now, could also imp o e he impac o
online p e en i e in e en ions h ough he inc ease o accep ance and
adhe ence owa d hese p og ams. We will ec ui a la ge sample o
pa icipan s om wo Eu opean coun ies and will con inue he ollow-
up o 12 mon hs. We will use a s uc u ed in e iew (CIDI) o assess he
cumula i e incidence o anxie y diso de s du ing ollow-up.
Ou s udy also p esen s se e al limi a ions. Fi s , he selec ion bias
could be ele an , pa icipan s who choose o pa icipa e may ha e a
di e en p o ile o hose who do no , his could limi ex e nal alidi y
and i should be no ed ha he p e ANS in e en ion could be less
e ec i e when applied as a gene al p og am. The Spanish p edic A isk
algo i hm, which p o ides p edic ions a 12 mon hs, has no been
alida ed in Po ugal. Howe e , he Eu opean p edic A algo i hm,
which p edic s anxie y a 6 and 24 mon hs and was de eloped wi h
Po uguese popula ion, is e y simila o he Spanish one. Ano he poin
o conside is ha he in e ence o his ial will be limi ed o ci izens
aged 18 o o e wi h In e ne access and a basic knowledge o i s
unc ioning. Howe e , he expansion/scalabili y o p e ANS in e en-
ion could be highe due o he pene a ion a e o he mobile phone in
Eu opean popula ion. A high p opo ion o d opou s om he RCT a e
expec ed. In o de o limi his isk, he p e ANS ool will send
Table 1
S udy a iables and assessmen s.
Ins umen s
a
Assessmen a ea Da a collec ion me hod Time o measu emen
Sc eening Baseline T6 T12
Sc eening ins umen s
GAD-7 Anxie y symp oms Online sel - epo x
CIDI Diagnosis o anxie y diso de s o pa icipan s wi h GAD-7 ≥10 Telephone call x
P ima y ou come
CIDI Diagnosis o anxie y diso de s Telephone call x x
Seconda y ou comes
GAD-7 Anxie y symp oms Online sel - epo x x x
PHQ-9 Dep essi e symp oms Online sel - epo x x x
P edic A P obabili y o he onse o anxie y diso de s a 12 mon hs Online sel - epo x x x
P edic D P obabili y o he onse o majo dep ession a 12 mon hs Online sel - epo x x x
SF-12 Heal h- ela ed quali y o li e Online sel - epo x x x
Eu oQol-5D Quali y Adjus ed Li e Yea s Telephone call x x x
CSRI Heal hca e esou ce use (cos s) Telephone call x x x
O he assessmen s
Duke-UNC-11 Pe cei ed unc ional social suppo Online sel - epo x x x
O he ques ions Sexual iden i y and o ien a ion Online sel - epo x x x
u-MARS Accep abili y and sa is ac ion wi h he in e en ion Telephone call x x
a
PHQ-9: Pa ien Heal h Ques ionnai e-9; CIDI: Composi e In e na ional Diagnos ic In e iew; GAD-7: Gene alized Anxie y Diso de -7; SF-12: 12-i em Sho Fo m;
CSRI: Clien Se ice Receip In en o y; u-MARS: Use Ve sion o he Mobile Applica ion Ra ing Scale.
P. Mo eno-Pe al e al.
In e ne In e en ions 34 (2023) 100640
9
au oma ed eminde s o ill in he ques ionnai es. In addi ion, he
esea ch eam will be a ailable o gi e answe s o he di e en p oblems
ha may appea in he ollow-up and o gi e pe sonalized suppo and
ad ice o hose subjec s who a e slow o espond o au oma ed e-
minde s o con inue pe o ming he asks inhe en in he ial. On he
o he hand, powe size calcula ions ook in o accoun ha he e will be a
30 % o cases los and MI will be used o deal wi h missing da a. Some
deg ee o con amina ion could happen due o he coexis ence in he
same amily o iends' g oups o pa icipan s o bo h con ol and
in e en ion a ms. This bias is di icul o con ol; howe e , his bias
would be agains he hypo hesis o he s udy. The in o ma ion bias is
also p obable bu he use o ques ionnai es o p o en alidi y, eliabili y
and sensi i i y o change, s anda diza ion o p ocedu es and aining o
in e iewe s will minimize his bias. Fu he mo e, e en hough a lack o
balancing a baseline is unlikely, adjus ed analyses will be conduc ed o
add ess con usion bias. Some pos - andomiza ion bias is possible (e.g.,
he use o anxioly ics o an idep essan s du ing ollow-up), which will be
add essed by ca ying ou measu emen s and analysis o hem be ween
in e en ion and con ol a ms. Ano he aspec ha should be no ed is
ha since we a e e alua ing a psychological, educa ional and social
in e en ion, i is e y di icul o blind he pa icipan s. As in o he sel -
guided heal h p og ams based on sma phones o o he de ices, he
adhe ence can be c i ical. The p e ANS in e en ion en ails pe sonal-
ized p e en ion plans based on each indi idual's le el and isk p o ile,
which can inc ease he mo i a ion and adhe ence in he popula ion. In
addi ion, a quali a i e e alua ion will be pe o med o knowing he
ba ie s and acili a o s o he be a e sion o p e ANS in e en ion and
ool. Imp o emen p oposals will be collec ed and implemen ed be o e
he RCT s a s. Also, echnological s a egies o mo i a e use s and o
imp o e i s adhe ence will be included in he p e ANS ool such as
gami ica ion o simple and in ui i e in e ace and in e ac ions. Finally,
i he p e ANS in e en ion was e ec i e and cos -e ec i e, i would be
di icul o de e mine which o he di e en componen s a e esponsible
o he p e en i e e ec , and how each in e ac s wi h he o he s.
Al hough we will conduc a seconda y analysis ha could p o ide in-
o ma ion abou media o s and mode a o s o he e ec , mo e s udies
speci ically di ec ed owa d ha goal will be needed.
The p e ANS in e en ion aims o ac i a e and empowe people, so
ha hey a e he main p o agonis s o hei own heal h, minimizing he
in e en ion o heal h se ices. I he p e ANS in e en ion we e e ec-
i e and cos -e ec i e in p e en ing anxie y diso de s, i s o e all impac
could be ele an due o i s scalabili y po en ial. The use o an inno a-
i e echnological ool ep esen s a minimal cos o heal h se ices and
due o i s po en ial scalabili y, he educ ion o cos o he heal h sys em
and he socie y would be ele an . The e o e, e en unde limi ed bud-
ge s, his economic in o ma ion could help decision-make s o in es
money in his new ool and p omo e i s use.
The p e ANS s udy will p o ide e idence on no el and inno a i e
in e en ion o he p e en ion o anxie y diso de s and he manage-
men o men al heal h. This e idence will open a new ield o esea ch on
pe sonalized p e en i e in e en ions.
E hics s a emen
This p o ocol in ol ing human pa icipan s was e iewed and
app o ed by he e hic commi ees: “E hics and Resea ch Regional
Commi ee o Malaga” and “E hics Commi ee o FPCEUP”. Pa icipan s
a e in o med ha he con iden iali y a e gua an eed ollowing he
Spanish, Po uguese and Eu opean da a p o ec ion laws, and he
execu ion o he p og am is pe o med h ough an enc yp ed and secu e
communica ions sys em. Pa icipan s will be in o med ha hey can
wi hd aw om he s udy a any ime wi hou any nega i e conse-
quences. Any modi ica ions o he p o ocol ha may impac ele an
changes o s udy p ocedu es (e.g., changes in eligibili y c i e ia, as-
sessmen s, in o ma ion on isk/bene i ) o adminis a i e ou ine
equi e a o mal amendmen o he p o ocol.
Da a managemen
The managemen o he s udy da a will be ca ied ou in acco dance
wi h Regula ion (EU) 2016/679 o he Eu opean Pa liamen and o he
Council, o Ap il 27 in 2016, ega ding he p o ec ion o na u al pe sons
wi h ega d o he p ocessing o pe sonal da a and he ee ci cula ion o
hese da a; and also in acco dance wi h Spanish laws: O ganic Law 3/
2018, o Decembe 5, on he P o ec ion o Pe sonal Da a and gua an ee
o digi al igh s, as well as Law 41/2002, o No embe 14, basic egu-
la ing au onomy o he pa ien and o igh s and obliga ions ega ding
in o ma ion and clinical documen a ion, among o he s.
All s udy pa icipan s will be in o med abou he p ocedu es o he
s udy and he use and euse o he da a. They will sign an in o med
consen o join he s udy, which, oge he wi h he s udy p o ocol, ha e
been alida ed by he compe en e hic commi ees. The in o med con-
sen documen includes he objec i es o he s udy, a desc ip ion o he
p ocedu e, an explana ion abou in e en ions and hei andomized
alloca ion p ocess, whom o con ac abou he esea ch, pa icipan s'
igh s, he po en ial bene i s in ol ed in he s udy, he cos s o he
pa icipan s (none), and in o ma ion on anonymized da a sha ing. A e
ec ui men , he pe sonal da a o he pa icipan s will be emo ed om
all da a and s o ed in a passwo d-p o ec ed enc yp ed da abase, each
pa icipan will ecei e a code ha will only be linked o he da a, excep
in case o medical eme gency.
To ensu e da a quali y, he esea ch coo dina o o pe son desig-
na ed by he will implemen and main ain quali y assu ance and con ol
p ocedu es wi h w i en s anda d ope a ing p ocedu es o ensu e ha
he s udy is conduc ed and ha he da a is gene a ed, documen ed, and
no i y in acco dance wi h he p o ocol. Quali y con ol p ocedu es will
be implemen ed s a ing wi h he da a en y sys em, and da a quali y
con ol checks will be pe o med on he da abase.
The da a, which will be collec ed in he amewo k o his p ojec ,
will be des ined o he s udy o anxie y p e en ion. Access o he da a
will be h ough an adminis a o use in a back-o ice, o h ough he
expo o CSV o ma . The da a will belong o he esea ch g oup ac-
co ding o he p i acy policy and will be loca ed in a da abase wi hin
se e s, which will be blocked wi h enc yp ed iles and passwo ds. The
p ojec esea ch eam will be esponsible o he cu a ion-pu i ica ion
and conse a ion o he da a. Fo he p ese a ion o he da a, pe i-
odic backup copies will be made.
Fo he ea men o he heal h da a o he pa icipan s, he p o-
isions o he Eu opean Da a P o ec ion Regula ion will be aken in o
accoun , which es ablishes he ollowing basic p inciples: anspa ency
and legali y, limi a ion o he pu pose, minimiza ion o da a, accu acy,
limi a ion o he conse a ion pe iod, in eg i y and con iden iali y, and
p oac i e esponsibili y. Following hese basic p inciples, da a p i acy
measu es ha e been applied p io o he launch o he p e ANS App,
implemen ing anonymiza ion measu es. Technology p oduce s we e
encou aged o ake he igh o da a p o ec ion in o accoun when
de eloping he app and o ensu e ha he da a con olle s and manage s
hey a e in a posi ion o ul ill hei obliga ions ega ding da a p o ec-
ion. And inally, he pa icipan s a e in o med abou wha will happen
wi h he use o he da a a he end o he s udy.
Dissemina ion policy
De ailed and sho epo s, lea le s and g aphic and ideo summa ies
will be p oduced wi h he help o expe s in communica ion o be
dissemina e among he a ge public and o he s akeholde s. The esul s
o his s udy, whe he posi i e, nega i e, o inconclusi e, will be sub-
mi ed o a pee - e iewed in e na ional jou nal o publica ion.
Funding
Spanish Minis y o Heal h, he Ins i u e o Heal h Ca los III, co-
unded by he Eu opean Social Fund “In es ing in you u u e” (g an
P. Mo eno-Pe al e al.