2013/2014
Daniela Vilas Boas Rosa Linhares
Validation of Control of Allergic
Rhinitis and Asthma Test for Children
(CARATKids) – a prospective
multicenter study
Mestrado Integrado em Medicina
Área: Alergologia
Trabalho efetuado sob a Orientação de:
Professor Doutor João A Fonseca
Trabalho organizado de acordo com as normas da revista:
Pediatric Allergy and Immunology
Daniela Vilas Boas Rosa Linhares
Validation of Control of Allergic
Rhinitis and Asthma Test for Children
(CARATKids) – a prospective
multicenter study
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Declarações!
P O R T O Projeto de Opcao do 6° ano - DECLARACAO DE INTEGRIDADE
F M U P FACULOADE DE MEDICINA
I ] UNIVERSIDADE DO PORTO
U N I O A D f C U R R C J L A s P R O J E T O DE O P C A O
Eu, Daniela Vilas Boas Rosa Linhares abaixo assinado, n° mecanografico 200806655 (080801070), estudante do 6° ano do Ciclo de Estudos Integrado em Medicina, na Faculdade de Medicina da Universidade do Porto, declaro ter atuado com absoluta integridade na elaboracao deste projeto de opcao.
Neste sentido, confirmo que NAO incorri em plagio (ato pelo qual urn individuo, mesmo por omissao, assume a autoria de urn determinado trabalho intelectual, ou partes dele). Mais declaro que todas as frases que retirei de trabalhos anteriores pertencentes a outros autores, foram referenciadas, ou redigidas com novas palavras, tendo colocado, neste caso, a citacao da fonte bibliografica.
Faculdade de Medicina da Universidade do Porto, 10/03/2014
PORTO
Projecto de Opcao do 6 ° ano - DECLARACAO DE REPRODUCAO p p FACUIDADE DE MEDICINA I UNIVERSIDAOE DO PORTO U N I D A D £ C U R R I C U L A R P R O J E T O DE O P 5 & 0 NOMEDaniela Vilas Boas Rosa Linhares
CARTAO DE CIDADAO ou PASSAPORTE (se estrangeiro) E-MAIL TELEFONE OU TELEMOVEL
13800065 [email protected] 916092772
NUMERO DE ESTUDANTE
200806655
DATA DE CONCLUSAO
2014
DESIGNACAO DA AREA DO PROJECTO
Alergologia
TITULO DISSERTACAO
Validation of Control of Allergic Rhinitis and Asthma Test for Children (CARATKids) - a prospective multicenter study
ORIENTADOR
Prof. Dr. Joao A Fonseca
E autorizada a reproducao integral desta Dissertacao para efeitos de investigacao e de divulgacao pedagogica, em programas e projectos coordenados pela FMUP.
Faculdade de Medicina da Universidade do Porto, 10/03/2014
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Trabalho(de(acordo!
com#as#normas#da#
revista!
Full$Title:!Validation!of!Control!of!Allergic!Rhinitis!and!Asthma!Test!for!Children!(CARATKids)!–!a! 1! prospective!multicenter!study! 2! ! 3! Authors:$ 4! Daniela$Vilas$Boas$Rosa$Linhares$ 5! CINTESIS!–!Faculty!of!Medicine!of!University!of!Porto! 6! Porto,!Portugal! 7! João$Almeida$Lopes$da$Fonseca$ 8! CINTESIS!–!Faculty!of!Medicine!of!University!of!Porto! 9! Immunoallergy!Department,!CUF!Porto!Institute! 10! Immunoallergy!Department,!CUF!Porto!Hospital! 11! Porto,!Portugal! 12! Luís$Miguel$Borrego$ 13! Immunoallergy!Department,!CUF!Descobertas!Hospital,!Lisbon! 14! Faculty!of!Medical!Sciences,!Department!of!Immunology,!NOVA,!CEDOC,!Lisbon! 15! Lisbon,!Portugal! 16! Águeda$Matos$ 17! Pediatric!Department,!Guimarães!Hospital! 18! Guimarães,!Portugal! 19! Ana$Margarida$Pereira$ 20! CINTESIS!–!Faculty!of!Medicine!of!University!of!Porto! 21! Immunoallergy!Department,!CUF!Porto!Institute! 22! Immunoallergy!Department,!CUF!Porto!Hospital! 23! Immunoallergy!Department,!Centro!Hospitalar!S.!João,!Porto! 24! Porto,!Portugal! 25! Ana$Sá$e$Sousa$ 26! CINTESIS!–!Faculty!of!Medicine!of!University!of!Porto! 27! Porto,!Portugal! 28! Ângela$Gaspar$ 29! Immunoallergy!Department,!CUF!Descobertas!Hospital,!Lisbon! 30! Lisbon,!Portugal! 31! Cândida$Mendes$ 32! Pediatric!Department,!Vila!Franca!de!Xira!Hospital! 33! Vila!Franca!de!Xira,!Portugal! 34! Carla$Moreira$ 35! Pediatric!Department,!Braga!Hospital! 36! Braga,!Portugal! 37! Eva$Gomes$ 38! Centro!Hospitalar!do!Porto,!Immunoallergy!Department! 39! CUF!Porto!Hospital,!Immunoallergy!Department! 40! Porto,!Portugal! 41! ! 42!
Filomena$Fernandes$Rebelo$ 43! Pediatric!Department,!Centro!Hospitalar!Oeste!Norte,!Caldas!da!Rainha!! 44! Caldas!da!Rainha,!Portugal! 45! José$Carlos$Cidrais$Rodrigues$ 46! Pediatric!Department,!Hospital!Pedro!Hispano,!Matosinhos!! 47! Matosinhos,!Portugal! 48! José$Manuel$Onofre$ 49! Pediatric!Department,!Santarém!Hospital! 50! Santarém,!Portugal! 51! Luís$Filipe$Azevedo$ 52! CINTESIS!–!Faculty!of!Medicine!of!University!of!Porto! 53! Porto,!Portugal! 54! Maria$Alfaro$ 55! Pediatric!Department,!Faro!Hospital! 56! Faro,!Portugal! 57! Maria$José$Calix$ 58! Pediatric!Department,!Hospital!São!Teotónio,!Viseu! 59! Viseu,!Portugal! 60! Rita$Amaral$ 61! CINTESIS!–!Faculty!of!Medicine!of!University!of!Porto! 62! Porto,!Portugal! 63! Rodrigo$RodriguesOAlves$ 64! Immunoallergy!Department,!Hospital!Divino!Espírito!Santo,!Ponta!Delgada! 65! Ponta!Delgada,!Açores,!Portugal! 66! Jaime$Correia$de$Sousa$ 67! Life!and!Health!Sciences!Research!Institute!(ICVS),!School!of!Health!Sciences,!University!of!Minho,! 68! Braga! 69! ICVS/3B's,!PT!Government!Associate!Laboratory,!Braga/Guimarães! 70! Braga,!Portugal! 71! Mário$MoraisOAlmeida$ 72! Immunoallergy!Department,!CUF!Descobertas!Hospital,!Lisbon! 73! CINTESIS!–!Faculty!of!Medicine!of!University!of!Porto,!Porto! 74! Lisbon,!Portugal! 75! ! 76! Running$Title:!Validation!of!CARATKids!! 77! Corresponding$Author:$ 78! João!Almeida!Lopes!da!Fonseca! 79! Faculty!of!Medicine!of!University!of!Porto,!! 80! Alameda!Hernâni!Monteiro!! 81! 4200]319!Porto,!Portugal! 82! [email protected]! 83! ! 84!
Word$Count:$ 85! • Abstract:!250!words! 86! • Main!Text:!2633!words! 87! ! 88! Tables$and$Figures:$ 89! • 3!tables! 90! • 2!figures! 91! ! 92! 1$Supplementary$file:$ 93! • 3!tables! 94! • 1!figure! 95! 96!
Authors:!Linhares!D,!Fonseca!JA,!Borrego!LM,!Azevedo!LF,!Pereira!AM,!Matos!A,!Sá]Sousa!A,!Gaspar! 97! A,!Mendes!C,!Moreira!C,!Gomes!E,!Fernandes!F,!Cidrais]Rodrigues!J,!Onofre!JM,!Alfaro!M,!Calix!MJ,! 98! Amaral!R,!Rodrigues]Alves!R,!Sousa!JC,!Morais]Almeida!M!for!the!CARATKids!study!group! 99! ! 100! Title:!Validation!of!Control!of!Allergic!Rhinitis!and!Asthma!Test!for!Children!(CARATKids)!–!a! 101! prospective!multicenter!study! 102! Journal$Title:!Pediatr!Allergy!Immunol! 103!
Abstract$
104! Background:!Control!of!Allergic!Rhinitis!and!Asthma!Test!for!Children!(CARATKids)!is!the!first! 105! questionnaire!that!assesses!simultaneously!allergic!rhinitis!and!asthma!control!in!children.!It!was! 106! recently!developed,!but!redundancy!of!questions!and!its!psychometric!properties!were!not!assessed.! 107! This!study!aimed!to!(i)establish!the!final!version!of!the!CARATKids!questionnaire!and!(ii)evaluate!its! 108! reliability,!responsiveness,!cross]sectional!validity,!and!longitudinal!validity.! 109! Methods:!A!prospective!observational!study!was!conducted!in!11!Portuguese!centers.!During!two! 110! visits!separated!by!6wk,!CARATKids,!visual!analog!scale!scales!and!childhood!asthma!control!test! 111! were!completed,!and!participant’s!asthma!and!rhinitis!were!evaluated!by!his/her!physician!without! 112! knowing!the!questionnaires’!results.!Data]driven!item!reduction!was!conducted,!and!internal! 113! consistency,!responsiveness!analysis,!and!associations!with!external!measures!of!disease!status!were! 114! assessed.!! 115! Results:!Of!the!113!children!included,!101!completed!both!visits.!After!item!reduction,!the!final! 116! version!of!the!questionnaire!has!13!items,!eight!to!be!answered!by!the!child!and!five!by!the! 117! caregiver.!Its!Cronbach’s!alpha!was!0.80,!the!Guyatt’s!responsiveness!index!was!]1.51,!and!a! 118! significant!(p<0.001)!within]patient!change!of!CARATKids!score!in!clinical!unstable!patients!was! 119! observed.!Regarding!cross]sectional!validity,!correlation!coefficients!of!CARATKids!with!the!external! 120! measures!of!control!were!between!0.45!and!]0.69!and!met!the!a!priori!predictions.!In!the! 121! longitudinal!validity!assessment,!the!correlation!coefficients!between!the!score!changes!of! 122! CARATKids!and!those!of!external!measures!of!control!ranged!from!0.34!to!0.46.! 123! Conclusion:!CARATKids!showed!adequate!psychometric!properties!and!is!ready!to!be!used!in!clinical! 124! practice.! 125!Keywords$
126! Allergic!rhinitis,!Asthma,!Child,!Questionnaires,!Patient]reported!outcomes! 127! ! 128! Offprint$Requests:$ 129! João!Almeida!Lopes!da!Fonseca! 130! Faculty!of!Medicine!of!University!of!Porto,!! 131! Alameda!Hernâni!Monteiro!! 132! 4200]319!Porto,!Portugal! 133! [email protected] 134!Introduction$
135! Asthma!and!allergic!rhinitis!(ARA)!are!chronic!inflammatory!diseases!of!the!airways!that!often! 136! coexist!in!children!(1).!Rhinitis!increases!the!risk!of!asthma!and!impairs!its!control!(2–4).!When!non] 137! controlled,!these!conditions!are!responsible!for!a!significant!decrease!in!patient’s!quality!of!life!(1).! 138! Currently,!clinical!asthma!control!is!defined!as!the!frequency!and!intensity!of!symptoms!and! 139! functional!limitations!that!a!patient!experiences!or!has!recently!experienced!as!a!consequence!of! 140! the!disease!and!includes!day!and!night!symptoms,!use!of!reliever!therapy,!activity!limitations,!and! 141! lung!function!measurements!(5).!Rhinitis!control!has!never!been!formally!defined.!Nevertheless,! 142! Demoly!et!al.!(6)!recently!argued!for!the!use!of!the!concept!of!rhinitis!control!as!a!way!to!improve! 143! clinical!decisions.! 144! CARAT10!was!the!first!tool!that!was!developed!and!validated!to!assess!ARA!control!in!adults!(age≥18! 145! yr)!(6–8).!In!children,!until!recently,!there!were!several!available!tools!evaluating!asthma!control,!but! 146! as!far!as!we!know,!there!was!no!tool!assessing!the!control!of!rhinitis!or!ARA.!Control!of!Allergic! 147! Rhinitis!and!Asthma!Test!for!Children!(CARATKids)!was!developed!to!evaluate!ARA!control!in! 148! children!with!6–12yr!old.!This!initial!version!of!CARATKids!has!17]item!and!was!developed!from! 149! CARAT!and!other!pediatric!questionnaires,!in!a!two]phase!study!with!consensus!meetings!between! 150! specialized!physicians!on!the!area,!and!cognitive!interviews!of!children!and!their!caregivers!(7);!it! 151! uses!a!dichotomic!scale!(Yes/No!answers),!with!easily!understandable!questions!and!images!for! 152! children.! 153! This!study!aims!to!(i)define!the!final!version!of!the!CARATKids!questionnaire!(item!reduction!and! 154! content!structure!and!layout!improvement)!and!(ii)to!evaluate!its!reliability,!responsiveness,!and! 155! cross]sectional!and!longitudinal!validity.! 156! ! 157!Methods$
158! Study$design$and$setting$$
159! A!multicentric!prospective!observational!study!was!conducted!in!eleven!centers!located!in!five!of!the! 160! seven!Portuguese!regions.!Allergists!and!pediatricians!were!invited!to!participate,!and!one!to!five! 161! physicians!at!each!center!joined!the!study.!This!study!comprised!two!visits,!3–6wk!apart,!and!was! 162! conducted!between!July!2012!and!February!2013.! 163! Participants$ 164! All!patients!between!6!and!12!yr!old,!with!a!previous!medical!diagnosis!of!asthma!and!allergic! 165! rhinitis,!followed!at!the!participating!centers,!for!at!least!three!months,!were!eligible.!Children!with! 166! other!respiratory!or!chronic!diseases!that!could!interfere!with!the!study!measurements,!as!well!as! 167! parents!and!children!unable!to!fill!the!questionnaire,!were!excluded.!The!study!was!approved!by!the! 168! Hospital!CUF!Descobertas’!ethics!committee,!and!each!patient’s!parents!gave!their!written!informed! 169! consent.! 170! Data$Collection$ 171! Questionnaires!were!completed!at!each!visit!by!children!and!their!caregivers,!namely!CARATKids,! 172! childhood!Asthma!Control!Test!(cACT),!and!visual!analog!scale!(VAS)!of!rhinitis!and!asthma!control.! 173! CARATKids’!initial!version!has!17!questions,!with!two!answer!options!–!‘Yes’,!scored!as!1!=!no!control! 174!(symptom/item!present);!and!‘No’,!scored!as!0!=!control!(symptom/item!not!present).!The!attending! 175! physician!performed!a!medical!evaluation!and!filled!out!VAS!of!rhinitis!and!asthma!control.! 176! Physicians!were!blinded!to!patient/caregiver’s!questionnaire!responses.!Characteristics!of!the! 177! questionnaire!according!to!patient]reported!outcomes!Ga2len!recommendations!are!presented!on! 178! Table!S1!(8).! 179! Data$Analysis$ 180! Sample!size!was!established!using!COSMIN!recommendations!(9).!To!assess!over!100!participants,! 181! with!an!attrition!rate!of!10%,!115!patients!were!planned!to!be!included.!Sample!characteristics!were! 182! described!by!standard!descriptive!statistics.!The!variables’!distribution!was!plotted!to!visually!assess! 183! the!distribution,!and!parametric!and!nonparametric!tests!were!used!as!appropriate.! 184! The!physicians’!VAS!assessing!asthma!or!rhinitis!control!were!categorized!as!dichotomous!variables,! 185! classifying!the!patient!as!controlled!or!uncontrolled.!Disease!control!was!defined!as!a!VAS! 186! measurement!to!be!greater!than!six!out!of!a!scale!ranging!from!0!(bad)!to!10!(good),!according!to! 187! previous!reports!(10).!This!was!applied!for!the!control!of!allergic!rhinitis!as!well!as!asthma!control.! 188! Asthma!control!was!also!classified!according!to!the!Global!Initiative!for!Asthma!(GINA)!guidelines!(5)! 189! and!to!cACT,!with!controlled!asthma!defined!as!a!score!of!19!or!less!(11).!A!patient!was!considered! 190! controlled!when!both!asthma!and!rhinitis!were!controlled,!taking!into!account!the!GINA! 191! classification!for!asthma!and!physician!VAS!classification!for!rhinitis.!The!rhinitis!severity!was! 192! classified!according!to!Allergic!Rhinitis!and!its!Impact!on!Asthma!(ARIA)!recommendations!(12).! 193! Patients!who!were!graded!between!5.0!and!6.0!in!the!second!visit’s!control!variation!VAS!of!both! 194! asthma!and!rhinitis!were!considered!to!be!clinically!stable.! 195! All!answers!were!analyzed!and!response!rates!computed.!Results!from!physician!assessment! 196! measures!and!children/caregiver’s!answers!in!each!visit!were!pooled!and!plotted!against!CARATKids! 197! scores!and!factors.! 198! Item$Reduction$ 199! Item!reduction!was!based!on!statistical!criteria!and!on!a!consensus!meeting!with!an!expert!panel! 200! held!in!May!2013.!Stepwise!logistic!regression!was!performed!to!reduce!the!17]item!working! 201! questionnaire.!Exploratory!factor!analysis!and!internal!consistency!analysis!were!also!performed!and! 202! taken!into!account!for!the!item!reduction.!An!item!was!considered!redundant,!and!it!was!discarded,! 203! if!one!of!the!following!occurred:!a)responses!over!95%!in!a!single!category!of!a!variable;!b)a!p]value! 204! of!less!than!0.10!in!logistic!regression!analysis;!c)considerable!cross]loading!(>0.300!in!more!than! 205! one!factor)!or!low!item]total!correlation!(<0.400)!or!increased!Cronbach’s!alpha!if!the!item!was! 206! deleted.! ! 207!
Evaluation$of$CARATKids$ 208! Control!of!Allergic!Rhinitis!and!Asthma!Test!for!Children!measurement!properties!were!assessed! 209! according!to!the!COSMIN!checklist!(9):!(i)reliability!(internal!consistency,!using!Cronbach’s!a;!test– 210! retest!reliability,!using!intraclass!correlation!coefficient!(ICC)),!(ii)responsiveness!(within]!patient! 211! change!in!CARATKids!score;!Guyatt’s!responsiveness!index!(GRI)),!(iii)discriminative!properties!and! 212! validity!–!(iii.a)concurrent!validity!(physician!assessment,!self]assessment,!and!cACT);! 213! (iii.b)longitudinal!validity!(physician!assessment,!self]!assessment,!and!cACT);!and!(iii.c)hypothesis! 214! testing,!with!a!priori!predictions!for!concurrent!validity!for!the!correlation!defined!as:!(i)0.5–0.7!with! 215! cACT;!(ii)0.4–0.7!with!the!symptoms!VAS;!(iii)0.4–0.6!with!the!physician’s!assessment).!Confidence! 216! intervals!(CI)!for!correlation!coefficients!were!calculated!using!bootstrap!methods.!Lower!and!upper! 217! limits!of!the!95%CI!corresponded!to!the!percentiles!2.5!and!97.5!of!the!distribution!of!the!sample! 218! statistics!after!thousand!replicates!(random!samples!with!replacement!of!the!same!size!as!the! 219! original!sample)!for!each!estimate.! 220! The!statistical!analysis!was!carried!out!using!SPPS!21.0!(SPSS!Inc.,!Chicago,!IL,!USA).!The!level!of! 221! significance!was!set!at!p<0.05.! 222! ! 223!
Results$
224! The!113!patients!included!were!assessed!by!23!physicians!at!11!outpatients’!clinics.!Twelve!patients! 225! (10.6%)!did!not!attend!the!second!visit.!The!general!characteristics!of!patients!are!summarized!in! 226! Table!1.!Of!the!103!with!complete!data!on!allergy,!98!were!positive!to!house!dust!mites!and!32!for! 227! pollens,!mostly!grass!pollen,!and!13!sensitized!to!cat!or!dog.! 228! Overall,!0.3%!of!all!CARATKids!questions!were!not!answered.!The!items!with!more!missing!items! 229! each!with!two!missings!(1.8%)!were!‘Wheezing’,!by!both!children!and!parents,!‘Rhinorrhoea’!and! 230! ‘Throat!symptoms’!by!children,!and!‘Nasal!Obstruction’!and!‘Dyspnoea’!by!parents.! 231! For!longitudinal!analysis,!full!data!on!disease!control!were!available!for!80!patients.!Twenty]nine! 232! patients!(36%)!were!classified!as!having!clinically!stable!asthma!and!rhinitis.!The!unstable!group! 233! included!51!patients,!15!with!both!unstable!asthma!and!rhinitis,!16!with!only!unstable!rhinitis,!and! 234! 20!with!only!unstable!asthma.! 235! Item$Reduction$ 236! Internal!consistency!was!better!when!questions!were!answered!by!the!parents!and!children! 237! separately!than!when!answered!together.!Moreover,!the!responses!of!parents!and!children! 238! separately!had!better!correlation!coefficients!with!comparative!measures!than!questions!answered! 239! by!parents!and!children!together!(data!not!shown).!The!expert!panel,!held!to!discuss!item!selection,! 240! decided!the!questions!should!be!answered!by!the!children!and!the!parents!separately!(Fig.!S1).!The! 241! item!‘Hospitalization’!was!eliminated,!because!it!had!more!than!95%!of!answers!‘No’.!Then,!using! 242! stepwise!logistic!regression,!the!items!‘Nasal!pruritus’,!‘Throat!symptoms’,!and!‘Ocular!symptoms’! 243! were!excluded!(Fig.!S1).!Internal!consistency!analysis!was!in!agreement!with!this!13]item!version!of! 244! the!questionnaire.!Exploratory!factor!analysis!identified!four!factors!and!had!no!contribution!to!the! 245! item!reduction.!The!final!questionnaire!had!13!questions.!Based!on!the!data!from!internal! 246! consistency!and!logistic!regression!analysis!and!the!associations!with!external!comparison!measures,! 247! eight!questions!are!best!answered!by!the!children!and!five!by!the!parents.! ! 248!Properties$and$Evaluation$of$CARATKids$ 249! Control!of!Allergic!Rhinitis!and!Asthma!Test!for!Children!had!a!median!(P25]P75)!score!of!4!(2–7)!in! 250! the!first!visit!and!of!3!(1–5)!in!the!second!one.!Nine!patients!(8.2%)!in!visit!1!and!13!(15.6%)!in!visit!2! 251! had!the!minimum!score!of!0,!and!2!(1.8%)!in!visit!1!and!1!(0.9%)!in!visit!2!had!the!maximum!score!of! 252! 13.!The!mean!(s.d.)!score!difference!between!the!two!visits!was!of!]1.46!(3.34),!p<0.001.!Control!of! 253! Allergic!Rhinitis!and!Asthma!Test!for!Children!scores!were!significantly!different!when!comparing! 254! patients!with!controlled,!uncontrolled,!and!partly!controlled!asthma,!and!when!comparing!children! 255! with!mild!rhinitis!with!those!with!moderate!to!severe!disease!(p<0.05).!Scores!differed!significantly! 256! between!physician’s!treatment!decision!groups!(reduction,!maintenance,!or!increase),!GINA! 257! classification!of!asthma!control,!and!ARIA!classification!of!severity!(Fig.!1!and!Table!S2).!In!both!visits,! 258! significant!differences!are!observed!in!CARATKids!scores!between!control!groups!defined!by!cACT! 259! (Fig.!1).! 260! In!the!internal!consistency!analysis,!the!Cronbach’s!alpha!was!0.80!for!CARATKids.! 261! All!correlation!coefficients!met!the!a!priori!predictions!(Table!2).!Coefficients!varied!between!0.430! 262! and!]0.689!(all!p<0.001).!Correlation!coefficient!of!CARATKids!scores!with!GINA!classification!of! 263! asthma!control!was!of!]0.60!(95%CI!]0.728;!]0.442)!and!of!0.430!(0.235;!0.584)!with!ARIA! 264! classification!of!rhinitis!severity!(p<0.001).! 265! Receiver!operating!characteristic!curves!for!CARATKids!are!shown!in!Fig.!2.!The!areas!under!the! 266! curve!for!CARATKids!ranged!from!0.761!(physician!evaluation!of!rhinitis!control)!to!0.826!(cACT).! 267! In!the!test–retest!reliability!analysis,!the!ICC!was!0.80!in!the!stable!group.!When!evaluating! 268! responsiveness,!we!observed!a!significant!within]patient!change!of!CARATKids!score!in!clinically! 269! unstable!patients,!not!only!when!both!the!conditions!were!unstable!(mean(s.d.)!change!of!] 270! 3.8(2.83),!p!<!0.001)!but!also!when!at!least!one!was!unstable!(]2.1(3.54),!p<0.001).!In!the!stable! 271! group,!there!was!a!non]significant!difference!(mean(s.d.)!of!]0.59(2.52),!p=0.23)!between!CARATKids! 272! scores!in!the!two!visits.!The!GRI!was!of!1.51!in!the!group!with!both!conditions!unstable.! 273! The!range!of!the!correlation!coefficients!between!the!variation!in!CARATKids!scores!and!the! 274! variation!in!physician!assessment!of!control!using!VAS!was!0.454!and!0.446,!meeting!the!a!priori! 275! prediction!(Table!2).! 276!
Discussion$
277! This!article!describes!the!clinical!evaluation!of!CARATKids,!the!first!questionnaire!developed!to! 278! concurrently!assess!asthma!and!allergic!rhinitis!control!in!6]!to!12]yr]old!children.!A!process!of!item! 279! reduction!from!the!initial!17]item!version!of!CARATKids!was!performed!to!reduce!redundancy!and! 280! improve!the!questionnaire’s!reliability!and!validity.!The!13]item!questionnaire!showed!to!have!good! 281! discriminative!properties.! 282! Of!the!13!items,!five!are!to!be!answered!by!parents!and!eight!by!children!(Fig.!S1).!Although!this! 283! method!of!a!twofold!answer!was!found!to!be!the!most!adequate!solution,!the!usability!of!the! 284! questionnaire!is!somehow!reduced!by!the!parent!and!child!response!method.!However,!previous! 285! studies!on!asthma!also!observed!divergence!between!children!and!parent]reported!variables,!with! 286! some!sets!of!questions!being!better!answered!by!each!of!them!(11,!13,!14).!In!fact,!cACT!also!has!a! 287! twofold!answer!method!(11).!The!questions!on!sneezing!and!other!nasal!symptoms!had!better! 288!results!when!answered!by!the!children,!while!parents!may!be!less!aware!of!the!frequency!of!these! 289! symptoms.!In!the!cognitive!interviews!performed!in!the!initial!stages!of!CARATKids!development,! 290! this!lack!of!concordance!was!already!observed!(7).! 291! The!internal!consistency!was!satisfactory!(15),!being!similar!or!better!than!other!questionnaires! 292! evaluating!asthma!control!in!children,!such!as!cACT!(11),!Asthma!Control!Questionnaire!(ACQ)!in! 293! Children!(CAN)!(16),!Test!for!Respiratory!and!Asthma!Control!in!Kids!(TRACK)!(17),!ACQ!in!children! 294! (18),!or!Asthma!Quiz!(19)!(Table!3);!however,!it!was!slightly!lower!than!the!one!in!adult’s! 295! questionnaires,!as!CARAT!(20)!and!Asthma!Control!Test!(ACT)!(21)!(Table!3).!The!areas!under!the! 296! curve!were!high!(0.761–0.826),!namely!when!compared!with!physician!assessment!of!control!and! 297! cACT!(Fig.!2)!assumed!as!comparators.!These!are!in!the!same!range!of!those!previously!observed!in! 298! studies!on!adults!and!are!higher!than!the!ones!reported!for!cACT!(Table!3).! 299! A!gold!standard!for!ARA!control!has!not!been!established!yet.!Therefore,!concurrent!validity!was! 300! assessed!using!different!external!measures!of!control,!based!on!physicians,!children,!and!caregivers’! 301! assessments.!A!priori!predictions!were!met,!and!all!coefficients!are!in!the!same!range!as!those! 302! observed!with!other!tools!to!assess!control,!both!in!children!and!adults!(Table!3).! 303! In!test–retest!reliability!analysis,!CARATKids!scores!showed!an!ICC!similar!or!better!than!those!of! 304! ACQ!in!children,!TRACK,!CAN,!ACT,!and!CARAT!(Table!3).! 305! Large!responsiveness,!greater!than!0.8!was!observed!(22).!Moreover,!the!magnitude!of!GRI!of! 306! CARATKids!(1.51)!was!similar!to!the!one!of!CARAT!(1.54).! 307! Regarding!longitudinal!validity,!correlation!coefficients!were!higher!than!a!priori!predictions!for! 308! physician!and!children!VAS!of!both!asthma!and!rhinitis!control!(Table!2),!but!not!for!cACT.!As!we! 309! could!not!find!longitudinal!validity!assessment!of!cACT,!it!is!difficult!to!interpret!the!low!correlation! 310! coefficient!we!observed!between!ΔCARATKids!scores!and!ΔcACT.!This!low!correlation!may!be! 311! related!to!differences!in!sensitivities!or!responsiveness!of!the!questionnaires.!In!any!case,!in!both! 312! visits,!significant!differences!were!observed!in!CARATKids!scores!between!cACT!control!groups!(Fig.! 313! 1).!The!only!control!questionnaires!for!children!with!published!longitudinal!validity!results!are!ACQ! 314! in!children!and!CAN.!The!CARATKids!longitudinal!results!are!similar!to!CAN!and!worse!than!ACQ!in! 315! children!(Table!3).!This!may!be!related!to!differences!in!the!study!design,!as!ACQ!for!children!was! 316! evaluated!in!a!single!center,!with!3!visits!in!4wk!(0,!1,!and!4wk)!that!included!only!35!children!(18).! 317! Moreover,!a!guideline]based!assessment!of!asthma!control!is!already!available,!while!the!control!of! 318! rhinitis!was!defined!by!physician]derived!measures!because!no!gold!standard!measure!is!available! 319! yet.!It!is!known!that!there!is!a!bias!associated!with!the!physician!assessment!of!control!(23),!which! 320! can!partly!explain!the!somewhat!lower!CARATKids!scores.!Nevertheless,!CARATKids!longitudinal! 321! validity!results!were!similar!to!those!of!control!questionnaires!in!adults!and!of!the!CAN! 322! questionnaire!(Table!3).! 323! This!study!has!several!limitations.!Interobserver!agreement!may!have!been!reduced!by!the!high! 324! number!of!observes!included,!as!data!were!collected!by!23!physicians!at!11!outpatients’!clinics.! 325! Nevertheless,!this!dispersion!of!data!collection!may!improve!the!generalizability!to!the!real]world! 326! clinical!practice.!Also,!patients!were!not!equally!distributed!across!the!range!of!asthma!and!rhinitis! 327! severity,!and!for!some!subgroups,!the!number!of!patients!was!low.!This!was!specially!relevant!for! 328! uncontrolled!asthma!subgroup!for!which!only!12!patients!were!accessed.!Furthermore,!CARATKids! 329! was!only!assessed!in!children!established!asthma!and!allergic!rhinitis!diagnosis;!therefore,!its! 330! performance!in!children!with!only!one!of!the!diseases!remains!unknown.! 331! Minimal!important!difference!and!cutoff!values!are!important!properties!that!were!not!objectives!of! 332!
this!study!and!should!be!defined!in!future!studies.!This!would!be!specially!important!to!use! 333! CARATKids!in!intervention!studies.!Nevertheless,!we!conducted!exploratory!analysis!of!the!cutoff! 334! values.!We!considered!one!point!for!each!‘Yes’!answer!and!classified!the!CARATKids!scores!as! 335! controlled!(<4),!insufficiently!controlled!(4,!5),!and!uncontrolled!(>5).!Uncontrolled!asthma!or!rhinitis! 336! can!be!ruled!out!with!a!score!of!three!or!less!and!ruled!in!with!a!score!higher!than!five!with!good! 337! sensitivity!and!specificity!(Table!S3).!The!clinical!usefulness!of!routine!assessment!of!control!in! 338! children,!using!questionnaires,!also!needs!to!be!assessed!in!long]term!studies.! 339! In!conclusion,!CARATKids,!the!first!questionnaire!assessing!allergic!rhinitis!and!asthma!control!for! 340! children!6–12!yr!old,!showed!adequate!psychometric!properties!to!be!used!in!clinical!practice.
!
341! Acknowledgments$ 342! We!thank!the!heads!of!the!departments!where!the!study!was!conducted,!the!physicians!that! 343! participated!in!the!data!collection:!Alberto!Gomes!Costa,!Cristina!Arede,!Graça!Sampaio,!Helder! 344! Ferreira,!Isabel!Andrade,!Luís!Araújo,!Susana!Piedade.! 345! Disclosure$ 346! None!of!the!authors!received!payments!or!services,!either!directly!or!indirectly,!from!a!third!party!in! 347! support!of!any!aspect!of!this!work. 348!Tables$
349! $ Visit$1$$ n=113$ Visit$2$n=101$ Age$mean$(SD)$years$ 8.75!(1.86)! 8.84!(1.82)! Gender$n$(%)$ ! ! Male$ 69!(61.1%)! 64!(63.4%)! Female$ 44!(38.9%)! 37!(36.6%)! cACT$score$(p25Op75)$ 23!(19]25)! 24!(21.3]26)! Physician$Assessment$n$(%)$ ! ! Asthma$Control$O$GINA$ ! ! Uncontrolled$ 12!(10.6%)! 4!(3.5%)! Partly$Controlled$ 36!(31.9%)! 18!(15.9%)! Controlled$ 46!(40.7%)! 65!(57.5%)! Rhinitis$O$ARIA$ ! ! Intermittent$ 43!(38.1%)! 50!(44.2%)! Persistent$ 66!(58.4%)! 49!(43.4%)! Mild$ 73!(64.6%)! 82!(72.6%)! Moderate/Severe$ 37!(32.7%)! 19!(16.8%)! VAS$Control$median$(p25Op75)$ ! ! Asthma$ 5!(8]9)! 9!(8]9.5)! Rhinitis$ 6!(4]8)! 8!(6]9)! Treatment$Decision$n$(%)$ ! ! Reduce$ 8!(7.1%)! 9!(9.1%)! Maintain$ 51!(45.5%)! 68!(68.7%)! Increase$ 53!(47.3%)! 22!(22.2%)! $ 350! Table$1$Characteristics!of!participants.!cACT,!childhood!Asthma!Control!Test;!GINA,!Global!Initiative! 351! for!Asthma;!ARIA,!Allergic!Rhinitis!and!its!Impact!on!Asthma;!VAS,!Visual!Analogue!Scale.! ! 352!$ Physician$Assessment$–$VAS/ΔVAS$ Children$Assessment$–$VAS/ΔVAS$ cACT/ΔcACT$ Asthma$Control$ Rhinitis$Control$ Asthma$Control$ Rhinitis$Control$
CARATKids$ (]0.678;]0.371)!]0.548! (]0.648;]0.308)!]0.499! (0.439;0.74)!0.608! (0.266;0.591)!0.446! (]0.805;]0.543)!]0.689! ΔCARATKids$ (]0.656;]0.163)!]0.446! (]0.687;]0.177)!]0.454! (0.19;0.687)!0.466! (0.172;0.663)!0.447! (]0.633;]0.033)!]0.344! $ 353! Table$2$Correlation!coefficients!between!CARATKids!with!external!measures!of!control!and!of! 354! between]visits!changes!(variation)!of!CARATKids!scores!(ΔCARATKids)!and!between]visits!changes!of! 355! external!measures!of!control.$Data!is!presented!as!Spearmen!correlation!coefficients!(95%CI).! 356! CARATKids,!Control!of!Allergic!Rhinitis!and!Asthma!Test!for!Children;!VAS,!Visual!Analog!Scale;!cACT,! 357! childhood!Asthma!Control!Test! ! 358!
$ consistency$Internal$ Concurrent$validity$ ROC$curves$(AUC)$ retest$ICC$TestO Responsiveness$ Longitudinal$validity$
For$Children$ ! ! ! ! ! !
CARATKids$ 0.80! 0.37]0.73,!all!p<0.001! 0.76]0.83! 0.80! Significant!within]patient!change! 0.32]0.44,!all!p<0.05! cACT$(11)$ 0.79! 0.47]0.68,!all!p<0.001! 0.67]0.71! NA! NA! NA! ACQ$in$children$
(18,$24)$ 0.75! 0.52]0.83! 0.60! 0.79! Significant!within]patient!change! 0.66]0.89! TRACK(17,$25)$ 0.75! NA! 0.78! 0.63! Significant!within]patient!change! NA! Asthma$
Quiz(19)$ 0.73! NA! NA! NA! NA! NA! CAN(16)$ 0.82! ]0.18];0.14! 0.73]0.77! 0.73! Significant!within]patient!change! ]0.34;]0.23!
For$Adults$ ! ! ! ! ! !
CARAT$(20,$26)$ 0.85! 0.48]0.71,!all!p<0.001! 0.82! 0.82! Significant!within]patient!change! 0.31]0.65! ACT$(21,$27)$ 0.85! 0.31]0.89,!all!p<0.001! 0.69! 0.77! Significant!within]patient!change! 0.29]0.81,!all!p<0.001! ACQ$(27,$28)$ NA! 0.19]0.76! 0.85]0.90! 0.90! Significant!within]patient!change! 0.15]0.73!
! 359! Table$3!When!available,!data!from!different!sources!were!used!and!the!higher!values!on!each! 360! questionnaire!description!are!presented.!CARATKids,!Control!of!Allergic!Rhinitis!and!Asthma!Test!for! 361! Children;!cACT,!childhood!Asthma!Control!Test;!ACQ,!Asthma!Control!Questionnaire;!TRACK,!Test!for! 362! Respiratory!and!Asthma!Control!in!Kids;!CAN,!Asthma!Control!Questionnaire!for!Children;!CARAT,! 363! Control!of!Allergic!Rhinitis!and!Asthma!Test;!ACT,!Asthma!Control!Test;!NA,!not!available.*Values!are! 364! for!patient!and!carer’s!versions,!respectively. 365!
Figures
! 366! $ 367! Figure$1$Mean!and!95%!confidence!intervals!of!CARATKids!scores!in!both!visits!1!and!2!with:!(a)! 368! physician’s!decision!of!treatment!reduction,!maintenance,!or!increase;!(b)!asthma!control!classified! 369! by!cACT;!(c)!GINA!classification!of!asthma!control;!and!(d)!ARIA!classification!of!rhinitis!severity.! 370! CARATKids,!Control!of!Allergic!Rhinitis!and!Asthma!Test!for!Children;!cACT,!childhood!Asthma! 371! Control!Test;!ARIA,!Allergic!Rhinitis!and!its!Impact!on!Asthma;!GINA,!Global!Initiative!for!Asthma.! ! 372!! 373! Figure$2!Receiver!operating!characteristic!curves!of!CARAT10!score!against!(a)!asthma!control! 374! classified!by!cACT;!physician!assessment!of!(b)!rhinitis!and!(c)!asthma!control.!ROC,!receiver! 375! operating!characteristic;!cACT,!childhood!Asthma!Control!Test;!VAS,!visual!analog!scale;!AUC,!area! 376! under!curve.
377! improve the questionnaire’s reliability and validity. The 13-item questionnaire showed to have good discriminative properties.
Of the 13 items, five are to be answered by parents and eight by children (Fig. S1). Although this method of a twofold answer was found to be the most adequate solution, the usability of the questionnaire is somehow reduced by the parent and child response method. However, previous studies on asthma also observed divergence between children and parent-reported variables, with some sets of questions being better answered by each of them (11, 13, 14). In fact, cACT also has a twofold answer method (11). The questions on sneezing and other nasal symptoms had better results when answered by the children, while parents may be less aware of the frequency of these symptoms. In the cognitive interviews performed in the initial stages of CARATKids development, this lack of concordance was already observed (7).
The internal consistency was satisfactory (15), being similar or better than other questionnaires evaluating asthma control in children, such as cACT (11), Asthma Control Questionnaire (ACQ) in Children (CAN) (16), Test for Respiratory and Asthma Control in Kids (TRACK) (17), ACQ in children (18), or Asthma Quiz (19) (Table 3); however, it was slightly lower than the one in adult’s questionnaires, as CARAT (20) and Asthma Control Test (ACT) (21) (Table 3). The areas under the curve were high (0.761–0.826), namely when compared with physician assessment of control and cACT (Fig. 2) assumed as
comparators. These are in the same range of those previously observed in studies on adults and are higher than the ones reported for cACT (Table 3).
A gold standard for ARA control has not been established yet. Therefore, concurrent validity was assessed using different external measures of control, based on physicians, children, and caregivers’ assessments. A priori predictions were met, and all coefficients are in the same range as those observed with other tools to assess control, both in children and adults (Table 3).
In test–retest reliability analysis, CARATKids scores showed an ICC similar or better than those of ACQ in children, TRACK, CAN, ACT, and CARAT (Table 3).
Large responsiveness, greater than 0.8 was observed (22). Moreover, the magnitude of GRI of CARATKids (1.51) was similar to the one of CARAT (1.54).
Regarding longitudinal validity, correlation coefficients were higher than a priori predictions for physician and children VAS of both asthma and rhinitis control (Table 2), but not for cACT. As we could not find longitudinal validity assessment of cACT, it is difficult to interpret the low correlation coefficient we observed between DCARATKids scores and DcACT. This low correlation may be related to differences in sensitivities or responsiveness of the question-naires. In any case, in both visits, significant differences were observed in CARATKids scores between cACT control groups (Fig. 1). The only control questionnaires for children with published longitudinal validity results are ACQ in Table 2 Correlation coefficients between CARATKids with external measures of control and of between-visits changes (variation) of CARATKids scores (DCARATKids) and between-visits changes of external measures of control
Physician Assessment– VAS/DVAS Children Assessment– VAS/DVAS
cACT/DcACT Asthma Control Rhinitis Control Asthma Control Rhinitis Control
CARATKids !0.548 (!0.678; !0.371) !0.499 (!0.648; !0.308) 0.608 (0.439;0.74) 0.446 (0.266;0.591) !0.689 (!0.805; !0.543) DCARATKids !0.446 (!0.656; !0.163) !0.454 (!0.687; !0.177) 0.466 (0.19;0.687) 0.447 (0.172;0.663) !0.344 (!0.633; !0.033) Data are presented as Spearmen correlation coefficients (95%CI). CARATKids, Control of Allergic Rhinitis and Asthma Test for Children; VAS, visual analog scale; cACT, childhood Asthma Control Test.
0.0 0.2 0.4 Sensi vity 1 - Specificity 0.6 0.8 1.0 ROC Curve cACT ROC Curve
Physician Assessment - VAS of Rhini s Control
ROC Curve
Physician Assessment - VAS of Asthma Control
0.0 0.2 0.4 0.6 0.8 1.0 1 - Specificity 0.0 0.2 0.4 0.6 0.8 1.0 1 - Specificity 0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0
AUC = 0.826 AUC = 0.761 AUC = 0.814
(a) (b) (c)
Figure 2 Receiver operating characteristic curves of CARAT10 score against (a) asthma control classified by cACT; physician assessment of (b) rhinitis and (c) asthma control. ROC, receiver operating characteristic; cACT, childhood Asthma Control Test; VAS, visual analog scale; AUC, area under curve.
ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 5
$References$
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Supplementary$File$
449! Name$of$the$tool$$ Control$of$Allergic$Rhinitis$and$Asthma$Test$for$Children$ Acronym$ CARATKids$ Author! Fonseca!JA,!Borrego!LM,!Linhares!D,!Morais]Almeida!A!for!the! CARATKids!study!group! Bibliographic!references!of!the! original!questionnaire!! Borrego!LM!et!al.!BMC!Pediatr.!2014!(7)! Linhares!D!et!al.!Pediatr!Allergy!Immunol.!2014! Target! Allergic!Rhinitis!and!Asthma! Population! Children!from!6!to!12!years!old! Administration! Self]administration! Original!language! Portuguese! Existing!translations! Under!development! Numbers!of!items! 13!(8!to!be!answer!by!children!and!5!by!parents)! Tool!dimensions! Not!available! Scaling!of!items! Yes!(1)!or!No!(0)! Scoring!of!items! 0!(Best)!to!13!(Worst)! List!of!items! Children!answer:!Nasal!Obstruction,!Sneezing,!Rinorrhoeae,! Dyspnoeae,!Wheezing,!Cough,!Symptoms!with!laught!or! exercise,!Daily!activities!limitation! Parents!answer:!Waking!up!at!night,!Symptoms!in!the!morning,! Missing!school/activities,!Medication!increase,!Nonscheduled! consultation! Minimal!important!difference! Not!assessed! Shortened!versions! Current!version! Performed!trials! Not!available! Copyright! Copyrighted:!its!use!for!individual!purposes!is!free!and!does!not! requires!any!authorization;!the!use!of!the!questionnaire!by!any! research!group,!to!aggregate!data!from!different!patients,! requires!a!communication!to!the!CARAT!group;!for]profit! organizations!or!the!use!of!the!questionnaire!with! commercial/marketing!purposes!will!require!case]by]case! authorization!from!the!CARAT!group!(www.caratnetwork.org)! Contact!information! João!A!Fonseca! Faculty!of!Medicine!of!University!of!Porto,!! Alameda!Hernâni!Monteiro!! 4200]319!Porto,!Portugal! [email protected]! Supplementary$File$–$Table$A.$Questionnaire!characteristics!according!to!Patient]reported! Outcomes’!recommendations!of!Ga2len!(8).!$ CARATKIDS$Scores$$ $ Visit$1$ Visit$2$ All$ 4!(0]13)! 3!(0]13)! Gender$ ! ! ! ! Male$ 4!(0]13)! p=0.577! 3!(0]11)! p=0.497! Female$ 5!(0]11)! 3!(0]13)! Physician$Assessment$ ! ! ! ! $$$Asthma$Control$O$GINA$ ! ! ! Uncontrolled$ 8.5!(5]13)! p<0.001$ 6.5!(3]11)! p=0.002$ Partly$Controlled$ 5!(2]13)! 5!(1]9)! Controlled$ 3!(0]11)! 2!(0]13)! $$$Rhinitis$O$ARIA$ ! ! ! ! Intermittent$ 4!(0]13)! p=0.341! 3!(0]9)! p=0.661! Persistent$ 5!(0]11)! 3!(0]13)! Mild$ 3!(0]11)! P<0.001$ 3!(0]13)! p=0.001$ Moderate/Severe$ 7.5!(0]13)! 7!(0]11)! $$$Treatment$Decision$ ! ! ! ! Reduce$ 3!(0]9)! p<0.001$ 2!(0]4)! p<0.001$ Maintain$ 3!(0]11)! 2!(0]11)! Increase$ 5.5!(0]13)! 6!(1]13)! $ 450! Supplementary$File$–$Table$B!CARATKids!scores!in!visit!1!and!2!by!gender,!by!GINA!and!ARIA! 451! classifications!and!by!physician!treatment!decision.!Results!are!presented!as!median!(min]max).! 452! GINA!]!Global!Initiative!for!Asthma;!ARIA!]!Allergic!Rhinitis!and!its!Impact!on!Asthma$ ! 453!
$ CutOoff$values$ Uncontrolled$ 3$ 5$ Asthma$OR$Rhinits$ Sensitivity! 0.803! ! Specificity! ! 0.929! Asthma$AND$Rhinitis$ Sensitivity! 0.914! ! Specificity! ! 0.929! $ 454! Supplementary$File$–$Table$C!Sensitivity!and!Specificity!for!CARATKids’!3!and!5!cut]off!values.!Each! 455! “yes”!answer!was!considered!1!point!and!CARATKids’!scores!were!classified!as!controlled!(<4),! 456! insufficiently!controlled!(4]5)!and!uncontrolled!(>5).!Specificity!and!Sensitivity!of!this!categorization! 457! was!computed,!both!when!uncontrolled!was!defined!as!uncontrolled!asthma!and!uncontrolled! 458! rhinitis!and!when!uncontrolled!was!defined!as!uncontrolled!asthma!or!uncontrolled!rhinitis.
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! 459!$ 460! Supplementary$File$–$Figure$A$CARATKids!initial!17!items!and!final!13]item.!The!lowlighted!items! 461! were!excluded!at!the!item!reduction!process;!the!orange!lined!boxes!contain!the!items!to!be! 462! answered!by!children!and!the!blue!ones!by!caregivers.!!Exclusion!of!items!was!based!on:!95%!of! 463! answer!“No”!for!“Hospitalization”!and!by!stepwise!logistic!regression!for!the!other!item
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464! ! ! Nasal Obstruction Nasal Pruritus ! Sneezing Rhinorrhoea Ocular Symptoms Cough Daily activities limitation Hospitalization ! Wheezing ! ! ! Missing school/ activities ! ! Nonscheduled consultation Throat Symptoms Dyspnoea Symptoms w/ laugh or exercise ! Waking up at night Symptoms in the morning Medication increase!
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Agradecimentos!
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Antes&de&&mais&gostaria&de&agradecer&à&pessoa&que&me&guiou&e&me&deu&a&oportunidade&de&fazer&parte& de&um&projeto&tão&desafiante&e&inovador&como&foi&o&desenvolvimento&deste&questionário:&o&Prof.&Dr.& João&Fonseca,&que&é&não&menos&do&que&a&pessoa&responsável&pelo&meu&contacto&com&a&investigação,& tendoCme&acompanhado&desde&o&meu&primeiro&ano.&DevoClhe&sem&dúvida&o&meu&interesse&por&esta& parte&mais&curiosa&da&medicina,&tendoCme&ensinado&a&importância&que&gerar&novo&conhecimento&tem& no&diaCaCdia&do&profissional&de&saúde.&Nos&6&anos&que&trabalhei&com&ele,&é&de&louvar&a&paciência&e& generosidade&com&que&sempre&me&recebeu,&tendoCme&passado&conhecimentos&inestimáveis,&e& valores&que&pretendo&e&espero&seguir&no&futuro.&A&entrega&que&tem&por&cada&projeto&e&a&vontade&de& conseguir&sempre&mais&e&melhor,&são&perspectivas&que&adquiri&como&minhas,&e&que&espero&um&dia& conseguir&reproduzir.&Adicionalmente,&o&facto&de&me&ter&permitido&contactar&desde&cedo&com&toda&a& maquinaria&da&investigação&médica,&marcou&e,&sem&dúvida,&direcionou&o&meu&processo&académico.& Por&isso&lhe&devo&um&grande&obrigada.& Tenho&de&agradecer&ainda&a&todos&os&coautores,&médicos&e&diretores&dos&serviços&onde&o&estudo&de& validação&do&CARATKids&foi&conduzido,&bem&como&a&alguns&investigadores&do&CIDES,&que& disponibilizaram&tempo&das&suas&atarefadas&rotinas&diárias¶&ajudar&no&desenvolvimento&deste& questionário.& E&porque¶&mim&esta&tese&representa&o&resultado&de&um&projeto&que&se&desenvolveu&ao&longo&de&3& anos,&não&posso&deixar&de&agradecer&também&às&pessoas&que&me&foram&acompanhando&no&processo,& como&os&meus&pais,&o&João,&ao&Francisco&e&à&Carla,&que&nestes&3&anos&ouviram&incontáveis&vezes&a& descrição&do&projeto,&os&avanços&e&recuos,&os&objetivos&e&as&frustrações,&e&que&com&muita&paciência&e& carinho,&me&foram&aconselhando&e&ajudando&a&cada&passo.&Por&último&um&obrigado&à&equipa&B’&que& me&pôs&a&pensar&o&que&fazer&a&seguir.& & & Daniela'Linhares' & & '!
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Normas'de'Publicação'da'Revista'' Pediatric)Allergy)and)Immunology)! Pediatric!Allergy!and!Immunology! ©"John"Wiley"&"Sons"A/S."Published"by"John"Wiley"&"Sons"Ltd" " Edited"By:"Ulrich"Wahn,"Berlin,"Germany" Impact"Factor:"3.376" ISI"Journal"Citation"Reports"©"Ranking:"2012:"7/23"(Allergy);"9/122" (Pediatrics);"56/137"(Immunology)" Online"ISSN:"1399V3038" ! ! ! Author!Guidelines! " PAI"is"only"accepting"manuscripts"electronically"via"ScholarOne"Manuscripts,"an"online" submission"site:"http://mc.manuscriptcentral.com/pai" Complete"instructions"for"preparing"and"submitting"manuscripts"online"are"provided"at"the" submission"site."If"you"need"assistance,"please"phone"1"434"817"2040"x"167"or"eVmail" [email protected]." Authors"submitting"a"paper"do"so"on"the"understanding"that"the"work"has"not"been" published"before,"is"not"being"considered"for"publication"elsewhere"and"has"been"read"and" approved"by"all"authors."All"human"and"animal"studies"must"be"approved"by"an"appropriate" ethics"committee"or"review"board"(depending"on"local"arrangements),"and"a"statement"to" this"effect"should"be"included"in"the"methods"section,"or"the"reasons"why"it"was"not" necessary"if"this"is"the"case."All"clinical"investigations"must"have"been"conducted"according" to"the"principles"expressed"in"the"Declaration"of"Helsinki"(http://www.wma.net)." The"vested"interests"of"authors"(such"as"company"affiliations"or"funding"relevant"to"the" study)"must"be"declared." Articles"must"be"written"in"correct!scientific!English"suitable"for"publication."Authors"whose" primary"language"is"not"English"should"obtain"assistance"with"writing"to"avoid"grammatical" problems."Although"articles"are"subject"to"review"and"editing,"the"journal"does"not"hold"itself" responsible"for"all"statements"made"by"contributors." Upon"submission"of"a"manuscript"all"coVauthors"should"also"be"registered"with"correct!and! updated!e9mail!addresses!and!academic!titles." The"work"shall"not"be"published"elsewhere"in"any"language"without"the"written"consent"of" the"publisher."The"articles"published"in"this"journal"are"protected"by"copyright,"which"covers" translation"rights"and"the"exclusive"right"to"reproduce"and"distribute"all"of"the"articles" printed"in"the"journal."No"material"published"in"the"journal"may"be"stored"on"microfilm"or" videocassettes"or"in"electronic"databases"and"the"like"or"reproduced"photographically" without"the"prior"written"permission"of"the"publisher." "
PAI"employs"a"plagiarism!detection!system."By"submitting"your"manuscript"to"this"journal" you"accept"that"your"manuscript"may"be"screened"for"plagiarism"against"previously" published"works." After"submission"of"a"manuscript"please"address"queries,"if"any,"concerning"the"status"of"the" manuscript"to"the"editorial"office"–"[email protected]." As"the"journal"follows"the"Vancouver"system"for"biomedical"manuscripts,"the"author"is" referred"to"the"publication"of"the"International"Committee"of"Medical"Journal"Editors:" Uniform"requirements"for"manuscripts"submitted"to"biomedical"journals."BMJ"1991;302:" 338V41." Line!numbering"All"texts"submitted"to"PAI"have"to"display"line"numbers"(1,"2,"3,"and"so"forth)" in"the"left"margin"of"the"manuscript."(Line"numbering"can"be"added"from"the""Page"Setup""or" "Format""menu"of"word"processing"programs.)"The"line"numbering"should"be"continuous" throughout"the"entire"text."Start"with"the"title"page"up"to"the"final"page."Do"not"begin" numbering"from"1"again"at"the"top"of"each"page." ! ORIGINAL!PAPERS!Information"concerning"the"format"of"the"manuscripts"for"all"original" papers:" Title!page"The"title"page"should"contain"the"following"information"in"the"order"given:" 1. full"title"of"manuscript,"concise"and"informative,"not"exceeding"100"characters;" 2. authors'"full"names;" 3. authors'"institutional"affiliations"including"city"and"country;" 4. a"running"title,"not"exceeding"40"characters"and"spaces;" 5. the"name,"address"and"eVmail"address"of"the"author"responsible"for"correspondence" about"the"manuscript;" 6. word"count;"number"of"tables"and"figures;" 7. material"in"the"electronic"repository,"if"applicable." " Abstract!page"A"separate"abstract"page"should"contain"the"following:" 1. authors'"surnames"and"initials;" 2. title"of"manuscript;" 3. title"of"journal"abbreviated"as"in"reference"list;" 4. the"word"Abstract"followed"by"a"summary"of"the"complete"manuscript"structured"as" follows"(max!250!words):" 1. background:"problem"that"prompted"the"study"and"aim(s)"of"the"study" 2. methods:if"the"sapece"is"short.,"only"the"primary"outcomes" 3. results:the"most"important"findings"only" 4. conclusions:the"most"important"conclusion"only" 5. key"words"(max"10);"listed"in"alphabetical"order;" 6. name"and"address"of"the"author"to"whom"requests"for"offprints"should"be"sent." " ! ! !
Main!text!The"text"is"limited"to:" • less"than"2,500"words"(not"including"abstract,"figure"legends"and"references" • structured"in"introduction,"methods,"results"and"discussion" • general"acknowledgments"for"consultations,"statistical"analyses,"and"the"like"should"be" listed"at"the"end"of"the"text," • up"to"30"references"in"the"Journal's"style"(see"below)" • up"to"6"among"figures"(or"panels"of"figures)"and/or"tables" If"the"manuscript"is"longer,"reasons"for"increase"in"length,"figure"or"table"number"or" reference"number"should"be"stated"in"the"cover"letter."In"general,"the"printed"version"of"the" manuscript"should"not"occupy"more"than"6"pages." References:!Number"references"consecutively"in"the"order"in"which"they"are"first"mentioned" in"the"text."List"all"authors"when"six"or"less;"when"seven"or"more,"list"first"three"and"add"et"al." Identify"references"in"text,"tables,"and"legends"by"Arabic"numerals"(in"parentheses)." References"(with"the"exception"of"review"articles)"must"not"exceed"30"in"number."Use"the" style"of"the"examples"below"which"are"based"on"the"format"used"by"US"National"Library"of" Medicine"in"Index"Medicus."For"abbreviations"of"journals,"consult"the"List"of"Journals" Indexed"printed"annually"in"the"January"issue"of"Index"Medicus."Avoid"using"abstracts"of" articles"as"references."Unpublished"observations,"personal"communications,"and"unaccepted" papers"may"not"be"used"as"references,"although"references"to"written,"not"verbal," communications"may"be"inserted"(in"parentheses)"in"the"text." Examples"of"correct"forms"of"references"are"given"below:" Journals:Chiba"Y,"Minagawa"T,"Mito"K,"et"al."Effect"of"breast"feeding"on"responses"of" systemic"interferon"and"virusVspecific"lymphocyte"transformation"in"infants"with"respiratory" syncytial"virus"infection."J"Med"Virol"1987:"21:"7V14." Books!and!monographs:!Stiehm"ER,"Fulginiti"VA."Immunologic"disorders"in"infants"and" children."Philadelphia:"WB"Saunders"1973." Chapter!in!book:!Holt"PG,"Turner"KJ."Regulation"of"IgE"synthesis"in"man"and"experimental" animals."In:"Lessof"MH,"Lee"TH,"Kemeny"DM,"eds."Allergy,"an"international"textbook."New" York:"John"Wiley"1987:"69V87." References"in"Articles"–"We"recommend"the"use"of"a"tool"such"as"EndNote"or"Reference" Manager"for"reference"management"and"formatting."EndNote"reference"styles"can"be" searched"for"here:"http://www.endnote.com/support/enstyles.asp."Reference"Manager" reference"styles"can"be"searched"for"here:"http://www.refman.com/support/rmstyles.asp" Figures!All"graphs,"drawings"and"photographs"are"considered"figures"and"should"be" numbered"in"sequence"with"Arabic"numerals"and"abbreviated"Fig(s)."Each"figure"should"have" a"legend"and"all"legends"should"be"typed"on"a"separate"sheet"and"numbered" correspondingly."Letters"on"figures"should"be"in"capitals."Figures"should"be"planned"to"fit"the" proportions"of"the"printed"page."It"is"the"policy"of"the"journal"for"authors"to"pay"for"the"full" cost"for"the"reproduction"of"their"colour"artwork."Therefore,"please"note"that"if"there"is" colour"artwork"in"your"manuscript"when"it"is"accepted"for"publication,"you"are"required" to"complete"and"return"a"Colour!Work!Agreement!form"before"your"paper"can"be" published."This"form"can"be"downloaded"online"here."Any"article"received"at"Wiley"with" colour"work"will"not"be"published"until"the"form"has"been"returned.""
Tables"!"Tables"may"be"placed"within"the"manuscript"file"and"they"should"supplement,"not" duplicate,"the"information"contained"in"the"text."They"should"be"on"separate"pages,"one" table"per"page,"and"should"be"numbered"consecutively"with"Arabic"numbers."Each"table" should"be"typed"on"a"separate"sheet,"with"due"regard"for"the"proportions"of"the"printed" page."A"brief"title"should"be"provided"directly"above"each"table."Any"abbreviations"should"be" defined"at"the"bottom"of"the"table." Offprints"Authors"will"receive"a"PDF"offprint"free"of"charge." Pediatric*Allergy*and*Immunology"collaborates"with"Wiley’s"open"access"journal"Immunity,* Inflammation*and*Disease"to"enable"rapid"publication"of"good"quality"research"that"we"are" unable"to"accept"for"publication"in"Pediatric*Allergy*and*Immunology."Authors"will"be"offered" the"option"of"having"the"paper,"along"with"any"related"peer"reviews,"automatically" transferred"for"consideration"by"the"Editor"of"Immunity,*Inflammation*and*Disease."Authors" will"not"need"to"reformat"or"rewrite"their"manuscript"at"this"stage,"and"publication"decisions" will"be"made"a"short"time"after"the"transfer"takes"place."The"Editor"of"Immunity,* Inflammation*and*Disease"will"accept"submissions"that"report"wellVconducted"research" which"reaches"the"standard"acceptable"for"publication."Immunity,*Inflammation*and*Disease" is"a"Wiley"Open"Access"journal"and"article"publication"fees"apply."For"more"information" please"go"to"www.immunityinflammationdisease.com."
