Sex-differences in the prevalence of Helicobacter pylori infection in pediatric and adult populations: Systematic review and meta-analysis of 244 studies

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ContentslistsavailableatScienceDirect

Digestive

and

Liver

Disease

j o u r n a l ho me p a g e :w w w . e l s e v i e r . c o m / l o c a t e / d l d

Review

Article

Sex-differences

in

the

prevalence

of

Helicobacter

pylori

infection

in

pediatric

and

adult

populations:

Systematic

review

and

meta-analysis

of

244 studies

Abdulrazak

Ibrahim

a

_,

_Samantha

_Morais

a

_,

_Ana

_Ferro

a

_,

_Nuno

_Lunet

a,b

_,

Bárbara

Peleteiro

a,b,∗

a_{EPIUnit—Instituto}_de_Saúde_Pública,_Universidade_do_Porto,_Porto,_Portugal

b_Departamento_de_Ciências_da_Saúde_Pública_e_Forenses_e_Educac¸_ão_Médica,_Faculdade_de_Medicina,_Universidade_do_Porto,_Porto,_Portugal

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received9February2017

Receivedinrevisedform9March2017

Accepted13March2017

Availableonline4April2017

Keywords: Helicobacterpylori Meta-analysis Sex Systematicreview

a

b

s

t

r

a

c

t

Background:ThemainoutcomeofHelicobacterpyloriinfection,i.e.gastriccancer,ismorefrequentin men,butthereisnocomprehensivesynthesisoftheevidenceonapotentialroleofsexintheacquisition and/orpersistenceofinfection.

Aims:ToquantifytheassociationbetweensexandH.pyloriinfectioninpediatricandadultpopulations, throughsystematicreviewandmeta-analysis.

Methods:PubMed®wassearched,frominceptiontoSeptember2015,toidentifypopulation-basedstudies reportingtheprevalenceand/orincidenceofH.pyloriinfectioninbothsexes.Oddsratios(OR)ordatato computethemwereextracted;adjustedestimateswerepreferred,wheneveravailable.TheDerSimonian andLairdmethodwasusedtocomputesummaryestimatesandrespective95%conﬁdenceintervals (95%CI),separatelyforchildrenandadults.

Results:Amongatotalof244studies,mostlycross-sectional,malesexwasassociatedwithagreater prevalenceofH.pyloriinfection,bothinchildren(102studies,OR=1.06,95%CI:1.01,1.12,I2₌_43.7%)_and adults(169studies,OR=1.12,95%CI:1.09,1.15,I2₌_68.5%)._An_{underrepresentation}_of_studies_showing_a negativeassociationbetweenmalesexandinfectionwasobserved(Egger’stest:p=0.006).

Conclusions:Althoughfurther researchisneededtounderstandthemechanismsbywhichsexmay inﬂuencetheacquisitionand/orpersistenceofinfection,ourresultssupportasmallcontributionof sexdifferencesintheprevalenceofinfectiontothemalepredominanceofH.pylori-relatedoutcomes, includinggastriccancer.

1. Introduction

Itisestimatedthathalfoftheadultpopulationisinfectedwith

Helicobacterpylori[1],butprevalencesrangebetween20%and90%

acrossregions[2].Inlessafﬂuentsettings,incidenceratesare

gen-erallyhighduringchildhoodandprevalenceincreasessteeplyin

thisperiod,whereasinmoredevelopedcountries,theratesof

infec-tionarelowerandtheproportionofpeopleinfectedincreasesmore

graduallythroughoutlife[3].

∗ Correspondingauthorat:DepartamentodeCiênciasdaSaúdePúblicaeForenses

eEducac¸ãoMédica,FaculdadedeMedicinadaUniversidadedoPorto,Al.Prof.

HernâniMonteiro,4200-319Porto,Portugal.Fax:+351225513653.

E-mailaddress:barbarap@med.up.pt(B.Peleteiro).

H.pyloriinfectionisthemostimportantriskfactorforgastric

cancer,andisestimatedtoaccountforapproximately80%ofall

casesworldwide[4],and90%fornoncardiacancers[5].Gastric

can-ceristwicemorefrequentamongmenthaninwomen[6],which

couldreﬂectsex-differencesintheprevalenceofH.pylori.Themost

recentmeta-analysisontheassociationbetweensexandH.pylori

infectionwaspublishedin2006[7].Itincluded28studieswithat

least500participants,andshowedthattheprevalenceofH.pylori

infectionwassigniﬁcantlyhigherinmales,butonlyamongadults.

Sincethen,severalstudieshavebeenconducted,expandingthe

rangeofavailableevidenceonthesubject,andanupdateof

previ-ousreviewsmayallowforabetterunderstandingofthepotential

roleofsexintheacquisitionand/orpersistenceofinfection.

There-fore,weaimedtoquantifytheassociationbetweensexandH.pylori

infectioninpediatricandadultpopulations,throughsystematic

reviewandmeta-analysis.

http://dx.doi.org/10.1016/j.dld.2017.03.019

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2. Materialandmethods

2.1. Systematicreviewoftheliterature

2.1.1. Identiﬁcationandselectionofthestudies

Apanelofthree researchers(AI,AF,SM)conductedasearch

onPubMed®,frominceptiontoSeptember2015,toidentify

origi-nalpopulation-basedstudiesreportingontheassociationbetween

sexandH.pyloriinfectionorprovidingsex-speciﬁcdataonthe

prevalenceand/orincidenceofH.pyloriinfection.Thereferences

retrievedwereanalyzedindependentlybytworeviewers,inline

with pre-deﬁned criteria to determine eligibility for inclusion

(Fig.1).Whenmorethanonereportreferredtothesamestudy,

theonepresentingtheresultswithmoredetail(e.g.,regardingthe

prevalenceaccordingtoagestrata),orprovidingdataforthelargest

samplewasconsidered,althoughanyofthereportscouldbeused

toobtaininformationonthestudycharacteristics.Disagreements

betweenreviewerswereresolvedbyconsensusorafterdiscussion

withanotherresearcher(BP).

The criteriafor exclusion of studieswere thefollowing: (1)

papersnotwritteninEnglish,Portuguese,Spanish,French,Italian

orPolish;(2)researchnotinvolvinghumans(e.g.,invitrooranimal

research);(3)non-eligiblepublicationtypes,suchasreviews,

edito-rials,comments,guidelinesorcasereports;(4)studiesspeciﬁcally

evaluatingsamplesexpectedtoyieldbiasedestimatesofthe

preva-lenceofH.pyloriinfectioninthegeneralpopulation(e.g.,subjects

undergoingendoscopyforpurposesotherthanscreening;blood

donors,universitystudents,healthcareprofessionals);(5)studies

includingonlyH.pylori-infectedsubjects(e.g.,eradicationtrials);

(6) studieswithdatanotrelated toH.pyloriprevalenceand/or

incidenceor addressingotheroutcomes (e.g.,cost-effectiveness

analyses); (7) studies with a non-systematic assessment of H.

pyloriinfectioninbiologicalsamples(e.g.,self-reported

informa-tion,secondarydataoninfectionstatusretrievedfromlaboratory

databases);(8)studiesnotevaluatingsamplesfrombothsexesor

notpresentingsex-speciﬁcdata;(9)multiplereportsofthesame

studyorstudiesevaluatingthesamesample.

2.1.2. Dataextraction

Twoinvestigators(AI,SM)evaluatedindependentlytheselected

studies to extract data regarding sampling procedures, sample

characteristicsandassessmentofH.pyloriinfectionstatus.

Differ-encesinthedataextractedbytheinvestigatorswerediscussed

untilconsensusandinvolvingathird researcher(BP)whenever

necessary.

EstimatesoftheassociationbetweensexandH.pylori

infec-tionwereextractedfromthearticlesselected,withthenecessary

detail to analyze separately thedata referring to children and

adults.Studieswereconsideredtoevaluatechildrenoradultswhen

themedian,meanormid-pointof participants´ıagewas<18or

≥18years,respectively;whennoage-speciﬁcestimateswere

avail-able,thestudieswereincludedinthegroupthatcorrespondedto

themedian,meanandmid-pointofparticipants´ıage.

Whencross-sectionaldatawasavailablefordifferentmoments

ofevaluationofthesamecohortstudy(e.g.baselineandendof

follow-up),eachoftheseobservationswastreatedasindependent

fromtheremaining.

Adjustedoddsratio(OR)andrespective95%conﬁdence

inter-vals(95%CI)weredirectlyabstractedwheneveravailable;whena

studyprovidedORestimatesadjusted foradifferentnumberof

potentialconfounders,theoneadjustedforthelargestnumberof

variableswasselected.Otherwise,crudeestimatesorthe

informa-tionneededtocomputethem,alongwith95%CI,wereextracted.

Studydesign was classiﬁedascross-sectional (including the

baselineevaluationofcohortstudiesandpre-intervention

evalua-tionsofrandomizedcontrolledtrials),case-controlorcohort.Study

yearwasdeﬁnedbytheyearinwhichcross-sectionalevaluations

orbaselineevaluationsoflongitudinalstudieswereconductedor

bythemid-pointoftheperiodofdatacollection,whenitspanned

overmorethanoneyear.Whentheperiodofdatacollectionwas

notreported,weassumedthepublicationyearminusthemedian

differencebetweenthepublicationyearanddateofdatacollection

inthearticlesforwhichthatinformationwasavailable.

For each study,the type of sample used todetect H.pylori

infection status was recorded and grouped into: serum (for

measurementofIgGantibodylevel),biopsy(evaluatedthrough

his-tology,rapidureasetestorculture),breath(assessedbyureabreath

test),stool (evaluatedbystoolantigen tests)ormixed samples

(usinganycombinationoftheprevious).

2.2. Meta-analysis

Themeta-analyseswereperformedseparatelyforchildrenand

adults.TheDerSimonianandLairdmethodwasusedtocompute

summaryORestimatesoftheassociationbetweensexandH.pylori

infection(males vs.females)andrespective95%CI.

Heterogene-itywasquantiﬁedusingtheI2 _statistic_[8]_._Visual_inspection_of

thefunnelplotsandEgger’sregressionasymmetrytestwereused

forassessmentofpublicationbias[9].Stratiﬁedanalyses

accord-ingtoagegroup,samplesize(using500subjectsasthecut-off,

correspondingtotheinclusioncriteriausedintheprevious

meta-analysisonthetopic[7]),geographiclocation,typeofstudy,type

ofsampleusedtodetectH.pyloriinfectionstatus,publicationyear

(using2006asthecut-off,correspondingtothepublicationdate

ofthemostrecentsystematicreviewonthetopic[7]),and

sur-veyyear(using1998asthecut-off,correspondingtothemedian

ofthestudiesincludedinthesystematicreview).Meta-regression

wasalsoconductedtoinvestigatethejointeffectofthesevariables

onheterogeneity[10].Thestatisticalanalysiswasperformedwith

STATA®,version11.2(StataCorporation,CollegeStation,TX,USA).

3. Results

Atotalof244studieswereincludedinthemeta-analysis,

pro-viding102estimatesforchildrenand169foradults(fromwhich

26recruitedbothchildrenandadultswithoutprovidingseparate

estimatesaccordingtoagegroup)(Fig.1andSupplementaryTable

1).Mosttargeted school-agedchildren andmiddle-agedadults.

Thestudiesevaluatedrecruitedbetween37and183,970

partic-ipants,werepublishedfrom1991to2016,andreferred todata

collectedbetween1971and2014.Thegreatmajorityofthe

stud-ieswasconductedinAsiancountries.Across-sectionaldesignand

theevaluationofserumsamplestoassessH.pyloriinfectionstatus

werethemostfrequent.

3.1. Studiesinchildren

Takingintoaccountthe102estimatesretrievedforchildren,the

overallsummaryORwas1.06(95%CI:1.01,1.12),withmoderate

heterogeneity(I2₌_43.7%)₍_Fig.₂_)._Using_only_adjusted_estimates,

the summary OR was 1.08 (95%CI: 0.96, 1.23), 23 estimates,

I2₌_68.9%,_whereas_a_summary_OR_of_1.05_(95%CI:_1.00,_1.12),₇₉

estimates, I2₌_26.6%, _was_obtained_when _using_only _crude

esti-mates. The visual inspection of the corresponding funnel plot

(Fig.3)suggestsanunderrepresentation ofsmallerstudieswith

negativeassociations,inaccordancewithEgger’sregression

asym-metrytest(p=0.006).

Stratiﬁed results are presented in Table 1. The association

betweenmalesexandH.pyloriinfectionwasstrongerinstudies

withasmallersamplesize(OR=1.14,95%CI:1.05,1.24,61

esti-mates,I2₌_25.8%),_in_those_conducted_in_Africa_(OR₌_1.27,_95%CI:

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Fig.1.Systematicreviewﬂowchart.

a_Search_expression_(from_inception_to_September_2015):_{(helicobacter}_pylori_OR_{campylobacter}_pylori)_AND_(incidence_OR_prevalence_OR_“risk_factors”_OR_determinants

OR(lifestyleORlifestyles)OR(tobaccoORsmokingORcigaretteORsmoke)OR(“dietarypattern”OR“dietarypatterns”OR“eatingpattern”OR“eatingpatterns”OR“food

pattern”OR“foodpatterns”)OR(dietORfruitsORvegetablesORantioxidants)OR(alcoholORdrinking)OR(saltORsaltedORnaclOR“sodiumchloride”ORsodiumOR

“processedmeat”OR“saltpreservedfoods”OR“smokedfood”)ORcoffeeORteaOR(obes*OR“bodymassindex”ORbmiORoverweight)OR(diabetesORglycemiaOR

hyperglycemiaOR“impairedfastingglucose”ORIFGOR“impairedglucosetolerance”)OR(crowdingORovercrowding)OR(“socioeconomicstatus”OR“socioeconomiclevel”

ORsesOR“bloodtype”OR“bloodgroup”OR“lewisantigen”))NOT(animals[mh]NOThumans[mh]).

detectinfectionstatus(OR=1.25,95%CI:1.04,1.50,14estimates,

I2₌_44.8%),_in_studies_performed_after₁₉₉₈_(OR₌_1.08,_95%CI:_1.01,

1.15,62estimates,I2₌_51.0%),_and_published_before₂₀₀₆_(OR₌_1.08,

95%CI:1.00,1.17,58estimates,I2₌_49.3%)._{Meta-regression}_showed

nosigniﬁcantimpactofthesevariablesonheterogeneity.

3.2. Studiesinadults

Takingintoaccountthe169estimatesfortheassociationamong

adults,theoverallsummaryORwas1.12(95%CI:1.09,1.15),with

highheterogeneity(I2₌_68.5%)₍_Fig.₄_)._Conducting_similar

anal-ysisusingonlyadjusted ORs resultedina slightly higher point

estimate,1.14(95%CI:1.07,1.21, 31estimates,I2₌_78.0%),_while

similarresultswereobtainedwhen usingonly crude estimates

(summaryOR=1.12,95%CI:1.08,1.15,138estimates,I2₌_65.1%).

Visualinspectionofthecorrespondingfunnelplotsuggestedno

publicationbias,inaccordancewithEgger’sregressionasymmetry

test(p=0.379)(Fig.5).

Thestratiﬁedanalysisaccordingtopopulationtype shows a

stronger association between male sex and H. pylori infection

whenusingstudiesthatonlyrecruitedadults(summaryOR=1.13,

95%CI:1.10,1.17,143estimates,I2₌_68.4%),_when_compared_with

thoserecruitingbothchildrenandadults(Table1).Thestrongest

associationbetweensexandH.pyloriinfectionwasfoundin

stud-iesperformedinOceania(summaryOR=1.37,95%CI:1.16,1.64,

10 estimates, I2₌_44.8%). _Higher _summary _estimates _were _also

observedinthoseusingserumsamplestodetectinfectionstatus

(summaryOR=1.14,95%CI:1.10,1.18,121estimates,I2₌_72.2%)._No

signiﬁcantdifferencesinthepointestimateswerefoundaccording

toagegroup,samplesize,publicationyearorsurveytimeperiod.

Meta-regressionshowednosigniﬁcantimpactofthesevariables

onheterogeneity.

Only three cohort studies provided data onthe association

betweensexandH.pyloriincidence,oneinchildrenandtwoin

adults.Onlyonestudyshowedastatisticallysigniﬁcantpositive

associationamong middle-aged adults (relative risk [RR]=1.64,

95%CI: 1.52, 1.78) [11], whereas the others presented

non-signiﬁcantassociations(RR=1.39,95%CI:0.71,2.71inadolescents

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Fig.2. ForestplotfortheassociationbetweensexandHelicobacterpyloriinfectioninchildren,usingwomenasthereferencecategory.

CI—conﬁdenceinterval;OR—oddsratio.

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Table1

AssociationbetweensexandHelicobacterpyloriinfectionfromstudiesinchildrenandinadults,accordingtostudycharacteristics.

Studycharacteristics Children Adults

Numberofstudies SummaryOR(95%CI) I2_(%) _Number_of_studies _Summary_OR_(95%CI) _I2_(%)

Allstudies 102 1.06(1.01,1.12) 43.7 169 1.12(1.09,1.15) 68.5

Usingonlyadjustedestimates 23 1.08(0.96,1.23) 68.9 31 1.14(1.07,1.21) 78.0

Usingonlycrudeestimates 79 1.05(1.00,1.12) 26.6 138 1.12(1.08,1.15) 65.1

Populationtype

Onlyadults – – – 143 1.13(1.10,1.17) 68.4

Bothchildrenandadults – – – 26 1.07(0.99,1.15) 69.9

Agegroup(years)

0–5inchildrenand18–39inadults 23 1.10(0.92,1.30) 52.4 28 1.03(0.96,1.11) 33.7

6–12inchildrenand40–69inadults 62 1.06(1.00,1.14) 42.3 132 1.14(1.10,1.17) 71.4

13–17inchildrenand≥70inadults 17 1.02(0.93,1.13) 35.9 9 1.14(0.99,1.32) 20.7

Samplesize <500 61 1.14(1.05,1.24) 25.8 62 1.10(1.01,1.19) 29.5 ≥500 41 1.01(0.94,1.08) 55.2 107 1.12(1.09,1.16) 76.2 Geographiclocation Africa 9 1.27(1.04,1.54) 50.9 2 0.85(0.60,1.20) 0.0 America 26 1.13(1.00,1.28) 58.6 26 1.11(1.01,1.22) 58.1 Asia 34 1.06(0.97,1.15) 29.7 82 1.11(1.07,1.15) 77.0 Europe 32 0.95(0.88,1.03) 18.3 49 1.12(1.08,1.18) 38.1 Oceania 1 1.13(0.58,2.21) – 10 1.37(1.16,1.64) 44.8 Typeofstudy Cross-sectional 102a _1.06_(1.01,_1.12) _43.7 ₁₅₇b _1.12_(1.09,_1.15) _70.1 Case-control – – – 12 1.12(1.01,1.24) 2.7

AssessmentofH.pyloriinfectionstatus

Serum 49c _1.02_(0.96,_1.09) _44.1 ₁₂₁d _1.14_(1.10,_1.18) _72.2 Biopsy – – – 12 1.02(0.86,1.20) 72.6 Breath 34 1.07(0.95,1.20) 44.5 27 1.11(1.09,1.13) 0.0 Stool 14 1.25(1.04,1.50) 44.8 2 1.14(0.92,1.41) 3.2 Mixedsamples 5 1.09(0.92,1.29) 0.0 7 1.09(0.97,1.23) 0.0 Publicationyear Before2006 58 1.08(1.00,1.17) 49.3 92 1.13(1.08,1.19) 68.1 After2006 44 1.04(0.97,1.11) 32.6 77 1.12(1.08,1.16) 66.3 Surveyyear Before1998 40 1.02(0.93,1.12) 28.9 74 1.14(1.09,1.20) 62.5 After1998 62 1.08(1.01,1.15) 51.0 95 1.11(1.07,1.15) 73.0

a_Includes_the_baseline_evaluation_of₂₉_cohort_studies_and_two_randomized_controlled_trials.

b _Includes_the_baseline_evaluation_of₂₃_cohort_studies_and_two_randomized_controlled_trials.

c _Includes_one_study_quantifying_anti-H._pylori_antibodies_in_saliva.

d _Includes_one_study_quantifying_anti-H._pylori_antibodies_in_urine.

Fig.3.FunnelplotfortheassociationbetweensexandHelicobacterpyloriinfection

inchildren,usingwomenasthereferencecategory.

OR—oddsratio.

4. Discussion

OurresultsshowamalepredominanceinH.pyloriprevalencein

bothpediatricandadultpopulations.Theassociationwasstronger

inadultsthaninchildren,andamongthelatterpublicationbias

mayhavecontributedtoanoverestimationofthesummaryOR.

Inthecurrentsystematicreview,theinclusioncriteriawereless

restrictivethaninthepreviousmeta-analysis[7],namelybecause

studies with smaller samples sizes were not excluded, which

allowedfortheanalysisof anoverall numberof studiesnearly

10timeshigher,despitesearchingonlyonedatabase(PubMed®),

andthereforeforamorecomprehensiveassessmentofthe

avail-ableevidenceonthistopic.Thepresentreviewincludedstudies

fromallcontinents,which wasone ofthelimitationsidentiﬁed

bytheauthorsofthepreviousmeta-analysis[7],butnoregional

differenceswereconsistentlyobservedinbothagestrata.

We opted for excluding studies speciﬁcally evaluating

sam-ples expectedtoyield biasedestimates of theprevalenceofH.

pylori infection in the general population. While the exclusion

ofsomepopulationsisconsensual,includingsubjectsundergoing

endoscopyforpurposesotherthanscreeningorhealthcare

profes-sionals,theexclusionofblooddonorsmaybequestioned,asthese

havebeenwidelyusedinepidemiologicalstudiesasrepresentative

ofthegeneralpopulation.Althoughthisgroupofsubjectsmaybe

asuitablesampletostudygeneticfactors[14],theydifferfromthe

generalpopulationinseveralaspects,namelysociodemographic

(6)

Fig.4. ForestplotfortheassociationbetweensexandHelicobacterpyloriinfectioninadults,usingwomenasthereferencecategory.

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Fig.5.FunnelplotfortheassociationbetweensexandHelicobacterpyloriinfection

inadults,usingwomenasthereferencecategory.

OR—oddsratio.

foracquiringH.pyloriinfection[15].Besidesthefactthatinsome

countriesblooddonorsarepaid[16],thereareguidelinesforblood

donation[17]thatmakethispopulationgenerallyhealthierthan

thegeneralpopulation,potentiallyleadingtobiasedestimates.

Unlikethepreviousmeta-analysis[7],weobserveda

signiﬁ-cantlyhigherfrequencyofinfectionamongboys,butthisseemsto

bedueessentiallytopublicationbias.Inourmeta-analysisthere

wasamuchhighernumberofstudiesfromwhichonlycrudeORs

couldberetrievedorcalculatedthanreportsofadjustedestimates.

Thisreﬂectsthefactthatassessingsexdifferencesininfection

sta-tuswasnotanobjectiveofmoststudies,orthatadjustedestimates

weremorelikely tobeprovided whenresultsshowedstronger

associations.

Among children, exposure to antibiotics, even to those not

speciﬁcallyindicated for H.pylori eradication, couldcontribute

toclearanceoftheinfectionandtoexplainsex-differences,since

a higher incidence of urinary tract infections in girls may be

associatedwitha greateruseofantibiotics [18].Among adults,

sex-differences in the prevalenceof H. pylori infection maybe

explainedbydifferencesintheexposuretoenvironmentalfactors

suchassmoking,whichhasbeenassociatedwithanincreasedrisk

ofH.pyloriinfection[12,19],andtothefailureofH.pylori

erad-ication[20,21].Sincetheprevalenceof smokingremains higher

inmencomparedwithwomen[22],thisiscompatiblewiththe

sex-differencesobservedintheprevalenceofinfectioninadults,

evenintheabsenceofsuchanassociationatyoungerages.

Phys-iologicaldifferences,namelysexhormones[23],mayalsoaffect

immunityandtheinﬂammatoryresponsetoH.pyloridifferentlyin

menandwomen;thesehormonescaninterfere,directlyor

indi-rectly,withthe cell receptorsaltering immunological response

(immune-modulators)[24].

5. Conclusions

Thisstudyprovidesthemostextensiveandrobustassessment

ofthesexdifferencesintheprevalenceofH.pyloriinfection.The

resultsconﬁrmtheincreasedprevalenceamongadultmenandare

compatiblewithalackofassociationatyoungerages.Although

fur-therresearchisneededtounderstandthemechanismsbywhich

sexmayinﬂuencetheacquisitionand/orpersistenceofinfection,

ourresultssupportasmallcontributionofsexdifferencesinthe

prevalenceof infectionto themale predominance ofH.

pylori-relatedoutcomes,includinggastriccancer.

Conﬂictofinterest

Nonedeclared.

Acknowledgements

Thisworkwassupportedby“FundoEuropeude

Desenvolvi-mentoRegional”(FEDER)fundsthroughthe“ProgramaOperacional

Factores de Competitividade” (POFC)—COMPETE

(FCOMP-01-0124-FEDER-021181)andbynationalfundsthroughthe“Fundac¸ão

para a Ciência e a Tecnologia” (PTDC/SAU-EPI/122460/2010),

and by the Epidemiology Research Unit—Institute of Public

Health, University of Porto (POCI-01-0145-FEDER-006862;

UID/DTP/047507/2013). Individual grants attributed to BP

(SFRH/BPD/75918/2011 and SFRH/BPD/108751/2015), AF

(PD/BD/105823/2014) and SM (SFRH/BD/102585/2014) were

supportedby“Fundac¸ãoparaa CiênciaeaTecnologia”,andthe

“ProgramaOperacionalPotencialHumano”(POPH/FSE).

AppendixA. Supplementarydata

Supplementarydataassociatedwiththisarticlecanbefound,in

theonlineversion,athttp://dx.doi.org/10.1016/j.dld.2017.03.019.

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