The Epidemiology of Irritable Bowel Syndrome in the US Military

Functional gastrointestinal disorders, including irritable bowel syndrome (IBS), represent a significant burden of disease in the United States and globally, ... AmericanCollegeofGastroenterology ClinicalandTranslationalGastroenterology ACGCaseReportsJournal AmericanCollegeofGastroenterology< ClinicalandTranslationalGastroenterology ACGCaseReportsJournal January2016-Volume111-Issue1 Previous Article Next Article ArticleasEPUB ExportAllImagestoPowerPointFile AddtoMyFavorites Colleague'sE-mailisInvalid YourName:(optional) YourEmail: Colleague'sEmail: Separatemultiplee-mailswitha(;). Message: Thoughtyoumightappreciatethisitem(s)IsawatOfficialjournaloftheAmericanCollegeofGastroenterology|ACG. Sendacopytoyouremail Yourmessagehasbeensuccessfullysenttoyourcolleague. Someerrorhasoccurredwhileprocessingyourrequest.Pleasetryaftersometime. EndNoteProciteReferenceManager Savemyselection ORIGINALCONTRIBUTIONS:FUNCTIONALGIDISORDERSRiddle,MarkSMD,DrPH1;Welsh,MarleenPhD2;Porter,ChadKMPH,PhD1;Nieh,ChipingPhD3;Boyko,EdwardJMD,MPH4;Gackstetter,GaryDVM,PhD2;Hooper,TomokoIMD,MPH,PhD2AuthorInformation 1NavalMedicalResearchCenter,SilverSpring,Maryland,USA 2UniformedServicesUniversityoftheHealthSciences,Bethesda,Maryland,USA 3HealthResearchandAnalysis,Rockville,Maryland,USA 4DepartmentofVeteransAffairs,PugetSoundHealthCareSystem,PugetSound,Washington,USA Correspondence:MarkS.Riddle,MD,DrPH,EntericDiseasesDepartment,NavalMedicalResearchCenter,SilverSpring,Maryland20910,USA.E-mail:[email protected] Received01August2015;accepted01November2015 Guarantorofthearticle:TomokoI.Hooper,MD,MPH,PhD. Specificauthorcontributions:Conceptionanddesignofthestudy:MarkS.Riddle,ChadK.Porter,TomokoI.Hooper,andEdwardJ.Boyoko;generation,collection,assembly,analysisand/orinterpretationofdata:MarleenWelsh,ChipingNeih,MarkS.Riddle,andChadK.Porter;draftingorrevisionofthemanuscript:allauthors;approvalofthefinalversionofthemanuscript:allauthors. Financialsupport:ThisworkwassupportedbytheMilitaryOperationalMedicineResearchProgram,USArmyMedicalResearchandMaterielCommand(FortDetrick,Maryland)andUniformedServicesUniversityoftheHealthSciencesintramuralgrantR0879D.ResourcesfromtheVAPugetSoundHealthCareSystemsupportedDrBoyko’sinvolvementinthisresearch. Potentialcompetinginterests:None. AmericanJournalofGastroenterology: January2016-Volume111-Issue1-p93-104 doi:10.1038/ajg.2015.386 Free Metrics Abstract OBJECTIVES:  Functionalgastrointestinaldisordersoccurmorefrequentlyamongdeployedveterans,althoughstudiesevaluatingtherelativeimpactofriskfactors,includingstressandantecedentinfectiousgastroenteritis(IGE),arelimited.Weexaminedriskfactorsfornew-onsetirritablebowelsyndrome(IBS)amongactivedutyparticipantsinthemilitary’sMillenniumCohortStudy. METHODS:  Medicalencounterdatafrom2001to2009,limitedtoCohortmembersonactiveduty,wereusedtoidentifyincidentIBScases(anyandhighlyprobable).IGEwasidentifiedusingmedicalencounterorself-report.CovariatedatawereobtainedfromtheMillenniumCohortStudysurveysandanalyzedusingCoxproportionalhazardsmethods. RESULTS:  Overall,41,175Cohortmembersmettheeligibilitycriteriaforinclusionand314new-onsetcasesofIBSwereidentifiedamongthese.Significantriskfactors(adjustedhazardratio,95%confidenceinterval)includedantecedentIGE(2.05,1.53–2.75),femalegender(1.96,1.53–2.52),numberoflifestressors(1:1.82,1.37–2.41;2:2.86,2.01–4.06;3+:6.69,4.59–9.77),andanxietysyndrome(1.74,1.17–2.58).LimitedtohighlyprobableIBS,astrongerassociationwithantecedentIGEwasobserved,particularlywhenbasedonmedicalencounterrecords(anyIGE:2.20,1.10–4.43;medicalencounterIGEonly:2.84,1.33–6.09).PrecedentanxietyordepressionandIGEinteractedwithincreasedIBSriskcomparedwithIGEalone. CONCLUSIONS:  TheseresultsconfirmpreviousstudiesontheassociationbetweensociodemographicorlifestressorsandIBS.IGEwassignificantlyassociatedwithIBSrisk.Whetherdeployedornot,USservicemembersoftenencounterrepeatedexposuretohighlevelsofstress,which,combinedwithotherenvironmentalfactorssuchasIGE,mayresultinlong-termdebilitatingfunctionalgastrointestinaldisorders. INTRODUCTION Functionalgastrointestinaldisorders,includingirritablebowelsyndrome(IBS),representasignificantburdenofdiseaseintheUnitedStatesandglobally,withanIBSprevalenceestimateof14%(ref.1).ArecentsystematicreviewfounddirectmedicalcostsrelatedtoIBSof$1,562–$7,547,andindirectcostsof$791–$7,737perpatientperyear(2).Inadditiontoincreaseddirectmedicalcarecosts,IBSnegativelyimpactsapatient’squalityoflife,resultinginincreasedfatigue,limitationsinphysicalcapabilities,andanoveralllowerperceptionofgeneralhealthcomparedwiththegeneralpopulation(3).AlthoughdataareemergingonthecomplexandvarieddiseasemechanismsofIBS,epidemiologicalstudiesremainimportanttofurtherelucidaterelationshipsbetweenriskfactorsanddiseasedevelopment(4).PreviousstudieshavedescribedIBSincidenceandriskfactorsamongtheUSmilitarymembersusingtheDepartmentofDefensemedicalencounterdatabases,confirmingothercivilianpopulation-basedstudiesidentifyinggenderandantecedentgastrointestinalinfectionasriskfactors(5).However,thesepreviousreports,whichreliedonexistingadministrativedatabasescontainingmedicalencounteranddemographicdata,lackedinformationonmanyconfounderssuchaslifestressorsandhealthbehaviors,whicharelikelyimportantinunderstandingriskandunderlyingcausalmechanismsforthiscondition.TofurtherexploreincidenceandriskfactorsforIBSintheUSmilitary,weuseddatafromtheMillenniumCohortStudy,alargeprospectivestudyofmilitaryservicemembers,tobetterunderstandassociationsbetweenmultipleexposuresandriskofdevelopingIBS. METHODS Studypopulation TheMillenniumCohortStudyisa21-yearlongitudinalstudyinitiatedin2001toprospectivelyfollowtheUSmilitarypersonnelfromallservicebranchestoevaluatetheimpactofmilitaryservice,includingdeployment,onshort-andlong-termhealth.Themethodologyhaspreviouslybeendescribed(6,7,8).Inbrief,itisalarge,population-basedcohortrepresentingallmilitaryservicebranchesandincludesregularactiveduty,Reserve,andNationalGuardpersonnel.Sincethefirstwaveofinvitationsin2001,over200,000participantshavebeenenrolledaspartoffourseparateaccessionpanels:panel1(July2001–June2003),N=77,047;panel2(June2004–February2006),N=31,110;panel3(June2007–December2008),N=43,439;andpanel4(April2011–April2013),N=50,052.Morethan70%ofthefirsttwopanelshavesubmittedatleastonefollow-upquestionnaire.Panel1wasdrawnfromapopulation-basedrandomsampleoftheUSmilitaryinOctober2000,withoversamplingofReserve/Guardpersonnel,women,andthosewithpreviousdeploymentexperienceinBosnia,Kosovo,orSouthwestAsia.Panels2and3samplednewaccessionsonly,thosewith1–3yearsofmilitaryservice,andoversampledforMarinesandwomen.Studyparticipantshavecompletedabaselinesurvey,andtheywillcontinuetoreceivefollow-upquestionnairesapproximatelyevery3years. ThepopulationforthisstudyincludedMillenniumCohortStudyparticipantswhocompletedabaselineandatleastonefollow-upquestionnairebetween2001and2009,whohadnotleftactivemilitaryserviceatthetimeofcompletingtheirfirstsurvey,andwerewithoutIBSorinflammatoryboweldisease(IBD)atbaseline.Excludedweresubjectswhoendorsedeveryprovider-basedillnessdiagnosisonanysurvey,aswellasthosemissinganydataforcovariatesofinterest.ThislatterexclusioncontributestoslightdifferencesinstudypopulationsforanyIBSandhighlyprobableIBS.FortheanyIBSmodel,allcaseswerecensoredatthedateofdiagnosis,anddataoncovariateswerecapturedfromthemostrecentsurveycompletedbeforediagnosis.Dependingonwhethertherewereincompleteormissingdataonthatsurvey,theparticipantmayormaynothavebeenincludedinthefinalanyIBSmodel.ForthehighlyprobableIBSmodel,casesthatdidnotmeetthestricterdefinitionofhighlyprobableIBSwereassignedanewcensoringdate,thereforecovariatedatacouldhavebeenchosenfromadifferentsurveythanfortheanyIBSmodel.Dependingonthestatusofmissingdata,thisresultedinparticipantsbeingincludedintheanyIBSmodelbutexcludedfromthehighlyprobableIBSmodelorviceversa.Thenumberofparticipantsaffectedbythischangeincensoringdateandsurveyassignmentforcovariateswassmall(anyIBS:n=13;highlyprobableIBS:n=17)anddidnotaffecttheinterpretationofanyofthefinalmodels. ParticipantswereenrolledintheMillenniumCohortStudyafterprovidingfullinformedconsent.TheIBSstudyprotocolwasapprovedbytheinstitutionalreviewboardsattheUniformedServicesUniversityoftheHealthSciencesandtheNavalHealthResearchCenter(ProtocolNHRC.2000.0007).Bothstudieswereconductedincompliancewithallapplicablefederalregulationsgoverningtheprotectionofhumansubjectsinresearch. IncidentIBS IncidentcasesofIBSwereidentifiedusingthemilitarymedicalencounterdatafromJuly2001toDecember2009,receivedfromtheTRICAREManagementActivity.Anypersonwithatleasttwomedicalencountersoccurringwithina365-dayperiodandcontainingtheInternationalClassificationofDiseases,9thRevision,ClinicalModification(ICD-9-CM)code564.1(IBS)inanydiagnosisfieldwasconsideredanincidentcaseofIBSanddefinedasanyIBS.Inaddition,amorespecificdefinitionofhighlyprobableIBSwasusedifanendoscopywasdocumentedviaprocedurecodes(451,4511–4516,4519,4523,4524)orCurrentProceduralTechnologycode(45330–45334,45338,45378,45379,45380,45382,45384,45385)betweenthetwomedicalencounters,andnoevidenceofadiagnosisofIBDbetweenthetwoIBSmedicalencounters.IBDwasdefinedaseitherself-reportofprovider-basedIBDdiagnosisontheMillenniumCohortsurveyortwoIBD-relatedmedicalencounters(ICD-9-CMcodes555.0,555.1,555.9,andall556subgroups)ina365-dayperiod. BaselineIBSandIBD AssessmentofbaselineIBSandIBDcasesbasedonmedicalencounterdataweresimilartoincidentIBSandIBDcasesexcludingthe365-dayperiod.IfIBSorIBDcasedefinitionsweremetbetween1June1998,andcompletionofthefirstsurveyforPanel1participantsorbetween1June2001,andcompletionofthefirstsurveyforPanel2participants,thoseCohortmemberswereexcluded.Participantswhoself-reportedbeingdiagnosedwithIBDbyamedicalprovideronthebaselinesurveywereconsideredbaselineIBDcasesandweresimilarlyexcluded. Antecedentinfectiousgastroenteritis Antecedentinfectiousgastroenteritis(IGE)datawerecollectedfrommedicalencounterrecordsandself-reportedpost-deploymenthealthassessments.OnlythoseeventsoccurringbetweencompletionofthebaselinesurveyandIBSdiagnosisorcensurewereconsidered.AnymedicalencountercontainingarelevantICD-9-CMcodeforIGE(all001subgroups,003.0,003.9,all004subgroups,005.4,all008.0subgroups,008.43,008.44,008.47,008.49,008.5,009.0–009.3,all005.8subgroups,005.9,006.0–006.2,006.9,all007subgroups,all008.6subgroups,and008.8)inanydiagnosisfieldwasdefinedasanIGEepisode.Inaddition,participantsweredeemedtohaveIGEiftheyself-reporteddiarrheaduringorafterdeploymentonapost-deploymenthealthassessment.Subjectswithnomedicalencountersorself-reportofIGEwereconsideredtonothaveIGE. Othercovariates Demographicandmilitarycharacteristics,includingdeployment,wereobtainedfromDefenseManpowerDataCenterrecords.MissingDefenseManpowerDataCenterdataweresupplementedwithinformationfromMillenniumCohortsurveyswhenavailable.AllbehavioralandmentalhealthcharacteristicswereassessedusingdatacollectedfromtheMillenniumCohortsurveys.Bodymassindexwascalculatedfromself-reportedheightandweight.Neversmokersweredefinedasthosewhohadsmoked<100cigarettesintheirlifetime.Amongsmokers,thosewhoreportedhavingsuccessfullyquitsmokingweredefinedasformersmokers,andallotherswerecategorizedascurrentsmokers.Non-drinkersweredefinedasthosewhoreportednodrinkinginatypicalweekorthosewhohad<12drinksinthepastyear.Moderatefemaledrinkersreportedhavingbetween1and7drinksinatypicalweek(oronaverage≤1drink/day),whereasheavyfemaledrinkersreportedhaving>7drinksinatypicalweek(or,onaverage,>1drink/day).Moderatemaledrinkersreportedhavingbetween1and14drinksinatypicalweek(or,onaverage,≤2drinks/day),whereasheavymaledrinkersreportedhaving>14drinksinatypicalweek(or,onaverage,>2drinks/day). SurveyquestionsrelatedtolifestressorswerecategorizedusingamodifiedversionoftheHolmes–RaheSocialReadjustmentScale(9).Stressrelatedtodivorce/separation,majorfinancialproblems,sexualassault,sexualharassment,physicalassault,illnessordeathofalovedone,andadisablingillnessorinjurywasassessedatbaseline(everexperienced)andineachfollow-upsurvey(preceding3years).Becauseonlyasmallnumberofstressorswereavailabletotalnumberofstressorswascountedratherthanassigningaweighttoeach. MentalhealthdatawerecollectedusingstandardizedsurveyinstrumentsembeddedintheMillenniumCohortsurvey,includingthePatientHealthQuestionnaire(PHQ)andthepost-traumaticstressdisorder(PTSD)Checklist-CivilianVersion.UsingdefinedcriteriaforthePHQ-9itemsthatconstitutethedepressionmodule,(10,11)depressionwasidentifiedifparticipantsreportedexperiencingoverthelast2weekseitheradepressedmood(littleinterestorpleasureindoingthings)oranhedonia(feelingdown,depressed,orhopeless),inadditiontorespondingtoexperiencingatotalof5ormoredepressionitems“morethanhalfthedays”or“nearlyeveryday.”AnxietywasidentifiedbyapositivescreenforeitherpanicsyndromeorotheranxietysyndromeonthePHQ.Panicsyndromewasassessedusinga15-itemmodulethataskedwhethertheparticipantshadexperiencedananxietyattackinthelastmonthandwhatsymptomstheymayhaveexperienced.Ifparticipantsendorsedall4questionsregardinganxietyattacksand4of11symptomslisted,theywereconsideredpositiveforpanicsyndrome.Inaddition,otheranxietysyndromeswereidentifiedusingcriteriadefinedbythePHQfora7-itemmodule;ifparticipantsendorsedexperiencing“feelingnervous,anxious,onedgeorworryingalotaboutdifferentthings”intheprior4weeksandendorsedexperiencing3ormoreoftheremaining6anxietysymptomson“morethanhalfthedays”,(11,12,13)theywereidentifiedasscreeningpositiveforanxiety.ThesurveyalsoincludedaquestionfromthePHQregardingcurrentmedicationuseforanxiety,depression,orstress.PTSDwasassessedusingtheChecklist-CivilianVersion-,astandardized17-itemsurveyinstrumentthatinquiresaboutPTSDsymptomsexperiencedinthepastmonth(14).Forthisstudy,PTSDwasidentifiedusingthesensitivecriteria,asdefinedbytheDiagnosticandStatisticalManualofMentalDisorders,4thedition,only.Allcovariateswereassessedatthetimeofthemostrecentsurveypriortothecensoringdateforeachparticipant,regardlessofdatasource. Timecensoringcalculations Foreachmemberofthestudypopulation,starttimefortheperiodofobservationwasdefinedasthedateofcompletionoffirstsurvey.Timewascensoredattheearliestof5dates:dateofIBSdiagnosis,dateofIBDdiagnosis,dateofseparationfrommilitaryservice,dateofdeath,orendofstudy. Statisticalanalysis SurvivalanalyseswereperformedusingthePHREGprocedureinSAS,Version9.3(SASInstitute,Cary,NC)foranyIBSandhighlyprobableIBS,modeledseparately.Theprimaryexposureofinterest,antecedentIGE,wasmodeledasatime-varyingcovariate.AntecedentIGEwasforcedintothemodel,andthenforwardselectionwasusedtoaddtheremainingvariablestothemodel,withaP<0.05thresholdforentryintothemodel.Inaddition,confoundersoftheIGE–IBSrelationshipwereincludedinthefinalmodeliftheychangedtheIGEparameterestimateby10%ormore.Interactionsbetweeneachcovariateinthemodelandthemainexposurevariablewereexamined.IfaninteractiontermwassignificantatP<0.05,Akaikeinformationcriterionwasusedtoselectbetweenmodelswithandwithouttheinteractionterm.IfAkaikeinformationcriteriondifferencebetween2modelswas>4,themodelwithoutaninteractiontermwasselectedformodelparsimonyandinterpretability(15).Twomethods,Martingaleresidualsandinteractionwithtime,wereusedtoassesstheproportionalhazardsassumption.Covariatesthatviolatedtheassumption(P<0.05)usingbothmethodsincludedmaritalstatusinanyIBSandallsourceIGEmodel,andmaritalstatusalongwithrace/ethnicityinanyIBSandmedicalencounterIGEmodel.AstratifiedCoxmodelwasusedwhenaviolationoftheproportionalhazardsassumptionwasobserved.Theseanalyseswererepeated,restrictingIGEtoonlythoseeventsidentifiedusingmedicalencounterdata. RESULTS Ofthe108,129participantsfromPanels1and2whocompletedabaselinequestionnaire,203wereexcludedforendorsingeveryprovider-baseddiagnosesonatleast1survey(pan-endorser).Participantswerealsoexcludediftheydidnotmeetthisstudy’sdefinitionof“activeduty,”meaningtheyremainedonactivedutyforthedurationofthestudy,separateddirectlyfromactiveduty,orenteredthereservesafteractivedutyonlyowingtotermfulfillment,leaving68,203participants.Inaddition,MillenniumCohortStudyparticipantswereexcludedbecausetheyhadnotcompletedafollow-upsurvey(n=18,999),reportingIBSorIBDatbaseline(n=482),havingseparatedfromthemilitarybeforecompletionoftheirbaselinesurvey(n=4,341),andmissingdataoncovariatesofinterest(n=3206).Thisresultedin41,175participantswith222,081.54person-yearsoffollow-upavailableforanalysesforanyIBSand41,179participantswith222,634.88person-yearsoffollow-upforhighlyprobableIBS(seeFigure1).Figure1.: Inflammatoryboweldisease(IBD)andirritablebowelsyndrome(IBS)inclusionandexclusioncriteriaforfinalstudypopulation.Demographic,military,andbehavioralhealthcharacteristicsofcohortmembersincludedforanyIBSarepresentedinTables1and2.Womenrepresentedslightlymorethanaquarterofparticipants,withthemajority(66.2%)ofparticipantsbeingofwhite,non-Hispanicrace/ethnicity.Smokinghistory,eitherformerorcurrent,wasfoundin˜42%.Amajorityofsubjects(56.3%)reportedoneormorelifestressors,whereasrelativefewreportedthattheyweretakingmedicationforamentalhealthissue(6.9%).Nearly60%hadoneormoredeployments.DescriptivecharacteristicsofcohortmembersinthehighlyprobableIBSpopulationhadsimilardistributionstocohortmembersforanyIBS(datanotshown).Table1:OveralldescriptivecharacteristicsofactivedutyMillenniumCohortparticipantsaTable2:Healthriskbehaviors,stressandcomorbidconditionsamongstudyparticipantsNew-onsetIBSwasidentifiedin314participants,withanestimatedincidenceof141.39/100,000person-years,whereastheincidenceofhighlyprobableIBSwassignificantlylowerat27.40/100,000person-yearsforatotalof61incidencecases.IGEwasassociatedwithanincreasedriskofIBSinallmodels;however,whenlimitedtomedicalencountersforIGEandhighlyprobableIBS,thelargesteffectestimatewasobserved(univariatehazardratio(HR),3.80;95%confidenceinterval(CI),1.79–8.08;Table3).AdditionalunivariateanalysesarealsodetailedinTable3.Ingeneral,restrictinganalysistothehighlyprobableIBSdefinitionand/ordocumentedmedicalencounterIGEdemonstratedconsistencyinthedirectionofeffectestimates,althoughbiastowardthenullorlossofstatisticalsignificanceduetosmallercellsizeswasalsoobserved.Table3:UnivariatehazardratiosintheMillenniumCohort,2001–2009aContinuedTable3:Continued.ThesignificantlyincreasedriskofIBSassociatedwithantecedentIGEpersistedintheadjustedmodelsforallsourceIGE(adjustedHR=2.05;95%CI,1.53–2.75)andformedicalencounterIGE(aHR,2.07;95%CI,1.44–3.01)(Table4).ModelsofhighlyprobableIBSshowedasimilarincreasedriskfollowinganyIGE(aHR,2.20;95%CI,1.10–4.43)andmedicalencounter-basedIGE(aHR,2.84;95%CI,1.33–6.09).Femalegender(aHR=1.96),Armyservice(aHR=0.67),moderatealcoholconsumption(aHR=0.68),bodymassindex(overweight:aHR=0.77;obese:aHR=0.67),numberoflifestressors(1:aHR=1.82;2:aHR=2.86;3+:aHR=6.69),anxietysyndrome(aHR=1.74),andnumberofdeployments(1:aHR=0.61;2+:aHR=0.52)remainedsignificantintheadjustedCoxmodelforanyIBSandallsourceIGE,whereasfemalegender(aHR=1.79),3+lifestressors(aHR=6.80),depressionsyndrome(aHR=2.29),anddeployments(1deployment:aHR=0.29;2+deployments:aHR=0.22)remainedassociatedwhenrestrictingtohighlyprobableIBSandallsourceIGE.SimilarHRsforcovariateswerefoundwhenrestrictinganalysistodocumentedmedicalencounterIGE,withonlyArmyservicebranchnolongersignificantintheanyIBSmodel.Table4:AdjustedhazardratiosfortheassociationbetweenIGEaandIBSintheMillenniumCohort,2001–2009bInadditiontotheprimaryeffects,interactionsbetweenIGEandothercovariates(e.g.,smoking,stress,deployment,anxiety,PTSD,anddepression)wereexplored.ConsistentinteractionsamonghighlyprobableIBSandbothIGEexposurecategorieswerefoundforbothdepressionandanxiety.Intheseinteractionmodels,thecombinationofmedicalencounterIGEandeitheranxietyordepressionandthecombinationofallsourceIGEanddepressionresultedinadifferentialriskofhighlyprobableIBScomparedwithstratificationbyIGEormentalhealthconditionalone,althoughthenumbersweresmall(Tables5and6).Table5:InteractionbetweenIGEanddepressionforriskofhighlyprobableIBSTable6:InteractionbetweenIGEandanxietyforriskofhighlyprobableIBSDISCUSSION OverallIBSincidence(anyIBSdefinition)wasestimatedat141.39(89.38male,293.81female)per100,000person-yearsinthisstudypopulation,whichislowerthan2previousstudiesincivilianpopulationsreportingincidencebetween200and260casesper100,000person-years(16,17).However,ourratesforwomenaresimilartothosereportedbyLockeetal.(16)forsimilaragestratafromOlmstedCounty,Minnesota.Anestedcase-controlstudyusingaDutchnationalmedicalencounterdatasystemestimateda1-yearincidenceof˜300per100,000person-yearsinindividualsnotreportinganantecedentacuteIGEepisode(18),whichisalsohigherthanourestimatedincidence.Somepossibleexplanationsforourlowerratesarethe“healthyworkereffect”amongactivedutymilitarypersonnel,under-representationoffemalegender,and/orpotentialdifferencesinhealthcare-seekingbehaviorofindividualsinthemilitarycomparedwithcivilianpopulations. Consistentwithpriorstudies,wefounda2–3-foldincreaseinIBSriskafterIGE,withhighereffectestimateswhenIBSandIGEweremorepreciselydefined.Althoughthesepointestimatesarelowerthanpooledeffectestimatesreportedinrecentsystematicreviews,(19,20)theydosupportapositiveassociationbetweenacuteentericinfectionandIBSandareconsistentwithindividualeffectestimatesrecentlyreportedinamedicalencountersystempopulation-basedDutchstudy(relativerisk,4.85;95%CI,2.02–11.63),aswellasastudyamongreturningUKveteransfromIraq(self-reportedIGE:oddsratio,2.59,95%CI,1.83–2.67;medicalencounterIGE:OR,4.34,95%CI,2.55–7.39)(18,21).Itislogicalthatstudydesignsbasedonmedicalencounterdatamayresultinlowereffectestimatescomparedwithactivesurveillancestudiesbecauseofdifferencesinnon-differentialmisclassificationofexposureand/oroutcomes,aswellaspopulation-uniqueeffectswithanactivedutyhealthierpopulationthatmaybelesssusceptibletodevelopingIBS. Interestingly,thisstudyidentifiedotherassociationsofparticularinterestinamilitarypopulation.AconsistentlyidentifiedincreaseinIBSriskwithPTSDhasbeendescribedinstudiesofwomenveterans(22,23).ArecentstudybyMaguenetal.ofapopulationofover600,000IraqandAfghanistanwarveteransfoundthatforbothmenandwomen,IBSwasthreetimesmorelikelytobepresentamongthosewithPTSDthanthosewithoutPTSD(24).OurfindingofincreasedriskofincidentIBSamongthosewithPTSDinunivariateanalysesisconsistentwiththesepriorreports.Therearebiologicalandpsychologicalexplanationsthatmightexplainthisassociation,suchasthereportedeffectofPTSDanddepressiononsystemicinflammation(25)andabnormalitiesinbrainfunction,thatcouldaffectpainperceptionandawarenessofvisceralstimuli(26).However,significantlyincreasedriskwasnotobservedinouradjustedmodel;thiscouldbeattributedtoinsufficientpowerortheuseofthemostproximalsurveydatatoassessPTSD.AdditionalstudiesfocusedonPTSDandchronicfunctionalgastrointestinaldisordersthatconsiderthetimingofassociation,aswellaspotentialcommonpathologicalpathwaysarewarranted.Anothermilitary-specificassociationwasobservedbetweendecreasedIBSriskandmultipledeployments.Additionalmeasuresofdeployment(i.e.,cumulativetimedeployed,deploymentbeforeOperationEnduringFreedom/OperationIraqiFreedom,self-reportofcombatexposurewhiledeployed)wereassessedinunivariateanalyses,andthesamepatternofreducedriskwasobserved(datanotshown).Thismaybeindicativeofahealthyworkereffectashasbeenpreviouslydescribed(27).Interestingly,whenamorespecificdefinitionofIBS(highlyprobableIBS)wasused,thisprotectiveeffectbecamemorepronounced. Asinpriorstudies,anumberofriskfactorswerefoundthatcontinuetosupportabiopsychosocialmodelofdisease.Asdescribedinotherstudies,wefoundthatthenumberoflifestressoreventsincreasedtheriskofIBS(28,29).Furthermore,wefoundthatself-reportedanxietyanddepressionwereindependentlyassociatedwithincreasedriskofIBS(univariateanalysesonly),similartootherstudies(28,29).However,thejointeffectoftheseconditions,incombinationwithIGEexposure,resultedinanincreasedIBSriskgreaterthantheriskfromeitheroftheseexposuresalone(Tables5and6).Ourunderstandingoftheimportanceofthetwo-way“cross-talk”betweenthebrainandthegutcontinuestogrow,particularlyhowgut–braininteractionswiththemicrobiomemightresultindysbiosisanddevelopmentofdiseaseinthepresenceofnervoussystemdisturbances.Multiplepotentialdirectandindirectpathwaysexistthroughwhichalteredgutmicrobiotacanmodulatethegut–brainaxis(30).Understressfulconditions,thehypothalamus–pituitary–adrenalaxisregulatescortisol,whichcanaltertheimmunesystem,gutpermeability,andbarrierfunction,andresultinachangeingutmicrobiotacomposition.ThishasbeendescribedrecentlyinmilitarytrainingsettingswhereSingaporeanArmyrapidresponsetroopsweremonitoredforpsychologicalandgastrointestinalsymptoms,aswellasimmunologicalandintestinalbiomarkersduringintensivecombattraining(31).Interestingly,theanticipatedincreasesinstress,anxiety,anddepressionwereassociatedwithgastrointestinalsymptoms(noninfectious)andmarkersofpro-inflammatoryimmuneactivationandincreasedintestinalpermeability.Althoughhumanparticipantstudieshaveshownthatriskoffunctionalgastrointestinaldisordersareassociatedwithpsychiatriccomorbidities(32,33,34),ithasalsobeendescribedinanimalmodelswheremicrobiomechanges(perhapsasaconsequenceofacuteinfection)canchangebehaviorandbrainneurochemistry(35).Thus,itisquiteplausiblethatthecombinationofacuteentericinfectionandpsychologicalstressinteractionscouldprovetobethepathophysiologicalbasisofsomechronicgastrointestinalsequelae(36,37).Arelevantmousemodel,whichhasindependentlyandconcomitantlyevaluatedstressandCitrobacterrodentiuminfection,hasbeendevelopedandprovidessupportforthismechanism(38).Ouremergingunderstandingoftheseconceptsprovidesaframeworktofurtherinvestigategut–brainaxisrelationshipsandultimatelyidentifypotentialsolutionsforchronicgastroenterologicalhealthconditionsthatarebeingobservedamongservicememberswhoarefrequentlyexposedtobothinfectionandstressduringtraininganddeploymentsituations(4,27). Thisstudyhadseverallimitations.Datawereobtainedfromexistingself-reportquestionnaires;however,thesurveyinstrumentsusedvalidatedquestionsandwereadministeredconsistently(39).Furthermore,clinicalexaminationsforconfirmationofbothself-reportedsymptomsandconditionscouldnotbeassumed,andICD-9-CM-basedmedicalencounterdataonIGEexposureandIBSoutcomesarealsopotentiallysusceptibletoerrorormisclassification.Specifically,withrespecttoourprimaryoutcomeofIBS,misclassificationforanill-definedcomplexofunexplainedGIsymptomsmayhavebeenascribedwithouttheapplicationofRomecriteria.Furthermore,whereasweexcludedfromeligibilitythosewithpre-existingIBD,wedidnotexcludethosewhomayhavehadothermimicconditions,suchasceliacdisease,tropicalsprue,orintestinalmalabsorption.Itispossiblethatcohortsubjectscouldhavehadthesepre-existingdiagnoseswhichweresubsequentlyproperlydiagnosedormisclassifiedasIBS.However,theclinicalincidenceoftheseconditionsisverylowinthispopulationandthuswouldunlikelyhavehadalargebiasonourresults(40,41).BecauseitwasnecessarytouseICD-9-CM-basedoutcomediagnosescontainedinmedicalencounterdata(IBSisnotamongthehealthconditionsonthesurvey),amorestrictdefinitionwhichrequiredconcomitantcolonoscopyvisitcodeswasused,andthecohortpopulationwaslimitedtoindividualsonactivedutywhoreceivedcareatmilitarytreatmentfacilities.SuchfactorscouldexplainboththerelativelylowIBSincidenceandtheeffectestimates.Furthermore,theexclusionofthosenotmeetingtheactivedutydefinition(˜37%)mayalsolimitgeneralizabilityandapplicationoftheseresultstoreserveandguardpopulations.Prospectivestudiesusingvalidatedandactivefunctionalgastrointestinaloutcomesurveillanceamongbothdeployedandgarrisonpopulations,aswellreserveandguardcomponentswouldbeofvalue. Thisstudyalsohadseveralstrengths.Itspopulation-based,prospectivecohortdesignallowedforbaselineandfollow-upassessments(usingtime-varyingcovariateswhenappropriate)amongindividuals.Inaddition,thedesignenabledestimatesofIBSincidenceandstrongstatisticalpowerforassessingprimaryeffects,whereascontrollingformultipleconfoundersandexploringnovel-riskfactors. Insummary,thesefindingsrepresentadditionaldatathatcontributetoanaccumulatingbodyofevidencelinkingacutegastrointestinalinfectionsandchronicgastrointestinalsequelae.Inadditiontoimportantfindingsfrommechanisticstudiesalsobeingreported,ourfindingsaddtothebeliefthatthisobservedphenomenonisnotexaggerated(42).Acoordinatedandresourcedresearchagendaisneededtounderstandtheheterogeneityinobservedriskanddiseaseoutcomesbasedonhost,agent,andenvironmentaldifferences,includingpathoetiologicalmechanisms(4).Moreurgentlyneededarepotentialmeasurestomitigatetheburdensomeconsequencesofacutegastroenteritis,whichareknowntohavesubstantialimpactonmedicalcarecostsandqualityoflifeamongmillionsofat-risktravelersanddeployedmilitarypersonnel. StudyHighlightsFigureACKNOWLEDGMENTS WethankAshleighPeoplesandKellyA.JonesfromtheNavalHealthResearchCenterforstatisticalsupport,andTheMillenniumCohortStudyTeam. DISCLAIMER TheviewsexpressedinthisresearcharethoseoftheauthorsanddonotnecessarilyreflecttheofficialpolicyorpositionoftheDepartmentoftheNavy,DepartmentofDefense,DepartmentofVeteransAffairs,ortheUnitedStatesGovernment.Approvedforpublicrelease;distributionisunlimited. COPYRIGHT SomeauthorsareemployeesoftheUnitedStatesGovernmentandmilitaryservicemembers.Thisworkwaspreparedaspartofofficialduties.Title17U.S.C.§105providesthat“CopyrightprotectionunderthistitleisnotavailableforanyworkoftheUnitedStatesGovernment”.Title17U.S.C.§101definesaUnitedStatesGovernmentworkasaworkpreparedbyamilitaryservicememberoremployeeoftheUnitedStatesGovernmentaspartofthatperson’sofficialduties. HUMANSUBJECTSRESEARCH HumanparticipantswereenrolledintheMillenniumCohortStudyafterprovidingfullinformedconsent.TheIBSstudyprotocolwasapprovedbytheinstitutionalreviewboardsattheUniformedServicesUniversityoftheHealthSciencesandtheNavalHealthResearchCenter(ProtocolNHRC.2000.0007).Bothstudieswereconductedincompliancewithallapplicablefederalregulationsgoverningtheprotectionofhumansubjectsinresearch.REFERENCES 1.HunginAP,ChangL,LockeGRetal.IrritablebowelsyndromeintheUnitedStates:prevalence,symptompatternsandimpact.AlimentPharmacolTher2005;21:1365–1375. CitedHere| ViewFullText|PubMed|CrossRef 2.NellesenD,YeeK,ChawlaAetal.Asystematicreviewoftheeconomicandhumanisticburdenofillnessinirritablebowelsyndromeandchronicconstipation.JManagCarePharm2013;19:755–764. CitedHere| PubMed|CrossRef 3.GralnekIM,HaysRD,KilbourneAetal.Theimpactofirritablebowelsyndromeonhealth-relatedqualityoflife.Gastroenterology2000;119:654–660. CitedHere| PubMed|CrossRef 4.DeisingA,GutierrezRL,PorterCKetal.Postinfectiousfunctionalgastrointestinaldisorders:afocusonepidemiologyandresearchagendas.GastroenterolHepatol(NY)2013;9:145–157. CitedHere 5.PorterCK,ChoiD,CashBetal.Pathogen-specificriskofchronicgastrointestinaldisordersfollowingbacterialcausesoffoodborneillness.BMCGastroenterol2013;13:46. CitedHere| PubMed|CrossRef 6.GrayGC,ChesbroughKB,RyanMAetal.ThemillenniumCohortStudy:a21-yearprospectivecohortstudyof140,000militarypersonnel.MilMed2002;167:483–488. CitedHere| PubMed|CrossRef 7.RyanMA,SmithTC,SmithBetal.MillenniumCohort:enrollmentbeginsa21-yearcontributiontounderstandingtheimpactofmilitaryservice.JClinEpidemiol2007;60:181–191. CitedHere| PubMed|CrossRef 8.SmithTC,JacobsonIG,HooperTIetal.HealthimpactofUSmilitaryserviceinalargepopulation-basedmilitarycohort:findingsoftheMillenniumCohortStudy,2001-2008.BMCPublicHealth2011;11:69. CitedHere| PubMed|CrossRef 9.HolmesTH,RaheRH.Thesocialreadjustmentratingscale.JPsychosomRes1967;11:213–218. CitedHere| PubMed|CrossRef 10.KroenkeK,SpitzerRL,WilliamsJB.ThePHQ-9:validityofabriefdepressionseveritymeasure.JGenInternMed2001;16:606–613. CitedHere| ViewFullText|PubMed|CrossRef 11.SpitzerRL,KroenkeK,WilliamsJB.Validationandutilityofaself-reportversionofPRIME-MD:thePHQprimarycarestudy.Primarycareevaluationofmentaldisorders.Patienthealthquestionnaire.Jama1999;282:1737–1744. CitedHere| ViewFullText|PubMed|CrossRef 12.SpitzerRL,WilliamsJB,KroenkeKetal.Utilityofanewprocedurefordiagnosingmentaldisordersinprimarycare.ThePRIME-MD1000study.Jama1994;272:1749–1756. CitedHere| ViewFullText|PubMed|CrossRef 13.SpitzerRL,WilliamsJB,KroenkeKetal.ValidityandutilityofthePRIME-MDpatienthealthquestionnaireinassessmentof3000obstetric-gynecologicpatients:thePRIME-MDPatientHealthQuestionnaireObstetrics-GynecologyStudy.AmJObstetGynecol2000;183:759–769. CitedHere| ViewFullText|PubMed|CrossRef 14.ForbesD,CreamerM,BiddleD.ThevalidityofthePTSDchecklistasameasureofsymptomaticchangeincombat-relatedPTSD.BehavResTher2001;39:977–986. CitedHere| PubMed|CrossRef 15.BurnhamK,AndersonD.Multimodelinference:understandingAICandBICinmodelselection.SocioMethRes2004;33:44. CitedHere 16.LockeGR3rd,YawnBP,WollanPCetal.IncidenceofaclinicaldiagnosisoftheirritablebowelsyndromeinaUnitedStatespopulation.AlimentPharmacolTher2004;19:1025–1031. CitedHere| ViewFullText|PubMed|CrossRef 17.GarciaRodriguezLA,RuigomezA,WallanderMAetal.Detectionofcolorectaltumorandinflammatoryboweldiseaseduringfollow-upofpatientswithinitialdiagnosisofirritablebowelsyndrome.ScandJGastroenterol2000;35:306–311. CitedHere| PubMed 18.KowalcykBK,SmeetsHM,SuccopPAetal.Relativeriskofirritablebowelsyndromefollowingacutegastroenteritisandassociatedriskfactors.EpidemiolInfect2014;142:1259–1268. CitedHere| ViewFullText|PubMed|CrossRef 19.ThabaneM,KottachchiDT,MarshallJK.Systematicreviewandmeta-analysis:theincidenceandprognosisofpost-infectiousirritablebowelsyndrome.AlimentPharmacolTher2007;26:535–544. CitedHere| ViewFullText|PubMed|CrossRef 20.HalvorsonHA,SchlettCD,RiddleMS.Postinfectiousirritablebowelsyndrome-ameta-analysis.AmJGastroenterol2006;101:1894–1899. CitedHere 21.GoodwinL,BourkeJH,ForbesHetal.IrritablebowelsyndromeintheUKmilitaryafterdeploymenttoIraq:whataretheriskfactors?SocPsychiatryPsychiatrEpidemiol2013;48:1755–1765. CitedHere| PubMed|CrossRef 22.WhiteDL,SavasLS,DaciKetal.Traumahistoryandriskoftheirritablebowelsyndromeinwomenveterans.AlimentPharmacolTher2010;32:551–561. CitedHere| ViewFullText|PubMed|CrossRef 23.SavasLS,WhiteDL,WiemanMetal.Irritablebowelsyndromeanddyspepsiaamongwomenveterans:prevalenceandassociationwithpsychologicaldistress.AlimentPharmacolTher2009;29:115–125. CitedHere| ViewFullText|PubMed|CrossRef 24.MaguenS,MaddenE,CohenBetal.AssociationofMentalhealthproblemswithgastrointestinaldisordersiniraqandafghanistanveterans.DepressAnxiety2014;31:160–165. CitedHere| ViewFullText|PubMed|CrossRef 25.vonKanelR,HeppU,KraemerBetal.Evidenceforlow-gradesystemicproinflammatoryactivityinpatientswithposttraumaticstressdisorder.JPsychiatrRes2007;41:744–752. CitedHere| PubMed|CrossRef 26.MayerEA,NaliboffBD,ChangL.Evolvingpathophysiologicalmodeloffunctionalgastrointestinaldisorders:implicationsfortreatment.Gastroenterology2002;68(Suppl587)3–9. CitedHere 27.PorterCK,GloorK,CashBDetal.RiskoffunctionalgastrointestinaldisordersinU.S.militaryfollowingself-reporteddiarrheaandvomitingduringdeployment.DigDisSci2011;56:3262–3269. CitedHere| ViewFullText|PubMed|CrossRef 28.VidelockEJ,AdeyemoM,LicudineAetal.Childhoodtraumaisassociatedwithhypothalamic-pituitary-adrenalaxisresponsivenessinirritablebowelsyndrome.Gastroenterology2009;137:1954–1962. CitedHere| PubMed|CrossRef 29.BennettEJ,TennantCC,PiesseCetal.Levelofchroniclifestresspredictsclinicaloutcomeinirritablebowelsyndrome.Gut1998;43:256–261. CitedHere| ViewFullText|PubMed|CrossRef 30.CryanJF,DinanTG.Mind-alteringmicroorganisms:theimpactofthegutmicrobiotaonbrainandbehaviour.NatRevNeurosci2012;13:701–712. CitedHere| PubMed|CrossRef 31.LiX,KanEM,LuJetal.Combat-trainingincreasesintestinalpermeability,immuneactivationandgastrointestinalsymptomsinsoldiers.AlimentPharmacolTher2013;37:799–809. CitedHere| ViewFullText|PubMed|CrossRef 32.WhiteheadWE,PalssonOS,LevyRRetal.Comorbidityinirritablebowelsyndrome.AmJGastroenterol2007;102:2767–2776. CitedHere| ViewFullText|PubMed|CrossRef 33.LydiardRB.Increasedprevalenceoffunctionalgastrointestinaldisordersinpanicdisorder:clinicalandtheoreticalimplications.CNSSpectr2005;10:899–908. CitedHere| PubMed|CrossRef 34.FullwoodA,DrossmanDA.Therelationshipofpsychiatricillnesswithgastrointestinaldisease.AnnuRevMed1995;46:483–496. CitedHere| PubMed|CrossRef 35.BercikP,DenouE,CollinsJetal.Theintestinalmicrobiotaaffectcentrallevelsofbrain-derivedneurotropicfactorandbehaviorinmice.Gastroenterology2011;141:599–609. CitedHere| PubMed|CrossRef 36.LyteM,VulchanovaL,BrownDR.Stressattheintestinalsurface:catecholaminesandmucosa-bacteriainteractions.CellTissueRes2011;343:23–32. CitedHere| PubMed|CrossRef 37.O'MalleyD,QuigleyEM,DinanTGetal.Dointeractionsbetweenstressandimmuneresponsesleadtosymptomexacerbationsinirritablebowelsyndrome?BrainBehavImmun2011;25:1333–1341. CitedHere| PubMed|CrossRef 38.SpreadburyI,Ochoa-CortesF,IbeakanmaCetal.Concurrentpsychologicalstressandinfectiouscolitisiskeytosustainingenhancedperipheralsensorysignaling.NeurogastroenterolMotil2015;27:347–355. CitedHere| ViewFullText|PubMed|CrossRef 39.SmithTC,SmithB,JacobsonIGetal.Reliabilityofstandardhealthassessmentinstrumentsinalarge,population-basedcohortstudy.AnnEpidemiol2007;17:525–532. CitedHere| PubMed|CrossRef 40.McCarrollMG,RiddleMS,GutierrezRLetal.Infectiousgastroenteritisasariskfactorfortropicalsprueandmalabsorption:acase-controlstudy.DigDisSci2015;60:3379–3385. CitedHere| PubMed|CrossRef 41.RiddleMS,MurrayJA,PorterCK.TheincidenceandriskofceliacdiseaseinahealthyUSadultpopulation.AmJGastroenterol2012;107:1248–1255. CitedHere| ViewFullText|PubMed|CrossRef 42.VerduEF,RiddleMS.Chronicgastrointestinalconsequencesofacuteinfectiousdiarrhea:evolvingconceptsinepidemiologyandpathogenesis.AmJGastroenterol2012;107:981–989. CitedHere| ViewFullText|PubMed|CrossRef ©TheAmericanCollegeofGastroenterology2016.AllRightsReserved.Viewfullarticletext Source TheEpidemiologyofIrritableBowelSyndromeintheUSMilitary:FindingsfromtheMillenniumCohortStudy OfficialjournaloftheAmericanCollegeofGastroenterology|ACG111(1):93-104,January2016. Full-Size Email +Favorites Export ViewinGallery Colleague'sE-mailisInvalid YourName:(optional) YourEmail: Colleague'sEmail: Separatemultiplee-mailswitha(;). Message: Thoughtyoumightappreciatethisitem(s)IsawatOfficialjournaloftheAmericanCollegeofGastroenterology|ACG. Sendacopytoyouremail Yourmessagehasbeensuccessfullysenttoyourcolleague. Someerrorhasoccurredwhileprocessingyourrequest.Pleasetryaftersometime. AddItem(s)to:   AnExistingFolder ANewFolder FolderName: Description: Theitem(s)hasbeensuccessfullyaddedto"". Thanksforregistering! Besuretoverifyyournewuseraccountinthenext24hours,bycheckingyouremailandclickingthe"verify"link. ThisarticlehasbeensavedintoyourUserAccount,intheFavoritesarea,underthenewfolder"". Login Youcanloginwithyourusernameoryouremailaddressalongwithyourchosenpassword ACGMemberAccess LogInHere LippincottJournalsSubscriberspleaseloginwithyourusernameoremailalongwithyourpassword. ForgotPassword? Don'thaveauseraccount? Registerwithusforfree tosavesearches,favoritearticlesandaccessemailcontentalerts. ForgotPassword? Enterandsubmittheemailaddressyouregisteredwith.Anemailwithinstructionstoresetyourpasswordwillbesenttothataddress. PasswordSent Linktoresetyourpasswordhasbeensenttospecifiedemailaddress. ArticleasEPUB ExportAllImagestoPowerPointFile AddtoMyFavorites Colleague'sE-mailisInvalid YourName:(optional) YourEmail: Colleague'sEmail: Separatemultiplee-mailswitha(;). Message: Thoughtyoumightappreciatethisitem(s)IsawatOfficialjournaloftheAmericanCollegeofGastroenterology|ACG. Sendacopytoyouremail Yourmessagehasbeensuccessfullysenttoyourcolleague. Someerrorhasoccurredwhileprocessingyourrequest.Pleasetryaftersometime. EndNoteProciteReferenceManager Savemyselection ArticlesinPubMedbyMarkSRiddle,MD,DrPH ArticlesinGoogleScholarbyMarkSRiddle,MD,DrPH OtherarticlesinthisjournalbyMarkSRiddle,MD,DrPH Dataistemporarilyunavailable.Pleasetryagainsoon. Thiswebsiteusescookies.Bycontinuingtousethiswebsiteyouaregivingconsenttocookiesbeingused.ForinformationoncookiesandhowyoucandisablethemvisitourPrivacyandCookiePolicy. Gotit,thanks!