Niddkibdgeneticsconsortium Phenotypeoperatingmanual Versiondate:May10,2006

NIDDKIBDGeneticsConsortium PhenotypeOperatingManualVersionDate:May10,2006

Theoriginalgoalofthisconsortiumwastorecruit350IBD-affected indexsubjectsinthegeneralformof250case/controlsand100trios(affected index subject/probandplusbothparents;either,neither,orboth parents,can beaffected) fromeachofthesixGeneticsResearchCenters(GRCs).JohnsHopkinsandCedars-Sinaiarerecruitingminoritypopulations,andtheirrecruitmentgoalsaresomewhatless.

Themodifiedgoal(April2006),basedonour repositorydemographicsthus far,istorecruitadditional AshkenaziJewishsubjects (UCorCD);additionalUC subjectsbutexcludeany UCcaseswithproctitisonly(ifpossible);Torontoshouldkeepcollecting pediatrictrios(UCorCD).These recommendationsdonotapplyto JohnsHopkinsorCedars-Sinai,thoughthey centers shouldmodifytheirrecruitmenttoinclude Ashkenazi JewishandUCsubjects.

Anindexsubjectshouldberecruitedonlyifhe/shebelievesasinglematchedcontrolorbothparents(seepage15)would bewillingto participate.Itisinevitablethatsomeparentsand controlswillrefusewhen asked atalaterdate,andin these cases,populationcontrolsshould beused (page15).Ifyouhaveanaccidental partial trio(e.g.amotherandindexsubjects,fatherlaterrefuses),pleasespeaktotheDCCbeforerecruiting apopulationcontrol.

Do not recruitblood-related indexsubjects,e.g.ifafatherandson arebothaffected andcanberecruited,butthemothercannot,you may onlyrecruiteitherthefatherorthesonasanindexsubject.

Onceanindexsubjecthasbeenrecruitedtodonateblood,aphenotypingformmust becompletedwith thecareful questioning ofthepatient andwiththeaid ofaclinician.Insomecases,(e.g.adoptedindex subjects),family IBD statuswill beunknown.Thisissimplefor thefather,motherandsecond-degreerelativessections,butforthesiblingssection, you must enter“0” forallfields.Whilethisdoesnot document thetrueanswer(‘unknown’),scientificallyitisasaccurateasfor someone who doesnot haveanysiblings(neitherhasknown affectedsiblings;neitherhasknown unaffectedsiblings).

TheMacroscopicDiseaseLocation,SurgeryandExtra-intestinalManifestationssectionsmustbecompletedbyaclinicianreviewingthepatient’schart.

Youmay recruitmorethan onematchedcontrolforan indexsubject(subject A).Thisisanacceptablesubstitutefor asecondindex subject(subjectB)thathasnomatchedcontrol.WhenregisteringthetwomatchedcontrolsontheIBDGCwebsite, besuretheyarebothlinkedtothecontrolwithwhomtheyarematched(subjectA).

Youmay also recruitaffectedsiblingsoftheindexsubject if both parentsoftheindexsubjecthavealso been recruited.Thesedonot count towardsyourindex subject orcontrol accrualsperse,butare usefulforanalyses.Do not recruit half-siblings,astheyareconsideredsecond-degreerelatives.

FollowingnotificationthatRutgersUniversityCellandDNARepository(RUCDR)hasreceivedasubjectorcontrolbloodsample, youmay proceedwithregisteringhim/her ontheIBDGCwebsite.Index subjectsmust beregistered priortocontrols,siblingsorparents.Therefore,(e.g.)ifyouareable todrawblood fromthe parentspriortothe indexsubject/child, pleasedonotregister anyoneuntilRUCDRhasalsoreceivedtheindexsubject/child’sblood.

FollowingregistrationontheIBDGCwebsite, youmay enterphenotypedatausingtheIBDGCwebsiteinterface.

Alwaysbe sure to checkwithindexsubject beforediscussing reasonsforthisstudywithcontrolsand/orfamily members.Anindexsubjectmay offeracontrolthat isunaware ofthepatient’sdisease.

INFLAMMATORYBOWELDISEASE(IBD)DEFINITIONSFORDIAGNOSIS

ThefollowingdiagnosticcriteriaareprovidedasguidelinestocompletedocumentationonindividualswithIBDenrolledintheNIDDK IBDGeneticsConsortium: InflammatoryBowel Disease (IBD)

A)Symptomsincludingoneormoreof:

diarrhea,rectalbleeding,abdominalpain,fever,complicatedperianaldisease,extraintestinalmanifestations, weightlossorfailuretothrive

AND

B)Symptomson twoormoreoccasionsseparated by atleast 8 weeksorongoingsymptomsofat least 6weeksduration.When therehasbeen asingleepisodeofcolitis(in someinstanceslessthen6 weeksduration)resultingincolectomy andresolutionofdiseasesymptoms, pathologyonthecolectomyspecimenshouldbeconsistentwithidiopathicIBDandmicrobiologystudiesshouldbenegative.

AND

C)Oneor moreofthefollowingprovidingobjectiveevidenceof inflammation:Endoscopic: Mucosaledema,erythema, lossof normalsubmucosalvasculature,

friability,ulceration,strictureformation,pseudopolyps,mucosaledema, erythema.Wherethereareonlyminorchanges(mucosaledema, erythema,lossofnormalsubmucosalvasculature,friability) mucosalbiopsiesshouldhavebeendonetoconfirmthepresenceofIBD.

Radiologic:Mucosalthickeningand/ornodularity,ulceration,stricture,pseudopolyps,fistulaformation,pseudosacculation.Minorchangesalone(mucosalthickeningand/ornodularity) shouldnotbesufficient to makeadiagnosisofIBD.

Histologic:Mucosalerosionor ulceration,architectural changesof crypts,Panethcellmetaplasia(incolon),transmuralinflammatoryinfiltrate*,fibrosisof muscularispropria*,noncaseatinggranuloma*

*Crohn’sdisease

IndividualswithIBDshouldbeclassifiedintooneof threecategories,based on mostrecentdiagnosis:

Crohn’sdisease (CD)

1)Evidenceofsmallintestinalinflammationwithendoscopically,radiologicallyorhistologicallydemonstratedulcerations,fistulization,mucosalfissuring,nodularityorcobblestoning,strictureformationorhistologicallydemonstratedtransmuralinflammationwith or withoutgranulomaformation.

2)Isolatedesophageal, gastricor duodenalinflammationwiththefindingofnon-caseatinggranuloma.

3)Colonicinflammationwhichispatchy(normalsegmentsseparatingareasofinflammation,asdescribed above) orassociatedwithoneormoreofthefollowingfeatures:completerectalsparing, multiple(>10) aphthoidulcers,deepulceration(intothemuscularispropria),transmuralinflammation,extensivefibrosisandwallthickening,fistulization,non-caseatinggranuloma.

4)Thepresenceof complexsuppurativeperianaldisease(i.e.morethanasuperficialfistulaoruncomplicatedsuperficialabscess).

5)Iftherearefewerthan 10aphthoid ulcersinthececum (andtherest ofthecolonappearsnormal) inapatient with smallboweldiseasethen thisshould becalledsmallbowel disease only. Similarly,ifthecolonisnormal except forthepresenceof afistulaextending frominflamed small bowel,thepatient shouldbesaidtohavesmall bowel disease alone.Ifthececumisinvolvedwith ulcerslargerthanaphthoidulcersorulcersthataredeeporiftheinvolvementhasresultedindeformity ofthececumthiswouldbeconsideredto becolonicinvolvement.

UlcerativeColitis(UC)

1)Superficialinflammationand/orulceration(involvingonlythemucosaandsubmucosa) of thecolonwhichiscontinuousfromtherectumextendingproximallywithoutskiplesionsorcompleterectalsparing(N.B. Relativerectalsparingisallowedforpatientsreceivingtopical rectaltherapy).

2)Noinflammationof thesmallintestine(“backwashileitis”isallowed -non-stenosingsuperficialinflammation oftheterminalilealmucosaassociatedwithseverepancolitiswhichresolvesfollowingmedicalor surgicaltreatment ofthecolitis).

3)NofeaturesofCrohn’sdiseaselisted above.

IndeterminateColitis(IC)

1)Confirmed IBDby A,Band Cabove.

2)Physicianunableto classifyindividualinto eitherCDor UCbasedonabovecriteriaand/orpatient hasfeaturesofbothCDandUCwith noneofthefeaturesdiagnosticofoneortheother.

Crohn’sDiseasePhenotypeForm

RegistrationInformation

1.IndividualID,Mother’sID,Father’sIDandFamilyNo.areall optional.Eachcentermay choosetoassign theseordisregard.

2.Gender.

3.Dateof BirthisinformatMM/DD/YYYY.

4.TheNIDDKIDnumberisbased onthesamplelabel IDnumber,whichisaffixedtotheform.ThecompleteConsortiumIDnumberisgenerateduponregistrationof subject using Consortium webinterface; thelast six digitswillcorrespond totheNIDDKIDnumber.

DemographicandDiagnosticInformation

1.Hispanic/Latino status(‘Yes’/‘No’/‘Unknown’)isself-reported.

2.Jewishstatus(‘Yes’/ ‘No’/‘Unknown’)isself-reported.Jewish,Ashkenazistatusof eachgrandparentshouldberecorded.

3.Raceisself-reported.Choose‘Other’underRacefor multiracialindividualsandfillinasrequired(upto20characters).

4.Yearof diagnosisreferstothe yearin whichadefinitive diagnosisofIBDwasmade.In a caseinwhich apatientisinitiallydiagnosedwith one form ofIBDandsubsequently hasthediagnosischanged fromoneformofIBDto anotherformofIBD,the dateoforiginaldiagnosisofIBDshould be used. However,themost recent disease diagnosis(CD,UCorIC)should beused.

5.Dateoflatestclinicalexam/encounterindicatesthedateofthemostrecentclinical,endoscopic, radiologicand/orpathologicrecordsinthestudyparticipant’srecord,andisrecorded asMM/DD/YYYY.

6.Family disease historyasreportedbytheindividualforallrelativeslisted.Relativesmust havebeendiagnosed withIBDto qualifyunder‘CD’,‘UC/IC’or‘IBDaffectedtypeunclear’.Doesnotrequireconfirmationbyrelativeorrelative’smedicalchart.‘IBDAffected, typeunclear’ referstoarelativewhomtheindividualknowshasbeendiagnosedwithIBDbutisn’tsure/cannotrecallwhattype.

7.Determinationoffamilytypeshouldinclude1stand2nddegreerelativeIBDaffection asreportedbythepatient/participant.UC orICin any 1stor2nddegreerelativewouldindicatemixedfamilytype.1stdegreerelativesincludeparents,fullsiblings, andchildren.2nddegreerelativesincludegrandparents, aunts/unclesandnieces/nephewsandhalf-siblings.

SmokingHistoryPriortoDiagnosis

1.Smokingisdefinedassmoking,onaverage,atleast1 cigarettedaily foraperiodofat least 3monthspriortodiagnosis.Pipeandcigarsmoking are notincluded.

2.AnEx-smokeratdiagnosisisdefinedassomeonewho hadstopped smoking atleast 4 weekspriortodiagnosisand wasnotsmokingat diagnosis.Ifpatienthashadmultipleepisodesof quittingandstartingsmokingcigarettesindicatetheyearwhen first started andtheyearlast quit.

3.IfpatientisaSmokerbut datesofstart andstop areunknown,leavedatesblank.

4.If patienthasneversmokedindicate‘No’,andleaveYearStarted/YearStopped

blank.

5.Ifsmoking history isunknown,check ‘Unknown’,and leave YearStarted/YearStoppedblank.

6.No. ofcigarettesperday:indicatethenumberof cigarettessmokeddaily. Wheresmokingamounthaschangedovertimeusetheamountat diagnosis(ifknown).Ifnot known,usetheamountsmoked atthedate closest tothetimeofdiagnosis.IfEx-smokeratdiagnosisusetheestimated meannumber ofcigarettesperdaypriortoquitting.Ifsubject isaSmokerorEx-smokerbutthenumberofcigarettesperdayisnot knownpleaseindicate‘Unknown’.Ifpatienthad neversmokedatdiagnosisorsmoking historyisunknown please leave fieldempty.

MacroscopicDiseaseLocation(check allthatapply)-mustbecompletedbyaclinician Mustbeconfirmedbymedical records.Ifregionhasnot been examined fordisease,enter‘Unknown’forthatregion.Check all areasofmacroscopicdisease at any timeduringthe course ofdisease.Ifthereareafewaphthoid ulcersinthececum (andtherestofthecolon appearsnormal)inapatientwithsmall bowel disease then thisshouldbecalledsmall bowel disease only.Similarly,if thecolonisnormalexcept forthepresenceofafistulaextendingfrominflamed small bowel,thepatientshouldbesaidto havesmallbowel disease only.Ifthe cecumisinvolved withulcerslargerthanaphthoidulcersorulcersthataredeeporiftheinvolvementhasresulted indeformityofthececumthiswouldbeconsideredtobecolonicinvolvement.

1.Location:Mucosal erythema,friabilityorgranularityisnotconsideredtobeindicativeofinvolvement. Mucosalulceration,cobblestoning,stricturingorbowelwallthickeningtypicallyindicatesinvolvement.Acceptablesourcesofinformationforclassification areupperandlowerendoscopy reports,bariumX-rays,operativereportsand pathologyresection specimenreports.Incaseswherethereisno informationormissing informationregardingevaluation ofaportion oftheGItract,extentshould be classified as‘Unknown’forthatlocation.Operativedescriptionsof normalappearingsmallbowelor colonshould notbeused to classify ‘No’forasite ifthat site hasneverbeen visualized by endoscopyor bariumradiography.Perianal diseaselocation issaid tobe present when anindividualhasahistoryof perianalorperinealabscess(es)and/or fistula,anal canalulcers,analstenosisor chronicedematousand violaceousskintags. Thisdoesnotincludeanal fissuresor hemorrhoids.

2.CDDiseaseBehavior:nonstricturing,nonpenetrating(B1),stricturing (B2)orpenetrating(B3).NonstricturingNonpenetrating Disease(B1)isdefined asuncomplicatedinflammatorydiseasewithoutevidenceofstricturingor penetrating disease. Stricturing Disease (B2)isdefined astheoccurrenceofconstantluminalnarrowingdemonstratedbyradiologic, endoscopic,orsurgicalexaminationcombinedwithprestenoticdilationand/or obstructivesignsorsymptomsbutwithoutevidence of penetratingdisease.Penetrating Disease(B3)isdefinedastheoccurrenceofbowelperforation, intraabdominalfistulas,inflammatory massesand/orabscessesat anytimeinthecourseofthe disease, andnotsecondarypostoperativeintra-abdominalcomplication.StricturingandpenetratingshouldbeclassifiedB3.

NB Perianalandrectovaginalfistula(s) donotcount, bythemselves, as‘penetratingfistulizing’.

Surgery-mustbecompletedbyaclinician

1.Surgeryforcomplication ortreatment of CD:must beconfirmed by chart.Ifunconfirmed,then check ‘No’.Ifnoinformation,check ‘Unknown’.

If Yes:

2.Bowelresection/strictureplastyincludes: a.Resectionor strictureplastyof stricturing disease

b.Resectionof diseasethathasbeencomplicatedbyfistulaor abscess

3.Diversionincludes:

a.Diversionproceduresperformedprior todefinitivesurgerysuchasresectionb.Diversionproceduresperformedtoallowhealingofperineal disease

4.Surgeryforfistula/abscessincludes:a.Surgicalfistulotomyb.Placementof aSeton

c.Intestinaldiversiontopermithealingofperinealdisease

d.Surgicalresectionofacomplicatedfistula(e.g.enterovesicalfistula)e.Surgicaldrainageofanabscess(e.g.perineal,intra-abdominal, iliopsoas)

f.Percutaneousdrainageof anintra-abdominalabscessthatisfollowedbysurgicalresectionofinvolvedintestine

5.Surgeryforfistula/abscessdoesnotinclude:

a.Simpleincisionand drainageofaperianal abscessperformedusing only localanesthetic

b.Percutaneousdrainageofintra-abdominalabscesswithoutresectionofinvolvedintestinewithin12months

c.Incidentalresectionofanenteroentericfistulathatoccursaspartofanintestinalresection

6.Yearof first operation:yearoffirstabdominalsurgery atorafterdiagnosis.

7.No. of operationsforabdominaldisease:(i.e.resection,strictureplasty,abscessdrainage):asingleoperationmay includetwotypesof surgeries(e.g.asingleoperationduringwhichboth‘bowelresection’and‘abscessdrainage’wereperformed).

8.No. ofoperationsforperinealdisease(includingdiversions):asingleoperationmayincludetwo types ofsurgeries(e.g.asinglesurgery forperinealabscessanddiversion)

9.Appendectomy:Shouldbenoted as‘Yes’evenifremovalwaspartofanothersurgery.IfYesindicate year.

Extra-IntestinalManifestations-mustbecompletedbyaclinician

Extraintestinalmanifestations(EIM)shouldbedocumentedinmedicalrecords(e.g.clinicalnote,radiologyreport,surgicalreport,pathologyreport).

1.Joints:pauciarticular(lessthan5 jointsinvolvedwithevidenceof effusion orswelling – usually large joints-andassociated withrelapsesofIBD); polyarticular (5jointsor more,symmetricinvolvementwitheffusionorswelling-usuallysmall joint-runsacourseindependent ofIBD often lasting many months);arthralgias(jointpainsbut noobjectiveevidenceof effusionor swelling)

arenotindicativeofjoint“involvement”intheabsenceof othermarkersofactivejointinflammationsuchaseffusionorswelling.

a.Largejointdiseaserelatedtodiseaseactivity: Fewerthan5(usuallylarge)jointsrelatedtodiseaseactivity

b.Smalljointunrelatedtodiseaseactivity: Five ormore(usuallysmall)jointsunrelatedtodiseaseactivity

c.Ankylosingspondylitis:requiresradiologicdocumentationoftypicalfindingsof sacroiliacinflammation, narrowingor sclerosisand/orinflammationorfusionof vertebralbodies

d.Sacro-iliitis:alsorequiresradiologicdocumentationoftypicalfindingsofsacroiliacinflammation,narrowingorsclerosisand/or inflammationorfusionofvertebralbodies

e.Non-specificjointinflammation:evidenceof effusionor swelling but doesnotfitany of theabovecategories

2.Skin:

a.Erythemanodosum:typicallyappearasraised,tender,redorvioletsubcutaneousnodulesthatare1to5cmindiameter.Thenodulesaremostcommonlylocatedontheextensor surfacesoftheextremities, particularlyover theanterior tibialarea

b.Pyoderma:ulcerativediseaseoftheskin.Theremay beoneormultiplelesions. Theyoccurmostcommonlyonthelegs,especiallythepretibialarea, but candevelopin anyareaofthebody,including theabdominalwalladjacenttothestomaaftercolectomy

3.Eyes:

a.Uveitis:intraocularinflammation.Diagnosisrequiresdocumentationoftypicalfindings.Aslitlampexaminationispreferable

b.Episcleritis:Defined bytheabruptonset ofmildinflammation oftheepiscleraof theeye.Requiresdocumentationoftypicalfindingsoflocalizedinflammation(erythema,increasedvascularity,nodularity)oftheepiscleraltissues

c.Undiagnosedocularinflammation:Wheretherehasbeeneyeinflammationbutthepresentation orfindingshavenot beentypical orwherethenatureoftheinflammationcannotbeclassifiedbasedupontheavailableinformation

4.Liver:

a.Primarysclerosingcholangitis:shouldbedocumentedwithtypicaldyecholangiographicor MRCPfindingsinsomeone with no otherknowncausesof secondarycholangitis. Abnormal liverenzymesor liverbiopsyalonearenotsufficientevidenceofsclerosingcholangitis

Ulcerative/IndeterminateColitis(UC/IC)PhenotypeForm

RegistrationInformation

1.Individual ID,Mother’sID,Father’sIDandFamilyNo.areall optional.Eachcentermay choosetoassign theseordisregard.

2.Gender.

3.Dateof BirthisinformatMM/DD/YYYY.

DemographicandDiagnosticInformation

1.Hispanic/Latino status(‘Yes’/‘No’/‘Unknown’)isself-reported.

2.Jewishstatus(‘Yes’/ ‘No’/‘Unknown’)isself-reported.Jewish,Ashkenazistatusof eachgrandparentshouldberecorded.

3.Raceisself-reported.Choose‘Other’underRacefor multiracialindividualsandfillinasrequired(upto20characters).

4.Yearof diagnosisreferstothe yearin whichadefinitive diagnosisofIBDwasmade.In a caseinwhich apatientisinitiallydiagnosedwith one form ofIBDandsubsequently hasthediagnosischanged fromoneformofIBDto anotherformofIBD,thedateoforiginaldiagnosisofIBDshould be used.However,themost recent disease diagnosis(CD,UCorIC)should beused.

5.Dateoflatestclinicalexam/encounterindicatesthedateofthemostrecentclinical,endoscopic, radiologicand/orpathologicrecordsinthestudyparticipant’srecord,andisrecorded asMM/DD/YYYY.

7.Determinationoffamilytypeshouldinclude1stand2nddegreerelativeIBD

affection asreportedby thepatient/participant.CDorICin any1stor2nddegreerelativewould indicatemixed familytypeifproband hasUC. CDorUCin any1stor2nddegreerelativewouldindicatemixedfamily typeifprobandhasIC.1stdegreerelativesincludeparents, fullsiblings, andchildren.2nddegreerelativesincludegrandparents,aunts/unclesandnieces/nephewsandhalf-siblings.

SmokingHistoryPriortoDiagnosis

1.Smokingisdefinedassmoking,onaverage,atleast1 cigarettedaily foraperiodofat least 3monthspriortodiagnosis.Pipeandcigarsmoking are notincluded.

3.IfpatientisaSmokerbut datesofstart andstop areunknown,leavedatesblank.

4.If patienthasneversmokedindicate‘No’,andleaveYearStarted/YearStopped

blank.

5.Ifsmoking history isunknown,check ‘Unknown’,and leave YearStarted/YearStoppedblank.

6.No. ofcigarettesperday:indicatethenumberof cigarettessmokeddaily. Wheresmokingamounthaschangedovertimeusetheamountat diagnosis(ifknown).Ifnot known,usetheamountsmoked atthedate closest tothetimeofdiagnosis.Ifex-smokeratdiagnosisusetheestimated meannumber ofcigarettesperdaypriortoquitting.IfsubjectisaSmokerorEx-smokerbutthenumberofcigarettesperdayisnot knownpleaseindicate‘Unknown’.Ifpatienthad neversmokedatdiagnosisorsmoking historyisunknown please leave fieldempty.

MacroscopicDiseaseLocation (check allthatapply)-mustbecompletedbyaclinicianMustbeconfirmedbychart.Check all areasofmacroscopic diseasethat apply at anytimeduringthecourseofdisease.Acceptablesourcesofinformationforclassification arecolonoscopyreports, bariumenemas, orcolectomygrosspathologyreports.

1.Proctitis:inflammationextendinguptonofurtherthan15 cmproximaltotheanorectaljunction

2.Left-sided(tosplenicflexure):inflammationextendinguptothesplenicflexure.If thiscategoryischecked,so shouldProctitis

3.Extensive(beyondsplenicflexure):inflammationextendingproximaltothesplenicflexure.If thiscategoryischecked foraUC patient,Proctitisand Left-sidedshould beaswell.

4.Periappendicealinflammation:documentedbycolonoscopywithorwithoutbiopsy.OftenaccompaniesExtensivedisease.

Furthermore,patientswithleft-sided disease orproctitisand with anisolatedpatch ofinflammationinthecaecumshouldberecordedashavingLeft-sideddiseaseonlyorProctitisonly,respectively.

Surgery-mustbecompletedbyaclinician

1.Surgeryforcomplication of UC: must be confirmedbychart.Ifunconfirmed,then check ‘No’.Ifno information,check‘Unknown’.

If Yes:

2.Surgeryfordysplasia/cancer:Whendysplasiaor cancer isonlyfoundpostoperativelyonthesurgicalspecimenbuttheindicationforsurgerywaseitheracutefulminant orchroniccontinuousdisease, dysplasia/cancershouldnotbeincludedasanindication forsurgery. Howeverthepresenceof dysplasia/cancershouldbeindicatedintheappropriatefield(see#6).

3.Surgeryforchroniccontinuousdisease:shouldbeindicatedwhenthereisneitheranindicationforfulminantcolitisnorfordysplasia/cancer

4.Surgeryforacutefulminantdisease:fulminantcolitisimpliesanacuteorsubacuteonset ofseverecolitis(withorwithoutsignsoftoxicity).Thismayoccuroveraperiodof2-12 weeksinsomeonewithout apriordiagnosisofulcerative colitis or in someonewithapriordiagnosisof ulcerativecolitisin whomthe disease hadbeenquiescentor stablepriortothefulminantexacerbationofdiseaseactivity.

5.Yearofsurgery (colectomy):yearoffirst abdominalsurgery at orafterdiagnosis.

6.Diagnosisofdysplasia/cancer(colorectal):Ifthepatienthashad diseaselessthan10 yearsoranegativesurveillancecolonoscopy thentheansweris“no”.Ifthepatienthashad disease morethan 10yearsand nosurveillance(i.e.no biopsyafter10 years ofdisease orbiopsyresultsnot available)theansweris“unknown”.Ifthepatienthashadconfirmeddysplasia/cancertheanswer is“yes”.

7.Appendectomy:Shouldbenoted as‘Yes’evenifremovalwaspartofanothersurgery.IfYesindicate year.

Extra-IntestinalManifestations-mustbecompletedbyaclinician

Extraintestinalmanifestations(EIM)shouldbedocumentedinmedicalrecords(e.g.clinicalnote,radiologyreport,surgicalreport,pathologyreport).

a.Largejointdiseaserelatedtodiseaseactivity: Fewerthan5(usuallylarge)jointsrelatedtodiseaseactivity

b.Smalljointunrelatedtodiseaseactivity: Five ormore(usuallysmall)jointsunrelatedtodiseaseactivity

c.Ankylosingspondylitis:requiresradiologicdocumentationoftypicalfindingsof sacroiliacinflammation, narrowingor sclerosisand/orinflammationorfusionof vertebralbodies

d.Sacro-iliitis:alsorequiresradiologicdocumentationoftypicalfindingsofsacroiliacinflammation,narrowingorsclerosisand/or inflammationorfusionofvertebralbodies

e.Non-specificjointinflammation:evidenceof effusionor swelling but doesnotfitany of theabovecategories

2.Skin:

a.Erythemanodosum:typicallyappearasraised,tender,redorvioletsubcutaneousnodulesthatare1to5cmindiameter.Thenodulesaremostcommonlylocatedontheextensorsurfacesoftheextremities,particularlyover theanterior tibialarea

b.Pyoderma:ulcerativediseaseoftheskin.Theremay beoneormultiplelesions. Theyoccurmostcommonlyonthelegs,especiallythepretibialarea,butcan developinany area ofthebody,includingtheabdominalwalladjacenttothestomaaftercolectomy

2.Eyes:

a.Uveitis:intraocularinflammation.Diagnosisrequiresdocumentationoftypicalfindings.Aslitlampexaminationispreferable

b.Episcleritis:Definedbytheabruptonsetofmildinflammationoftheepiscleraoftheeye.Requiresdocumentationoftypicalfindingsof localizedinflammation(erythema,increasedvascularity,nodularity) of theepiscleraltissues

c.Undiagnosedocularinflammation:Wheretherehasbeeneyeinflammationbutthepresentation orfindingshavenot beentypical orwherethenatureoftheinflammationcannotbeclassifiedbasedupontheavailableinformation

3.Liver:

a.Primarysclerosingcholangitis:shouldbedocumentedwithtypicaldyecholangiographicor MRCPfindingsinsomeonewithno otherknowncausesof secondarycholangitis.Abnormalliverenzymesor liverbiopsyalonearenotsufficientevidenceofsclerosingcholangitis

UnaffectedPhenotypeFormforcontrols

RegistrationInformation

1.IndividualIDandPedigreeIDareoptional.Eachcentermay chooseto assign theseordisregard.

2.Gender.

3.Dateof BirthisinformatMM/DD/YYY.

4.TheNIDDKID numberisbased onthesample label IDnumber,affixed totheform.ThecompleteConsortiumIDnumberisgeneratedupon registrationofsubject usingConsortium web interface; thelast six digitswill correspond to NIDDKID number.

5.RelationshiptoProband: mustbeoneofi)parent,ii) spouse/domesticpartner,iii)friend*oriv)populationcontrol*.Categoriesiiandiii mustalso fitchecklist profilefully.Domesticpartnerreferstoanon-friendperson,notmarriedtobutcohabitatingwith,theproband.Categoryiv mustfulfillrequirementsbelow(6).You mayalsorecruitfullsiblings,if he/sheisaffected.

6.PopulationControl: Mustbelinked toan index subject.Must matchthat indexsubjectbyi)race,ii)ethnicity(Jewish and Hispanic/Latino status),and3)age: mustbewithin 10yearsoftheindexsubject.Thepopulation controlmust berecruited atthesameGRC(andsatellitecenter ifapplicable) astheindexsubject.

7.ControlChecklist:Samerace/ethnicityasindexsubjectisasself-reported.MatchedJewish ethnicitymust alsomatch Ashkenazistatus(e.g.ifprobandhas2-4 AshkenaziJewish grandparents, control must haveany of2,3or4Ashkenazi grandparents.Ifprobandhasonly1Ashkenazi grandparentbutallareJewish,controlmusthave1or0 Ashkenazi grandparents,but 2ormoremust be Jewish). No family historyofIBDrefersto 1stand2nddegreerelatives(parents,siblings,offspring,aunts/uncles,grandparents,nieces/nephews).

DemographicInformation

1.Hispanic/Latino status(‘Yes’/‘No’/‘Unknown’)isself-reported.

2.Jewishstatus(‘Yes’/ ‘No’/‘Unknown’)isself-reported.Jewish,Ashkenazistatusof eachgrandparentshouldberecorded.

3.Raceisbased onself-reporting.Choose‘Other’underRaceformultiracialindividualsand fillin asrequired(upto20 characters).

4.If duration ofcohabitationofspouse/domesticpartner islessthan 1 year,indicate‘0’.

SmokingHistory

1.Indicateif controlisCurrent smoker, Ex-smoker,Non-smokerorUnknown.

2.If controlhassmoked lessthan100 cigarettesinhis/herlifetime,he/sheisconsideredtobeanon-smoker.

3.If controlhashadmultipleepisodesof quittingandstartingsmokingcigarettesindicatetheyearwhenfirststartedand theyearlast quit,unlesscurrentlysmoking.

4.If Current smoker,leaveYearstoppedblank.

Surgery

1. Indicate ‘Yes’,‘No’or‘Unknown’andenteryearofappendectomy ifknown.

•Ifindexsubjectisunder18,non-triocontrolsmaybebetweentheagesof18-24years,withnosmokinghistory.

Abscess:

Glossary

A localized collection ofpusinpart ofthebody formedbytissuedisintegration andsurrounded byan inflamedarea.

AnkylosingSpondylitis:

Arthritisoftheaxialskeleton manifestedbyback pain and progressive stiffnessofthespine.

B1:

CDDiseaseBehavior, nonstricturing, nonpenetrating.Definedasuncomplicatedinflammatorydiseasewithoutevidenceofstricturingorpenetratingdisease.

B2:

CDDiseaseBehavior,stricturing.Definedastheoccurrenceofconstant luminalnarrowingdemonstratedbyradiologic, endoscopic,orsurgicalexaminationcombinedwithprestenoticdilationand/orobstructivesignsorsymptomsbutwithoutevidenceofpenetratingdisease.

B3:

CDDiseaseBehavior,penetrating.Definedastheoccurrenceofbowelperforation,intraabdominalfistulas,inflammatory massesand/orabscessesatanytimeinthecourseofthedisease, andnot secondarypostoperativeintra-abdominalcomplication.NBPerianalandrectovaginalfistula(s)donotcount,bythemselves, as‘penetratingfistulizing’.

Cecum:

Thelargeblind pouchforming thebeginningof thelargeintestine.Alsocalledblindgut.

Endoscopy:

Examinationoftheinteriorofahollowbodyorgan byuseofanendoscope.

Episcleritis:

Definedbytheabrupt onset ofmild inflammationoftheepiscleraoftheeye.Requiresdocumentationoftypicalfindingsoflocalizedinflammation(erythema,increasedvascularity, nodularity) oftheepiscleraltissues.Theepiscleraisahighlyvascularconnectivetissuethatissuperficialtothesclera oftheeye.

ErythemaNodosum:

Typicallyappearasraised,tender,red orviolet subcutaneousnodulesthat are1to5 cmin diameter.Thenodulesaremost commonlylocated ontheextensorsurfacesoftheextremities,particularlyovertheanteriortibialarea.

Ex-smoker:

Someonewho hassmoked priorto diagnosis,butwasnot smoking at time ofdiagnosis.

Fistula:

Anabnormal duct orpassageresultingfrominjury,disease,ora congenitaldisorderthatconnectsan abscess,cavity, orholloworgantothebodysurfaceortoanotherholloworgan.

Macroscopic:

Largeenoughtobeperceivedorexaminedwithoutmicroscopy.

Non-smoker:

Apersonwho hasneversmoked,at time ofdiagnosis.

Non-specificjointinflammation:

Evidenceof effusionorswellingbutdoesnotfitanyoftheothercategories.

PercutaneousDrainage:

Drainageperformedthrough theskinoraccomplishedbyaneedle.

PopulationControl:

Mustbelinked toan indexsubject.Must match that indexsubject byi)race,ii)ethnicity(Jewish and Hispanic/Latino status),and3)age:must bewithin 10 yearsoftheindexsubject. Thepopulation controlmust berecruited atthesameGRC(andsatellitecenterifapplicable)astheindexsubject.

PrimarySclerosingcholangitis:

Achronicprogressivedisorderofunknownetiology,characterizedbyinflammation,fibrosis,and stricturing of medium size and largeductsinthe intrahepaticandextrahepaticbiliarytree(bileductsin-andoutsidetheliver).

Pyoderma:

Ulcerativediseaseoftheskin.Theremaybeoneormultiplelesions.Theyoccurmostcommonlyonthelegs,especiallythepretibial area,butcandevelop inanyarea ofthebody, includingtheabdominalwalladjacenttothestomaaftercolectomy.

Resection:

Excision of a portionorallof anorgan orother structure.

Sacro-iliitis:

Arthritisofthesacroiliacjoint.

Seton:

Oneormore threadsorhorsehairsora strip of linenintroduced beneath the skin byaknifeorneedletoprovidedrainage.

Smoker:

Someonesmoking at timeofdiagnosis.

Strictureplasty:

Surgicalprocedureforwideningastructuredsegmentofintestinethatinvolvesincisionand closure in opposingdirections.

Undiagnosedocularinflammation:

Wheretherehasbeeneyeinflammation butthepresentation orfindingshavenotbeentypicalorwherethenatureoftheinflammationcannot beclassifiedbased upontheavailableinformation.

Uveitis:

Intraocularinflammation.Diagnosisrequiresdocumentationoftypicalfindings.A slitlampexaminationispreferable.

Niddkibdgeneticsconsortium Phenotypeoperatingmanual Versiondate:May10,2006

TABLEOFCONTENTS

Crohn’sdisease (CD)

UlcerativeColitis(UC)

IndeterminateColitis(IC)

Crohn’sDiseasePhenotypeForm

RegistrationInformation

DemographicandDiagnosticInformation

SmokingHistoryPriortoDiagnosis

Ulcerative/IndeterminateColitis(UC/IC)PhenotypeForm

DemographicandDiagnosticInformation

SmokingHistoryPriortoDiagnosis

UnaffectedPhenotypeFormforcontrols

RegistrationInformation

DemographicInformation