www.RomeCriteria.org1729

Rome III1780

1743N Sartorius, WHO ICD-10, 1994 classification is a way of seeing the world at a point in time. There is no doubt that scientific progress and experiencewith the use of these guidelines will ultimately require their revision and update.A

Vision of Rome FoundationPromote clinical recognition and legitimization of FGIDsDevelop a scientific understanding of the pathophysiological mechanisms to achieve optimum treatment1703

Medline Citations for Irritable Bowel Syndrome1555b# citations

Rome PublicationsGastroenterology International Journal1989199019941999200020061st IBS criteria1992-19955 Rome I publications2003Rome FoundationGastroenterology Supplement+Rome III BookDegnon Assoc.16831st FGID classificationRome I BookLittle BrownRome IIGut SupplementRome II BookDegnon Assoc.

IBSRome Criteria Medline Citations1555a

Rome IIIRationale for Diagnostic Criteria1686

Rome III - Rationale for Symptom Criteria1203Symptoms not explained by abnormal motilitySymptoms defined by multiple factorsMotilityVisceral hypersensitivityInflammation and mucosal immune dysfunctionBrain-gut dysfunctionEpidemiological supportFactor analysis defines symptom-based subgroupsFrequencies similar across populations Treatment implicationsProvides diagnostic standardsFor clinical trials and clinical careModeled after DSM system in psychiatry

FGID - Conceptual ModelPhysiologyMotilitySensationInflammationAltered bacterialfloraFGID Symptoms BehaviorBrainCNSGutENSPsychosocialFactors LIfe stress Psychologic state Coping Social supportEarly Life Genetics EnvironmentOutcome Medications MD visits Daily function Quality of life1035

Rome IIIRationale for Diagnostic CriteriaAdministrative Structure1687

1682Rome Foundation, Inc. 1996Rome Committees14 Committees87 Members18 CountriesIntnl. Resource Committee12 PharmaceuticalsFDA, IFFGD, NIHAdministration2 Committees16 Members4 CountriesGeorge DegnonCarlar BlackmanKathy HaynesWorking Teams6 Committees28 Members7 CountriesCD Committee

Rome IIIRationale for Diagnostic CriteriaAdministrative StructureActivities/Projects1689

Rome III Book August, 2006Gastroenterology 13th Issue April, 2006Reduced Versions of ChaptersNew Working Teams Severity, Brain Imaging, Role of Physiology in FGIDsSponsored Research (Epidemiology, Validation, Spanish Translation of Rome III)Validated Questionnaire with Red FlagsTranslations in numerous languagesWeb site: www.romecriteria.orgCD Slide Set (6 Committees) - 20081690aRome III Activities/Projects

UPDATE SLIDEOutcomes physiology

Rome III Working TeamsGuidelines for Brain Imaging in the FGIDsEmeran Mayer, USA, Chair Qasim Aziz, UK, Co-ChairDouglas Bremner, USAMark Kern, USABrad Kuo, USARichard Lane, USABruce Naliboff, USAIrene Tracey, UKGuidelines for Severity in the FGIDsDouglas A. Drossman, USA, ChairLin Chang, USA, Co-ChairNicholas Bellamy, AustraliaHugo Gallo Torres, FDA, USATony Lembo, USAFermin Mearin, SpainNancy Norton, IFFGD, USAPeter Whorwell, UK1796

Basic Science Jack Wood, USA, ChairLionel Bueno, France John Kellow, AustraliaEpidemiology Fermin Mearin, Spain, ChairGeorge Longstreth, USAPaul Moayyedi, CanadaNick Talley, USADiagnosis and Criteria Arnold Wald, USA, ChairBrooks Cash, USAEnrico Corazziari, ItalyTony Lembo, USAStu Spechler, USAJan Tack, BelgiumRome III CD Committees1797

Psychosocial, HRQOL, Brain Imaging Ami Sperber, Israel, ChairElspeth Guthrie, UKRona Levy, USABruce Naliboff, USAKevin Olden, USAManagement, Treatment Trial Design - William Chey, USA, ChairLin Chang, USAMichel Delvaux, FranceE. Jan Irvine, CanadaW. Grant Thompson, CanadaPediatric Carlo Di Lorenzo, USA, ChairMarc Benninga, NetherlandsErnesto Guiraldes, ChileJeffrey Hyams, USAPaul Hyman, USARome III CD Committees1798

Rome III Rationale for Diagnostic CriteriaAdministrative StructureActivities/ProjectsTimeline for Slide Set Committees1691

Rome III Timeline for CD CommitteesBoard selects Chair/Co-Chairs* October 2005Chairs/Co-Chairs select committees* December 2005Chairs/Co-Chairs conference call December 2005Content Development FebruaryMay 2006Orientation/Process Learning at DDW May 2006Graphic Development I MayDecember 2006CD Committee Meeting I January 2007Graphic Development II January-April 2007CD Committee Meeting II May 2007Graphic Development III May-October 2007Submission to Board and Release January 2008* Criteria: 1) Research record, 2) Intl. recognition, 3) Ability to work in group4) Geographical diversity 1781

Rome III CommitteesRationale for Diagnostic CriteriaAdministrative StructureActivities/ProjectsTimeline for Slide Set CommitteesChapter Structure1693

Rome III Committees Chapter StructureCriteria Related ChaptersIntroductionDiagnostic EntitiesDefinitionEpidemiologyDiagnostic CriteriaJustification for Change in CriteriaClinical EvaluationPhysiological FeaturesPsychological FeaturesTreatmentRecommendations for Future ResearchContent Area ChaptersRevised chapters maintain same structureNew chapter formats created by chair/co-chair1694

Rome III CommitteesRationale for Diagnostic CriteriaAdministrative StructureActivities/ProjectsTimeline for Slide Set CommitteesChapter StructureChanges for Rome III1695

Time Frame: Criteria fulfilled in last 3 months with symptom onset at least 6 months prior to diagnosisClassification Changes: Rumination now a Functional Gastroduodenal Disorder FAPS is a separate Category (not Functional Bowel)Two Pediatric Categories: Neonate/Toddler Child/AdolescentFunctional Dyspepsia De-emphasized for Research Postprandial Distress Syndrome Epigastric Pain SyndromeMore Restrictive Criteria for GB and SO DysfunctionStool Consistency to Identify IBS Subtypes1777Changes for Rome III Classification and Criteria

Rome III Criteria* Irritable Bowel Syndrome

Improvement with defecationRecurrent abdominal pain or discomfort at least 3 days/monthIn the last 3 months associated with 2 or more :Onset associated with a change in frequency of stoolOnset associated with a change in form (appearance) of stoolandandLongstreth GF, Gastroenterology 20061782* Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis.

0255075100%Hard or lumpy stools0255075100% Loose or watery stoolsIBS-UIBS-CIBS-MIBS-DRome III Subtypes of IBS1709

Functional Dyspepsia (B1a)Rome IIIPostprandial Distress Syndrome(B1a)EpigastricPainSyndrome(B1b)1792EPSPDSFD

Diagnostic Criteria* for Functional DyspepsiaRome III* Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis.1793Must include one or more of the following:AndNo evidence of structural disease (including at upper endoscopy) that is likely to explain the symptomsBothersome postprandial fullnessEarlysatiationEpigastricpainEpigastricburningororor

Diagnostic Criteria* forPostprandial Distress SyndromeRome III* Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis.1794Must include one or both of the following:Bothersome postprandial fullnessoccurring after ordinary-sized mealsat least several times a weekEarly satiationthat prevents finishing a regular mealand occurs at least several times a weekor

Diagnostic Criteria* forEpigastric Pain SyndromeMust include all of the following:Rome III* Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis.1795generalized or localized to other abdominal or chest regionsrelieved by defecation or flatulencefulfilling criteria for gallbladder or sphincter of Oddi disordersPain or burning which is:intermittent,localized to the epigastrium of at least moderate severity, at least once per week,and NOT:

Rome IIIDiagnostic Criteria: Must include episodes of pain located in the epigastrium and/or right upper quadrant and ALL of the following:Episodes lasting 30 minutes or longerRecurrent symptoms occurring at different intervals (not daily) Pain:Builds up to a steady levelIs moderate to severe enough to interrupt daily activitiesIs not relieved by:Bowel movementsPostural changeAntacidsOther structural symptoms that could explain symptoms are excludedSupportive Criteria: The pain may present with one or more of:Association with nausea or vomitingRadiates to the back and/or right infra subscapular regionAwakens from sleep in the middle of the night1800Functional Gall Bladder and Sphincter of Oddi Disorders

Rome IIIDiagnostic Criteria: Must include ALL of the following:Functional Gall Bladder DisorderCriteria for functional gallbladder and sphincter of Oddi disorderGallbladder is presentNormal liver enzymes, conjugated bilirubin, and amylase/lipase

1801

Diagnostic Criteria: Must include BOTH of the following:Criteria for functional gallbladder and sphincter of Oddi disorderNormal amylase/lipase

Functional Biliary Sphincter of Oddi DisorderRome III1802Supportive Criterion:Elevated serum transaminases, alkaline phosphatase, or conjugated bilirubin temporarily related to at least two pain episodesDiagnostic Criteria: Must include BOTH of the following:Functional Pancreatic Sphincter of Oddi DisorderCriteria for functional gallbladder and sphincter of Oddi disorderAbnormal amylase/lipase

Rome III CommitteesRationale for Diagnostic CriteriaAdministrative StructureActivities/ProjectsTimeline for CommitteesChapter StructureChanges for Rome IIIIssues and Limitations1698

Rome III Committees Issues and LimitationsCriteria Not Fully Evidence BasedLimited data for most functional GI disorders Original criteria by consensusChanges based on new evidenceNew changes need validation The Field is Expanding and GrowingInformation not set in stoneKnowledge can quickly become outdated Classifications will change e.g., OrganificationNeed for Quality ControlDisclosure of relationships with PharmaceuticalsConfidentiality statementsInternational Resource CommitteeEmbargo on information until final editing stages

1778

Future Issues for Rome FoundationGlobal educational programsSupport for validation studiesPartner with regulatory agenciesWorking team initiativesMechanism for research supportDiversification in structure

1703

Whats new?Functional dyspepsiaDyspepsia as previously defined unhelpfulDe-emphasize functional dyspepsiaNew syndromes suggested for research: PDS and EPSNausea and vomitingTwo new syndromes (CIN and CVS)

Definition of Dyspepsia

Pain or discomfort centered in the upper abdomenRome Working Teams I and II Talley et al. Gut 1999;45:II37-42Rome III discards this definition

Functional Dyspepsia: Rationale for Changes from Rome II No single symptom present in all patients with functional dyspepsiaConsiderable variation in symptom pattern between patients Despite Rome II recommendations, studies still include heartburn and acid regurgitation as dyspepsia11Armstrong et al. Can J Gastroenterol 2002; 16; 439-50 Peura et al. Am J Med 2004; 116: 740-8 Moayyedi et al. Gastroenterology 2004; 127: 1329-37

Dyspepsia Usually Polysymptomatic99% >2; > 80% >5; < 0.1% 1 symptomAliment Pharmacol Ther. 2003;17:1481-91

Functional Dyspepsia (FD): Rome II12 weeks (within 12 months) of persistent or recurrent dyspepsia (pain or discomfort centered in upper abdomen)No evidence of organic disease likely to explain symptoms (including EGD)Not irritable bowel syndrome (IBS)Subgroups (ulcer-like, dysmotility-like) based on predominant symptomTalley et al. Gut 1999;45(Suppl. 1):I2831

Subdividing FD by Predominant SymptomKaramanolis et al. Gastroenterology 2006; 130:296-303 Prevalence (% of patients)n = 720; 489 women; mean age, 41 05101520253035404550Delayed solidemptyingDelayed liquidemptyingHypersensitivityto gastricdistentionImpairedaccommodationH. pyloriinfection Predominant discomfort (n=562)Predominant pain (n=158)** GE Delay Hypersens

Sens 85% 33%

Spec 25% 44%

Unexplained pain or discomfort centered in upper abdomen (Rome II FD)De-emphasize FDNot one disorderLack of evidence for the predominant symptom as criterionSupport from factor analysis in tertiary care and in general populationExpert opinion

Functional DyspepsiaRome III functional dyspepsiaEPSPDSFD

Functional DyspepsiaRome IIIPostprandial Distress Syndrome

EpigastricPainSyndrome

EPSPDSFD FD retained for clinical practice PDS and EPS proposed for research based on factor analysis and expert opinion

Diagnostic Criteria* forPostprandial Distress Syndrome (PDS)* Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis.Must include one or both of the following:Bothersome postprandial fullnessoccurring after ordinary-sized mealsat least several times a weekEarly satiationthat prevents finishing a regular mealand occurs at least several times a weekorRome III

Factor Analysis Supports EPS and PDS45% of the U.S. population report upperGI symptomsTelephone survey of 21,128 adults Camilleri et al. Clin Gastroenterol Hepatol. 2005;3:543-52

Factor analyses in populations and referral practice All found a meal related factor

Study

Population

n

Result

Westbrook 2002

Population sample

2300

3 dyspeptic symptom factors

Fischler 2003

Tertiary care

438

4 dyspeptic symptom factors

Jones 2003

Population sample

888

3 dyspeptic symptom factors

Kwan 2003

Tertiary care

1012

3 dyspeptic symptom factors

Whitehead 2003

Tertiary care

1041

4 dyspeptic symptom factors

Camilleri 2005

Population sample

21128

3 dyspeptic symptom factors

Piessevaux submitted

Population sample

2025

3 or 4 dyspeptic symptom factors

Tack in preparation

Tertiary care

638

3 dyspeptic symptom factors

Diagnostic Criteria* forEpigastric Pain Syndrome (EPS)Must include all of the following:* Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis.Pain or burning which is:Intermittent,Localized to the epigastrium of at least moderate severity, at least once per week,and NOT:Rome IIIgeneralized or localized to other abdominal or chest regionsrelieved by defecation or flatulencefulfilling criteria for gallbladder or sphincter of Oddi disorders

Distinct Dyspepsia Subgroups: New Data EPS 135 (39%)CIN n=37 (11%)PDS (early satiety)114 (32%)25 (7%)16 (5%)9 (3%)7 (2%)Comparison of overlap of subgroups between observed and expected * Assuming the subgroups were independent Choung et al. DDW 2006Olmsted County population data

Rome IIIOverlap with GERD

Heartburn does not exclude a diagnosis of FD (PDS or EPS)if dyspepsia persists despite a trial of adequate acid suppression

Evidence: expert opinion

Rome IIIOverlap with IBS

Coexisting IBS no major impact on symptom pattern or putative pathophysiological mechanisms Corsetti et al. Am J Gastroenterol. 2004;99:1152-9 ** P

Nausea and VomitingCyclic vomiting syndrome (CVS) now a recognized syndrome in adultsAJG 2001; 96: 684-8

Rome III

Cyclic vomiting syndrome (CVS)At least 3 months, with onset at least 6 month previously, of:Stereotypical episodes of vomiting regarding onset (acute) and duration (less than one week)3 or more discrete episodes in the prior yearAbsence of nausea and vomiting between episodes

Supportive criteria: History of migraine headaches or a family history of migraine headaches

Rome III

Chronic idiopathic nausea (CIN)Separate from FD (factor analyses)

Bothersome nausea, occurring at least several times per week in the last 3 months

Not usually associated with vomiting

Absence of abnormalities at upper endoscopy or metabolic disease that explains the nausea

Rome III: Whats new?Functional dyspepsiaDyspepsia as previously defined unhelpful: focus on early satiation and/or postprandial fullness and/or epigastric painDe-emphasize functional dyspepsiaNew syndromes suggested for research: PDS and EPSNausea and vomitingTwo new syndromes (CIN and CVS)

Functional Bowel DisordersIrritable Bowel SyndromeFunctional BloatingFunctional ConstipationFunctional DiarrheaUnspecified Functional Bowel Disease

Introduction of a frequency threshold of 3 days/ month over 3 months for symptoms Reduction of the duration of symptoms before one can make firm diagnosis from 12 to 6 months Refining of subtypesMain Changes in IBS Criteria

Rome II Diagnostic criteria for IBSAt least 12weeks, which need not be consecutive, in the preceding 12months of abdominal discomfort or pain that has two of three features: Relieved with defecation; and/orOnset associated with a change in frequency of stool; and/or Onset associated with a change in form (appearance) of stool.Thompson et al Gut 1999;45 Suppl 2:II43-II47

Rome III Diagnostic Criteria for IBS*Recurrent abdominal pain or discomfort 3 days per month in the last three monthsassociated with two or more of the followingImprovement with defecation; and/orOnset associated with a change in frequency of stool; and/orOnset associated with a change in form (appearance) of stool* Criteria fulfilled for the last 3 months with symptom onset 6 months prior to diagnosis

Subclassifying IBSWhy bother?Important for choosing therapies which alter bowel habitSubtypes likely to have different pathophysiologyTransitStool consistencyRectal sensitivity?

Previous Features Used to Subclassify IBS PatientsDiarrhea-predominant 1 or more of 2,4,or 6and none of 1,3,or 5(or 2 of 2, 4 or 6 and 1 of 1 or 5 but not 3)Constipation-predominant 1 or more of 1,3,or 5and none of 2,4,or 6 (or 2 of 1, 3 or 5 and 1 of 2, 4 or 6)1.Fewer than three bowel movements a week 2.More than three bowel movements a day 3.Hard or lumpy stools4.Loose (mushy) or watery stools 5.Straining during a bowel movement 6.Urgency (having to rush to have a bowel movement)

Problems With Old SystemComplex to apply and caused confusion in both patients and clinicians!Multidimensional but different dimensions dont correlate wellFailed to deal adequately with patients with both hard and loose stools

IBS Patients with Features of Both Constipation and Diarrhea are Common

Rome III subtyping is based on Stool Consistency aloneAssessed from stool form

Defining Stool ConsistencyBristol Stool Form ScaleHard NormalLoose

Why Stool Consistency as Main Determinant of Subtype?Correlates best with colonic transit

Colonic Transit & Stool FormColonic transittime (hours)Bristol stool form score123456780400O'Donnell et al Br Med J 1990;300:439-40

Why Stool Consistency as Main Determinant of Subtype?Correlates best with colonic transitCorrelates best with what patients and community samples think of as diarrhoea Principle determinant of incontinenceOther features occur in IBS with both loose & hard stoolsStool frequency 3/dayUrgency, Sense of incomplete evacuation

Association of bowel symptoms with stool consistencyTillisch et al Am J Gastroenterol. 2005; 100:896-904

Proposed New Subtyping Based on Stool Consistency AloneIBS with constipation - IBS-CIBS with diarrhoea - IBS-DIBS mixed type - IBS-M(IBS unsubtyped - IBS-U)

IBS-mixed : patients with both hard & loose stools over periods of hours or days

Alternating IBS Patients who change subtype over periods of weeks and months

Rome III Subtypes of IBS02550751000255075100IBS-MIBS-DIBS-CIBS-U%Loose or Watery Stools% Hard or Lumpy Stools

Quantifying Stool FormPain: grade 0-10 0= absent 5=moderate 10 very severeStool form1= separate hard lumps, like nuts6 = fluffy pieces with ragged edges2= sausage shaped but lumpy 7 = watery, no solid pieces 3= like a sausage or snake, but with cracks on its surface4= like a sausage or snake, smooth and soft5= soft blobs with clear cut edges

Changes to IBS classificationRome III SummaryNo change to basic criteriaLength of time needed to define chronicity reduced to 6 monthsThreshold 3 days / month introduced for frequency of pain / discomfortSubtyping simplified (stool consistency)Stability of subtypes and link to other features like visceral sensitivity and response to treatment remain to be determined

FUNCTIONAL GALLBLADDER AND SPHINCTER OF ODDI DISORDERS

NOT EXPLAINED BY STRUCTURAL ABNORMALITIESMotility abnormalities of the Gallbladder, the Biliary, and Pancreatic Sphincter of Oddi

DIAGNOSTIC CRITERIA FOR FUNCTIONAL GALLBLADDER AND SPHINCTER OF ODDI DISORDERSPain located in the epigastrium and/or right upper quadrant

Recurrent symptoms occurring at different intervals (not daily)Episodes lasting 30 minutes or longer The pain builds up to a steady levelThe pain is moderate to severe enough to interrupt the patients daily activities or lead to an emergency department visitNot Relieved by Bowel Movements Postural Change Antacids Supportive Criteria The pain may present with one or more of the following: Associated with nausea and vomiting Radiates to the back and/or right infra subscapular regionAwakens from sleep in the middle of the nightEVIDENCE : CONSENSUS

Structural alterationsROME III ALGORITHM FOR FUNCTIONAL GB DISORDERSDiagnostic criteria for functional GB and SO disorders LFTs/pancreatic, enzyme, USEsophagogastroduodenoscopyNormal findingsAppropriate investigation andtreatmentCholecystectomyReassessEVIDENCE C

Structural alterations explaining the symptomsROME III ALGORITHM FOR FUNCTIONAL BILIARY SO DISORDERS CholecystectomizedDiagnostic criteria for functional GB and SO disordersLFTs/pancreatic enzymes, USEsophagogastroduodenoscopyEUS, MRCPAppropriate Investigation and treatmentBiliaryType IBiliaryType IIBiliaryType III Pain andOne or two of type I criteria Pain andNone of the type I criteria Milwaukee Classification Pain and LFTs in 2 occasions andAt ERCP Dilated CBD >12mm and Delayed contrast drainageMilwaukee Classification Revised Pain and LFTs in 2 occasions andAT US Dilated CBD >8mm EVIDENCE : CONSENSUS

Structural alterations explaining the symptomsROME III ALGORITHM FOR FUNCTIONAL BILIARY SO DISORDERSCholecystectomizedDiagnostic criteria for functional GB and SO disorders LFTs/pancreatic enzymes, USEsophagogastroduodenoscopyEUS, MRCPAppropriate Investigation and treatmentBiliaryType IIESBiliaryType IIIESReassessesEVIDENCE: B

Structural alterations explaining the symptomsROME III ALGORITHM FOR FUNCTIONAL BILIARY SO DISORDERSCholecystectomizedDiagnostic criteria for functional GB and SO disorders LFTs/pancreatic enzymes, USEsophagogastroduodenoscopyEUS, MRCPAppropriate Investigation and treatmentBiliaryType IIBiliaryType IESReassessesEVIDENCE: C

ROME III ALGORITHM FOR FUNCTIONAL BILIARY SO DISORDERSAppropriate Investigation and treatmentESBILI[CHOLEDOCHO]SCINTIGRAPHYEVIDENCE B

ROME III ALGORITHM FOR FUNCTIONAL PANCREATIC SO DISORDERSEVIDENCE BSphincterotomyReassess

Functional EsophagealFunctionalBilliaryFunctionalAnorectalFunctionalGastroduodenalIBS & Functional Bowel

Rationale for Changing to Ordinal Scales to Measure Symptom FrequencyRome II questionnaire applied the same frequency threshold to all symptomsSome symptoms are not clinically meaningful unless they occur daily while others are significant if they occur at allRome II questions were difficult to understand because they incorporated multiple frequency thresholdsScales for judging relative severity would be useful

Goals of the Questionnaire Development and Validation ProcessDevelop a questionnaire that incorporates the Rome III criteria as an aid to diagnosisInsure that questions are understandableValidate the questionnaire & the criteria by comparing to diagnoses made by clinicians

Study ICompare 4 Alternative Response ScalesSubjects 120 healthy controls & 84 FGIDDesign: 4 versions of the questionnaire were completed in counterbalanced orderBinary: No or rarely vs. oftenSpecific Frequency: Monthly, weekly, dailyRelative Frequency: Occasionally, often, alwaysBothersome: A little bit, moderately, quite a bit

Subjects are Inconsistent in How They Use the Binary Response ScaleFrequency of Abdominal Pain or Discomfort

Principal Findings of Study I For intermediate symptom frequencies, ordinal scales are more reliable Specific Frequency Scales give the best balance between sensitivity & specificity but Relative Frequency Scales perform almost as wellBothersome Scale performs similar to Relative Frequency Scale but is not appropriate to some symptoms

Two Scales Selected for Rome IIISpecific Frequency ScaleNeverLess than 1 day a monthOne day a monthOne day a weekMore than 1 day a weekEvery dayRelative Frequency ScaleNever or rarelySometimesOftenMost of the timeAlways

Questionnaire DevelopmentRome board suggested initial questionsWorking teams provided additional itemsQuestionnaire Committee met for 2 days to insure that the questions matched the diagnostic criteriaData from the validation study were referred back to the Rome board & working teams for revisions to criteria & thresholds

Sample QuestionIn the last 3 months, how often did you have discomfort or pain anywhere in your abdomen?Never Less than 1 day a monthOne day a monthTwo to three days a monthOne day a weekMore than one day a weekEvery day

Study II: Validation StudySubjects554 healthy controls (75% participation)399 FGIDs (66% participation)328 IBS, 27 constipation, 10 FD, 32 miscellaneousThere were 4 study sites: UNC, Mayo Clinic, University of Michigan, & University of TorontoTest retest agreement on diagnosis assessed in 53 controls & 51 patients over 2 weeks

Understandability18 of 77 questions were rated difficult to understand by 1% or more of subjects4 questions were rated difficult by 2%All but one of these 18 questions were revisedNo revision for, In the last 3 months, how often did you feel uncomfortably full after a regular sized meal. (Rated difficult by 1.2%)

Selecting Frequency Thresholds so ThatLess Than 10% of Controls are AbnormalFrequency of Abdominal Pain or Discomfort

Frequency of Abdominal Pain or DiscomfortSelecting Frequency Thresholds so That Less Than 10% of Controls are Abnormal

Effects of Different Thresholdson Sensitivity & Specificity 539 healthy controls & 326 IBS patients Abdominal painSensitivity SpecificityFrequency thresholdof IBS Dx of IBS Dx

Specificity: Percent of Healthy Controls Who Would be Misclassified

Reliability: Test-Retest Agreement Over a 2-Week Interval

SpecificityTest-Retest AgreementIBS87.8%81.7%Constipation96.5%93.3%Diarrhea99.1%96.2%Functional dyspepsia94.1%84.6% Postprandial distress99.3%85.6% Epigastric pain100%98.1% Chronic idiopathic nausea99.1%96.2%

ConclusionsA major innovation of Rome III is ordinal scale with individual frequency thresholdsRome III diagnostic questionnaire is reliable:Questions reflect the criteria & are understandableTest-retest reliability is excellentSpecificity of diagnostic criteria is excellent

Application of Diagnostic CriteriaConsensus derived criteria

Questionnaire

Validation

Published trial and survey data

Can it be applied to my patient?

To Interpret Data Obtained UsingRome III Questionnaire, I Must Consider:Was the questionnaire altered?What was the purpose of the study?How was the study population selected?Can the data (evidence) from that trial or survey be applied to my patient?

1. Was the Questionnaire Altered?Questions how were they asked?

Also, algorithms, inclusions and exclusionsDetermined by consensus, existing dataTo suit their study, investigators may adjust:Time requisite (acute vs. chronic)Cut-off levels for inclusionExclusions

Frequency Scale Cut-offsHow often in last 3 months did you have pain?a. Neverb. Once a month or lessc. Two to three times/month

d. Once a weeke. Several times a weekf. Every day

Cut-offs determine who is included!1. (cont) Was the questionnaire altered?

Rome III

Frequency Scale Cut-offsHow often in last 3 months did you have pain?a. Neverb. Once a month or less

c. Two to three times/monthd. Once a weeke. Several times a weekf. Every day

Cut-offs determine who is included!1. (cont) Was the questionnaire altered?

Survey

Frequency Scale Cut-offsHow often in last 3 months did you have pain?a. Neverb. Once a month or lessc. Two to three times/monthd. Once a weeke. Several times a weekf. Every day

Cut-offs determine who is included!1. (cont) Was the questionnaire altered?

Clinical trial

ExclusionsQ8. ..did you often have heartburn..?Q9. ..did you .. have difficulty swallowing..?

Rome II coding:Functional heartburn; Q8=yes, and no to dysphagiaFunctional dysphagia; Q9=yes, and no to heartburn

If yes to both, neither disorder exists because, according to the coding, one excludes the other.Data not applicable to excluded patients.1. (cont) Was the questionnaire altered?

2. What was the Purpose of the Study?To aid diagnosis

To select subjects for clinical research

To survey populations

2. What was the Purpose of the Study?To aid diagnosisSeverity/frequency relevantInclusiveSymptoms nowTo select subjects for clinical researchSeverity/frequency more relevantExclusiveSymptoms nowTo survey populationsSeverity/frequency less importantInclusiveSymptoms ever, or during defined period

3. How was the Study Population Selected?Were Rome III criteria used?How were subjects recruited (adverts, tertiary care, CROs)?Were there investigator adjustments (e.g. time requirement, cut-offs, exclusions)?

4. Can Data from a Trial or Survey be Applied to my Patient?Does my patient fulfill the same criteria?Is he or she similar to the study population?Do the time requisites, scales, and exclusions used in the study exclude my patient?In a trial where placebo effect>therapeutic gain, will my patient realize a similar placebo effect?

Summary: When Applying Results of a Study where the Rome Criteria were Used, Ask:How were criteria translated into questions: Time requirement, cut-offs, and exclusions?Were there unique adjustments for:Clinical Trial?- severe cases nowEpidemiological survey?- include all casesClinical Practice?- precisionDoes my local population or my patient resemble the studys population?Will my management help my patient achieve as great a placebo effect as those in the study?

Use of the Rome CriteriaClinicalTrialsClinicalResearchClinicalPractice

Existing TrialsExpert PanelsRegulatory AuthoritiesExisting TrialsImproved methodologyMeta-analysesNegative trials?Regulatory AuthoritiesEMEA PTC 2003FDA AdvicesExpert PanelsDefinition of a Responder, Vienna 1998European Panel, APT 2003Rome I, Rome II

Challenges for FGIDs clinical trialsNatural course of the conditionUnstable symptom patternFluctuating intensityMulticomponent pathophysiologyMultiple therapeutic targetsMultiple endpointsBias of outcome measuresHigh placebo responseDifficulty to maintain double maskingContamination by parallel interventionsLack of placebo control for some interventionsPsychotherapy, hypnotherapy, sphincterotomyAvoiding harmFGID non-life-threatening

Definition of the Studied PopulationCompromise between the largest target in the population and a strictly homogenous group Clearly define the FGID to be treatedDefine subgroupsTransit abnormalitiesExplicit inclusion/exclusion criteriaGenderSymptoms intensityComorbiditiesTreatment exclusions

The Standard Trial DesignSuperiority trialThe most robust design: parallel groups, randomized allocation, double blindSingle interventionPlacebo-controlled

Percentage of respondersWeeks02040600246810121416**********TreatmentFollow-up*******p < 0.001*p < 0.058070503010Camilleri et al. Lancet 2000; 355: 1035-1040.010203040506070-213579111315TegaserodPlaceboFollow-upRun-inNovick et al. APT 2002; 16:1877-1888.

From Rome II to Rome IIIUnsolved issues with standard designDuration of the treatment intervention4 weeks versus 12 weeksLonger treatments: 6 monthsOutcome measures

Alternative trial designsOn-demand or Pro Re Nata (PRN) treatmentsTreatment Re-treatment design

Treatment Re-treatmentPlaceboActive DrugRNRActive DrugEMEA PTC 2003PlaceboNRRNo symptomSymptoms +Active DrugPlaceboActive DrugNRCarry-overUnblinding of the interventionEnrichment in respondersNatural cycle of symptomsEthical considerations

Tack et al. Gut 2005; 54: 1707-1713

Definition of Outcome MeasuresPrimary outcomeGlobal assessmentAdequate reliefDefinition of a responderSymptom questionnairePain assessmentSecondary outcomesMechanism of interventionSymptoms influenced by a specific pharmacodynamic effectQuality of lifeHealth economics

Tolerance and safety

Definition of a ResponderSomewhatCompletelyMarkedlySymptom Relief25 %75 %50 %100 %Time

ConclusionRome criteria have driven significant methodological advances over the last two decades for the design of FGIDs clinical trials.

Alternative designs need to be further explored but should not replace standard comparative trials.

Outcome measures and definition of a responder are critical issues influencing the clinical relevance of the results.

Slide 1502: New Issues for Rome IIIMODIFY MODIFYMODIFYSlide 1502: New Issues for Rome IIITime of 12 months designed to avoid giving a chronic disease label to transient symptoms eg due to infection etc Reduced time needed to establish chronicity to 6 months unlikely that new diagnosis will emerge or that symptoms will disappear if have lasted 6 months Better and faster investigations mean that other diagnoses are rapidly eliminatedThreshold of >3 days per month based on ? Designed to exclude trivial complaints 3/ month

Problems that many patients have both features to some extent end up being excluded from either diagnosisFurther using multiple dimensions Further recognised that straining can often be present even when stool is loose and frequency correlates poorly with other parameters determined by many factors including social and psychological factorsEvidence that mixed pattern is quite commonAlso that stool consistency is most important concern since it relates to urgency This is an important group as hsown in the next slideMearin used slightly different criteria requiring subjects ot have 1 of three rome II criteria to qualify for any one categoryTilisch figures are clasified by stool consistencyNot all figures add up to 100% since around 5% were not classified into given categoriesAs is shown on the next slideChange sequence to emphasise they are part of IBS spectrum share many features particularly the central ones but differ with respect to bowel patternPrefer mixed to alternators If use Tillisch recent data then get following distribution