www.RomeCriteria.

org

1729

Rome III

1780

A classification is a way of seeing the

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

1743

Vision of Rome Foundation

Promote clinical recognition and
legitimization of FGIDs
Develop a scientific understanding of
the pathophysiological mechanisms
to achieve optimum treatment

1703

Medline Citations for Irritable Bowel Syndrome

700
600
500
400
#
citations
300
200
100
0
1963 1967 1971 1975 1979 1983 1987 1991 1995 1999 2003
1555b

Rome Publications

1 FGID
classification
st

1st IBS
criteria

1989

1990

Gastroenterology
International
Journal

1992-1995
5 Rome I
publications

2003
Rome
Foundation

2006

Gastroenterology
2000
Supplement
1999
+
1994
Rome II Rome II Book
Rome III Book
Gut
Degnon Assoc.
Rome I Book
Degnon Assoc.
Little Brown Supplement

1683

IBS

Rome Criteria Medline Citations

105
100
90
80
70
60

#
50
citations
40
30
20
10
0

1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

Year

1555a

Rome III

Rationale for Diagnostic Criteria

1686

Rome III - Rationale for Symptom Criteria

Symptoms not explained by abnormal motility

Symptoms defined by multiple factors

Motility
Visceral hypersensitivity
Inflammation and mucosal immune dysfunction
Brain-gut dysfunction

Epidemiological support

Factor analysis defines symptom-based subgroups

Frequencies similar across populations

Treatment implications
Provides diagnostic standards

For clinical trials and clinical care

Modeled after DSM system in psychiatry

1203

FGID - Conceptual Model

Early Life
Genetics
Environment

Psychosocial
Factors
LIfe stress
Psychologic state
Coping
Social support

Brain
CNS

Gut
ENS

Physiology
Motility
Sensation
Inflammation
Altered bacterial
flora

FGID

Symptoms
Behavior

Outcome
Medications
MD visits
Daily function
Quality of life
1035

Rome III

Rationale for Diagnostic Criteria

Administrative Structure

1687

Rome Foundation,

Inc. 1996

Board of Directors

D. Drossman (President)
E. Corazziari
M. Delvaux
R. Spiller
J. Kellow

Italy
France
UK
Australia

USA

N. Talley
W.G. Thompson
W. Whitehead
L. Chang

USA
Canada
USA
USA

Administration
George Degnon
Carlar Blackman
Kathy Haynes
Rome Committees

Working Teams

CD Committee

14 Committees
87 Members
18 Countries

2 Committees
16 Members
4 Countries

6 Committees
28 Members
7 Countries

Intnl. Resource
Committee
12 Pharmaceuticals
FDA, IFFGD, NIH
1682

Rome III

Rationale for Diagnostic Criteria

Administrative Structure
Activities/Projects

1689

Rome III Activities/Projects

Rome III Book August, 2006

Gastroenterology 13th Issue April, 2006
Reduced Versions of Chapters
New Working Teams
Severity,
Brain Imaging,
Role of Physiology in FGIDs

Sponsored Research (Epidemiology, Validation,

Spanish Translation of Rome III)
Validated Questionnaire with Red Flags
Translations in numerous languages
Web site: www.romecriteria.org
CD Slide Set (6 Committees) - 2008

1690a

 UPDATE SLIDE
Outcomes
physiology

Rome III Working Teams

Guidelines for Brain Imaging in the FGIDs

Emeran Mayer, USA, Chair
Qasim Aziz, UK, Co-Chair
Douglas Bremner, USA
Mark Kern, USA
Brad Kuo, USA
Richard Lane, USA
Bruce Naliboff, USA
Irene Tracey, UK

Guidelines for Severity in the FGIDs

Douglas A. Drossman, USA, Chair
Lin Chang, USA, Co-Chair
Nicholas Bellamy, Australia
Hugo Gallo Torres, FDA, USA
Tony Lembo, USA
Fermin Mearin, Spain
Nancy Norton, IFFGD, USA
Peter Whorwell, UK

1796

Rome III CD Committees

Basic Science Jack Wood, USA, Chair

Lionel Bueno, France
John Kellow, Australia

Epidemiology Fermin Mearin, Spain, Chair

George Longstreth, USA
Paul Moayyedi, Canada
Nick Talley, USA

Diagnosis and Criteria Arnold Wald, USA, Chair

Brooks Cash, USA
Enrico Corazziari, Italy
Tony Lembo, USA
Stu Spechler, USA
Jan Tack, Belgium

1797

Rome III CD Committees

Psychosocial, HRQOL, Brain Imaging Ami Sperber, Israel, Chair

Elspeth Guthrie, UK
Rona Levy, USA
Bruce Naliboff, USA
Kevin Olden, USA
Management, Treatment Trial Design - William Chey, USA, Chair
Lin Chang, USA
Michel Delvaux, France
E. Jan Irvine, Canada
W. Grant Thompson, Canada
Pediatric Carlo Di Lorenzo, USA, Chair
Marc Benninga, Netherlands
Ernesto Guiraldes, Chile
Jeffrey Hyams, USA
Paul Hyman, USA

1798

Rome III

Rationale for Diagnostic Criteria

Administrative Structure
Activities/Projects
Timeline for Slide Set Committees

1691

Rome III Timeline for CD Committees

Board selects Chair/Co-Chairs* October 2005

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

1781

Rome III Committees

Rationale for Diagnostic Criteria

Administrative Structure
Activities/Projects
Timeline for Slide Set Committees
Chapter Structure

1693

Rome III Committees Chapter Structure

Criteria Related Chapters

Introduction
Diagnostic Entities
Definition
Epidemiology
Diagnostic Criteria
Justification for Change in Criteria
Clinical Evaluation
Physiological Features
Psychological Features
Treatment
Recommendations for Future Research

Content Area Chapters

Revised chapters maintain same structure

New chapter formats created by chair/co-chair
1694

Rome III Committees

Rationale for Diagnostic Criteria

Administrative Structure
Activities/Projects
Timeline for Slide Set Committees
Chapter Structure
Changes for Rome III

1695

Changes for Rome III Classification and Criteria

Time Frame: Criteria fulfilled in last 3 months with symptom

onset at least 6 months prior to diagnosis

Classification Changes:
Rumination now a Functional Gastroduodenal Disorder
FAPS is a separate Category (not Functional Bowel)

Two Pediatric Categories:

Neonate/Toddler
Child/Adolescent

Functional Dyspepsia De-emphasized for Research

Postprandial Distress Syndrome
Epigastric Pain Syndrome

More Restrictive Criteria for GB and SO Dysfunction

Stool Consistency to Identify IBS Subtypes
1777

Rome III Criteria*

Irritable Bowel Syndrome
Recurrent abdominal pain or discomfort at least 3 days/month
In the last 3 months associated with 2 or more :

Improvement
with
defecation

and

Onset
associated with
a change in
frequency of
stool

and

Onset
associated with
a change in
form
(appearance) of
stool

* Criteria fulfilled for the last 3 months with symptom onset at least
6 months prior to diagnosis.
Longstreth GF, Gastroenterology 2006

1782

Rome III Subtypes of IBS

100

75

%
Hard or lumpy 50
stools
IBS-C

IBS-M

IBS-U

IBS-D

25

0
0

25

50

75

100

% Loose or watery stools

1709

Rome III

Functional Dyspepsia (B1a)

FD

Postprandial
Distress
Syndrome
(B1a)

PDS

EPS

Epigastric
Pain
Syndrome
(B1b)

1792

Rome III

Diagnostic Criteria* for Functional Dyspepsia

Must include one or more of the following:
Bothersome
postprandial
fullness

or

Early
satiation

or

Epigastric
pain

or

Epigastric
burning

And

No evidence of structural disease (including

at upper endoscopy) that is likely to explain
the symptoms

* Criteria fulfilled for the last 3 months with symptom onset at least
6 months prior to diagnosis.

1793

Rome III

Diagnostic Criteria* for

Postprandial Distress Syndrome
Must include one or both of the following:
Bothersome
postprandial fullness
occurring after
ordinary-sized meals
at least several times
a week

or

Early satiation
that prevents finishing
a regular meal
and occurs at least
several times a week

* Criteria fulfilled for the last 3 months with symptom onset at least
6 months prior to diagnosis.

1794

Rome III

Diagnostic Criteria* for

Epigastric Pain Syndrome
Must include all of the following:

Pain or burning which is:

intermittent,
localized to the epigastrium of at least moderate severity,
at least once per week,
and NOT: generalized or
relieved by
fulfilling
localized to
other
abdominal or
chest regions

defecation or
flatulence

criteria for
gallbladder or
sphincter of
Oddi disorders

* Criteria fulfilled for the last 3 months with symptom onset at least
6 months prior to diagnosis.

1795

Rome III

Functional Gall Bladder and Sphincter of Oddi Disorders

Diagnostic 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 longer
Recurrent symptoms occurring at different intervals (not daily)
Pain:
Builds up to a steady level
Is moderate to severe enough to interrupt daily activities
Is not relieved by:
Bowel movements
Postural change
Antacids
Other structural symptoms that could explain symptoms are
excluded

Supportive Criteria: The pain may present with one or more of:
Association with nausea or vomiting
Radiates to the back and/or right infra subscapular region
Awakens from sleep in the middle of the night

1800

Rome III

Functional Gall Bladder Disorder

Diagnostic Criteria: Must include ALL of the following:
Criteria for
functional
gallbladder and
sphincter of
Oddi disorder

Gallbladder
is present

Normal liver
enzymes,
conjugated
bilirubin, and
amylase/lipase

1801

Rome III

Functional Biliary Sphincter of Oddi Disorder

Diagnostic Criteria: Must include BOTH of the following:
Criteria for
functional
gallbladder and
sphincter of Oddi
disorder

Normal
amylase/lipase

Supportive Criterion:

Elevated serum transaminases, alkaline phosphatase, or conjugated

bilirubin temporarily related to at least two pain episodes

Functional Pancreatic Sphincter of Oddi Disorder

Diagnostic Criteria: Must include BOTH of the following:
Criteria for
functional
gallbladder and
sphincter of Oddi
disorder

Abnormal
amylase/lipase

1802

Rome III Committees

Rationale for Diagnostic Criteria

Administrative Structure
Activities/Projects
Timeline for Committees
Chapter Structure
Changes for Rome III
Issues and Limitations

1698

Rome III Committees Issues and Limitations

Criteria Not Fully Evidence Based

Limited data for most functional GI disorders

Original criteria by consensus
Changes based on new evidence
New changes need validation

The Field is Expanding and Growing

Information not set in stone

Knowledge can quickly become outdated
Classifications will change e.g., Organification

Need for Quality Control

Disclosure of relationships with Pharmaceuticals

Confidentiality statements
International Resource Committee
Embargo on information until final editing stages
1778

Future Issues for Rome Foundation

Global educational programs
Support for validation studies
Partner with regulatory agencies
Working team initiatives
Mechanism for research support
Diversification in structure
1703

Whats new?
Functional dyspepsia
Dyspepsia as previously defined unhelpful
De-emphasize functional dyspepsia
New syndromes suggested for research: PDS and EPS

Nausea and vomiting

Two new syndromes (CIN and CVS)

Definition of Dyspepsia
Pain or discomfort centered in the
upper abdomen
Rome Working Teams I and II

Rome III discards this definition

Talley et al. Gut 1999;45:II37-42

Functional Dyspepsia: Rationale for

Changes from Rome II
No single symptom present in all patients with functional
dyspepsia
Considerable variation in symptom pattern between patients
Despite Rome II recommendations, studies still include heartburn
and acid regurgitation as
dyspepsia1

Armstrong 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 Polysymptomatic

Aliment Pharmacol Ther. 2003;17:1481-91

99% >2; > 80% >5; < 0.1% 1 symptom

Functional Dyspepsia (FD): Rome II

12 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
symptom
Talley et al. Gut 1999;45(Suppl. 1):I2831

Subdividing FD by Predominant Symptom

50

GE Delay

n = 720; 489 women; mean age, 41

*

45
40
Prevalence (% of
patients)

35
30
25

Hypersens

Sens

85%

33%

Spec

25%

44%

20
15
10
5
Predominant discomfort (n=562)

0
Delayed solid

Delayed liquid

Hypersensitivity

Impaired

H. pylori

emptying

emptying

to gastric

accommodation

infection

distention

Karamanolis et al. Gastroenterology 2006; 130:296-303

Predominant pain (n=158)

Unexplained pain or discomfort centered in upper

abdomen (Rome II FD)
Not one disorder
Lack of evidence for the
predominant symptom as
criterion
Support from factor analysis in
tertiary care and in general
population
Expert opinion

De-emphasize FD

Functional Dyspepsia
FD

PDS

EPS

Rome III functional dyspepsia

Bothersome
postprandial
fullness

or

Early
satiation

or

Epigastric
pain

or

Epigastric
burning

Functional Dyspepsia
FD
Postprandial
Distress
Syndrome

PDS

EPS

Epigastric
Pain
Syndrome

Rome III

FD retained for clinical practice

PDS and EPS proposed for research based on
factor analysis and expert opinion

Rome III

Diagnostic Criteria* for

Postprandial Distress Syndrome (PDS)
Must include one or both of the following:

Bothersome
postprandial fullness

or

that prevents finishing a

occurring after
ordinary-sized meals
at least several times
week

Early satiation
regular meal

and occurs at least

several times a week

* Criteria fulfilled for the last 3 months with symptom onset at least
6 months prior to diagnosis.

Factor Analysis Supports EPS and PDS

45% of the U.S. population report upper
GI symptoms

Telephone 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
Westbrook 2002

Population
Population sample

n
2300

Result
3 dyspeptic symptom factors

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

Population sample 21128

3 dyspeptic symptom factors

Fischler 2003

Camilleri 2005

Piessevaux submitted Population sample

2025

3 or 4 dyspeptic symptom factors

Tack in preparation

638

3 dyspeptic symptom factors

Tertiary care

Rome III

Diagnostic Criteria* for

Epigastric Pain Syndrome (EPS)

Must include all of the following:

Pain or burning which is:

Intermittent,
Localized to the epigastrium of at least moderate
severity, at least once per week,
and NOT:

generalized or
localized to other
abdominal or
chest regions

relieved by
defecation or
flatulence

fulfilling criteria
for gallbladder
or sphincter of
Oddi disorders

* Criteria fulfilled for the last 3 months with symptom onset at least
6 months prior to diagnosis.

Distinct Dyspepsia Subgroups:

New Data
Olmsted County population data

EPS
135
(39%)

9 (3%)
7 (2%)

25
(7%)

Comparison of overlap of subgroups

between observed and expected

CIN
n=37
(11%)
16
(5%)

PDS (early
satiety)
114 (32%)

Choung et al. DDW 2006

Observed (n)

Expected
(n)

p-value

EPS
vs. CIN

16

35

0.006

EPS
vs. PDS

32

83

<0.001

PDS
vs. CIN

23

33

0.078

* Assuming the subgroups were independent

Rome III
Overlap 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 III
50

Overlap with IBS

45

Coexisting IBS no
major impact on
symptom pattern
or putative
pathophysiologica
l mechanisms

35

Dyspepsia
Dyspepsia + IBS

Prevalence (%of patients)

40

30

* P<0.05

25
20
15
10
5
0
Delayed emptying H. pylori positive Hypersensitivity

Impaired
accommodation

Corsetti et al. Am J Gastroenterol. 2004;99:1152-9

Nausea and Vomiting

Cyclic vomiting syndrome (CVS) now a recognized
syndrome in adults

AJG 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 year
Absence 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 dyspepsia
Dyspepsia as previously defined unhelpful: focus on early
satiation and/or postprandial fullness and/or epigastric pain
De-emphasize functional dyspepsia
New syndromes suggested for research: PDS and EPS

Nausea and vomiting

Two new syndromes (CIN and CVS)

Functional Bowel Disorders

Irritable Bowel Syndrome
Functional Bloating
Functional Constipation
Functional Diarrhea
Unspecified Functional Bowel Disease

Main Changes in IBS Criteria

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 subtypes

Rome II
Diagnostic criteria for IBS
At least 12 weeks, which need not be consecutive, in the
preceding 12 months of abdominal discomfort or pain that
has two of three features:
Relieved with defecation; and/or
Onset associated with a change in
and/or

frequency of stool;

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 months
associated with two or more of the following
Improvement with defecation; and/or
Onset associated with a change in frequency of stool; and/or
Onset 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 IBS
Why bother?
Important for choosing therapies which alter bowel habit
Subtypes likely to have different pathophysiology
Transit
Stool consistency
Rectal sensitivity?

Previous Features Used to Subclassify

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

Problems With Old System

Complex to apply and caused confusion in both patients and
clinicians!
Multidimensional but different dimensions dont correlate
well
Failed to deal adequately with patients with both hard and
loose stools

IBS Patients with Features of Both

Constipation and Diarrhea are Common
Reference

IBS-D

IBS-C

IBS-M

Mearin 2003

209

10

24

37

Tillisch 2005

1102

32

17

32

Drossman
2005

317

36

34

31

Rome III subtyping is based on

Stool Consistency alone
Assessed from stool form

Defining Stool Consistency

Bristol Stool Form Scale

Hard

Normal

Loose

Why Stool Consistency as Main

Determinant of Subtype?
Correlates best with colonic transit

Colonic Transit & Stool Form

80

Colonic transit
time (hours)

40

0
1

Bristol stool form score

O'Donnell et al Br Med J 1990;300:439-40

Why Stool Consistency as Main

Determinant of Subtype?
Correlates best with colonic transit
Correlates best with what patients and community
samples think of as diarrhoea
Principle determinant of incontinence
Other features occur in IBS with both loose & hard stools
Stool frequency <3/weeks or >3/day
Urgency, Sense of incomplete evacuation

Association of bowel symptoms with

stool consistency

Tillisch et al Am J Gastroenterol. 2005; 100:896-904

Proposed New Subtyping Based on Stool

Consistency Alone
IBS with constipation
IBS with diarrhoea
IBS mixed type
(IBS unsubtyped

- IBS-C
- IBS-D
- IBS-M
- 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 IBS

100

75

% Hard or
Lumpy Stools

50

IBS-C
17%

IBS-M
46%

IBS-U
3.9%

IBS-D
32%

25

25

50

75

%Loose or Watery Stools

Tillisch et al Am J Gastroenterol. 2005;100:896-904

100

Quantifying Stool Form

Date

Pain

Pain
Severity

Urgency
Y/N

Bloating
Y/N

2 3

Pain: grade 0-10

0= absent
5=moderate
10 very severe
Stool form
1= separate hard lumps, like nuts
6 = fluffy pieces with ragged edges
2= sausage shaped but lumpy
7 = watery, no solid pieces
3= like a sausage or snake, but with cracks
on its surface
4= like a sausage or snake, smooth and soft
5= soft blobs with clear cut edges

Changes to IBS classification

Rome III Summary
No change to basic criteria
Length of time needed to define chronicity reduced to 6
months
Threshold 3 days / month introduced for frequency of
pain / discomfort
Subtyping 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
Motility abnormalities of the Gallbladder, the
Biliary, and Pancreatic Sphincter of Oddi
Epigastric or right
upper quadrant pain

NOT EXPLAINED BY STRUCTURAL ABNORMALITIES

DIAGNOSTIC CRITERIA FOR FUNCTIONAL GALLBLADDER AND

SPHINCTER OF ODDI DISORDERS
Epigastric or right upper
quadtrant pain

severe

Pain located in the

epigastrium and/or
right upper quadrant

PAIN

Recurrent symptoms
occurring at different
intervals (not daily)

Steady

moderate
mild

30 min

time

E
C
EN

Episodes lasting 30 minutes or longer The

pain builds up to a steady level

Not
1.
2.
3.

Relieved by
Bowel Movements
Postural Change
Antacids

D
I
EV

N
CO

E
S

The pain is moderate to

severe enough to
interrupt the patients
daily activities or lead to
an emergency department
visit

S
N

S
U

Supportive Criteria
The pain may present with one or more of
the following:
a. Associated with nausea and vomiting
b. Radiates to the back and/or right
infra subscapular region
c. Awakens from sleep in the middle of
the night

ROME III ALGORITHM FOR FUNCTIONAL GB DISORDERS

Diagnostic criteria for functional GB and SO disorders
LFTs/pancreatic, enzyme, US
Esophagogastroduodenoscopy
Structural

E
D
I
EV

alterations
Normal findings

Appropriate
investigation and
treatment

GB CCK cholescintigraphy
GBEF < 40%

GBEF > 40%

Cholecystectomy

Reassess

C
E
NC

ROME III ALGORITHM FOR FUNCTIONAL BILIARY SO

DISORDERS

Structural
alterations explaining
the symptoms

Cholecystectomized
Diagnostic criteria for functional GB and SO disorders
LFTs/pancreatic enzymes, US
Esophagogastroduodenoscopy
EUS, MRCP

Appropriate
Investigation
and treatment
Milwaukee
Classification
Pain and
Milwaukee
LFTs in Revised
Classification
2
occasions
Pain and and
At
LFTs
ERCPin 2 occasions
and
Dilated CBD >12mm
ATand
US

Dilated
CBD
>8mm
Delayed
contrast
drainage

Biliary
Type I

Biliary
Type II

Biliary
Type III

Pain and
One or two of type
I criteria

E
C
S
N
U
E
S
D
I
N
E
EV
S
N
O
C

Pain and
None of the type
I criteria

ROME III ALGORITHM FOR FUNCTIONAL BILIARY SO

DISORDERS
Cholecystectomized

Diagnostic criteria for functional GB and SO disorders

LFTs/pancreatic enzymes, US
Esophagogastroduodenoscopy
EUS, MRCP
Structural
alterations explaining
the symptoms
Appropriate
Investigation
and treatment

:
E
C
N
E
D
I B
V
E

Biliary
Type I

Biliary
Type II

Biliary
Type III

ES

Abnormal
SOM
ES

ERCP
with SOM

Normal
SOM
Reassesses

ROME III ALGORITHM FOR FUNCTIONAL BILIARY SO

DISORDERS
Cholecystectomized

Diagnostic criteria for functional GB and SO disorders

LFTs/pancreatic enzymes, US
Esophagogastroduodenoscopy
EUS, MRCP
Structural
alterations explaining
the symptoms

Biliary
Type I

Biliary
Type II

Pharmacological
trials

Appropriate
Investigation
and treatment

:
E
C
N
E
D
I C
V
E

Biliary
Type III

No
response
Abnormal
SOM
ES

ERCP
with SOM

Normal
SOM
Reassesses

Response

ROME III ALGORITHM FOR FUNCTIONAL BILIARY SO

DISORDERS
Cholecystectomized ,
Criteria for functional GB and SO Disorders
Clinical history, LFTs/pancreatic enzymes, US
Esophagogastroduodenoscopy
EUS, MRCP
Structural
alterations
explaining
the
symptoms

Biliary
Type I

Biliary
Type II

Biliary
Type III

BILI[CHOLEDOCHO]SCINTIGRAPHY
Appropriate
Investigation
and
treatment

ES

E
C

N
E
D Abnormal
I
SOM
EV
ES

Pharmacological
trials
No
response
ERCP
with SOM

Normal
SOM
Reassesses

Response

ROME III ALGORITHM FOR FUNCTIONAL PANCREATIC

SO DISORDERS
Criteria for functional GB and SO disorders,
Elevated amylase and lipase
No obvious association with alchool, gallstones, drugs, Ca 2+
US, Esophagogastroduodenoscopy, CT, EUS,MRCP

Diagnostic ERCP
Structural

No Structural

abnormalities

abnormalities

E
C

N
E
D
Sphincterotomy
I
V
E

SO manometry
Abnormal

Normal
Reassess

Functional
Esophageal

Functional
Abdominal Pain

Functional
Billiary

Functional
Gastroduodenal

Rome III
Diagnostic
Questionnaire

IBS &
Functional Bowel

Functional
Anorectal

Rationale for Changing to Ordinal Scales to

Measure Symptom Frequency
Rome II questionnaire applied the same frequency threshold to
all symptoms
Some symptoms are not clinically meaningful unless they occur
daily while others are significant if they occur at all
Rome II questions were difficult to understand because they
incorporated multiple frequency thresholds
Scales for judging relative severity would be useful

Goals of the Questionnaire Development

and Validation Process
Develop a questionnaire that incorporates the Rome III
criteria as an aid to diagnosis
Insure that questions are understandable
Validate the questionnaire & the criteria by comparing
to diagnoses made by clinicians

Study I
Compare 4 Alternative Response Scales
Subjects 120 healthy controls & 84 FGID
Design: 4 versions of the questionnaire were completed
in counterbalanced order
Binary: No or rarely vs. often
Specific Frequency: Monthly, weekly, daily
Relative Frequency: Occasionally, often, always
Bothersome: A little bit, moderately, quite a bit

Subjects are Inconsistent in How They Use the

Binary Response Scale
Frequency 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 well
Bothersome Scale performs similar to Relative
Frequency Scale but is not appropriate to some
symptoms

Two Scales Selected for Rome III

Specific Frequency Scale

Relative Frequency Scale

Never

Never or rarely

Less than 1 day a month

Sometimes

One day a month

Often

One day a week

Most of the time

More than 1 day a week

Always

Every day

Questionnaire Development
Rome board suggested initial questions
Working teams provided additional items
Questionnaire Committee met for 2 days to insure
that the questions matched the diagnostic criteria
Data from the validation study were referred back to
the Rome board & working teams for revisions to
criteria & thresholds

Sample Question
In the last 3 months, how
often did you have discomfort
or pain anywhere in your
abdomen?

Never
Less than 1 day a month
One day a month
Two to three days a month
One day a week
More than one day a week
Every day

Study II: Validation Study

Subjects
554 healthy controls (75% participation)
399 FGIDs (66% participation)

328 IBS, 27 constipation, 10 FD, 32 miscellaneous

There were 4 study sites: UNC, Mayo Clinic, University of
Michigan, & University of Toronto
Test retest agreement on diagnosis assessed in 53 controls &
51 patients over 2 weeks

Understandability
18 of 77 questions were rated difficult to understand by
1% or more of subjects
4 questions were rated difficult by 2%
All but one of these 18 questions were revised
No 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 That

Less Than 10% of Controls are Abnormal
Frequency of Abdominal Pain or
Discomfort

Selecting Frequency Thresholds so That

Less Than 10% of Controls are Abnormal
Frequency of Abdominal Pain or
Discomfort

Effects of Different Thresholds

on Sensitivity & Specificity
539 healthy controls & 326 IBS patients
Abdominal pain
Frequency threshold

Sensitivity Specificity
of IBS Dx of IBS Dx

>1 day a week

48.5%

98.2%

1 day a week

55.5%

94.3%

2-3 days per month

70.7%

87.8%

Specificity: Percent of Healthy

Controls Who Would be
Misclassified
Misdiagnosed
Estimated
Controls

Specificity

IBS

12.2%

87.8%

Constipation

3.5%

96.5%

Diarrhea

0.1%

99.1%

Functional dyspepsia

5.9%

94.1%

Postprandial distress

0.7%

99.3%

Epigastric pain

100%

Chronic idiopathic nausea

0.9%

99.1%

Reliability: Test-Retest Agreement

Over a 2-Week Interval
Specificity

Test-Retest
Agreement

IBS

87.8%

81.7%

Constipation

96.5%

93.3%

Diarrhea

99.1%

96.2%

Functional dyspepsia

94.1%

84.6%

Postprandial distress

99.3%

85.6%

Epigastric pain

100%

98.1%

Chronic idiopathic nausea

99.1%

96.2%

Conclusions

A major innovation of Rome III is ordinal scale with

individual frequency thresholds
Rome III diagnostic questionnaire is reliable:
Questions reflect the criteria & are understandable
Test-retest reliability is excellent
Specificity of diagnostic criteria is excellent

Application of Diagnostic Criteria

Consensus derived criteria
Questionnaire
Validation
Published trial and survey data
Can it be applied to my patient?

To Interpret Data Obtained Using

Rome III Questionnaire, I Must Consider:
1. Was the questionnaire altered?
2. What was the purpose of the study?
3. How was the study population selected?
4. Can the data (evidence) from that trial or
be applied to my patient?

survey

1. Was the Questionnaire Altered?

Questions how were they asked?
Also, algorithms, inclusions and exclusions
Determined by consensus, existing data
To suit their study, investigators may adjust:
Time requisite (acute vs. chronic)
Cut-off levels for inclusion
Exclusions

1. (cont) Was the questionnaire altered?

Frequency Scale Cut-offs

How often in last 3 months did you have pain?
a. Never
b. Once a month or less
c. Two to three times/month
d. Once a week
e. Several times a week
f. Every day

Rome III

Cut-offs determine who is included!

1. (cont) Was the questionnaire altered?

Frequency Scale Cut-offs

How often in last 3 months did you have pain?
a. Never
b. Once a month or less

Survey

c. Two to three times/month

d. Once a week
e. Several times a week
f. Every day

Cut-offs determine who is included!

1. (cont) Was the questionnaire altered?

Frequency Scale Cut-offs

How often in last 3 months did you have pain?
a. Never
b. Once a month or less
c. Two to three times/month
d. Once a week
e. Several times a week
f. Every day

Clinical trial

Cut-offs determine who is included!

1. (cont) Was the questionnaire altered?

Exclusions
Q8. ..did you often have heartburn..?
Q9. ..did you .. have difficulty swallowing..?
Rome II coding:
Functional heartburn; Q8=yes, and no to dysphagia
Functional dysphagia; Q9=yes, and no to heartburn
1. If yes to both, neither disorder exists because,
according to the coding, one excludes the other.
2. Data not applicable to excluded patients.

2. What was the Purpose of the Study?

1. To aid diagnosis

2. To select subjects for clinical research

3. To survey populations

2. What was the Purpose of the Study?

1. To aid diagnosis
Severity/frequency relevant
Inclusive
Symptoms now
2. To select subjects for clinical research
Severity/frequency more relevant
Exclusive
Symptoms now
3. To survey populations
Severity/frequency less important
Inclusive
Symptoms 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:
1. How were criteria translated into questions:
Time requirement, cut-offs, and exclusions?

2. Were there unique adjustments for:

Clinical Trial?
Epidemiological survey?
Clinical Practice?

- severe cases now

- include all cases
- precision

3. Does my local population or my patient resemble the

studys population?
4. Will my management help my patient achieve as great a
placebo effect as those in the study?

Use of the Rome Criteria

Clinical
Trials

Clinical
Research
Clinical
Practice

Existing Trials
Improved methodology
Existing
Trials
Meta-analyses
Negative trials?

Regulatory Authorities
Regulatory
Authorities
EMEA PTC
2003
FDA Advices

Expert Panels
Definition of a Responder, Vienna 1998
Expert
Panels
European Panel, APT 2003
Rome I, Rome II

Challenges for FGIDs clinical trials

Natural course of the condition
Unstable symptom pattern
Fluctuating intensity
Multicomponent pathophysiology
Multiple therapeutic targets
Multiple endpoints
Bias of outcome measures
High placebo response
Difficulty to maintain double masking
Contamination by parallel interventions
Lack of placebo control for some interventions
Psychotherapy, hypnotherapy, sphincterotomy
Avoiding harm
FGID non-life-threatening

Definition of the Studied Population

Clearly define the FGID to be treated

Define subgroups
Transit abnormalities
Explicit inclusion/exclusion criteria
Gender
Symptoms intensity
Comorbidities
Treatment exclusions

Compromise between the largest target in the

population and a strictly homogenous group

The Standard Trial Design

Superiority trial
The most robust design:
parallel groups, randomized allocation, double
blind

Single intervention
Placebo-controlled
Placebo
Run-in

Treatment Phase
Intervention

Run-out

70

Percentage of responders

80

*p < 0.05
**p < 0.001

70
60
50

*
* * * * * *
* * *

60
*

50

* * *

40

40

30

30
20
10

20

Alosetron (n = 237)
Placebo (n = 221)
Treatment

Follow-up

0
0

6
8
Weeks

10

12

Camilleri et al.
Lancet 2000; 355: 1035-1040.

14

16

Tegaserod
Placebo

10
0

-2

Run-in

11 13 15
Follow-up

Novick et al.
APT 2002; 16:1877-1888.

From Rome II to Rome III

Unsolved issues with standard design
Duration of the treatment intervention
4 weeks versus 12 weeks
Longer treatments: 6 months

Outcome measures

Alternative trial designs

On-demand or Pro Re Nata (PRN) treatments
Treatment Re-treatment design

Treatment Re-treatment
EMEA PTC 2003
NR
Carry-over
Active Drug

Unblinding
Active Drug
R

of the intervention
Enrichment in
responders
Placebo
Natural cycle of symptoms
NR
Ethical considerations
No symptom

Active Drug

Active Drug

R
Placebo

NR

Symptoms +
Placebo

RT
NR

50

Responders (%)

Active drugst
40

1 T

4 weeks

RT

Active drug

1stT
symp(37%
R)

4 weeks

No symp

Tegaserod
Placebo
Placebo

30

Placebo

NR

20
=9.3%

=16.6%

=9.1%

=15.91%

10
0

IBS-C
symptoms

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

Abdominal
discomfort/pain

Definition of Outcome Measures

Primary outcome
Global assessment
Adequate relief
Definition of a responder

Symptom questionnaire
Pain assessment

Secondary outcomes
Mechanism of intervention
Symptoms influenced by a
specific pharmacodynamic
effect
Quality of life
Health economics

Tolerance and safety

Definition of a Responder
Symptom Relief

Completely

Markedly

Somewhat
25 %

50 %

75 %

100 %

Time

Conclusion
Rome 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.