Factor analysis of bowel symptoms in US and Italian populations

Digestive and Liver Disease 35 (2003) 774–783

Alimentary Tract

Factor analysis of bowel symptoms in US and Italian populations夽 W.E. Whitehead a , G. Bassotti a,d,∗ , O. Palsson b , E. Taub c , E.C. Cook, III c , D.A. Drossman a a

UNC Center for Functional Gastrointestinal and Motility Disorders, University of North Carolina at Chapel Hill, Chapel Hill, USA b Eastern Virginia School of Family Medicine, Virginia, USA c University of Alabama at Birmingham, Alabama, USA d GI Section, Department of Clinical and Experimental Medicine, University of Perugia, Via Enrico Dal Pozzo, 06100, Perugia, Italy Received 13 March 2003; accepted 27 June 2003

Abstract Background and aims. Functional gastrointestinal disorders are diagnosed by the presence of a characteristic set of symptoms. Aims of this study were to validate the Rome symptom criteria by factor analysis and to determine whether symptoms cluster in the same way in different cultures. Methods. One thousand forty-one gastroenterology clinic patients in the US (response rate 53%) and 228 family members accompanying clinic patients in Italy (84%) completed a previously validated symptom questionnaire. Factor analysis identified clusters of symptoms which are highly correlated with each other, and these were compared to the Rome diagnostic criteria. Results. In the US, 13 factors were identified. The irritable bowel factor was composed of three core symptoms corresponding to the Rome II classification system. Two dyspepsia factors were identified which correspond to the ulcer- and motility-like subtypes proposed in the Rome I classification system. All symptoms of constipation formed a single cluster as proposed in the Rome II classification system. Symptom clusters in the US agreed well with symptom clusters identified in Italian subjects. Conclusions. Empirically derived symptom clusters agree in most respects with the Rome II classification system and support their validity. These symptom clusters are independent of cultural differences in diet and behaviour. © 2003 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Constipation; Factor analysis; Functional dyspepsia; Functional gastrointestinal disorders; Irritable bowel syndrome

1. Introduction There is no consensus on the pathophysiological basis for the functional gastrointestinal disorders including irritable bowel syndrome (IBS) and functional dyspepsia (FD). As a result, they are diagnosed on the basis of the presence of a characteristic set of symptoms and the absence of signs or symptoms suggestive of a different disease [1]. Because there is no pathophysiological marker for these disorders, it has been difficult to identify a gold standard against which symptom criteria can be validated. One approach has been to compare diagnoses based on symptom criteria to the diagnoses of experienced clinicians [2–4]. In 夽 This study was previously published in abstract form [Am. J. Gastroenterol. 91 (1996) 2000]. ∗ Corresponding author. Fax: +39-075-584-7570. E-mail address: [email protected] (G. Bassotti).

the only such study to address the validity of the Rome criteria by this technique, Vanner and colleagues reported that the Rome I criteria [4] have a specificity and positive predictive value of 98% or greater when patients are first screened for the presence of six red-flag symptoms (documented weight loss, nocturnal symptoms, blood mixed in the stools, recent antibiotic use, family history of colon cancer and relevant abnormalities on physical examination). The sensitivity of the Rome I criteria in this study was 65%. Although these results are encouraging as regards the validity of the Rome criteria, it is possible that the clinicians in this and similar studies are unlike other physicians in that they have previously been taught to use the Rome criteria for the diagnosis of IBS; this could lead to some confounding of dependent and independent variables. An alternative approach to validating symptom criteria is to use principal components factor analysis to empirically identify clusters of symptoms and to compare them to the

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W.E. Whitehead et al. / Digestive and Liver Disease 35 (2003) 774–783

Rome criteria, which were developed through the consensus of expert clinicians. The rationale for this approach is that, if gastrointestinal symptoms cluster together consistently in large samples of people and in independent samples, it is reasonable to infer that the symptoms have a common etiology and define a specific clinical condition. Thus, factor analysis is an empirical technique for identifying functional gastrointestinal disorders and for determining which symptoms are useful for diagnosing them. Once this is done, the degree of concordance between the symptoms making up these empirically derived factors and the symptoms identified by the consensus (Rome) criteria constitutes a measure of the validity of the consensus criteria [5]. Several investigators have used factor analysis to investigate the validity of the Rome classification system for functional gastrointestinal disorders. In the first such study, Whitehead and colleagues [6] used a 21-item symptom checklist in a community sample of middle-aged women and in an independent sample of young women recruited through Planned Parenthood Clinics in a large metropolitan area. They found a group of three symptoms (pain relieved by defecation, pain associated with a change in the frequency of stools and pain associated with a change in the consistency of stools) which defined an IBS factor. This same research group subsequently reported (1) a factor analysis of 1344 undergraduate students [7] using the same 21-item symptom checklist, and (2) an independent factor analysis of symptom questions in the Rome I diagnostic criteria in a population-based sample of 5430 adults who were the respondents in the US Householder Study [5]. In both instances, the same triad of symptoms formed the core of the IBS factor. Talley and colleagues [8] used a questionnaire they had developed [9] to test a population-based sample of 730 Australian adults, and identified the same core set of symptoms as characteristic of IBS. The only factor analysis study published which has failed to identify an IBS factor associated with this cluster of symptoms was the study by Agreus and colleagues [10], and it is likely that this discrepant result was due to the use of a questionnaire which did not include these core symptoms. With the exception of the US Householder Survey [5], none of the factor analysis studies published so far have tested the full range of functional gastrointestinal disorders identified by the Rome classification system [1]; they have been restricted to IBS and functional dyspepsia. In addition, the questionnaires used in previous studies have often been limited in the range of symptoms they assessed. The aims of this study were (1) to evaluate the full set of functional gastrointestinal disorders by employing a comprehensive, validated questionnaire [11]; (2) to assess the clustering of symptoms in gastroenterology clinic patients rather than in a community sample; (3) to evaluate the generalisability of findings by performing a similar analysis in a group of Italian subjects and (4) to compare the symptom clusters identified by factor analysis to the Rome I and Rome II consensus

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criteria as a measure of the convergent validity of the Rome criteria.

2. Materials and methods At the University of North Carolina, consecutive new patients were invited to complete a symptom questionnaire until 1081 had returned valid questionnaires. These patients were attending a gastroenterology referral clinic, and all had gastrointestinal complaints. However, they were not selected for having functional gastrointestinal disorders, and their symptoms varied widely. In Italy, the GI symptom questionnaire was completed by 228 of the family members of patients attending gastroenterology referral clinics in Perugia. In both countries, only adults (minimum age 18) were studied, but there was no upper age limit. This study was reviewed and approved by the Committee for the Protection of Human Subjects at the University of North Carolina at Chapel Hill. The questionnaire was developed by three of the authors (WEW, ET and EC) by a process which has been previously described. In brief, questions thought to be relevant to the diagnosis of functional gastrointestinal disorders were drawn from all existing questionnaires known to the authors and were supplemented by asking experts in functional GI disorders to review the questionnaire and to suggest additional questions. Care was also taken to ensure that the diagnostic criteria for all the Rome I diagnoses [1] were included in the questionnaire. Next the questionnaire was evaluated by groups of undergraduate students to ensure that the questions could be understood by lay persons. The questionnaire was revised based on the comments of the students and their suggestion for rewording, and the revised questionnaire was then given to a new group of students in a recursive fashion until the students felt confident that they understood what the questions meant and the investigators felt that the students were correctly interpreting the questions. Subsequently, the test-retest reliability of the questionnaire in adult medical patients was evaluated and found to be acceptable [11]. After the English version of the questionnaire had been validated, the questionnaire was translated into Italian by another of the authors (GB), who is an Italian gastroenterologist fluent in both English and Italian. No explicit test of the validity or reliability of this translation took place. Several questions were included in the questionnaire to see if they might help to differentiate functional from organic gastrointestinal disorders. These included three questions on fever and chills (occurring during a bowel movement or associated with abdominal pain or a change in stool consistency) plus a question on the presence of black tarry stools. In preliminary analyses, these questions always aggregated together rather than with other symptom clusters. Consequently, these questions were eliminated from the final analysis.

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Questions were also included to identify patients with known organic diseases or medical histories that could explain gastrointestinal symptoms. These questions referred to: diagnosis of peptic ulcer, liver disease, pancreatitis, gallbladder disease, gastrointestinal tract cancer, ulcerative colitis, Crohn’s disease, haemorrhoids, rectal prolapse or rectocele; pregnancy within the past 6 months; abdominal or pelvic surgery; or laparoscopy or laparotomy. These questions were not entered into the factor analysis but were used to exclude subjects from some analyses. The questionnaires were coded into a computer database and analysed by BMDP statistical software [12]. Principal components factor analysis was employed, and Varimax rotation was used to ensure that the factors were as independent as possible. Initially, all factors with eigenvalues greater than 1.0 were extracted, but a smaller number of factors was selected for the final statistical model to avoid factors with single symptoms loading on them. In order to make separate factor analyses comparable, we solved for 13 factors in each sample (guided by the number of factors identified in the total US sample). To compare the factor analysis to the Rome classification system, we listed the symptoms considered to be diagnostic of each functional gastrointestinal disorder in the Rome criteria and looked at the loading of these variables on each of the empirically derived factors. A factor loading is an index of the strength of association of this variable with the other variables in the factor. Factor loadings greater than 0.4 were considered to be ‘significant’ loadings. The empirically derived criteria would be considered to confirm the Rome classification system if all the symptom criteria for a Rome diagnosis loaded strongly (high factor loadings) on a single factor. This method of tabling the data also allowed us to identify additional symptoms in the questionnaire which loaded on the same factor but were not listed by the Rome consensus committee as diagnostic criteria. Once the factor analysis had been performed on both the US and Italian samples of subjects, we compared the symptoms which loaded most strongly on each factor in order to match the factors in the Italian sample to factors identified in the US sample. Having done this, we calculated the degree of concordance by computing a Pearson product–moment correlation coefficient which compared the factor loadings across all variables. The same technique was used to compare factor solutions in the total sample to the subset of subjects who did not report an organic explanation for their gastrointestinal symptoms in both the US and Italian samples.

3. Results Demographic characteristics of the two samples are given in Table 1. In the US clinic, 1041 patients completed the questionnaire, which was 53% of those to whom it was dis-

Table 1 Demographics

Sample Size Age (Mean ± S.D.) Female percent

US

Italian

1041 44.5 ± 15.0 64.8

228 41.5 ± 17.2 55.3

Marital status (%) Married Single Divorced Widowed Refused

57.5 18.6 16.8 5.8 1.2

55.3 36.0 1.3 5.3 2.2

Ethnic origin (%) Caucasian African descent Other minority group Refused

78.3 17.4 3.1 1.2

95.6 1.3 0 3.1

Annual income (%) <$15,000 $15,000–29,999 $30,000–50,000 >$50,000 Refused

25.8 23.2 22.1 24.6 4.3

11.8 40.8 18.4 5.3 2.2

Occupation (%) Professional Managerial Trade Labourer

31.6 19.2 11.9 15.9

25.9 3.5 21.5 13.2

tributed. In the Italian clinic, 270 subjects were invited to participate, and 228 (84%) returned a completed questionnaire. The two samples were comparable with respect to age, gender and socio-economic status. The US sample contained a higher proportion of subjects who were of African descent. 3.1. Factor analysis of US patient sample compared to Rome I criteria Table 2 shows the correspondence between the empirically derived factors (all subjects in the US patient sample) and the Rome I diagnostic classification system. The factor analysis identified 17 factors with eigenvalues greater than 1. However, we chose a 13-factor solution because this gave the most interpretable factors. All 13 factors corresponded to Rome diagnoses as shown in Table 2. The correspondence to Rome I and Rome II diagnostic criteria are discussed in greater detail below. 3.1.1. Irritable bowel syndrome, constipation and diarrhoea Table 3 shows the symptoms which the Rome criteria associate with IBS. The Rome I criteria [13] require one of the three symptoms of the first set (pain relieved by defecation, pain associated with a change in the frequency of stools or pain associated with a change in the consistency of stools) plus two symptoms of the second set. By contrast, the Rome

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Table 2 Factors which correspond to Rome I diagnoses in the US sample F1a

F2

Esophageal disorders Globus Rumination syndrome Functional chest pain Functional heartburn Functional dysphagia

F3

F4

F5

F6

F7

F8

F9

F10

F11

F12

F13

xx xx xx xx

Gastroduodenal disorders Functional dyspepsia Ulcer-like dyspepsia Dysmotility-like dyspepsia

xx xx

Aerophagia Bowel disorders Irritable bowel Bloating Constipation Diarrhoea

xx xx xx xx xx

Chronic abdominal pain

xx

Anorectal disorders Functional incontinence Anorectal pain Levator ani Proctalgia fugax Dyschezia Variance explained (eigenvalues)

xx

xx 4.72

4.70

3.95

3.62

3.55

3.26

3.13

3.12

2.80

2.78

2.45

1.94

1.86

a

Factors are numbered in order of the amount of variance explained for a specific sample, e.g. factor F1 accounts for more of the variation between individual subjects in their symptoms than does factor F2.

II criteria [14] require only two of the three symptoms of the first set. Factor 10 includes all symptoms in the first set of symptom criteria for IBS (Table 3) plus three other symptoms which may be useful for identifying patients with IBS (bottom of Table 3). However, the other set of symptoms in the Rome I criteria (middle portion of Table 3), which relates to abnormal bowel habits and bloating, separates into three discrete factors: Factor 1 (constipation), Factor 4 (diarrhoea) and Factor 11 (bloating). (See Table 4 for additional details on constipation and diarrhoea.). 3.1.2. Constipation and diarrhoea Factor 1 is a constipation factor (Table 4), but it includes symptoms usually thought of as being associated with pelvic floor dyssynergia (straining, feeling of incomplete evacuation, digital facilitation, trouble letting go) as well as symptoms thought of as being associated with slow transit constipation (hard stools, less than three bowel movements per week). Factor 4 is a Diarrhoea factor which contains significant loadings on two of the three symptoms specified by the Rome I criteria [13] and a marginal loading on the third (bowel movements larger than normal). Additional symptoms loading on the Diarrhoea factor include a strong urge for defecation, an increased frequency of defecation and incontinence.

3.1.3. Dyspepsia The Rome classification system subdivides dyspepsia into ulcer- and dysmotility-like subtypes [15]. Although Talley and colleagues reported on the basis of epidemiological data that this distinction was not supported [16], factor analysis does support it. As shown in Table 5, Factor 13 contains three symptoms associated with the Rome I definition of ulcer-like dyspepsia: pain unrelated to eating, pain relieved by eating and pain relieved by antacids. Factor 5 contains four symptoms associated with the Rome I definition of dysmotility-like dyspepsia: early satiety, nausea, vomiting and retching. The related symptom of decreased appetite also loads on this factor. 3.1.4. Heartburn Factor 3 (Table 6) is an uncomplicated heartburn or gastroesophageal reflux factor including symptoms of heartburn, heartburn triggered by eating, heartburn relieved by antacids, heartburn which is worse when lying down or bending over, and heartburn triggered by stress or emotions. Both the Rome I [17] and the Rome II criteria [18] suggest that functional heartburn can be distinguished from gastroesophageal reflux because it is not associated with objective evidence of acid reflux. This distinction is not possible to make with symptoms alone. However, the strong loading of

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Table 3 Irritable bowel syndrome loadings for the Rome I consensus criteria F1

F4

F10

Dyspepsia Chronic upper abdominal pain

Abdominal pain which is Relieved by defecation, or Associated with a change in BM frequency Associated with a change in BM consistency

0.72 0.66

Ulcer-like dyspepsia UGI pain plus >3 of Well-localised in the epigastrum Relieved by food >25% of times Relieved by antacids Pain before meals, with hunger Pain awakens from sleep Relapses and remissions >2 weeks

0.66

0.54 0.75 0.69 0.73 0.73 0.68 0.58 0.58 0.56

Non-Rome symptoms How long was pain present? Pain is intermittent Pain in lower abdomen

Table 4 Constipation and diarrhoea loading of the Rome I consensus criteria F1a

Non-Rome symptoms Trouble letting go of stools Massage abdomen for BM Press with fingers around anus Fingers in vagina for BM Takes long time for BM Frequency of stools, average

F11

0.51

0.66 0.44 0.67 0.67

0.57 0.70 0.73 0.77

0.60

Bloating Distention, frequency Bloated feeling, frequency

0.57 0.56

Non-Rome symptoms Bloating worse after eating Bloating worse after drinking milk

0.62 0.52

a

F13

See legend to Table 3.

heartburn triggered by stress on this factor is suggestive of a functional disorder. 3.1.5. Functional esophageal disorders Factor 6 (dysphagia) and Factor 9 (globus) are distinct factors (Table 6) as suggested by the Rome criteria [17,18]. However, functional chest pain is not distinct from symptoms of dysphagia, contrary to the Rome criteria.

0.73 0.69 0.58 0.54 0.63 0.67 0.65 0.42 0.54 −0.41

0.73 0.75 0.34

Non-Rome symptoms Strong urge Usual frequency of BMs Incontinence of stool BM without urge Borborygmi

0.68 0.64 0.54 0.40 0.44

See legend to Table 3.

F5

F4

Functional diarrhoea ≥2 of the following symptoms Mushy/watery BM >75% of time >3 BM per day Increased stool weight

a

Dysmotility-like dyspepsia UGI discomfort plus >3 of Early satiety Post-prandial fullness/bloating Nausea Retching Vomiting Bloating in upper abdomen UGI pain aggravated by eating Non-Rome symptom Decreased appetite

0.49 0.56 0.50

Factor loadings refer to correlation coefficients that show the strength of association of each individual symptom in the questionnaire to the factor (hypothetical disorder). There is a factor loading for each symptom in the questionnaire, but only factor loadings greater than 0.40 are shown in the table. Factors on which none of the symptoms in column 1 (symptoms defining IBS by the Rome criteria) loaded at least 0.40 are omitted from the table.

Functional constipation Straining Hard stools Incomplete evacuation Less than 3 BM per week

F2a

F11

Rome criteria symptoms

≥2 of the following symptoms >25% of time Stool frequency <3 per week Stool frequency >3 per day Hard stools Loose stools Straining Urgency Incomplete evacuation Mucus Distention (visible) Bloating

Table 5 Functional dyspepsia loading of the Rome I consensus criteria

3.1.6. Aerophagia and rumination syndrome Factor 8 (Table 7) corresponds to the Rome definition of aerophagia [15,16]. Note that there are additional symptoms associated with aerophagia which are not mentioned by the Rome criteria but which appear to be logically related to aerophagia; these are intentional belching, belching unrelated to meals and increased flatus. Factor 12 corresponds to rumination syndrome as defined by the Rome criteria [17,18]: it has strong loadings for rumination (rechewing vomitus) and for the symptom, ‘regurgitation stops when the vomitus turns sour’. 3.1.7. Functional abdominal pain Factor 2 (Table 8) is a general pain factor with similarities to the Rome I diagnosis of functional abdominal pain [13]. It contains loadings for abdominal pain and for interruption of

W.E. Whitehead et al. / Digestive and Liver Disease 35 (2003) 774–783 Table 6 Esophageal disorders: chest pain and heartburn loading of the Rome I consensus criteria F3a

F6

Functional chest pain Midline chest pain

0.49

Non-Rome symptoms Difficult to swallow when chest pains

0.57

Functional heartburn Frequency of heartburn Triggered by eating Triggered by emotion or stress Worse when laying down or bending Worse during day Non-Rome symptoms Heartburn relieved by antacids Reflux of sour fluid into throat

Functional abdominal pain Continuous abdominal pain No relation to eating/defecation Loss of daily function

0.79 0.40 0.77 0.73

Non-Rome symptoms Food sticks in lower esophagus

0.70

Non-Rome symptoms Food sticks with lump Lump relieved by dry swallows Lump relieved by swallowing food

0.80 0.79 0.74

See legend to Table 3.

daily activities by symptoms. In addition, the pain is characterised as diffuse, it awakens the individual during the night, and it is associated with abdominal tenderness. 3.1.8. Functional anorectal pain Factor 7 (Table 8) includes symptoms of both levator ani syndrome (rectal pain or aching, episodes lasting longer than Table 7 Gas-related disorders: aerophagia and bloating loading of the Rome I consensus criteria

Aerophagia Frequent swallowing Only transient relief by belching

0.38 0.67

Non-Rome symptoms Intentional belching Belching after meals Belching unrelated to meals Flatus frequency

0.76 0.71 0.64 0.43

Rumination syndrome Regurgitation Ruminate (rechew vomitus) Stops when vomitus turns sour Nausea is absent Vomiting is absent a

See legend to Table 3.

0.60 0.72 0.67 0.61 0.56 0.54 0.51 0.48 0.41

Non-Rome symptoms Pain during defecation Sharp pain in rectum or anus Burning, stinging during BM 0.81

a

F7

0.74

Rectal pain Rectal pain or aching Episodes last longer than 20 min

Globus Lump in throat between meals

F8a

F2a

Non-Rome symptoms Size of pain area Pain awakens from sleep When did pain start? Diffuse pain Abdominal tenderness Upper GI pain Lower GI pain Pain exacerbated by eating

Functional dysphagia Frequency of food sticking Difficulty drinking

a

Table 8 Functional abdominal pain and proctalgia loading of the Rome I consensus criteria

F9

0.73 0.77 0.50 0.75 −0.76

779

0.73 0.77 0.64 0.62 −0.56

See legend to Table 3.

20 min, pressure in the rectum) and proctalgia fugax (sharp pain in the rectum) [19,20]. However, it does not include symptoms of haemorrhoids or fissure (see negative loading for burning or stinging during a bowel movement). 3.2. Comparison of Italian and US samples Table 9 shows the 13 factors identified in the Italian sample and shows that 11 of these 13 factors corresponded closely to factors identified in the US sample. The principal difference was that the US functional abdominal pain factor (Factor 2) and the IBS factor (Factor 10) merged into a single Italian abdominal pain factor (Factor 1). This Italian pain factor correlated (r = 0.62) with the US functional abdominal pain factor and (r = 0.76) with the US IBS factor, demonstrating that it was an amalgam of both factors.

F12

3.3. Comparison of analyses in all US subjects to analyses limited to subjects with no organic basis for their gastrointestinal symptoms

0.36 0.84 0.84

The analyses described above included all subjects in the US and Italian samples, including some subjects who reported that they had a history of organic gastrointestinal diseases that could possibly have caused or contributed to their gastrointestinal symptoms. When the analyses were limited to subjects who denied any history of these organic diseases (i.e. peptic ulcer, liver disease, pancreatitis, gallbladder disease, gastrointestinal tract cancer, ulcerative colitis, Crohn’s disease, haemorrhoids, rectal prolapse or rectocele, pregnancy within the past 6 months, abdominal or pelvic surgery,

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Table 9 Agreement between US and Italian samples correlations between factor loadings for corresponding factors Factor

All subjects

Subjects with no organic disease explanation

US

Italy

US/Italy

US

Italy

US/Italy

Dysphagia Globus Heartburn Belching Ulcer-like dyspepsia Nausea and vomiting Bloating Rumination Pain Chronic/generalised pain Irritable bowel Constipation Diarrhoea Rectal pain

F6a F9 F3 F8 F13 F5 F11 F12

F9 F5 F2 F10 F7 F3 F6 –

0.647b 0.719 0.878 0.808 0.671 0.726 0.610 –

F6 F8 F3 F5 F11 F4 F10 F12

F11 F8 F2 F5 F7 F3 – –

0.727 0.748 0.840 0.803 0.652 0.511 – –

F2a F10 F1 F4 F7

F1 F1 F4 F8 F11

0.621b 0.764 0.839 0.566 0.678

F1

F1

0.866

F2 F7 F9

F4 F9 F6

0.516 0.548 0.664

a Factors are numbered in order of the amount of variance explained for a specific sample, e.g. factor F1 accounts for more of the variation between individual subjects in their symptoms than does factor F2. In columns 2 and 3 (and also in columns 5 and 6), the factors for the US sample are paired with the factors in the Italian sample with which they share the most content; thus, F6 in the total US sample corresponds to F9 in the total Italian sample. b Correlations were computed by identifying similar factors in two samples and then computing the Pearson correlation coefficient showing the relationship between factor loadings across all variables. Factor loadings refer to the contribution (strength of association) of each individual symptom in the questionnaire to the factor. All correlation coefficients shown were significant at P < 0.001.

or laparoscopy or laparotomy), there was a substantial reduction in the subject pool (n = 370 for the US sample). Nevertheless, as shown in columns 5–7 of Table 9, the results of the analysis were nearly identical. This is shown by similar factor numbers in column 2 versus column 5 (US sample) and similar factor numbers in column 3 versus column 6 (Italian sample). It is also shown by similar, highly significant correlations between the symptoms loading on corresponding factors in the US and the Italian samples (column 4 versus column 7 in Table 9). To further evaluate whether there were differences between the factor analyses based on all subjects and factor analyses restricted to subjects who denied any history of organic gastrointestinal disease, we identified similar factors in the whole sample and in the purely functional subset and computed the Pearson correlation coefficient showing the relationship between factor loadings across all variables. This was analogous to the way we compared US to Italian samples. Only minor differences were found. (A) In the subset of patients with no organic disease explanation for symptoms, a single general pain factor (Factor 1) was identified which correlated (r = 0.82) with functional abdominal pain in the whole study population and (r = 0.68) with IBS in the whole study population. This merging of the two pain factors in the more restricted study group is likely due to more limited statistical power. Eleven of the remaining 12 factors in the group with no organic disease explanation for symptoms showed good agreement with corresponding factors in the whole US study population with a median r = 0.94. (B) For the Italian sample, the only difference was that there was no bloating factor in the subsets of subjects with no history of organic disease. The remaining 10

factors showed good agreement with the total Italian sample, with a median r = 0.92.

4. Discussion Factor analysis is a powerful technique for summarising the correlations among symptoms and thereby identifying clusters of symptoms which aggregate together over large numbers of patients. As such it provides an empirical basis for discovering syndromes which may have a common etiology. This study provides empirical support to the Rome classification system by showing that there are clusters of symptoms which correspond to most of the classifications recommended by the Rome committees, and it extends previous studies by showing that these symptom clusters can be seen in a very different cultural group of Italian subjects as well as in gastroenterology clinic patients. Previous studies have been limited to mostly healthy community samples of US, Swedish or Australian subjects. Despite a high degree of concordance, however, this study also identifies differences between symptom clusters empirically derived by factor analysis and the Rome criteria. For IBS, the Rome I diagnostic criteria [13] (Table 3) required one of a set of three pain-related symptoms plus at least two of an additional set of symptoms related to altered bowel habits, bloating and mucus per rectum. Previous factor analyses showed that the first three symptoms formed the core of an irritable bowel syndrome factor. However, the second set of symptoms failed to aggregate with these pain-related symptoms but instead formed separate factors for constipation, diarrhoea and bloating. On the strength of

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these previous factor analysis studies, the Rome committee updated the Rome criteria (Rome II) [14] by specifying that patients must endorse at least two of the first set of three symptoms, but that the second set of symptoms was not required for the diagnosis of IBS. This study supports the revised criteria by showing again that the first three symptoms form the IBS factor. Additional symptoms aggregating with the IBS factor were pain in the lower abdomen (below the umbilicus), and pain that was intermittent rather than continuous. These may be useful additional symptom criteria. Note, however, that the symptom of abdominal pain exacerbated by eating did not show a significant correlation with the irritable bowel factor despite recent speculation that it should be included as a diagnostic criterion for IBS [21]. The Rome I and Rome II classification systems also distinguish functional abdominal pain from IBS. Functional abdominal pain is defined in Rome II as a constant or nearly constant pain which is disruptive to the individual’s work or social activities and which is unrelated to eating, defecation, or stress [14]. The factor analysis of the whole US sample of 1041 patients supports the distinction between functional abdominal pain and IBS (Table 9). However, in the analysis of smaller data sets of Italian subjects or US subjects without an organic basis for their symptoms, the functional abdominal pain and irritable bowel factors merged into a single factor (Table 9). This suggests that functional abdominal pain and IBS are different syndromes, but that it may be difficult to reliably distinguish between them on the basis of symptoms alone. The Rome II classification system [14] addresses this problem by stipulating that if the patient meets criteria for IBS, chronic functional abdominal pain cannot be diagnosed. Some investigators have speculated that there is no distinction between IBS and functional dyspepsia and that both represent manifestations of a generalised irritable gut syndrome [8,10]. However, this study identified separate factors for functional dyspepsia and IBS, suggesting that they are different disorders. Moreover, this analysis supports the distinction between ulcer- and dysmotility-like subtypes of functional dyspepsia: as shown in Table 5, Factor 13 consisted of abdominal pain which occurs independent of meals and is relieved by eating and by antacids, which is consistent with ulcer-like dyspepsia, whereas Factor 5 appeared to be a dysmotility-like syndrome defined by nausea, vomiting, early satiety and decreased appetite. Factor 5 is consistent with recent physiological evidence that there exists a syndrome of early satiety and weight loss associated with impaired gastric accommodation to a meal [22]. Thus, the results of this factor analysis are consistent with the Rome I classification of functional dyspepsia [15]. It was not possible to relate these study findings to the Rome II classification system for functional dyspepsia [23] because Rome II bases the distinction between ulcer- and dysmotility-like dyspepsia on whether the most bothersome upper gastrointestinal symptom was pain versus non-painful

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discomfort; this question was not asked in the current study. Although there is good evidence for the existence of two distinct physiological mechanisms for constipation—slow transit constipation related to impaired colon motility and pelvic floor dyssynergia related to pelvic floor dysfunction— the Rome II classification system did not propose identifying these two subtypes of constipation by different symptom clusters [20]. Instead, the Rome committees proposed that patients be identified only as having functional constipation on the basis of the presence of two or more of a set of symptoms which included symptoms often thought to be related to slow transit (i.e. infrequent and hard stools) as well as symptoms often thought to be related to pelvic floor dyssynergia (i.e. trouble letting go, digital facilitation of defecation). This study is consistent with the Rome II criteria in showing (Table 4) that all symptoms of constipation aggregate into a single cluster. Thus, physiological investigations such as whole gut transit time and anorectal manometry appear to be necessary to identify subtypes of constipation. The Rome I and Rome II criteria distinguish two subtypes of functional rectal pain: levator ani syndrome and proctalgia fugax [19,20]. Table 8 shows that there is a distinct syndrome of functional anorectal pain which can be distinguished from haemorrhoids or fissure because the pain is not characterized as burning or stinging. However, the subclassification between levator ani syndrome and proctalgia fugax was not supported by this factor analysis. Table 6 shows that there is a distinct heartburn syndrome which is consistent with the Rome I and Rome II definitions of functional heartburn [17,18]. However, it is not possible on the basis of symptoms alone to distinguish functional heartburn from gastroesophageal reflux. Similarly, it is not possible to distinguish functional dysphagia (Table 6) from dysphagia due to achalasia or other organic cause. Table 6 also shows that functional chest pain aggregates with symptoms of dysphagia and may not be a distinct entity. These findings are consistent with a technical review and practice guidelines on the indications for esophageal manometry, which concluded that unexplained chest pain and other esophageal motility disorders characterised by spasm or hypermotility cannot be reliably diagnosed by esophageal manometry, and there may be no useful distinctions among them [24]. Readers should bear in mind that factor analysis has one major limitation: it tries to put each symptom into a unique cluster. Although unique and specific symptoms are the best diagnostic markers, some symptoms which are important are nevertheless common to more than one disorder. For example, among infectious diseases, fever is a sign common to many diseases but specific to none. Among functional gastrointestinal disorders, abdominal pain could play a similar role. Another potential limitation of the study is that the subjects were recruited in different ways in the US sample (tertiary care clinic) and Italy (family members of patients

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in primary care clinics). Despite this difference, however, the symptoms defining functional gastrointestinal disorders showed striking similarities. Thus, rather than being a limitation of the study, this diversity serves only to increase the generalisability of the findings. This study extends previous studies by showing (a) that the results of factor analysis are not dependent on the particular questions used in any one survey; (b) that the symptom clusters were essentially unchanged when the analysis was restricted to patients with no known organic basis for their symptoms and (c) that the same symptom clusters were identified in Italian and US samples. Future studies should incorporate red-flag symptoms such as those described by Vanner and colleagues [4] into symptom questionnaires and should investigate whether it is possible to reliably distinguish organic disease from functional disorders on the basis of patient reported signs and symptoms. Studies are also needed to compare cross-cultural differences in IBS between countries with greater differences in diet and health care delivery systems.

Conflict of interest statement None declared.

List of abbreviations FD, Functional dyspepsia; IBS, Irritable bowel syndrome.

Acknowledgements Supported in part by grants KO5 MH00133 and RO1 DK31369.

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