Reply. We thank Drs Siah and Gwee for their interest in our study, in which we reported an exploratory factor analysis of Rome IV symptoms (Clevers et al), which we refer to as the Rome IV exploratory model (R4EM) similar to Siah and Gwee

Clevers, E.

Palsson, O.S.

Simrén, M.

Sperber, A.D.

Tack, J.

Törnblom, H.

Van Oudenhove, L.

Whitehead, W.E.

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Reply. We thank Drs Siah and Gwee for theirinterest in our study, in which we reported an exploratory factor analysis of Rome IV symp-toms (Clevers et al1), which we refer to as the Rome IV exploratory model (R4EM) similar to Siah and Gwee. The Rome IV consensus uses an anatomic basis to subdivideTable 1. Comparison of the Rome IV, AFGID, and R4EM Symptom Factors in AdultsRome IV AFGID R4EMEsophageal A1. Chest pain Chest pain and heartburn Chest pain and heartburnA2. Functional heartburnA3. Reflux hypersensitivityA4. Globus Globus, dysphagia, odynophagia Globus, dysphagia, odynophagiaA5. Functional dysphagiaGastroduodenal B1a. Postprandial Distress Syndrome (PDS) Upper abdominal symptomsB1b. Epigastric Pain Syndrome (EPS)B2a. Gastric belchingB2b. Esophageal belchingB3a. Chronic nausea, vomiting Regurgitation, nausea, vomiting Nausea, vomitingB3b. Cyclic vomitingB3c. Cannabinoid hyperemesisB4. RuminationBowel C1. IBS Abdominal pain with diarrhea IBSC3. Diarrhea DiarrheaC2. Constipation ConstipationC4. Bloating, distensionPain D. Abdominal pain Abdominal painOutside Rome IV Meal-related bowel symptomsUpper abdominal pain with constipationBloating, fullness, belching, flatulenceIBS, irritable bowel syndrome.functional gastrointestinal disorders (Table 1). In theirLetter to the Editor,2 Drs Siah and Gwee made 2 points.First, they stated that R4EM did not quite mirror theRome IV diagnostic classification. Although we agree thatnot all disorders defined in Rome IV were captured bythe exploratory factor analysis in R4EM, our confirma-tory factor analysis showed empirically that agreementwith the Rome IV diagnostic classification in R4EM wasquite good (Table 1). R4EM thus largely reinforces theRome IV criteria and their use in research and clinicalcare.Second, Siah and Gwee highlight similarities betweenR4EM and an Asian Rome III factor analysis by Siah et al(Asian Functional Gastrointestinal Disorder [AFGID]Symptom Clusters).3 We agree that both studies shareimportant similarities. For instance, both identified aglobus/dysphagia factor, a heartburn/chest pain factor,and a nausea/vomiting factor (Table 1). The main find-ings of AFGID were symptom factors characterized byupper abdominal symptoms, associated with bowelfunction. This type of overlapping conditions is notconsidered in the Rome consensus and its predominantlyanatomic subdivision. The question is how specific this isto the questionnaire used in AFGID and symptom ex-pressions or perceptions in Asia, or whether this is aninherent flaw in the Rome approach.4Drs Siah and Gwee argue that overlap between upper-and lower-tract symptoms also is present in R4EMbecause loose stools after a meal was part of the diarrheafactor in our analysis. However, this refers to the timingof bowel symptoms in relation to an upper gastrointes-tinal event (meal intake), rather than location of bowel-associated symptoms in the upper abdomen. Theoccurrence of bowel symptoms in relation to a meal isnot novel and is well established in the literature.5,6The current R4EM analyses found that the lower GIsymptoms were not significantly associated with upperGI symptom locations, and vice versa, as shown inTable 1. Hence, taken together, the R4EM adheres mostclosely to the Rome IV consensus and differs moresignificantly from the AFGID findings.However, although factor analysis is a useful tool tovalidate the Rome questionnaire, this type of analysis isalso sensitive to wording and content of questions andvarious statistical choices, and should be interpretedcritically. When comparing the findings of AFGID andR4EM, one needs to take into account that AFGID wasconducted in patients presenting to gastroenterologyclinics, which may already account for some of the dif-ferences. In addition, R4EM used the Rome IV question-naire, and, hence, confirming categories close to the RomeIV criteria should not come as a surprise. The AFGIDquestionnaire was based on the Rome III consensus, butadapted and expanded, taking into account Asian lan-guages, culture, and symptom expressions.3 Because theseadaptations were not performed in R4EM, the currentanalysis cannot deny the relevance of these adaptations.We are highly appreciative of the contribution of DrsSiah and Gwee, and colleagues in their AFGID report andin the current letter.2,3 It is also our opinion that theRome questionnaire, enriched with the questions andconcepts as used in AFGID, should be used in a largepopulation of patients (and perhaps the generalpopulation) in the West, to determine whether or notthe overlapping factors also are found in this part ofthe world, which would be a major step ahead inEGBERT CLEVERS, PhDTranslational Research Center forGastrointestinal DisordersUniversity of LeuvenLeuven, BelgiumDepartment of Internal Medicine andClinical Nutrition, Institute of MedicineSahlgrenska Academy, University of GothenburgGothenburg, SwedenWILLIAM E. WHITEHEAD, PhDOLAFUR S. PALSSON, PhDCenter for Functional Gastrointestinal andMotility DisordersUniversity of North Carolina at Chapel HillChapel Hill, North CarolinaAMI D. SPERBER, MDFaculty of Health Sciences,Ben-Gurion University of the NegevBeer-Sheva, IsraelHANS TÖRNBLOM, MDDepartment of Internal Medicine andClinical Nutrition, Institute of MedicineSahlgrenska Academy, University of GothenburgGothenburg, SwedenLUKAS VAN OUDENHOVE, MDJAN TACK, MDTranslational Research Center forGastrointestinal DisordersUniversity of LeuvenLeuven, BelgiumMAGNUS SIMRÉN, MDDepartment of Internal Medicine andClinical Nutrition, Institute of MedicineSahlgrenska Academy, University of GothenburgGothenburg, SwedenCenter for Functional Gastrointestinal andMotility DisordersUniversity of North Carolina at Chapel HillChapel Hill, North Carolinadeveloping a universal symptom analysis and categorization system. Meanwhile, in the West, the Rome IV subdivision seems to have a solid basis for current use in clinical practice and research, while we continue research to increase our knowledge and insights. The Rome Foundation will soon publish the results of a 32-country global epidemiologic study including 8 countries from Asia. Although that study’s questionnaire was not enriched with the questions and concepts used in AFGID as discussed earlier, it will provide an excellent opportunity to look further into potential differences between East and West based on the Rome IV diagnostic questionnaire and many potentially associated factors that might explain some of the differences, if found.References1. Clevers E, et al. Clin Gastroenterol Hepatol 2018;16:1252–1259.e5.2. Siah KTH, et al. Clin Gastroenterol Hepatol 2018. Epub ahead ofprint.3. Siah KTH, et al. Gut 2018;67:1071–1077.4. Holtmann GJ, et al. Gut 2018;67:1911–1915.5. Posserud I, et al. United Eur Gastroenterol J 2013;1:358–367.6. Van Oudenhove L, et al. Gastroenterology 2016;150:866–874.Conflicts of interestThe authors disclose no conflicts.

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