Participants and Setting



SUPPLEMENTARY METHODSParticipants and SettingWe recruited individuals who self-identified as having IBS registered with three UK organizations. These were the IBS network, the registered charity for people living with the condition, TalkHealth, an online social health community providing information about various medical conditions, and ContactMe-IBS, a dedicated register allowing individuals with IBS not receiving specialist care currently to participate in research. This cohort has been described elsewhere. PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CbGFjazwvQXV0aG9yPjxZZWFyPjIwMTk8L1llYXI+PFJl

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ZE5vdGU+AG==

ADDIN EN.CITE.DATA 1 2 There were no exclusion criteria, other than an inability to understand written English. We approached all individuals registered with these organizations, via a postal and electronic mailshot, between December 2017 and December 2018. This correspondence directed them to a website, where they were able to access further information about the study. Those interested could complete a web-based questionnaire, with their responses stored in a secure online database. We received approval for the study from the University of Leeds research ethics committee in November 2017. Data Collection and SynthesisDemographic and Symptom DataWe collected basic demographic data, and asked respondents to state whether they had seen a primary care physician or a gastroenterologist about their IBS symptoms. We captured lower gastrointestinal symptom data using the Rome III and Rome IV questionnaires, PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaGl0ZWhlYWQ8L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFy

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ADDIN EN.CITE.DATA 5 6 We assessed severity of IBS symptoms using the IBS severity scoring system (IBS-SSS). ADDIN EN.CITE <EndNote><Cite><Author>Francis</Author><Year>1997</Year><RecNum>576</RecNum><DisplayText><style face="superscript">7</style></DisplayText><record><rec-number>576</rec-number><foreign-keys><key app="EN" db-id="205z2fee50v20jea9xrpapzi2v9dta2de5vw" timestamp="1403259204">576</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Francis, C. Y.</author><author>Morris, J.</author><author>Whorwell, P. J.</author></authors></contributors><titles><title>The irritable bowel severity scoring system: A simple method of monitoring irritable bowel syndrome and its progress</title><secondary-title>Aliment Pharmacol Ther</secondary-title></titles><periodical><full-title>Aliment Pharmacol Ther</full-title></periodical><pages>395-402</pages><volume>11</volume><reprint-edition>NOT IN FILE</reprint-edition><dates><year>1997</year></dates><urls></urls></record></Cite></EndNote>7 This measures presence, severity, and frequency of abdominal pain, presence and severity of abdominal distension, satisfaction with bowel habit, and degree to which IBS symptoms are affecting, or interfering with, the person’s life. The maximum score is 500 points: <75 points indicates remission of symptoms; 75-174 points mild symptoms; 175-299 points moderate symptoms; and 300-500 points severe symptoms.Assessment of Mood and Extra-Intestinal SymptomsWe collected anxiety and depression data using the hospital anxiety and depression scale (HADS). ADDIN EN.CITE <EndNote><Cite><Author>Zigmond</Author><Year>1983</Year><RecNum>2008</RecNum><DisplayText><style face="superscript">8</style></DisplayText><record><rec-number>2008</rec-number><foreign-keys><key app="EN" db-id="205z2fee50v20jea9xrpapzi2v9dta2de5vw" timestamp="1403259239">2008</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Zigmond, A. S.</author><author>Snaith, R. P.</author></authors></contributors><titles><title>The hospital anxiety and depression scale</title><secondary-title>Acta Psychiatr Scand</secondary-title></titles><periodical><full-title>Acta Psychiatr Scand</full-title></periodical><pages>361-370</pages><volume>67</volume><reprint-edition>NOT IN FILE</reprint-edition><dates><year>1983</year></dates><urls></urls></record></Cite></EndNote>8 The total HADS score ranges from a minimum of 0 to a maximum of 21 for either anxiety or depression. We collected extra-intestinal symptom data using the patient health questionnaire-12 (PHQ-12), ADDIN EN.CITE <EndNote><Cite><Author>Spiller</Author><Year>2010</Year><RecNum>2048</RecNum><DisplayText><style face="superscript">9</style></DisplayText><record><rec-number>2048</rec-number><foreign-keys><key app="EN" db-id="205z2fee50v20jea9xrpapzi2v9dta2de5vw" timestamp="1407938696">2048</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Spiller, R. C.</author><author>Humes, D. J.</author><author>Campbell, E.</author><author>Hastings, M.</author><author>Neal, K. R.</author><author>Dukes, G. E.</author><author>Whorwell, P. J.</author></authors></contributors><titles><title>The Patient Health Questionnaire 12 Somatic Symptom scale as a predictor of symptom severity and consulting behaviour in patients with irritable bowel syndrome and symptomatic diverticular disease</title><secondary-title>Aliment Pharmacol Ther</secondary-title></titles><periodical><full-title>Aliment Pharmacol Ther</full-title></periodical><pages>811-20</pages><volume>32</volume><dates><year>2010</year></dates><isbn>1365-2036 (Electronic)&#xD;0269-2813 (Linking)</isbn><work-type>Research Support, Non-U S Gov&apos;t</work-type><urls></urls></record></Cite></EndNote>9 derived from the validated PHQ-15. ADDIN EN.CITE <EndNote><Cite><Author>Kroenke</Author><Year>2002</Year><RecNum>955</RecNum><DisplayText><style face="superscript">10</style></DisplayText><record><rec-number>955</rec-number><foreign-keys><key app="EN" db-id="205z2fee50v20jea9xrpapzi2v9dta2de5vw" timestamp="1403259213">955</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kroenke, K.</author><author>Spitzer, R. L.</author><author>Williams, J. B. W.</author></authors></contributors><titles><title>The PHQ-15: Validity of a new measure for evaluating the severity of somatic symptoms</title><secondary-title>Psychosom Med</secondary-title></titles><periodical><full-title>Psychosom Med</full-title></periodical><pages>258-266</pages><volume>64</volume><reprint-edition>NOT IN FILE</reprint-edition><dates><year>2002</year></dates><urls></urls></record></Cite></EndNote>10 The total PHQ-12 score ranges from a minimum of 0 to a maximum of 24. Assessment of Gastrointestinal Symptom-specific Anxiety and Perceived StressWe used the 15-item visceral sensitivity index (VSI), ADDIN EN.CITE <EndNote><Cite><Author>Labus</Author><Year>2004</Year><RecNum>3784</RecNum><DisplayText><style face="superscript">11</style></DisplayText><record><rec-number>3784</rec-number><foreign-keys><key app="EN" db-id="205z2fee50v20jea9xrpapzi2v9dta2de5vw" timestamp="1540742515">3784</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Labus, J. S.</author><author>Bolus, R.</author><author>Chang, L.</author><author>Wiklund, I.</author><author>Naesdal, J.</author><author>Mayer, E. A.</author><author>Naliboff, B. D.</author></authors></contributors><auth-address>Center for Neurovisceral Sciences and Women&apos;s Health, VA GLA Healthcare System, Los Angeles, CA 90073, USA.</auth-address><titles><title>The Visceral Sensitivity Index: Development and validation of a gastrointestinal symptom-specific anxiety scale</title><secondary-title>Aliment Pharmacol Ther</secondary-title></titles><periodical><full-title>Aliment Pharmacol Ther</full-title></periodical><pages>89-97</pages><volume>20</volume><edition>2004/07/01</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Anxiety/*diagnosis/etiology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Irritable Bowel Syndrome/*psychology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Predictive Value of Tests</keyword><keyword>Psychometrics</keyword><keyword>Quality of Life</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Surveys and Questionnaires/standards</keyword><keyword>Viscera</keyword></keywords><dates><year>2004</year><pub-dates><date>Jul 1</date></pub-dates></dates><isbn>0269-2813 (Print)&#xD;0269-2813</isbn><accession-num>15225175</accession-num><urls></urls><electronic-resource-num>10.1111/j.1365-2036.2004.02007.x</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>11 which measures gastrointestinal symptom-specific anxiety. Replies to each item are provided on a six-point scale from “strongly disagree” (scored as 0) to “strongly agree” (scored as 5). There are no validated cut offs to define low, medium, or high levels of gastrointestinal symptom-specific anxiety, so we divided these data into equally sized tertiles. We utilized the 10-item version of the Cohen perceived stress scale (CPSS) to assess perceived stress, which is derived from the original 14-item instrument. ADDIN EN.CITE <EndNote><Cite><Author>Cohen</Author><Year>1983</Year><RecNum>3778</RecNum><DisplayText><style face="superscript">12</style></DisplayText><record><rec-number>3778</rec-number><foreign-keys><key app="EN" db-id="205z2fee50v20jea9xrpapzi2v9dta2de5vw" timestamp="1540733663">3778</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cohen, S.</author><author>Kamarck, T.</author><author>Mermelstein, R.</author></authors></contributors><titles><title>A global measure of perceived stress</title><secondary-title>J Health Soc Behav</secondary-title></titles><periodical><full-title>J Health Soc Behav</full-title><abbr-1>Journal of health and social behavior</abbr-1></periodical><pages>385-96</pages><volume>24</volume><edition>1983/12/01</edition><keywords><keyword>Adult</keyword><keyword>Affective Symptoms/psychology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Life Change Events</keyword><keyword>Male</keyword><keyword>Psychometrics</keyword><keyword>Stress, Psychological/*diagnosis</keyword><keyword>Students/psychology</keyword><keyword>Tobacco Use Disorder/psychology</keyword></keywords><dates><year>1983</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>0022-1465 (Print)&#xD;0022-1465</isbn><accession-num>6668417</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>12 It is considered to be psychometrically reliable and comparable with its predecessor, ADDIN EN.CITE <EndNote><Cite><Author>Cohen</Author><Year>1988</Year><RecNum>3816</RecNum><DisplayText><style face="superscript">13</style></DisplayText><record><rec-number>3816</rec-number><foreign-keys><key app="EN" db-id="205z2fee50v20jea9xrpapzi2v9dta2de5vw" timestamp="1544515771">3816</key></foreign-keys><ref-type name="Book Section">5</ref-type><contributors><authors><author>Cohen, S.</author><author>Williamson, G. M.</author></authors><secondary-authors><author>S. Spacapan &amp; S. Oskamp </author></secondary-authors></contributors><titles><title>Perceived stress in a probability sample in the United States.</title><secondary-title>The social psychology of health</secondary-title></titles><pages>31-67</pages><dates><year>1988</year></dates><pub-location>Oxford</pub-location><publisher>Newbury Park, CA</publisher><urls></urls></record></Cite></EndNote>13 and measures the degree to which the individual feels they have experienced stress in the previous month. Again, there are no validated cut offs to define low, medium, or high levels of perceived stress, so again we divided these data into equally sized tertiles.SUPPLEMENTARY RESULTSLatent Class Analysis in the Rome III CohortIn this cohort, as with the Rome IV cohort, the best LCA solution was achieved with seven clusters, as indicated by the lowest value of the BIC(LL) (Supplementary Figure 2). An overview of the seven-cluster result is provided in Supplementary Figure 3, and more detail is presented in Supplementary Figure 4, with radar plots depicting the specific symptom profile for each cluster. The characteristics of the seven clusters were almost identical to those identified in the Rome IV cohort analysis. Cluster Assignment Among Those Individuals Not Meeting Rome III or IV Criteria for IBSThere were 271 individuals who, although they identified as having IBS, met neither the Rome III nor Rome IV criteria for IBS. In the case of Rome IV, this was because, in 235 people (86.7%), their GI symptoms were mild, although 89 (37.9%) of these reported psychological symptoms. When we applied the Rome IV-derived model to these 271 people, 146 (53.9%) were assigned to cluster 3, with low overall gastrointestinal symptoms and low psychological burden, and 89 (32.8%) to cluster 2, with low overall gastrointestinal symptoms and high psychological burden. The findings for the Rome III criteria, and applying the Rome III-derived model, were similar.10-fold Cross-validation for the Rome IV and Rome III Latent Class AnalysesThe misclassification statistic for the Rome IV cohort seven-cluster LCA was 12.2%, compared with 14.8% when 10-fold cross-validation was carried out. This suggests we could expect the model to perform similarly, if applied to a different dataset containing the same variables. When we undertook the cross-validation process manually and drew radar plots to characterize the clusters resulting from each iteration, seven clusters of very similar appearance occurred each time, matching the characteristics of the seven clusters described in our original analysis. The results from 10-fold cross-validation in the Rome III cohort were broadly similar; the misclassification statistic for the Rome III cohort seven-cluster LCA was 14.4%, compared with 16.4% when 10-fold cross-validation was carried out.Supplementary Figure 1. Values of BIC(LL) Plotted for Each Specification of the Number of Clusters in the Rome IV Cohort.Lowest value of BIC(LL) indicates the optimum number of clusters. The model converges on a 7-cluster solution being the best fit for the model.BIC(LL): Bayesian information criterion of the log-likelihood.Supplementary Figure 2. Values of BIC(LL) Plotted for Each Specification of the Number of Clusters in the Rome III Cohort.Lowest value of BIC indicates the optimum number of clusters. The model converges on a 7-cluster solution being the best fit for the model.BIC(LL): Bayesian information criterion of the log-likelihood. Supplementary Figure 3. Latent Class Analysis in a Cohort of 1080 People with Rome III IBS. 606425083820689610083820Cluster 1 (22%): Diarrhea and urgency with low psychological burdenCluster 1 (22%): Diarrhea and urgency with low psychological burden3949700213995624840092075609492192803609600038735692785032385Cluster 2 (21%): Low overall gastrointestinal symptom severity with high psychological burdenCluster 2 (21%): Low overall gastrointestinal symptom severity with high psychological burden0231775Latent class analysis1080 people with Rome III IBSLatent class analysis1080 people with Rome III IBS394335047625696595031750Cluster 3 (20%):Low overall gastrointestinal symptom severity with low psychological burden0Cluster 3 (20%):Low overall gastrointestinal symptom severity with low psychological burden6127750635039433501727203949700274320394970026797039497002616203949700274320615315054610695960035560Cluster 4 (17%):Diarrhea, abdominal pain, and urgency with high psychological burden Cluster 4 (17%):Diarrhea, abdominal pain, and urgency with high psychological burden 6959600116205Cluster 5 (7%):Constipation, abdominal pain, and bloating with high psychological burden0Cluster 5 (7%):Constipation, abdominal pain, and bloating with high psychological burden6178550154305633060915430564826671543056634726154305678678515430561890797809763411397809761849001377956336959137795648901713779566410761377956793135137795695325099695Cluster 6 (7%):High overall gastrointestinal symptom severity with high psychological burdenCluster 6 (7%):High overall gastrointestinal symptom severity with high psychological burden6195429614716347489614716191250114935694055089175Cluster 7 (6%):Constipation and bloating with low psychological burdenCluster 7 (6%):Constipation and bloating with low psychological burden32232603527425D00D-1905003572510C00C3135630264795000-27559026974800032194505596890F00F3129280475805500314896555816500-26670063627032689801498600B00B-1562101536700A00ASupplementary Figure 4. Profiles of the Seven Latent Class Clusters Identified in the Rome III Cohort.-285750607631500-2120907763510G00G-1866905642610E00E-28575039808150035312354445= adjusted cohort mean= adjusted cohort meanCluster 1: Diarrhea and urgency with low psychological burden.Cluster 2: Low overall gastrointestinal symptom severity with high psychological burden.Cluster 3: Low overall gastrointestinal symptom severity with low psychological burden.Cluster 4: Diarrhea, abdominal pain, and urgency with high psychological burden.Cluster 5: Constipation, abdominal pain, and bloating with high psychological burden.Cluster 6: High overall gastrointestinal symptom severity with high psychological burden.Cluster 7: Constipation and bloating with low psychological burden.BM: bowel movement; SOB: shortness of breath; TATT: tired all the timeSupplementary Table 1. Variables Used in the Latent Class AnalysisVariableType of variableScale of MeasurementReason for including in the modelGastrointestinal SymptomsFrequency of abdominal pain (or discomfort*) anywhere in the abdomen in past 3 monthsOrdinal9-point scale from “Never” (0) to “Multiple times per day or all the time” (8)All of these variables for quantifying gastrointestinal symptoms were taken from Rome Foundation questionnaires. These are the recognized “gold standard” for diagnosing IBS, and are widely used.Frequency of abdominal pain being closely related to a bowel movementOrdinal11-point scale from “0%” (never) to “100%” (always)Frequency with which abdominal pain improved or resolved following a bowel movementOrdinal11-point scale from “0%” (never) to “100%” (always)Frequency with which stools became softer or harder than usual in association with abdominal painOrdinal11-point scale from “0%” (never) to “100%” (always)Frequency with which stools became more or less frequent than usual in association with abdominal painOrdinal11-point scale from “0%” (never) to “100%” (always)Frequency with which abdominal pain started or got worse after a mealOrdinal11-point scale from “0%” (never) to “100%” (always)Frequency with which abdominal pain restricted usual activitiesOrdinal11-point scale from “0%” (never) to “100%” (always)Frequency of hard or lumpy stools in last 3 monthsOrdinal5-point scale from “0%” (never or rarely) to “100%” (always)Frequency of loose, mushy, or watery stools in the last 3 monthsOrdinal5-point scale from “0%” (never o rarely) to “100%” (always)Frequency of fecal urgency over last 3 monthsOrdinal9-point scale from “Never” (0) to “Multiple times per day or all the time” (8)Frequency of fecal incontinence over last 3 monthsOrdinal9-point scale from “Never” (0) to “Multiple times per day or all the time” (8)Frequency of abdominal bloating or distension over last 3 monthsOrdinal9-point scale from “Never” (0) to “Multiple times per day or all the time” (8)Extraintestinal SymptomsAll individual items of the PHQ-12 and the frequency experienced in the last 4 weeks:Back painArm, leg, joint painPeriod pain/period problemsHeadachesChest painDizzinessFainting spellsHeart pounding/racingShortness of breathPain/problems during sexFeeling tired or low in energyTrouble sleepingOrdinal3-point scale: “Never” (0), “A little” (1), or “A lot” (2)Reporting symptoms referable to multiple body systems, also referred to as somatization, is recognized as being associated with IBS and other functional GI disorders. The PHQ-12 questionnaire is a widely used and validated method for measuring this.MoodPresence of anxiety, as measured by the total score of the HADS-Anxiety questionnaireOrdinal3-point scale: normal (0), borderline (1), or abnormal (2)Abnormal mood is well-recognized as being an important factor in IBS. The HADS questionnaire for quantifying the presence of anxiety and/or depression are widely used and validated for this purpose.Presence of depression, as measured by the total score of HADS-Depression questionnaireOrdinal3-point scale: normal (0), borderline (1), or abnormal (2)HADS: hospital anxiety and depression scale; IBS: irritable bowel syndrome; PHQ-12: patient health questionnaire-12* Discomfort was included, in addition to pain, for the Rome III definition of IBS, as per Rome III criteria.Supplementary Table 2. Characteristics of Latent Class Clusters in the Rome III Cohort.Cluster 1Diarrhea and urgency with low psychological burden(n = 236)Cluster 2Low overall GI symptom severity with high psychological burden(n = 225)Cluster 3Low overall GI symptom severity with low psychological burden(n = 212)Cluster 4Diarrhea, abdominal pain, and urgency with high psychological burden(n = 185)Cluster 5Constipation, abdominal pain, and bloating with high psychological burden(n = 81)Cluster 6High overall GI symptom severity with high psychological burden(n = 80)Cluster 7Constipation and bloating with low psychological burden(n = 61)P value*Mean age (SD)53.3 (15.4)48.6 (15.2)48.3 (16.4)46.8 (14.1)40.0 (13.5)46.4 (13.6)47.66 (13.6)<0.001Female (%)202 (85.6)181 (80.4)167 (78.8)161 (87.0)78 (96.3)70 (87.5)56 (91.8)0.002Seen a gastroenterologist with IBS (%)132 (55.9)136 (60.4)104 (49.1)119 (64.3)40 (49.4)53 (67.1)62 (59.0)0.014High VSI scores (%)53 (22.5)73 (32.6)27 (12.7)97 (52.4)47 (58.8)60 (75.9)15 (24.6)<0.001High CPSS scores (%)31 (13.1)72 (32.0)21 (9.9)92 (50.0)43 (53.1)66 (82.5)14 (23.0)<0.001Severe symptoms on IBS-SSS (%)59 (25.2)73 (32.4)23 (10.8)100 (54.3)55 (67.9)69 (86.3)17 (27.9)<0.001Subtype on BSFSIBS-C (%)10 (4.2)38 (17.0)49 (23.1)4 (2.2)46 (56.8)3 (3.8)45 (73.8)IBS-D (%)149 (63.1)61 (27.2)70 (33.0)105 (56.8)2 (2.5)26 (32.5)5 (8.2)IBS-M (%)65 (27.5)116 (51.8)81 (38.2)74 (40.0)32 (39.5)47 (58.8)10 (16.4)IBS-U (%)12 (5.1)9 (4.0)12 (5.7)2 (1.1)1 (1.2)4 (5.0)1 (1.6)<0.001IBS after acute enteric infection (%)34 (14.4)28 (12.5)37 (17.5)24 (13.0)9 (11.1)12 (15.2)3 (4.9)0.269BSFS: Bristol stool form scale; GI: gastrointestinal; IBS-SSS: irritable bowel syndrome symptom severity score; CPSS: Cohen perceived stress scale; VSI: visceral sensitivity index.* P value for Pearson χ2 for comparison of categorical data and one-way ANOVA for comparison of means. ADDIN EN.REFLIST REFERENCES1. Black CJ, Yiannakou Y, Houghton LA, et al. Epidemiological, clinical, and psychological characteristics of individuals with self-reported irritable bowel syndrome based on the Rome IV vs Rome III criteria. Clin Gastroenterol Hepatol 2019; doi: 10.1016/j.cgh.2019.05.037 doi: 10.1016/j.cgh.2019.05.037 2. Black CJ, Yiannakou Y, Houghton LA, et al. Anxiety-related factors associated with symptom severity in irritable bowel syndrome. Neurogastroenterol Motil 2020:e13872. doi: 10.1111/nmo.13872 3. Whitehead WE, and the Validation Working Team Committee in association with the Rome Questionnaire C. Development and validation of the Rome III diagnostic questionnaire. In: Drossman DA, editorRome III: The functional gastrointestinal disorders, 3rd editionVirginia: Degnon Associates Inc 2006:835-53.4. Palsson OS, Whitehead WE, van Tilburg MA, et al. Rome IV diagnostic questionnaires and tables for investigators and clinicians. Gastroenterology 2016;150:1481-91. 5. Longstreth GF, Thompson WG, Chey WD, et al. Functional bowel disorders. Gastroenterology 2006;130:1480-91.6. Mearin F, Lacy BE, Chang L, et al. Bowel disorders. Gastroenterology 2016;150:1393-407. 7. Francis CY, Morris J, Whorwell PJ. The irritable bowel severity scoring system: A simple method of monitoring irritable bowel syndrome and its progress. Aliment Pharmacol Ther 1997;11:395-402.8. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983;67:361-70.9. Spiller RC, Humes DJ, Campbell E, et al. The Patient Health Questionnaire 12 Somatic Symptom scale as a predictor of symptom severity and consulting behaviour in patients with irritable bowel syndrome and symptomatic diverticular disease. Aliment Pharmacol Ther 2010;32:811-20.10. Kroenke K, Spitzer RL, Williams JBW. The PHQ-15: Validity of a new measure for evaluating the severity of somatic symptoms. Psychosom Med 2002;64:258-66.11. Labus JS, Bolus R, Chang L, et al. The Visceral Sensitivity Index: Development and validation of a gastrointestinal symptom-specific anxiety scale. Aliment Pharmacol Ther 2004;20:89-97. 12. Cohen S, Kamarck T, Mermelstein R. A global measure of perceived stress. Journal of health and social behavior 1983;24:385-96. 13. Cohen S, Williamson GM. Perceived stress in a probability sample in the United States. In: Oskamp SSS, ed. The social psychology of health. Oxford: Newbury Park, CA 1988:31-67. ................
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