The term upper gastrointestinal disorders (UGID) covers

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2004;2: Responsiveness and Interpretation of a Quality of Life Questionnaire Specific to Upper Gastrointestinal Disorders CHRISTINE DE LA LOGE,* ELYSE TRUDEAU,* PATRICK MARQUIS, DENNIS A. REVICKI, ANNE M. RENTZ, VINCENZO STANGHELLINI, NICHOLAS J. TALLEY, PETER KAHRILAS, # JAN TACK,** and DOMINIQUE DUBOIS *Mapi Values, Lyon, France; Mapi Values, Boston, Massachusetts; MEDTAP International, Inc., Bethesda, Maryland; Department of Internal Medicine and Gastroenterology, University of Bologna, Bologna, Italy; Department of Medicine, University of Sydney, Sydney, Australia; # Division of Gastroenterology, Northwestern University, Chicago, Illinois; **Department of Gastroenterology, University of Leuven, Leuven, Belgium; and Johnson & Johnson Pharmaceutical Services, LLC, Beerse, Belgium Background & Aims: The Patient Assessment of Upper Gastrointestinal Disorders Quality of Life (PAGI-QOL) has been developed and validated to assess quality of life in gastroesophageal reflux disease, dyspepsia, and gastroparesis. The aim of this work was to assess responsiveness of the PAGI-QOL to clinical changes and provide guidance for the interpretation of score changes. Methods: The analysis was based on 2 observational multicenter, longitudinal, 8-week observation studies, one in the United States and one in 5 European countries. The Overall Treatment Effect scale completed by patients and clinicians at 8 weeks was used to define groups of improved, worsened, and stable patients. Responsiveness was assessed by describing the change in PAGI-QOL scores for each of these groups, comparing these changes over time, and calculating effect sizes and standardized response means. These data were used to define the minimal clinically important difference. Results: A total of 1736 patients with upper gastrointestinal disorders were analyzed. High sensitivity to change over time was demonstrated, with effect sizes and standardized response means in improved patients for the PAGI-QOL total score ranging from A change of 0.4 for the PAGI-QOL total score might be considered as the minimal clinically important difference when comparing pretreatment and post-treatment PAGI-QOL total scores. Conclusions: The PAGI-QOL questionnaire is a responsive and clinically relevant instrument for assessing quality of life in patients with upper gastrointestinal disorders. The term upper gastrointestinal disorders (UGID) covers a spectrum of diseases sharing common symptoms. This research concentrates on 3 common UGID in Western countries: gastroesophageal reflux disease (GERD), 1 dyspepsia, 2,3 and gastroparesis. 4,5 Diagnosis for these 3 disorders is based largely on patients complaints, and it is therefore important to ask the patients to rate the severity of their symptoms and the impact that they have on their quality of life (QoL). The need to obtain such self-rated data is being increasingly recognized, 6 especially in diseases such as UGID, in which objective end points are generally not identified. This scarcity of objective measures has meant that QoL and more general patient-reported outcomes (PRO) are increasingly used in clinical trials as efficacy end points. It is therefore important to develop instruments whose rigor matches that of other measures performed in such studies. The effectiveness of this strategy therefore depends on the existence of QoL instruments developed and tested in these disorders that have been shown to give accurate, relevant, and responsive results in clinical trial settings. Disease-specific instruments are known to be more responsive to clinical changes than generic instruments and are therefore more appropriate for clinical trials designed to evaluate specific treatment effects. 6 At the onset of this project, an extensive review of the literature was performed to identify existing PRO instruments specific to UGID disorders. 7 The findings of the literature review indicated that several QoL instruments existed. However, the instruments identified were lacking at least one of the following desired features: (1) proven reliability, validity, and responsiveness; (2) adapted to the 3 main UGID populations, i.e., GERD, dyspepsia, and gastroparesis; and (3) available in a large Abbreviations used in this paper: ES, effect sizes; GERD, gastroesophageal reflux disease; HRQoL, health-related quality of life; MID, minimal important difference; OTE, Overall Treatment Effect; PAGI- QOL, Patient Assessment of Upper Gastrointestinal Disorders Quality of Life instrument; PRO, patient-report outcomes; QoL, quality of life; SRM, standardized response mean; UGID, upper gastrointestinal disorders by the American Gastroenterological Association /04/$30.00 PII: /S (04)

2 September 2004 RESPONSIVENESS AND INTERPRETATION OF THE PAGI-QOL 779 number of languages. It was therefore decided to develop an instrument with these desired features. The Patient Assessment of Upper Gastrointestinal Disorders Quality Of Life instrument (PAGI-QOL) was created from interviews of patients with GERD (n 55), dyspepsia (n 41), and gastroparesis (n 28) performed in 6 different countries (France, Germany, Italy, Poland, Sweden, and the United States). It was then finalized and successfully evaluated for reliability (Cronbach s alpha ranged from , and intraclass correlation coefficients were over 0.70 except for the relationship scale [0.61]), concurrent validity (correlation with SF-36 summary scores ranged from ), and clinical or known groups validity (PAGI-QOL scores showed excellent discriminant properties; patients who had spent some days in bed, had missed some days at work, or were kept from usual activities had much lower PAGI-QOL scores than those who did not [P ]) during an international validation study in GERD, dyspepsia, and gastroparesis populations. Results at country and at disease level were consistent with pooled results. The development and psychometric evaluation of the PAGI-QOL are described in a separate manuscript in preparation. Once the psychometric properties of an instrument have been successfully evaluated, the challenge then becomes one of deciding the significance of any changes observed, just as with traditional medical criteria, and describing their clinical implications credibly to physicians or regulators who will ultimately decide intervention strategies on the basis of the results. This international validation study enabled reliable collection of longitudinal QoL and clinical data in these 3 UGID populations. The objective of this article is to provide an evaluation of the responsiveness and clinical significance of the PAGI-QOL questionnaire in these 3 UGID populations. Methods Patients Two studies were set up, the first one in the United States with the initial American-English version of the questionnaire, followed by a multicenter study in Europe including patients from France, Germany, Italy, Poland, and the Netherlands as soon as validated translations of the questionnaire became available. The first study in the United States included patients with dyspepsia, GERD, and gastroparesis selected from the Upper Gastrointestinal Epidemiology Survey database (dyspepsia and GERD) or via clinical centers (gastroparesis). In Europe, the study was conducted in patients with dyspepsia and GERD (100 patients per condition and per country were planned, leading to 1000 patients overall), identified through physician offices (general practitioners or gastroenterologists). Entry criteria for dyspepsia patients included 1 of the 3 following symptom criteria: (1) early satiety ( 2 days/week) plus postprandial fullness ( 2 days/week) but no constipation or vomiting; (2) frequent nausea ( 1 day/week) with or without vomiting; (3) Rome II diagnostic criteria 8 : pain or discomfort centered in the upper abdomen (and no evidence of organic disease that is likely to explain the symptoms and no evidence that dyspepsia is exclusively relieved by defecation or associated with the onset of a change in stool frequency or form). GERD patients had to experience heartburn ( 2 days/ week) and either a bitter, sour, acid taste or fluid/food in the mouth. Gastroparesis patients had to have a documented diagnosis of gastroparesis with symptoms for at least 6 months to be included in the study. Exclusion criteria for all 3 conditions included anyone with a history of gastric surgery or cancer of the gastrointestinal tract, uncontrolled serious chronic disease, inability to complete the questionnaires because of cognitive impairment or inadequate language skills, a concomitant psychiatric disorder, or existing enrollment in a clinical trial for their UGID symptoms. Study Design and Patient-Reported Outcomes Instruments Both the American and the European studies were observational, multicenter, longitudinal studies with an 8-week observation period. The PAGI-QOL was administered at study inclusion and again 8 weeks later. The final version of the PAGI-QOL instrument consists of 30 items, each with response options based on a 6-point Likert scale and with a recall period of the previous 2 weeks. The items are grouped into 5 dimensions: Daily Activities (10 items related to avoiding or having difficulties with daily activities), Clothing (2 items, one related to feeling constricted and one related to the frustration felt about not being able to dress as wanted), Diet and Food Habits (7 items related to restrictions made and induced frustration), Relationship (3 items describing the impact of the disease on relationships with their partner, relatives, and friends), and Psychological Well-being and Distress (8 items describing disease impact on feelings or emotional state) (see Appendix). A score per dimension as well as a total score can be calculated. The PAGI-QOL scores range from 0 (lowest QoL) to 5 (highest QoL). The Overall Treatment Effect (OTE) scale is a set of 3 items used to rate the change in UGID symptoms. 9,10 Patients and clinicians (except for GERD and dyspepsia patients in the United States) were asked to complete the OTE at 8 weeks and indicate whether the UGID-related symptoms had improved, remained the same, or worsened since the last evaluation. If the subjects indicated an improvement or worsening, they were asked to rate the degree of improvement or worsening respectively on a 7-point scale from Almost the same, hardly better (worse) at all (1) to A very great deal better (worse) (7),

3 780 DE LA LOGE ET AL. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 2, No. 9 leading to an OTE score ranging from 7 (a very great deal worse) to 7 (a very great deal better). For the American GERD and dyspepsia samples, all data collection was completed by telephone interviews; therefore only the patientrated OTE is included. Responsiveness and Minimal Important Difference Responsiveness refers to the ability of an instrument to detect changes in clinical status, intervening health events, interventions of known or expected efficacy, or direct reports of change by patients or providers. 11 Responsiveness was evaluated by using the patient and the clinician OTE scales completed at week 8. Three patient groups were created according to OTE scores: Improved for OTE scores 2, Stable for OTE scores between 1 and 1, and Worsened for OTE scores 2. Subgroups of improved and worsened patients were also defined to obtain more detailed descriptions about the magnitude of PAGI-QOL score changes. These data were used to estimate the minimal important difference (MID) for the PAGI-QOL total score. The MID can be defined as the smallest difference in score for the domain of interest, which patients perceive as beneficial and which mandates, in the absence of contradictory factors, a change in the patient s management. 10,12 In another context, Juniper et al. 13 have defined the MID, with the same 15-point OTE scale, as the change in score obtained for patients reporting an improvement a little to somewhat better ( 2 and 3 for the OTE score). Statistical Analysis Responsiveness of the PAGI-QOL was assessed by calculating Effect Sizes (ES) and Standardized Response Mean (SRM) for improved, stable, and worsened patients (formula of ES and SRM). The ES and SRM were interpreted as follows: 0.20 was considered as small, 0.5 as moderate, and 0.8 as large effects. 14,15 Comparison of subgroups of patients was performed by an analysis of variance adjusted for age and gender. In addition, the Wilcoxon signed rank test was used to assess whether the change over time was significant within each of these subgroups. Results A total of 1736 patients with UGID completed the PAGI-QOL questionnaire at baseline, whereas 1471 completed the week 8 assessment and were therefore selected to assess responsiveness of the PAGI-QOL. There were 761 patients (43.84%) with dyspepsia, 807 (46.49%) with GERD, and 168 (9.68%) with gastroparesis. The population was distributed as follows: 258 (14.86%) French patients, 213 (12.27%) German patients, 200 (11.52%) Italian patients, 235 (13.54%) Polish patients, 214 (12.33) Dutch patients, and 616 (35.48%) American patients. The overall mean age of the patients was years, and a majority (61.75%) were women. The number of patients with GERD was slightly higher than those with dyspepsia and included slightly fewer women (56.4% vs. 64.4%). The number of patients with gastroparesis was far smaller than the number of patients with either GERD or dyspepsia and had the highest proportion of women. Patients demographic characteristics are summarized in Table 1. In addition to this, in the European study, the use and type of medication received were documented. Results indicate that two thirds of these patients (73.32%) were currently treated for their UGID, with more than half of the patients who were currently treated taking antisecretory agents (56.17%), one third taking prokinetics (34.07%), and one third taking antacids (31.23%). Patient Assessment of Upper Gastrointestinal Disorders Quality of Life Baseline Scores in Gastroesophageal Reflux Disease, Dyspepsia, and Gastroparesis Patients The baseline PAGI-QOL total score was significantly lower for gastroparesis patients ( ) than for dyspepsia patients ( ), which in turn was marginally lower than for GERD patients ( ) (P when comparing the 3 conditions). This applied consistently across all dimensions of the questionnaire, as shown in Figure 1. It is also worth mentioning that, as often seen with health-related quality of life (HRQoL) measures, gender differences were observed. For the total score, for example, men and women had an average score of 3.69 (standard deviation, 0.9) and 3.34 (standard deviation, 0.99), respectively, indicating lower QoL in women. The difference was highly statistically significant (P ). This implies that adjustment for gender might be recommended when assessing between-group differences. Responsiveness to Change Over Time A total of 693 patients were classified as improved, 623 as stable, and 136 as worsened according to patients answers to the OTE scale. The assessment of responsiveness according to the clinicians OTE was performed in a smaller number of patients because of the fact that the clinicians OTE was not available for American GERD and dyspepsia patients. When classifying patients according to the clinicians OTE scale, 624 patients were classified as improved, 431 as stable, and 84 as worsened. Figure 2 provides the average change in PAGI-QOL scores in each improved, worsened, and stable group as

4 September 2004 RESPONSIVENESS AND INTERPRETATION OF THE PAGI-QOL 781 Table 1. Demographic Characteristics of Baseline Population (n 1736) Baseline characteristics and subject disposition GERD Dyspepsia Gastroparesis Total Number of subjects included Gender Female (%) 455 (56.38) 490 (64.39) 127 (75.60) 1072 (61.75) Male (%) 352 (43.62) 269 (35.35) 39 (23.21) 660 (38.02) Missing data (%) 0 (0) 2 (0.26) 2 (1.19) 4 (0.23) Concomitant disease (n 558 a ) (n 562 a ) (n 168) (n 1288 a ) No (%) 272 (48.75) 317 (56.41) 31 (18.45) 620 (48.14) Yes (%) 286 (51.25) 245 (43.59) 133 (79.17) 664 (51.55 Missing data (%) 0 (0) 0 (0) 4 (2.38) 4 (0.31) Age Mean years Range Education Primary/elementary (%) 124 (15.37) 107 (14.06) 4 (2.38) 235 (13.54) Secondary/high school (%) 439 (54.40) 414 (54.40) 69 (41.07) 922 (53.11) College degree (%) 174 (21.56) 178 (23.39) 53 (31.55) 405 (23.33) Postgraduate degree (%) 58 (7.19) 56 (7.36) 21 (12.50) 135 (7.78) Other (%) 11 (1.36) 5 (0.66) 19 (11.31) 35 (2.02) Missing data (%) 1 (0.12) 1 (0.13) 2 (1.19) 4 (0.24) Living/domestic situation Living alone (%) 174 (21.56) 191 (25.10) 26 (15.48) 391 (22.52) Living with partner or spouse (%) 571 (70.76) 487 (63.99) 112 (66.67) 1170 (67.40) Other (%) 59 (7.31) 78 (10.25) 28 (16.67) 165 (9.50) Missing data (%) 3 (0.37) 5 (0.66) 2 (1.19) 10 (0.58) Working status Working (full-time, part-time) (%) 418 (51.80) 445 (58.48) 70 (41.67) 933 (53.74) Retired (or early retirement) (%) 215 (26.64) 155 (20.37) 19 (11.31) 389 (22.41) Unemployed (looking for a job) (%) 27 (3.35) 28 (3.68) 7 (4.17) 62 (3.57) Other (e.g., homemaker, student) (%) 142 (17.60) 131 (17.21) 70 (41.67) 343 (19.76) Missing data (%) 5 (0.62) 2 (0.26) 2 (1.19) 9 (0.52) a Information not available in the American GERD and dyspepsia samples. defined by the patient OTE score. The difference between groups was consistently highly statistically significant (all P values ). Improved patients. As can be seen in Table 1, a significant increase (P ) in mean QoL scores was reported among patients defined as clinically improved through their patient OTE for all dimensions ranging from 0.40 ( 0.93) for Relationship to 0.73 ( 1.00) for Diet and Food Habits (mean change for the total score, 0.62 [ 0.74]). These changes resulted in positive ES of 0.37 or greater (lowest SRM 0.49). The maximum ES for improved patients were observed on the PAGI-QOL Figure 1. Distribution of PAGI-QOL scores at baseline per disease. s, Dyspepsia (n 761);, GERD (n 807);, gastroparesis (n 168). Abbreviations are shown in Table 2. Figure 2. Baseline to 8-week mean change in PAGI-QOL scores according to patients answers to OTE scale. Abbreviations are shown in Table 2.

5 782 DE LA LOGE ET AL. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 2, No. 9 Figure 3. Baseline to 8-week mean change in PAGI-QOL total score in each condition according to patients answers to OTE scale. total score (ES 0.65; SRM 1.01) and the lowest for the Relationship dimension (ES 0.37; SRM 0.49). Worsened patients. Among patients defined as clinically worsened on the basis of the patients OTE, a slight decrease in mean scores was reported for most PAGI-QOL scores (except for Psychological Well-being and Distress [ ] and Diet and Food Habits [ ]), indicating that patients experienced a slight deterioration in their QoL. The changes in scores were, however, not found to be statistically or clinically significant, with P values for the Wilcoxon signed rank test 0.05 (except for Daily Activities; P ) and ES varying from 0.14 for Daily Activities (SRM 0.20) to 0.03 for Diet and Food Habits (SRM 0.04). Stable patients. For patients defined as stable (patients OTE score ranging from 1 to 1), a slight increase in mean QoL scores was reported for all dimensions, indicating that they had experienced a slight improvement in their QoL. These changes in scores were statistically significant, with P values of Wilcoxon signed rank test ES were, however, 0.20, ranging from 0.06 for Relationship (SRM 0.08) to 0.20 for the PAGI-QOL total score (SRM 0.28), indicating that this improvement was small. Figure 3 provides the average change in improved, stable, and worsened groups for the PAGI-QOL total score for each condition. In all 3 conditions, the changescore difference between improved, stable, and worsened patients was highly statistically significant (all P values ). As expected, a significant positive change was seen in improved patients for all 3 conditions; the highest change was for gastroparesis ( ). ES ranged from A slight improvement in the PAGI-QOL total score was also seen in stable patients for all 3 conditions ( , P for dyspepsia; , P for GERD; and , P for gastroparesis). ES were, however, low, ranging from In worsened patients, different trends were obtained in each condition: a decrease for GERD ( ; P ), an increase for gastroparesis ( ; P ), and a change close to 0 for dyspepsia ( ; P ). ES/SRM were 0.31/ 0.44 for GERD, 0.21/0.37 for gastroparesis, and 0.03/ 0.05 for dyspepsia. Responsiveness of the PAGI-QOL scores was confirmed when looking at results obtained in each improved, stable, and worsened groups as defined from the clinicians OTE. Results related to the improved group (Table 2) indicate slightly higher change in scores and ES than those obtained with the patients OTE. Responsiveness of the PAGI-QOL scores was also assessed at country level, and results were consistent with the overall sample. Because of the wealth of information, detailed results for each country are not provided in this article. Table 2. Responsiveness of the PAGI-QOL Subscales and Total Score in Improved Patients Improved patients according to patients answer to OTE (N ) Improved patients according to clinicians answer to OTE (N ) Dimensions Mean STD P value a ES1 b SRM c Mean STD P value a ES1 b SRM c DA-Daily activities DI-Diet PSY-Psychological CLO-Clothing REL-Relationship Total STD, standard deviation. a Wilcoxon signed rank test. b ES1 (Mean2 Mean1)/SD(W0)(Total). c SRM (Mean2 Mean1)/SD(W8 W0)(Stables).

6 September 2004 RESPONSIVENESS AND INTERPRETATION OF THE PAGI-QOL 783 Figure 4. Baseline to 8-week mean change in PAGI-QOL total score according to patients and clinicians answers to OTE scale. Y axis shows the change in PAGI-QOL scores from improvement (top) to worsening (bottom). X axis shows OTE scores for the patient OTE/ clinician OTE. n the number of subjects that were included to obtain the mean changes for each level of the OTE score by the patient vs. by the clinician. Minimal Important Difference In addition to the description of the PAGI-QOL change scores according to improved, stable, and worsened status, we also performed a more detailed analysis according to the following OTE score subcategories: 6 and 7 (a great to a very great deal better), 4 and 5 (moderately to a good deal better), 2 and 3 (a little to somewhat better), 1 to 1 (almost the same), 2 and 3 (a little to somewhat worse), 4 and 5 (moderately to a good deal worse), 6 and 7 (a great to a very great deal worse) (Figure 4). Patients who rated themselves a little to somewhat better had their PAGI-QOL total score increased by 0.36 ( 0.63 and 95% confidence interval, ) on average during the 8-week follow-up period, whereas the mean change obtained for patients defined by clinicians as a little to somewhat better was 0.47 ( 0.74 and 95% confidence interval, ). Taking into consideration these results, we recommend a change in total score of 0.4 to be used to define a clinically meaningful improvement when comparing pretreatment and post-treatment data. Furthermore, the change in the PAGI-QOL total score for each group as defined through the patients OTE showed a linear trend between the OTE and the PAGI- QOL total score, with a score difference between each consecutive level of improvement being around Patients who rated themselves a little to somewhat better (minimal improvement) had an increase in their PAGI-QOL total score of 0.36 ( 0.63), which is 0.19 more than patients who rated themselves unchanged or almost the same. Patients who rated themselves moderately to a good deal better (moderate improvement) had an increase in their PAGI-QOL total score of 0.61 ( 0.68), which is 0.25 more than patients who rated themselves a little to somewhat better. Patients who rated themselves a great to a very great deal better (large improvement) had an increase in their PAGI-QOL total score of 0.84 ( 0.82), which is 0.23 more than patients who rated themselves moderately to a good deal better. To put these results into context, a difference of 0.20 roughly corresponds to a 2-point difference on the OTE scale and to the difference obtained between large ( a great to a very great deal better ) and moderate ( moderately to a good deal better ) improvements; moderate and minimal ( a little to somewhat better ) improvements; or minimal improvements and stability. Discussion Traditionally, physicians working in the field of UGID have dealt with objective investigations such as endoscopy and Helicobacter pylori testing with which they have developed and quantified desirable targets for change. QoL results are less immediately intuitive, because these measures have no familiar units, and the meaning of a given numeric change is not obvious. For clinicians to become familiar with interpreting QoL data, the level of clinical significance needs to be well established. Several approaches can be used to define clinical significance. Distribution-based interpretation relies on statistics derived from the instrument, such as ES, whereas anchor-based interpretation uses external criteria such as another scale or clinical measure to establish an interpretable relationship with the new instrument. 16 A combination of approaches allows a greater confidence in applying this established level of clinical significance. The PAGI-QOL has been shown to be a valid and reliable patient-reported QoL questionnaire for assessing QoL in GERD, dyspepsia, and gastroparesis. The international validation study with 1747 patients with GERD, dyspepsia, or gastroparesis allowed us to finalize and validate the PAGI-QOL instrument. In its final version it includes 30 questions across 5 dimensions: Daily activities, Diet and food habits, Psychological well-being and distress, Clothing, and Relationship. Detailed results relating to the international validation of the PAGI-QOL are reported in a separate manuscript in preparation.

7 784 DE LA LOGE ET AL. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 2, No. 9 The assessment of responsiveness and the calculation of the MID were derived by using the OTE scale completed by both the patient and the clinician. This scale allowed us to relate changes in patients QoL to patients and clinicians estimate of the global rating of change. The PAGI-QOL questionnaire proved to be responsive in being able to discriminate between improved/impaired/stable patients by using both OTE measures (P ). ES obtained in improved patients ranged from for the total score, depending on the condition and the method of calculation. The relatively high level of correlations between the 5 domains (ranging from ) allows the calculation of a total QoL score. This PAGI-QOL total score provides the highest reliability and best responsiveness in most cases compared to the dimension scores. It is therefore more likely to be used as the primary QoL end point in clinical trials, and for this reason, the MID was calculated for the total score only. The mean change in the PAGI-QOL total score obtained for patients classified as a little to somewhat better, as rated by the patient and by the clinician, led us to propose a total change score of 0.40 for the MID estimation. This threshold might be used to assess within-group change in the absence of a control group by comparing pretreatment and post-treatment data and might also be useful to estimate the number needed to treat. 10 Further work needs to be done to develop experience in clinical interpretation, especially in relation to the type of UGID, and to provide confirmation of a 0.40 threshold for the MID. When comparing the PAGI-QOL total score across different treatment strategies or against a placebo, we would recommend using a smaller threshold. The use of a control group in the context of a randomized clinical trial allows the so-called placebo effect to be controlled for. The difference between treatment strategies is therefore expected to be lower than the within-group change, the within-group change resulting from a combination of treatment and placebo effects. The differences in the PAGI-QOL total score change between large/moderate improvements, moderate/minimal improvements, and minimal improvements/stability groups were therefore examined. The difference in the total score between these groups of increasing improvement was around This threshold could be useful in the context of randomized clinical trials, when defining an expected and clinically relevant difference between treatment groups to calculate the sample size needed or the statistical power obtained for a given sample size. The MID and the guidance for interpretation were based on grouping levels of improvement in pairs rather than considering each individually. This approach was adopted to be consistent with other work in the field 13 and to create fewer improvement groups, therefore ensuring enough patients per group to provide stable results. The PAGI-QOL has been developed in parallel to a Symptom questionnaire, the PAGI-SYM (information on the development and psychometric characteristics of the PAGI-SYM is summarized in a separate report 6 ). The PAGI instrument including both QoL and symptoms sections allows a comprehensive measure of disease-specific symptoms and QoL outcomes for patients with UGID. Both the PAGI-QOL and PAGI-SYM questionnaires are available in many languages (Austrian German, Belgian Dutch, Belgian French, Czech, Danish, French, German, Greek, Hungarian, Hebrew, Israeli- Russian, Italian, Dutch, Polish, Portuguese, Slovak, Afrikaans, South African English, Spanish, Swedish, and US and UK English). Because the assessment of treatment efficacy in UGID is mainly based on patient complaints, and there is a lack of clear objective criteria, tools like the PAGI instrument have a potentially essential role in developing optimal measurement and evaluation strategies for these conditions. Although the level of reliability, validity, and responsiveness obtained in this international study were extremely appealing, we recognize some drawbacks in the methodology. In our study, the diagnosis criteria used to recruit patients within each condition were not as stringent as would be found in a clinical trial setting. The lack of clear objective diagnosis criteria for each condition led us to recruit a broader population than the actual targeted populations. However, we believe that in the context of scale validation, working on a broader sample is not a major issue. On the contrary, working on a broader sample of patients from least to most severe and from well- to less well-defined diagnosis provides more confidence that the scale will be valid for all types of patients with UGID. We also believe that validation should be seen as a never ending process, and that ongoing accumulation of research evidence regarding a scale s validity is needed to demonstrate the scale s usefulness in a wide variety of research applications and patient populations. Future use of the PAGI-QOL should allow further confirmation of the validity and sensitivity of the instrument in the targeted populations. A major strength of the PAGI-QOL is the cross-cultural approach that was adopted from the very initial step of domain identification including patient input from different countries, ensuring that it is adapted to a wide range

8 September 2004 RESPONSIVENESS AND INTERPRETATION OF THE PAGI-QOL 785 of cultures to the final step of validation. The PAGI-QOL together with the PAGI-SYM is already available in 22 languages. As previously mentioned, a number of QoL instruments have been developed to measure QoL in UGID. However, at the time when this project was initiated, none of them fulfilled all desired features. The QOLRAD, a 25-item scale assessing QoL in GERD and dyspepsia, for example, had been developed and successfully validated in several languages. At that time, however, some of the target languages were not available, and no data related to responsiveness were published. Since then, the QOLRAD has demonstrated high responsiveness in a clinical trial setting in GERD patients. 17 Other disease-specific instruments might now be available with appealing features, and it would be interesting to further compare the psychometric properties and the responsiveness of these different diseasespecific instruments. The responsiveness of the PAGI-QOL has been clearly demonstrated in a large international population with several upper gastrointestinal conditions. The high responsiveness obtained together with the good cross-cultural psychometric properties leads us to be confident that future studies will confirm the PAGI-QOL as a useful UGID-specific PRO instrument to assess treatment efficacy in international clinical trial settings. References 1. Spechler SJ. Epidemiology and natural history of gastro-oesophageal reflux disease. Digestion 1992;51(suppl 1): Talley NJ, Stanghellini V, Heading RC, Malagelada JR, Tytgat GNJ. Functional gastroduodenal disorders. In: Corazziari E, Talley NJ, Thompson WG, Whitehead WE, eds. The functional gastrointestinal disorders. 2nd ed. McLean, VA: Degnon Associates, 2000: Drossman DA, Li Z, Andruzzi E, Temple RD, Talley NJ, Thompson WG, Whitehead WE, Janssens J, Funch-Jensen P, Corazziari E, Richter JE, Koch GG. U.S. householder survey of functional gastrointestinal disorders: prevalence, sociodemography, and health impact. Dig Dis Sci 1993;38: Horowitz M, Fraser RJ. Gastroparesis: diagnosis and management. Scand J Gastroenterol Suppl 1995;213: Soykan I, Sivri B, Sarosiek I, Kiernan B, McCallum RW. Demography, clinical characteristics, psychological and abuse profiles, treatment, and long-term follow-up of patients with gastroparesis. Dig Dis Sci 1998;43: Chassany O, Sagnier P, Marquis P, Fullerton S, Aaronson N, Group ERIoQA. Patient-reported outcomes: the example of healthrelated quality of life a European guidance document for the improved integration of HRQoL assessment in the drug regulatory process. Drug Info J 2002;36: Rentz AM, Battista C, Trudeau E, Jones R, Sloan S, Mathur S, Frank LB, Revicki DA. Symptom and health-related quality of life measures for use in selected gastrointestinal disease studies: a review and synthesis of the literature. Pharmacoeconomics 2001;19: Drossman DA, Corazziari E, Talley NJ, Thompson WG, Whitehead WE, Rome II Multinational Working Teams. Rome II: the functional gastrointestinal disorders. 2nd ed. McLean, VA: Degnon Associates, Jaeschke R, Singer J, Guyatt GH. Measurement of health status: ascertaining the minimal clinically important difference. Control Clin Trials 1989;10: Guyatt GH, Osoba D, Wu AW, Wyrwich KW, Norman GR. Methods to explain the clinical significance of health status measures. Mayo Clin Proc 2002;77: Staquet MJ, Hays D, Fayers PM. Quality of life assessment in clinical trials. New York: Oxford University Press, Crosby RD, Kolotkin RL, Williams GR. Defining clinically meaningful change in health-related quality of life. J Clin Epidemiol 2003;56: Juniper EF, Guyatt GH, Willan A, Griffith LE. Determining a minimal important change in a disease-specific Quality of Life Questionnaire. J Clin Epidemiol 1994;47: Cohen J. Statistical power analysis for the behavioral sciences. 2nd ed. Hillsdale, NJ: Lawrence Erlbaum Associates, Kazis LE, Anderson JJ, Meenan RF. Effect sizes for interpreting changes in health status. Med Care 1989;27(suppl): S178 S Lydick E, Yawn BP. Clinical interpretation of health-related quality of life data. In: Staquet MJ, Hays D, Fayers PM, eds. Quality of life assessment in clinical trials. New York: Oxford University Press, Talley NJ, Fullerton S, Junghard O, Wiklund I. Quality of life in patients with endoscopy-negative heartburn: reliability and sensitivity of disease specific instruments. Am J Gastroenterol 2001;96: Address requests for reprints to: Christine de la Loge, M.S., Mapi Values, 27, rue de la Villette, Lyon, France. cdelaloge@mapi.fr. Supported by Johnson & Johnson Pharmaceutical Services, LLC. For information on, or permission to use, the PAGI-QOL questionnaire in all languages, please contact: Dominique Dubois, Johnson & Johnson Pharmaceutical Services, LLC, Turnhoutseweg 30, 2340 Beerse, Belgium. Phone: (32) ; fax: (32) ; ddubois@psmbe.jnj.com.

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