Sensitivity to change and minimal clinically important difference of the angioedema control test

Abstract Background The Angioedema Control Test (AECT) is a patient‐reported outcome measure developed and validated for the assessment of disease control in patients with recurrent angioedema. Its sensitivity to change and minimal clinically important difference (MCID) have hitherto not been established. Methods Patients with recurrent angioedema due to chronic spontaneous urticaria, hereditary angioedema, or acquired C1‐inhibitor deficiency were repeatedly asked to complete the AECT along with the Angioedema Quality of Life Questionnaire (AE‐QoL), Dermatology Life Quality Index (DLQI), and anchors for disease control and whether treatment was sufficient during routine care visits. The sensitivity to the change of the AECT was determined by correlating changes in its scores over time with changes in the applied anchors. The MCID was determined using anchor‐based and distributional criterion‐based approaches. Results Eighty‐six cases were used for this analysis. Changes in AECT scores correlated well with AE‐QoL changes (but less with changes in the DLQI) as well as other applied anchors, demonstrating its sensitivity to change. The MCID was found to be three points for improvement of angioedema control. The available number of cases with meaningful deterioration in our dataset was too low to reach a definite conclusion on the MCID for deterioration of angioedema control. Conclusion The AECT is a valuable tool to assess changes in disease control in patients with recurrent angioedema over time. The lowest AECT score change that reflects a meaningful improvement of disease control to patients (MCID) is three points.

angioedema, it is important to have valid and reliable tools to capture the actual disease status. 12,13Therefore, several patient-reported outcome measures (PROMs) have been developed for patients with recurrent angioedema, [14][15][16] including the Angioedema Control Test (AECT). 6,8The AECT has been developed and validated to assess disease control in patients with recurrent angioedema. 17,18Previous studies have shown that it is well suited for routine practice, 19,20 clinical research, [21][22][23][24][25] and therapeutic trials 26 given its retrospective approach, brevity, and simple scoring.The AECT has excellent internal consistency and test-retest reliability, as well as high convergent validity and good known-groups validity. 18,27The cut-off scores for identifying patients with well-controlled disease and poorly controlled disease have been established at ≥10 and <10, respectively. 18,27r both clinical practice and trials, it is imperative to know the ability of the AECT to determine changes over time, for example, before and after treatment adjustment.However, as of yet, this property of the AECT has not been investigated.Apart from dichotomising AECT scores in poor or good angioedema control, the interpretation of AECT score changes is difficult because it is currently unclear which score changes are meaningful to patients.In other words, the minimal clinically important difference (MCID), that is, the smallest change that patients would identify as a noticeable and meaningful improvement, of the AECT is unknown.To address these gaps of knowledge, the current study aimed to determine the sensitivity to change and MCID of the AECT.

| Patient population
Consecutive German-speaking patients with recurrent angioedema aged 12 years or older treated at the Angioedema Center of Reference and Excellence (ACARE, https://acare-network.com) 28of the Institute of Allergology of the Charité-Universitätsmedizin Berlin were invited to participate.Informed consent was obtained from all individual participants included in the study.The participants were asked to complete the German version of the AECT along with other PROMs during several successive routine care visits.This study was approved by the ethics committee of the Charité-Universitätsmedizin Berlin (EA4/020/20).

| Angioedema control test
The AECT is an angioedema-specific, valid, and reliable questionnaire that assesses disease control.It can be used in all patients with recurrent angioedema, that is, mast cell-mediated (e.g.chronic spontaneous urticaria) and bradykinin-mediated (e.g.HAE-C1INH) angioedema.Two separate versions, with a recall period of 4 weeks and 3 months are available.The present study used the version with a 4 week recall period. 17The AECT consists of four questions with five answer options each (scored with 0-4 points).Accordingly, AECT scores range from 0 to 16 points, with 16 points indicating complete disease control.Cut-off scores for well versus poorly controlled disease have been established at ≥10 and <10, respectively. 18,27rticipants were asked to answer the AECT at baseline and at a follow-up visit.

| Patients' self-assessment of global disease control, change in global disease control, and treatment sufficiency
Along with the AECT, all patients were asked to self-rate their global angioedema control during the past 4 weeks on a 5-point Likert scale (Pat-GA-control, answer options: 'completely controlled', 'well controlled', 'moderately controlled', 'hardly controlled', 'not at all controlled').In addition, they indicated if their angioedema treatment in the past 4 weeks was 'sufficient' or 'not sufficient'.At the follow-up visit, patients were also asked to self-rate the global change in angioedema control in comparison to the last time they filled out the AECT on a 7-point Likert scale (Pat-GA-control-change, answer options: 'improvement to complete control', 'clearly better controlled', 'slightly better controlled', 'no change in control', 'slightly worse controlled', 'clearly worse controlled', 'deterioration to complete lack of control').The treating physicians of the patients were asked to fill out these questions from their perspective as well (Phy-GA-control and Phy-GA-control-change).

| Quality of life measures
The Angioedema Quality of Life Questionnaire (AE-QoL) is an angioedema-specific, validated health-related quality of life (QoL) measure with a recall period of 4 weeks.It contains 17 questions from which a total score on a 0-100 scale can be computed. 15,29The Dermatology Life Quality Index (DLQI) is a health-related QoL measure for dermatological disorders with a recall period of 7 days.It contains 10 questions from which a sum score on a 0-30 scale can be computed. 30Higher scores for the AE-QoL and DLQI are both indicative of a higher QoL impairment.The patients filled out both questionnaires along with the AECT at both visits.Figure 1 shows the study flow diagram including the information obtained and anchors used at the baseline and follow-up visits.Patients who visited the out-patient clinic more than two times during the course of this study could fill-out additional follow-up visit questionnaires.

| Responsiveness
Responsiveness is the ability of an instrument to determine meaningful changes in the patient's disease status over time.It is commonly reported through the minimal clinically important difference (MCID).A change equal to or higher than the MCID can be considered a meaningful change.To determine the MCID of the AECT, we applied anchor-based and distributional criterion-based approaches, as described previously. 31,32The anchor-based approaches were applied by computing the mean intra-individual differences of AECT total and individual question scores between assessments with different Pat-GA-control ratings (defined as a change of one step, e.g. from no at all controlled to hardly controlled,  33 The distributional criterion approach to calculate the MCID indirectly is based on the finding that one-half of the standard deviation (SD) of an instrument's results may represent a good approximation of its MCID. 32Accordingly, the SD of all baseline AECT total scores was computed and subsequently divided by two.Another distribution-based approach is one standard error of the mean (SEM), as this may represent an approximation of the MCID as well. 34

| Sensitivity analysis
If patients filled out more than two rounds of questionnaires, these additional cases were included in the analyses.As a sensitivity analysis, all analyses were repeated with one pair of questionnaires from unique individuals.

| Statistical analysis
All statistical analyses were conducted in R version 4.0.3. 35The statistical methods applied are described in the respective methods and/or results sections of this manuscript.p ≤ 0.05 was considered statistically significant.Missing data were not imputed.Data from eight cases concerning patients' assessment of global angioedema control and whether or not treatment was sufficient were removed due to implausibility.

| The AECT shows high sensitivity to change
The AECT total score change over time correlated significantly with the patients' and physicians' global impression of change in disease control, assessed by Pat-GA-control-change and Phy-GA-controlchange, respectively.AECT changes were also correlated with those of the Pat-GA-control, Phy-GA-control, AE-QoL, and DLQI scores as well as with treatment sufficiency (Table 2).The strength of the correlation of AECT changes and anchor results was high (r > 0.5), except for the DLQI (r = 0.3) and Pat-GA-control-change (r = 0.3).
For 18 cases, treatment changed from insufficient to sufficient, which was associated with a mean improvement in the AECT total score of 6.0 points.For three cases, treatment changed from sufficient to insufficient, which was associated with a mean deterioration in the AECT total score of 6.3 points.Treatment was and remained insufficient for 10 cases, associated with a mean change of 0.0 points -7 of 10 in the AECT total score.Treatment was and remained sufficient for 37 cases, associated with a mean improvement of 1.0 point in the AECT total score.

| The MCID of the AECT is three points
Four anchor-based approaches were used to determine the MCID of the AECT.First (Table 3), for cases who reported relevant improvement of disease control, that is, one step in the Pat-GA-control, the mean (�SD) change in the AECT value was 4.5 � 2.6 (median: 4.5 points, IQR: 2.8-6.0 points).Second, cases with a pertinent improvement in quality of life, that is, a one-step (6-11 points)   improvement in the AE-QoL, showed a change in AECT of 2.9 � 2.9 points (median: 3.0 points, IQR: 2.0-4.0 points).Third, by ROC curve analysis, the cut-off point for AECT improvement with the best balance of sensitivity (86%) and specificity (91%) was found to be three points, based on the change in Pat-GA-control (Table 4, Figure 2A).
In addition, we calculated the MCID of the AECT by the use of two distributional criterion approaches.First, we divided the SD of all baseline AECT total score values (4.9) by two, which resulted in an MCID of 2.5 points.Second, the calculation of the SEM yielded an AECT MCID of 0.5 points.

| Sensitivity analyses
Repeating the analyses described above using only data from unique individuals (n = 66) resulted in comparable correlation coefficients and MCID estimates (data not shown).

| DISCUSSION
Here we report, for the first time, sensitivity to change and responsiveness of the AECT as well as its MCID.The AECT is an easy to use and validated PROM developed to assess disease control in patients with recurrent angioedema. 18It is available in many languages 36 and widely used in clinical trials and routine practice as recommended by current international guidelines. 6,8 found that changes in the AECT correlate well with anchor instruments that measure changes in angioedema control, healthrelated QoL, and treatment sufficiency.A limitation of our study is the low number of cases experiencing deteriorating disease control in our sample.Thus, the available data do not allow for the computation of the MCID for deterioration.The MCID for improvement (three points) cannot simply be applied to deterioration, since it is known that these often differ.A meta-analysis of 118 prospective cohort studies showed that generally smaller estimates for improvement compared with deterioration are found. 37Furthermore, the cause F I G U R E 2 ROC curves.(A) Area under the ROC curve for AECT changes related to improvement versus non-improvement in patients' self-rated global angioedema control = 0.95 (95% confidence interval: 0.90-1.00).(B) Area under the ROC curve for AECT changes related to improvement versus non-improvement in patients' self-rated angioedema-related quality of life = 0.96 (95% confidence interval: 0.89-1.00).AECT, Angioedema Control Test; ROC, receiver operating characteristic.

2. 3 . 1 |
Sensitivity to change Sensitivity to change is the ability of a PROM to detect change over time in the patient's disease status, regardless of whether this change is clinically relevant or meaningful.To assess the sensitivity to the change of the AECT, we computed the rank correlation coefficient (Spearman's rho) for AECT total and individual question score changes between two different time points with changes in the AE-QoL, DLQI, Pat-GA-control, Phy-GA-control and treatment sufficiency.The rank correlation coefficient was also calculated for the AECT score changes with the patients' and physicians' global impression of change in disease control, that is, the Pat-GA-controlchange and Phy-GA-control-change, respectively, at the follow-up visit.
or from well controlled to moderately controlled) and AE-QoL change (defined as a change of one step.A one-step change was defined as an AE-QoL change of 6 to <12 points as the MCID of the AE-QoL is 6 points. 29A two-step change was defined as an AE-QoL change of 12 to <18 points).In addition, the intra-individual variation of AECT total and individual question scores in case of stable disease (unchanged PAT-GA-control or AE-QoL) were analysed.For the use of Pat-GA-control and AE-QoL for these responsiveness analyses, the correlation (Spearman's rho) of their changes and AECT score changes should be 0.5 or higher.Finally, the Pat-GA-control was used to perform a receiver operating characteristic (ROC) curve analysis to identify the best cut-off point for clinically meaningful changes in the AECT total score.For this analysis, patients were categorised as F I G U R E 1 Study flow chart.At the baseline and follow-up visit demographics, the AECT and several anchors were obtained.AECT, Angioedema Control Test; AE-QoL, Angioedema Quality of Life Questionnaire; DLQI, Dermatology Life Quality Index.subjects with a change in angioedema control (defined as at least one-step change in their global angioedema control rating) and subjects without a change in angioedema control.Likewise, ROC curve analysis was performed with patients divided into groups based on change in AE-QoL scores (e.g. at least one-step change, which was defined as an AE-QoL change of at least 6 points).The ROC cut-off point was chosen by getting the smallest sum of percentages of false positive and false negative classifications ([1-

FIJEN ET AL. T A B L E 3 6 Note:
Magnitude of AECT total and individual question score changes (mean � SD) during improved or deteriorated angioedema control assessed by patients (e.g.one-step change in global control means from not at all controlled to hardly controlled, completely controlled to well controlled, etc.) and improved or deteriorated AE-QoL (one-step The AE-QoL score ranges were based on the MCID of the AE-QoL, that is, 6 points.Abbreviations: AECT, Angioedema Control Test; AE-QoL, Angioedema Quality of Life questionnaire; SD, standard deviation; Q1-4, Questions 1-4 of the AECT.
However, the correlation of a change in the total AECT score with a patients' global impression of change in angioedema control assessed at the followup visit was lower than expected.We believe this is due to recall bias, an assumption strengthened by the observation that, in contrast, a good correlation between changes in the AECT score and changes in the patients' assessed global angioedema control was found.The availability of an MCID is critical for the interpretation of results obtained by a PROM.By applying anchor-based and distributional criterion-based approaches, we found the MCID of the AECT to be between 2.5 and 4.5 points.We clearly favour the meanchange and ROC curve analysis anchor-based approaches over the distributional-based approaches, since they represent more direct and patient-centred methods and are generally accepted to have higher clinical relevance.Therefore, we recommend three points to be used as the MCID for the AECT score for improvement in angioedema control.In other words, an increase in the AECT score by three points or more can be regarded as a meaningful change to the patient.
Performance of the AECT at various cut-off values in screening for a meaningful improvement in global angioedema control and AE-QoL (6 or more points).
T A B L E 4Abbreviations: AECT, Angioedema Control Test; AE-QoL, Angioedema Quality of Life questionnaire.FIJEN ET AL.