The acromegaly treatment satisfaction questionnaire (Acro-TSQ): turkish adaptation, validity, and reliability study

The patient-reported outcome becomes important to evaluate the situation perceived by the patients and to develop new strategies. This study aims to adapt the Acromegaly Treatment Satisfaction Questionnaire (Acro-TSQ), which was specially developed for patients with acromegaly, into Turkish by conducting a validity and reliability study. After the translation and back-translation process, Acro-TSQ was filled in by face-to-face interviews with 136 patients diagnosed with acromegaly and currently receiving somatostatin analogue injection therapy. Internal consistency, content validity, construct validity, and reliability of the scale were determined. Acro-TSQ had a six-factor structure and explained 77.2% of the total variance in the variable. The Cronbach alpha value calculated for internal reliability showed high internal consistency (Cronbach’s alpha = 0.870). Factor loads of all items were found to be between 0.567 and 0.958. As a result of EFA analysis, one item fell into a different factor in the Turkish version of the Acro-TSQ, different from its original form. CFA analysis shows that acceptable fit values are obtained for fit indices. The Acro-TSQ, a patient-reported outcome tool, shows good internal consistency, and good reliability, suggesting it is an appropriate assessment tool for patients with acromegaly in the Turkish population.


Introduction
Acromegaly is a rare and slowly progressing disease caused by an increase in growth hormone (GH) and insulin-like growth factor-1 (IGF-1). Prolonged exposure to the excess hormone can cause structure disturbance and systemic findings such as acral growth, facial overgrowth, hyperhidrosis, osteoarthritis, sleep apnea, impaired respiratory function, carpal tunnel syndrome, colon polyps, and metabolic and cardiovascular diseases. In addition, changes in physical appearance can cause emotional distress [1].
Management of acromegaly encompasses surgery, radiotherapy, and medical approach; they have some advantages and disadvantages. Generally, surgery is considered the first line treatment option, however, if remission cannot be achieved after surgery, the other treatment modalities should be considered. Somatostatin analogs (SSAs) such as octreotide, lanreotide, or pasireotide are the most commonly utilized first-line medical therapy for acromegaly patients when surgery cannot succeed [2]. SSAs administered as intramuscular (octreotide long-acting repeatable (LAR)) or deep subcutaneous injections (lanreotide depot) have common side effects such as injection site reactions and gastrointestinal (GI) symptoms. Despite normalization of GH and IGF-1, symptoms of acromegaly may persist. Life-long injections and ongoing symptoms significantly burden the functionality of patients with acromegaly, well-being, and daily life activities [3].
The treatment strategy aimed at improving mortality and morbidity by providing hormonal control in patients with acromegaly has yielded successful results. Although the quality of life (QoL) of patients with acromegaly shows somewhat improvement after treatment, it remains a major concern as it is still lower compared to the normal population [4]. Patients generally report lower QoL scores in the active phase of the disease than in the controlled phase. Acromegaly patients often complain of joint pain, fatigue, and neuropsychological problems due to irreversible joint abnormalities, body composition, and macroscopic brain architecture changes [5].
Disease-specific questionnaires offer the opportunity to assess patients' self-perceived status and identify patients who require further evaluation and treatment. Patientreported outcomes (PROs) evaluation in acromegalic patients are becoming increasingly popular [6,7]. The Acromegaly Treatment Satisfaction Questionnaire (Acro-TSQ) is a new PRO measure and has been developed specifically for use on acromegaly patients receiving injectable SSAs treatment [8]. Acro-TSQ assesses symptom interference, treatment satisfaction, and convenience, injection site interference, GI side effect interference, and Emotional Reaction.
The World Health Organization defines the quality of life as an individual's perceptions of their position in life in the context of the culture and value systems in which they live and about their goals, expectations, standards, and concerns [9]. Thus, questionnaires and tools developed for the assessment of the quality of life should be verified according to the cultural and linguistic structure of the society in which they are used. Therefore, we aimed to confirm the validity and reliability of the Turkish version of Acro-TSQ for use in clinical practice.

Subjects and methods
Design and type of the study This is a cross-sectional and methodological study to determine the reliability and validity of the Acro-TSQ in acromegaly patients in Turkish Society.

Sample of the study
This study was conducted with acromegaly patients in four different tertiary care centers in Turkey between October 2020 and October 2021. Inclusion criteria for the research: Age over 18 years, acromegaly patients who had been on SSA treatment for at least least three months. Illiterate people answered the questions accompanied by their literate relatives. Exclusion criteria for the research: Diagnosis of known neurocognitive disorders, patients unable to communicate, patients with no concent and patients taking pegvisomant. In validity and reliability studies, it is recommended that the sample size be at least fivefold the number of items in the scale [10]. Therefore, this study aimed to reach at least 125 people considering the risk of loss during the study, an additional eleven people were included in the study. Finally, the study was completed with 136 people in line with the literature recommendation.

Data collection procedure and tools
Researchers collected data by face-to-face interview method and using "Personal Information Form" and "Acro-TSQ". Acro-TSQ was completed by the patients themselves.
The questions in the Personal Information Form are as follows; age, gender, height, weight, body mass index, living with, marital status, education status, occupation, monthly income, smoking, alcohol use, acromegaly treatment methods, current preparations, illness status, and other comorbid diseases.
The Acro-TSQ was developed by Fleseriu et al. in 2019 [8]. This scale has 27 items and 6 subscales. 2 items in the scale directly question oral SSA treatment. (Q24 and Q25). Since there is no oral SSA treatment in our country, these 2 items were excluded from the evaluation. Thus, a scale question consisting of 25 items was used. Acro-TSQ scoring is provided in the supplement file.

Translation and cross-cultural adaptation
To adapt the scale to Turkish, permission was obtained from Chiasma Inc. (acquired by Amryt Pharma). The language validity of the scale was evaluated by highly qualified translators using the translation-back translation method. The translation of the scale was done at different times by ten independent specialists, including six English language specialists, two Turkish language specialists, and two native medical doctors. Afterward, a single scale form was created with the consensus of the specialist. As a second step, the Turkish translation of the scale was translated back into its original language by two independent specialists who are fluent in both languages. The original version of the scale and the translated version were compared by a native English speaker, and thus the final version of the scale was created. This version is given in the supplement file.

Data analysis
We first ran an exploratory factor analysis (EFA) to determine the factorial structure of the scale. To test if the data is suitable for conducting EFA, Kaiser-Meyer-Olkin's (KMO) measure of sampling adequacy and Bartlett's test of sphericity were run. In EFA, we extracted the factors by using principal component analysis. As most of the factors correlated with one another, promax, an oblique rotation, was used to rotate the factors. Next, we conducted a confirmatory factor analysis (CFA) to verify the factorial structure of the scale. Then, we ran a reliability analysis for estimating the internal consistency of the scale through Cronbach's alpha. We used SPSS 24 to run EFA and reliability analysis and AMOS 23 extension of SPSS for CFA.

Sample characteristics
Of those included in the study, 49.3% were female and 50.7% were male. The mean age of all participants was 51.9 ± 12.6 years. The literacy rate of the participants was quite high (95.6%). Patients included in the study had at least one history of transsphenoidal surgery. Most of these patients were under control with at least one medical agent (85.3%) ( Table 1). these error terms. The modification indices improved the model's goodness of fit although some of the fit indices did not improve (Fig. 1).

Reliability analysis
Cronbach's alpha of the Turkish version of the Acro-TSQ was 0.87. For the internal consistency reliability of each subscale, Cronbach's alpha estimates were measured as 0.85 for SI, 0.87 for TC, 0.89 for ISI, 0.90 for GII, 0.71 for TS, and 0.90 for ER. All of the factors appeared to have good levels of internal consistency.

Patient-reported outcome
Items other than scale scoring in the Acro-TSQ scale were analyzed. According to this; approximately 1 in 5 patients (19.9%) reported experiencing symptoms related to acromegaly despite treatment within 4 weeks of the last injection. Within 4 weeks of SSA injection, 33.1% of patients reported that they experienced treatment-related gastrointestinal side effects. After SSA treatment, 66.9% of the patients stated that they did not experience any side effects related to the injection site. All patient-reported outcome data is shown in Table 3.

Exploratory factor analysis
KMO was 0.764, which confirmed the sampling adequacy. Barlett's sphericity test was significant, indicating that there is no redundancy among variables and the data is suitable for factor analysis. (χ2 = 1989,629, df = 210, p < 0.001). EFA with forced six-factor extraction explained 77,2% of the total variance. Factor 1 reflected TC; factor 2 ER; factor 3 SI; factor 4 GII; factor 5 ISI; and factor 6 TS. All of the items were loaded on the factors as they were in the original scale except for item number 18 (Upset because dependent on others). However, we did not delete the item from the scale as it is still relevant to the factor that loaded on, which is an emotional reaction. There were no cross-loaded factors in the study, and all factor loadings were above 0.45. Almost all of the loadings were above 0.70. Total-item correlation coefficients, factor variance and factor loading values showing the distribution of items on factors are given in Table 2.

Confirmatory factor analysis
In the first CFA model with a six-factor structure, we used modification indices because some fit indices were below acceptable values. Given that factor loadings in Acro-TSQ were higher than 0.40, we decided to keep all of the items in the scale. The modification indices indicated that there were high correlations of error covariances between 5 and 8, between 6 and 8, and between 2 and 26. We applied these index measures and ran another CFA model by correlating The higher the Cronbach Alpha coefficient of a scale, the more consistent the items that make up the scale are assumed to be with each other. In the literature, it is reported that a Cronbach's alpha coefficient between 0.60 and 0.80 indicates that the scale is reliable, and ≥ 0.80 indicates that the scale is highly reliable [14,15]. The Cronbach alpha coefficient of Acro-TSQ confirms that the Turkish validity and reliability of the scale are quite high.
Although biochemical control is achieved with injection therapy, some patients report worsening symptoms of acromegaly or symptoms associated with injection therapy towards the end of the injection interval [16]. Therefore, measuring patient-reported outcomes is recommended in addition to biochemical assessment in clinical practice to capture the patients' perspective. In the meta-analysis of 53 studies evaluating the quality of life of patients with acromegaly, 14 different scales were used, but only one, the Acromegaly Quality of Life Questionnaire (AcroQoL) has been validated in acromegaly [17]. Recently, the Acromegaly Disease Activity Tool (ACRODAT®) [18] and SAGIT® [19] have been developed. However, the tools have limitations in addressing patient-reported symptoms and potential adverse effects in clinical practice. The Acro-TSQ is a tool that comprehensively addresses the efficacy of treatment and possible side effects and has been developed and validated in a way that acromegaly patients can self-administer [8].
In a multi-center study using the Acro-TSQ, 67% of patients reported experiencing symptoms of acromegaly after the last injection. In this study, 92% of patients reported that their symptoms affected their daily life, 84% of their leisure time activities, and 87% of their work activities [20]. In another study of 195 patients, 52% of patients reported that their acromegaly symptoms worsened towards the end of the dosing interval and 62% reported that these symptoms affected their daily lives [21]. The reason for this lower rate in our study may be related to the high rate of disease control, cultural differences, and living conditions.
In general, SSAs are safe and well-tolerated medicines. The most commonly reported side effects of SSAs are gastrointestinal (GI) symptoms which occur in approximately 30% of patients and are usually mild in severity and transient [22]. In the study by Fleseriu et al., 74% of patients had GI side effects after SSA injections and these effects were observed up to day 56 (mean 8 days). GI side effects affected daily life in 65% of patients, leisure time activities in 67%, and work activities in 62% [20]. In another long-term follow-up study, only 8% of patients complained of transient gastrointestinal side effects that did not require discontinuation of treatment [23]. Differences in gastrointestinal of this study. The results showed that the scale can be used in the Turkish population in terms of language, construct validity and reliability.
An exploratory and confirmatory factor analysis evaluates the appropriateness of a scale in terms of construct validity. One method used in factor identification is the method defined by Kaiser, which states that eigenvalues greater than '1' represent a factor [11]. The ratio of variance explained in multi-factor scales should be at least 50% for a statistically valid exploratory factor analysis [12,13]. The exploratory factor analysis conducted in our study revealed that the Acro-TSQ showed a structure appropriate to the original scale, and the scale items had sufficient validity and were sufficiently related to the scale.
CFA confirmed that the scale conformed to the original structure. We preferred not to permanently remove these items from the scale, even though the factor loadings of some items in the scale were less than satisfactory and fell into several sub-factors. The main factor here is that the CFI value is above the acceptable fit value even without removing the items. In addition, other CFA results also support that this scale has robust validity and reliability. In our study, question 18, which was classified under the 'Treatment Convenience' subscale in the original questionnaire, was downgraded to the 'Emotional Reaction' subscale in hormonal responses due to ethnic differences or changes in the microbiota of gut may underlie these differences in the literature. Potential side effects of SSAs include pain, lumps/nodules, itching, and bruising at the injection site. The most commonly reported side effect after injection in a series of 195 patients was pain at 70% [21]. In another study, pain (83%) was the most commonly reported injection siterelated symptom. When assessed with the Acro-TSQ, 74% of patients reported being bothered by injection site reactions during the first few days [24]. In the study by Fleseriu et al. 77% of patients reported side effects related to the injection site [20]. Of these patients assessed with the Acro-TSQ, 67% were bothered by these side effects in the first few days and 57% reported that their work and activities of daily living were affected. The reason why injection site-related side effects were lower in our study may be that these effects were not questioned separately. However, the patient's level of discomfort from these side effects was higher than in the literature. These differences may also be related to the fact that the studies were conducted in different ethnic communities and the roles of individuals in social life.

Limitations
This study has several limitations. First, since acromegaly is a rare disease closely associated with comorbidities, it was not possible to exclude patients with comorbidities. Second, since the scale involves retrospective questioning, patients may have some recall difficulties. Lastly, our study was unable to confirm the validity of the Turkish Acro-TSQ scale as we did not have other scales for treatment satisfaction in our dataset. We recommend future research to test the relationship between the Turkish Acro-TSQ and other related factors (e.g., anxiety, depression, and life quality).

Conclusion
This study proved that the Turkish form of Acro-TSQ developed by Fleseriu [8] is a valid and reliable scale. This scale is an effective tool for detecting the ongoing disease burden, treatment-related side effects, and impact on daily living and work activities, as reported directly by the patient, even if biochemical control is achieved with SSA. These results emphasize the importance of collecting and monitoring patient-reported outcomes in clinical management to improve the quality of life of acromegaly patients.