Transcultural Validation of A Spanish Version of The Quality of Life In Epidermolysis Bullosa Questionnaire


 Introduction: Epidermolysis bullosa (EB) is a relatively infrequent genodermatosis for which there is still no cure, and which impacts on the quality of life of those affected by it. The Quality of Life evaluation in Epidermolysis Bullosa (QoLEB) questionnaire was specifically developed for English-speaking persons with EB. Objectives: To undertake the transcultural adaptation and analysis of the psychometric properties of a Spanish version of the QoLEB questionnaire. Method: We designed an observational study to implement the process of translation and validation of the scale in accordance with World Health Organisation guidelines. We assessed the content validity of the Spanish version, with the participation of 33 adult patients who presented with 4 principal subtypes of EB. Subjects were examined and evaluated using the QoLEB and Short Form-36 (SF-36) questionnaires. Results: The Spanish version of the QoLEB displayed excellent internal consistency and content validity, α=0.91. Test-retest reliability was likewise excellent (ps=0.93), as was reliability among subtypes (range ps=0.82–0.93). The functional part of the QoLEB correlated well with the SF-36 physical component summary (ps=0.70). The emotional QoLEB was moderately correlated with the SF-36 mental component summary (ps=0.49). Significant discriminant validity existed between the global score of the questionnaire (p=0.033) and the functional scale (p=0.003). Conclusion: The Spanish version of the QoLEB questionnaire can be recommended for use in any subsequent studies seeking to assess the efficacy of possible treatments and care programmes in this group.


Introduction
Inherited epidermolysis bullosa (EB) is a term that encompasses a clinical and genetically heterogeneous group of low-prevalence blistering diseases, whose chief characteristic is extreme fragility of the skin and mucous membranes. This disorder gives rise to the formation of blisters in response to minimal trauma or even spontaneously (1). It is a chronic disease for which there is currently no cure, with the result that all care and treatment received by persons affected by EB is necessarily palliative and aimed at improving the quality of life of patients and their families (2).
EB has great repercussions on the quality of life, and many studies have con rmed this from a both a quantitative and qualitative perspective (3). In 2009, the rst instrument purpose-designed to analyse how EB affects the quality of life of those affected by it was drawn up and validated, thereby providing pertinent information for therapeutic and research purposes (4,5). The questions in this Quality of Life evaluation in Epidermolysis Bullosa (QoLEB) questionnaire analyse the consequences of the disease on the patient, by assessing the functional and emotional aspects of EB sufferers' quality of life. This tool has since been translated into and validated in different languages and cultures (5)(6)(7), affording reliable comparisons and making it possible to evaluate the effectiveness of EB-speci c interventions conducted in various non-English-speaking countries (7).
Other quality-of-life assessment instruments, both generic and dermatology-speci c, have also been used in a number of EB studies (3)(4)(5)(7)(8)(9)(10). Yet the accuracy of measurements in EB is questionable (4,7,10). One of these instruments is the SF-36 questionnaire, a very complete tool which is usually used to assess health-related quality of life globally, rather than speci cally in relation to a given disease (11).

Objective
This study aimed to develop a valid and culturally appropriate Spanish translation of the QoLEB questionnaire for use in Spain.
As a number of authors have noted (4)(5)(6)(7)(8)(9)(10)12), EB measuring instruments must be developed which can be used both in clinical practice and for research into the disease. To ensure measurement quality, it is essential that any such instrument undergo a validation process. Furthermore, this process must not only be conducted when the instrument is drawn up in the original language, but must then be repeated when the structure is altered and/or there is a change in the language in which the instrument is applied. Validating a version in a language other than the original consists of culturally adapting the questionnaire to the medium in which it is sought to be used and retesting it to ensure that it retains the appropriate psychometric characteristics to measure what it was designed to measure (13). 2020 saw the publication of the rst systematic review of quality of life in EB, in which the authors conclude that the quality of life of this population must be evaluated with EB-speci c instruments, such as the QoLEB questionnaire (10).
Although a Spanish version of this questionnaire has been validated in Mexico, we nevertheless felt it advisable for this questionnaire to be speci cally adapted to the cultural medium in which it was sought to be used, i.e., Spain. The aim of this study was thus to validate a Spanish version of the QoLEB for Spain, study its correlation with the SF-36, and ascertain the degree of correlation of the results of this sample of Spanish patients with those reported by other similar papers in the literature.

Patient and Public Involvement
This study had the authorization and the support of the Association of Patients in Epidermolysis bullosa in Spain: NGO DEBRA Piel de Mariposa.
The Patient Association was involved in the design and conduct of this research, including the establishment of the research question, outcomes, and the design and the execution phases of the intervention. It is remarkable its constant support in the dissemination of the research and the results that are obtained.

SF-36 questionnaire
The SF-36 questionnaire has been translated into and validated in Spanish and assesses both positive and negative aspects of health. The nal questionnaire covers 8 domains which represent the health concepts most frequently used in the main health questionnaires, as well as the aspects most closely related to the disease and its treatment. The instrument's 36 items cover the following scales: physical function; role physical; bodily pain; general health; vitality; social function; role emotional; and mental health (14). The 8 domains can be grouped into 2 main health components, the physical component summary (PCS) and the mental component summary (MCS) (7,14).
SF-36 scale scores of 0 to 100 have been widely used and enjoy popularity, thanks to the direct translation of their maximums and minimums to best and worst health statesrespectively. Even so, the authors propose norm-based scoring for the new component summaries of the SF-36, whose principal advantage is that the results are directly interpretable with respect to the reference population (14,15). Hence, scores based on the norm, above or below 50, respectively indicate better or worse states of health than the mean for the reference population (14).
Our methodology based on World Health Organisation guidelines (16) for translation and transcultural adaptation of an EB quality-of-life assessment instrument, encompassing ve steps: informed consent; translation of the questionnaire from English into Spanish, followed by back translation into English again; review by a committee of experts; preliminary tests; and statistical analysis.
The methods applied in this validation process are similar to those described in the original paper on the validation of the Dutch QoLEB (7). We feel that our study meets all the requirements demanded by the validation process of a questionnaire adapted to EB, and expresses the results in a way that is straightforward and easily understandable.

Translation of the QoLEB into Spanish
Development of the Spanish version of the QoLEB began with its translation and intercultural adaptation by a translator whose native language was Spanish. The questionnaire was translated by a panel of experts in rare diseases and EB. The resulting version was then back-translated into English by another independent translator whose mother tongue was English, and reviewed and revised again to ensure that the QoLEB translated into Spanish conveyed the same meaning as the English original. Finally, this last revision was used to create the de nitive Spanish version of the QoLEB. The Spanish QoLEB is given in Appendix I.

Recruitment and design
This cross-sectional study was conducted with the collaboration of families belonging to a non-governmental organisation (NGO) known as DEBRA Piel de Mariposa, the only EB patient and family association in Spain, which currently gives support to over 300 families.
All EB-affected adult members of the NGO, Debra Piel de Mariposa, were eligible for study purposes: the inclusion criteria required patients to have Spanish as their mother tongue and be of full legal age. Following the same procedure as in other similar studies (4-7), participants were classi ed into 4 principal groups: EB simplex (EBS); junctional EB (JEB); dominant dystrophic EB (DDEB); and recessive dystrophic EB (RDEB). Those patients who decided to participate received two questionnaires, the QoLEB in Spanish and the SF-36, which they then completed and returned via e-mail, except for 3 cases who had to do this by telephone in strict compliance with the approved script. Four weeks later, the participants were asked to complete and return the Spanish-language QoLEB for a second time, in order to assess the reproducibility of the replies.
Of the 33 adult patients who participated in the questionnaires, 100% completed the QoLEB. Two patients failed to complete the SF-36 questionnaires and were excluded from the analysis: however, they were taken into account for the re-test of the QoLEB instrument in Spanish.

Analysis
A oor effect and ceiling effect was considered for individual items, in cases where ≥ 80% of the participants obtained the highest or lowest possible scores in the rst QoLEB in Spanish.
The reliability of the Spanish QoLEB was determined by analysis of internal consistency with Cronbach's alpha (α), based on data drawn from the rst QoLEB that was completed. A value of α ≥ 0.7 was regarded as acceptable, ≥ 0.8 as good, and ≥ 0.9 as excellent (7). Convergent validity was evaluated by comparison between the Spanish QoLEB questionnaire and the SF-36, a generic quality-of-life questionnaire already validated for use in Spanish (14). This was compared against the results reported by other studies on QoLEB questionnaires translated into other languages and cultures, such as the Mexican and Dutch QoLEB questionnaires.
The degree of test-retest reliability was estimated by reference to the ρs (correlation value) between the general QoLEB scores registered the rst and second time respectively, with a ρs of ≥ 0.7 being regarded as acceptable and ≥ 0.8 as excellent. The level of signi cance was set at 5% (p ≤ 0.05) for all comparisons.

Results
Ascertainment of the content validity of the Spanish version of the QoLEB entailed translation of the instrument into Spanish followed by its back translation into English, without this showing validity problems. The results of the reliability tests displayed excellent internal consistency and construct validity, α = 0.91. Similarly, internal consistency and construct validity was good-to-excellent for the respective EB subtypes (range α = 0.83-0.93). Overall test-retest reliability was excellent (ps = 0.93), as was reliability in the subtypes (range ps = 0.82-0.93).
The mean time for completing the questionnaire was 5.72 minutes, with no participant taking more than 15 minutes, and the questionnaire response time was considered short.
With respect to the SF-36 questionnaire, in terms of correlation the results obtained indicated that the functional part of the QoLEB was well correlated with the SF-36 PCS (physical component summary) (ps = 0.70), and the emotional QoLEB was moderately correlated with the SF-36 MCS (ps = 0.49).

Assessment of the QoLEB
A con rmatory factor model was used to validate the QoLEB questionnaire in Spanish. Our analysis con rmed that the questionnaire signi cantly separated items pertaining to functional and emotional elements.
From these results, it could be seen that the functional and emotional variables were correlated (covariance 0.67) and that items had signi cant factor loadings with coe cients of 0.44 to 0.72 (see Fig. 1). In addition, the results showed that there were no oor or ceiling effects, since the proportion of maximum or minimum scores in each of the questions did not exceed 70% of subjects surveyed. Table I shows the results of the Spanish version of the QoLEB, with a breakdown by sex cohort and EB subtype. Women had a lower health-related quality of life than did men, though these differences did not reach statistical signi cance. There was a statistically signi cant exception in the emotional section of the Spanish QoLEB (p = 0.007). In general terms, the EBS and DDEB subtypes displayed a better health-related quality of life on most of the scales than did the RDEB and JEB groups. These differences attained discriminant validity for the functional scale (p = 0.003) and global score (p = 0.033), but not for the emotional scale. Among the different groups, there were signi cant differences in the functional section between the EBS-RDEB (p = 0.008) and DDEB-RDEB groups (p = 0.020), and also in total scores between the EBS and RDEB groups (p = 0.085). Table II shows the level of the impact on participants' quality of life, by the type of disease affecting them: 35% of interviewees reported a severe-tovery severe impact on their quality of life, as opposed to 26% who reported experiencing a slight-to-very slight impact; the remaining 39% reported a moderate impact. Similarities were observed with regard to the scores registered for the EBS and DDEB subtypes, and some slight differences with respect to JEB and RDEB. The results of the 17 individual QoLEB questions are listed in Table III.
While 100% of patients interviewed experienced pain, 18% of these reported experiencing constant pain; in terms of relationships with family and friends, EB affected 42% of participants, though in most of these cases it affected them slightly; 51% had some di culty in eating, and the same percentage needed some type of aid for bathing or showering; and 39% experienced some limitation in writing, with this limitation being especially important in those affected by RDEB, among whom 27% were unable to write. All persons interviewed reported some limitation when it came to engaging in sports, with 81% having to avoid all or some sports; 61% reported experiencing limitations in the home, though these were slight in the great majority of cases; this percentage rose to 70% when movements took place outside the house, where scores were observed to rise with respect to those obtained in the question that analysed how EB affected movements within and around the home. Practically the same percentage was obtained, speci cally 72%, when it came to shopping, and this same gure was obtained in response to the question about how EB affected the family's nancial status. EB caused 82% of the patients interviewed to feel frustrated, 51% to feel embarrassed, 76% to feel worried or anxious, 57% to feel depressed, and 63% to feel uneasy.  EB had a greater impact on health-related quality of life among women than among men, but the differences did not prove signi cant (Table IV). Comparing these between subgroups, statistical signi cance was achieved on the physical function scale between the EBS-JEB (p = 0.026) and EBS-RDEB groups (p = 0.024); and statistically signi cant differences were also found on the general health scale between the EBS and RDEB groups (p = 0.014). As

Discussion
This study shows that the QoLEB, in its Spanish version, is a valid and reliable scale which makes it possible to measure the quality of life of persons who suffer from EB in Spain.
The internal consistency of the QoLEB in Spanish is high, α = 0.91, a result similar to that obtained in the validation of both the original (α = 0.931) and Dutch questionnaires (α = 0.905). Convergent validity is high, since the chi-squared test and factor loadings indicate that there is a high proportion of variance in common. Discriminant validity between the SF-36 and Spanish-version QoLEB questionnaires is high, HTMT = 0.681 (heterotrait-monotrait ratio of correlations), with the result being less than 0.85.
In general, the average scores obtained in the Spanish version of the QoLEB were higher than those recorded in the Dutch questionnaire, as was also the case in the scores reported for the original English questionnaire and in data collected on EB-affected adults in Brazil.
In our study, women with EB report a greater impact on their quality of life than do men. These results are also found in the Dutch review (7) and, moreover, the same conclusions appear in two more articles listed in the systematic review of "quality of life in people with epidermolysis bullosa" published in 2020 (10).
A greater standard deviation appears in the study population in the responses obtained in the SF-36 than in those obtained in the Spanish QoLEB, a nding that suggests a wider variation among individuals by subtype in the rst 2 questionnaires. The same occurs in the Dutch results. Our results also coincide with the results obtained in the rst systematic review on quality of life and EB (10), in which the data obtained on the RDEB and JEB subtypes show a worse quality of life, in general terms, than in the EBS and DDEB groups.
As happens with the Dutch QoLEB and Brazilian-Portuguese QoLEB, in the Spanish QoLEB signi cant differences among EB subtypes are seen on the functional and global scales but not on the emotional scale.
Although we had intended to compare and assess whether there might be differences between the Mexican and Spanish versions of the QoLEB questionnaires, this was ruled out by the impossibility of obtaining the Mexican QoLEB.

Conclusion
Epidermolysis bullosa is a low-prevalence disease which has a signi cant impact on the quality of life of EB-sufferers and their families. The need to have quality-of-life assessment instruments in Spanish for this group will enable us to obtain reliable measurements on which to plan effective actions and intervention strategies. The results obtained support the questionnaire's construct validity and underscore its suitability for the task. In conclusion, the validation of this questionnaire in Spanish will help optimise and evaluate the care offered to patients with EB in Spain, and this Spanish version of the QoLEB has been shown to be a valid and short instrument for assessment of health-related quality of life among persons with epidermolysis bullosa.

Declarations
Ethics approval. Ethical approval was granted by the research ethics committee of the National University of Distance Education (UNED) in Spain, which reference number is 33-2020.

Consent for publication: Not applicable
Availability of data and materials. The datasets used and analysed during the current study are available from the corresponding author on reasonable request. Please contact author for data requests. Funding.None.
Competing interests. The authors declare that they have no competing interests.
Author's contribution to the paper. MP, FM and AV had a substantial contribution to the conception and design of the work. AV carried out the acquisition and interpretation of data for the work. AA performed the statistical analysis. All authors read and approved the nal manuscript 1 . World Health Organization. Process of translation and adaptation of instruments.
http://www.who.int/substance_abuse/research_tools/translation/en/ 2009. Figure 1 Con rmatory factor analysis of the results of the Spanish version of the QoLEB

Supplementary Files
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