Development of the EPP-QoL
The EPP-Qol was developed through a process of expert clinical consultation. Before the development of a modern treatment for EPP there was no standardised form of patient reported assessment. The clinical study team considered that the Dermatology Life Quality Index lacked face validity in the assessment of EPP because certain key features of the condition are not reflected in the questions. In order to develop the EPP-QoL the clinical experts held a series of round table meetings to agree on the concepts to measure and to discuss the development of the item wording. The instrument then went through rounds of review before its content was considered finalised. Informal assessments of the instrument by several groups of EPP patients were undertaken to provide feedback on the items and wording. The measure had not been formally validated prior to the initiation of this trial programme.
The psychometric validation was conducted on data collected from two trials: trial CUV029 (conducted over a 9 month period in Europe and included 6 site visits) and trial CUV030 (conducted over a 6 month period in the US and included 4 site visits).
Erythropoietic protoporphyria-quality of life (EPP-QoL)
The EPP-QoL was designed to assess quality of life in EPP patients. It was originally designed as a unidimensional instrument that included 15 items measuring various aspects of quality of life, including the impact of EPP on well-being, ability to partake in social/leisure/outdoor activities on sunny days, the choice of clothes worn on sunny days, and issues around transportation. The items are scored using a 4-point Likert scale ranging from 0 to 3, − 3-0, or − 2-1 depending on the item. The scale is scored additively, resulting in a maximum of 35 and a minimum of − 10. The higher the score, the more the quality of life is impaired. The recall period for the EPP-QoL is 2 months. The instrument was provided to patients for completion every 2 months during the clinical trials. Completion rate was 93%.
The approach to the psychometric analysis was informed by Fayers & Machin  and Revicki et al. . The focus of the psychometric analysis was on exploring the psychometric structure of the instrument through factor analysis. Following this, the performance of the identified domains was examined in terms of reliability and validity. Reliability assessments explored measurement error. The validity assessments were designed to determine what the domains were measuring and how changes in the domain scores can be interpreted. The analyses were limited in their scope because this was secondary analysis of clinical trial data which meant that the analyses were constrained to available data collection points and variables.
Exploratory factor analysis
An exploratory factor analysis (EFA) was used to identify the structure of the EPP-QoL (e.g. whether the unidimensional structure could be supported). Factors with an eigenvalue of 1 or more were extracted. Different rotations were examined, including oblique and orthogonal approaches. The suitability of the data for conducting an EFA was assessed on the Kaisser-Mayer-Olkin Measure of Sampling Adequacy and Bartlett’s Test of Sphericity.
The performance of each item of the EPP-QoL was assessed to explore the frequency of responses (to identify heavily skewed items or items with large floor or ceiling effects). A skewed distribution of responses was defined where fewer than 10% of responses occurred in two adjacent scale points. This was used to highlight problematic items .
Each item was reviewed in terms of poor functioning based on the findings from the EFA and the item analysis. Evidence of poor functioning items was based on whether the item did not fit the emerging factor structure; or there was evidence of skew, floor or ceiling effects or high rates of missing responses. If there was substantial evidence that an item was functioning poorly then the item could be removed from the measure. The factor analysis suggested that the items grouped into two broad domains that were labelled EPP Symptoms and EPP Wellbeing (see below). Analyses of reliability and validity therefore explored the performance of these two domain scores.
Internal consistency (Cronbach’s alpha) was estimated for EPP Symptoms & EPP Wellbeing using data from visit 3 only. To explore test-retest reliability of the scale, data were analysed from the middle period of the trial (visits 3 and 4). Participants were considered to be stable if they had experienced no phototoxicity prior to visit 3 and visit 4. The intra-class correlation coefficient (ICC) and Pearson’s correlation were estimated for the EPP Symptoms and EPP Wellbeing domain scores.
The performance of the EPP Symptoms and Wellbeing domains was tested in terms of its relationship to other markers of disease severity or outcomes as well as other measures of HRQL. This analysis focused on the Dermatology Life Quality Index (DLQI) which is the most widely used patient reported measure of health status or HRQL used in dermatology. However, it is a generic dermatology tool not specific to EPP and has not been specifically validated in EPP patients to the best of our knowledge.
The DLQI data can be used to express an overall impact of the dermatological condition on the patients’ life quality. Cut-off scores have been published (0–1 No effect on patients’ life; 2–5 small effect; 6–10 moderate effect; 11–20 very large effect; 21–30 extremely large effect) . Participants were divided into groups based upon these cut-off scores and the differences in EPP scores were estimated. The EPP-QoL domain scores were also benchmarked against the severity of recent phototoxicity episodes as rated by the patient in a diary (Table 1).
The sensitivity of the EPP scores was estimated in terms of effect sizes. The EPP scores were explored to test the extent to which they changed as a result of a phototoxicity event. Simple effect sizes were estimated for patients who reported moving from experiencing some photoxicity at Visit 3 to experiencing none at Visit 4.
Minimal important difference
The trial data included two subjective markers of health status that were used as anchors to estimate minimal change – the DLQI and peak phototoxicity severity. These variables were used as a proxy for the degree of difference between groups that would be considered important. The MID estimates were calculated as the arithmetic difference between mean values for different groups of patients defined either in terms of peak phototoxicity or DLQI grades.
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