Disease-specific patient-reported outcome measures (PROMs) are fundamental to understanding the impact on, and expectations of, patients with genetic disorders, and can facilitate constructive and educated conversations about treatments and outcomes. However, generic PROMs may fail to capture disease-specific concerns. Here we report the development and validation of a Gaucher disease (GD)-specific PROM for patients with type 1 Gaucher disease (GD1) a lysosomal storage disorder characterized by hepatosplenomegaly, thrombocytopenia, anemia, bruising, bone disease, and fatigue.
The questionnaire was initially developed with input from 85 patients or parents of patients with GD1 or GD3 in Israel. Owing to few participating patients with GD3, content validity was assessed for patients with GD1 only. Content validity of the revised questionnaire was assessed in 33 patients in the US, France, and Israel according to US Food and Drug Administration standards, with input from a panel of six GD experts and one patient advocate representative. Concept elicitation interviews explored patient experience of symptoms and treatments, and a cognitive debriefing exercise explored patients’ understanding and relevance of instructions, items, response scales, and recall period. Two versions of the questionnaire were subsequently developed: a 24-item version for routine monitoring in clinical practice (rmGD1-PROM), and a 17-item version for use in clinical trials (ctGD1-PROM). Psychometric validation of the ctGD1-PROM was assessed in 46 adult patients with GD1 and re-administered two weeks later to examine test–retest reliability. Findings from the psychometric validation study revealed excellent internal consistency and strong evidence of convergent validity of the ctGD1-PROM based on correlations with the 36-item Short Form Health Survey. Most items were found to show moderate, good, or excellent test–retest reliability.
Development of the ctGD1-PROM represents an important step forward for researchers measuring the impact of GD and its respective treatment.
Deborah Elstein: Paid consultant to Takeda during the content psychometric validation phases of the study; independent researcher during the initial development phase and during the later stages of manuscript development
Koonal Shah: At the time the study was carried out
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Gaucher disease (GD) is an autosomal recessive disorder characterized by a deficiency in the lysosomal enzyme acid β-glucosidase (GCase), caused by pathogenic variation in the
The importance of individualized patient-centric monitoring is now widely recognized, both with regard to individual patient management and for informing commissioning of healthcare services, and the US Food and Drug Administration (FDA) has issued guidance as to how these measures should be incorporated in clinical trial design [
In this evolving environment, PROMs that convincingly provide evidence of significant improvements in HRQoL with consequent individual and societal benefits will be crucial to treatment-approval processes across the board, but especially for rare disorders such as GD, for which sustained, effective therapy should result in healthy and “normal” life expectancy. At a population level, disease-specific PROMs can inform healthcare commissioning, while at an individual level, a disease-specific PROM can facilitate patient/physician dialogue based on HRQoL responses. This might more clearly indicate the individual patient’s current mindset and expectations, enlighten clinical management, and in turn, motivate patients to be active participants in their care.
A GD-specific PROM (the GD1-PROM) was originally developed and circulated by Deborah Elstein to afford greater insight into the condition of the HRQoL of patients with GD1. Further work resulted in development of two versions of the GD1-PROM: a routine monitoring version for clinical practice, and a version for use in clinical trials. Here we describe the content and psychometric validation of the GD1-PROM, as well as required measurement properties per FDA guidance [
The initial version of the questionnaire was based on input from patients receiving treatment at the Shaare Zedek Medical Center, Jerusalem. It was designed to be comparable with the SF-36 questionnaire [
The initial version of the questionnaire was administered to 21 adult patients and six parents of pediatric patients aged < 12 years at the Gaucher Clinic at Shaare Zedek Medical Center, Jerusalem, under the directorship of Professor Zimran for routine follow-up (Fig. Overview of the development and validation of the ctGD1-PROM.
A panel of experts provided input into a third version of the questionnaire, with no changes requested (Fig.
Following the development of the initial questionnaire, a content validation study was conducted to develop/adapt and assess the questionnaire to confirm its suitability for use in clinical practice as well as in clinical trials (Fig.
The planned sample size was determined based on the principle of “concept saturation”. Concept saturation is commonly defined as the point at which no new and important concepts relevant to the research question are identified emerging from iterative rounds of interviews (i.e. collecting additional data will not likely add to the understanding of how participants perceive the concept of interest) [
Qualitative analysis of transcripts was conducted using the computer-assisted qualitative data analysis software program, ATLAS.ti.16. Transcripts were analyzed using thematic analysis methods, and participant quotes that pertained to the main research objectives were highlighted and assigned corresponding concept codes.
A total of 33 patients ≥ 12 years of age with GD1 or GD3 were recruited into the content validation study: 23 participated in round 1 of the qualitative interviews (18 adults and five adolescents) and 10 participated in round 2 (nine adults and one adolescent) (Fig. Content validation: demographic characteristics of the study population Characteristic Round 1 n = 23 Round 2 n = 10 Total n = 33 Mean (range) age, years 35.7 (13–67) 50.9 (15–73) 40.3 (13–73) Sex, n (%) Female 14 (60.9) 7 (70.0) 21 (63.6) Ethnicity, n (%)* White 11 (47.8) 7 (70.0) 18 (54.5) Ashkenazi Jewish 11 (47.8) 3 (30.0) 14 (42.4) Other 4 (17.4) 0 4 (12.1) Highest educational level (adults only), n (%) Some high school 1 (4.3) 0 1 (3.0) High school diploma or General Educational Development (GED) 3 (13.0) 1 (10.0) 4 (12.1) Some years of college 3 (13.0) 1 (10.0) 4 (12.1) Certificate program 1 (4.3) 0 1 (3.0) University/college 3 (13.0) 2 (20.0) 5 (15.2) Graduate or professional degree 5 (21.7) 4 (40.0) 9 (27.3) Other 1 (4.3) 1 (10.0) 2 (6.1) N/A or missing 6 (26.1) 0 7 (21.2) Mean (range) duration of disease, years 26.2 (1–60) 35.0 (14–63) 26.8 (1–63) Disease severity (as rated by the recruiting clinician), n (%) Very mild 1 (4.3) 0 1 (3.0) Mild 5 (21.7) 2 (20.0) 7 (21.2) Moderate 14 (60.9) 4 (40.0) 18 (54.5) Severe 3 (13.0) 3 (30.0) 6 (18.2) Very severe 0 1 (10.0) 1 (3.0) *Multiple answers given
Recruited participants took part in a 90-min combined concept elicitation and cognitive debriefing interview. The focus of this portion of the interview was to establish how GD affects patients with respect to their symptoms, impacts on functioning/HRQoL, and treatment experience. The concepts elicited were used to develop a conceptual model for GD, which detailed the overall patient experience of GD following the theory of the Wilson and Cleary model [
Concept elicitation interviews resulted in 11 core symptoms of GD and seven core impact categories being reported by patients (Fig. Content validation: conceptual model. Content validation: key symptoms of GD reported by patients. Content validation: impact on HRQoL domains reported by patients.
Evaluation of concept elicitation interviews was completed at the symptom level by dividing transcripts into three sets of 10 interview transcripts. For adult patients with GD1, most symptom concepts emerged in the first two sets of interviews, with only kidney pain and seizures emerging in the final set of interviews. The rare nature of GD3 and the low number of adolescent participants led to challenges in recruiting adequate sample sizes for comparative analyses between GD1 and GD3, and between adults and adolescents.
The aim of the cognitive debriefing component was to ask patients about their understanding of instructions and item wording, and about the relevance and comprehensiveness of the items included. The cognitive debriefing section also assessed the appropriateness of the response options and recall period for all items.
In round 1 of the cognitive debriefing interviews, 23 patients were debriefed on the 30-item questionnaire. Part 1 (questions 1–23) employed a “yes/no/not relevant” response scale and part 2 (questions 24–30) employed a 0–10 numeric rating scale. Many items were well understood by patients; however, some items appeared to lack conceptual relevance. The findings were discussed with the expert panel and carefully reviewed against regulatory criteria on the development of PROMs. In line with the FDA PROM guidance [
In round 2 of the cognitive debriefing interviews, 10 patients were debriefed on the revised 31-item version of the questionnaire. Most items were well understood by all patients and considered relevant by ≥ 50% of the sample. However, eight items were not understood by one adult participant each. The participant-level findings also indicated that while half of the participants understood all items, the other half had difficulty with only one or two isolated items. Further modifications made to the questionnaire included the removal of seven items, including three items from part 1 and four items from part 2, owing to a lack of conceptual relevance. Addition of a “not applicable or prefer not to say” response was made to 13 of the 5-point (0–4) verbal response scale questions in part 1. All response anchors in part 2 were reversed so that a higher score indicates a higher level of impact, as this made the most sense to participants.
After concept elicitation and cognitive debriefing interviews, the questionnaire was modified to consist of 15 questions with a 6-point verbal response scale (part 1), and nine questions using a 0–10 numeric rating scale (part 2), resulting in a 24-item questionnaire that is relevant and easily understood for patients with GD of varying levels of educational ability (Table Overview of the rmGD1-PROM and ctGD1-PROM questions and structure Part No. of questions Topics Scale ctGD1-PROM and rmGD1-PROM 1A 4 Restriction of activities, education, and work 6-point verbal response scale 1 Concern about emotional burden 1B 2 Context of GD concerns relating to general health and medication 5-point verbal response scale 1 Context of GD concerns relating to other medical concerns 2 1 Dependence on others 0–10 numeric rating scale 6 Presence/severity of symptoms 1 Satisfaction with treatment 1 Concern about the future rmGD1-PROM only 6 Concern about comorbidities, disease burden, and cost 6-point verbal response scale 1 Context of GD concerns relating to other medical concerns 5-point verbal response scale
Owing to an expectation that some items, although considered clinically relevant by GD experts, would not be expected to change over the course of a clinical trial, coupled with advice from the UK National Health Service (NHS) Research Ethics Committee that some items may be distressing for patients, the decision was made that the full 24-item version of the questionnaire would be pursued for routine monitoring in clinical practice (rmGD1-PROM; Additional file
Psychometric validation, including validity and reliability, was assessed by means of a patient survey study administered to patients aged ≥ 18 years with confirmed GD1 who were receiving treatment at the Royal Free London NHS Foundation Trust, London, UK, under the care of Dr. Derralynn Hughes. Patients received by post an invitation letter, information sheet, and consent form, along with the main survey and a pre-paid envelope for its return. A reminder letter was sent to participants 4 weeks later. The survey comprised the GD-PROM, the SF-36, and questions on socio-demographics (including age, sex, ethnicity, and occupational status) and disease history (including self-assessment of health status, time since initial diagnosis, and date of last visit to the specialist center). The survey was re-administered two weeks after the initial administration to examine test–retest reliability. Responses were entered into an Excel database designed specifically for the study by two analysts independently, with a third senior analyst comparing the two sets of data for discrepancies, referring to the paper questionnaires to resolve any differences.
In addition to survey completion, data on disease severity extracted from the Gaucher Outcomes Survey (GOS) registry (an ongoing registry for patients with GD, in which participating patients were enrolled, irrespective of treatment status or treatment type (NCT03291223) [
Consent to participate in the study was obtained from participants at the same time as completion of the questionnaire. The study protocol and related documents were approved by the NHS Research Ethics Committee before initiation of any study procedures. Background characteristics were examined using descriptive statistics, and sensitivity analyses were used to assess the impact on psychometric analyses of excluding patients who completed the questionnaires >24 months after their last GD-related health appointment.
Fifty patients completed the survey. Of these, three did not provide consent to participate in the study so were excluded from the analysis. One further respondent did not complete the ctGD1-PROM but completed the rest of the survey, so was also excluded from the analysis. In total, 46 initial ctGD1-PROM surveys and 23 follow-up surveys were analyzed (Fig. Psychometric validation: demographics characteristics of the study population Main sample (N = 46) Test–retest sample (n = 23) Characteristic n % n % Age, years 25 9 19.6 4 17.4 35 13 28.3 6 26.1 45 3 6.5 1 4.3 55 12 26.1 5 21.7 65 5 10.9 5 21.7 ≥75 4 8.7 2 8.7 Gender Male 23 50.0 10 43.5 Female 22 47.8 12 52.2 Missing 1 2.2 1 4.3 Ethnicity White 45 97.8 22 95.7 Other 1 2.2 1 4.3 Occupational status Employed part-time 8 17.4 3 13.0 Employed full-time 14 30.4 6 26.1 Self-employed 4 8.7 1 4.3 Unemployed 5 10.9 2 8.7 Retired 13 28.3 9 39.1 Missing 2 4.3 2 8.7 Time since diagnosis <1 year 2 4.3 0 0.0 1 3 6.5 1 4.3 5 5 10.9 4 17.4 10 6 13.0 2 8.7 ≥20 years 29 63.0 16 69.6 Missing 1 2.2 0 0.0 Current health Very good 7 15.2 4 17.4 Good 20 43.5 9 39.1 Fair 13 28.3 6 26.1 Bad 4 8.7 3 13.0 Very bad 2 4.3 1 4.3 Gaucher disease severity state Mild (GD1-DS3 score < 3.00) 21 45.7 12 52.2 Moderate (GD1-DS3 score 3.00 7 15.2 2 8.7 Marked (GD1-DS3 score 6.00 11 23.9 3 13.0 Severe (GD1-DS3 score 9.00 7 15.2 6 26.1
Initial results showed strong evidence of convergent validity, based on correlations between overall and item-level ctGD1-PROM scores and the physical and mental component summary scores of the SF-36. Overall correlation coefficients were > 0.7, Psychometric validation: correlations between the ctGD1-PROM items and SF-36 PCS and MCS scores Items Correlation with PCS Correlation with MCS Coefficient ( ( Coefficient ( ( GD Education/job 0.739 ✓ ✓ 0.792 ✓ ✓ GD Friends 0.594 ✓ ✓ 0.722 ✓ ✓ GD Intimate 0.633 ✓ ✓ 0.702 ✓ ✓ GD Hobbies leisure 0.684 ✓ ✓ 0.724 ✓ ✓ GD Emotional burden 0.616 ✓ ✓ 0.742 ✓ ✓ GD General-specific med 0.205 x x 0.383 ✓ ✓ GD Concerns Gaucher 0.139 x x 0.023 x x GD Current med. concerns 0.172 x x 0.358 ✓ ✓ GD Dependent 0.715 ✓ ✓ 0.274 x ✓ GD Abdomen 0.478 ✓ ✓ 0.415 ✓ ✓ GD Fatigued 0.680 ✓ ✓ 0.609 ✓ ✓ GD Physical weakness 0.750 ✓ ✓ 0.615 ✓ ✓ GD Bone pain 0.787 ✓ ✓ 0.594 ✓ ✓ GD Depressed 0.514 ✓ ✓ 0.808 ✓ ✓ GD Worried 0.566 ✓ ✓ 0.819 ✓ ✓ GD Future 0.567 ✓ ✓ 0.647 ✓ ✓ GD Satisfied 0.656 ✓ ✓ 0.691 ✓ ✓
In terms of reliability, the overall Cronbach’s alpha for the ctGD1-PROM was 0.928, indicating excellent internal consistency (Table Psychometric validation: internal consistency reliability statistics for the ctGD1-PROM Item Item-test correlation Item-rest correlation Inter-item correlation Cronbach’s alpha GD Education/job 0.658 0.605 0.434 0.925 GD Friends 0.783 0.745 0.422 0.921 GD Intimate 0.576 0.514 0.442 0.927 GD Hobbies leisure 0.741 0.696 0.426 0.922 GD Emotional burden 0.848 0.821 0.415 0.919 GD General-specific med 0.356 0.276 0.464 0.933 GD Concerns Gaucher 0.208 0.118 0.476 0.936 GD Current med. concerns 0.364 0.286 0.463 0.932 GD Dependent 0.594 0.533 0.439 0.926 GD Abdomen 0.616 0.553 0.438 0.926 GD Fatigued 0.802 0.767 0.420 0.921 GD Physical weakness 0.868 0.844 0.413 0.919 GD Bone pain 0.868 0.843 0.413 0.919 GD Depressed 0.834 0.805 0.417 0.920 GD Worried 0.870 0.846 0.413 0.919 GD Future 0.792 0.757 0.421 0.921 GD Satisfied 0.826 0.795 0.417 0.920 0.431 0.928 Psychometric validation: test–retest intraclass correlations of the ctGD1-PROM (n = 23) Item Observations ICC 95% confidence interval GD Education/job 22 0.509 0.118 0.763 GD Friends 23 0.682 0.384 0.851 GD Intimate 22 0.613 0.264 0.820 GD Hobbies leisure 23 0.757 0.508 0.889 GD Emotional burden 22 0.626 0.297 0.824 GD General-specific med 23 0.567 0.204 0.791 GD Concerns Gaucher 23 0.625 0.303 0.821 GD Current med. concerns 22 0.530 0.141 0.775 GD Dependent 22 0.500 0.107 0.757 GD Abdomen 22 0.974 0.939 0.989 GD Fatigued 22 0.816 0.606 0.919 GD Physical weakness 22 0.900 0.775 0.957 GD Bone pain 22 0.798 0.575 0.911 GD Depressed 22 0.482 0.075 0.749 GD Worried 22 0.512 0.123 0.764 GD Future 22 0.843 0.598 0.937 GD Satisfied 23 0.399 0.014 0.693 0.893 0.750 0.954
Known-groups validity was not demonstrated, indicating that the measure was unable to distinguish between severity groups based on the GD1-DS3. For the majority of items, patients in the moderate severity group had the highest mean response. Only one item (GD Bone Pain) showed increasing response with increasing severity. Using the analysis of variance (ANOVA) F-test, only one item (GD General-specific med) gave a
PROMs are now widely recognized as being crucial for assessment of the impact of disease and its treatment. However, there are few validated, disease-specific PROMs for rare diseases. Small sample sizes and heterogeneous study populations create substantial barriers to their development, with additional obstacles related to representative sampling, data collection, and statistical power. As a result, most rare diseases employ generic questionnaires for both clinical monitoring and clinical trials; however, these often fail to target the specific disease-related issues that patients experience [
The format of the proposed ctGD1-PROM is based on decades of experience with patients and personal involvement in clinical trials for GD. This cumulative expertise, supplemented with information from patient and disease registries, makes us comfortable in asserting that we have identified the issues that matter most to patients with GD1. We have also paid attention to how disease dynamics affect patients’ psychosocial health. GD is not only clinically heterogeneous at the time of diagnosis but also has a disease trajectory marked by periods of quiescence that may be unpredictably interrupted by complications and exacerbations. The effect of current treatments on later-life GD-related disorders, such as Parkinsonism, peripheral neuropathy, and malignancies (e.g. monoclonal gammopathy of undetermined significance/myeloma, other hematologic cancers, hepatocellular carcinoma), is unknown. The effects of this prognostic uncertainty need to be captured when assessing HRQoL. The ctGD1-PROM presented here is the first PROM for GD that documents these GD-specific patient concerns. This study therefore represents an important breakthrough in QoL research for this rare disease.
As GD is a rare disease, it was important not to impose too many sampling quotas that could restrict recruitment into the content validation study. Demographically, there was an adequate representation of males and females, and different education levels (important for cognitive debriefing). In line with literature that reports GD as particularly prevalent among Jews of Ashkenazi descent [
The findings of qualitative interviews for content validation indicated that patients with GD experience a wide range of different disease manifestations that negatively impact their QoL. Signs and symptoms most commonly identified included tiredness or fatigue, bone pain, joint pain, pain (predominantly in the limbs, back, or stomach), bone fractures, bleeding, swelling (predominantly in the joints), abdominal swelling or distension, weakness, bruising, and visual problems, consistent with the previous findings [
Results of psychometric validation analyses show that the ctGD1-PROM performs reasonably well in terms of several key psychometric properties. Data completeness was acceptable, with the majority of respondents providing all the required data and no single ctGD1-PROM item accounting for more than two missing values. Strong evidence of convergent validity was found, based on correlations with two key SF-36 summary scores, and internal consistency was found to be excellent, with a very high Cronbach’s alpha coefficient for the overall questionnaire. Test–retest reproducibility was also found to be acceptable, with two items failing to show moderate reliability in this regard. However, neither the individual items nor the proposed overall questionnaire scores were able to discriminate well between the severity groups based on the GD1-DS3, the benchmark disease severity scoring system for GD1. This may be a reflection of the small sample size, the predominance of patients reporting their current health as good or very good, or a possible effect of weighting factors related to the construct of the GD1-DS3 total score, where patients may attribute a greater impact of certain items than the score allows. Further evaluation is required to assess the applicability of the ctGD1-PROM to patients with severe disease and/or not receiving treatment. The very high level of homogeneity between the items of the questionnaire, as shown by the magnitude of the Cronbach’s alpha coefficient, could indicate that some items are asking the same question, albeit in different ways. To further examine this argument, an exploratory factor analysis with a larger study sample is required. Consideration could also be given to the evaluation of the ctGD1-PROM in longitudinal studies to assess the responsiveness of the questionnaire in capturing changes in HRQoL over time. Qualitative research with patients to establish their perceptions of changes in their health as part of the longitudinal assessment could also be valuable for the assessment.
The part 1B items were found to behave differently from the rest of the items. While part 1A and part 2 items describe health and QoL problems and restrictions that respondents experience as a result of their GD, the three-question part 1B items focus on the impact of their medication or on the extent to which all of their medical concerns were GD related. Some of the psychometric analyses (e.g. internal consistency and convergent validity) show that these items do not perform as well as the other items. However, one of these three items—GD general-specific med—was the only one that appeared to be able to distinguish between known severity groups based on ANOVA F-testing.
There are some limitations to the study. It should be recognized that while the content validation study design provided considerable depth of insight and descriptions regarding the patient experience, caution should be employed when drawing conclusions. Adolescents and patients with GD3 were under-represented in the sample; therefore, it was not possible to draw any firm conclusions regarding any similarities or differences between the GD1/GD3 and adult/adolescent experience of GD. As a result, psychometric testing was undertaken only in adults with GD1. Another limitation of the content validation part of the study was the small sample size (n = 33), although saturation was achieved in the GD1 sample, confirming adequacy in this population. For the psychometric validation study, the target of 50 respondents was achieved, but four patients did not provide consent or failed to complete the ctGD1-PROM. Given the rarity of the disease, it was not feasible to recruit a larger sample using a single UK clinical center, and in an attempt to expand the pool of data, further psychometric validity evaluations are planned for patients with GD1 resident in Israel. However, evaluation in other, more diverse populations of patients with GD1, with varying patient characteristics and from other geographic regions, e.g. Eastern Europe, Latin America, Japan, China, India, and Africa, is needed to validate the GD-PROM in other populations, cultures, and languages.
In conclusion, both the routine monitoring and clinical trial versions of the GD1-PROM represent important steps forward towards the development of PROMs for researchers measuring the impact of GD and its respective treatment. Further validation in different populations will inform the appropriateness of the ctGD1-PROM for capturing the impact of GD on HRQoL and as a fit-for-purpose measure that meets regulatory requirements for clinical trial use.
The authors would like to acknowledge the contribution by Jeshika Singh to the psychometric evaluation component of the study, who sadly died before the study completed. The authors would also like to thank the patients who participated in this study, as well as Professor Gordon Guyatt, Dr. Patricia Miller (both at McMaster University in Hamilton, Ontario, Canada), Tanya Collin-Histed (of the International Gaucher Alliance), and Jeremy Manuel, OBE (Honorary President of the International Gaucher Alliance and former Chair of the European Gaucher Alliance), for their involvement in reviewing early drafts of the questionnaire, and Rinad Nabulsi, MD, for translation of the questionnaire into Arabic. Under the direction of the authors, Lindsay Napier, PhD, CMPP, employee of Excel Medical Affairs, provided writing assistance for this manuscript. Editorial assistance in formatting, proofreading, copy-editing, and fact-checking also was provided by Excel Medical Affairs.
DE conceived the study. N Bonner and CP carried out content validation analyses. DF, AL, KS, LL, and RM carried out psychometric validation analyses. AZ and DAH were involved in data collection. N Belmatoug, PD, DAH, IVDS, NW, ÖG-A, DE, JS and RS were involved in data analysis. All authors contributed to the writing of the manuscript, reviewed each draft, and approved the final version. All authors read and approved the final manuscript.
The study was funded by Takeda Pharmaceuticals International AG. Takeda Development Center Americas, Inc. provided funding to Excel Medical Affairs for support in writing and editing this manuscript. Open-access funding was provided by Takeda Development Center Americas, Inc.
Data supporting the conclusions of this article are available on reasonable request.
Written informed consent was obtained from participants. The content validation study was approved by Salus, an international independent review board (IRB). Additionally, local IRB approval was gained in Israel. The psychometric validation study was approved by the NHS Research Ethics Committee.
Not applicable.
DE was a paid consultant for Takeda at the time the psychometric validation part of the study was carried out. N Belmatoug was paid for speaking, travel grants, and scientific boards from Sanofi/Genzyme and Takeda. Her institution received research grants from Sanofi/Genzyme and Takeda. PD received speaker honoraria, advisory board honoraria, and institutional research support from Takeda. ÖG-A acts as a consultant and has received speaker honorarium from Takeda and Pfizer. DAH has received consulting fees and fees for non-CME/CE services from Genzyme, Sanofi, and Takeda. IVDS has no conflicts of interest to declare. NW has received consulting fees and honoraria from Takeda, Sanofi-Genzyme, and Pfizer. N Bonner and CP are employees of Adelphi Values. DF, AL, LL, RM, and KS are or were employees of PHMR at the time the study took place. JS and RS are employees of Takeda and stockholders of Takeda Pharmaceuticals Company Limited. AZ has received honoraria from Pfizer, Takeda, and BioEvents, and consultancy fees from Prevail Therapeutics, Avrobio, Insightec, and Takeda.
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