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Patient reported outcomes for phosphomannomutase 2 congenital disorder of glycosylation (PMM2-CDG): listening to what matters for the patients and health professionals

Abstract

Background

Congenital disorders of glycosylation (CDG) are a growing group of rare genetic disorders. The most common CDG is phosphomannomutase 2 (PMM2)-CDG which often has a severe clinical presentation and life-limiting consequences. There are no approved therapies for this condition. Also, there are no validated disease-specific quality of life (QoL) scales to assess the heterogeneous clinical burden of PMM2-CDG which presents a challenge for the assessment of the disease severity and the impact of a certain treatment on the course of the disease.

Aim and methods

This study aimed to identify the most impactful clinical signs and symptoms of PMM2-CDG, and specific patient and observer reported outcome measures (PROMs and ObsROMs, respectively) that can adequately measure such impact on patients’ QoL. The most burdensome signs and symptoms were identified through input from the CDG community using a survey targeting PMM2-CDG families and experts, followed by family interviews to understand the real burden of these symptoms in daily life. The list of signs and symptoms was then verified and refined by patient representatives and medical experts in the field. Finally, a literature search for PROMs and ObsROMs used in other rare or common diseases with similar signs and symptoms to those of PMM2-CDG was performed.

Results

Twenty-four signs/symptoms were identified as the most impactful throughout PMM2-CDG patients’ lifetime. We found 239 articles that included tools to measure those community-selected PMM2-CDG symptoms. Among them, we identified 80 QoL scales that address those signs and symptoms and, subsequently, their psychometric quality was analysed. These scales could be applied directly to the PMM2-CDG population or adapted to create the first PMM2-CDG-specific QoL questionnaire.

Conclusion

Identifying the impactful clinical manifestations of PMM2-CDG, along with the collection of PROMs/ObsROMs assessing QoL using a creative and community-centric methodology are the first step towards the development of a new, tailored, and specific PMM2-CDG QoL questionnaire. These findings can be used to fill a gap in PMM2-CDG clinical development. Importantly, this methodology is transferable to other CDG and rare diseases with multiple signs and symptoms.

Background

The World Health Organization defines Quality of Life (QoL) as “an individual’s perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns” [1]. One of the aspects of QoL is health-related quality of life (HrQoL). HrQoL is a multi-domain concept that encompasses physical, emotional, mental, and social functioning. It can be measured in a variety of ways, such as general scales, disease- or symptom-specific tools, which reflect upon the subjective perspective of a person regarding their condition [2]. Although general scales can be used for different diseases, they are less sensitive to detect small, yet important clinical differences in treatment effects [3]. These important differences are better measured using disease- or symptom-specific HrQoL scales, which will be more sensitive as they assess specific hallmarks of the disease or symptom. Concerning rare diseases, the study of QoL is challenging due to methodological issues as well as to limited literature on those conditions. Small patient populations, disease heterogeneity and scarcity of medical knowledge and specialists hamper the understanding of the burden of these diseases [4, 5]. This highlights the importance of ensuring a community-centric approach, including the professionals’ experience and the patients’ voice. Involving both stakeholder groups not only maximizes data collection but also data meaningfulness, ultimately contributing to the creation of sensitive and disease-tailored QoL tools. This is vital to delivering and appraising potential therapeutics.

Patient-reported outcome measures (PROMs) and observer-reported outcome measures (ObsROMs) are quantitative tools to obtain reports of patient outcomes directly from patients or their family/professional caregivers, respectively. They have been increasingly utilised as clinical endpoints, particularly with the aim to detect changes in the HrQoL in response to treatments [6]. They allow a deeper understanding of treatment impact and report domains that are not just clinically important but also meaningful for the patients [7]. They have been extremely useful, especially in chronic illnesses [6, 8] and are recommended by regulatory agencies such as the Food and Drug Administration and the European Medicine Agency, to support the approval of new therapies and medical labelling claims [9, 10].

Congenital disorders of glycosylation (CDG) are a growing family of rare diseases that affect the synthesis and attachment of sugar ‘trees’ (glycans) of proteins and lipids. These defects often have severe, multi-organ implications for the patients, since about 50% of human proteins are glycosylated and glycans play essential roles in all biological processes [11]. PMM2-CDG is the most common CDG, and it is due to autosomal recessive variants in the PMM2 gene, which encodes the enzyme phosphomannomutase 2, essential for N-glycosylation. This enzyme is responsible for the synthesis of N-linked oligosaccharides by converting mannose 6-phosphate to mannose 1-phosphate [12]. PMM2-CDG clinical presentation is dominated by neurologic abnormalities such as psychomotor disability, seizures, hypotonia and ataxia, besides multiple organ involvement resulting in chronic disability, poor QoL and premature death [13]. Some potential treatments, such as liposome-encapsulated mannose 1-phosphate administration, are undergoing clinical studies [14]. More recently, a trial with acetazolamide showed improvement of the ataxia [15]. Moreover, in a single-patient paediatric trial with epalrestat, improvements in ataxia and also in growth were observed [16]. However, specific tools are needed to measure QoL in PMM2-CDG to understand if a treatment has a significant impact.

Currently, there are no disease-specific QoL PROMs/ObsROMs for PMM2-CDG. Here, we used a community-centric approach, involving CDG medical professionals and families in the design and conduction of the study. We aimed to gather PROMs and ObsROMs that are specific for the most impactful PMM2-CDG clinical signs and symptoms. For that purpose, we surveyed PMM2-CDG families and clinicians following PMM2-CDG patients to understand which are the most onerous signs and symptoms, and interviewed families to understand the real burden of those clinical manifestations in everyday life. Considering the input of these stakeholders, we reviewed the literature about the PROMs and ObsROMs used in other rare and common diseases with similar signs and symptoms to PMM2-CDG. Those tools could potentially be validated and applied directly to the PMM2-CDG population or adapted to create the first PMM2-CDG-specific QoL questionnaire.

Methods

  1. 1.

    Set up of the patient and medical advisory committees

Two advisory committees were established to provide expert insights regarding the understanding and particularities of the disease and to guide decision making throughout this project. Patient experts, specifically 11 family caregivers, and 9 medical experts were invited to participate in the committees. A summary of the project and an explanation of their roles were provided if they agreed to participate. Communications were mainly done by email or by video calls when necessary.

  1. 2.

    Quantitative analysis of PMM2-CDG symptoms’ impact (PMM2-CDG Symptoms’ Impact Survey)

A survey was constructed to assess the impact of the signs and symptoms from infancy to adulthood. Two versions were used, one targeting PMM2-CDG families and the other targeting medical experts. Electronic samples of the survey are available at https://www.surveymonkey.com/r/HCPCOM (medical experts’ version) and https://www.surveymonkey.com/r/PATCOMM (version adapted to families). The survey included an exhaustive list of signs and symptoms reported in the OMIM database (MIM: 212065) but also reported by CDG families. Family experiences included both personal communications and social media reports in the CDG Global Alliance Facebook Group, a social media platform uniting worldwide CDG patients and professionals perceived as a safe environment where the community openly shares questions, concerns, and experiences. The information derived from this group complies with the terms and conditions of the platform and with the privacy settings of the participants. It was shared in a voluntary manner with all participants of the group and fell under the objectives of the group (i.e., promoting shared knowledge between families, doctors, and researchers). This was a complementary step to validate and complete the information collected through other sources, therefore, the information was not transcribed and thus is not traceable ans constitute no risk of harm to the participants. Anonymity was maintained in all instances. Printed surveys were distributed at the beginning of the 4th World Conference on CDG for Families and Professionals, held in Lisbon on the 26th and 27th July 2019. Given that most PMM2-CDG patients are unable to provide self-reports due to the fact that (1) most are of paediatric age and (2) have considerable cognitive impairment, patients' views were evaluated and conveyed by patients' families. Observer and proxy reports have been commonly used in studies where self-reports cannot be obtained [17,18,19]. Therefore, patients’ caregivers answered the survey voluntarily following written and verbal information about the study. Respondents were asked to classify the daily life impact of each of the symptoms/clinical manifestations on a scale of 1—“No impact” to 5—“Extremely negative impact” considering each phase of the patient’s life (infancy: 0–3 years; childhood: 4–10 years; adolescence: 11–17 years; and adulthood: 18 years and older). To increase data collection, respondents could answer to more than one age range as long as they felt comfortable and confident in doing so (e.g., the caregiver of an adolescent patient could answer both the infancy, childhood and adolescent sections). An “I don't know/cannot answer” option was available to improve data collection and quality. Additionally, respondents were given the chance to share relevant information that they felt was missing in the survey by including an optional text field: “If there are other symptoms you find impactful, please list them here and rate the magnitude of their impact (using the same scale)”. The surveys were collected by the end of the conference. The final impact level of each clinical manifestation was calculated using the mean value of all respondents for each given age range. The 7 symptoms with higher impact level for each age range for both families and professionals were summed up, yielding a final list of 16 unique impactful symptoms (7 symptoms × 4 age ranges × 2 target groups = 56–40 duplicates = 16 unique symptoms). To analyse the differences between the families’ and clinicians’ perspectives, for each sign/symptom, a two-way ANOVA test with multiple comparisons and Sidak’s correction was performed yielding an adjusted p-value. Statistical significance was considered if adjusted p-value < 0.05.

  1. 3.

    Qualitative insights of PMM2-CDG symptoms’ impact

Interviews were designed and led to gather insights about the real-word impact of the signs and symptoms identified in the survey as being “the most impactful” from families’ perspectives (Additional file 1: Table 1). All medical and difficult terms were referred to in lay-language and further explained when required by the participant to ensure their understanding. Deidentified transcripts were obtained from seven interviews of mothers of PMM2-CDG patients which were part of our patient committee. Demographics of the patients included in the interviews are available in Additional file 1: Table 2. The interviewees were prompted to share patient experiences in greater depth. Hence, questions were open-ended to avoid bias and were not read verbatim to permit free-flowing discussion. The collected insights were used to guide our article selection to make it more specific and targeted to the patient’s needs.

  1. 4.

    Review of the literature

    1. a.

      Search strategy

      The community-identified burdensome signs ans symptoms guided a literature review strategy to identify and gather specific PROMs and ObsROMs. The PubMed database was queried with pre-defined search terms on September 11th, 2020. The search query was based on three groups of search terms: (1) QoL related, (2) PROMs/ObsROMs related terms, and (3) impactful signs and symptoms previously identified—connected by the Boolean operator “AND” (Additional file 1: Table 3). Keywords within the same group were connected using the operator “OR”. For some signs and symptoms and given the fact that PMM2-CDG is a rare metabolic disorder, the keywords “metabolic” or “rare disease” were added to the combination to provide more specific results. Resulting articles from the search were exported and duplicated articles were eliminated. References of relevant articles were screened, and additional articles were included by author referral (Fig. 1).

    2. b.

      Study selection and data extraction

      Resulting articles were screened based on predefined inclusion and exclusion criteria. Studies had to be written in English and measure HrQoL for one or more of the previously identified impactful signs/symptoms, by means of a PROM or ObsROM. Articles using clinician-reported outcomes, performance outcomes, interviews and reviews were excluded. Furthermore, studies reporting caregiver QoL and that explicitly affirmed the use of non-English translations of the PROMs/ObsROMs were excluded. Nevertheless, articles describing the use of foreign (non-English) questionnaires for which an English translation is available were included (e.g., Deglutition Handicap Index, Izumo scale). Article titles and abstracts were screened and, subsequently, the full-text versions of the remaining articles were evaluated according to the inclusion/exclusion criteria (Fig. 1). Article content analysis and data extraction was performed by a group of 4 researchers, specifically regarding the PROMs employed to measure the QoL, the participants' cohort and disease(s)/sign(s)/symptom(s) assessed. For some sign(s)/symptom(s), no specific tool was found. In these cases, some adequate items or subscales were secondarily captured by the inclusion of other tools.

    3. c.

      Quality analysis

Table 1 Impact scores (n) for selected signs and symptoms by age range and according to families and clinicians’ perspectives
Table 2 Summary of the characteristics of included articles
Table 3 Symptom/disease-specific quality of life tools per impactful symptom/category
Fig. 1
figure 1

Overview of the study workflow

The purpose of the quality analysis was not to perform a systematic review of the psychometric properties of the included instruments, but rather to identify and compare them in terms of their psychometric properties, namely Content, Criterion and Construct Validity, Internal Consistency, Agreement, Reliability, Responsiveness, Floor and Ceiling effect and Interpretability (Additional file 3). To do so, this analysis was based on the original development and/or validation articles of the instruments. Thus, translations or validations to other languages besides English were not considered. One instrument could not be evaluated (Scoliosis Research Society-30) as its development and validation articles were not available. Also, three instruments (Short Inflammatory Bowel Disease Questionnaire, Pittsburgh Insomnia Rating Scale, and College of Optometrists in Vision Development Quality of Life Questionnaire) were evaluated exclusively based on the available abstracts.

The analysis was made using the Quality Criteria for Measurement Properties of Health Status Questionnaire developed by Terwee et al., (2007) for the design, methods, and outcomes of the development and validation studies [20]. Based on these criteria, each psychometric property was evaluated with (+)—positive rate; (?)—indeterminate or doubtful rate; (–)—negative rate; or (0)—no information available. Some adaptations of the criteria were needed:

  1. 1.

    for Construct Validity evaluation, the criteria for a positive rating requires that specific hypotheses have been formulated and at least 75% of the results are in accordance with them. However, given that for the majority of the articles, hypotheses were not explicitly presented by the authors, we had to analise if the goal of development and/or validation of the instrument was met;

  2. 2.

    for Internal Consistency, the criteria of the sample size being N = 7 \(\times\) the number of items and N > 100 was not considered for two reasons. First, because of the great variability in the number of items between questionnaires, and second, because we are dealing with symptom/condition-specific questionnaires, and therefore, the clinical samples of validation articles are usually smaller than if we were dealing with an healthy population.;

  3. 3.

    when in doubt about meeting less objective criteria (e.g., convincing arguments that gold standard is ‘‘gold’’, for Criterion Validity), the properties were classified with a positive rating if the validation methodology was clearly described and the authors clearly justified their conclusions well.

Results

  1. 1.

    Selection of the most impactful symptoms by the community and the expert committees

    The PMM2-CDG symptoms’ impact survey had 42 respondents: 23 family representatives and 19 PMM2-CDG medical experts. A list of the topmost impactful symptoms was then obtained considering the sum of the 7 most impactful manifestations across the 4 age ranges considered according to both families and clinicians and excluding duplicates. This resulted in a list of 16 signs and symptoms (Table 1).

    There was a good level of agreement between the perspectives of families and clinicians, particularly for the infancy period. For this age group, only seizures were rated with a statistically significant difference (q < 0.001) between families (IS = 1.78, n = 18) and clinicians (IS = 3.67, n = 18). Significant differences between the views of both stakeholders were predominant for the childhood group. During this timeframe, dysphagia (IS = 2.00, n = 19 for families and IS = 3.93, n = 15 for clinicians, q = 0.003) and seizures (IS = 2.05, n = 19 for families and IS = 3.87, n = 16, q = 0.001) were perceived to have a much higher negative impact by clinicians while for families a moderate negative impact was reported. The presence of sex development issues was also associated with a bigger impact by the medical doctors (IS = 2.53, n = 15) in comparison to PMM2-CDG families (IS = 1.14, n = 14; q = 0.031). Concerning stroke-like episodes, an extremely negative impact on adolescent PMM2-CDG patients was perceived by clinicians (IS = 4.08, n = 12) while none to slight negative impact (IS = 1.25, n = 4) were alleged by family members (q = 0.013). The same tendency was seen for the adult group. Lastly, although not statistically significant, clinicians tended to rate kyphosis/scoliosis with a more pronounced negative impact than families during adolescence and childhood. The same happened regarding peripheral neuropathy, particularly in the childhood and adulthood group (Table 1).

    The analysis of the qualitative data shared on the survey as well as the revision of the most impactful signs and symptoms by the family and medical committees resulted in the inclusion of 6 additional clinical manifestations, namely sleep disturbances, liver problems, coagulopathy, food allergies, cardiomyopathy, and pericardial effusion.

  2. 2.

    Families’ perspectives about the real-world impact of the most impactful symptoms

    Semi-structured interviews with open-ended questions were led with family members of PMM2-CDG patients which allowed them to express the burden of living with the disease and the consequences of specific clinical manifestations in family life. The summary results of the interviews encompassing the experiences with the complete list of clinical manifestations are described in Additional file 2. This information allowed us to refine and further tailor our article and QoL assessment tools selection to the experiences of PMM2-CDG families. As an example, osteopenia/osteoporosis, clinically characterized by low bone density, occurs in PMM2-CDG patients at a later stage in life, but with significant consequences for the patient's daily life. One family member stated that “[osteoporosis] causes pain when she is sitting in the wheelchair as well as getting up and sitting down. We are afraid of bone fractures so we avoid physical activities and falls as they are frightening. (…) She is being treated every 6 months at the hospital with a bone cancer treatment which has a lot of side effects during 5 days. She is in a frustrated state, with fever, pain to touch, she can’t move and is incontinent” (mother of a 40 years-old PMM2-CDG patient). In another experience, having osteopenia/osteoporosis limits the management of other clinical manifestations: “due to osteopenia, he can’t have surgery of the scoliosis because of the bone fragility. He cares about it [scoliosis] when he is in the wheelchair because it is very noticeable. There is not enough space on his body for the intestines and his lungs and sometimes he has very fast and short breathing” (mother of a 25 years-old PMM2-CDG patient). This guided the QoL tools selection by making sure osteopenia/osteoporosis specific tools included items referring to pain, fear of fractures/falls, self-image, impact in care or treatment impact.

  3. 3.

    Review of the literature results according to the community-selected symptoms real-world qualitative information

    The review of the literature concerning the application of PROMs specific for the community-selected impactful PMM2-CDG symptoms/manifestations resulted in the inclusion of 239 articles (Fig. 1). The characteristics of the included articles are summarized in Table 2. Most articles (58.1%) included small participant cohorts of ≤ 100 participants. While 29.9% reported cohorts of > 100 to < 500 participants, only 12% of the studies reported more than > 500 participants. Studies of adult populations represent most of the included studies (78%). Only 10% of the included studies focused on pediatric populations and 12% included both adult and pediatric populations. QoL self-reports were described by most studies (94.2%) whilst proxy-reports or a combination of both accounted for 2.1% and 3.7% of the studies, respectively. Among the included articles, 14 disease groups were represented. Particularly prevalent in our study sample were diseases of the digestive, visual, and circulatory system followed by diseases of the musculoskeletal system, the connective tissue, and the nervous system.

    The review of the included articles allowed the identification of 80 tools. These tools were grouped by signs/symptoms in Table 3. The list of references supporting the inclusion of such tools can be found in Additional file 1: Table 4. From the 22 groups of signs and symptoms, specific QoL tools were found for 15 of them (Table 3). No specific tools were found for 7 of the most impactful clinical manifestations, particularly for developmental delay, intellectual disability, hypotonia, pericardial effusion, peripheral neuropathy, stroke-like episodes, or symptoms related to deficient sexual development. However, even though no specific instruments were found for behavior, developmental or intellectual problems, other included tools specific for other symptoms/diseases include subscales or items specific for those areas (e.g., mood swings, depression, physical, mental, and social functioning, etc.).

  4. 4.

    Quality assessment of included questionnaires

The quality of the 80 instruments was analyzed using specific criteria from Terwee et al. (2007) (Additional File 3) [20]. Most instruments were evaluated with positive rating ( +) for Content Validity (93.7%), Construct Validity (77.5%), Internal Consistency (71%) and Reliability (60.8%). For Agreement (73.4%), Floor and Ceiling Effect (67.1%), and Responsiveness (55.7%), no sufficient information was found for most of the instruments. Lastly, regarding Criterion Validity and Interpretability analysis, the greater part of the information was unavailable (35.4% and 24%, respectively) or indeterminate (22.5% and 59.4%, respectively).

Discussion and future perspectives

Patient-centered outcomes have gained recognition in health technology assessment and clinical trial settings. Besides, they provide unique insights into the disease’s natural history in terms of QoL and its fluctuations over time. Rather than just measuring clinically important outcomes, they offer the opportunity to access “patient-important” outcomes, meaningful to them when evaluating treatments or care [21]. For complex, chronic and/or rare diseases—with holistic challenges and for which the definition of disease biomarkers or clinical endpoints is puzzling—patient-reported QoL is of major importance providing a direct interpretation of the patient’s response to treatment or care [22]. However, the scarcity of valid QoL PROMs and ObsROMs for most rare diseases and the challenges of validating the current available tools, pose a problem to adequately appraise potential treatments. Creative and pragmatic solutions are warranted to overcome difficulties related to small patient cohorts, the cost of tools’ development, and the urgency for making new therapies available [4, 5].

In this study, we applied an innovative methodology to accelerate the development of a PMM2-CDG-specific QoL questionnaire, while assuring its adequacy and meaningfulness by including the views and experiences of families and medical experts. By including both stakeholders’ quantitative and qualitative input in the design of our literature search, we identified QoL instruments that matter the most. The differences in the perception of the most burdensome signs and symptoms between patients/caregivers and clinicians underscore patient/caregiver engagement and participation in all stages of the development of PROMs or ObsROMs as the only way to safeguard the relevance, adequacy, and comprehensibility of these tools [23]. However, particularly in rare, heterogeneous diseases, complementing the individual experience with the knowledge of medical experts is critical. While patients and family caregivers can highlight “hidden” aspects of the disease that are not clear or do not seem important to doctors, the latter can provide a wider perspective on the frequency, severity, and impact of clinical manifestations by studying patient cohorts. Furthermore, clinicians will consider potential disease complications that patients may have not yet experienced. Importantly, conducting qualitative interviews complemented the quantitative results on “What is more important?” with “How and why is it more important?”. In other words, listening to the description of the patient/family experience with illness (i.e., narrative medicine) provides meaning and understanding but also identifies the real impact of the disease outside clinics [24]. For CDG, this approach successfully reported the experiences of CDG parents, identifying major healthcare and educational needs [25]. This community-centric approach also allowed us to detect changes in the impact of clinical manifestations over time. Specifically, infections were shown to be burdensome in infancy but not in adulthood. Contrastingly, skeletal manifestations (kyphosis/scoliosis and osteopenia) did not pose a problem until later in life. Even though there are reports of these time-dependent clinical occurrences [26, 27], there are no reports of their burden or impact on QoL for most clinical manifestations. Some pioneer attempts using patient-reported data were made to evaluate the impact of certain manifestations; however, they lacked the use of solid and validated questionnaires for that purpose [26, 28]. Our study responds to this gap by identifying the manifestations that families and experts prioritize across age ranges and by providing specific tools that can measure QoL related to those symptoms.

Our quantitative results highlight that both stakeholder groups (families and professionals) rated neurological signs as the most impactful across all age ranges, particularly hypotonia, developmental delay, ataxia, dysarthria, and intellectual disability. This was corroborated by the qualitative interviews since these are manifestations that impact all domains of QoL (physical, social, and mental functioning as well as the capacity to perform daily living activities) throughout the patients’ lives. Of note, these are also some of the most frequent clinical signs in PMM2-CDG patients [13]. Other neurological occurrences were also prioritized with lower impact scores, namely seizures and stroke-like episodes. These are mainly rare clinical events reported to happen in 13% and 7% of patients, respectively, but have been described as some of the most QoL-impacting issues in PMM2-CDG [13, 29, 30]. Surprisingly, much more pronounced impact scores are suggested by clinicians compared to families concerning these neurological manifestations. Considering the low frequency of these clinical signs, it is probable that the impact of these manifestations is underrated due to clinical representation bias. In fact, only 9/23 (39%) of families reported any kind of QoL impact (from mild to extreme) derived from stroke-like episodes at some point of the patient’s lives. Even though this percentage is still higher than the reported frequency, it might explain the low impact score from families since most of them rated stroke-like episodes as having no impact on their lives (IS = 1). Nevertheless, family-derived qualitative data indicates the physical, psychological, and mental burden attributed to these manifestations. Contrastingly, none of the seven family members interviewed were able to describe how peripheral neuropathy impacts their day-to-day life. Even though peripheral neuropathy was present in some of their clinical reports, the real and physical consequences (e.g., pain to touch, numbness, altered sensations) were not perceived by the interviewed families, which might explain the differences of impact perception compared to medical professionals. These observations show the importance of complementing patient-reported data with medical knowledge and experience. Given the low number of interviews performed, further studies should secure bigger patient cohorts of worldwide and differently aged patients and representation of the full clinical spectrum and severity of PMM2-CDG to further understand the burden of the disease accurately.

Other system-related manifestations were prioritized concordantly by families and professionals, namely ophthalmologic manifestations, infections, overheating episodes, behavioral problems, kyphosis/scoliosis, and osteopenia. On the contrary, families and doctors rated dysphagia and sex development deficiencies differently. Since dysphagia is often a consequence of hypotonia, while doctors have this knowledge, families might not have had the opportunity to become familiar about the difference between “dysphagia” and “difficulty swallowing due to muscle weakness (hypotonia)”. In fact, families rated hypotonia with high impact scores. A similar issue arises considering that food allergies were included as a QoL-impacting manifestation. Even though food allergies have been pointed out as having a negative impact in PMM2-CDG patients’ QoL [26], interviewed families did not experience this clinical issue. Moreover, the medical committee pinpointed that food allergies are extremely rare in PMM2-CDG but food intolerances are rather common. This inconsistency raises the possibility that families consider food “allergy” and “intolerance” interchangeable terms. Therefore, efforts should be taken to improve the communication between the medical teams and families, raise health literacy levels and contribute to the proper disease understanding and management. An action that could be taken in the future to help manage and minimise these differences encompasses creating and distributing glossaries explaining medical and difficult terms in lay-language to empower families to participate confidently. This methodology has proven helpful and effective in other people-centric studies [26, 31].

Some general patient-reported clinical assessment tools have already been used in clinics for PMM2-CDG, particularly the Goal Attainment Scale and the patient-centred measures from Patient-Reported Outcomes Measurement Information System (PROMIS) [32, 33]. However, none of these reflect the most impactful conditions presented by the patients. Our methodology answered this gap and allowed us to tailor our search for adequate PRO tools for most of the included disease manifestations. Importantly, 94.2% of the articles reporting the use of the 80 QoL tools identified used them as self-reports. This is normally considered as the best practice since it does not require interpretation by a proxy.[34] However, most included articles also reported PROMs use in mono-organ and non-neurologic diseases, mostly allowing the use of self-reporting. In the case of PMM2-CDG, the cognitive and motor impairment, as well as communication difficulties due to dyspraxia will restrain most patients to self-report how they feel and function. Proxy assessments—a proxy responding to a QoL tool aimed for self-reporting as they believe the patient would rate the items)—need to be put into place as a solution, as performed for other debilitating diseases [19, 35]. Typically, proxy reports tend to overestimate the QoL impact compared to self-rating, but it might depend on several factors (e.g., QoL domain, disease severity or difficulty of carer’s tasks). Nonetheless, in several instances, proxy-reports were found to correlate with self- assessments. Besides, we believe that the over or underestimation of QoL from proxies can be systematic and therefore, changes across time and following an intervention should be captured. Measuring clinical severity alongside proxy-reports might be a way to ensure their reliability [33]. However, we cannot discard that a minority of PMM2-CDG patients might be able to express themselves and provide QoL self-ratings. Different rating methods and creative tools should be available to ensure their inclusion.

We also aimed to objectively analyze the psychometric quality of the questionnaires, since they will be the basis for the development of a future PMM2-CDG QoL questionnaire. Our results showed that some psychometric properties are, in general, objectively calculated. Even so, for Construct Validity most articles did not explicitly present the hypotheses. This is a common and potential risk, as the instrument may not represent the intended construct [20]. On the contrary, most instruments showed a positive Content Validity rating, considered the most important psychometric property of a tool [36]. Since health-related questionnaires are essential to assess the impact of a disease or treatment, Agreement should be accessed in validation articles to define the absolute measurement error, required for evaluative purposes to distinguish clinically meaningful changes. However, properties such as Agreement, Floor and Ceiling effect, Responsiveness, Interpretability and Criterion Validity are rarely reported. Thus, future validations should include the assessment of these psychometric dimensions.

The recent advances in drug development programs and increase in clinical research for PMM2-CDG urge for a disease-appropriate and responsive HrQoL measure. This study is a step towards the development of this PMM2-CDG QoL questionnaire assuring the engagement and participation of families and doctors since its inception. Following efforts should adopt the same methodology complementing clinically important factors (doctors’ views) with aspects that make life worth living (patients’ and families’ views). Looking forward, item selection from the gathered questionnaires following standard development procedures and item reduction should follow a programmed decision system including all stakeholders and resorting to nominal groups and cognitive interviews.

Limitations of this study

There were several limitations to this study. This is a pilot study that shows the potential of a community-centric methodology in PROMs development. Nevertheless, our results should be interpreted cautiously given the small sample participating in the impact survey and interviews. Even though our study aimed to include families representing different severities as well as different age ranges, the low number of families participating in the impact survey and the interviews are not representative of the full spectrum of PMM2-CDG clinical presentation, severity, and heterogeneity. As an example, we reached very limited representation of families of adult patients (n = 4 on the impact survey and n = 1 in the qualitative interviews). Next efforts should be taken to increase patient representation and capture the huge variability of clinical presentation of PMM2-CDG. Additionally, both in the questionnaire and interview, data on phenotypic severity should be collected to allow the stratification of the patient population according to disease severity and investigate if and how that affects HrQoL tool identification and, consequently PROMs development and/or administration.

We queried the PubMed database and no other sources because the project is led by a non-profit organisation without external funding. Non-English articles and articles using translated versions of the questionnaires were not included for practical reasons resulting in limited negative evidence. Although we are aware that we did not include all available instruments for the symptoms assessed, our methodology answered the main goal of this study—to identify the main questionnaires used across the impactful signs and symptoms. In our QoL tool quality analysis, the evaluation was centred on the criteria developed by Terwee et al., (2007), which are primarily opinion-based, and for which there is no empirical evidence to support explicit quality criteria in this field. However, it allowed us to establish a method of quality comparison between instruments. Also, there are some measurement properties that, despite being identified, are not assessed through the predefined criteria. Hence, there may be a need to “refine” or adapt these guidelines so that future comparative questionnaire analysis could be more accurate. Furthermore, the quality ratings do not consider a systematic review of validation studies associated with each questionnaire and depend on the availability of information on original development and validation articles. Finally, we cannot conclude that questionnaires with the highest number of positive ratings are necessarily the best ones, since some validation properties are more critical than others, depending on the aim of the questionnaire (e.g., discriminative questionnaires require a high level of reliability to be able to distinguish between people, while evaluative questionnaires require a high level of agreement to be able to measure essential changes). However, although important, this limitation did not interfere with the purpose of our analysis.

Conclusions

Accurately measuring HrQoL using a PMM2-CDG-specific QoL questionnaire including the most concerning domains/symptoms from both the family and medical perspectives will benefit therapy development and approval but also for establishing the natural history of the disease in terms of QoL. In turn, it will require and benefit from the combined efforts from all stakeholders, particularly families, researchers, clinicians, and pharma representatives as shown in this study. As for other rare diseases, creative and new approaches for the development of such scales need to be applied, particularly given the clinical heterogeneity of PMM2-CDG throughout time and between patients. This study provides a solution for this matter particularly by surveying the patient and medical community about the most impactful symptoms through the lifespan of a patient providing a list of adequate tools/items for the development of a new specific scale.

Availability of data and materials

All data generated or analysed during this study are included in this published article [and its Additional files].

Abbreviations

COA:

Clinical Outcomes Assessment

CDG:

Congenital Disorder(s) of Glycosylation

(Hr)QoL:

(Health-related) Quality of Life

PRO(M):

Patient-Reported Outcome (Measure)

ObsROM:

Observer-Reported Outcomes Measure

References

  1. WHOQOL - Measuring Quality of Life| The World Health Organization n.d. https://www.who.int/tools/whoqol (accessed June 24, 2022).

  2. GH Guyatt DH Feeny DL Patrick 1993 Measuring health-related quality of life Ann Intern Med 118 622 629 https://doi.org/10.7326/0003-4819-118-8-199304150-00009

    Article  PubMed  CAS  Google Scholar 

  3. M Vries De R Ouwendijk AG Kessels MW Haan De K Flobbe MGM Hunink 2005 Comparison of generic and disease-specific questionnaires for the assessment of quality of life in patients with peripheral arterial disease J Vasc Surg 41 261 268 https://doi.org/10.1016/J.JVS.2004.11.022

    Article  PubMed  Google Scholar 

  4. WR Lenderking M Anatchkova R Pokrzywinski A Skalicky ML Martin H Gelhorn 2021 Measuring health-related quality of life in patients with rare disease J Patient-Reported Outcomes 5 1 7 https://doi.org/10.1186/S41687-021-00336-8/METRICS

    Article  Google Scholar 

  5. A Whittal M Meregaglia E Nicod 2021 The use of patient-reported outcome measures in rare diseases and implications for health technology assessment Patient 14 485 503 https://doi.org/10.1007/S40271-020-00493-W

    Article  PubMed  PubMed Central  Google Scholar 

  6. C Pascoal S Brasil R Francisco D Marques-Da-Silva A Rafalko J Jaeken 2018 Patient and observer reported outcome measures to evaluate health-related quality of life in inherited metabolic diseases: a scoping review Orphanet J Rare Dis https://doi.org/10.1186/S13023-018-0953-9

    Article  PubMed  PubMed Central  Google Scholar 

  7. PR Deshpande S Rajan BL Sudeepthi CPA Nazir 2011 Patient-reported outcomes: a new era in clinical research Perspect Clin Res 2 137 https://doi.org/10.4103/2229-3485.86879

    Article  PubMed  PubMed Central  Google Scholar 

  8. S Bele A Chugh B Mohamed L Teela L Haverman MJ Santana 2020 Patient-reported outcome measures in routine pediatric clinical care: a systematic review Front Pediatr 8 364 https://doi.org/10.3389/FPED.2020.00364/BIBTEX

    Article  PubMed  PubMed Central  Google Scholar 

  9. Medicines Agency E. Committee for Medicinal Products for Human Use (CHMP). Appendix 2 to the guideline on the evaluation of anticancer medicinal products in man. The use of patient-reported outcome (PRO) measures in oncology studies. 2016.

  10. Administration F and D. Patient-reported outcome measures: use in medical product development to support labeling claims n.d. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/patient-reported-outcome-measures-use-medical-product-development-support-labeling-claims (accessed February 3, 2022).

  11. P Lipiński A Tylki-Szymańska 2021 Congenital disorders of glycosylation: what clinicians need to know? Front Pediatr 9 926 https://doi.org/10.3389/FPED.2021.715151/BIBTEX

    Article  Google Scholar 

  12. IJ Chang M He CT Lam 2018 Congenital disorders of glycosylation Ann Transl Med 6 477 https://doi.org/10.21037/ATM.2018.10.45

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. R Altassan R Péanne J Jaeken R Barone M Bidet D Borgel 2019 International clinical guidelines for the management of phosphomannomutase 2-congenital disorders of glycosylation: diagnosis, treatment and follow up J Inherit Metab Dis 42 5 28 https://doi.org/10.1002/JIMD.12024

    Article  PubMed  CAS  Google Scholar 

  14. Glycomine Announces First Dosing in Phase 1 Clinical Study of GLM101, a Potential Treatment for PMM2-CDG | Glycomine n.d. https://www.glycomine.com/glycomine-announces-first-dosing-in-phase-1-clinical-study-of-glm101-a-potential-treatment-for-pmm2-cdg/ (accessed February 15, 2022).

  15. AF Martínez-Monseny M Bolasell L Callejón-Póo D Cuadras V Freniche DC Itzep 2019 AZATAX: Acetazolamide safety and efficacy in cerebellar syndrome in PMM2 congenital disorder of glycosylation (PMM2-CDG) Ann Neurol 85 740 751 https://doi.org/10.1002/ANA.25457

    Article  PubMed  Google Scholar 

  16. AN Ligezka S Radenkovic M Saraswat K Garapati W Ranatunga W Krzysciak 2021 Sorbitol Is a severity biomarker for PMM2-CDG with therapeutic implications Ann Neurol 90 887 900 https://doi.org/10.1002/ANA.26245

    Article  PubMed  CAS  Google Scholar 

  17. KE Flynn 2021 PROM proposal: analyzing proxy reports of patient-reported outcome measures Circ Cardiovasc Qual Outcomes 14 e008529https://doi.org/10.1161/CIRCOUTCOMES.121.008529

    Article  PubMed  Google Scholar 

  18. K Kroenke TE Stump PO Monahan 2022 Agreement between older adult patient and caregiver proxy symptom reports J Patient-Reported Outcomes 6 1 12 https://doi.org/10.1186/S41687-022-00457-8

    Article  Google Scholar 

  19. S Schmidt M Power A Green R Lucas-Carrasco E Eser E Dragomirecka 2010 Self and proxy rating of quality of life in adults with intellectual disabilities: results from the DISQOL study Res Dev Disabil 31 1015 1026 https://doi.org/10.1016/J.RIDD.2010.04.013

    Article  PubMed  Google Scholar 

  20. CB Terwee SDM Bot MR Boer de DAWM Windt van der DL Knol J Dekker 2007 Quality criteria were proposed for measurement properties of health status questionnaires J Clin Epidemiol 60 34 42 https://doi.org/10.1016/J.JCLINEPI.2006.03.012

    Article  PubMed  Google Scholar 

  21. T Morel SJ Cano 2017 Measuring what matters to rare disease patients: reflections on the work by the IRDiRC taskforce on patient-centered outcome measures Orphanet J Rare Dis 12 1 13 https://doi.org/10.1186/S13023-017-0718-X/TABLES/7

    Article  Google Scholar 

  22. L Rajmil L Perestelo-Pérez M Herdman 2010 Quality of life and rare diseases Adv Exp Med Biol 686 251 272 https://doi.org/10.1007/978-90-481-9485-8_15

    Article  PubMed  Google Scholar 

  23. B Wiering D Boer de D Delnoij 2017 Patient involvement in the development of patient-reported outcome measures: a scoping review Health Expect 20 11 https://doi.org/10.1111/HEX.12442

    Article  PubMed  Google Scholar 

  24. T Greenhalgh B Hurwitz 1999 Narrative based medicine: why study narrative? BMJ Br Med J 318 48 https://doi.org/10.1136/BMJ.318.7175.48

    Article  CAS  Google Scholar 

  25. C Cardão L Barros R Francisco D Silva VR Ferreira 2021 Experiences of parents with children with congenital disorders of glycosylation: what can we learn from them? Disabil Health J https://doi.org/10.1016/J.DHJO.2021.101065

    Article  PubMed  Google Scholar 

  26. R Francisco C Pascoal D Marques-Da-silva S Brasil FM Pimentel-Santos R Altassan 2020 New insights into immunological involvement in congenital disorders of glycosylation (CDG) from a people-centric approach J Clin Med 9 2092 https://doi.org/10.3390/JCM9072092

    Article  PubMed Central  CAS  Google Scholar 

  27. M Schiff C Roda ML Monin A Arion M Barth N Bednarek 2017 Clinical, laboratory and molecular findings and long-term follow-up data in 96 French patients with PMM2-CDG (phosphomannomutase 2-congenital disorder of glycosylation) and review of the literature J Med Genet 54 843 851 https://doi.org/10.1136/JMEDGENET-2017-104903

    Article  PubMed  CAS  Google Scholar 

  28. D Marques-da-Silva R Francisco FV Reis dos L Forbat R Lagoa PA Videira 2019 An electronic questionnaire for liver assessment in congenital disorders of glycosylation (LeQCDG): a patient-centered study JIMD Rep 44 55 64 https://doi.org/10.1007/8904_2018_121

    Article  PubMed  CAS  Google Scholar 

  29. M Serrano 2021 Stroke-like episodes in PMM2-CDG: when the lack of other evidence is the only evidence Front Pediatr 9 717864https://doi.org/10.3389/FPED.2021.717864

    Article  PubMed  PubMed Central  Google Scholar 

  30. F Pettinato G Mostile R Battini D Martinelli A Madeo E Biamino 2021 Clinical and radiological correlates of activities of daily living in cerebellar atrophy caused by PMM2 mutations (PMM2-CDG) Cerebellum 20 596 https://doi.org/10.1007/S12311-021-01242-X

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. R Francisco S Brasil C Pascoal J Jaeken M Liddle PA Videira 2022 The road to successful people-centric research in rare diseases: the web-based case study of the Immunology and Congenital Disorders of Glycosylation questionnaire (ImmunoCDGQ) Orphanet J Rare Dis 17 1 18 https://doi.org/10.1186/S13023-022-02286-W/FIGURES/5

    Article  Google Scholar 

  32. L Turner-Stokes 2009 Goal attainment scaling (GAS) in rehabilitation: a practical guide Clin Rehabil 23 362 370 https://doi.org/10.1177/0269215508101742

    Article  PubMed  Google Scholar 

  33. AN Ligezka A Mohamed C Pascoal VDR Ferreira S Boyer C Lam 2022 Patient-reported outcomes and quality of life in PMM2-CDG Mol Genet Metab 136 145 151 https://doi.org/10.1016/J.YMGME.2022.04.002

    Article  PubMed  CAS  Google Scholar 

  34. Fayers PM, Machin D. Quality of life : the assessment, analysis, and reporting of patient-reported outcomes n.d.

  35. K Hilari S Byng 2009 Health-related quality of life in people with severe aphasia Int J Lang Commun Disord 44 193 205 https://doi.org/10.1080/13682820802008820

    Article  PubMed  Google Scholar 

  36. CB Terwee CAC Prinsen A Chiarotto MJ Westerman DL Patrick J Alonso 2018 COSMIN methodology for evaluating the content validity of patient-reported outcome measures: a Delphi study Qual Life Res 27 1159 1170 https://doi.org/10.1007/S11136-018-1829-0

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. AI Tröster R Pahwa JA Fields CM Tanner KE Lyons 2005 Quality of life in Essential Tremor Questionnaire (QUEST): development and initial validation Parkinsonism Relat Disord 11 367 373 https://doi.org/10.1016/J.PARKRELDIS.2005.05.009

    Article  PubMed  Google Scholar 

  38. A Schrag C Selai C Mathias P Low J Hobart N Brady 2007 Measuring health-related quality of life in MSA: the MSA-QoL Mov Disord 22 2332 2338 https://doi.org/10.1002/MDS.21649

    Article  PubMed  Google Scholar 

  39. CP Green CB Porter DR Bresnahan JA Spertus 2000 Development and evaluation of the Kansas City Cardiomyopathy Questionnaire: a new health status measure for heart failure J Am Coll Cardiol 35 1245 1255 https://doi.org/10.1016/S0735-1097(00)00531-3

    Article  PubMed  CAS  Google Scholar 

  40. S Heo DK Moser B Riegel LA Hall N Christman 2005 Testing the psychometric properties of the Minnesota Living with Heart Failure questionnaire Nurs Res 54 265 272 https://doi.org/10.1097/00006199-200507000-00009

    Article  PubMed  Google Scholar 

  41. B Riegel DK Moser D Glaser B Carlson C Deaton R Armola 2002 The Minnesota living with heart failure questionnaire: sensitivity to differences and responsiveness to intervention intensity in a clinical population Nurs Res 51 209 218 https://doi.org/10.1097/00006199-200207000-00001

    Article  PubMed  Google Scholar 

  42. A Rentz E Flood C Altisent M Bullinger R Klamroth RP Garrido 2008 Cross-cultural development and psychometric evaluation of a patient-reported health-related quality of life questionnaire for adults with haemophilia Haemophilia 14 1023 1034 https://doi.org/10.1111/J.1365-2516.2008.01812.X

    Article  PubMed  CAS  Google Scholar 

  43. S Mackensen Von M Bullinger P Arranz G Auerswald J Aznar M Berg van den 2004 Development and testing of an instrument to assess the Quality of Life of Children with Haemophilia in Europe (Haemo-QoL) Haemophilia 10 Suppl 1 17 25 https://doi.org/10.1111/J.1355-0691.2004.00875.X

    Article  Google Scholar 

  44. NL Young CS Bradley CD Wakefield D Barnard VS Blanchette PJ McCusker 2006 How well does the Canadian Haemophilia Outcomes-Kids’ Life Assessment Tool (CHO-KLAT) measure the quality of life of boys with haemophilia? Pediatr Blood Cancer 47 305 311 https://doi.org/10.1002/PBC.20618

    Article  PubMed  Google Scholar 

  45. Yorkston KM, Bombardier C, Hammen VL. Dysarthria from the viewpoint of individuals with dysarthria. Mot Speech Disord Adv Assess Treat 1994:19–36.

  46. V Piacentini A Zuin D Cattaneo A Schindler 2011 Reliability and validity of an instrument to measure quality of life in the dysarthric speaker Folia Phoniatr Logop 63 289 295 https://doi.org/10.1159/000322800

    Article  PubMed  Google Scholar 

  47. L Hartelius M Elmberg R Holm AS Lövberg S Nikolaidis 2008 Living with dysarthria: evaluation of a self-report questionnaire Folia Phoniatr Logop 60 11 19 https://doi.org/10.1159/000111799

    Article  PubMed  Google Scholar 

  48. M Walshe RK Peach N Miller 2009 Dysarthria impact profile: development of a scale to measure psychosocial effects Int J Lang Commun Disord 44 693 715 https://doi.org/10.1080/13682820802317536

    Article  PubMed  Google Scholar 

  49. RN Rinkel IM Verdonck-de Leeuw EJ Reij Van NK Aaronson R Leemans 2008 Speech Handicap Index in patients with oral and pharyngeal cancer: better understanding of patients’ complaints Head Neck 30 868 874 https://doi.org/10.1002/HED.20795

    Article  PubMed  Google Scholar 

  50. CA McHorney DE Bricker AE Kramer JC Rosenbek JA Robbins KA Chignell 2000 The SWAL-QOL outcomes tool for oropharyngeal dysphagia in adults: I. Conceptual foundation and item development Dysphagia 15 115 121 https://doi.org/10.1007/S004550010012

    Article  PubMed  CAS  Google Scholar 

  51. CA McHorney D Earl Bricker J Robbins AE Kramer JC Rosenbek KA Chignell 2000 The SWAL-QOL outcomes tool for oropharyngeal dysphagia in adults: II. Item reduction and preliminary scaling Dysphagia 15 122 133 https://doi.org/10.1007/S004550010013

    Article  PubMed  CAS  Google Scholar 

  52. CA McHorney JA Robbins K Lomax JC Rosenbek K Chignell AE Kramer 2002 The SWAL-QOL and SWAL-CARE outcomes tool for oropharyngeal dysphagia in adults: III. Documentation of reliability and validity Dysphagia 17 97 114 https://doi.org/10.1007/S00455-001-0109-1

    Article  PubMed  Google Scholar 

  53. V Woisard MP Andrieux M Puech 2006 Validation of a self-assessment questionnaire for swallowing disorders (Deglutition Handicap Index) Rev Laryngol Otol Rhinol (Bord) 127 315 325

    CAS  Google Scholar 

  54. V Woisard B Lepage 2010 The, “Deglutition Handicap Index” a self-administrated dysphagia-specific quality of life questionnaire: temporal reliability Rev Laryngol 131 19 22

    CAS  Google Scholar 

  55. PC Belafsky DA Mouadeb CJ Rees JC Pryor GN Postma J Allen 2008 Validity and reliability of the Eating Assessment Tool (EAT-10) Ann Otol Rhinol Laryngol 117 919 924 https://doi.org/10.1177/000348940811701210

    Article  PubMed  Google Scholar 

  56. J Wilmskoetter H Bonilha I Hong RJ Hazelwood B Martin-Harris C Velozo 2019 Construct validity of the Eating Assessment Tool (EAT-10) Disabil Rehabil 41 549 559 https://doi.org/10.1080/09638288.2017.1398787

    Article  PubMed  Google Scholar 

  57. AK Silbergleit L Schultz BH Jacobson T Beardsley AF Johnson 2012 The Dysphagia handicap index: development and validation Dysphagia 27 46 52 https://doi.org/10.1007/S00455-011-9336-2

    Article  PubMed  Google Scholar 

  58. A Dunngalvin C Cullinane DA Daly BMJ Flokstra-De Blok AEJ Dubois JB Hourihane 2010 Longitudinal validity and responsiveness of the Food Allergy Quality of Life Questionnaire—parent form in children 0–12 years following positive and negative food challenges Clin Exp Allergy 40 476 485 https://doi.org/10.1111/J.1365-2222.2010.03454.X

    Article  PubMed  CAS  Google Scholar 

  59. RK Doorn Van LMF Winkler KH Zwinderman ML Mearin HM Koopman 2008 CDDUX: a disease-specific health-related quality-of-life questionnaire for children with celiac disease J Pediatr Gastroenterol Nutr 47 147 152 https://doi.org/10.1097/MPG.0B013E31815EF87D

    Article  PubMed  Google Scholar 

  60. E Irvine Q Zhou AK Thompson 1996 The Short Inflammatory Bowel Disease Questionnaire: a quality of life instrument for community physicians managing inflammatory bowel disease. CCRPT Investigators. Canadian Crohn’s Relapse Prevention Trial Am J Gastroenterol 91 1571 1578

    PubMed  CAS  Google Scholar 

  61. MJ Alcalá F Casellas G Fontanet L Prieto JR Malagelada 2004 Shortened questionnaire on quality of life for inflammatory bowel disease Inflamm Bowel Dis 10 383 391 https://doi.org/10.1097/00054725-200407000-00009

    Article  PubMed  Google Scholar 

  62. BA Hahn LJ Kirchdoerfer S Fullerton E Mayer 1997 Evaluation of a new quality of life questionnaire for patients with irritable bowel syndrome Aliment Pharmacol Ther 11 547 552 https://doi.org/10.1046/J.1365-2036.1997.00168.X

    Article  PubMed  CAS  Google Scholar 

  63. DL Patrick DA Drossman IO Frederick J Dicesare KL Puder 1998 Quality of life in persons with irritable bowel syndrome: development and validation of a new measure Dig Dis Sci 43 400 411 https://doi.org/10.1023/A:1018831127942

    Article  PubMed  CAS  Google Scholar 

  64. DA Drossman DL Patrick WE Whitehead BB Toner NE Diamant Y Hu 2000 Further validation of the IBS-QOL: a disease-specific quality-of-life questionnaire Am J Gastroenterol 95 999 1007 https://doi.org/10.1111/J.1572-0241.2000.01941.X

    Article  PubMed  CAS  Google Scholar 

  65. V Velanovich 2007 The development of the GERD-HRQL symptom severity instrument Dis Esophagus 20 130 134 https://doi.org/10.1111/J.1442-2050.2007.00658.X

    Article  PubMed  CAS  Google Scholar 

  66. E Eypasch JI Williams S Wood-Dauphinee BM Ure C Schmulling E Neugebauer 1995 Gastrointestinal Quality of Life Index: development, validation and application of a new instrument Br J Surg 82 216 222 https://doi.org/10.1002/BJS.1800820229

    Article  PubMed  CAS  Google Scholar 

  67. D Khanna RD Hays GS Park Y Braun-Moscovici MD Mayes TA McNearney 2007 Development of a preliminary scleroderma gastrointestinal tract 1.0 quality of life instrument Arthritis Rheum 57 1280 1286 https://doi.org/10.1002/ART.22987

    Article  PubMed  Google Scholar 

  68. JM Blazeby T Conroy E Hammerlid P Fayers O Sezer M Koller 2003 Clinical and psychometric validation of an EORTC questionnaire module, the EORTC QLQ-OES18, to assess quality of life in patients with oesophageal cancer Eur J Cancer 39 1384 1394 https://doi.org/10.1016/S0959-8049(03)00270-3

    Article  PubMed  CAS  Google Scholar 

  69. AHG Davies G Larsson J Ardill E Friend L Jones M Falconi 2006 Development of a disease-specific Quality of Life questionnaire module for patients with gastrointestinal neuroendocrine tumours Eur J Cancer 42 477 484 https://doi.org/10.1016/J.EJCA.2005.10.025

    Article  PubMed  CAS  Google Scholar 

  70. G Yadegarfar L Friend L Jones LM Plum J Ardill B Taal 2013 Validation of the EORTC QLQ-GINET21 questionnaire for assessing quality of life of patients with gastrointestinal neuroendocrine tumours Br J Cancer 108 301 https://doi.org/10.1038/BJC.2012.560

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. JP Baxter PM Fayers AW McKinlay 2008 The development and translation of a treatment-specific quality of life questionnaire for adult patients on home parenteral nutrition Eur e-J Clin Nutr Metab 3 e22 e28 https://doi.org/10.1016/J.ECLNM.2007.10.001

    Article  Google Scholar 

  72. JP Baxter PM Fayers F Bozzetti D Kelly F Joly G Wanten 2019 An international study of the quality of life of adult patients treated with home parenteral nutrition Clin Nutr 38 1788 1796 https://doi.org/10.1016/J.CLNU.2018.07.024

    Article  PubMed  Google Scholar 

  73. K Furuta S Ishihara S Sato T Miyake N Ishimura K Koshino 2019 Development and verification of the Izumo Scale, new questionnaire for quality of life assessment of patients with gastrointestinal symptoms Nihon Shokakibyo Gakkai Zasshi 106 1478 1487

    Google Scholar 

  74. NJ Talley M Verlinden M Jones 2001 Quality of life in functional dyspepsia: responsiveness of the Nepean Dyspepsia Index and development of a new 10-item short form Aliment Pharmacol Ther 15 207 216 https://doi.org/10.1046/J.1365-2036.2001.00900.X

    Article  PubMed  CAS  Google Scholar 

  75. G Guyatt A Mitchell EJ Irvine J Singer N Williams R Goodacre 1989 A new measure of health status for clinical trials in inflammatory bowel disease Gastroenterology 96 804 810

    Article  PubMed  CAS  Google Scholar 

  76. JR Love EJ Irvine RN Fedorak 1992 Quality of life in inflammatory bowel disease J Clin Gastroenterol 14 15 19 https://doi.org/10.1097/00004836-199201000-00005

    Article  PubMed  CAS  Google Scholar 

  77. C Hopkins S Gillett R Slack VJ Lund JP Browne 2009 Psychometric validity of the 22-item Sinonasal Outcome Test Clin Otolaryngol 34 447 454 https://doi.org/10.1111/J.1749-4486.2009.01995.X

    Article  PubMed  CAS  Google Scholar 

  78. JF Piccirillo MG Merritt ML Richards 2002 Psychometric and clinimetric validity of the 20-Item Sino-Nasal Outcome Test (SNOT-20) Otolaryngol Head Neck Surg 126 41 47 https://doi.org/10.1067/MHN.2002.121022

    Article  PubMed  Google Scholar 

  79. SS Birring B Prudon AJ Carr SJ Singh L Morgan ID Pavord 2003 Development of a symptom specific health status measure for patients with chronic cough: Leicester Cough Questionnaire (LCQ) Thorax 58 339 343 https://doi.org/10.1136/THORAX.58.4.339

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. TR Haher JM Gorup TM Shin P Homel AA Merola DP Grogan 1999 Results of the Scoliosis Research Society instrument for evaluation of surgical outcome in adolescent idiopathic scoliosis. A multicenter study of 244 patients Spine 24 1435 1440 https://doi.org/10.1097/00007632-199907150-00008

    Article  PubMed  CAS  Google Scholar 

  81. M Asher SM Lai D Burton B Manna 2003 The reliability and concurrent validity of the scoliosis research society-22 patient questionnaire for idiopathic scoliosis Spine 28 63 69 https://doi.org/10.1097/00007632-200301010-00015

    Article  PubMed  Google Scholar 

  82. MA Asher SM Lai RC Glattes DC Burton A Alanay J Bago 2006 Refinement of the SRS-22 health-related quality of life questionnaire function domain Spine 31 593 597 https://doi.org/10.1097/01.BRS.0000201331.50597.EA

    Article  PubMed  Google Scholar 

  83. A Caronni F Zaina S Negrini 2014 Improving the measurement of health-related quality of life in adolescent with idiopathic scoliosis: the SRS-7, a Rasch-developed short form of the SRS-22 questionnaire Res Dev Disabil 35 784 799 https://doi.org/10.1016/J.RIDD.2014.01.020

    Article  PubMed  Google Scholar 

  84. J Corona H Matsumoto DP Roye MG Vitale 2011 Measuring quality of life in children with early onset scoliosis: development and initial validation of the early onset scoliosis questionnaire J Pediatr Orthop 31 180 185 https://doi.org/10.1097/BPO.0B013E3182093F9F

    Article  PubMed  Google Scholar 

  85. RJ Feise S Donaldson ER Crowther J Michael Menke JG Wright 2005 Construction and validation of the scoliosis quality of life index in adolescent idiopathic scoliosis Spine 30 1310 1315 https://doi.org/10.1097/01.BRS.0000163885.12834.CA

    Article  PubMed  Google Scholar 

  86. A Caronni L Sciumè S Donzelli F Zaina S Negrini 2017 ISYQOL: a Rasch-consistent questionnaire for measuring health-related quality of life in adolescents with spinal deformities Spine J 17 1364 1372 https://doi.org/10.1016/J.SPINEE.2017.05.022

    Article  PubMed  Google Scholar 

  87. A Caronni S Donzelli F Zaina S Negrini 2019 The Italian Spine Youth Quality of Life questionnaire measures health-related quality of life of adolescents with spinal deformities better than the reference standard, the Scoliosis Research Society 22 questionnaire Clin Rehabil 33 1404 1415 https://doi.org/10.1177/0269215519842246

    Article  PubMed  Google Scholar 

  88. ZM Younossi M Stepanova L Henry A Racila B Lam HT Pham 2017 A disease-specific quality of life instrument for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis: CLDQ-NAFLD Liver Int 37 1209 1218 https://doi.org/10.1111/LIV.13391/SUPPINFO

    Article  PubMed  Google Scholar 

  89. ZM Younossi M Stepanova I Younossi A Racila 2019 Validation of Chronic Liver Disease Questionnaire for nonalcoholic steatohepatitis in patients with biopsy-proven nonalcoholic steatohepatitis Clin Gastroenterol Hepatol 17 2093 2100.e3 https://doi.org/10.1016/J.CGH.2019.01.001

    Article  PubMed  Google Scholar 

  90. ZM Younossi G Guyatt M Kiwi N Boparai D King 1999 Development of a disease specific questionnaire to measure health related quality of life in patients with chronic liver disease Gut 45 295 https://doi.org/10.1136/GUT.45.2.295

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. DA Revicki AM Rentz N Harnam VS Thomas P Lanzetta 2010 Reliability and validity of the National Eye Institute Visual Function Questionnaire-25 in patients with age-related macular degeneration Investig Ophthalmol Vis Sci 51 712 717 https://doi.org/10.1167/IOVS.09-3766

    Article  Google Scholar 

  92. JJ Nichols GL Mitchell M Saracino K Zadnik 2003 Reliability and validity of refractive error-specific quality-of-life instruments Arch Ophthalmol 121 1289 1296 https://doi.org/10.1001/ARCHOPHT.121.9.1289

    Article  PubMed  Google Scholar 

  93. FM Costela K Pesudovs MA Sandberg C Weigel-Difranco RL Woods 2020 Validation of a vision-related activity scale for patients with retinitis pigmentosa Health Qual Life Outcomes 18 1 11 https://doi.org/10.1186/S12955-020-01427-8/FIGURES/5

    Article  Google Scholar 

  94. SR Hatt DA Leske YS Castañeda SM Wernimont L Liebermann CS Cheng-Patel 2019 Development of pediatric eye questionnaires for children with eye conditions Am J Ophthalmol 200 201 217 https://doi.org/10.1016/J.AJO.2019.01.001

    Article  PubMed  PubMed Central  Google Scholar 

  95. SR Hatt DA Leske T Yamada EA Bradley SR Cole JM Holmes 2010 Development and initial validation of quality-of-life questionnaires for intermittent exotropia Ophthalmology https://doi.org/10.1016/J.OPHTHA.2009.06.038

    Article  PubMed  Google Scholar 

  96. SR Hatt DA Leske EA Bradley SR Cole JM Holmes 2009 Development of a quality-of-life questionnaire for adults with strabismus Ophthalmology https://doi.org/10.1016/J.OPHTHA.2008.08.043

    Article  PubMed  Google Scholar 

  97. VK Gothwal S Bharani R Kekunnaya P Chhablani V Sachdeva NK Pehere 2015 Measuring Health-Related Quality of Life in Strabismus: a modification of the adult Strabismus-20 (AS-20) Questionnaire using Rasch analysis PLoS ONE 10 e0127064https://doi.org/10.1371/JOURNAL.PONE.0127064

    Article  PubMed  PubMed Central  Google Scholar 

  98. C Owsley G McGwin K Scilley K Kallies 2006 Development of a questionnaire to assess vision problems under low luminance in age-related maculopathy Investig Ophthalmol Vis Sci 47 528 535 https://doi.org/10.1167/IOVS.05-1222

    Article  Google Scholar 

  99. GDB Ribeiro AGZ Bach CM Faria S Anastásia HC Almeida de 2014 Quality of life of patients with strabismus Arq Bras Oftalmol 77 110 113 https://doi.org/10.5935/0004-2749.20140027

    Article  Google Scholar 

  100. W Maples 2000 Test-retest reliability of the College of Optometrists in Vision Development Quality of Life Outcomes Assessment Optometry 71 579 585

    PubMed  CAS  Google Scholar 

  101. M Kothari S Balankhe R Gawade S Toshnival 2009 Comparison of psychosocial and emotional consequences of childhood strabismus on the families from rural and urban India Indian J Ophthalmol 57 285 https://doi.org/10.4103/0301-4738.53053

    Article  PubMed  PubMed Central  Google Scholar 

  102. C Mckeon B Wick LA Aday C Begley 1997 A case-comparison of intermittent exotropia and quality of life measurements Optom Vis Sci 74 105 110 https://doi.org/10.1097/00006324-199702000-00022

    Article  PubMed  CAS  Google Scholar 

  103. T Takashima T Yokoyama S Futagami K Ohno-Matsui H Tanaka T Tokoro 2001 The quality of life in patients with pathologic myopia Jpn J Ophthalmol 45 84 92 https://doi.org/10.1016/S0021-5155(00)00305-1

    Article  PubMed  CAS  Google Scholar 

  104. ES Graaf van de J Felius H Kempen-du Saar CWN Looman J Passchier H Kelderman 2009 Construct validation of the Amblyopia and Strabismus Questionnaire (A&SQ) by factor analysis Graefe’s Arch Clin Exp Ophthalmol 247 1263 https://doi.org/10.1007/S00417-009-1112-8

    Article  Google Scholar 

  105. K Pesudovs E Garamendi DB Elliott 2004 The Quality of Life Impact of Refractive Correction (QIRC) Questionnaire: development and validation Optom Vis Sci 81 769 777 https://doi.org/10.1097/00006324-200410000-00009

    Article  PubMed  Google Scholar 

  106. BA Raphael KM Galetta DA Jacobs CE Markowitz GT Liu ML Nano-Schiavi 2006 Validation and test characteristics of a 10-item neuro-ophthalmic supplement to the NEI-VFQ-25 Am J Ophthalmol https://doi.org/10.1016/J.AJO.2006.06.060

    Article  PubMed  Google Scholar 

  107. Y Chen X Chen J Chen J Zheng J Xu X Yu 2016 Longitudinal impact on quality of life for school-aged children with amblyopia treatment: perspective from children Curr Eye Res 41 208 214 https://doi.org/10.3109/02713683.2015.1011280

    Article  PubMed  Google Scholar 

  108. MC Brown SC Schallhorn KA Hettinger SE Malady 2009 Satisfaction of 13,655 patients with laser vision correction at 1 month after surgery J Refract Surg https://doi.org/10.3928/1081597X-20090611-03

    Article  PubMed  Google Scholar 

  109. S Schallhorn M Brown J Venter K Hettinger S Hannan 2014 The role of the mesopic pupil on patient-reported outcomes in young patients with myopia 1 month after wavefront-guided LASIK J Refract Surg 30 159 165 https://doi.org/10.3928/1081597X-20140217-02

    Article  PubMed  Google Scholar 

  110. S Schallhorn M Brown J Venter D Teenan K Hettinger H Yamamoto 2014 Early clinical outcomes of wavefront-guided myopic LASIK treatments using a new-generation hartmann-shack aberrometer J Refract Surg 30 14 21 https://doi.org/10.3928/1081597X-20131029-02

    Article  PubMed  Google Scholar 

  111. RJ McLean GDE Maconachie I Gottlob J Maltby 2016 The development of a Nystagmus-Specific Quality-of-Life Questionnaire Ophthalmology 123 2023 2027 https://doi.org/10.1016/J.OPHTHA.2016.05.033

    Article  PubMed  Google Scholar 

  112. DB Erickson F Stapleton P Erickson R Toit Du E Giannakopoulos B Holden 2004 Development and validation of a multidimensional quality-of-life scale for myopia Optom Vis Sci 81 70 81 https://doi.org/10.1097/00006324-200402000-00004

    Article  PubMed  Google Scholar 

  113. X Badia L Prieto M Roset A Díez-Pérez 2000 Development of the ECOS-16 clinical questionnaire for the assessment of the quality of life in patients with osteoporosis Med Clin 114 Suppl 68 75

    Google Scholar 

  114. X Badia A Díez-Pérez R Lahoz L Lizán X Nogués J Iborra 2004 The ECOS-16 questionnaire for the evaluation of health related quality of life in post-menopausal women with osteoporosis Health Qual Life Outcomes 2 1 11 https://doi.org/10.1186/1477-7525-2-41/FIGURES/1

    Article  Google Scholar 

  115. SL Silverman 2000 The Osteoporosis Assessment Questionnaire (OPAQ): a reliable and valid disease-targeted measure of health-related quality of life (HRQOL) in osteoporosis Qual Life Res 9 767 774

    Article  Google Scholar 

  116. JM Chandler AR Martin C Girman PD Ross B Love-McClung E Lydick 1998 Reliability of an Osteoporosis-Targeted Quality of Life Survey Instrument for use in the community: OPTQoL Osteoporos Int 8 127 135 https://doi.org/10.1007/BF02672508

    Article  PubMed  CAS  Google Scholar 

  117. M McClung B Love C Rosen C Kessenich J Stock J Overdorf 1995 Evaluation of a new osteoporosis quality-of-life questionnaire (OQLQ) for women with osteoporosis and back pain J Bone Miner Res 10 S255

    Google Scholar 

  118. DJ Cook GH Guyatt JD Adachi RS Epstein EF Juniper PA Austin 1999 Development and validation of the mini-osteoporosis quality of life questionnaire (OQLQ) in osteoporotic women with back pain due to vertebral fractures. Osteoporosis Quality of Life Study Group Osteoporos Int 10 207 213 https://doi.org/10.1007/S001980050217

    Article  PubMed  CAS  Google Scholar 

  119. C Loge de la K Sullivan R Pinkney P Marquis C Roux PJ Meunier 2005 Cross-cultural validation and analysis of responsiveness of the QUALIOST(R): QUAlity of Life questionnaire in OSTeoporosis Health Qual Life Outcomes 3 1 10 https://doi.org/10.1186/1477-7525-3-69/TABLES/5

    Article  Google Scholar 

  120. G Baker A Jacoby 1994 Development of an instrument to assess quality of life in children with epilepsy and learning disability Epilepsia 35 S47

    Google Scholar 

  121. D Buck M Smith R Appleton GA Baker A Jacoby 2007 The development and validation of the Epilepsy and Learning Disabilities Quality of Life (ELDQOL) scale Epilepsy Behav 10 38 43 https://doi.org/10.1016/J.YEBEH.2006.10.010

    Article  PubMed  Google Scholar 

  122. JA Cramer K Perrine O Devinsky K Meador 1996 A brief questionnaire to screen for quality of life in epilepsy: the QOLIE-10 Epilepsia 37 577 582 https://doi.org/10.1111/J.1528-1157.1996.TB00612.X

    Article  PubMed  CAS  Google Scholar 

  123. JA Cramer K Perrine O Devinsky L Bryant-Comstock K Meador B Hermann 1998 Development and cross-cultural translations of a 31-item quality of life in epilepsy inventory Epilepsia 39 81 88 https://doi.org/10.1111/J.1528-1157.1998.TB01278.X

    Article  PubMed  CAS  Google Scholar 

  124. JA Cramer LE Westbrook O Devinsky K Perrine MB Glassman C Camfield 1999 Development of the Quality of Life in Epilepsy Inventory for Adolescents: the QOLIE-AD-48 Epilepsia 40 1114 1121 https://doi.org/10.1111/J.1528-1157.1999.TB00828.X

    Article  PubMed  CAS  Google Scholar 

  125. M Sabaz JA Lawson DR Cairns MS Duchowny TJ Resnick PM Dean 2003 Validation of the quality of life in childhood epilepsy questionnaire in American epilepsy patients Epilepsy Behav 4 680 691 https://doi.org/10.1016/J.YEBEH.2003.08.012

    Article  PubMed  Google Scholar 

  126. SW Goodwin AI Lambrinos MA Ferro M Sabaz KN Speechley 2015 Development and assessment of a shortened Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-55) Epilepsia 56 864 872 https://doi.org/10.1111/EPI.13000

    Article  PubMed  Google Scholar 

  127. CH Bastien A Vallières CM Morin 2001 Validation of the Insomnia Severity Index as an outcome measure for insomnia research Sleep Med 2 297 307 https://doi.org/10.1016/S1389-9457(00)00065-4

    Article  PubMed  Google Scholar 

  128. Moul D, Pilkonis P, Miewald J, Carey T, DJ B. Preliminary study of the test–retest reliability and concurrent validities of the Pittsburgh Insomnia Rating Scale (PIRS). Sleep 25(Abstract Suppl 2002 2002;25:A256–247.

  129. SM Webb X Badia MJ Baarahona A Colao CJ Strasburger A Tabarin 2008 Evaluation of health-related quality of life in patients with Cushing’s syndrome with a new questionnaire Eur J Endocrinol 158 623 630 https://doi.org/10.1530/EJE-07-0762

    Article  PubMed  CAS  Google Scholar 

  130. SJ Hassan EA Weymuller 1993 Assessment of quality of life in head and neck cancer patients Head Neck 15 485 496 https://doi.org/10.1002/HED.2880150603

    Article  PubMed  CAS  Google Scholar 

  131. MS Litwin RD Hays A Fink PA Ganz B Leake RH Brook 1998 The UCLA Prostate Cancer Index: development, reliability, and validity of a health-related quality of life measure Med Care 36 1002 1012 https://doi.org/10.1097/00005650-199807000-00007

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors would like to acknowledge the members of the medical and patient committees for the input, advice and experiences shared for the guidance of this study. Namely, to AM, SP, JP, LR, MC, RF, TR and JB for being part of the patient committee and to JJ, EM, LB, DCo, DCa, CTL, RA, CL and AE for integrating the medical committee. We also want to acknowledge the volunteers from the NOVA Sci & Tech Volunteer program that helped with the organisation of this project.

Funding

This work was supported by the CDG & Allies—Professionals and Patient Associations International Network (CDG&Allies-PPAIN) and by national funds from FCT—Fundação para a Ciência e a Tecnologia, I.P., in the scope of the Project UIDP/04378/2020 and UIDB/04378/2020 of the Research Unit on Applied Molecular Biosciences—UCIBIO, the Project LA/P/0140/2020 of the Associate Laboratory Institute for Health and Bioeconomy—i4HB C.P. and R.F. were funded by Fundação para a Ciência e Tecnologia with the Grants SFRH/BD/138647/2018 and (SFRH/BD/124326/2016) respectively.

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Authors and Affiliations

Authors

Contributions

VRF, PAV and LB developed the concept and design of this study. CP, IF, CT, EA and AS performed all the search methodology. CP, IF, CT and EA also performed results analysis and the writing of this manuscript. SB, RF, ANL, EM, HP, JJ, PAV, LB and VRF critically revised the manuscript for important intellectual content. All authors gave final approval of the version to be published.

Corresponding author

Correspondence to V. dos Reis Ferreira.

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Ethics approval and consent to participate

Participants voluntarily agreed to participate in the study after informed consent.

Consent for publication

Not applicable.

Competing interests

Horacio Plotkin declares a financial interest as an employee for Glycomine, Inc, which might be considered as a competing interest. The other authors declare that they have no known competing interests.

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Supplementary Information

Additional file 1

. Supplementary information of the methodology and results of the study: additional information concerning the semi-structured interviews guide (Table 1), the demographics of interviewed patients (Table 2), search keywords (Table 3) and the list of references of the included QoL tools (Table 4).

Additional file 2

. Data collection sheet of semi-structured interviews and respective results.

Additional file 3

. Quality assessment of included questionnaires.

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Pascoal, C., Ferreira, I., Teixeira, C. et al. Patient reported outcomes for phosphomannomutase 2 congenital disorder of glycosylation (PMM2-CDG): listening to what matters for the patients and health professionals. Orphanet J Rare Dis 17, 398 (2022). https://doi.org/10.1186/s13023-022-02551-y

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Keywords

  • Outcome assessment
  • Patient reported outcomes
  • Observer reported outcomes
  • Quality of life
  • Rare diseases
  • PMM2-CDG
  • People-centricity