The PompeQoL questionnaire: Development and validation of a new measure for children and adolescents with Pompe disease.

Genetic disorders pose great challenges for affected individuals and their families, as they must cope with the irreversible nature of the disease and a life-long dependence on medical assistance and treatment. Children and adolescents dealing with Pompe disease (PD) often struggle to keep up with their peers in physical activities. To gain valuable insights into their subjective experiences and better understand their perception and coping related to daily challenges linked to their condition and treatment, the use of standardized questionnaires is crucial. This study introduces the novel PompeQoL 1.0 questionnaire for children and adolescents with PD, designed for comprehensive assessment of both disease-specific FDH and HRQoL through self- and proxy reports. Content validity was ensured through patients' and parents' involvement at the initial stages of development and in subsequent cognitive debriefing process. Participants found the questionnaire easy to understand, answerable, relevant, and comprehensive. Adjustments based on feedback from patients and their parents improved its utility as a patient- and observer-reported outcome measure. After careful item examination, 52 items were selected, demonstrating moderate to excellent test-retest reliability for most scales and initial evidence for satisfactory construct validity. The PompeQoL questionnaire stands as a valuable screening instrument for both clinical and research purposes. Future research should prioritize additional revisions and larger validation studies, focusing on testing the questionnaire in clinical practice and trials. Nevertheless, the PompeQoL 1.0 stands out as the first standardized measure providing insights into disease-specific FDH and HRQoL among children and adolescents with various forms of PD.

Development of an observer-reported outcome measure to capture the signs and impact of fever distress symptoms in infants and young children.

PURPOSE: This qualitative study aimed to construct an observer-reported outcome measure (ObsRO) to evaluate fever distress in young children. METHODS: A literature review was conducted to identify fever-related concepts. Clinical experts were interviewed for feedback on these concepts. Parents of young children were interviewed to identify behaviours the child exhibited during a recent fever episode. Fever sign and behaviour concepts endorsed by ≥ 20% parents were used to create items for the draft ObsRO. Parents of young children who recently had fever completed the ObsRO and gave feedback during two successive rounds of cognitive interviews. RESULTS: Twenty-five parents participated in the concept elicitation. Mean child age was 2.7 years (range: 0.6-5.8 years). Fever sign and behaviour concepts endorsed by ≥ 20% participants were high temperature (80%), skin hot to touch (32%), skin redness/flushing (32%), reduced appetite/drink (96%), needy/clingy/irritable (48-92%), less active/interactive (68-84%) and lethargic (64-88%). Eighteen items, four in the Fever Signs Module and 14 in the Fever Behaviours Module, were developed for the draft ObsRO. Chosen recall period was 24 h. Thirty participants (Round 1: n = 17; Round 2: n = 13), participated in cognitive interviews. Mean child age was 2.4 years (range 0.3-5.8). Round 1 feedback resulted in two Fever Signs items being combined. Three Fever Behaviour items were deleted, six revised and four unchanged. No changes were made following Round 2 feedback. Most participants understood all aspects of the ObsRO and found it user-friendly. CONCLUSION: The ObsRO will undergo further development in validation studies testing measurement properties of each item.

Infant with Clefts Observation Outcomes Instrument (iCOO): A New Outcome for Infants and Young Children with Orofacial Clefts.

OBJECTIVE: We evaluated the measurement properties for item and domain scores of the Infant with Clefts Observation Outcomes Instrument (iCOO). DESIGN: Cross-sectional (before lip surgery) and longitudinal study (preoperative baseline and 2 days and 2 months after lip surgery). SETTING: Three academic craniofacial centers and national online advertisements. PARTICIPANTS: Primary caregivers with an infant with cleft lip with or without cleft palate (CL ± P) scheduled to undergo primary lip repair. There were 133 primary caregivers at baseline, 115 at 2 days postsurgery, and 112 at 2 months postsurgery. MAIN OUTCOME MEASURE(S): Caregiver observation items (n = 61) and global impression of health and function items (n = 8) across eight health domains. RESULTS: Mean age at surgery was 6.0 months (range 2.7-11.8 months). Five of eight iCOO domains have scale scores, with Cronbach's alphas ranging from 0.67 to 0.87. Except for the Facial Skin and Mouth domain, iCOO scales had acceptable intraclass correlation coefficients (ICCs) ranging from 0.76 to 0.84. The internal consistency of the Global Impression items across all domains was 0.90 and had acceptable ICCs (range 0.76-0.91). Sixteen out of 20 (nonscale) items had acceptable ICCs (range 0.66-0.96). As anticipated, iCOO scores 2 days postoperatively were generally lower than baseline and scores 2 months postsurgery were consistent with baseline or higher. The iCOO took approximately 10 min to complete. CONCLUSIONS: The iCOO meets measurement standards and may be used for assessing the impact of cleft-related treatments in clinical research and care. More research is needed on its use in various treatment contexts.

Caregiver Observations of Infant Well-Being Before and After Cleft Lip Surgery.

OBJECTIVE: To evaluate the sensitivity to change of daily ratings of the comfort (COMF) and behavioral/emotional health (BEH) domains of the Infants with Clefts Observation Outcomes Instrument (iCOO) at 3 time points, and to assess the association of post-surgical interventions on iCOO ratings. DESIGN: The COMF and BEH domains were completed by caregivers before (T0), immediately after (T1), and 2-months after (T2) cleft lip (CL) surgery. Analyses included descriptive statistics, correlations, t-tests, and generalized estimating equations. PARTICIPANTS: Caregivers (N = 140) of infants with CL with/without cleft palate. MAIN OUTCOME MEASURES: The COMF and BEH domain scores of the iCOO: Scale (SCALE), a summary of observable signs; and Global Impression (IMPR), a single item measuring caregivers' overall impression. RESULTS: Daily COMF and BEH SCALE and IMPR scores changed significantly during T1 (P's < 0.001) but not T0 or T2. Day 1 and 7 T0 scores were significantly higher than Day 1 and 7 T1 scores (P's <0.001 to <0.012) but similar at T2 (P's > 0.05). After CL surgery, the combined use of immobilizers and nasal stents and the use of multiple feeding methods with treatment for gastroesophageal reflux were associated with lower daily scores in COMF and BEH SCALE and IMPR (P's: 0.040 to <0.001). CONCLUSIONS: COMF and BEH iCOO scores were sensitive to daily changes in infant well-being following CL surgery. Future studies should further investigate impact of post-surgical treatments on infant well-being.

Assessing physical symptoms, daily functioning, and well-being in children with achondroplasia.

This study's purpose was to provide qualitative evidence to support the development of two observer-reported outcome measures assessing the physical symptoms/complications of achondroplasia in children and impacts on children's quality of life. Individual/focus group concept elicitation interviews were conducted with parents of children aged 2 to <12 years with achondroplasia and experts. Qualitative analysis of transcripts, based on an adapted grounded theory approach, informed item generation and measure development. Cognitive debriefing (CD) interviews were conducted with parents to confirm relevance and understanding. Thirty-six parents participated in concept elicitation interviews. The analysis identified major physical symptoms/complications and impacts of achondroplasia, which informed the development of the Achondroplasia Child Experience Measures (ACEMs): ACEM-Symptom and ACEM-Impact. ACEM-Symptom was comprised of eight major symptoms/complications including pain (58%), ear infections/fluid in ear (56%), and low stamina/tiring easily (56%). ACEM-Impact consisted of 31 major impacts in the domains of daily functioning, emotional well-being, social well-being, and need for assistance/adaptive devices. Impacts on functioning included difficulty reaching objects/high places (89%) and toileting (67%). Emotional impacts included feeling different (53%) and feeling frustrated/annoyed (47%). Social impacts included difficulty participating in sports/physical play (86%) and being treated as younger than age (83%). Following CD interviews with 16 additional parents, validation-ready ACEM measures were generated. The study improves our understanding of the experiences of children with achondroplasia and provides evidence supporting the content validity of the ACEMs. Validated ACEMs may be used to assess potential benefits of future treatments for comorbidities of achondroplasia.

Content validity of a novel patient-reported and observer-reported outcomes assessment to evaluate ocular symptoms associated with infectious conjunctivitis in both adult and pediatric populations.

BACKGROUND: Acute infectious conjunctivitis is a common condition most frequently caused by viruses or bacteria. Clinical outcome assessments have been used to assess signs and symptoms of bacterial and viral conjunctivitis, but have not been evaluated for content validity. We aimed to develop content-valid patient- (PRO) and observer-reported outcome (ObsRO) instruments to assess symptoms of ocular discomfort associated with viral or bacterial conjunctivitis in adult and pediatric patients. METHODS: Draft items were developed from a previous review of published studies from 2001 to 2015. Patients and caregivers of patients with a diagnosis of viral or bacterial conjunctivitis within the past 6 months were recruited. Concept elicitation with open-ended questions explored signs and symptoms, followed by cognitive interviewing to assess clarity and relevance of the draft items. Patients aged ≥8 years were interviewed for the PRO; parents/caregivers of children aged 1-10 years were interviewed for the ObsRO. Interviews were conducted in three rounds to allow changes. Concept saturation was documented using a saturation grid. Cognitive interview data were analyzed iteratively and focused on clarity, relevance and inconsistent interpretation of the instrument's content. RESULTS: Overall, 23 patients or parents/caregivers participated (round 1, n = 10; round 2, n = 6; round 3, n = 7). Data saturation was reached by the 16th interview. The most frequent spontaneously reported signs/symptoms were: discharge, red/pink eyes, itchiness, swelling/puffiness, watery eyes, pain, burning and foreign body sensation. Itching, pain/burning/stinging and foreign body sensation were most commonly reported as the top three most bothersome symptoms. Interview results indicated that items on pain, itching and foreign body sensation for the PRO and pain or discomfort for the ObsRO were relevant to the patients' experience of conjunctivitis and were clear and easy to understand. CONCLUSIONS: PRO and ObsRO items were found to be clear, relevant and appropriate in assessing key viral and bacterial conjunctivitis symptoms in adult and pediatric patients.

Psychometric Assessment of the Rett Syndrome Caregiver Assessment of Symptom Severity (RCASS).

Rett syndrome is a severe neurodevelopmental disorder that affects about 1 in 10,000 females. Clinical trials of disease modifying therapies are on the rise, but there are few psychometrically sound caregiver-reported outcome measures available to assess treatment benefit. We report on a new caregiver-reported outcome measure, the Rett Caregiver Assessment of Symptom Severity (RCASS). Using data from the Rett Natural History Study (n = 649), we examined the factor structure, using both exploratory and confirmatory factor analysis, and the reliability and validity of the RCASS. The four-factor model had the best overall fit, which covered movement, communication, behavior, and Rett-specific symptoms. The RCASS had moderate internal consistency. Strong face validity was found with age and mutation type, and convergent validity was established with other similar measures, including the Revised Motor-Behavior Assessment Scale, Clinical Severity Scale, Clinical Global Impression Scale, and the Child Health Questionnaire. These data provide initial evidence that the RCASS is a viable caregiver-outcome measure for use in clinical trials in Rett syndrome. Future work to assess sensitivity to change and other measures of reliability, such as test-retest and inter-rater agreement, are needed.

The development of an archive of patient-reported outcome measures (PROMs) in oncology: The Italian PRO4All project.

BACKGROUND: Choosing the most adequate measure of patient-reported outcomes (PROs) for a specific medical condition is not straightforward. This study aimed to develop a comprehensive archive of patient-reported outcome measures (PROMs), observer-reported outcome measures (ObsROMs) and caregiver-reported outcome measures (CROMs) in oncology and identify their main characteristics and target outcome domains. MATERIALS AND METHODS: As part of the Italian PRO4All Project, we retrieved questionnaires through an extensive search of online databases. We developed a data extraction form to collect information on cancer type, questionnaire variant(s), recall period, and scoring system. We performed a content analysis of the questionnaires to assign each item a specific outcome domain according to a predefined 38-item taxonomy. RESULTS: A total of 386 PROMs (n = 356), ObsROMs (n = 13) and CROMs (n = 17) were identified and described; of these, 358 were also analyzed in their content. 47.3 % of the instruments were cancer type-specific, 45.1 % were generic for cancer and 7.9 % were developed for the general population but also recommended in oncology. The great majority (92.2 %) were patient-reported. In 50.3 % the recall period was "last week". The mean number of items per questionnaire was 22.0 (range: 1-130). 7794 items were assigned an outcome domain, the most frequent being emotional functioning/wellbeing (22 %), physical functioning (15.7 %), general outcomes (10.1 %) and delivery of care (8.9 %). CONCLUSIONS: There are a variety of patient and caregiver-reported measures in oncology. This archive can guide researchers and practitioners in selecting the most suitable measures and fostering a patient-centered approach in clinical trials, clinical practice, and regulatory activities.

Development of patient- and observer-reported outcome measures to assess COVID-19 signs and symptoms in children and adolescents.

BACKGROUND: The Symptoms of Infection with Coronavirus-19 (SIC) is a 30-item patient-reported outcome measure to evaluate the presence and severity of COVID-19 signs/symptoms in adults. This study expanded the context of use of the adult SIC among adolescents aged 12-17 years and supported a pediatric adaptation (the Pediatric SIC [PedSIC]) for caregiver assessment of signs/symptoms in children aged < 12 years. METHODS: Draft versions of the PedSIC and reference materials containing sign/symptom definitions for adolescents, based on an assessment of the reading level of SIC items by a professional linguist, were developed to facilitate accurate completion of the SIC by adolescents and observer-report (PedSIC) by caregivers. For adolescents, reference materials were intended to provide definitions for selected signs/symptoms identified to have a higher reading level. Iterative rounds of cognitive debriefing interviews were conducted from November 2020 to January 2021 to evaluate adolescent understanding of the SIC reference materials and inform refinement of the PedSIC for caregivers of children too young to reliably self-report. Participants were identified via databases of individuals who previously expressed interest in participating in qualitative research and were then screened for eligibility. Recruitment quotas were established to improve sample diversity. Thematic analysis and descriptive statistics were used to assess qualitative and demographic data, respectively. RESULTS: Nine healthy adolescents (mean [SD, range] age, 14 [1.76, 12-17] years, 56% female, 22% non-White; round 1, n = 6; round 2, n = 3) and 17 caregivers (mean [SD, range] age, 34 [6.28, 26-41] years, 59% female, 35% non-White; round 1, n = 9; round 2, n = 8) were interviewed. Adolescents understood the majority of signs/symptoms (22 of the 30 SIC items) without assistance or use of the reference materials during the cognitive debriefing interview. Definitions were added to the reference materials for 5 additional items, and clarifications provided to existing definitions for 3 items. Seven observer-report (PedSIC) items were modified following feedback from caregivers of healthy young children. Reference materials (similar to those for adolescent use) were developed to support caregiver understanding of the intent of the PedSIC items collecting input from children ages ≥ 5- < 12 years. CONCLUSIONS: Results support using the SIC, PedSIC, and their associated reference materials to evaluate the presence and severity of COVID-19 signs/symptoms in adolescents and children aged < 12 years via caregiver-supported report, respectively.

Evaluation of Measurement Properties of Supportive Environment Assessment Scales for Dementia Special Care Units: A COSMIN Systematic Review.

OBJECTIVES: To identify, critically appraise, compare, and summarize the measurement properties of existing instruments that assess the supportive environment of dementia special care units (DSCUs). DESIGN: Systematic review of measurement properties consistent with Consensus-based standards for the selection of health measurement instruments (COSMIN) guidelines. SETTINGS AND PARTICIPANTS: PubMed, Embase, Web of Science, CINAHL, CNKI, Wanfang, VIP, and SinoMed were searched from inception to July 21, 2023. Studies that (1) measured the supportive environment for DSCUs using any type of assessment instrument and (2) evaluated 1 or more psychometric properties of a DSCU's supportive environment assessment instruments were included. METHODS: Two reviewers independently screened, selected, extracted data, and assessed risk of bias. RESULTS: Fourteen studies were identified that reported the psychometric properties of 8 assessment instruments. The Therapeutic Environment Screening Survey for Nursing Homes (TESS-NH) exhibited relatively better results on methodological risk of bias and quality of the psychometric properties. None of the instruments reported the evaluations on hypothesis testing, cross-cultural validity/measurement invariance, measurement error, or responsiveness. Based on the summary of 32 dimensions from 8 assessment instruments, this review established 7 functional constructs for the supportive environment for DSCUs: safety maintenance, space design, external resources, sensory stimulation, humanistic care, residual function development, and professional care. In addition, this study also initially developed a conceptual framework for the supportive environment of DSCUs. CONCLUSION AND IMPLICATIONS: TESS-NH received the rating of "best methodological quality" and outperformed other weakly recommended scales. Further studies should pay attention to developing or revalidating scales for assessing the supportive environment of DSCUs in large multicenter samples following the COSMIN methodology. Furthermore, the conceptual framework for the DSCU supportive environment will provide a theoretical reference for facilitating their hierarchical establishment and governance within diverse long-term care facilities by state authorities.

Psychometric Validation of the ViSIO-PRO and ViSIO-ObsRO in Retinitis Pigmentosa and Leber Congenital Amaurosis.

INTRODUCTION: Retinitis Pigmentosa (RP) and Leber Congenital Amaurosis (LCA) are rare inherited retinal degenerative disorders. The Visual Symptom and Impact Outcomes patient-reported outcome (ViSIO-PRO) and observer-reported outcome (ViSIO-ObsRO) instruments were developed in this population to assess visual function symptoms and impacts on vision-dependent activities of daily living (ADL) and distal health-related quality of life (HRQoL). This study aimed to explore the psychometric properties of the ViSIO-PRO and ViSIO-ObsRO in RP/LCA. METHODS: The 49-item ViSIO-PRO and 27-item ViSIO-ObsRO instruments were completed by 83 adult and adolescent patients and 22 caregivers of child patients aged 3-11 years with RP/LCA, respectively, at baseline and 12-16-day follow-up. Concurrent measures were also administered at baseline. Psychometric analyses assessed item (question) properties, dimensionality, scoring, reliability, validity, and score interpretation. RESULTS: Item responses were mainly evenly distributed across the response scale, and inter-item correlations were mostly moderate to strong (> 0.30) at baseline within hypothesized domains. Item deletion was informed by item properties, qualitative data, and clinical input and supported retention of 35 ViSIO-PRO items and 25 ViSIO-ObsRO items. Confirmatory factor analysis in line with pre-hypothesized domains supported a four-factor model assessing visual function symptoms, mobility, vision-dependent ADL, and distal HRQoL. A bifactor model supported calculation of total scores and four domain scores. Internal consistency was high for domain and total scores (Cronbach's alpha > 0.70) and test-retest reliability for total scores was strong between baseline and 12-16-day follow-up (intraclass correlation coefficients 0.66-0.98). Convergent validity was supported by strong correlations in a logical pattern with concurrent measures. Mean baseline scores differed significantly between severity groups. Distribution-based methods provided initial insights to guide interpretation of scores. CONCLUSIONS: Findings supported item reduction and established scoring of the instruments. Evidence of reliability and validity as outcome measures in RP/LCA was also reported. Further research is ongoing to explore responsiveness of the ViSIO-PRO and ViSIO-ObsRO instruments and interpretation of change scores.

The Amblyopia Quality of Life (AmbQoL): Development and Content Validation of a Novel Health-Related Quality of Life Instrument for Use in Adult and Pediatric Amblyopia Populations.

INTRODUCTION: Amblyopia is a neurodevelopmental vision disorder, characterized by poor vision in one or both eyes. Given the lack of existing clinical outcome assessments (COA) considered fit-for-purpose for amblyopia clinical trials, this study developed new COAs to assess amblyopia symptoms and health-related quality of life (HRQoL) impacts in adult and pediatric amblyopia populations that conform with best practice standards and regulatory guidelines. METHODS: Findings from a targeted qualitative literature review informed the development of three versions of the new Amblyopia Quality of Life Questionnaire (AmbQoL): a patient-reported outcome measure (PRO) for individuals aged 13 years and older, a PRO for children aged 9-12 years, and an observer-reported outcome measure (ObsRO) for caregivers of children aged 4-8 years. Qualitative interviews were conducted with the target populations, and with ophthalmologists experienced in treating amblyopia patients to evaluate the content validity for further development of the AmbQoL. A translatability assessment was conducted to ensure cultural appropriateness and usability across multiple languages. Feedback from Food and Drug Administration (FDA) was also sought on the instruments, and clinical experts provided input at key stages. RESULTS: Interviews were conducted with 112 patients/caregivers and ten ophthalmologists from the USA, France, and Germany. The instructions, items, and response options were well understood across all AmbQoL versions. Feedback from the patients, caregivers, ophthalmologists, the translatability assessment, the FDA, and the expert clinicians informed minor wording modifications to enhance clarity and translatability. Some items were removed due to low relevance. The study resulted in a 23-item adult/adolescent PRO, 24-item child PRO, and 12-item ObsRO, each employing a 7-day recall period. CONCLUSION: Each AmbQoL version has documented support for its face and content validity for use in amblyopia populations aged ≥ 4 years. Further research is necessary to evaluate the psychometric measurement properties of the AmbQoL instruments to enable their use in amblyopia treatment trials.

Measuring dengue illness intensity: Development and content validity of the dengue virus daily diary (DENV-DD).

BACKGROUND: Dengue is the most prevalent arboviral infection causing an estimated 50-60 million cases of febrile illness globally per year, exacting considerable disease burden. Few instruments exist to assess the patient illness experience, with most based on healthcare provider assessment, lacking standardization in timepoints and symptom assessment. This study aimed to evaluate the content validity of the novel 'Dengue Virus Daily Diary (DENV-DD)', designed to measure symptom intensity and disease burden within outpatient infant to adult populations. METHODS: The Dengue Illness Index Report Card was used as a foundation to create the DENV-DD, consisting of patient- and observer-reported outcome (PRO/ObsRO) instruments. In two South American dengue-endemic communities, qualitative combined concept elicitation and cognitive debriefing interviews were conducted among individuals and caregivers of children with symptomatic laboratory-confirmed dengue. Interviews were conducted across two rounds allowing DENV-DD modifications. A small-scale quantitative assessment of the DENV-DD was also conducted with data from an independent Dengue Human Infection Model (DHIM) to generate early evidence of feasibility of DENV-DD completion, instrument performance and insight into the sign/symptom trajectory over the course of illness. RESULTS: Forty-eight participants were interviewed (20 adults, 20 older children/adolescents with their caregivers, 8 caregivers of younger children). A wide spectrum of signs/symptoms lasting 3-15 days were reported with fever, headache, body ache/pain, loss of appetite, and body weakness each reported by > 70% participants. DENV-DD instructions, items and response scales were understood, and items were considered relevant across ages. DHIM data supported feasibility of DENV-DD completion. CONCLUSIONS: Findings demonstrate content validity of the DENV-DD (PRO/ObsRO instruments) in dengue-endemic populations. Psychometric and cultural validity studies are ongoing to support use of the DENV-DD in clinical studies.

Dengue is the most common viral infection transmitted to humans by mosquitos, and affects an estimated 50­60 million individuals globally per year. However, there are few resources for understanding and capturing the patient experience of dengue throughout illness. Most research studies are based on healthcare provider assessment, which lack consistency in terms of assessment time points and the signs/symptoms assessed. The 'Dengue Illness Index Report Card (DII-RC)' was used as a foundation to create the new 'Dengue Virus Daily Diary (DENV-DD)' to better capture the patient experience of symptom intensity and dengue disease burden for the duration of illness. Forty-eight individuals and caregivers of younger children from Peru and Ecuador who recently had symptomatic dengue were interviewed to understand the patient experience over the time of illness and to test whether the DENV-DD is understood by patients and caregivers and includes all relevant and important signs/symptoms and health-related quality of life impacts. Nine individuals with active dengue infection also completed the DENV-DD daily for 28-days as part of a clinical study. We found that > 70% of patients experienced fever, headache, body ache/pain, loss of appetite and body weakness. The DENV-DD instructions, questions and response option(s) were well understood, feasible to complete and the concepts assessed by the DENV-DD were relevant to the dengue experience. Our study adds to the understanding of the dengue illness experience and supports the DENV-DD for use in future dengue studies as an assessment of signs/symptoms throughout the duration of illness.

Assessing asthma symptoms in children: qualitative research supporting the development of the Pediatric Asthma Diary-Child (PAD-C) and Pediatric Asthma Diary-Observer (PAD-O).

BACKGROUND: Pediatric asthma has been identified by regulators, clinicians, clinical trial sponsors, and caregivers as an area in need of novel fit-for-purpose clinical outcome assessments (COAs) developed in accordance with the U.S. Food and Drug Administration's (FDA's) regulatory guidance for evaluating clinical benefit in treatment trials. To address this gap, the Patient-Reported Outcome (PRO) Consortium's Pediatric Asthma Working Group has continued development of 2 COAs to assess asthma signs and symptoms in pediatric asthma clinical trials to support efficacy endpoints: a PRO measure, the Pediatric Asthma Diary-Child (PAD-C) for children 8-11 years old (y.o.) and an observer-reported outcome measure, the Pediatric Asthma Diary-Observer (PAD-O) for caregivers of children 4-11 y.o. This qualitative research aimed to generate evidence regarding the content validity of the PAD-C and PAD-O. METHODS: Semi-structured combined concept elicitation and cognitive interviews were conducted with a diverse sample of U.S. participants (15 children 8-11 y.o. and 30 caregivers of children 4-11 y.o.). All children had clinician-diagnosed mild to severe asthma. Interviews explored the experience of pediatric asthma and assessed the understanding and relevance of both measures. Interviews were conducted across 3 iterative rounds to allow for modifications. RESULTS: Concept elicitation findings demonstrated that the core sign/symptom and impact concepts assessed in the PAD-C (cough, hard to breathe, out of breath, wheezing, chest tightness, and nighttime awakenings/symptoms) and PAD-O (cough, difficulty breathing, short of breath, wheezing, and nighttime awakenings/signs) correspond to those most frequently reported by participants; concept saturation was achieved. All PAD-C and PAD-O instructions and core items were well understood and considered relevant by most participants. Feedback from participants, the Pediatric Asthma Working Group, advisory panel, and FDA supported modifications to the measures, including addition of 1 new item to both measures and removal of 1 caregiver item. CONCLUSIONS: Findings provide strong support for the content validity of both measures. The cross-sectional measurement properties of both measures and their user experience and feasibility in electronic format will be assessed in a future quantitative pilot study with qualitative exit interviews, intended to support the reliability, construct validity, final content, and, ultimately, FDA qualification of the measures.

Pediatric asthma is one of the most common chronic diseases in children. However, there are problems of underdiagnosis, poor disease management, and undertreatment for many pediatric asthma patients, pressuring healthcare systems worldwide. Evaluating asthma symptoms is an important part of the development of treatments for pediatric asthma. However, there are few clinical outcome assessments (COAs) developed in line with regulatory guidance to directly assess symptom severity and evaluate the benefit of new treatments in children with asthma. In this study, we continued the development of the Pediatric Asthma Diary­Child (PAD-C) and the Pediatric Asthma Diary­Observer (PAD-O), according to regulatory guidance, to assess asthma signs and symptoms in children 4 through 11 years old and address this unmet need. The study aimed to explore the experience of pediatric asthma and assess how well-understood and relevant the measures are. Three rounds of qualitative interviews were conducted with 15 children 8 through 11 years old and 30 caregivers of children 4 through 11 years old with asthma. Results show that both measures are well-understood and assess the relevant and important aspects of pediatric asthma reported by children and caregivers. Findings provide evidence supporting the PAD-C and PAD-O as measures of symptom severity and their future use in pediatric asthma treatment trials. Further research is underway to evaluate their measurement properties and assess the user experience and feasibility of electronic completion, to ultimately support the PAD-C and PAD-O in an ongoing COA qualification process by the United States Food and Drug Administration.

Qualitative exploration of the visual function impairments and impacts on vision-dependent activities of daily living in Retinitis Pigmentosa and Leber Congenital Amaurosis: content validation of the ViSIO-PRO and ViSIO-ObsRO measures.

BACKGROUND: Retinitis Pigmentosa (RP) and Leber Congenital Amaurosis (LCA) are rare inherited retinal degenerative disorders. The associated visual impairments have significant impacts on patients' vision-dependent activities of daily living (ADL), mobility, and distal health-related quality of life (HRQoL). To adequately capture patient and caregiver perspectives in clinical trials, patient and observer-reported outcome instruments must demonstrate sufficient evidence of content validity in the target population. This study aimed to explore the patient experience of RP/LCA and assess the content validity of the Visual Symptom and Impact Outcomes PRO (ViSIO-PRO) and ObsRO (ViSIO-ObsRO) instruments in RP/LCA. METHODS: A total of 66 qualitative, combined concept elicitation (CE) and cognitive debriefing (CD) interviews were conducted (33 adults, 10 adolescents, 8 children and 15 caregivers of children) in the US, France, Germany, and Canada. Patients had a clinical and genetic diagnosis of RP/LCA from a range of genotypes. CE results were used to further inform the development of a conceptual model and CD interviews assessed the relevance and understanding of the 44-item ViSIO-PRO and 26-item ViSIO-ObsRO instruments. Interviews were conducted across two iterative rounds to allow item modifications. RESULTS: Findings were consistent across RP/LCA genotypes. Night blindness, reduced peripheral vision, vision in very bright lighting and light/dark adaptation were the most frequently reported visual function symptoms impacting vision-dependent ADL and mobility. Impacts on distal HRQoL domains were also reported. The ViSIO-PRO and ObsRO items were well understood by participants and relevant across genotypes. The instructions, 7-day recall period and response scales were well understood and endorsed. Participant and expert clinician feedback supported modifications to item wording, the addition of six new ViSIO-PRO items and one new ViSIO-ObsRO item, and the removal of one ViSIO-PRO item due to lack of relevance. CONCLUSIONS: Findings support the content validity of the ViSIO-PRO and ViSIO-ObsRO instruments for use across RP/LCA genotypes. Ongoing research to evaluate the psychometric validity of the instruments will support future use of the instruments as efficacy endpoints in clinical trials and in general clinical practice to track disease severity and impact of disease on functioning.

Development of Novel Patient-Reported Outcome (PRO) and Observer-Reported Outcome (ObsRO) Instruments in Retinitis Pigmentosa (RP) and Leber Congenital Amaurosis (LCA): ViSIO-PRO and ViSIO-ObsRO.

INTRODUCTION: Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are rare inherited retinal degenerative disorders resulting in visual impairments and impacts on patients' vision-dependent activities of daily living (ADL), mobility and distal health-related quality of life (HRQoL). This study aimed to conduct qualitative research to understand the patient experience of RP/LCA across genotypes and inform development of patient- and observer-reported outcome (PRO/ObsRO) instruments in RP/LCA. METHODS: Research activities included a qualitative literature review and review of existing visual function PRO instruments in RLBP1 RP, and concept elicitation (CE) and cognitive debriefing (CD) interviews of existing PRO instruments with patients with RLBP1 RP, expert clinicians, and payers. In wider RP/LCA, a social media listening (SML) study and a qualitative literature review was conducted, while psychometric evaluation of a PRO instrument in LCA was performed. Input from expert clinicians was sought at key stages. RESULTS: Findings from the qualitative literature reviews identified a range of visual function symptoms which had significant impacts on patients' vision-related ADL and distal HRQoL. Patient interviews identified additional visual function symptoms and impacts not previously reported in published literature. These sources informed development and refinement of a conceptual model displaying the patient experience of RP/LCA. Review of existing visual function PRO instruments, and CD interviews evaluating their content validity, confirmed that no existing instrument provides a comprehensive assessment of all concepts relevant to patients with RP/LCA. This highlighted the need for development of the Visual Symptom and Impact Outcomes PRO and ObsRO instruments to adequately assess the patient experience of RP/LCA. CONCLUSIONS: Results informed and supported development of the instruments to assess visual functioning symptoms and vision-dependent ADL, mobility and distal HRQoL in RP/LCA, in accordance with regulatory standards. Next steps to further support use in RP/LCA clinical trials/practice includes content and psychometric validation of the instruments in this population.

Content validity of a newly developed observer-reported measure for pediatric asthma in children aged 2-5 years.

BACKGROUND: An observer-reported outcome (ObsRO) measure assessing both symptom control and health-related quality of life (HRQoL) in children with asthma younger than 6 years is lacking. The objective of this study was to evaluate the content validity of the Pediatric Asthma Questionnaire (PAQ), a newly developed 6-item ObsRO measure for caregivers of children aged 2-5 years diagnosed with asthma. RESULTS: In-depth, qualitative interviews were conducted with 15 parents or caregivers. The first part of the interview was an open-ended discussion whereby participants were asked to describe their observations of their child's asthma symptoms and HRQoL impacts followed by a cognitive debriefing of a draft version of the PAQ. The most frequently reported symptoms were coughing (n = 15, 100%), wheezing (n = 14, 93%), and trouble breathing (n = 10, 67%). Overall, participants found the PAQ easy to complete and relevant to their child's experience with asthma, with most reporting the instructions, response scales, and recall period for the items to be appropriate. The majority of participants (93%) believed they could accurately report on the items included in the PAQ based on their observations of their child's asthma symptoms and impacts, or reliably get the information from the child's teacher, school, or caregiver when their child was not in their presence. One item was modified based on feedback about the phrase "oral steroids" to clarify modes of administration. A few other minor changes were incorporated into the PAQ following suggestions from participants, including replacing the phrase "how often" with "how many days" in one of the items to improve clarity and overall consistency with the response options. CONCLUSION: Qualitative data support the content validity of the PAQ as a fit-for-purpose and well-understood 6-item observer-reported outcome measure to evaluate both symptoms and asthma-specific HRQoL impacts experienced by pediatric asthma patients aged 2-5 years for use in clinical and real-world studies.

Novel Questionnaires for Assessing Signs and Symptoms of Eosinophilic Esophagitis in Children.

BACKGROUND: Pediatric patients with eosinophilic esophagitis (EoE) experience heterogeneous symptoms and the patient's age may preclude reliable self-report of symptoms. OBJECTIVE: The goal of this study was to develop a patient-reported outcome and an observer-reported outcome questionnaire to evaluate the signs and symptoms of EoE in pediatric patients (≥1 to <12 y of age) in a clinical trial setting. METHODS: A concept-focused literature review, expert advice meetings, and concept elicitation interviews with pediatric EoE patients and their caregivers were conducted to identify disease-related signs and symptoms. Instructions, items, and response options were drafted. Cognitive debriefing interviews were conducted to evaluate children's and caregivers' ability to understand and respond to the questionnaires and to evaluate the comprehensiveness of the concepts measured. RESULTS: Results from the literature review, expert advice meetings (n = 6), and concept elicitation interviews (n = 24) informed the development of the Pediatric Eosinophilic Esophagitis Sign/Symptom Questionnaire intended for use by patients (PESQ-P) with EoE 8 years or older to younger than 12 years and an observer-reported outcome questionnaire planned for use by caregivers of patients (PESQ-C) 1 year old or older to younger than 12 years. Both questionnaires measure the same concepts; the PESQ-P assesses the frequency, duration, and/or severity of symptoms and the PESQ-C assesses the presence/absence of the signs/symptoms. The cognitive debriefing interviews (n = 17) demonstrated that participants were able to comprehend and complete the questionnaires as intended. CONCLUSIONS: This study provides evidence of the content validity of 2 novel questionnaires, PESQ-P and PESQ-C, designed to evaluate the symptom experience of pediatric EoE patients in a clinical trial setting.

Good practices for the translation, cultural adaptation, and linguistic validation of clinician-reported outcome, observer-reported outcome, and performance outcome measures.

Within current literature and practice, the category of patient-reported outcome (PRO) measures has been expanded into the broader category of clinical outcome assessments (COAs), which includes the subcategory of PRO, as well as clinician-reported outcome (ClinRO), observer-reported outcome (ObsRO), and performance outcome (PerfO) measure subcategories. However, despite this conceptual expansion, recommendations associated with translation, cultural adaptation, and linguistic validation of COAs remain focused on PRO measures, which has created a gap in specific process recommendations for the remaining types. This lack of recommendations has led to inconsistent approaches being implemented, leading to uncertainty in the scientific community regarding suitable methods. To address this gap, the ISOQOL Translation and Cultural Adaptation Special Interest Group (TCA-SIG) has developed recommendations specific to each of the three COA types currently lacking such documentation to support a standardized approach to their translation, cultural adaptation, and linguistic validation. The recommended process utilized to translate ObsRO, ClinRO and PerfO measures from one language to another aligns closely with the industry standard process for PRO measures. The substantial differences between respondent categories across COA types require targeted approaches to the cognitive interviewing procedures utilized within the linguistic validation process, including the use of patients for patient-facing text in ClinRO measures, and the need to interview the targeted observers for ObsROs measures.

Development of a novel observer reported outcome tool as the primary efficacy outcome measure for a rare disease randomized controlled trial.

We developed an Observer-Reported Outcome (ObsRO) survey instrument to be applied in a multicenter, placebo-controlled, crossover randomized controlled trial of dichloroacetate in children with pyruvate dehydrogenase complex deficiency. The instrument quantifies a subject's at-home level of functionality, as reported by a parent/caregiver, who were instrumental in providing the clinical descriptors and domains that formed the instrument's content. Feasibility testing of the ObsRO tool showed it to be easy to use and comprehensive in capturing the major clinical functional limitations of affected children and requires less than 5min for a parent/caregiver to complete daily.