Observer-reported Outcome Measures Research Articles

Assessing Treatment Burden in Pediatric Hemophilia: Validation of the Observer-Reported Child Hemophilia Treatment Experience Measure (Child Hemo-TEM)

Background: Despite treatment safety and efficacy advancements for children with hemophilia (CwH), home treatment can be complicated and burdensome. Treatment burdens are major contributing factors to adherence issues. The Child Hemo-TEM is a patient-centric outcome measure developed following the United States (US) Food and Drug Administration guidance for patient-reported outcome measure development. Designed to assess the treatment burden for CwH, the measure is a caregiver observer-reported outcome (ObsRO) measure where questions are answered by the caregiver about the child's treatment experience based on what the caregiver has seen, heard, or been told by the child. Aim: The purpose of this study was to psychometrically validate the Child Hemo-TEM ObsRO. Methods: Data was collected through a cross-sectional, web survey from a population of caregivers of CwH aged 2 to < 12 years in the US. The survey consisted of the Child Hemo-TEM, sociodemographic items, child's hemophilia medical history, and supporting items/measures required to assess the measure's psychometric properties. The survey took up to 45 minutes to complete and was administered at a single time point. To be eligible for the study, caregivers needed to be: aged ≥ 18 years; a caregiver of a male child with a diagnosis of severe to moderate hemophilia A or B, with a factor level of < 2%, with or without an inhibitor, and currently receiving either prophylactic or on-demand treatment; and living in the same residence as the child over the past 2 weeks. Recruitment was conducted by a patient advocacy group and a professional market research firm. Recruitment quotas were targeted to ensure a diverse population and mix of frequency of prophylactic treatment(s) and treatment administration type. All psychometric analyses were conducted following an a-priori statistical analysis plan, which included examination of measurement characteristics, item reduction, factor analysis, measure scoring, internal consistency, reliability, and validity. Results: Caregivers ( n=187) of CwH completed the web survey. The respondents were, on average, 37.8 years of age, mothers (84.0%), and predominantly White/Caucasian (74.3%). Twelve items were dropped from the validation-ready, 19-item measure: 5 items due to high ceiling effects at baseline (>50%) mirrored by the Rasch results and 1 item as it was highly correlated with a retained item. Further, as there were only a small number of children who self-injected, 6 items designed to assess child self-injection were removed. The remaining items underwent further psychometric testing. An exploratory factor analysis generated a single, 7-item factor. The Child Hemo-TEM was found to be internally consistent with a Cronbach's α of 0.855. A-priori validity hypotheses were adapted to match the final factor structure. Hypothesized associations were predominantly confirmed with a few exceptions. For convergent validity (Pearson's r significance set at α = 0.05), a few of the associations, although significant, were below 0.30 (Table 1). The Child Hemo-TEM was able to discriminate between levels of self-complaining about their infusions (p < 0.001), psychological stress reported by parent (p < 0.001), and ease/difficulty of their medication in its current form, among other variables. Based on psychometric findings and taking into consideration learnings from the concept elicitation during measure development, the brief, 7-item Child Hemo-TEM was finalized with 1 domain capturing information from all the hypothesized concepts of treatment concerns (3 items), adherence (1 item), physical impact (1 item), and interference with daily life (2 items) (Figure 1). A five-point Likert response scale with ranges from “Never” to “Always”, or a “Don't know” option, is used. Conclusion: The Child Hemo-TEM ObsRO has been found to be conceptually sound with adequate evidence to support its reliability and validity. Incorporation of the measure into both clinical and research settings will help assess the pediatric patient's experience of living with hemophilia as well as aid clinicians in tailoring treatments to patient characteristics and situations. Future studies are needed to assess test-retest reproducibility, sensitivity to change, and meaningful change thresholds of this new measure.

Understanding Treatment Burden in Pediatric Hemophilia: Development of the Child Hemophilia Treatment Experience Measure (Child Hemo-TEM)

Background: Currently available hemophilia treatments have resulted in significant improvements in quality of life. However, children with hemophilia (CwH) may still experience considerable treatment burden due to technical, physical, logistical, and emotional aspects of treatment administration. Aims: The objective of the current study was to examine the treatment experiences of CwH with the aim of developing a patient-centered measure of hemophilia to assess treatment burden in CwH, in accordance with the United States Food and Drug Administration guidelines for patient-reported outcome (PRO) measure development. Methods: Concept elicitation (CE) data included a review of the current hemophilia literature and 1-1.5-hour interviews with 4 clinical experts, 25 CwH, and 25 caregivers of CwH. A clinical expert was defined as a hematologist or nurse who currently had at least a 50% patient load in hemophilia and had been providing care to CwH for ≥ 5 years. CwH had to: be male; be between the ages of 8 to < 12 years; have a diagnosis of hemophilia A or B, with or without an inhibitor, and a factor level of < 2%; and currently be receiving, by caregiver administering or self-administering (with or without assistance), either on-demand or prophylactic treatment for hemophilia via factor replacement therapy or a bypassing agent. For caregivers to be eligible, their CwH had similar eligibility criteria except that they had to be < 12 years of age. The child, caregiver, and clinician CE interview transcripts were analyzed using Dedoose software. The information was synthesized and coded based on grounded theory principles. Based on this analysis, a theoretical model of the treatment experiences of CwH was developed and items reflecting the major and minor aspects of, distal consequences, and modifiers to the experience were included. Items reflecting the major concepts were generated and cognitive debriefing (CD) was conducted with 12 children and 15 caregivers. Results: For the CE, the average age of the child participants was 9.6 years (median 10, range 8-11). Sixty-four percent ( n=16) of the sample was White/Caucasian, all had severe hemophilia, the majority ( n=23, 92%) had hemophilia A, and had been treated with factor for an average of 8.9 years (median 9, range 7-11). The average age of caregivers' CwH was 6.3 years (median 6, range 2-11). Forty-four percent of children ( n=11) were White/Caucasian, all had severe hemophilia, the majority ( n=22, 88%) had hemophilia A, and had been receiving treatment for an average of 6.0 years (median 5.5, range 2-11.5). The treatment experience issues most frequently reported by 50% or more by either or both child participants or caregivers of CwH were: Ease of Use: inserting the needle; Adherence: missing or delaying treatments and difficulty keeping track of schedule/remembering to do treatment; Emotional Impacts and Treatment Concerns: feeling nervous, anxious or scared; proud/good about oneself; emotionally resolved/used to treatment; and stress; Physical Impacts: pain and scarring/scar tissue; and Interference with Daily Life: needing to stop activities to do treatment (see Table 1 for list of issues reported by ≥ 10% of either one or both child or caregiver and percent endorsements). Based on the theoretical model (see Figure 1), a preliminary measure was generated, and the CD was completed. As a result of the CD, a decision was made to develop only a caregiver observer-reported outcome (ObsRO) measure to capture the experiences of children aged < 12 years. The decision to not develop a PRO was based on the interviews with children aged 10 to < 12 years, which resulted in 10 out of the 12 respondents using an incorrect timeframe when answering one or more items, about one-third answered one or more items related to the impact of a bleed and not their treatment, and over half of the children had issues with comprehension with one or more items and/or trouble navigating layout/skip pattern. Following CD, the validation-ready version of the measure, the Child Hemo-TEM, was finalized. Conclusion: This study has identified key aspects of the treatment experience of CwH, which support thecontent validity of the Child Hemo-TEM ObsRO. Compared to generic measures, condition- and age-specific instruments, should have greater face validity, be more responsive to change over time, and may be more useful to both clinicians and researchers to assess the hemophilia treatment burden of CwH.

Analysis of Hyperphagia Questionnaire for Clinical Trials (HQ-CT) scores in typically developing individuals and those with Prader-Willi syndrome

The Hyperphagia Questionnaire for Clinical Trials (HQ-CT) is an observer-reported outcome measure that has been widely used in interventional studies to assess changes in hyperphagic behaviors in individuals with Prader-Willi syndrome (PWS). However, HQ-CT scores in the wider PWS population and the general population have not been reported. Here we report HQ-CT scores from more than 400 individuals with PWS and 600 typical individuals, aged 5–26. Overall, HQ-CT scores were significantly higher in those with PWS compared to typically developing individuals at all ages evaluated. In addition, while HQ-CT scores in the typically developing population decreased with age, scores increased with age in PWS. To further understand the variability of HQ-CT scores in the PWS population, semi-structured interviews were conducted with caregivers of a small subset of adults with PWS who had unexpectedly low HQ-CT scores. These caregivers reported that strict adherence to a food routine, food security measures and supervised food preparation reduced the frequency and intensity of hyperphagic behaviors measured by HQ-CT. Thus, hyperphagic behaviors are captured by the HQ-CT for most individuals with PWS, but for some individuals residing in settings with highly structured food routines, HQ-CT scores may not fully reflect the extent of PWS-associated hyperphagia.

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)

BackgroundPediatric 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.MethodsSemi-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.ResultsConcept 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.ConclusionsFindings 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.

Qualitative Exploration of the Visual Function Impairments and Health-Related Quality of Life Impacts of Amblyopia in Adult and Pediatric Populations.

Amblyopia is a reduction in vision in one or both eyes due to impaired development of the visual pathway. This study explored the experience of amblyopia and treatment from the patient, caregiver, and clinician perspectives. A targeted literature review, including a review of social media listening (SML) studies, was conducted. Next, qualitative interviews were conducted with amblyopia patients, caregivers of children with amblyopia, and ophthalmologists with experience treating patients with amblyopia. The findings informed the development of a disease model. Amblyopia clinical experts provided input at key stages. Twelve data sources were reviewed, including qualitative studies in the literature and SML studies. Overall, 133 patients/caregivers were interviewed (23 adults, 16 adolescents, 47 child-caregiver dyads), plus 10 ophthalmologists from the United States, France, and Germany. Reduced visual acuity, impaired depth perception, impaired peripheral vision, and double vision were the most frequently reported symptoms. Amblyopia impacted daily activities (reading, using digital devices), the ability to move around, school/work (productivity, seeing the board in class), emotional well-being (frustration, sadness), and social functioning (difficulty socializing). Treatments, including patching and corrective lens, also impacted daily activities (using digital devices, sports/leisure), mobility (bumping into things), and work/school (tasks taking longer) as well as emotional well-being (embarrassment), and social functioning (bullying/stigma). The findings contribute valuable insights into the adult and pediatric experience of amblyopia from a multi-stakeholder perspective. The findings were used to critically assess existing clinical outcome assessments and supported the development of patient- and observer-reported outcome measures for use in amblyopia clinical trials.

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.

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. 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 13years and older, a PRO for children aged 9-12years, and an observer-reported outcome measure (ObsRO) for caregivers of children aged 4-8years. 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. 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. Each AmbQoL version has documented support for its face and content validity for use in amblyopia populations aged ≥ 4years. Further research is necessary to evaluate the psychometric measurement properties of the AmbQoL instruments to enable their use in amblyopia treatment trials.

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

BackgroundThe 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.MethodsDraft 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.ResultsNine 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.ConclusionsResults 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.

Return to Driving After Hip Arthroscopy: A Systematic Review and Meta-analysis.

Hip arthroscopy is an increasingly common procedure; however, recommendations for safely returning to driving after hip arthroscopy vary among surgeons. To systematically review and analyze the current available evidence on the optimal time to safely return to driving after hip arthroscopy. Systematic review; Level of evidence, 3. A systematic review and meta-analysis was performed in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Two authors independently conducted a literature search throughout August 2021 using the PubMed, Google Scholar, Embase, and Cochrane databases. A total of 1425 articles were reviewed, and 5 articles were included. All included articles used brake reaction time (BRT) as an observer-reported outcome measure. A meta-analysis was performed to compare pre- and postoperative BRT values. Study sample sizes and mean BRT values were collected per each included study. First, data were analyzed for the right and left hips combined; then, a subgroup analysis stratified by laterality was performed. The BRT values were divided according to time periods of measurement: preoperatively and 2, 4, 6, and 8 weeks postoperatively. The included studies evaluated safety to return to driving after hip arthroscopy in 160 patients. Of these, 142 patients were treated for femoroacetabular impingement, while 18 patients underwent hip arthroscopy for other diagnoses. The mean weighted age was 33.7 ± 9.0 years, 47.5% of the patients were female, and the right hip was affected in 71.2%. The preoperative range of BRT was 566 to 1960 ms, and postoperative BRT range was 567 to 1840 ms at 1 to 2 weeks and 523 to 1860 ms at 3 to 12 weeks. Meta-analysis found the studies to be moderately heterogenic (P = .06). There were no statistically significant differences in BRT between the preoperative period and at 2, 4, 6, and 8 weeks postoperatively. Return to driving is likely safe as early as 2 to 4 weeks after right-sided hip arthroscopy, and 2 weeks after a left-sided procedure, as driving performance returns to the preoperative level. CRD42021274460 (PROSPERO identifier).

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

BackgroundCongenital 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 methodsThis 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.ResultsTwenty-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.ConclusionIdentifying 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.

Development of the Patient- and Observer-Reported PRUCISION Instruments to Assess Pruritus and Sleep Disturbance in Pediatric Patients with Cholestatic Liver Diseases.

IntroductionUnderstanding how patients experience their disease is a vital step in optimal disease management, and patient- and observer-reported outcome (PRO and ObsRO, respectively) measures can add important details to clinical information that is obtained as novel treatments are developed. Instruments that measure meaningful symptoms and impacts from the perspective of pediatric patients with cholestatic liver disease or their caregivers are needed. This study aimed to identify salient concepts in pediatric cholestatic liver disease, develop novel PRO and ObsRO instruments, and establish the instruments’ content validity.MethodsRelevant signs, symptoms, and impacts of cholestatic liver disease were identified through a literature review, interviews with expert clinicians, and concept elicitation interviews with children and caregivers of children who had progressive familial intrahepatic cholestasis (PFIC), Alagille syndrome, biliary atresia, or primary sclerosing cholangitis. Additional cognitive debriefing interviews with patients and caregivers were performed to ensure that participants could understand the instructions, questions, and response scales of the PRO and ObsRO instruments, with modifications made as necessary to improve comprehension and/or usability.ResultsA total of 36 interviews with patients and caregivers were conducted. Pruritus and sleep disturbance (e.g., difficulty falling or staying asleep due to itch) were identified as the most problematic symptom and significant impact, respectively, of the pediatric cholestatic liver diseases assessed. The ObsRO and PRO instruments, called PRUCISION, focus on these key disease features in the morning and evening. Several modifications were made to the draft instruments following cognitive interviews. The final PRUCISION PRO and ObsRO measures are designed as an electronic diary to be completed twice daily. The response scales include pictorial, verbal, and numeric scales.ConclusionNovel PRO and ObsRO PRUCISION instruments were created that evaluate the patient experience of cholestatic pruritus in children with PFIC and other cholestatic liver diseases. The content validity of the PRUCISION instruments is established.

Understanding patient and caregiver perspectives using a dyad approach for data collection: A systematic review of the literature

Treatments outside of a clinical setting may be managed independently by the pediatric patient, independently by a caregiver, or by the patient and caregiver together. Best practices for pediatric clinical outcome assessment (COA) recommend patient-reported outcome (PRO) and/or observer-reported outcome (ObsRO) measures to assess the patient experience of a condition or its treatment. However, a dyad approach where patients and caregivers can complete assessments together may be useful for assessing a shared treatment experience that may not be adequately captured by a PRO and/or an ObsRO. A systematic, targeted literature review of empirical literature was conducted to identify and describe published studies detailing dyad patient-caregiver outcome reporting approaches. The search was run in the MEDLINE®, Embase, and PsycINFO® databases using the OvidSP platform and was limited to English-language studies published within 10 years of the conducted search on 28 September 2021, and 13 articles were selected for full-text review based on pre-specified criteria. Advantages and disadvantages for use of a dyad data collection approach are discussed. Though not appropriate for all settings, dyad data collection may be useful for situations where the best practice approach to measurement does not capture all relevant perspectives, or the use of PRO and ObsRO also does not comprehensively capture all relevant concepts. In following, it may offer a pragmatic solution that can minimize the use of proxy assessment and limit missing data, particularly in research involving a shared patient and caregiver treatment experience. Experience Framework This article is associated with the Staff & Provider Engagement lens of The Beryl Institute Experience Framework (https://www.theberylinstitute.org/ExperienceFramework). Access other PXJ articles related to this lens. Access other resources related to this lens.

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

BackgroundAn 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.ResultsIn-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.ConclusionQualitative 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.

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

This qualitative study aimed to construct an observer-reported outcome measure (ObsRO) to evaluate fever distress in young children. 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. Twenty-five parents participated in the concept elicitation. Mean child age was 2.7years (range: 0.6-5.8years). 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 24h. Thirty participants (Round 1: n = 17; Round 2: n = 13), participated in cognitive interviews. Mean child age was 2.4years (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. The ObsRO will undergo further development in validation studies testing measurement properties of each item.

Irregular sleep wake rhythm disorder (ISWRD) signs and symptoms reported directly from patients with dementia and caregivers

AbstractBackgroundSleep‐wake disturbances appear early in the course of Alzheimer’s disease (AD) and other dementias and are not uncommonly associated with disruption in circadian rhythms, such as Irregular Sleep‐Wake Rhythm Disorder (ISWRD; ICD‐10 code G47‐23). ISWRD is also associated with behavioural and functional symptoms. The objective of this study (E2006‐A001‐111; NCT04300569) was to identify signs and symptoms of ISWRD important to patients and caregivers of patients with dementia and ISWRD. The data informed a novel questionnaire, filling a measurement gap as no questionnaires specific to ISWRD in the AD population are available.MethodThis cross‐sectional, qualitative, non‐interventional, telephone study interviewed patients and their caregivers. Caregivers were interviewed apart from the patient; patients were interviewed with caregivers present. All participants were from the US; data were collected in English and Spanish. Interview transcripts were analysed using ATLAS.ti software.Result15 patient/caregiver dyads and 5 caregiver‐only subjects were interviewed. For the patient group (n=20; 5 not interviewed), mean age was 79.0 (8.3)y and 75% were male. For the caregiver group (n=20), mean age was 67.5 (14.5)y and 20% were male. Both caregivers and patients noted fragmented nighttime and daytime sleep‐wake patterns, but also reported functional consequences of ISWRD. Nighttime examples included waking, wandering, and refusing to go back to sleep. Daytime examples included falling asleep at inappropriate places; appearing sleepy; losing concentration due to sleepiness; sleepiness interfering with personal care and leisure activities; needing to postpone, change, or avoid activities due to sleepiness; adverse emotional impacts, and sundowning. Few differences in terms, or their meaning, were identified between language of data collection. Based on the differing quality of patient and caregiver reports, the potential for patient anosognosia, and the ability of caregivers to observe signs and behaviours, the data suggested a caregiver‐completed observer‐reported outcome (ObsRO) measure is most appropriate for ISWRD evaluation.ConclusionConcepts reported by patients and caregivers uncovered ISWRD observations and functional consequences appropriate for a novel ObsRO measure that can be used in future studies of ISWRD. Support: Eisai Inc.

Development of the SMA independence scale–upper limb module (SMAIS–ULM): A novel scale for individuals with Type 2 and non-ambulant Type 3 SMA

BackgroundThe amount of assistance required to perform daily activities for individuals with Type 2 and non-ambulant Type 3 spinal muscular atrophy (SMA) is often cited as meaningful for quality of life, and important to routinely assess. MethodsThe SMA Independence Scale (SMAIS), a patient-reported outcome measure for individuals with SMA aged ≥12 years, and an observer-reported outcome measure for caregivers of individuals aged ≥2 years, was developed and evaluated in two phases. In Phase 1, 30 draft items were developed following review of the literature. Semi-structured interviews were then conducted with individuals with SMA and caregivers to establish content validity, resulting in a 29-item measure. In Phase 2, classical test theory and Rasch measurement theory methods were used to examine the cross-sectional and longitudinal measurement performance of the SMAIS in two independent datasets. ResultsPhase 1 qualitative findings supported the relevance, acceptability, and comprehensibility of 29 items. In Phase 2, psychometric analyses indicated that the five response options were poorly discriminated and were thus collapsed to three options for subsequent analyses. Items showed statistical misfit, implying that the SMAIS was not assessing a single underlying construct. Based on conceptual evaluation of the items, and assessment of item performance, a more targeted 22-item upper limb score was derived. Reliability and validity analyses confirmed acceptable measurement properties of this score. ConclusionsQualitative and quantitative analyses support the use of the 22-item SMAIS–Upper Limb Module in individuals with Type 2 and non-ambulant Type 3 SMA, aged ≥2 years.

Content validation of observer-reported sickle cell pain diaries (SCPD-CS and SCPD-CN): results from interviews with caregivers

BackgroundPatients with sickle cell disease (SCD) experience daily pain and acute episodes known as sickle cell pain crises (SCPCs). The Sickle Cell Pain Diary-Caregiver Report (SCPD-C) is an observer-reported diary for use by caregivers of children ages < 12 years with SCD. This study reports on the content validity of the SCPD-C.MethodsThe SCPD-C was developed based on a literature review, measurement expert input, and a patient advisory board including clinicians. Three rounds of interviews (including both concept elicitation and cognitive debriefing methodologies) were conducted with caregivers of children with SCD aged < 12 to evaluate the content validity of the SCPD-C.ResultsAcross three rounds of interviews, caregivers confirmed concepts in the SCPD-C and described observed impacts that were important and were added. Overall, caregivers evaluated the SCPD-C as easy to understand, with some minor adaptations for clarity. Additionally, the diary was split into two versions based on the child’s age and school enrollment status (SCPD-CS for school-aged and SCPD-CN for non-school age children).ConclusionsCaregivers provided valuable input that led to important additions and changes to the measures. The SCPD-CS and SCPD-CN are appropriate and fit-for-purpose observer-reported outcome measures of SCPC-related pain frequency and severity, and impacts on health-related quality of life.

Measuring Meaningful Benefit-Risk Tradeoffs to Promote Patient-Focused Drug Development in Prader-Willi Syndrome: A Discrete-Choice Experiment.

Background. Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder causing quality of life impairments such as insatiable hunger (hyperphagia) and obesity. We explored caregivers’ willingness to assume treatment risk in exchange for reduced hyperphagia according to a PWS-validated observer-reported outcome measure. Methods. We partnered with PWS patient organizations to develop a discrete-choice experiment exploring caregivers’ benefit-risk tradeoffs for emerging PWS treatments. The treatment benefit was a reduction in hyperphagia (as measured by a 0-, 5-, or 10-point change on the Hyperphagia Questionnaire for Clinical Trials [HQ-CT]). Treatment risks included weight gain (none, 5%, 10%), added risk of skin rash (none, 10%, 20%), and risk of liver damage (none, 1 in 1000, 10 in 1000). Preference models were estimated using mixed logistic regression and maximum acceptable risk. We explored differences in preferences across familial caregivers of patients with and without hyperphagia. Results. Four hundred sixty-eight caregivers completed the online survey. The majority of caregivers reported that patients experienced hyperphagia (68%) and half of patients experienced obesity (52%). Caregivers of patients without hyperphagia were willing to accept greater weight gain (16.4% v. 8.1%, P = 0.004) and a higher risk of skin rash (11.7% v. 6.2% P = 0.008) as compared to caregivers of patients with hyperphagia. Caregivers of patients with hyperphagia would accept a higher risk of liver damage as compared to caregivers of patients without hyperphagia (11.9 out of 1000 v. 6.4 out of 1000, P = 0.04). Conclusions. This research demonstrates that caregivers are willing to accept risk in exchange for a five-point improvement on the HQ-CT, a smaller marginal improvement than had been previously classified as meaningful. Patient experience with hyperphagia is a modifier in how much risk caregivers will accept.

PRO1 Meaningful Change Thresholds for the Aberrant Behavior Checklist-Community Fragile X Syndrome (ABC-CFXS) in Children and Adolescents with FXS

The ABC-C is an observer-reported outcome measure that has been validated in individuals with intellectual disabilities and autism spectrum disorders. An FXS-specific domain structure of the ABC-C (henceforth the ABC-CFXS), which is more representative of the FXS phenotype, has been established. To aid score interpretation, a responder threshold (RT) representing individual patient-level change indicative of treatment benefit was established for three ABC-CFXS subscales (Social Avoidance [SA], Irritability, and Socially Unresponsive/Lethargic [SUL]) measuring the primary and key secondary endpoints in ZYN2-CL-016 (CONNECT-FX), a Phase 3 study of ZYN002 (transdermal cannabidiol) in FXS (NCT03614663). Anchor-based methods supplemented with visual plots were used to estimate the RT for change from Baseline to Week 12 in the three ABC-CFXS subscales. Anchors included domain-specific (DS) Caregiver Global Impression of Severity and Change (CaGI-S/C) items for DS behavioral problems as well as CaGI-S/C items for overall behavior (OB). Higher scores on the ABC-CFXS indicate more severe behavior problems. Identification of the amount of change on the CaGI-S/C representing meaningful change was informed by qualitative interviews with 25 caregivers of children with FXS. Caregivers of children with FXS reported that even small improvements in their child’s behavior would be meaningful. In the analyses (n=193), patients with a 1-category improvement on the CaGI-S DS and OB items had a mean (SD) change of -3.0 (2.96) and -3.6 (2.64), -9.8 (9.65) and -8.9 (9.43), and -5.4 (6.46) and -6.8 (6.92) points on the ABC-CFXS SA, Irritability, and SUL subscales, respectively. A similar pattern of mean change was observed for the CaGI-C DS and OB items. A change from Baseline to Week 12 of 3, 9, and 5 points on the ABC-CFXS SA, Irritability, and SUL subscales can be interpreted as a meaningful change indicative of treatment benefit for an individual patient with FXS.

WITHDRAWN: Development of the SMA Independence Scale–Upper Limb Module (SMAIS–ULM): A novel scale for individuals with Type 2 and non-ambulant Type 3 SMA

Abstract Background The amount of assistance required to perform daily activities for individuals with Type 2 and non-ambulant Type 3 spinal muscular atrophy (SMA) is often cited as meaningful for quality of life, and important to routinely assess. Methods The SMA Independence Scale (SMAIS), a patient-reported outcome measure for individuals with SMA aged ≥12 years, and an observer-reported outcome measure for caregivers of individuals aged ≥2 years, was developed and evaluated in two phases. In Phase 1, 30 draft items were developed following review of the literature. Semi-structured interviews were then conducted with individuals with SMA and caregivers to establish content validity, resulting in a 29-item measure. In Phase 2, classical test theory and Rasch measurement theory methods were used to examine the cross-sectional and longitudinal measurement performance of the SMAIS in two independent datasets. Results Phase 1 qualitative findings supported the relevance, acceptability, and comprehensibility of 29 items. In Phase 2, psychometric analyses indicated that the five response options were poorly discriminated and were thus collapsed to three options for subsequent analyses. Items showed statistical misfit, implying that the SMAIS was not assessing a single underlying construct. Based on conceptual evaluation of the items, and assessment of item performance, a more targeted 22-item upper limb score was derived. Reliability and validity analyses confirmed acceptable measurement properties of this score. Conclusions Qualitative and quantitative analyses support the use of the 22-item SMAIS–Upper Limb Module in individuals with Type 2 and non-ambulant Type 3 SMA, aged ≥2 years.

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.