Generalized pairwise comparisons of prioritized outcomes are a powerful and patient-centric analysis of multi-domain scores.

BACKGROUND: Generalized pairwise comparisons (GPC) can be used to assess the net benefit of new treatments for rare diseases. We show the potential of GPC through simulations based on data from a natural history study in mucopolysaccharidosis type IIIA (MPS IIIA). METHODS: Using data from a historical series of untreated children with MPS IIIA aged 2 to 9 years at the time of enrolment and followed for 2 years, we performed simulations to assess the operating characteristics of GPC to detect potential (simulated) treatment effects on a multi-domain symptom assessment. Two approaches were used for GPC: one in which the various domains were prioritized, the other with all domains weighted equally. The net benefit was used as a measure of treatment effect. We used increasing thresholds of clinical relevance to reflect the magnitude of the desired treatment effects, relative to the standard deviation of the measurements in each domain. RESULTS: GPC were shown to have adequate statistical power (80% or more), even with small sample sizes, to detect treatment effects considered to be clinically worthwhile on a symptom assessment covering five domains (expressive language, daily living skills, and gross-motor, sleep and pain). The prioritized approach generally led to higher power as compared with the non-prioritized approach. CONCLUSIONS: GPC of prioritized outcomes is a statistically powerful as well as a patient-centric approach for the analysis of multi-domain scores in MPS IIIA and could be applied to other heterogeneous rare diseases.

Sanfilippo syndrome: consensus guidelines for clinical care.

Sanfilippo syndrome is a group of rare, complex, and progressive neurodegenerative lysosomal storage disorders that is characterized by childhood dementia. The clinical management of patients with progressive neurological decline and multisystem involvement requires a multidisciplinary team with experience in the management of neurodegenerative disorders. Best practice guidelines for the clinical management of patients with these types of rare disorders are critical to ensure prompt diagnosis and initiation of appropriate care. However, there are no published standard global clinical care guidelines for patients with Sanfilippo syndrome. To address this, a literature review was conducted to evaluate the current evidence base and to identify evidence gaps. The findings were reviewed by an international steering committee composed of clinical experts with extensive experience in managing patients with Sanfilippo syndrome. The goal was to create a consensus set of basic clinical guidelines that will be accessible to and informed by clinicians globally, as well as providing a practical resource for families to share with their local care team who may not have experience with this rare disease. This review distills 178 guideline statements into an easily digestible document that provides evidence-based, expert-led recommendations for how to approach common management challenges and appropriate monitoring schedules in the care of patients with Sanfilippo syndrome.

Caregivers' assessment of meaningful and relevant clinical outcome assessments for Sanfilippo syndrome.

OBJECTIVES: Sanfilippo syndrome is a rare multisystem disease with no approved treatments. This study explores caregiver perspectives on the most impactful symptoms and patient-relevant clinical outcomes assessments. The pediatric onset and progressive neurodegenerative nature of Sanfilippo limits use of self-report in clinical research. This study obtains Sanfilippo caregiver data to support the selection of fit-for-purpose and patient-relevant clinical outcome assessments (COAs). METHODS: We conducted an asynchronous online focus group (n = 11) followed by individual interviews with caregivers (n = 19) of children with Sanfilippo syndrome. All participants reported on the impact of disease symptoms and level of unmet treatment need across Sanfilippo symptom domains. Focus group participants reviewed existing assessments relating to 8 symptom domains (15 total assessments) and provided feedback on meaningfulness and relevance. Focus group data were used to reduce the number of assessments included in subsequent interviews to 8 COAs across 7 symptom domains: communication, eating, sleep, mobility, pain, behavior and adapting. Interview respondents provided data on meaningfulness and relevance of assessments. Data were coded using an item-tracking matrix. Data summaries were analyzed by caregivers' responses regarding meaningfulness; relevance to Sanfilippo syndrome; and based on caregiver indication of missing or problematic subdomains and items. RESULTS: Participants' children were 2-24 years in age and varied in disease progression. Caregivers reported communication and mobility as highly impactful domains with unmet treatment needs, followed closely by pain and sleep. Domains such as eating, adaptive skills, and behaviors were identified as impactful but with relatively less priority, by comparison. Participants endorsed the relevance of clinical outcome assessments associated with communication, eating, sleep, and pain, and identified them as highly favorable for use in a clinical trial. Participants specified some refinements in existing assessments to best reflect Sanfilippo symptoms and disease course. DISCUSSION: The identification of impactful symptoms to treat and relevant and meaningful clinical outcome assessments supports patient-focused drug development. Our results inform targets for drug development and the selection of primary and secondary outcome assessments with high meaningfulness and face validity to Sanfilippo syndrome caregivers. Assessments identified as less optimal might be refined, replaced, or remain if the clinical trial necessitates.

Understanding disease symptoms and impacts and producing qualitatively-derived severity stages for MPS IIIA: a mixed methods approach.

BACKGROUND: MPS IIIA is a rare, degenerative pediatric genetic disease characterized by symptoms impacting cognition, mobility and behavior; the mean age of death is around 15 years of age. Currently, there are no approved therapies for MPS IIIA. METHODS: A two-year, multi-center, prospective, descriptive cohort study was conducted to document the natural history course of MPS IIIA. In the context of this study, semi-structured interviews were performed with parents of children at study entry and one year later. Interview transcripts were analyzed using thematic analysis methods to identity concepts of interest to children and parents, identify what factors impacted parents' burden the most, and develop qualitatively-derived disease severity stages. Children were sorted into these stages according to the symptoms their parents described at the entry interview. This sorting was compared quantitatively to the sorting of children at baseline according to the child's calendar age and their BSID development quotient (DQ). RESULTS: 22 parents in France, Germany, the Netherlands and the UK were interviewed. Children ranged in age from 28 to 105 months (mean 61.4 months). The conceptual models for children's symptoms and impacts and parents' impacts provided a detailed and comprehensive picture of what it is like for children of various ages and their parents to live with MPS IIIA. Four factors were identified as mediating the burden perceived by parents: state support, family support, time since diagnosis, and parent coping strategy. Four disease stages were developed, accounting for both the presence and the severity of MPS IIIA symptoms. The comparison of children's sorting into these stages with the BSID DQ and the child's calendar age showed strong statistical associations. CONCLUSIONS: The findings of this qualitative research embedded in a natural history study add to the current understanding of MPS IIIA as a complex disease that impacts every aspect of the lives of children and their families. This study demonstrates the unique potential of mixed methods research in rare diseases to address some of the current limitations of more traditional quantitative approaches by providing an individualized, detailed understanding of the patient experience.

An observational, prospective, multicenter, natural history study of patients with mucopolysaccharidosis type IIIA.

Mucopolysaccharidosis type IIIA (MPS IIIA, also known as Sanfilippo syndrome) is a rare genetic lysosomal storage disease characterized by early and progressive neurodegeneration resulting in a rapid decline in cognitive function affecting speech and language, adaptive behavior, and motor skills. We carried out a prospective observational study to assess the natural history of patients with MPS IIIA, using both standardized tests and patient-centric measures to determine the course of disease progression over a 2-year period. A cohort of 23 patients (7 girls, 16 boys; mean age 28-105 months at baseline) with a confirmed diagnosis of MPS IIIA were assessed and followed up at intervals of 3-6 months; cognitive function was measured using Bayley Scales of Infant and Toddler Development 3rd edition (BSID-III) to derive cognitive development quotients (DQ). Daily living, speech/language development and motor skills were measured using the Vineland Adaptive Behavior Scale (VABS-II). Sleep-wake patterns, behavior and quality-of-life questionnaires were also reported at each visit using parent/caregiver reported outcome tools. All patients had early onset severe MPS IIIA, were diagnosed before 74 months of age, and had cognitive scores below normal developmental levels at baseline. Patients less than 40 months of age at baseline were more likely to continue developing new skills over the first 6-12 months of follow-up. There was a high variability in cognitive developmental age (DA) in patients between 40 and 70 months of age; two-thirds of these patients already had profound cognitive decline, with a DA ≤10 months. The highest cognitive DA achieved in the full study cohort was 34 months. Post hoc, patients were divided into two groups based on baseline cognitive DQ (DQ ≥50 or <50). Cognitive DQ decreased linearly over time, with a decrease from baseline of 30.1 and 9.0 points in patients with cognitive DQ ≥50 at baseline and cognitive DQ <50 at baseline, respectively. Over the 2-year study, VABS-II language scores declined progressively. Motor skills, including walking, declined over time, although significantly later than cognitive decline. No clear pattern of sleep disturbance was observed, but night waking was common in younger patients. Pain scores, as measured on the quality-of-life questionnaire, increased over the study period. The findings of this study strengthen the natural history data on cognitive decline in MPS IIIA and importantly provide additional data on endpoints, validated by the patient community as important to treat, that may form the basis of a multidomain endpoint capturing the disease complexity.

Issues of COVID-19-related distance learning for children with neuronopathic mucopolysaccharidoses.

The COVID-19 pandemic has impacted the education of children around the world, forcing a large proportion of teaching to be carried out remotely. The implications of this disruption have yet to be fully elucidated, but initial assessments suggest that COVID-19-related school closures and reliance on virtual learning may have a long-term negative impact on educational attainment and future earnings as well as life expectancy of children in the United States. Among children with neurodegenerative disorders, such as neuronopathic mucopolysaccharidoses (MPS disorders), the effects of the pandemic are likely to be even greater. We aim to shine a spotlight on the impact of COVID-19 on the education, treatment and general wellbeing of children and families affected by MPS disorders by highlighting the important role that educators and therapists play in supporting the neurocognitive function and quality of life of children with neuronopathic MPS disorders. This article will serve as a resource that caregivers, educators, clinicians and therapists can use when considering how best to advocate for children with neuronopathic MPS disorders in circumstances where in-school teaching or in-clinic treatment is compromised or not possible. Given that the current pandemic is likely to have a prolonged course and impact and that similar epidemics and pandemics are a near certainty in the future, it is essential that steps are taken to support the learning and care of children with neuronopathic MPS disorders. We must prioritize strategies to safely resume this fragile community's access to in-person education and supportive care, and to address gaps that have emerged during prolonged pauses in access, whenever possible.

Parent Experiences of Sanfilippo Syndrome Impact and Unmet Treatment Needs: A Qualitative Assessment.

INTRODUCTION: Sanfilippo syndrome (MPS III) is a rare, degenerative condition characterized by symptoms impacting cognitive ability, mobility, behavior, and quality of life. Currently there are no approved therapies for this severe life-limiting disease. Integrating patient and caregiver experience data into drug development and regulatory decision-making has become a priority of the Food and Drug Administration and rare disease patient communities. METHODS: This study assesses parents' perceptions of their child's Sanfilippo syndrome disease-related symptoms using a research approach that is consistent with the Center for Drug Evaluation and Research (CDER) guidance. This study was initiated by the Cure Sanfilippo Foundation, and all steps in the research process were informed by a multidisciplinary advisory committee, with an objective of informing biopharmaceutical companies and regulatory agencies. We explored caregiver burden, symptoms with greatest impact, and meaningful but unmet treatment needs. Data were collected from 25 parents through three focus groups and a questionnaire. Transcripts were coded and analyzed using inductive thematic analysis, and descriptive analysis of quantitative data was conducted. RESULTS: Participating parents' children ranged in age from 4 to 36 years. Participants endorsed high caregiving burden across all stages of the disease. Analysis revealed multiple domains of unmet need that impact child and family quality of life, including cognitive-behavioral challenges in communication, relationships, behavior, anxiety, and child safety; and physical health symptoms including sleep, pain, and mobility. Participants reported placing high value on incremental benefits targeting those symptoms, and on a treatment that would slow or stop symptom progression. CONCLUSION: Even modest treatment benefits for Sanfilippo syndrome were shown to be highly valued. Despite high caregiver burden, most parents expressed a willingness to "try anything," including treatments with potentially high risk profiles, to maintain their child's current state.

Analysis of the caregiver burden associated with Sanfilippo syndrome type B: panel recommendations based on qualitative and quantitative data.

BACKGROUND: Sanfilippo syndrome type B (Sanfilippo B) belongs to a group of rare lysosomal storage diseases characterized by progressive cognitive decline from an early age, acute hyperactivity, and concomitant somatic symptoms. Caregivers face a unique set of challenges related to the complex nature of Sanfilippo B, but the burden and impact on quality of life (QoL) of caregivers is poorly defined and best practice guidance for clinicians is lacking. METHODS: An international clinical advisors meeting was convened to discuss key aspects of caregiver burden associated with Sanfilippo B based on findings from qualitative and quantitative research undertaken to identify and quantify the nature and impact of the disease on patients and caregivers. RESULTS: Providing care for patients with Sanfilippo B impinges on all aspects of family life, evolving as the patient ages and the disease progresses. Important factors contributing toward caregiver burden include sleep disturbances, impulsive and hyperactive behavior, and communication difficulties. Caregiver burden remained high throughout the life of the patient and, coupled with the physical burden of daily care, had a cumulative impact that generated significant psychological stress. CONCLUSION: A Sanfilippo-specific QoL questionnaire is needed that is directed at caregiver needs and burden and best practice management of these domains.

Optimal driving conditions are the most common injury conditions for child pedestrians.

OBJECTIVES: Motor vehicle-pedestrian crashes are one of the leading causes of serious injury in children. Prior studies have focused on child and traffic factors contributing to these crashes. The objective of the current study was to examine the role of driving conditions on the occurrence of motor vehicle crashes involving child pedestrians. METHODS: Detailed information was abstracted for the period January 1994 to December 1999 from the Philadelphia Police Department accident reports for all pediatric (age <18 years) pedestrian crashes in a single, urban county. Data included pedestrian age, road and weather conditions, illumination, pedestrian location, and intent, time of day, and date of incident. RESULTS: For the 6-year period of review, there were 3823 children under 18 years of age struck by motor vehicles (range 518 to 726 crashes per year), representing an average of 1.7 per day and a rate of 181 crashes per 100,000 children per year. The mean age was 7.9 years +/- 3.9 (range 1 to 17 years). Crashes occurred when the street was dry (>90%), with no adverse weather conditions (>90%), and during daylight hours or under streetlights (>92%). The most frequent day of the week was Friday (18.1%). The most common time of day was 3:00 to 6:00 PM (38.7%). The spring months (39.1%) predominated, with May (14.0%) being the most common month and January the least. When the circumstances were known, children were struck crossing in midblock 87.9% of cases and crossing behind a vehicle 38.8% of the time; only 4.8% were struck while playing in the street. Injuries as reported by the police exceeded minor in 32.3% with an overall fatality rate of 0.7%. CONCLUSIONS: Urban pediatric pedestrian crashes are common and occur most frequently during optimal driving conditions (good lighting, a dry road, and good weather). The data also suggest that pedestrian crashes are related to the saturation of the streets with children (optimal play conditions) compounded by poor street-crossing technique. Prevention efforts should reinforce the fact that optimal driving conditions are also likely to represent optimal conditions for child play and may increase the risk for pediatric pedestrian injuries through increased exposure.

Assessment of pain after injury in the pediatric patient: child and parent perceptions.

BACKGROUND/PURPOSE: Pain is an inevitable consequence of injury. Accurate assessment and treatment of a child's pain after injury is essential. This study sought to describe children's pain with injury and to elucidate the concordance of parental and self-reported pain in a pediatric traffic-injured population. METHODS: Children (5 to 17 years) admitted for traffic-related injuries and 1 parent were invited to participate in the study. Consented participants were interviewed within 1 month of injury. Participants were asked to rate current and worst pain on 2 validated pediatric pain assessment scales (Bieri Faces Pain Scale and Color Analogue Scale). Demographic, crash, and injury data were abstracted from the medical record. RESULTS: Data from 276 child-parent dyads show that most children reported clinically significant pain initially after injury. Greater "worst pain" ratings did not correlate with injury severity but were associated with loss of consciousness and extremity fracture. Generally, parent-report of child's pain was concordant with child self-report. CONCLUSIONS: This study shows the feasibility of pain assessment for pediatric injury using 2 validated scales and the appropriateness of parental report when the child is not able to provide self-report. Because pain was not correlated with injury severity, pain assessment and intervention for all children with traumatic injuries is strongly recommended.

Estimates of the incidence and costs associated with handlebar-related injuries in children.

BACKGROUND: The US Consumer Product Safety Commission is considering handlebar regulation regarding impact performance to address the risk of abdominal and pelvic organ injuries in bicyclists. OBJECTIVE: To provide national estimates of incidence and costs of handlebar-related abdominal and pelvic organ injuries. DESIGN AND SETTING: Censuses of hospital discharge data from 19 states were extrapolated to determine national estimates. The percentage of abdominal and pelvic injuries associated with handlebars was estimated based on a case series from a pediatric trauma center. Costs were estimated using standard methods. PARTICIPANTS: All subjects younger than 20 years treated as inpatients and discharged from acute care hospitals for non-motor vehicle bicycle-related injury in 19 states in 1997 and at a pediatric trauma center located in one of the states between January 1, 1996, and December 31, 2000. MAIN OUTCOME MEASURES: Incidence of bicycle-related handlebar abdominal and pelvic organ injury, total hospital charges, lifetime medical payments, lifetime productivity loss, and lifetime monetized quality-adjusted life-years. RESULTS: An estimated 1147 subjects (95% confidence interval, 1082-1215; 1.49 per 100 000 subjects 19 years and younger) in the United States had serious non-motor vehicle-involved bicycle-related abdominal or pelvic organ injury leading to hospitalization in 1997, and 886 (95% confidence interval, 828-944; 1.15 per 100 000 subjects 19 years and younger) of these injuries likely were associated with handlebars. The estimated national costs associated with handlebar-related abdominal and pelvic organ injuries were $9.6 million in total hospital charges, $10.0 million in lifetime medical costs (including claims processing), $11.5 million in lifetime productivity losses, and $503.9 million in lifetime monetized quality-adjusted life-years. CONCLUSIONS: Handlebar-related abdominal and pelvic organ injuries pose a serious health risk to children and result in substantial health care costs. Requirements for safer handlebar designs may provide one avenue to achieve a health and economic benefit.

Acute stress disorder symptoms in children and their parents after pediatric traffic injury.

OBJECTIVE: The American Academy of Pediatrics highlights the important role of pediatricians in recognizing adverse child responses to tragic events, such as traffic crashes. One challenge in effectively identifying children and their parents with troubling psychological responses to trauma is that little is known about the normal range of acute psychological responses in children and their parents in the immediate aftermath of traumatic events, making identification of adverse child responses difficult. Within the first month after a traumatic event, individuals may display reexperiencing, avoidance, and hyperarousal symptoms as well as dissociation (eg, feelings of unreality or emotional numbing). The presence of these responses, collectively known as acute stress disorder (ASD), alerts providers to those who may be at risk for ongoing difficulties. For beginning to develop an evidence base to guide pediatric care providers in addressing acute traumatic responses, the aim of the current investigation was to describe systematically the range and type of symptoms of ASD in children and their parents after pediatric traffic injury. METHODS: A prospective cohort study was conducted of traffic-injured children, who were 5 to 17 years of age and admitted to the hospital for treatment of injuries from traffic crashes, and their parents. All children who met eligibility criteria between July 1999 and May 2000 were invited to participate in the study. After consent/assent was obtained, children and their custodial parents (or guardians) were interviewed within 1 month after injury via a structured assessment to determine the circumstances of the crash and the presence of ASD symptoms. Relevant demographic and clinical information (eg, age, race, gender, date of injury) was abstracted from the medical records of subjects. A survey instrument to assess the presence of ASD symptoms was completed by both the child and his or her guardian. All children completed the Child Acute Stress Questionnaire, and all parents completed the Stanford Acute Stress Reaction Questionnaire. Responses were scored for the presence of dissociation, reexperiencing, avoidance, and/or hyperarousal symptoms as well as broad distress (symptoms present in every category). RESULTS: Symptoms of ASD were commonly observed in the children and parents. Eighty-eight percent of children and 83% of parents reported having at least 1 clinically significant symptom; this affected 90% of the families. Broad distress was observed for a large minority: 28% of children and 23% of parents. No statistically significant association was found between child broad distress and either child age (r = -0.12) or child injury severity score (r = -0.05). chi(2) analyses revealed no significant association between broad distress and child gender, child race, or mechanism of injury. No statistically significant association was found between parent broad distress and child age (r = -0.06) or child injury severity score (r = 0.09). chi(2) analyses revealed no significant association between parent broad distress and child gender or parent presence at the crash scene. Associations were found between parent broad distress and race in that fewer white parents reported broad distress. In addition, mechanism of injury was associated with parent broad distress: more parents reported broad distress when their children were involved in pedestrian-motor vehicle crashes, and fewer parents reported broad distress when their children were injured in a bicycle fall. CONCLUSIONS: Pediatric care providers can expect to see some ASD symptoms in most children and parents in the immediate aftermath of traffic-related injury. Brief education is appropriate to explain that these symptoms are normal reactions that are likely to resolve. If symptoms persist for >1 month or are particularly distressing in their intensity, then referral for psychological care may be necessary for treatment of posttraumatic stress disorder. Given the high prevalence of pediatric traffic crashes and the underdiagnosis of posttraumatic stress disorder, probing for recent crash exposure might be appropriate during routine child health maintenance. The following are recommendations for pediatricians: 1) routinely call the family several days and 1 to 2 weeks after a traffic injury and ask about behavioral symptoms and family function; 2) make use of the ongoing physician-patient relationship to explore symptom presence and intensity and any functional impairment in the injured child; a brief office visit with the child and parents could serve this purpose; 3) be sure to explore the effect that the child's injury has had on the family; remember that the parent's experience posttraumatic stress symptoms after pediatric traffic-related injuries and these symptoms may limit the parent's ability to support the child; 4) provide supportive care and give families the opportunity to discuss the crash and their current feelings; do not force families to talk about the crash; 5) although any child in a traffic crash or his or her parent is at risk for posttraumatic symptomatology, regardless of injury severity, particular attention should be paid to the parents of child pedestrians who are struck by motor vehicles. These parents experience posttraumatic symptoms more commonly than parents of children in other traffic crashes.