Four clinicians were successfully recruited to participate in CE. Of these four, two also participated in CI. One new clinician was recruited to participate in CI, for a total of three clinicians.
Of the four clinicians completing CE interviews, two specialized in genetics, one was a behavioral psychologist, and one was a psychiatrist who works with both adults and children. The clinicians currently treated an average of 14 patients (range 2–30) with AS, and had treated an average of 65 patients (range 40–100) with AS over the course of their careers. Three clinicians practiced primarily in an academic setting affiliated with a children’s hospital, while one practiced privately and at a children’s hospital.
For CI, two of the clinicians from CE completed interviews. While an expert on AS, one of these clinicians was not an expert on gait, the focus of the instruments under evaluation. One new clinician participated in this phase, a physical therapist (PT) who had no current patients with AS, but had treated 10 over the course of his career. This PT practiced in an academic setting affiliated with a children’s hospital.
A total of 36 caregivers were interviewed for CE; however, two participants were found to lack molecular confirmation based on questionnaire responses (1 child and 1 adolescent) and were removed from the dataset, resulting in a total of 34 caregiver interviews representing three patient age groups (11 children, 11 adolescents, and 12 adults). Patients had a mean (SD) age of 15.7 (7.43) years (range 5–35 years), and the racial/ethnic breakdown was 88.2% White/Caucasian, 2.9% Asian, and 8.8% Hispanic. Patients had a mean (SD) of 12.8 (6.6) years since diagnosis (Table 1). All caregiver participants were female, and the mean (SD) age was 45.8 (10.2) years. More than half the sample (58.9%) had a college degree or higher, and 76.5% were employed full- or part-time (Table 2). Saturation was attained by the 26th interview, supporting the adequacy of the sample.
Thirty-three of the original 34 caregivers also participated in CI. One caregiver did not participate in CI, as the participant’s child was determined to be non-ambulatory during the course of the interview. While technically ineligible, the participant was still able to provide valuable insight on the impacts of AS. As such, it was decided to include this participant’s data in the CE analysis but to replace them for Phase 2 (CI). Three new caregivers, who had previously shown interest in the study, were screened and enrolled in the study for CI only for a total sample of 36 caregivers completing CI (See Table 3 for caregiver characteristics and Table 4 for patient characteristics).
Conceptual Model Development
A preliminary conceptual model was drafted based on the results of a previously conducted literature review [17, 18]. The conceptual model was refined upon completion of the concept elicitation interviews. The final model (Figs. 1, 2, and 3) demonstrates the signs, symptoms and characteristics of AS, as well as impacts on both the patients and the caregivers. Sample quotes illustrating selected concepts from each domain represented in the model are provided in Tables 5 and 6.
Cognitive and Executive Function
Difficulties and/or disorders related to cognitive and executive functioning are key defining characteristics of AS. These include deficits in intellectual functioning, seizures, short attention span, hyperactivity/restlessness, impulsivity, an impaired recognition of danger, and memory issues. All were discussed in the interviews. Memory issues were included in the preliminary model based on the literature but were not mentioned during the interviews.
Of particular note, seizures (34, 100%), difficulty paying attention (34, 100%), and hyperactivity/restlessness (30, 88%) were reported by the majority of caregivers and clinicians. A number of caregivers (13, 38%) described an improvement in their child’s seizures with increasing age, with none reporting that seizures had worsened. However, a few noted that the seizures changed in other ways, such as seizure type or trigger(s). The improvement of seizures over the lifespan was corroborated by the clinicians, who all reported that seizures tended to be more severe in childhood and improved in adolescence or adulthood. Caregivers, as well as one of the clinicians, also noted improvement in attention and hyperactivity/restlessness with age.
The social-emotional domain describes the patient in relation to his/her interactions with others and related emotions. These include communication difficulties, anxiety, being overly friendly with strangers, gregariousness and a happy demeanor, as well as lacking social inhibitions/being socially inappropriate, being easily excitable, resistance to/difficulty with change, and frustration.
Communication difficulties were especially important and were discussed by all caregivers and clinicians during CE. Most caregivers described their child as ‘non-verbal,’ though some reported use of limited verbal language. Communication might improve over time in the form of increased number of signs, gestures or word approximations, but patients, in general, remained non-verbal across the lifespan. Communication difficulties could lead to frustration for both patient and caregiver, as well as behavioral problems due to the patient’s inability to express wants or needs.
Patients with AS were noted to be happy and social, with a tendency towards over-friendly behavior with strangers. Most caregivers (32, 94%) also reported that their child was easily excitable. There was variability in whether or not excitability changed over the lifespan, and some noted a close relationship to anxiety.
Anxiety was reported by most caregivers (27, 79%) and all of the clinicians. Of the 27 patients with anxiety, nine were adults, eight were children, and ten were adolescents. Caregivers perceived anxiety in their child through his/her actions, body language, and vocalizations. Anxiety could be triggered by crowds, new environments, poor sleep, and/or meeting new people.
Emotional-expressive behaviors were noted in the qualitative interviews and include behaviors that individuals with AS might use as a means to communicate or express themselves. All caregivers reported that their child, either previously or currently, exhibits some form of the following behaviors: aggressive behavior (26, 76%), inappropriate laughing (26, 76%), acting in an uncooperative/stubborn/demanding way (14, 41%), destructive behavior (11, 32%), and yelling (10, 29%). Included in the definition of aggressive behaviors were hitting (15, 44%), hair pulling (14, 41%), pinching (10, 29%) and general aggressiveness (9, 26%). Caregivers commonly reported that these behaviors were instrumental and goal-driven. All four clinicians also discussed behavioral issues as a characteristic of AS, with two clinicians particularly noting the resulting family impact.
Caregivers offered a variety of tactics for managing emotional-expressive behaviors, including going outside, separating from the situation, giving the individual a break, and taking the patient to a quiet place. Only one caregiver described the behaviors as only a concern of the past. Changes in behaviors over time were highly variable. Six caregivers reported neither a positive nor negative change, eight reported improvement with increasing age, and ten reported worsening over time. Eight of the ten caregivers reporting worsening behavior over time are caregivers of children or teens rather than adults.
Sensory-compulsive behaviors include water fascination, fascination with paper or other crinkly objects, stereotyped behavior, compulsions, abnormal food behaviors, and mouthing/chewing inedible objects. Rituals was included in the preliminary model but not reported during CE. Of all of the reported sensory-compulsive behaviors, the most frequently reported were water fascination (29, 85%) and obsession with food (14, 41%). Water fascination was described as loving to swim and take baths, enjoying moving water, and/or bubbles. Among those who reported a change over time, caregivers of children and adults most commonly reported a decrease, whereas caregivers of teens reported no change.
None of the caregivers reporting on an obsession with food noted improvement over time. Three caregivers reported a worsening over time, and the others reported no change.
The physical domain includes problems with mobility, difficulty with fine and gross motor skills, eating problems, reflux, constipation, and sleep problems, among others. Ear infections, gagging (not related to eating), and reflux were not included in the preliminary model and were added based on clinician and/or caregiver interviews, while physical impacts of laughing were not noted during interviews but included in the preliminary model.
The majority of caregivers (33, 97%) and all clinicians reported problems with mobility. Common themes included balance-related problems, difficulty with gait, ataxia, the need for assistance or assistive devices, and problems with stairs. Muscular issues were noted to be age-specific, such as hypotonia in young children followed by hypertonia, spasticity and possibly contracture as they age.
The majority of caregivers (27, 79%) reported sleep problems, such as difficulty falling and staying asleep, need for less sleep, and not being able to sleep alone, among others. All clinicians also reported sleep problems as a common characteristic of AS. Many caregivers reported that the patient took and benefited from sleep aids, such as melatonin and trazodone. Fifteen caregivers, and three of the clinicians, reported that sleep problems improved with increasing age. Nine (75%) caregivers of adults reported sleep problems versus 10 caregivers of adolescents (91%) and eight caregivers of children (73%).
Individuals with AS experience multiple impacts on activities of daily living, school, and social and community-related interactions. In general, individuals with AS lack independence and must rely on their caregivers for assistance to complete all of the basic activities of daily living. This need for total assistance continues across the lifespan.
Individuals with AS also experience challenges in school, due to absenteeism for health and sometimes behavior-related issues, and general challenges in learning and focusing, due to a short attention span and having cognitive deficits. They also can experience difficulties in participating in school functions, such as field trips or other group activities.
Patients are very impacted socially, despite their desire to interact with others, as their behaviors, such as the hair-pulling and hitting, can drive others away, impacting relationships inside and outside the home. Drooling, for example, can also create a social barrier. Physical challenges associated with walking or heat sensitivity can make it difficult to keep up with others, participate in play, or get around in the community.
The mental and physical health, work, home and social lives of caregivers are also impacted. The need to constantly be on alert causes stress, worry and anxiety, frustration, and fear. Caregivers also experience physical health issues, such as back pain from lifting or assisting their child and bruising, scratching and other injuries from aggressive behaviors. Sleep deprivation and exhaustion were frequently noted due to their child’s sleep problems.
Caregivers are also impacted at work, with some changing jobs or careers, working from home, decreasing hours, or leaving the workforce entirely. Those who continue to work face issues with absenteeism and productivity.
Caregivers have difficulty completing tasks around the home, such as chores and errands. Life often revolves around the individual with AS, impacting decisions on family activities and causing challenges in caring for other children. It can also be a challenge ensuring the child doesn’t destroy or damage the home due to their behaviors.
Caregivers also report difficulty with friendships, intimate relationships, and family relationships. They feel isolated and at times unsupported by others and have difficulty participating in social activities and planning and taking vacations.
In general, all three clinicians who participated in CI correctly interpreted the items and response options of the MPOMA-G, but there were a few issues noted with regard to item interpretation. Specifically, issues related to the items on step symmetry, step continuity, and trunk sway and their associated response options. Further clarification as to what should be considered when answering these questions was needed. Some of the clinicians felt that the MPOMA-G might be difficult to answer based on the age of the patient and their ability and/or motivation to walk. For instance, it may be difficult to use if a child or adult could only take a few steps. One clinician noted it may be easier if the scoring was done using a video recording of the patient walking instead of in person.
Overall, most items of the MPOMA-G were rated as highly relevant for use in AS by at least two out of three clinicians. As noted previously, one clinician, while an expert on AS, was not an expert on gait. This particular clinician rated some items as only moderately relevant for children with AS and suggested consideration be given to whether or not an individual is just learning to walk. Specifically, this included the right and left swing foot and the right and left foot clearance items.
Two of the three clinicians provided lower relevancy ratings for the step symmetry item for children with AS, and one also provided a lower rating for the adults. One clinician had a concern for consistency in his/her measurements, both with regard to adults and children with AS.
One clinician rated step continuity less relevant for both children and adults with AS, as he/she felt it was less studied and a more difficult concept to understand. All clinicians rated the trunk sway item as highly relevant for both children and adults with AS. One clinician rated walk stance as moderately relevant for both children and adults with AS. See Table 7 for sample quotes.
One clinician reported that the Zeno Walkway™ was very relevant for individuals with AS and was a tool that could provide measurement in several key areas, such as gait speed, base of support, and angle of toe out. Another clinician noted that one benefit of the Zeno Walkway™ was that it was more objective than the MPOMA-G, but that it did not capture everything that might be important to measure, such as step symmetry and step continuity. See Table 7 for sample quotes.
Most participants found the PEDI-CAT to be easy to understand and answer and relevant to AS. Some items required further clarification. For example, a few caregivers noted difficulty answering DA083 (using a TV remote) and DA098 (using a keypad) because they were not sure if they should be thinking about intention or just physical ability. See Table 8 for sample quotes.
Participants interpreted relevancy differently. Items received lower ratings if the patient had already mastered the skill, was unable to perform the activity, was not allowed to perform the task for safety concerns, and/or if the skill was viewed as less important. The majority of participants found the items highly relevant, as they relate to activities necessary for independence.
The ABC-C was generally found to be easy to understand and complete. Item relevancy varied, but the majority of items (33 out of 58 items) were rated as highly relevant by at least 42% of caregivers. All items were rated as highly relevant by at least two caregivers (2, 6%). Some items (e.g., Item 9. ‘Talks excessively’) were considered less relevant due to the mostly non-verbal nature of this population. These items need further clarification to note whether body gestures or vocalizations should be considered when responding. See Table 8 for sample quotes.
Items related to activity levels were also problematic for some. Questions on underactivity were less relevant for children with AS, who tend to be more hyperactive, while the hyperactivity items were less relevant for some teens and adults, who had outgrown hyperactivity. Items on isolation or lack of interest in social interactions were also reported to be less relevant.
Overall, caregivers found the ADAMS instructions and response scale to be clear and easy to understand and complete. However, some items were interpreted inconsistently, such as Item 1. ‘Nervous,’ Item 7. ‘Tense,’ Item 10. ‘Sad,’ and Item 23. ‘Listless.’
Relevancy ratings varied considerably, with more caregivers giving ratings of ‘not at all relevant’ than ‘extremely relevant.’ For instance, Item 5. ‘Sleeps more than normal’ was problematic. While sleep was considered important, oversleeping was not a concern. Items relating to communication were also problematic. See Table 8 for sample quotes.
The Morning Diary was found to be highly relevant for use with children and adults with AS. A majority of caregivers found that the questions in the four primary groups of items—night waking, disruptive behavior, subject coming out of the bedroom, and caregiver sleeping with subject—to be highly relevant. However, the instrument’s wording and dual diary structure, with some questions designed to capture the caregiver’s experience and some to capture the patient’s experience, caused confusion, demonstrating a need for the instrument to be further refined. For example, on the question in the caregiver diary on night waking, some caregivers were unsure as to what should be considered. See Table 8 for sample quotes. Some caregivers also expressed concern about their ability to answer some of the questions, particularly if they were not awake or physically present to observe their child.