Core Data Elements
Based on the initial clinical expert meeting, 138 possible data capture fields were identified and included for the subsequent Delphi review. Table 1 lists the key demographic and clinical data domains proposed by the key opinion leaders (KOLs) for the GARDIAN. There was consensus on the removal of ten initially proposed variables (country of birth, country of residence, nerve conduction velocity/ electromyography indication for test), electrocardiogram, cerebrospinal fluid testing, gastrology and general surgery, dyspepsia, constipation, and reflux. Although not all agreed, the proposed data variable, transfer capacity of the lung TLCO gas transfer exchange, also was removed.
Table 1. Key demographic and clinical data domains for the neuronopathic Gaucher disease registry
Domains
|
Example Items
|
Demographics
|
Age, sex, ethnicity, self-reported heritage/ancestry (maternal and paternal), consanguinity, educational achievements and abilities, working status, living arrangements, family history of Parkinson’s disease
|
Diagnostic information
|
Gaucher type, age at diagnosis (any type), genetic testing performed for diagnosis, genetic and phenotypic profile, symptoms and severity at diagnosis, other testing at diagnosis (e.g., neurological, laboratory), saccades and mSST
|
Health status
|
Body mass index, fertility status, physical and mental health status
|
Clinical symptomatology
|
Symptoms (e.g., developmental, hematological, neurological, respiratory, skeletal)
|
Testing
|
Laboratory tests (e.g., BFC, Hb, platelets, chitotriosidase, and imaging (e.g., DEXA, spleen ultrasound, EEG, brain MRI, spinal x-ray, chest CT)
|
Treatment
|
Prescription medication (type, dose, adverse events), supplements, procedures/surgery (tracheostomy, splenectomy)
|
Healthcare resource utilization
|
Specialist visits and hospitalizations
|
Aids and home improvements
|
Aids (e.g., glasses, hearing aids, canes) and home improvements (e.g., ramps, stair lift, walk-in shower)
|
Patient/caregiver burden and quality of life
|
Symptoms (e.g., pain, fatigue, anxiety, depression, sleep), physical function, self-care, social and emotional impact
|
Abbreviations: BFC, blood full count; CT, computed tomography; DEXA, dual-energy x-ray absorptiometry; EEG, electroencephalogram; Hb, hemoglobin; MRI, magnetic resonance imaging; mSST, modified Severity Scoring Tool [26].
Additional recommendations from KOLs were that the GARDIAN should use a common coding standard or ontology to create a lean and simple data set that is compliance eligible. Also, that a new neuronopathic-specific severity scoring scale should be developed that incorporates and measures both the visceral and neurological manifestations of nGD.
The symptoms and impacts identified fall into seven domains: nGD symptoms, physical functioning, self-regulation, socio-emotional functioning, support services, and caregiver-specific impacts as described below (Table 2). The feedback received were that having bone deformity and tremors, including seizures or fits, are core symptoms that can affect movement and have wide-ranging impacts. Studies have emphasized the frequent and disabling nature of bone-related pathology, including frequent bone crises, impaired gait, and parkinsonian symptoms [27–29]. Pain and discomfort can be a consistent part of daily life. Symptoms can vary widely across patients, where some individuals are very limited in their mobility, whereas others are able to live independently with some support from personal assistants and nurses. Cognitive impacts revolve around inability to focus and feeling overwhelmed with multiple things to process at one time. Lack of balance, tremors, and fatigue, have impacts on physical functioning, including walking, and sitting. Fine motor skills sometimes prove to be problematic; some individuals require assistance when dressing, bathing, using utensils, or preparing food. Many patients struggle to make friends, and they may only interact with family members and staff in the medical community. This can lead to feeling isolated and socially excluded. Resulting emotional impacts may include anxiety, depression, and stress. Nevertheless, patients may also show resilience whilst facing physical and psychological difficulties.
Table 2. Neuronopathic GD symptoms and impacts identified by clinical experts and caregivers/patients
Concept
|
Clinical Expert
Input
|
Patient/Caregiver Input
|
Symptoms
|
|
|
Fatigue
|
X
|
X
|
Pain in small joints
|
X
|
|
Pain in large joints
|
X
|
|
Salivation/drooling
|
X
|
X
|
Chewing/swallowing/choking
|
X
|
X
|
Bone/muscle pain, including back pain
|
X
|
X
|
Nerve pain
|
X
|
X
|
Balance/coordination/feel wobbly
|
X
|
X
|
Seizure/jerky movements
|
X
|
X
|
Impaired speech
|
|
X
|
Trouble concentrating/staying focused
|
|
X
|
Feeling overwhelmed/memory trouble
|
|
X
|
Physical Function
|
|
|
Sitting
|
X
|
X
|
Using utensils/Writing
|
X
|
X
|
Walking
|
X
|
X
|
Reaching for objects independently
|
X
|
|
Performing hobbies
|
|
X
|
Self-Regulation
|
|
|
Dressing
|
X
|
X
|
Hygiene
|
X
|
X
|
Toileting
|
X
|
|
Sleeping
|
X
|
X
|
Prepare food
|
|
X
|
Socio-Emotional Functioning
|
|
|
Attending school/work
|
X
|
X
|
Recognizing significant others
|
X
|
X
|
Feelings isolated/lonely
|
X
|
X
|
Irritability/anger
|
X
|
X
|
Anxiety
|
X
|
X
|
Happy/unhappy
|
X
|
X
|
School/work stress
|
|
X
|
Stressful traveling outside of home
|
|
X
|
Concern about treatment side effects
|
|
X
|
Concern about caregiver burden
|
X
|
|
Support Services/Coping
|
|
|
Receiving physical support services
|
X
|
X
|
Accommodations made at school/work
|
|
X
|
Receiving/using emotional support
|
|
X
|
Connected to others with Gaucher Disease
|
|
X
|
Supportive healthcare providers
|
|
X
|
Clinical study participation
|
|
X
|
Caregiver Impacts
|
|
|
Stress in caregiving
|
X
|
X
|
Fatigue
|
X
|
X
|
Anxious about patient’s health
|
X
|
X
|
Positive/hopeful about patient’s health
|
X
|
X
|
Stress in traveling with patient
|
|
X
|
These outcomes informed the content of a draft nGD-PRO and nGD-ObsRO. It was determined the nGD-PRO can be administered to patients who are at least 12 years of age and whose caregiver affirmatively responds to the question: Is the child you care for with Gaucher disease able to answer questions about how they feel and function? The nGD-ObsRO items focus on the same patient outcomes captured in the nGD-PRO; however, because the nGD-ObsRO captures only patient outcomes that can be observed, each item within this measure asks the caregiver to provide a response “based on what you observed or what the patient told you.” The response scale for all of the items is the 11-point numerical rating scale, where respondents can choose a number between 0 and 10. To enhance interpretation of the numbers, descriptive categories are included along the scale.
nGD PRO and nGD ObsRO Cognitive Interview Findings
A total of nine caregivers and six patients from the US, UK, China, Mexico, Egypt, and Japan participated in the cognitive interviews (Table 3).
Table 3. Participants of the nGD PRO and nGD ObsRO cognitive interviews
Subject (Residence [# participants])
|
Patient age
|
Patient gender
|
Caregiver relation (age)
|
United Kingdom (3 CGs, 2 PTs)
|
CG_UK_01
|
11 years
|
Female
|
Mother (36 years)
|
CG_UK_02
|
24 years
|
Male
|
Father (63 years)
|
CG_UK_03
|
4 years
|
Male
|
Mother (36 years)
|
PT_UK_01
|
24 years
|
n/r
|
n/a
|
PT_UK_02
|
26 years
|
n/r
|
n/a
|
China (2 CGs, 1 PT)
|
PT_CH_01
|
25 years
|
Male
|
Father (53 years)
|
CG_CH_01
|
13 years
|
n/r
|
Father (38 years)
|
CG_CH_02
|
11 years
|
Male
|
Mother (42 years)
|
Egypt (1 CG, 1PT)
|
CG_EG_01
|
14 years a
|
Male
|
n/a
|
PT_EG_01
|
14 years a
|
Male
|
Mother (42 years)
|
Mexico (1 CG, 1 PT)
|
PT_MX_02
|
16 years b
|
Female
|
n/a
|
CG_MX_01
|
16 years b
|
Female
|
Father (59 years)
|
Japan (1 CG)
|
CG_JP_01
|
7 years
|
Male
|
Father (40 years)
|
United States (1 CG)
|
CG_US_01
|
13 years
|
Male
|
Mother (50 years)
|
a Same patient
b Same patient
Abbreviations: CG, caregiver; ObsRO, observer reported outcome; n/a, not available; nGD, neuronopathic Gaucher disease; n/r, not reported; PRO, patient reported outcome; PT, patient
Overall, the PRO and ObsRO were well-received. As noted by the moderator in China: “The caregivers are very grateful that we can pay attention to this disease, and they think that the questionnaire is very comprehensive and asks about the things that patients usually experience.” In the first wave of cognitive interviews (Wave 1), the English versions of the nGD-PRO and nGD-ObsRO were tested in the US and UK. Based on the feedback in Wave 1, translations were developed of the PRO and ObsRO for each target language: Spanish, Arabic, Japanese, Simplified Chinese, French, and German. In Wave 2, the Spanish, Arabic, Simplified Chinese, and Japanese versions were tested in Mexico, Egypt, China, and Japan, respectively. Revisions to the measures based on the findings from Waves 1 and 2 are summarized in Table 4. Although no participants were recruited from France or Germany, the French and German translated versions were revised accordingly based on the feedback from the other participating countries.
Based on Wave 1, the original reference period of the last 7 days was extended to the last 14 days to capture outcomes more comprehensively. One caregiver indicated that the last 7 days is not a sufficient time period to characterize disease impacts, one noted that the patient’s infusions are a few weeks apart and thus a longer reference period would more accurately reflect treatment impacts, and one felt a longer time period was optimal because some of the questions ask about what the patient was feeling.
Wave 1 also informed item-specific revisions. For example, an item asking about nerve pain was revised to refer only to ‘pins and needles and numbness’; the term ‘nerve pain’ was removed because this was not well understood: “I think the tingling and numbness is easier to understand, but nerve pain is a little difficult” (CG_UK_01); “When he has seizures, he definitely has this type of pain [pins and needles]” (CG-UK02). In addition, a few caregivers noted that the patients may not need help walking, but they may need to rest after walking for a period of time: “It’s walking for long distance, he doesn’t need help, but he needs rest” (CG_UK_01). Thus, a new item was added to capture the need to rest with standing or walking. The symptoms captured in the measures include fatigue; bone, joint, or back pain; and numbness or pins and needles. Although all of the ObsRO items have an option for ‘did not observe/did not appear to have’ that can be endorsed as appropriate, the caregiver participants generally found it easy to report on the magnitude of these symptoms experienced by the patient: “Nine points, he is very tired” (CG_CH_01); “He really doesn’t feel fatigued unless he does physical activity” (CG_MX_01); “He was fine when he got up in the morning. In the afternoon, the teacher told me that he felt very tired when he was in class and when he came back in the evening” (CG_CH_02); “He wakes at night with pains in his legs” (CG_UK_03). “He tells me that his leg hurts when he feels pain” (CG_EG_01); “the knee [is where he has numbness or tingling]” (CG_CH_01); “He has a very painful back, 9 points. Because my son has osteoporosis, his waist hurts every day when he gets up. He just talks about pain every day” (CG_CH_01);“Three points; Because he used to have severe pain, now he has taken [medication], and now he has relieved a lot. I used to massage his legs every night, and now his pain has eased a lot” (CG_CH_02).
The two cognitive symptom items, ‘trouble concentrating or staying focused’ and ‘trouble remembering things’, were relatively easy to answer for the caregivers: “He stays focused for only short periods of time” (CG_UK_01); “He is very good at concentration and memorizing” (CG_EG_01); “He has a little difficulty, especially when doing homework. The teacher also reported that he was unable to concentrate during class…He plays with the pen and bites the pen” (CG_CH_02); “He forgets very quickly in his studies. I dictate Chinese with him every night. When he dictates the next night, he forgets it again. I dictated to him repeatedly, but he couldn't remember it” (CG_CH_02); “I would choose 2; at times, she is very focused on what she was initially doing, but she is very easily distracted.” (CG_MX_01).
The caregivers also found it easy to report on the patient’s emotions; the measures capture being anxious or panicky, frustrated or angry, happy, and sad. The caregivers were highly sensitive to the patients’ feelings: “My daughter is very cheerful, and so, when she’s anxious or she feels worried, or she’s scared, or feels panic, you start noticing her being nervous, she looks to one side and the other, she tells you what she feels herself. Or we see that she’s anxious, that she’s nervous; she starts pinching her fingers, pulling her hair, that is, those are reflexes she has as a reaction to fear…It’s very easy to spot her moods.” (CG_MX_01); “I would say most of the time he’s happy” CG_UK_01; “But then he has his moments where he’s having a tantrum and he’s miserable” (CG-UK03); “When we walk out of our house, he puts his hands over his ears because he doesn’t like to hear the sound of cars going past” (CG-UK03).
Table 4. Key item revisions made based on cognitive interviews
Original
|
Issue
|
Revision
|
First Wave (English versions tested in US and UK)
|
Recall period for all items is “last 7 days”
|
A longer recall period would more accurately reflect patient experience
|
Recall period for all items revised to “last 14 days”
|
On average, how much nerve pain (e.g., feeling pins and needles, sharp tingling or numbness) did the patient have over the last 7 days based on what you observed or what the patient told you?
|
The term “nerve pain” did not resonate with participants; they identified with “feeling pins and needles and numbness”
|
Did the patient have numbness or pins and needles the last 14 days based on what you observed or what the patient told you?
|
A few caregivers noted that the patients had to stop and rest after walking for a select period
|
New concept raised: needing to rest after walking
|
Did the patient need to rest after standing or walking for a period of time over the last 14 days
|
How much drooling/salivating or secretions have you experienced over the last 14 days?
|
PTs and CGs and PTs indicated that ‘dribbling’ was more aligned with disease impact versus ‘salivating’
|
Did you have drooling or dribbling over the last 14 days?
|
Did you feel overwhelmed by too much information and/or had trouble remembering what comes next over the last 14 days?
|
Recommend asking only about trouble with memory as feeling overwhelmed can be interpreted as separate and being related to feeling stressed
|
Did you have trouble remembering things over the last 14 days?
|
Second Wave (Simplistic Chinese, Spanish, Arabic, and Japanese versions)
|
Have you needed assistance sitting upright as in a chair over the last 14 days?
|
Suggested removing ‘upright’ as some patients cannot physically sit upright because their back is deformed due to the disease
|
Have you needed assistance sitting in a chair over the last 14 days?
|
How often did you prepare food or cook food without help over the last 14 days?
|
Suggestion to be more specific about needing help as well as type of meal
|
Overall, did you need help preparing simple meals (for example, making a sandwich) over the last 14 days?
|
Did you have difficulty performing any hobbies or your daily activities, including using a computer/iPad over the last 14 days?
|
This item is asking about multiple concepts, i.e., sports and daily activities; in addition, using a computer not considered hobby.
|
Did you have difficulty performing your choice of hobbies or activities over the last 14 days?
|
Did you feel happy or positive over the last 14 days?
|
The word ‘positive’ was not well understood among participants across countries.
|
Did you feel happy over the last 14 days?
|
The final measures comprise 33 items that focus on the patient’s symptoms, functional status, and well-being. Additionally, the ObsRO includes items focusing on caregiver impacts. Many of the cognitive interview participants confirmed the relevance of the items: “The symptoms of this disease are basically in it. The questions asked by the doctor are the same as your questionnaire.” (CG_CH_01); “This questionnaire is quite comprehensive.” (CG_CH_02); “It’s very interesting because these are questions that we are not normally asked; others always focus on the beginning, and not on what they have been living through in the last 14 days.” (CG_MX_01).