Cluster analysis of kidney function decline among males with Fabry disease in a large United States electronic health records database.

BACKGROUND: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by deficient α-galactosidase A activity. The spectrum of disease includes phenotypes ranging from "classic" to "later-onset," with varying kidney disease progression. Identifying patterns of declining kidney function and involvement of other major organs in patients with FD is important to guide therapy decisions. METHODS: Clusters of patients with FD and similar estimated glomerular filtration rate (eGFR) decline and age were created using agglomerative clustering of data captured between 2007 and 2020 in the United States Optum Market Clarity database. Male patients with a diagnosis of FD and two or more eGFR values ≥6 months apart were included. Disease progression was compared with a control cohort of patients without an FD diagnosis. RESULTS: eGFR values from 234 male patients with FD were analysed, yielding seven clusters. Five clusters demonstrated disease progression from "natural" eGFR decline, with a slight decrease in kidney function and eGFR usually within the normal range, to rapid, early decline in eGFR and cardiac complications. When compared with the control cohort, a more rapid decline and a higher percentage of cardiac hypertrophy, heart failure, arrhythmias and stroke were noted in the study group. An inflection point was observed in each cluster when deterioration of kidney function accelerated. CONCLUSIONS: Clustering of male patients with FD by decline in kidney function, organ involvement and phenotype through analysis of real-world data provides a reference that could help determine the optimal time for initiation of FD-specific treatment and facilitate management decisions made by healthcare professionals.

Clinical relevance of globotriaosylceramide accumulation in Fabry disease and the effect of agalsidase beta in affected tissues.

Fabry disease (FD) is a rare lysosomal storage disorder, characterized by a reduction in α-galactosidase A enzyme activity and the progressive accumulation of globotriaosylceramide (GL3) and its metabolites in the cells of various organs. Agalsidase beta, an enzyme replacement therapy (ERT), is approved for use in patients with FD in Europe, Canada, Australia, South America, and Asia, and is the only ERT approved for use in the United States. In this review, we discuss the clinical relevance of GL3 accumulation, the effect of agalsidase beta on GL3 in target tissues, and the association between treatment-related tissue GL3 clearance and long-term structure, function, or clinical outcomes. Accumulation of GL3 in the kidney, heart, vasculature, neurons, skin, gastrointestinal tract and auditory system correlates to cellular damage and irreversible organ damage, as a result of sclerosis, fibrosis, apoptosis, inflammation, and endothelial dysfunction. Damage leads to renal dysfunction and end-stage renal disease; myocardial hypertrophy with heart failure and arrhythmias; ischemic stroke; neuropathic pain; skin lesions; intestinal ischemia and dysmotility; and hearing loss. Treatment with agalsidase beta is effective in substantially clearing GL3 in a range of cells from the tissues affected by FD. Agalsidase beta has also been shown to slow renal decline and lower the overall risk of clinical progression, demonstrating an indirect link between treatment-related GL3 clearance and stabilization of FD.

Patient and caregiver preferences for haemophilia A treatments: A discrete choice experiment.

INTRODUCTION: Long-acting products are changing the haemophilia A treatment landscape by giving patients and caregivers treatment options with varying product attributes. AIM: A discrete choice experiment (DCE) was used to elicit treatment attribute preferences among patients with haemophilia A and caregivers of children with haemophilia A. MATERIALS & METHODS: A survey of sociodemographics and preferences was completed by an online panel of adult patients with haemophilia A and caregivers of children (<18 years) with haemophilia A. The DCE included a series of questions in which respondents chose their preferred option from pairs of hypothetical treatment profiles with systematic variation in the levels of six attributes (safety concerns with too much clotting, bleed protection, dosing frequency, length of time the product has been approved for use, product type and joint health studies). Preference weights and relative attribute importance scores were estimated using random parameters logit models. RESULTS: One hundred and thirteen patients (mean age: 35.5 years) and 96 caregivers (mean age of child: 10.3 years) were included. For patients with haemophilia A, the top three attributes ranked from the most to least important were: (a) dosing frequency; (b) bleed protection; and (c) safety concerns with too much clotting. For caregivers of children with haemophilia A, the ranking was as follows: (a) safety concerns; (b) bleed protection; and (c) dosing. CONCLUSIONS: Patients with haemophilia A viewed dosing as the most important driver of treatment decision-making whereas caregivers of children with haemophilia A valued safety the most.

Development of the Fabry Disease Patient-Reported Outcome (FD-PRO): a new instrument to measure the symptoms and impacts of Fabry Disease.

BACKGROUND: The systematic collection of disease-specific symptoms and impacts on the lives of patients with Fabry Disease (FD) can offer unique insights into the patient experience, yet no disease-specific tool to measure FD symptoms exists. This study describes the development of the Fabry Disease Patient-Reported Outcome (FD-PRO). METHODS: A targeted literature search, interviews with key opinion leaders (KOLs), and concept elicitation (CE) interviews with patients identified the most frequent signs and symptoms associated with FD and their impact on daily life. Cognitive interviews evaluated patients' ability to understand the FD-PRO instructions and respond to the items on the draft FD-PRO instrument. RESULTS: The targeted literature search identified key signs and symptoms in domains that were confirmed in KOL interviews. In CE interviews with 37 treated and treatment-naïve patients, neuropathic pain symptoms (95% treated, 82% treatment-naïve), temperature intolerance (95% treated, 88% treatment-naïve), energy difficulties (95% treated, 94% treatment-naïve), hearing/vision impairment (95% treated, 71% treatment-naïve), and gastrointestinal symptoms (80% treated, 59% treatment-naïve) were most frequently mentioned. Results were similar for men and women in both treated and treatment-naïve groups. While treatment-naïve patients in general expressed fewer and milder symptoms compared to treated patients, the overall sets of symptoms expressed by the two groups were similar. The most severe symptoms were neuropathic pain, stomach pain, burning pain, and fatigue. The most bothersome symptoms were stomach pain, breathing difficulty, fatigue, neuropathic pain, and constipation. The most frequent impacts were in the work/school limitations domain for both treated and treatment-naïve patients. The impacts with the highest difficulty ratings were stress, limited outdoor activity, and guilt. Cognitive interviews with 14 treated and treatment-naïve patients resulted in the refinement of FD-PRO items and language. CONCLUSIONS: The FD-PRO is a novel, disease-specific instrument that measures the patient experience in Fabry disease. Such tools are valuable in capturing the burden of disease in patients with FD and demonstrating the value of treatment in clinical trials.

Fabry Disease Patient-Reported Outcome (FD-PRO) demonstrates robust measurement properties for assessing symptom severity in Fabry disease.

BACKGROUND: Fabry disease (FD) is a rare, genetic disease, that if untreated, progresses to irreversible and life-threatening renal, cardiac, and cerebrovascular events. FD symptoms impact daily functioning and quality of life, but no disease-specific measure of these symptoms has been psychometrically tested. METHODS: The Fabry Disease Patient-Reported Outcome (FD-PRO) consists of 19 items that measure neuropathic symptoms (pain, tingling, numbness and burning in upper/lower extremities), headache, abdominal pain, heat intolerance, swelling, tinnitus, fatigue, hearing/vision impairment, hypohidrosis (diminished sweating) and difficulty engaging in regular physical activities in the past 24 h. Measurement properties of the instrument were evaluated among 139 adult (≥ 18 years) FD diagnosed patients (enzyme deficiency in males; GLA genotyping in females) including enzyme replacement (ERT) treated or treatment-naïve patients, classic or late-onset phenotypes from ten countries and eighteen sites. Patients completed the FD-PRO daily on a handheld electronic diary for 4 weeks; demographic, other patient and clinician reported outcomes were also collected. RESULTS: The mean age of patients was 43 years; with even sex distribution (female: 53%) and majority was ERT treated (72%). Patient compliance was high; ≥ 87% completed at least 4 FD-PRO entries each week (mean completion time: < 3 min in week one). Empirical evaluation of item properties via inter-item correlations, exploratory factor analysis and item-response theory models suggested that a total symptom score (TSS) could be calculated. Due to redundancy among items, a "neuropathy parcel" and an "audiovisual parcel" were created in generating the TSS (items within a parcel averaged and treated as a single item). Two items were excluded from TSS: sweating (did not correlate with other items) and difficulty engaging in regular physical activities (measure of impact, not symptoms). Internal consistency (Cronbach's alpha) of the TSS was ≥0.89 across weeks; test-retest reliability (intraclass correlation coefficient) was ≥0.91. The TSS was correlated with conceptually similar clinical and patient reported assessments as expected (r > |0.4|) and discriminated moderate/severe from least severe FD groups in known-groups validity analyses. CONCLUSIONS: The FD-PRO instrument is a novel disease-specific instrument that assesses classic and non-classic symptoms, with strong psychometric properties and appropriate for use in clinical studies.

Validation of the Overactive Bladder-Bladder Assessment Tool (OAB-BAT): A Potential Alternative to the Standard Bladder Diary for Monitoring OAB Outcomes.

BACKGROUND: An advisory board concluded that a new, comprehensive overactive bladder (OAB) patient-reported outcome (PRO) measure should be developed in accordance with regulatory guidelines. The OAB-Bladder Assessment Tool (OAB-BAT) was developed with qualitative input from OAB patients and experts to measure symptoms, bother, impacts, and satisfaction with treatment. OBJECTIVE: Psychometric evaluation of the OAB-BAT assessing PRO OAB symptoms, bother, and impacts during a 7-d recall period. DESIGN, SETTING, AND PARTICIPANTS: Psychometric testing was conducted for a 28-d observational study of 170 OAB patients. Eligibility criteria included clinician-confirmed OAB diagnosis with at least eight micturitions per day. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Assessments included the OAB-BAT, a 7-d bladder diary, and co-validating OAB PROs. Analysis included classical and modern test theories. A scoring algorithm was developed and psychometric properties were assessed. RESULTS AND LIMITATIONS: The majority of participants were women (72.4%) with moderate OAB symptom severity (53.5%). More than one-third of participants (34.1%) were incontinent. Responses were well balanced across bother and impact items, while symptom frequency items showed sparse responses. Analysis supported an eight-item unidimensional model based on bother and impacts. No items performed differently by gender or continence status. The OAB-BAT showed internal consistency (ω=0.918), retest reliability (two-way random intraclass correlation coefficient=0.81), and convergent validity with the OAB-q (r>0.4). Known groups showed the expected trend. Comparisons between OAB-BAT scores and components of the bladder diary showed a moderate effect size (r>0.4). CONCLUSIONS: The eight-item OAB-BAT with 7-d recall is valid and reliable as an OAB PRO measure. Structural modeling, balanced with content validity considerations, produced robust scores. The OAB-BAT is a useful addition to the clinical assessment of patients, designed to complement the use of bladder diaries for monitoring OAB outcomes, in clinical trial and clinical practice environments. Future studies will need to assess the treatment satisfaction items in a larger sample of patients receiving OAB treatment. PATIENT SUMMARY: We tested a questionnaire designed to assess overactive bladder (OAB) symptoms, bother, satisfaction, and impacts by asking patients to complete it on a weekly basis. We found that the questionnaire accurately captures the symptoms and impacts that are most important to patients with OAB. We conclude that the questionnaire could be a useful instrument and, after further assessment in clinical practice and research, a possible alternative to a bladder diary in measuring OAB outcomes.

Patient and caregiver perspectives on burden of disease manifestations in late-onset Tay-Sachs and Sandhoff diseases.

BACKGROUND: The GM2 gangliosidoses (GM2), Tay-Sachs and Sandhoff diseases, are rare, autosomal recessive genetic disorders caused by mutations in the lysosomal enzyme ß-hexosaminidase A (HEXA) or ß-hexosaminidase B (HEXB) genes, respectively. A minority of patients have a late-onset form of disease that presents from late-childhood to adulthood and has a slowly progressive course with prolonged survival. Little research has been published documenting patient experiences with late-onset Tay-Sachs and Sandhoff diseases and how the disease impacts their daily lives and functioning. This study explored the most frequent symptoms and functional impacts experienced by patients with late-onset GM2 gangliosidosis through interviews with patients and caregivers. METHODS: A qualitative research study design was employed, using three focus groups and 18 one-on-one interviews with patients who were recruited at the National Tay-Sachs and Allied Diseases Annual Family Conference. Transcripts were generated from the discussions, and patient quotes were analyzed using a content analysis approach. Concepts were aggregated into symptom and functional impacts, and the frequency of mention in the focus groups and individual interviews was calculated. KEY FINDINGS: Many of the frequently described symptoms [muscle weakness (n = 19, 95%), "clumsy" gait (n = 12, 60%), fatigue (n = 10, 50%)] and impacts [difficulty walking (n = 19, 95%), falling (n = 17, 85%), and climbing stairs (n = 16, 80%)] disclosed by patients and caregivers were similar to those previously reported in the literature. However, less frequently described symptoms such as gastrointestinal issues (n = 4, 20%) and coughing fits (n = 5, 25%) have been expanded upon. This study evaluated the immediate impact of these symptoms on the patients' lives to highlight the burden of these symptoms and the functional limitations on daily living activities, independence, and emotional well-being. The findings were used to develop a conceptual disease model that could serve as a foundation for patient-centered outcomes in clinical trials and provide insights to the medical community that may benefit patient care. CONCLUSIONS: This study contributes to the current understanding of symptoms associated with late-onset GM2 gangliosidosis, and further identifies the many consequences and impacts of the disease. These symptoms and impacts could be measured in clinical trials to examine the effects of novel treatments from the patient perspective.

Potential organ donors referred to Ontario neurosurgical centres.

PURPOSE: Eleven hospitals in Ontario are adult neurosurgical centres (ONCs). Patients transferred to ONCs from community hospitals with acute intracranial emergencies often have non-survivable injuries, and may be returned to the referring hospital for end-of-life care. These referring hospitals may not be familiar with neurological determination of death, or organ donation. Our objective was to determine the number of patients with severe brain injuries assessed in ONC emergency departments where progression to brain death may be reasonably expected, and to determine their outcome. METHODS: A one-year retrospective cohort study was undertaken using a convenience sample of patients transferred to eight ONCs for neurosurgical assessment, with evidence of either (a) brain death in the emergency department, or (b) severe brain injury who met criteria of a reasonable likelihood of progression to brain death. The outcome of these patients to disposition from the ONC was determined by chart review. RESULTS: Three thousand four hundred and forty-seven patients were identified of whom 141 met inclusion criteria. Eleven patients (7.8%) were pronounced dead in the emergency department, 96 (68.1%) patients were admitted, and 34 (24.1%) were transferred back to their referring hospital. Fourteen patients (9.9%) became organ donors: two died in the emergency department and 12 died following admission. CONCLUSIONS: A significant number of patients transferred to ONCs have an injury with a likelihood of progressing to brain death, but only a small proportion of these patients become organ donors. Emergency department triage, assessment and admission decisions for patients with intracranial catastrophes should consider diagnostic criteria for brain death and recognition of donor potential as part of end-of-life care.