Test-retest reliability of a mobile application of the patient reported outcomes burdens and experiences (PROBE) study.

INTRODUCTION: The Patient Reported Outcomes, Burdens, and Experiences (PROBE) questionnaire is a patient-reported outcome tool that assesses quality of life and disease burden in people with haemophilia (PWH). AIM: To assesses the test-retest reliability of PROBE when completed using the mobile phone application. METHODS: We recruited PWH, including carriers, and individuals with no bleeding disorders who attended haemophilia-related workshops or via social media. Participants completed PROBE three times (twice on the app: T1 and T2, and once on the web, T3). Test-retest reliability was analysed for T1 versus T2 (app to app, time period one) and T2 versus T3 (app to web, time period two). RESULTS: We enrolled 48 participants (median age = 56 [range 27-78] years). Eighteen participants (37.5%) were PWH and seven (14.6%) were carriers. On general health domain questions, we found almost perfect agreement, except for a question on the frequency of use of pain medication in the last 12 months [Kappa coefficient (κ) .72 and .37 for time period one and two, respectively] and any use of pain medications (κ .75) for time period two. For haemophilia-related questions, we found substantial to perfect agreement, except for the questions on the number of joint bleeds in the previous 6 months for time period one (κ .49) and the number of bleeds in the previous two weeks for time period two (κ .34). CONCLUSIONS: The results demonstrate the reliability of the PROBE app. The app can be used interchangeably with the paper and web platforms for PROBE administration.

Reported prevalence of von Willebrand disease worldwide in relation to income classification.

INTRODUCTION: The diagnosis of von Willebrand disease (VWD) is complex and challenging, especially when diagnostic resources are limited. This results in a lack of consistency in identifying and reporting the number of people with VWD and variations in the VWD prevalence worldwide. AIM: To analyze the reported prevalence of VWD worldwide in relation to income classification. METHODS: Data on the VWD prevalence from the World Federation of Hemophilia Annual Global Survey, national registries of Australia, Canada, and the United Kingdom, and the literature were analysed. The income level of each country was classified according to the World Bank. RESULTS: The mean VWD prevalence worldwide was 25.6 per million people. The VWD prevalence for high-income countries (HIC) of 60.3 per million people was significantly greater (p < .01) than upper middle (12.6), lower middle (2.5) and low (1.1) income countries. The type 3 VWD prevalence for HIC of 3.3 per million people was significantly greater (p < .01) than lower middle (1.3) and low income (0.7) countries. The reported VWD prevalence was greater among females than males. CONCLUSION: The reported VWD prevalence varied considerably across and within income classifications. The variability of type 3 VWD prevalence was less than the VWD prevalence (all types). The variability in detection and diagnosis of type 1 VWD presents a challenge in forming a consistent prevalence value across countries and income classifications.

Von Willebrand Disease: Gaining a global perspective.

INTRODUCTION: Recent guidelines for von Willebrand Disease (VWD) highlighted the challenges in diagnosis and management. Identifying the number of persons with VWD (PwVWD) internationally will help target support to aid diagnosis of PwVWD. AIM: To examine international registration rates of PwVWD, the influence of income status, geographical region and the age and sex profile. Cumulatively, these data will be used to inform future strategy from the World Federation of Haemophilia (WFH) to address unmet clinical and research needs. METHODS: Data from the 2018/2019 WFH Annual Global Survey (AGS) were analysed, providing a global perspective on VWD registration. RESULTS: Registration rates are lowest in South Asia (0.6/million population) and highest in Europe/Central Asia (50.9/million population, 0.005%), but below the expected prevalence rate (0.1%). National economic status impacted VWD registration rates, reflecting variation in access to optimal healthcare infrastructure. Females represented the majority of PwVWD globally, however, in low-income countries (LIC) males predominated. Age profile varied, with markedly higher rates of paediatric registrations in North America, Middle East and North Africa and South Asia. Rates of type 3 VWD registrations were significantly influenced by economic status (81% of VWD diagnoses in LIC), suggesting only the most severe VWD types are diagnosed in resource limited settings. CONCLUSION: Significant variation in registration rates of PwVWD exist internationally and is influenced by income status and the presence of HTC networks. Improved understanding of registration rates will enable targeting of advocacy to improve awareness, diagnosis and support for PwVWD internationally. KEY POINTS: Registration rates of People with Von Willebrand Disease (PwVWD) vary internationally and are influenced by national income status Although females represent the majority of PwVWD globally, in low income countries (LIC) males predominated, possibly related to stigma surrounding gynaecological bleeding. Rates of type 3 VWD registration were significantly influenced by economic status (81% of VWD diagnoses in LIC), suggesting only the most severe VWD types are diagnosed in resource limited settings.

Evaluation of the sexual health in people living with hemophilia.

BACKGROUND: Knowledge about sexual health, difficulty with sexual activity and intimacy (sexual difficulty), in people with hemophilia is little understood. OBJECTIVES: The objectives were to determine the prevalence of sexual difficulty in people living with hemophilia (PWH) compared to people with no bleeding disorders (PWNoBD), and to determine factors associated with it. METHODS: This was an analysis of the PROBE study. We recruited individuals who had hemophilia A or B (PWH) and PWNoBD who were 18 years old or older. We calculated proportions of participants with sexual difficulty and odds ratios (ORs) adjusted for sex and age with 95% confidence intervals. RESULTS: There were 2007 PWH and 1972 PWNoBD. Mean (standard deviation) age was 41 (15) years in PWH and 42 (13) years in PWNoBD. Sexual difficulty was reported in 302 (15.1%) PWH and 79 (4.0%) PWNoBD. The odds of sexual difficulty were significantly higher in PWH (OR 3.82, 95% CI 2.85, 5.11). Among PWH, older age, experiencing acute or chronic pain in the past 12 months, bleeds within the past two weeks, ≥3 spontaneous joint bleeds (past six months), limitation of range of motion of any joints, and any life- or limb-threatening bleeds in the past 12 months were associated with sexual difficulty. CONCLUSIONS: Sexual difficulty is more prevalent in people living with hemophilia and associated with markers of disease severity. Sexual health issues should be incorporated in comprehensive hemophilia care, future research, and hemophilia related health policy.

Converting factor and nonfactor usage into a single metric to facilitate benchmarking the resources consumed for haemophilia care across jurisdictions and over time.

INTRODUCTION: The World Federation of Hemophilia started measuring factor utilization at the country level as IU/capita (International Units of factor concentrates used per country population) in 2001 for its Annual Global Survey. IU/capita have been used to benchmark a country's usage over time and for advocacy. The introduction of a common metric usage spanning across standard half-life (SHL), and extended half-life (EHL) clotting factor concentrates (CFCs) and emicizumab would be a valuable simplification for national healthcare policymaking and industrial production planning. AIM: Develop and examine a method of converting IU of SHL or EHL, and milligrams of emicizumab into a single metric. METHODS: We developed conversion factors from manufacturer's recommended dose for prophylaxis with SHL, EHL, and emicizumab as reported on the licensing information for the United States and Europe. We validate the accuracy of these conversion factors against real-world usage data. RESULTS: The prescribing information in the United States and Europe is marginally different. The SHL/EHL conversion factors are higher when calculated based on the prescribing information than on real-world studies, which are considered more representative of clinical practice. The best estimate of the SHL/EHL conversion factors for FVIII and FIX were 1.04 and 1.87. The conversion factor for emicizumab to SHL is 70 IU/mg. CONCLUSION: We have generated robust estimates of conversion factors for currently used treatment options for prophylaxis in haemophilia. Usage of a single, harmonized metric will facilitate benchmarking across different countries or longitudinally irrespective of the case-mix of treatment options.

Non-severe haemophilia: Is it benign? - Insights from the PROBE study.

INTRODUCTION: There are limited data on the impact of haemophilia on health status and health-related quality of life (HRQL) in people with non-severe (mild and moderate) haemophilia. AIM: To evaluate the health status of people living with mild or moderate haemophilia. METHODS: Data on respondents with no bleeding disorder (NoBD), mild and moderate haemophilia patients were drawn from the PROBE study. Respondents were enrolled using network patient organizations. This analysis was performed as a cross-sectional study. Primary outcomes were reported bleeding, acute and chronic pain, activities of daily living and HRQL. RESULTS: A total of 862 respondents with NoBD (n = 173), mild (n = 102) and moderate (n = 134) haemophilia were eligible, with a median age of 33, 42 and 43, respectively. In relation to haemophilia-related sequalae, 53% of male and 29% of female patients with mild and 83% of males with moderate haemophilia had more than 2-3 bleeds in the last 12 months. Reporting of acute and chronic pain is less in those with NoBD compared to the mild and moderate cohorts for both genders. Multivariate analysis demonstrates significant reductions in quality of life using VAS, EQ-5D-5L and PROBE for males with mild and moderate haemophilia (P ≤ .001) with only PROBE indicating a significant reduction for females with mild (P = .002). CONCLUSION: People affected by mild or moderate haemophilia report a significant HRQL impact due to haemophilia-related bleeding. Future research is needed to identify the optimal care management of patients with mild and moderate haemophilia.

Modelling future usage and cost of factor and emicizumab to treat haemophilia A for the US Western States Region IX haemophilia treatment centres.

INTRODUCTION: Increased usage of emicizumab in the United States will affect standard half-life (SHL) and extended half-life (EHL) products usage and cost. AIM: To model the usage and cost of SHL and EHL products, and emicizumab to treat haemophilia A (HA) in the 13 Western States Region IX haemophilia treatment centres (HTCs.) (California, Nevada, Hawaii and Guam). METHODS: We modelled product usage and cost using decision analysis methods. VARIABLES: epidemiology/demographics, treatment and product cost. Data were from the US Western States Region IX, US Centers for Disease Control and Prevention, American Thrombosis and Hemostasis Network and the literature. RESULTS: Prior to EHL products and emicizumab, the usage of SHL products was ~300 million international units (IUs) or 6.8 IUs/capita and a cost of $430 million. With the uptake of EHL and emicizumab, the 2025 estimated usage of factor (SHL and EHL) was 270 million IUs (5.4 IU per capita) and 1,993 grams (40 micrograms/capita) for emicizumab and a cost of $532 million. As the number of HA patients in the region increases by 59%, factor usage increases by 20%, emicizumab usage increases by 26%, and cost increases to $650 million. CONCLUSION: The entrance of emicizumab into the market may radically change the use of SHL and EHL products. Our model suggests that emicizumab use will likely increase total product costs. While our estimates are most useful for the United States, the effect of emicizumab on factor use will likely be similar in other parts of the world.

The World Federation of Hemophilia Annual Global Survey 1999-2018.

INTRODUCTION: The World Federation of Hemophilia (WFH) strives to achieve care for all patients with inherited bleeding disorders through research, advocacy, capacity building and education. The WFH developed and implemented the Annual Global Survey (AGS), through which comprehensive demographic and treatment data on bleeding disorders are collected each year from its constituent non-governmental national organizations. AIM: To describe the development, methodology and achievements of the WFH AGS over the past 20 years. METHODS: The AGS is a yearly cross-sectional survey. Data are collected using a standardized form (available online and on paper), quality checked and reviewed, and published in English, French and Spanish. Over time, the AGS has been modified in response to changes in treatment landscape or emerging new issues. RESULTS: Over the past 20 years, the AGS has reported an increase in the number of countries participating in the survey, a tripling in the number of people identified with rare bleeding disorders and an increase in the amount of factor used to treat people with haemophilia. Yet, a large treatment inequity gap still exists across the globe. In response to this gap, the WFH has analysed the AGS reports which has stimulated further development in quality of care indicators, estimates of the global prevalence of haemophilia, patient-level data collection efforts like the World Bleeding Disorders Registry and the Gene Therapy Registry. CONCLUSION: The AGS has provided evidence to support research, programme planning and development activities of the WFH.

Establishing the Prevalence and Prevalence at Birth of Hemophilia in Males: A Meta-analytic Approach Using National Registries.

Background: The large observed variability in hemophilia prevalence prevents robust estimation of burden of disease. Objective: To estimate the prevalence and prevalence at birth of hemophilia and the associated life expectancy disadvantage. Design: Random-effects meta-analysis of registry data. Setting: Australia, Canada, France, Italy, New Zealand, and the United Kingdom. Participants: Male patients with hemophilia A or B. Measurements: Prevalence of hemophilia as a proportion of cases to the male population, prevalence of hemophilia at birth as a proportion of cases to live male births by year of birth, life expectancy disadvantage as a 1 - ratio of prevalence to prevalence at birth, and expected number of patients worldwide based on prevalence in high-income countries and prevalence at birth. Results: Prevalence (per 100 000 males) is 17.1 cases for all severities of hemophilia A, 6.0 cases for severe hemophilia A, 3.8 cases for all severities of hemophilia B, and 1.1 cases for severe hemophilia B. Prevalence at birth (per 100 000 males) is 24.6 cases for all severities of hemophilia A, 9.5 cases for severe hemophilia A, 5.0 cases for all severities of hemophilia B, and 1.5 cases for severe hemophilia B. The life expectancy disadvantage for high-income countries is 30% for hemophilia A, 37% for severe hemophilia A, 24% for hemophilia B, and 27% for severe hemophilia B. The expected number of patients with hemophilia worldwide is 1 125 000, of whom 418 000 should have severe hemophilia. Limitation: Details were insufficient to adjust for comorbid conditions and ethnicity. Conclusion: The prevalence of hemophilia is higher than previously estimated. Patients with hemophilia still have a life expectancy disadvantage. Establishing prevalence at birth is a milestone toward assessing years of life lost, years of life with disability, and burden of disease. Primary Funding Source: None.

Exploring regional variations in the cross-cultural, international implementation of the Patient Reported Outcomes Burdens and Experience (PROBE) study.

BACKGROUND: The Patient Reported Outcomes Burdens and Experience (PROBE) study has developed and validated the PROBE questionnaire for assessing patient-reported outcomes in people with haemophilia and participants without bleeding disorders. OBJECTIVE: To explore the regional variations in the international implementation of the PROBE questionnaire. METHODS: Data were collected from participants in four regions (Western Pacific, South America, North America and Europe). Participants were able to choose English or translated versions of the PROBE questionnaire into their first language. We used analysis of variance methods and multivariable regression to determine the relative contribution of the variance explained by region controlling for haemophilia diagnosis, age group and levels of educations. We also explored interactions between region and the other components. RESULTS: We used 862 questionnaires from 14 countries. Mean age of participants was 40.03 years (standard deviation 13.89), and 73.67% were male. After adjusting, region contributed 0.44%-7.98% of the variance component in subitem scores and 0.26% in the PROBE score. Years of education contributed 0.34% in the PROBE score. Age and haemophilia diagnosis contributed 3.42% and 22.42% of the PROBE score. CONCLUSIONS: The results demonstrate that the PROBE questionnaire is valid to implement for assessing health status among patients with haemophilia and participants without bleeding disorders across regions.

Test-retest properties of the Patient Reported Outcomes, Burdens and Experiences (PROBE) questionnaire and its constituent domains.

BACKGROUND: The Patient Reported Outcomes, Burdens and Experiences (PROBE) study aims to develop and validate questionnaire for assessing health status in patients with haemophilia and participants without bleeding disorders. OBJECTIVE: To investigate the test-retest properties of the PROBE questionnaire. METHODS: The PROBE questionnaire covers four domains and is comprised of 29 questions. People with haemophilia (PWH) and participants without bleeding disorder were invited to participate in this study. All participants were asked to complete the PROBE questionnaire three times (paper-based survey on two consecutive days: T1 and T2 and then a web-based version: T3). Test-retest properties and percentage agreement were analysed. RESULTS: A total of 63 participants were enrolled in this study with a median age of 50 (range: 17-76) years. Of these, 30 (47.6%) were PWH. On the questions common to PWH and participants without bleeding disorder, Kappa coefficients ranged from 0.69 to 1.00, indicating substantial to almost perfect agreement (T1 vs T2). For haemophilia-related questions (T1 vs T2), Kappa coefficients ranged from 0.5 to 1.0. Of these, 5 of 11 items were in perfect agreement (Kappa = 1.0). The web-based questionnaire (T3) showed substantial to almost perfect agreement with the paper version (T1 test-retest properties were comparable between PWH and individuals without a bleeding disorder). CONCLUSIONS: The results suggest that PROBE is a reliable tool to assess patient-reported outcomes for PWH and benchmark data in participants without bleeding disorder. The web-based questionnaire and the standard paper-based version can be used interchangeably.

Psychometric properties of the Patient Reported Outcomes, Burdens and Experiences (PROBE) questionnaire.

OBJECTIVE: To assess the psychometric properties of the Patient Reported Outcomes, Burdens and Experiences (PROBE) questionnaire. METHODS: This study was a cross-sectional, multinational study. Participants were enrolled if they were more than 10 years old and people with haemophilia A or B or people without a bleeding disorder. Participants were invited through non-governmental patient organisations in 21 countries between 01/27/2016 and 02/23/2017. The following psychometric properties: missing data, floor and ceiling effects, exploratory factor analysis and internal consistency reliability were examined. A PROBE Score was derived and assessed for its convergent and known groups validity. RESULTS: The study analysed the data on 916 participants with median age of 37.0 (IQR 27.0 to 48.0) years, 74.8% male. In the domain assessing patient-reported outcomes (PROs), more than 15% of participants presented a ceiling effect for all items but two, and a floor effect for one item. Factor analysis identified three factors explaining the majority of the variance. Cronbach's alpha coefficient indicated good internal consistency reliability (0.84). PROBE items showed moderate to strong correlations with corresponding EuroQol five dimension 5-level instrument (EQ-5D-5L) domains. The PROBE Score has a strong correlation (r=0.67) with EQ-5D-5L utility index score. The PROBE Score has a known groups validity among various groups. CONCLUSIONS: The results of this study suggest that PROBE is a valid questionnaire for evaluating PROs in people with haemophilia as well as control population. The known-group property of PROBE will allow its use in future clinical trials, longitudinal studies, health technology assessment studies, routine clinical care or registries. Additional studies are needed to test responsiveness and sensitivity to change. TRIAL REGISTRATION NUMBER: NCT02439710; Results.

Modeling primary immunodeficiency disease epidemiology and its treatment to estimate latent therapeutic demand for immunoglobulin.

PURPOSE: Estimating the underlying demand for immunoglobulin (Ig) is important to ensure that adequate provision is made for patients with primary immune deficiency (PID) in the context of the competing demands for Ig and to ensure optimal therapeutic regimens. The concept of latent therapeutic demand (LTD) was used to estimate evidence-based requirements and compared to the actual Ig consumption in different countries. The estimates were performed for common variable immunodeficiency (CVID) and X-linked Agammaglobulinaemia (XLA), the two most commonly studied PIDs using Ig. METHODS: The LTD model for CVID and XLA was derived using decision analysis methodology. Data for the epidemiology and treatment variables were obtained from peer-reviewed publications, clinical registries and publicly-available patient surveys. Incomplete data records from registries were excluded from analysis. The variables impacting LTD were ranked in order of sensitivity through a tornado diagram. The uncertainty surrounding the variables was modeled using probabilistic distributions and evaluated using Monte Carlo simulation. RESULTS: Treatment dosage and prevalence were determined to be the most sensitive variables driving demand. The average potential usage of Ig for the treatment of CVID and XLA was estimated at 72 g per 1,000 population, which is higher than the estimated Ig usage in CVID and XLA of 27-41 g per 1,000 population in the US. CONCLUSION: The potential demand for treating CVID and XLA exceeds the currently observed usage of Ig in these disorders. Variable usage in different countries is due to varying prevalence and dosage practices. Under-reporting in patient registries represents a major obstacle to calculating the true prevalence of CVID and XLA. Modeling demand relies heavily upon accurate prevalence and practice estimates which reemphasize the importance of accurate registries and improved registry methods. As better data becomes available, revision of model variables provides opportunities to anticipate and prepare for evolving patient needs.