A Comparative Study of Different Methods of Handling Missing Data in Patient Reported Outcomes, Burdens and Experiences (PROBE) Score Algorithm among People with Hemophilia

Ibrahim Q, Iorio A, Curtis R, Nichol M, Noone D, Stonebraker J, Skinner M, Germini F, and the PROBE investigators.
A Comparative Study of Different Methods of Handling Missing Data in Patient Reported Outcomes, Burdens and Experiences (PROBE) Score Algorithm among People with Hemophilia. THSNA 2022.

Background

The patient reported outcomes, burdens and experiences (PROBE) questionnaire measures quality of life in people with hemophilia and healthy controls. A score is calculated as the average of nine core questions. There is currently no validated method for calculating the PROBE score when data are missing.

Objective

Our objectives were to identify domains within the questionnaire and compare strategies for estimating the PROBE score when:
1. ≥50% item scores within a domian were available,
2. only one item score within a domain was available,
3. ≥50% item scores were available irrespective of any domain,
4. 8 out of 9 item scores were available.

Method

Scores with ICC ≥0.5 were grouped into a domain. We created one simulated data set for each combination of 1) types of missing data: MCAR, MAR, and MNAR, 2) 10, 15, and 20% missing values, and 3) the four strategies described above. A strategy with mean of absolute errors (MAE) + SD <0.05, and calibration intercepts and slopes not systematically different from 0 and 1, respectively, was considered acceptable.

Results

Among 3217 participants four item scores had ICC ≥0.5 and were grouped into a domain, pain or difficulty in daily activities (Cronbach’s alpha of 0.8). Strategies 1 and 4 performed better (MAE ± SD: 0.02 ± 0.02 for MCAR and MAR) followed by strategies 2 and 3 (Table 1). Strategy 1 estimated PROBE score accurately for MCAR and MAR data (Table 2), and slightly under-estimated the score in case of MNAR data.

Conclusion<

We recommend estimating PROBE scores as a simple average of the available item scores if at least one item within pain/difficulty in daily activities domain is available or 8 out of 9 items are available irrespective of the domain.

View Poster: HERE

The Patient Reported Outcomes Burdens and Experiences (PROBE) Study Questionnaire Development and Validation

Skinner M, Chai-Adisaksopha C, Noone D, Curtis R, Frick N, Nichol M, O’Mahony B, Page D, Pastarnak A, Stonebraker J, Iorio A and the Patient Reported Outcomes Burdens and Experiences (PROBE) Study Investigator Group. The Patient Reported Outcomes Burdens and Experiences (PROBE) Study Questionnaire Development and Validation (Abstract). NHF (2019).

Objectives

The health status of people living with hemophilia (PWH) has not been systematically investigated globally. There is a substantial need to improve capacity to collect and interpret relevant patient-reported outcomes (PRO) data to support patient-centered research and optimal care of PWH. PROBE aimed to: 1) implement a structured data collection of PRO across countries to build a robust evidence base for comparative effectiveness research, evidence-based decision making, and advocacy, 2) explore the measurement properties of the PROBE questionnaire and 3) assess the feasibility of PROBE for assessing health status among PWH and participants without bleeding disorders across regions. Three intermediate objectives were identified: develop a patient-led research network; develop a standardized questionnaire to gather PRO; and perform a feasibility study of implementing the PROBE questionnaire.

Methods

Data collection from April 2015 to February 2017. 2,101 surveys were collected through all study phases across 24 countries. 1,541 met study criteria for analysis. Clinical Trial registration: NCT02439710.

Summary

The PROBE questionnaire consists of four major sections: demographic data, general health problems, hemophilia-related health problems and health-related quality of life. Outcomes of importance to PWH and metrics to consider for measurement were determined.

Domains for outcomes of importance to measure reduced burden of living with hemophilia include (metrics): Life and Family (family life, marital status, children, current health status); Education/School and Employment (attendance, educational attainment, employment duration, underemployment) and Activities (impact on activities of daily living, mobility impairment, assistance required).

Domains for reduced complications associated with hemophilia and treatment (metrics): Joint Disease (joint status); Pain, Depression/Anxiety (chronic/acute pain, pain interference, pain occurrence, pain medication, depression); and Other Comorbidities (HIV/HCV, obesity, resource utilization, mortality, longevity).

PROBE questionnaire validation studies established face validity, relevance, clarity and completeness (Skinner, Pilot and Feasibility Studies 2018); test-retest reliability (reproducibility) (Chai‐Adisaksopha, Haemophilia 2019); a core analytic framework (psychometric properties) (Chai‐Adisaksopha BMJ Open2018); and cross-cultural validation (Chai‐Adisaksopha, Haemophilia 2019).

Conclusions

The PROBE questionnaire established and assessed patient-important outcomes in PWH and control participants, with a demonstrated short completion time using both paper and electronic versions. PROBE proved the feasibility to engage diverse patient communities in the structured generation of real-world outcome research at all stages. Results demonstrate that the PROBE questionnaire is valid for assessing PROs and health status among PWH and participants without bleeding disorders across regions. 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. Longitudinal PRO data collection using an instrument such as PROBE will be useful within clinical development programs, clinical management settings and to support access to care initiatives.

View Poster: PROBE Study questionnaire development and validation

Impact of Switching to Prophylaxis with Recombinant Factor IX Fc Fusion Protein Concentrate on Patient Reported Outcomes in People with Haemophilia B Using the PROBE Questionnaire

O’Donovan M, Johnston K, Singleton E, Benson J, Ryan K, O’Connell N. Impact of Switching to Prophylaxis with Recombinant Factor IX Fc Fusion Protein Concentrate on Patient Reported Outcomes in People with Haemophilia B Using the PROBE Questionnaire [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/impact-of-switching-to-prophylaxis-with-recombinant-factor-ix-fc- fusion-protein-concentrate-on-patient-reported-outcomes-in-people-with-haemophilia-b-using-the- probe-questionnaire/. Accessed July 22, 2020.

Background

In 2017 all patients with severe Haemophilia B in Ireland switched to prophylaxis with recombinant factor IX Fc fusion protein (rFIXFc) concentrate from treatment with standard half-life (SHL) recombinant FIX. The Patient Reported Outcomes, Burdens and Experiences (PROBE) questionnaire was developed to assess patient reported outcomes (PRO). Ithas four major sections; demographics, general health problems, haemophilia related health problems and health related quality of life.

Aims

To evaluate impact of switching to prophylaxis with rFIXFc from treatment with SHL FIX on PRO at two years after switchover.

Methods

Following ethical approval and informed consent, patients completed PROBE questionnaires pre switchover and at 24 months. Descriptive statistics were used for analysis.

Results

23 paired responses from 23 patients, median age 49 (31-72) years, with severe Haemophilia B were analysed. Acute pain, chronic pain and use of pain medication were reported at high rates at both 0 months (48%, 83% & 83%) and 24 months (64%, 74% & 95%). There was a reduction in chronic pain (83% to 74%) after 24 months of treatment with rFIXFc with a corresponding reduction in difficulties with activities of daily living (ADL). At 0 months, 61% reported :53difficulties with ADL. In comparison, at 24 months 68% reported :53 ADL difficulties, with greatest improvement seen with doing heavy domestic tasks (17%), bending down (13%), walking (13%) and going upstairs (13%). There was a reduction in reported number of bleeds; 50% :53 bleeds/annum in year prior to switchover, compared to 87% :53 bleeds/annum at 24months, with 35% reporting no bleeds.

Conclusions

From this initial data analysis there is a PRO benefit following a switch to rFIXFc prophylaxis with improvement in ADL, reduced chronic pain and bleeding rates. To further understand the patient experience post rFIXFc switch we plan to continue data analysis and perform qualitative interviews.

View Poster: Impact on switching to prophylaxis

Non-Severe Hemophilia Is Not Benign? – Insights from the PROBE Study

Chai-Adisaksopha C, Curtis R, Frick N, Nichol M, Noone D, Germini F, O’Mahony B, Page D, Stonebraker J, Skinner M, Iorio A, PROBE . Non-Severe Hemophilia Is Not Benign? – Insights from the PROBE Study [abstract]. Res Pract Thromb Haemost. 2020;4(Suppl 1). https://abstracts.isth.org/abstract/non-sever-hemophilia-is-not-benign-insights-from-the-probe-study/. Accessed June 29, 2020.

Introduction

There are limited data on the impact of haemophilia on health status and health-related quality of life (HRQL) in people affected by non-severe haemophilia.

Aim

To evaluate the health status of people living with mild or moderate haemophilia.

Methods

A cross-sectional, multinational study was conducted as part of the Patient Reported Outcomes, Burdens and Experiences (PROBE) project. Respondents without bleeding disorder (NoBD) and those with mild or moderate hemophilia were included. Respondents were asked to complete the PROBE questionnaire, which contains haemophilia-related questions, general health questions and HRQL. Results were compared between unaffected individuals and people with mild or moderate hemophilia.

Results

A total of 862 respondents, of whom 143 with moderate haemophilia, 143 with mild haemophilia and 575 with NoBD were included. Median age (first-third quartile) was 33 (23-46),42 (25-55) and 43 (35-54), respectively.  In relation to bleeding in the previous 12 months, respondents with mild reported less bleeding frequency than those with moderate haemophilia, with similar patterns of bleeding frequency seen in both male and female cohorts. Reporting of acute pain is less in those with NoBD compared to the mild to moderate cohorts for both genders (male – 33%, 67%, 77%; female 38%,52%, 67%, respectively). Thirteen percent of those with NoBD reported an impact on activities of daily living compared with mild and moderate haemophilia who reported of 35% and 61%, respectively. The impact on quality of life due to mild haemophilia compared to those with NoBD was a reduction of 5.2%, 5.0% and 9.3% in VAS, EQ-5D-5L and PROBE Score respectively (p≤0.001).

Conclusion

People affected by mild or moderate hemophilia encountered a significant amount of haemophilia related sequalae. Future research is needed to identify the optimal management of moderate and mild hemophilia patients, with particular focus on early identification of patients with a severe clinical phenotype.

View Poster: Mild and moderate hemophilia

Education Levels in People with Hemophilia – Insights from the PROBE Study

Kucher A, Noone D, Chai-Adisaksopha C, Curtis R, Frick N, Iorio A, Nichol M, O’Mahony B, Page D, Skinner M, Stonebraker J. Education in people with Hemophilia – Insights from the PROBE Study. Abstracts MTD-PP-045 (548). Haemophilia. 2020;26(S4):3-140. https://doi.org/10.1111/hae.13941

Introduction

Education is one of the key components relating to quality of life. The aim of this analysis was to examine the reported educational level of men with hemophilia in the PROBE study and compare it to the national average reported by the United Nations Development Programme (UNDP).

Methods

Annually, the UNDP Educational Index (EI), reports the highest degree of education an individual has completed. PROBE collects self-reported data on years of education. Data from all phases of PROBE were compiled on male PWH >25 years of age. To minimize the impact of patient duplication bias in the data set, for each pair of individuals from the same country, with the same hemophilia type and severity, born in the same year, and who reported the same number of years of education, one was excluded from the analysis. In total, 746 PWH from 17 countries, with a mean [SD] age of 45.4 [14.7] were analyzed. 80% had hemophilia A and 65% had severe hemophilia. Data was grouped by country and GNI category.

Results

The mean number of years of education reported was 15.5 [4.5] years with a range of 2-33 years with similar dispersion in both high (15.6 [4.3]) and upper middle-income countries (15.5 [4.7]). There was no significant difference in years of education reported between severe patients and mild/moderate patients by country or GNI category. In relation to EI, the mean UNDP data for high and upper middle-income countries whom participated in PROBE were 0.884 and 0.729 respectively; the mean EI data for the same countries were 0.951 and 0.853 for all PWH respectively and 0.936 and 0.859 for those with severe hemophilia (p<0.01).

Conclusions

EI calculated on PROBE data indicates that PWH aim to receive a higher education than those in the general population. This finding may be due to selection bias for the PROBE population or to PWH pursuing higher education in the face of career limitations imposed by hemophilia to increase their quality of life.  Further investigation is required to understand the finding.

View Poster: Education Level in Hemophilia Community

Changing community needs for those with a Bleeding Disorder in Poland

Gajewski B, Sumera A, Kaczmarek R, Kucher A, Noone D, Page D, Skinner M.
PP-75 (1160578) Changing community needs for those with a bleeding disorder in Poland. (2022), Abstracts. Haemophilia, 28: 5-97. https://doi.org/10.1111/hae.14537

Introduction

Treatment and care have improved for those with a bleeding disorder(BD) in Poland.  There is a generation who is ageing and a younger population with adequate care, each requiring different services.

Methods

In early 2020, a fully anonymised survey on access to haemophilia centre services was developed and fielded on-line through the Polish haemophilia society. The PROBE questionnaire was included.

Results

284 people with a bleeding disorder, parents or caregivers (PwBD) responded to the survey (Figure). The mean distance from the PwBD home to a haemophilia centre was 56 (±61) kms and a comprehensive care centre (CCC) was 258 (±147) km. The mean reported appointment waiting time nationally was 1.7 (±2.9) months. In PwBD reporting home treatment, 94% report access at home. Of these, 41% receive home delivery. The national mean of the EQ-5D utility and PROBE score for PwBD  was 0.748 (±0.219) and 0.730 (±0.135), respectively.  The mean for those without a bleeding disorder in Poland in the full PROBE dataset was 0.882 (±0.219) and 0.845 (±0.104), respectively. The majority of PwBD indicate they would like clinics, nursing facilities and physiotherapy to be available through telemedicine in the future. Excluding those currently attending a CCC, 30% would prefer telemedicine be delivered through the CCC rather than their local centre.

Summary

There is a still a clear gap in quality of life between those with and without a BD in Poland. There is an increasing and changing need for services and care nationally which needs to be addressed for overall improvement of quality of life for PwBD in Poland.

View Poster: Poland Study