A New Approach to Assessing Children’s Interpretation of Severity Qualifiers in a Multi-Attribute Utility Instrument–The EQ-5D-Y-5L: Development and Testing

Introduction The beta EQ-5D-Y-5L is a new patient-reported outcome measure (PROM) for children aged 8–15 years that is currently under development by the EuroQol Group. The EQ-5D-Y-5L is similar to the EQ-5D-Y but has five levels of severity per dimension rather than three. The increased number of levels increases the granularity of the responses but possibly has also increased the difficulty of distinguishing between levels. The EuroQoL’s Version Management Committee (VMC) required a robust method to determine how well children distinguish between the five EQ-5D-Y-5L ordinal severity qualifiers (i.e. ‘no problems’ through to ‘extreme problems’), which are a critical aspect of both health measurement and the valuation of health states. Objective This paper describes the development, testing, selection, and piloting of such a method. Methods Following a literature review and consultation with the wider VMC and a Language Support Services agency, a range of exercises were developed to assess the ordering and comprehension of the five severity qualifiers. Three exercises were pre-tested with children in Spain and New Zealand. One exercise, preferred and understood by children, was then piloted. Results Five children in Spain and 11 in New Zealand tested the three exercises. In both countries, all children found the three exercises easy to understand and complete. Of the 12 children who expressed a preference, nine said they preferred the card ranking. Card ranking also allowed the interviewer to observe difficult choices being made as the children physically rearranged the card order until they settled on their final order. Following rigorous assessment of translatability and cultural portability by an independent Language Support Service, card ranking was piloted in South Africa (n = 9) and in Indonesia (n = 10), where it highlighted severity qualifier order inversions that would otherwise not have been detected. Conclusion The card ranking exercise was found to be a preferred and acceptable means of testing the ordering of translations of severity qualifiers among children. Additional formal testing of the exercise in other countries and languages is now underway. The approach developed and tested by the VMC for cognitive debriefing of beta EQ-5D-Y-5L language/country versions may also be useful in determining the adequacy of translated qualifiers in debriefing of adult EQ-5D-5L versions and other PROMs

A systematic literature review of preference-based health related quality-of-life measures applied and validated for use in childhood and adolescent populations in sub-Saharan Africa

Objectives: Consideration of health status in children and adolescents now includes broader concepts such as health-related quality-of-life (HRQoL). Globally, there is a need for relevant preference-based HRQoL measures (PBMs) for use in children and adolescents, yet measurement of HRQoL in these groups presents particular challenges. This article systematically reviews the available generic childhood PBMs and their application and cross-cultural validation in sub-Saharan African (sSA). Methods: A systematic review of published literature from January 1, 1990, to February 8, 2017, was conducted using MEDLINE (through OvidSP), EMBASE (OvidSP), EconLit (EBSCOhost), PsycINFO, Web of Science, and PubMed. Results: A total of 220 full-text articles were included in a qualitative synthesis. Ten generic childhood PBMs were identified, of which 9 were adapted from adult versions and only 1 was developed specifically for children. None of the measures were originally developed in sSA or other resource-constrained settings. The Health Utilities Index Mark 3 (HUI3) and the EQ-5D-Y were the only measures that had been applied in sSA settings. Further, the HUI3 and the EQ-5D-Y were the only generic childhood PBM that attempted to establish cross-cultural validation in sSA. Five of the 6 of these validation studies were conducted using the EQ-5D-Y in a single country, South Africa. Conclusions: The findings show that application of generic childhood PBMs in sSA settings has hitherto been limited to the HUI3 and EQ-5D-Y. Most adaptations of existing measures take an absolutist approach, which assumes that measures can be used across cultures. Nevertheless, there is also need to ensure linguistic and conceptual equivalence and undertake validation across a range of sSA cultural contexts

A qualitative study on the feasibility and acceptability of institutionalizing health technology assessment in Malawi

OBJECTIVE: The objective of this study was to assess the feasibility and acceptability of institutionalizing Health Technology Assessment (HTA) in Malawi. METHODS: This study employed a document review and qualitative research methods, to understand the status of HTA in Malawi. This was complemented by a review of the status and nature of HTA institutionalization in selected countries.Qualitative research employed a Focus Group Discussion (FGD ) with 7 participants, and Key Informant Interviews (KIIs) with12 informants selected based on their knowledge and expertise in policy processes related to HTA in Malawi.Data extracted from the literature was organized in Microsoft Excel, categorized according to thematic areas and analyzed using a literature review framework. Qualitative data from KIIs and the FGD was analyzed using a thematic content analysis approach. RESULTS: Some HTA processes exist and are executed through three structures namely: Ministry of Health Senior Management Team, Technical Working Groups, and Pharmacy and Medicines Regulatory Authority (PMRA) with varyingdegrees of effectiveness.The main limitations of current HTA mechanisms include limited evidence use, lack of a standardized framework for technology adoption, donor pressure, lack of resources for the HTA process and technology acquisition, laws and practices that undermine cost-effectiveness considerations. KII and FGD results showed overwhelming demand for strengthening HTA in Malawi, with a stronger preference for strengthening coordination and capacity of existing entities and structures. CONCLUSION: The study has shown that HTA institutionalization is acceptable and feasible in Malawi. However, the current committee based processes are suboptimal to improve efficiency due to lack of a structured framework. A structured HTA framework has the potential to improve processes in pharmaceuticals and medical technologies decision-making.In the short to medium term, HTA capacity building should focus on generating demand and increasing capacity in cost-effectiveness assessments. Country-specific assessments should precede HTA institutionalization as well as recommendations for new technology adoptions

Soluble biomarkers associated with chronic lung disease in older children and adolescents with perinatal HIV infection.

OBJECTIVE: HIV-associated chronic lung disease (HCLD) is a common comorbidity in children and adolescents in sub-Saharan Africa (SSA). The pathogenesis of HCLD is unclear and may be driven by underlying dysregulated systemic immune activation and inflammation. We investigated the association between 26 plasma soluble biomarkers and HCLD. DESIGN: Case--control analysis of baseline biomarker data from 336 children and adolescents (6-19 years old) with perinatal HIV infection (PHIV) and HCLD (cases) and 74 age-matched and sex-matched controls with PHIV but no CLD. HCLD was defined as having a forced expiratory volume in one second (FEV1) z score less than -1 with no reversibility. METHODS: Cryopreserved plasma collected at recruitment was used in a multiplex bead assay (Luminex) to measure baseline levels of soluble biomarkers. Logistic regression alongside data-reduction and techniques quantifying the interconnectedness of biomarkers were used to identify biomarkers associated with odds of HCLD. RESULTS: Biomarkers of general immune activation and inflammation (β2M, CRP, sCCL5, GCSF, IFN-γ, IP-10), T-cell activation (sCD25, sCD27), platelet activation (sCD40-L), monocyte activation (sCD14), coagulation (D-Dimer), cellular adhesion (E-selectin), and extracellular matrix degradation (MMP-1, MMP-7, MMP-10) were associated with increased odds of HCLD. Exploratory PCA and assessment of biomarker interconnectedness identified T-cell and platelet activation as centrally important to this association. CONCLUSION: HCLD was associated with a large number of soluble biomarkers representing a range of different pathways. Our findings suggest a prominent role for T-cell and platelet activation in HCLD

Growth Profiles of Children and Adolescents Living with and without Perinatal HIV Infection in Southern Africa: A Secondary Analysis of Cohort Data

Impaired linear growth and slower pubertal growth can be associated with perinatal HIV infection. We characterised growth relative to population norms, among the full adolescent period in southern Africa to better understand processes leading to morbidity in adulthood. We conducted a secondary analysis of 945 adolescents aged 8-20 years from urban Malawi and Zimbabwe; we included children with HIV (CWH), an uninfected comparison group from a cohort study, and CWH with co-morbid chronic lung disease (CLD) from a randomised controlled trial. We used latent class analysis of anthropometric Z-scores generated from British 1990 reference equations at two annual time-points, to identify growth trajectory profiles and used multinomial logistic regression to identify factors associated with growth profiles. Growth faltering (one or more of weight-for-age, height-for-age, or BMI-for-age Z-scores < -2) occurred in 38% (116/303) of CWH from the cohort study, 62% (209/336) of CWH with CLD, and 14% (44/306) of HIV-uninfected participants. We identified seven different growth profiles, defined, relatively, as (1) average growth, (2) tall not thin, (3) short not thin, (4) stunted not thin, (5) thin not stunted, (6) thin and stunted and (7) very thin and stunted. Females in profile 3 exhibited the highest body fat percentage, which increased over 1 year. Males at older age and CWH especially those with CLD were more likely to fall into growth profiles 4-7. Improvements in height-for-age Z-scores were observed in profiles 6-7 over 1 year. Interventions to target those with the worst growth faltering and longer-term follow-up to assess the impact on adult health are warranted

The impact of long-term azithromycin on antibiotic resistance in HIV-associated chronic lung disease

Selection for resistance to azithromycin (AZM) and other antibiotics such as tetracyclines and lincosamides remains a concern with long-term AZM use for treatment of chronic lung diseases (CLD). We investigated the impact of 48 weeks of AZM on the carriage and antibiotic resistance of common respiratory bacteria among children with HIV-associated CLD. Nasopharyngeal (NP) swabs and sputa were collected at baseline, 48 and 72 weeks from participants with HIV-associated CLD randomised to receive weekly AZM or placebo for 48 weeks and followed post-intervention until 72 weeks. The primary outcomes were prevalence and antibiotic resistance of Streptococcus pneumoniae (SP), Staphylococcus aureus (SA), Haemophilus influenzae (HI) and Moraxella catarrhalis (MC) at these timepoints. Mixed-effects logistic regression and Fisher's exact test were used to compare carriage and resistance, respectively. Of 347 (174 AZM, 173 placebo) participants (median age 15 years (IQR 13–18), female 49%), NP carriage was significantly lower in the AZM (n=159) compared to placebo (n=153) arm for SP (18% versus 41%, p<0.001), HI (7% versus 16%, p=0.01) and MC (4% versus 11%, p=0.02); SP resistance to AZM (62% (18 out of 29) versus 13% (8 out of 63), p<0.0001) or tetracycline (60% (18 out of 29) versus 21% (13 out of 63), p<0.0001) was higher in the AZM arm. Carriage of SA resistant to AZM (91% (31 out of 34) versus 3% (1 out of 31), p<0.0001), tetracycline (35% (12 out of 34) versus 13% (4 out of 31), p=0.05) and clindamycin (79% (27 out of 34) versus 3% (1 out of 31), p<0.0001) was also significantly higher in the AZM arm and persisted at 72 weeks. Similar findings were observed for sputa. The persistence of antibiotic resistance and its clinical relevance for future infectious episodes requiring treatment needs further investigation

"The effect of 48-weeks azithromycin therapy on levels of soluble biomarkers associated with HIV-associated chronic lung disease".

OBJECTIVES: HIV-associated immune activation contributes to chronic lung disease (CLD) in children and adolescents living with HIV. Azithromycin has immunomodulatory and anti-microbial properties that may be useful for treating HIV-associated CLD (HCLD). This study describes the effect of azithromycin on expression of plasma soluble biomarkers in children and adolescents with HCLD. METHODS: This study was nested within a multi-site double-blind, placebo controlled, randomised controlled trial (RCT) of azithromycin in individuals aged 6-19 years with HCLD (defined as FEV1 z-score < -1) in Malawi and Zimbabwe (BREATHE (NCT02426112)). Participants were randomized 1:1 to once-weekly oral azithromycin with weight-based dosing, for 48 weeks, or placebo. Twenty-six plasma soluble biomarkers were measured on a MagPix Luminex instrument at enrolment, after 48-weeks of treatment and 24-weeks after treatment cessation. Mixed effects models were constructed to compare biomarker expression across treatment and placebo groups. RESULTS: Weekly azithromycin was associated with reduced levels of C-Reactive Protein (CRP), E-Selectin, Matrix metalloproteinase 10 (MMP-10). Treatment effects for all soluble biomarkers were not sustained 24-weeks after treatment cessation with biomarker expression returning to pre-treatment levels. CONCLUSIONS: We observed real-world effects of azithromycin on acute inflammation, neutrophil accumulation, and extracellular matrix degradation, that were not sustained after treatment cessation. These results are pertinent when using azithromycin for its immunomodulatory properties, or targeting pathways represented by the soluble biomarkers in this study

Childhood health-related quality of life in context of economic evaluation in Malawi

Background & aims: Preference-based measurements (instruments) of childhood health-related quality of life (HRQoL) in sub-Saharan Africa (sSA) are limited. This thesis set out: i) to identify existing childhood preference-based HRQoL instruments; ii) to explore how the existing instruments are adapted for use in sSA and; iii) to establish if the adaptation process aligns with local health perceptions in Malawi. Methods: Step 1: Systematic review and selection of childhood preference-based HRQoL instruments This step involved: i) a literature review to identify existing childhood preference-based HRQoL measures, and their use in sSA settings; and ii) assessing identified instruments in terms of their psychometric properties and adherence to utility theory to inform the selection of measures for cross-cultural adaptation in Malawi. Step2: Cross-cultural adaptation of childhood preference-based HRQoL instruments The adaptation process included the following two stages. i) Translation: Two independent translators forward and backward translated selected instruments (EQ-5DY, EQ-5D-Y-5L, PedsQL™ 4.0 child self-report, and PedsQL™ 4.0 teen self-report) into Chichewa language for Malawi. The translated versions were piloted (cognitive interviews) in a sample of participants (n=38), aged 8-17years from the main referral hospital and primary and secondary schools within Blantyre city, the commercial capital of Malawi. ii) Cognitive interviews process: a) Self completion of the questionnaire For the EQ-5D-Y-5L only, a card exercise was employed to assess the correct hierarchical ranking of response options. All the Chichewa translated instruments were administered to different sets of participants for self-completion. If necessary, children who struggled to understand instruction for self-completion of the questionnaires were given assistance but not on how to respond to them. b) Cognitive interviews Each child participating in the interviews then took part in a one-to-one interview about their understanding of the questionnaire. The interviews were open ended, and participants were asked to comment on how they understood each question and response options. Following piloting and making necessary changes, pre-final Chichewa versions were sent to developers for approval. Step 3: Psychometric validation The approved Chichewa versions were administered to a larger sample (n=298, age 8-17 years) consisting of healthy (n=95) and sick (chronic and acute, n=194) children to assess psychometric performance. The EQ-5D-Y and EQ-5D-Y-5L have five dimensions each with three and five response options respectively. The PedsQL™ 4.0 has 23 items and five response options each. The EQ-5D-Y and EQ-5D-Y-5L scores were generated in two different ways. HRQoL sum scores were generated by adding numeric values of response levels and utility scores were generated using USA utility values to evaluate psychometric performance and utility performance (empirical validity) respectively. The PedsQL™ 4.0 scores were generated following an algorithm provided by the instrument developers. The instruments performance were then assessed using standardized psychometric criteria: item performance (missing data >5%); internal consistency reliability (Cronbach a ³0.7); and validity (convergent of EQ-5DY sum scores and PedsQL™ 4.0 scores >0.4; discriminant: no association between HRQoL scores with gender & grade; known groups between healthy and sick groups: effect size >0.5). Additionally, since the EQ-5D-Y and EQ-5D-Y-5L are utility instruments, they were assessed for empirical validity (relative efficiency of the EQ-5D-Y-5L relative to the EQ-5D-Y, where >1 means the former performing better than the latter). Content validity was later evaluated by firstly developing a conceptual framework for health from four focus group discussions (FGDs) composed of 6-12 participants, aged 8-17 years. The framework was conceptualized using axial and selective coding FGDs to generate main concepts which were considered important by children and adolescents in a Malawian setting. The concepts from the model were compared against those of the existing EQ-5D-Y dimensions to assess if the EQ-5D-Y contains all the relevant dimensions that children and adolescent consider important in this setting. Results: Ten preference-based HRQoL instruments were identified and none of these had been developed in low- and/or middle- income countries. Of these, only two (HUI3 and EQ-5D-Y had been used in a sSA setting. : i) EQ-5D-Y (preference-based), and ii) PedsQL™ 4.0 selfreport (non preference-based) were selected for cross-cultural adaptation into Chichewa and subsequently psychometrically validated in a Malawian setting. i) Translation: There were several conceptual and linguistic problems identified from the translation process. Most of these were identified and resolved by translators during the consensus process. However, translation issues such as those referring to ‘life’, ‘health’, and ‘healthy’ were problematic. Some translation issues including those pertaining to qualifiers for responses and dimension equivalence were only resolved during cognitive interviews. ii) Cognitive interviews process: a) Self-completion of the questionnaires Children, <12 years, struggled to self-complete questionnaire without interviewer assistance. b) Cognitive interviews on conceptual issues and questionnaire Children related the EQ-5D-Y ‘looking after oneself’ dimension to lack of provision such as soap instead of functional ability. ‘Kusamba’ in PedsQL™ 4.0 translated ‘to bath’ was found to imply a menstrual cycle and the translation was subsequently revised. Four rounds of card ranking exercise were necessary to establish appropriate EQ-5D-Y-5L hierarchical ordering. iii) Psychometric validation: There was little problem with missing data except in children aged 8-12 years. The Cronbach assessment of internal consistency reliability was acceptable and above the threshold (a>0.7) for all instruments. The correlation of EQ-5D-Y (EQ-5D-Y-5L) sum scores and PedsQL™ 4.0 overall scores was >0.4, providing evidence of convergent validity; but the correlation between some of the EQ-5D-Y dimensions and PedsQL™ 4.0 self-report sub-scales was mixed. There was no association between HRQoL scores with gender and age but the association with school grade (p<0.05) showed lack of discriminant validity. For empirical validity, the EQ-5D-Y-5L was 31%-91% less efficient than the EQ-5D-Y at detecting differences in health status using external measures. A new conceptual framework describing health for Malawi children/young people was developed with seven concepts. Some concepts like ‘God-given ‘and ‘acceptanceof illness’ have rarely been included in generic health instruments. Only two concepts in the model were at the same level as two EQ-5D-Y dimensions. Discussion and conclusion: Health, life and healthy were complex terms to translate, and even with help from cognitive interviews these were found to be problematic. The cognitive interviews were instrumental in isolating translation problems and appropriate hierarchical ordering. The psychometric findings demonstrate that the Chichewa (Malawi) PedsQL™ 4.0 child self-report and PedsQL™ 4.0 teen self-report established reliability, but evidence of their validity was mixed. While the PedsQL™ 4.0 child self-report met most psychometric criteria, the missing data and lack of known-groups validity means this should be used with caution in younger children and in those with different health conditions. The study did not find much difference between the EQ-5D-Y and EQ-5D-Y-5L in terms of missing data, reliability and known-group validity. The EQ-5D-Y had problems with knowngroups validity. The EQ-5D-Y-5L demonstrated reliability and validity except discriminant validity with grade. Whereas the EQ-5D-Y-5L performed better than the EQ-5D-Y in terms of discriminant validity, the latter outperformed the EQ-5D-Y-5L in the utilization of response options as well as in terms of empirical validity. The EQ-5D-Y and EQ-5D-Y-5L were found to be reliable for use among children and adolescents in relation to economic evaluation. However, psychometric testing is required for test re-test reliability and responsiveness that could not be carried out in this study due to COVID-19 restrictions. Additionally, the conceptual framework developed demonstrates that HRQoL instruments do not align with local perceptions of health. There are some elements of content validity missing and also concepts that could not translate easily limit the content of these instruments in this setting. In conclusion, this doctorate research produced Chichewa versions which have potential for use in this setting among children and adolescents but with caveats. This thesis documents the cross-cultural adaptation and validation processes of the EQ-5D-Y, EQ-5D-Y-5L and PedsQL™ 4.0 self-report for use among children and adolescents in Malawi

Psychometric performance of the Chichewa versions of the EQ-5D-Y-3L and EQ-5D-Y-5L among healthy and sick children and adolescents in Malawi

Objectives: The EuroQol Group has developed an extended version of the EQ-5D-Y-3L with five response levels for each of its five dimensions (EQ-5D-Y-5L). The psychometric performance has been reported in several studies for the EQ-5D-Y-3L but not for the EQ-5D-Y-5L. This study aimed to psychometrically evaluate the EQ-5D-Y-3L and EQ-5D-Y-5L Chichewa (Malawi) versions. Methods: The EQ-5D-Y-3L, EQ-5D-Y-5L and PedsQL™ 4.0 Chichewa versions were administered to children and adolescents aged 8–17 years in Blantyre, Malawi. Both of the EQ-5D-Y versions were evaluated for missing data, floor/ceiling effects, and validity (convergent, discriminant, known-group and empirical). Results: A total of 289 participants (95 healthy, and 194 chronic and acute) self-completed the questionnaires. There was little problem with missing data ( 0.05) with respect to gender and age, but not for school grade (p < 0.05). For empirical validity, the EQ-5D-Y-5L was 31–91% less efficient than the EQ-5D-Y-3L at detecting differences in health status using external measures. Conclusions: Both versions of the EQ-5D-Y-3L and EQ-5D-Y-5L had issues with missing data in younger children. Convergent validity, discriminant validity with respect to gender and age, and known-group validity of either measures were also met for use among children and adolescents in this population, although with some limitations (discriminant validity by grade and empirical validity). The EQ-5D-Y-3L seems particularly suited for use in younger children (8–12 years) and the EQ-5D-Y-5L in adolescents (13–17 years). However, further psychometric testing is required for test re-test reliability and responsiveness that could not be carried out in this study due to COVID-19 restrictions

Patient‐incurred cost of inpatient treatment for Tuberculosis in rural Malawi

Objectives: To mitigate the economic burden of tuberculosis (TB), it is important to fully understand the costs of TB treatment from the patient perspective. We therefore sought to quantify the patient-incurred cost of TB treatment in rural Malawi, with specific focus on costs borne by patients requiring inpatient hospitalization