Development of data processing algorithm to calculate adherence for adults with cystic fibrosis using inhaled therapy - a multi-center observational study within the CFHealthHub learning health system.

OBJECTIVES: To develop a robust algorithm to accurately calculate 'daily complete dose counts' for inhaled medicines, used in percent adherence calculations, from electronically-captured nebulizer data within the CFHealthHub Learning Health System. METHODS: A multi-center, cross-sectional study involved participants and clinicians reviewing real-world inhaled medicine usage records and triangulating them with objective nebulizer data to establish a consensus on 'daily complete dose counts.' An algorithm, which used only objective nebulizer data, was then developed using a derivation dataset and evaluated using internal validation dataset. The agreement and accuracy between the algorithm-derived and consensus-derived 'daily complete dose counts' was examined, with the consensus-derived count as the reference standard. RESULTS: Twelve people with CF participated. The algorithm derived a 'daily complete dose count' by screening out 'invalid' doses (those <60s in duration or run in cleaning mode), combining all doses starting within 120s of each other, and then screening out all doses with duration < 480s which were interrupted by power supply failure. The kappa co-efficient was 0.85 (0.71-0.91) in the derivation and 0.86 (0.77-0.94) in the validation dataset. CONCLUSIONS: The algorithm demonstrated strong agreement with the participant-clinician consensus, enhancing confidence in CFHealthHub data. Publishingdata processing methods can encourage trust in digital endpoints and serve as an exemplar for other projects.

"I think most people feel like healthcare professionals tell them to take their treatments and judge them for not taking them": reflexive thematic analysis of the views of adults with cystic fibrosis on how treatment adherence is discussed in healthcare.

OBJECTIVE: Previous research exploring patient-practitioner communication in relation to adherence in cystic fibrosis (CF) is limited. This UK study explored the views of adults with CF on how treatment adherence (related to all CF treatments) is discussed in routine CF care. METHODS: 12 White British adults (ten females; aged 20-37 years; mean 30.1 years) with CF participated in semi-structured interviews. RESULTS: Three overarching themes were developed through reflexive thematic analysis: (1) 'The power of language'; (2) 'Healthcare professionals do not recognise the importance of context'; and (3) '"Admitting" non-adherence is difficult'. The way in which adherence is discussed in adult CF care is viewed as paternalistic and infantilising. Participants reported that healthcare professionals do not always consider the desire to balance treatment-taking with living a normal life. Unwelcome responses from healthcare professionals, and the inability to accurately self-report the amount of treatment taken made it difficult to 'admit' non-adherence. CONCLUSIONS: A culture change is needed in CF care such that people who struggle to take their treatments are not labelled as disobedient, wilfully disobeying orders from healthcare professionals in positions of authority. Instead, an open, honest, non-judgemental approach, as recommended by healthcare agencies for over a decade, should be adopted.

A model-based economic analysis of the CFHealthHub intervention to support adherence to inhaled medications for people with cystic fibrosis in the UK.

BACKGROUND: Adherence to preventative inhaled therapies in people with cystic fibrosis (CF) is low, resulting in potentially avoidable health losses and the need for costly rescue therapies. OBJECTIVES: To estimate the cost-effectiveness of the CFHealthHub (CFHH) intervention to support adherence to inhaled medications. METHODS: A state transition model was developed to assess the cost-effectiveness of the CFHH intervention versus usual care from the perspective of the UK National Health Service and Personal Social Services over a lifetime horizon. Costs and health outcomes were discounted at a rate of 3.5 percent per annum. Costs were valued at 2021/22 prices. The model structure includes health states defined by survival status, level of lung function, and transplant history. Treatment effects were modeled by changing the probabilities of transitioning between lung function states and reducing exacerbation rates. Model parameters were informed by the CFHH trial, CF Registry data, routine cost databases, literature, and expert opinion. Deterministic and probabilistic sensitivity analyses were undertaken to assess uncertainty. RESULTS: The CFHH intervention is expected to generate additional health gains and cost savings compared with usual care. Assuming that it is delivered for 10 years, the CFHH intervention is expected to generate 0.17 additional quality-adjusted life years and cost savings of GBP 1,600 (EUR 1,662) per patient. CONCLUSIONS: The CFHH intervention is expected to dominate usual care, irrespective of the duration over which the intervention is delivered. The modeled benefits and cost savings are smaller than initially expected and are sensitive to relative treatment effects on lung function.

Modelling Successful Self-Management in Adults With Cystic Fibrosis: Vicarious Self-Efficacy From Videos of 'People Like Me'.

Background Self-efficacy is an important determinant of treatment adherence, and peer modelling of success can provide vicarious self-efficacy. A series of patient stories ('talking heads' videos) were developed with people with cystic fibrosis (CF) as part of the CFHealthHub multi-component adherence intervention, aiming to demonstrate success with daily therapy in 'people like me'. Methodology One-to-one semi-structured interviews exploring patients' experiences, barriers and facilitators of nebuliser adherence were audio and video-recorded between October 2015 and August 2016. Interview transcripts were reviewed to identify descriptions of problem-solving and sustained treatment success. Positive stories potentially providing vicarious descriptions of success were selected as video clips. Results In total, 14 adults with CF were recruited from five UK CF centres. Each participant contributed a median of five (interquartile range: 3-6) video clips, and a total of 57 unique clips were uploaded onto the CFHealthHub digital platform. Nine of those clips spanned two categories, hence, there were 66 clips across 16 categories. Conclusions The videos were well received though some adults were concerned that comparisons with peers might create anxiety by highlighting the possibility of future decline or current relative underperformance. It is important to sensitively support choice when providing resources aiming to increase vicarious self-efficacy. Our experience may guide the development of similar videos for people with other long-term conditions.

Objective Nebuliser Adherence Data as "Proof" of Adherence in the Management of Cystic Fibrosis: A Qualitative Interview Study.

Purpose: Low adherence to medication via nebulisers is linked to poor clinical outcomes for people with Cystic Fibrosis (PWCF). Advances in technology allow electronic monitoring of nebuliser usage and feedback of objective adherence data to PWCF and clinical teams caring for them. CFHealthHub is a new intervention that collects and displays objective adherence data in easy-to-read formats with the aim of improving nebuliser adherence and health. There is little understanding of how objective adherence data is perceived by PWCF and healthcare professionals (HCPs). Patients and Methods: A qualitative study using semi-structured interviews with 22 PWCF and 31 HCPs who had used the CFHealthHub intervention. Results: Objective adherence data was welcomed by the majority of PWCF in the sample, and HCP delivering the intervention, because the data allowed PWCF to reflect on patterns of adherence or non-adherence. Ease of use and characteristics of data display were important, particularly the use of a "traffic light" system to allow PWCF to easily see if they were meeting their adherence targets. For PWCF objective adherence data was used as "proof to self", offering reassurance to high adherers, and a wake-up call to those with lower levels of adherence. It could also provide 'proof to others' where PWCF had higher levels of adherence than HCP or family members believed. The data could sometimes change HCP perceptions of PWCF's identities as poor adherers. Where adherence was not high, data was used to facilitate honest discussions between PWCF and HCPs about how to increase adherence. HCPs perceived that it was important to use the data positively to motivate, rather than criticise, PWCF. Conclusion: Objective nebuliser adherence data in CFHealthHub can offer proof of adherence to PWCF and HCPs. It is important to use it constructively to facilitate discussions on how to improve adherence.

Implementing the use of objective medication adherence data in routine clinical practice via the digital CFHealthHub platform: situation analysis and strategy development using the theoretical domains framework.

BACKGROUND: Preventative inhaled treatments preserve lung function and reduce exacerbations in cystic fibrosis (CF). Self-reported adherence to these treatments is over-estimated. An online platform (CFHealthHub) has been developed with patients and clinicians to display real-time objective adherence data from dose-counting nebulisers, so that clinical teams can offer informed treatment support. METHODS: In this paper, we identify pre-implementation barriers to healthcare practitioners performing two key behaviours: accessing objective adherence data through the website CFHealthHub and discussing medication adherence with patients. We aimed to understand barriers during the pre-implementation phase, so that appropriate strategy could be developed for the scale up of implementing objective adherence data in 19 CF centres. Thirteen semi-structured interviews were conducted with healthcare practitioners working in three UK CF centres. Qualitative data were coded using the theoretical domains framework (TDF), which describes 14 validated domains to implementation behaviour change. RESULTS: Analysis indicated that an implementation strategy should address all 14 domains of the TDF to successfully support implementation. Participants did not report routines or habits for using objective adherence data in clinical care. Examples of salient barriers included skills, beliefs in consequences, and social influence and professional roles. The results also affirmed a requirement to address organisational barriers. Relevant behaviour change techniques were selected to develop implementation strategy modules using the behaviour change wheel approach to intervention development. CONCLUSIONS: This paper demonstrates the value of applying the TDF at pre-implementation, to understand context and to support the development of a situationally relevant implementation strategy.

Self-management intervention to reduce pulmonary exacerbations by supporting treatment adherence in adults with cystic fibrosis: a randomised controlled trial.

INTRODUCTION: Recurrent pulmonary exacerbations lead to progressive lung damage in cystic fibrosis (CF). Inhaled medications (mucoactive agents and antibiotics) help prevent exacerbations, but objectively measured adherence is low. We investigated whether a multi-component (complex) self-management intervention to support adherence would reduce exacerbation rates over 12 months. METHODS: Between October 2017 and May 2018, adults with CF (aged ≥16 years; 19 UK centres) were randomised to the intervention (data-logging nebulisers, a digital platform and behavioural change sessions with trained clinical interventionists) or usual care (data-logging nebulisers). Outcomes included pulmonary exacerbations (primary outcome), objectively measured adherence, body mass index (BMI), lung function (FEV1) and Cystic Fibrosis Questionnaire-Revised (CFQ-R). Analyses were by intent to treat over 12 months. RESULTS: Among intervention (n=304) and usual care (n=303) participants (51% female, median age 31 years), 88% completed 12-month follow-up. Mean exacerbation rate was 1.63/year with intervention and 1.77/year with usual care (adjusted ratio 0.96; 95% CI 0.83 to 1.12; p=0.64). Adjusted mean differences (95% CI) were in favour of the intervention versus usual care for objectively measured adherence (9.5% (8.6% to 10.4%)) and BMI (0.3 (0.1 to 0.6) kg/m2), with no difference for %FEV1 (1.4 (-0.2 to 3.0)). Seven CFQ-R subscales showed no between-group difference, but treatment burden reduced for the intervention (3.9 (1.2 to 6.7) points). No intervention-related serious adverse events occurred. CONCLUSIONS: While pulmonary exacerbations and FEV1 did not show statistically significant differences, the intervention achieved higher objectively measured adherence versus usual care. The adherence difference might be inadequate to influence exacerbations, though higher BMI and lower perceived CF treatment burden were observed.

The CFHealthHub Learning Health System: Using Real-Time Adherence Data to Support a Community of Practice to Deliver Continuous Improvement in an Archetypal Long-Term Condition.

CFHealthHub is a learning health system active in over 50% of adult CF Centres in England, supporting people with CF to develop habits of self-care around adherence to preventative inhaled therapy. This is achieved through the delivery of a behaviour change intervention, alongside collection of objective adherence data. As is common to long-term conditions, adherence to prescribed therapy is low, despite clear evidence of beneficial long-term impact on outcomes. This article explains how CFHealthHub is underpinned by coherent conceptual frameworks. We discuss how application of implementation and quality improvement strategies has facilitated CFHealthHub's progression from a pilot study to a large, randomised control trial and now to a learning health system, becoming embedded within routine care. CFHealthHub is now able to support real-time health technology assessments, quality improvement and research trials and is in the process of being implemented in routine clinical care across participating centres.

Prospectively predicting Pseudomonas aeruginosa infection/s using routine data from the UK cystic fibrosis register.

RATIONALE AND AIMS: Lung health of people with cystic fibrosis (PwCF) can be preserved by daily use of inhaled therapy. Adherence to inhaled therapy, therefore, provides an important process measure to understand the success of care and can be used as a quality indicator. Defining adherence is problematic, however, since the number of prescribed treatments varies considerably between PwCF. The problem is less pronounced among those with Pseudomonas aeruginosa (PA), for whom at least three daily doses of nebulized therapy should be prescribed and who thus constitute a more homogeneous group. The UK CF Registry provides routine data on PA status, but data are only available 12 months after collection. In this study, we aim to prospectively identify contemporary PA status from historic registry data. METHOD: UK CF Registry data from 2011 to 2015 for PwCF aged ≥16 was used to determine a pragmatic prediction rule for identifying contemporary PA status using historic registry data. Accuracy of three different prediction rules was assessed using the positive predictive value (PPV). The number and proportion of adults predicted to have PA infection were determined overall and per center for the selected prediction rule. Known characteristics linked to PA status were explored to ensure the robustness of the prediction rule. RESULTS: Having CF Registry defined chronic PA status in the two previous years is the selected definition to predict a patient will have PA infection within the current year (population-level PPV = 96%-97%, centre level PPV = 85%-100%). This approach provides a subset of data between 1852 and 1872 patients overall and a range of 8 to 279 patients per center. CONCLUSION: Historic registry data can be used to contemporaneously identify a subgroup of patients with chronic PA. Since this patient group has a narrower treatment schedule, this can facilitate a better benchmarking of adherence across centers.

The effect of acute maximal exercise on the regional distribution of ventilation using ventilation MRI in CF.

BACKGROUND: The importance of exercise in the management of people with CF is well recognised, yet the effect of exercise on lung function is not well understood. FEV1 is insensitive to the detection of small changes in lung function. Ventilation MRI and LCI are both more sensitive to mild lung disease than FEV1 and may be better suited to assess the effects of exercise. Here we assessed the short-term effects of maximal exercise on the distribution of ventilation using ventilation MRI and LCI. METHODS: Patients with CF and a range of lung disease were assessed. Baseline LCI and ventilation MRI was followed by a maximal cardio-pulmonary exercise test (CPET). Repeated ventilation MRI was performed within 30 minutes of exercise termination, followed by LCI and finally by FEV1. RESULTS: 13 patients were recruited and completed all assessments. Mean (SD) age was 25 (10) years and mean (SD) FEV1 z-score was -1.8 (1.7). Mean LCI at baseline was 8.2, mean ventilation defect percentage on MRI (VDP) was 7.3%. All patients performed maximal CPET. Post-exercise, there was a visible change in lung ventilation in 85% of patients, including two patients with increased ventilation heterogeneity post-CPET who had normal FEV1. VDP and LCI were significantly reduced post-exercise (p < 0.05) and 45% of patients had a significant change in VDP. CONCLUSIONS: Acute maximal exercise directly affects the distribution of ventilation on ventilation MRI in patients with CF. This suggests that exercise is beneficial in CF and that ventilation MRI is suitable to assess airway clearance efficacy.

Feasibility study for supporting medication adherence for adults with cystic fibrosis: mixed-methods process evaluation.

OBJECTIVES: To undertake a process evaluation of an adherence support intervention for people with cystic fibrosis (PWCF), to assess its feasibility and acceptability. SETTING: Two UK cystic fibrosis (CF) units. PARTICIPANTS: Fourteen adult PWCF; three professionals delivering adherence support ('interventionists'); five multi-disciplinary CF team members. INTERVENTIONS: Nebuliser with data recording and transfer capability, linked to a software platform, and strategies to support adherence to nebulised treatments facilitated by interventionists over 5 months (± 1 month). PRIMARY AND SECONDARY MEASURES: Feasibility and acceptability of the intervention, assessed through semistructured interviews, questionnaires, fidelity assessments and click analytics. RESULTS: Interventionists were complimentary about the intervention and training. Key barriers to intervention feasibility and acceptability were identified. Interventionists had difficulty finding clinic space and time in normal working hours to conduct review visits. As a result, fewer than expected intervention visits were conducted and interviews indicated this may explain low adherence in some intervention arm participants. Adherence levels appeared to be >100% for some patients, due to inaccurate prescription data, particularly in patients with complex treatment regimens. Flatlines in adherence data at the start of the study were linked to device connectivity problems. Content and delivery quality fidelity were 100% and 60%-92%, respectively, indicating that interventionists needed to focus more on intervention 'active ingredients' during sessions. CONCLUSIONS: The process evaluation led to 14 key changes to intervention procedures to overcome barriers to intervention success. With the identified changes, it is feasible and acceptable to support medication adherence with this intervention. TRIAL REGISTRATION NUMBER: ISRCTN13076797; Results.

A comparison of the CFHH criteria against the Leeds criteria in determining the Pseudomonas aeruginosa status among adults with cystic fibrosis.

BACKGROUND: Pseudomonas aeruginosa (PA) status influences management decisions in cystic fibrosis (CF) but diagnostic approaches vary. We evaluated the ability of the CFHealthHub (CFHH) criteria, which consist of two major and four minor statements, in diagnosing chronic PA infection among adults with CF. METHODS: In this retrospective cross-sectional analysis, we compared the CFHH criteria against the Leeds criteria. Data were collected between 1st January and 31st December 2016 from all adults with CF receiving care at Sheffield, excluding those with lung transplantation (n = 7) or on ivacaftor (n = 13). The CFHH criteria PA status were cross-tabulated against the Leeds criteria, and clinical outcomes between chronic PA vs non chronic PA for both criteria were compared. RESULTS: This analysis included 186 adults with CF (90 females, median age 27 years, median baseline FEV1 78.5%). The CFHH criteria diagnosed more cases of chronic PA (116/186, 62.4% vs 79/186, 42.5%), and 37/107 cases of non-chronic PA according to the Leeds criteria were deemed chronic PA by the CFHH criteria. The magnitude of difference in %FEV1 decline between chronic PA vs non chronic PA was slightly greater for the CFHH criteria (-0.6%, 95% CI -1.8 to 0.6%) compared to the Leeds criteria (-0.2%, 95% CI -1.3 to 1.0%). CONCLUSIONS: The CFHH criteria detected more chronic PA cases yet still retained similar levels of discrimination for health outcomes in comparison to the Leeds criteria. These findings provide preliminary evidence for the validity of the CFHH criteria among adults with CF.

The assessment of short and long term changes in lung function in CF using 129Xe MRI.

INTRODUCTION: 129Xe ventilation MRI is sensitive to detect early CF lung disease and response to treatment. 129Xe-MRI could play a significant role in clinical trials and patient management. Here we present data on the repeatability of imaging measurements and their sensitivity to longitudinal change. METHODS: 29 children and adults with CF and a range of disease severity were assessed twice, a median [IQR] of 16.0 [14.4,19.5] months apart. Patients performed 129Xe-MRI, lung clearance index (LCI), body plethysmography and spirometry at both visits. Eleven patients repeated 129Xe-MRI in the same session to assess the within-visit repeatability. The ventilation defect percentage (VDP) was the primary metric calculated from 129Xe-MRI. RESULTS: At baseline, mean (sd) age=23.0 (11.1) years and FEV1 z-score=-2.2 (2.0). Median [IQR] VDP=9.5 [3.4,31.6]%, LCI=9.0 [7.7,13.7]. Within-visit and inter-visit repeatability of VDP was high. At 16 months there was no single trend of 129Xe-MRI disease progression. Visible 129Xe-MRI ventilation changes were common, which reflected changes in VDP. Based on the within-visit repeatability, a significant short-term change in VDP is >±1.6%. For longer-term follow up, changes in VDP of up to ±7.7% can be expected, or ±4.1% for patients with normal FEV1. No patient had a significant change in FEV1, however 59% had change in VDP >±1.6%. In patients with normal FEV1, there were significant changes in ventilation and in VDP. CONCLUSIONS: 129Xe-MRI is a highly effective method for assessing longitudinal lung disease in patients with CF. VDP has great potential as a sensitive clinical outcome measure of lung function and endpoint for clinical trials.

Mechanisms of Action of a Web-Based Intervention With Health Professional Support to Increase Adherence to Nebulizer Treatments in Adults With Cystic Fibrosis: Qualitative Interview Study.

BACKGROUND: Adherence to nebulizer treatments in adults with cystic fibrosis (CF) is often low. A new complex intervention to help adults with CF increase their adherence to nebulizer treatments was tested in a pilot randomized controlled trial (RCT) in 2 UK CF centers. Patients used a nebulizer with electronic monitoring capabilities that transferred data automatically to a digital platform (CFHealthHub) to monitor adherence over time and to a tailored website to display graphs of adherence data and educational and problem-solving information about adherence. A trained interventionist helped patients identify ways to increase their adherence. OBJECTIVE: This study aims to explore the mechanisms of action underpinning the intervention. METHODS: A qualitative interview study was conducted concurrently with a pilot RCT. In total, 25 semistructured interviews were conducted with 3 interventionists at 2 time points, 14 patients in the intervention arm of the trial, and 5 members of the multidisciplinary teams offering wider care to patients. A framework approach was used for the analysis. RESULTS: The intervention was informed by a theoretical framework of behavior change. There was evidence of the expected behavior change mechanisms of action. There was also evidence of additional mechanisms of action associated with effective telehealth interventions for self-management support: relationships, visibility, and fit. Patients described how building a relationship with the interventionist through face-to-face visits with someone who cared about them and their progress helped them to consider ways of increasing adherence to medication. Rather than seeing the visibility of adherence data to clinicians as problematic, patients found this motivating, particularly if they received praise about progress made. The intervention was tailored to individuals, but there were challenges in how the intervention fitted into some patients' busy lives when delivered through a desktop computer. CONCLUSIONS: The mechanisms of action associated with effective telehealth interventions for self-management operated within this new intervention. The intervention was modified to strengthen mechanisms of action based on these findings, for example, delivery through an app accessed via mobile phones and then tested in an RCT in 19 UK CF centers. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number 13076797; http://www.isrctn.com/ISRCTN13076797.

Investigating the Temporal Relationships between Symptoms and Nebuliser Adherence in People with Cystic Fibrosis: A Series of N-of-1 Observations.

Treatment adherence in adults with cystic fibrosis (CF) is poor. One of the reasons identified for lack of adherence to nebulised treatments is that patients may not experience any immediate relief in their symptoms or notice changes as a result of taking their treatment, thus many report that they do not perceive there to be consequences of non adherence. The aim of the study was to investigate the temporal relationships between symptoms and adherence to nebulised treatments in adults with CF using an N-of-1 observational design. Six participants were recruited for a six-week period during which time they completed a daily online respiratory symptom questionnaire. Adherence to treatment was measured throughout the duration of the study using an eTrack® nebuliser that logged date and time of treatments taken. Data generated from each participant was analysed separately. There were significant relationships between pain and adherence for three participants, tiredness and adherence for one participant and cough and adherence for one participant. For all of these findings, the symptom and adherence were experienced on the same day. Extending the monitoring period beyond six weeks may provide increased insight into the complex relationship between symptoms and adherence in CF.

Understanding FEV1 for the purpose of cystic fibrosis registry comparisons: Does bias in annual review FEV1 affect between-centre comparison within the UK? An analysis of registry data.

RATIONALE, AIMS, AND OBJECTIVE: We previously demonstrated that annual review %FEV1 underestimates lung health of adults with CF compared with %FEV1 captured during periods of clinical stability. This has implications in the comparisons against registries with encounter-based FEV1 , such as the United States. It is uncertain whether this bias affects between-centre comparison within the United Kingdom. Previous funnel plot analyses have identified variation in annual review %FEV1 according to centre size; hence, we investigated whether paired differences between annual review and best %FEV1 also vary according to centre size. METHODS: This registry analysis included 18 adult CF centres in the United Kingdom with ≥80% completeness for best FEV1 data in 2014. Mean discrepancy between annual review and best %FEV1 is a surrogate for the extent by which annual review %FEV1 underestimates lung health, and was plotted against centre size. A local polynomial regression (LOESS) curve was used to explore the relationship between the two variables. An appropriate model is fitted based on the LOESS curve to determine the strength of relationship between discrepancies in %FEV1 and centre size. RESULTS: There is an inverted U-shaped relationship between mean discrepancies in %FEV1 and centre size. A regression of the paired mean difference in %FEV1 against centre size showed a significant improvement in the goodness of fit for a quadratic model (R2  = 23.8% for a quadratic model compared with 0.4% for a linear one; P = 0.048 for the quadratic term). CONCLUSIONS: Annual review %FEV1 underestimated lung health of adults from small and large centres in the United Kingdom to a greater extent compared with medium-sized centres. A plot of %FEV1 against centre size (eg, funnel plot comparison) would be affected by systematic bias in annual review %FEV1 . Therefore, annual review %FEV1 is an unreliable metric to compare health outcomes of adult CF centres within the United Kingdom.