Methodological Challenges in Treatment Mediation Analysis: Examples from Studies Targeting Psychological Factors in Patients with Musculoskeletal Pain

This PhD project was nested within the Psychological Workstream of the Spinal Pain Programme,a National Institute for Health Research (NIHR) funded programme of work (Grant code RPPG-0707-10131) obtained at the Research Institute for Primary Care and Health Sciences by Elaine Hay and colleagues. The idea for this project was devised following discussion of the development of an intervention to target illness perceptions to improve functional outcomes for patients with low back pain. Previous Research Institute work had focused on prognostic studies and evidence had been gathered on what factors influenced patient outcome, but little work had been carried out to investigate whether these same factors could also be effectively targeted during treatment. This PhD project was devised to address this gap in knowledge. Throughout the course of this PhD project I have developed the ideas in this thesis under the guidance of my supervisors (Jonathan Hill, Daniëlle van der Windt and Chris Main (Chris took over from Kevin Vowles, who supervised me until August 2012)). My supervisors advised on the planning of all the analyses presented and on the writing and structure of the included chapters. I designed the analysis plans, conducted all analyses and wrote all chapters. I received guidance on search strategies from Joanne Jordan and Nadia Corp (Chapter 4), and the critical appraisal of the studies included in Chapter 4 was aided by Jemma Cowen. Elaine Thomas provided statistical guidance on Chapters 5 and 6 and Kelvin Jordan and Anne Smith provided guidance on the Latent Growth Modelling presented in Chapter 7. All of the data presented in this thesis was collected prior to my appointment at the Research Institute. I was provided with cleaned datasets from Nadine Foster (BeBACK data presented in Chapter 5), Jonathan Hill (STarT Back data presented in Chapter 6) and Michael Von Korff (Back In Action data presented in Chapter 7). Data from the IMPACT service (Chapter 8) was provided by Julie Ashworth, which did require cleaning by myself prior to use

Why and how back pain interventions work: What can we do to find out?

Mediation analysis is a useful research method that potentially allows identification of the mechanisms through which treatments affect patient outcomes. This chapter reviews the theoretical framework, research designs and statistical approaches used in mediation analysis. It describes what can be learnt from previous mediation research, much of which has investigated mediating factors of psychosocial interventions in other health conditions. It also summarises the few treatment-mediation studies of psychosocial interventions conducted in back pain. This chapter shows that there is emerging evidence about the role of some psychological factors as potential treatment mediators, such as self-efficacy and catastrophising. Mediation analysis can equally be applied to non-psychological factors. Pre-planned and appropriately conducted mediation analysis in adequately powered clinical trials would be a step forward in understanding treatment effects in back pain and improving patient management

Testing a model of consultation-based reassurance and back pain outcomes with psychological risk as a moderator: A prospective cohort study.

Objectives: Reassurance is an essential part of treatment for low back pain (LBP), but evidence on effective methods to deliver reassurance remains scarce. The interaction between consultation-based reassurance and patients’ psychological risk is unknown. Our objective was to investigate the relationship between consultation-based reassurance and clinical outcomes at follow-up, in people with and without psychological risk. Methods: We tested the associations between specific reassurance components (data gathering, relationship building, generic reassurance, and cognitive reassurance), patients’ psychological risk (the presence of depression, anxiety, catastrophizing, or fear-avoidance), and postconsultation outcomes including, satisfaction and enablement, disability, pain, and mood at 3-month follow-up. Results: Adjusted linear regression models using data from patients who had recently consulted for LBP in primary care (n=142 in 43 practices) indicated that all reassurance components were strongly associated with increased satisfaction, whereas generic reassurance was significantly associated with postconsultation enablement. Generic reassurance was also associated with lower pain at 3 months, whereas cognitive reassurance was associated with increased pain. A significant interaction was observed between generic reassurance and psychological risk for depression at 3 months: high rates of generic reassurance were associated with lower depression in low-risk patients, but with higher rates of depression for high-risk groups. Discussion: The findings support the hypothesis that different components of reassurance are associated with specific outcomes, and that psychological risk moderates this relationship for depression. Clinicians reassuring behaviors might therefore have the potential to improve outcomes in people with LBP, especially for patients with higher psychological risk profiles

Pre-habilitation for patients awaiting total knee replacement in the United Kingdom National Health Service:A review of publicly facing information

INTRODUCTION: Approximately 14,000 - 21,500 individuals per year are dissatisfied with the outcome of their Total Knee Replacement (TKR) in the UK National Health Service (NHS). National Institute of Clinical Excellence (NICE) guidelines recommend that future research should evaluate whether a 'full programme of pre-habilitation' can improve outcomes for patients awaiting TKR. The aim of this review was to describe current pre-habilitation practice for patients awaiting TKR in the UK NHS, to inform future research. METHODS: Two reviewers independently undertook electronic searches for publicly available information sheets (PIS) from websites of UK NHS Trusts that included detail about pre-habilitation for patients awaiting TKR. One reviewer extracted data, and a second reviewer verified this. RESULTS: Fifty PIS, nine information videos and one web page from 59 NHS Trusts were identified. NHS Trusts most commonly provide patients with advice on pre-operative rehabilitation via a single appointment, combined with a PIS (36/59; 61.0%). NHS Trusts use appointments, PIS and video to provide patients awaiting TKR with information regarding pain control (46/58; 79.3%), exercise therapy (46/58; 79.3%), what to expect on the day of surgery and in-patient stay (58/58; 100%), lifestyle interventions (27/58; 46.6%), and adverse events (44/58; 75.9%). CONCLUSION: NHS Trusts commonly provided patients awaiting TKR with 'advice on pre-operative rehabilitation', however no NHS Trust provided a comprehensive programme of pre-habilitation. The results of this study will inform the development of a comprehensive, multi-modal pre-habilitation programme, to be tested in a future high-quality randomised controlled trial

Mediators of Treatment Effect in the Back In Action Trial:Using Latent Growth Modeling to Take Change Over Time Into Account

Objectives: To test whether change in fear-avoidance beliefs was a mediator of the effect of treatment on disability outcome, and to test an analytical approach, latent growth modeling, not often applied to mediation analysis. Methods: Secondary analysis was carried out on a randomized controlled trial designed to compare an intervention addressing fear-avoidance beliefs (n=119) with treatment as usual (n=121) for patients with low back pain, which found the intervention to be effective. Latent growth modelling was used to perform a mediation analysis on the trial data to assess the role of change in fear-avoidance beliefs on disability outcome. The product of coefficients with bias-corrected bootstrapped confidence intervals was used to calculate the mediating effect. Results: A statistically significant mediating effect of fear-avoidance beliefs on the effect of treatment on disability outcome was found (standardized indirect effect −0.35; bias-corrected 95% CI, −0.47 to −0.24). Poor fit of the model to the data suggested that other factors not accounted for in this model are likely to be part of the same mediating pathway. Discussion: Fear-avoidance beliefs were found to mediate the effect of treatment on disability outcome. Measurement of all potential mediator variables in future studies would help to more strongly identify which factors explain observed treatment effects. Latent growth modelling was found to be a useful technique to apply to studies of treatment mediation, suggesting that future studies could use this approach

Critical items for assessing risk of lung and colorectal cancer in primary care: a Delphi study

Background Patients with lung or colorectal cancer often present late and have a poor prognosis. Identifying diagnostic indicators to optimally assess the risk of these cancers in primary care would support early identification and timely referral for patients at increased risk. Aim To obtain consensus regarding potential diagnostic indicators that are important for assessing the risk of lung or colorectal cancer in primary care consulters presenting with lung or abdominal symptoms. Design and setting A Delphi study was conducted with 28 participants from primary and secondary care and academic settings in the UK and Europe. Method Indicators were obtained from systematic reviews, recent primary studies and consultation with experts prior to the Delphi study being conducted. Over three rounds, participants rated each diagnostic indicator in terms of its importance, ranked them in order of importance, and rated each item as crucial or not crucial to assess during a GP consultation. Results The final round resulted in 25 items remaining for each type of cancer, including established cancer symptoms such as rectal bleeding for colorectal cancer and haemoptysis for lung cancer, but also less frequently used indicators such as patients’ concerns about cancer. Conclusion This study highlights the items clinicians feel would be most crucial to include in the clinical assessment of primary care patients, a number of which have rarely been noted in the previous literature. Their importance in assessing the risk of lung or colorectal cancer will be tested as part of a large prospective cohort study (CANDID)

Reasons why osteoarthritis predicts mortality:Path analysis within a Cox proportional hazards model

Objectives To identify potentially modifiable factors that mediate the association between symptomatic osteoarthritis (OA) and premature mortality. Methods A population-based prospective cohort study; primary care medical record data were linked to self-report information collected by questionnaire in adults aged 50 years and over (n=10 415). OA was defined by primary care consultation and moderate-to-severe pain interference in daily life. A Cox proportional hazards analysis determined the total effect (TE) of OA on mortality after adjustment for potential confounders. Within the Cox model, path analysis was used to decompose the TE to assess the indirect and direct effects for selected potential mediators (anxiety, depression, unrefreshed sleep and walking frequency). Results are expressed as HRs with 95% CIs derived from bootstrap resampling. Results OA was significantly associated with mortality (TE-adjusted HR 1.14; 95% CI 1.00 to 1.29). The indirect effects for walking frequency were 1.05 (95% CI 1.04 to 1.06), depression 1.02 (95% CI 1.02 to 1.03), anxiety 1.01 (95% CI 1.00 to 1.02) and unrefreshed sleep 1.01 (95% CI 1.00 to 1.01). Conclusions The analysis indicates that encouraging people to walk and get out and about' in addition to targeting OA could be protective against excessive mortality. The findings also suggest that depression, anxiety and unrefreshed sleep have a role in premature mortality for people with OA; however, this has low clinical significance

Protocol of a feasibility randomised controlled trial of Empowered Conversations: training family carers to enhance their relationships and communication with people living with dementia. [version 1; peer review: 3 approved]

Background: Communication difficulties can cause frustration, low mood, and stress for people living with dementia and their carer. Carers should be offered training on adapting their communication skills. However, it is not common for skills-based education to examine emotional aspects of care and the effect of dementia on relationships. The Empowered Conversations (EC) training course was developed in response to a gap in service provision and has been adapted to a virtual format (Zoom). It addresses the specific psychological, relationship, and communication needs of informal and family dementia carers. The primary aim of the study is to investigate the feasibility of conducting a multi-centre randomised controlled evaluation trial of EC.  Secondary aims include exploring the acceptability of delivering the intervention online and examining the optimum way of establishing cost-effectiveness. Methods: The feasibility trial uses a pragmatic data-collector blind parallel two-group RCT design with two arms (EC intervention plus treatment as usual, and treatment as usual waitlist control). There will be a 2:1 allocation in favour of the EC-training intervention arm. 75 participants will complete baseline outcome measures exploring their role as a carer, including their physical and mental health, attitudes to caring, quality of life, and use of health and social care services. These will be repeated after six-months. Participants allocated to the treatment group who complete the course will be invited to participate in a qualitative interview discussing their experience of EC. Discussion: The study will investigate recruitment pathways (including facilitators and barriers to recruitment), estimate retention levels and response rates to questionnaires, obtain additional evidence regarding proof of concept, and consider the most appropriate primary outcome measures and methods for evaluating cost-effectiveness. The results of the feasibility study will be used to inform the development of a multicentre randomised controlled trial in the United Kingdom. Registration: ISRCTN15261686 (02/03/2022

Mechanisms for reducing low back pain: a mediation analysis of a multifaceted intervention in workers in elderly care

Purpose A multifaceted workplace intervention consisting of participatory ergonomics, physical training, and cognitive–behavioural training (CBT) has shown effectiveness for reducing low back pain (LBP). However, the mechanisms of action underlying these intervention components are not well understood. Methods This was a mediation analysis of a cluster-randomised controlled trial of a multifaceted intervention in 420 workers in elderly care. Mediation analysis was carried out via structural equation modelling. Potential mediators investigated were: fear-avoidance beliefs, perceived muscle strength, use of assistive devices at work and perceived physical exertion at work. LBP outcomes assessed were: days with LBP, LBP intensity and days with bothersome LBP. Results There were no significant indirect effects of the intervention on LBP outcomes. There were significant effects of the intervention on both fear-avoidance measures [β = − 0.63, 95% CI (1.23, 0.03); β = − 1.03, 95% CI (− 1.70, − 0.34)] and the use of assistive devices [β = − 0.55, 95% CI (− 1.04, − 0.05)], but not on perceived muscle strength [β = − 0.18, 95% CI (− 0.50, 0.13)] or physical exertion [β = − 0.05, 95% CI (− 0.40, 0.31)]. The only potential mediator with a significant effect on LBP outcomes was physical exertion, which had a significant effect on LBP intensity [β = 0.14, 95% CI (0.04, 0.23)]. Conclusions A multifaceted intervention consisting of participatory ergonomics, physical training, and CBT was able to decrease fear-avoidance beliefs and increase use of assistive devices in the workplace. However, these changes did not explain the effect of any of the intervention components on days with LBP, LBP intensity and days with bothersome LBP