Computationally efficient methods for fitting mixed models to electronic health records data

Motivated by two case studies using primary care records from the Clinical Practice Research Datalink, we describe statistical methods that facilitate the analysis of tall data, with very large numbers of observations. Our focus is on investigating the association between patient characteristics and an outcome of interest, while allowing for variation among general practices. We explore ways to fit mixed effects models to tall data, including predictors of interest and confounding factors as covariates, and including random intercepts to allow for heterogeneity in outcome among practices. We introduce: (1) weighted regression and (2) meta-analysis of estimated regression coefficients from each practice. Both methods reduce the size of the dataset, thus decreasing the time required for statistical analysis. We compare the methods to an existing subsampling approach. All methods give similar point estimates, and weighted regression and meta-analysis give similar standard errors for point estimates to analysis of the entire dataset, but the subsampling method gives larger standard errors. Where all data are discrete, weighted regression is equivalent to fitting the mixed model to the entire dataset. In the presence of a continuous covariate, meta-analysis is useful. Both methods are easy to implement in standard statistical softwareThe authors are grateful to the CPRD team at the University of Cambridge. In particular, we thank Carol Wilson and Anna Cassel for providing access to the case study datasets that they spent much time preparing for analysis. Kirsty Rhodes was funded by Medical Research Council Unit Programmes U105260558 and MC_UU_00002/5. Rebecca Turner and Ian White were funded by Medical Research Council Unit Programmes U105260558 and MC_UU_12023/2

Label-invariant models for the analysis of meta-epidemiological data.

Rich meta-epidemiological data sets have been collected to explore associations between intervention effect estimates and study-level characteristics. Welton et al proposed models for the analysis of meta-epidemiological data, but these models are restrictive because they force heterogeneity among studies with a particular characteristic to be at least as large as that among studies without the characteristic. In this paper we present alternative models that are invariant to the labels defining the 2 categories of studies. To exemplify the methods, we use a collection of meta-analyses in which the Cochrane Risk of Bias tool has been implemented. We first investigate the influence of small trial sample sizes (less than 100 participants), before investigating the influence of multiple methodological flaws (inadequate or unclear sequence generation, allocation concealment, and blinding). We fit both the Welton et al model and our proposed label-invariant model and compare the results. Estimates of mean bias associated with the trial characteristics and of between-trial variances are not very sensitive to the choice of model. Results from fitting a univariable model show that heterogeneity variance is, on average, 88% greater among trials with less than 100 participants. On the basis of a multivariable model, heterogeneity variance is, on average, 25% greater among trials with inadequate/unclear sequence generation, 51% greater among trials with inadequate/unclear blinding, and 23% lower among trials with inadequate/unclear allocation concealment, although the 95% intervals for these ratios are very wide. Our proposed label-invariant models for meta-epidemiological data analysis facilitate investigations of between-study heterogeneity attributable to certain study characteristics

Patients' and nurses' views on providing psychological support within cardiac rehabilitation programmes: a qualitative study.

OBJECTIVE: To explore patients' and nurses' views on the feasibility and acceptability of providing psychological care within cardiac rehabilitation services. DESIGN: In-depth interviews analysed thematically. PARTICIPANTS: 18 patients and 7 cardiac nurses taking part in a pilot trial (CADENCE) of an enhanced psychological care intervention delivered within cardiac rehabilitation programmes by nurses to patients with symptoms of depression. SETTING: Cardiac services based in the South West of England and the East Midlands, UK. RESULTS: Patients and nurses viewed psychological support as central to good cardiac rehabilitation. Patients' accounts highlighted the significant and immediate adverse effect a cardiac event can have on an individual's mental well-being. They also showed that patients valued nurses attending to both their mental and physical health, and felt this was essential to their overall recovery. Nurses were committed to providing psychological support, believed it benefited patients, and advocated for this support to be delivered within cardiac rehabilitation programmes rather than within a parallel healthcare service. However, nurses were time-constrained and found it challenging to provide psychological care within their existing workloads. CONCLUSIONS: Both patients and nurses highly value psychological support being delivered within cardiac rehabilitation programmes but resource constraints raise barriers to implementation. Consideration, therefore, should be given to alternative forms of delivery which do not rely solely on nurses to enable patients to receive psychological support during cardiac rehabilitation. TRIAL REGISTRATION NUMBER: ISCTRN34701576

"I've made this my lifestyle now": a prospective qualitative study of motivation for lifestyle change among people with newly diagnosed type two diabetes mellitus

This is the final published version. Available from BMC via the DOI in this record.The datasets generated and/or analysed during the current study are not publicly available due to the level of personal information that is contained in the qualitative transcripts.Background: Diagnosis with Type 2 Diabetes is an opportunity for individuals to change their physical activity and dietary behaviours. Diabetes treatment guidelines recommend theory-based, patient-centred care and advocate the provision of support for patient motivation but the motivational experiences of people newly diagnosed with diabetes have not been well studied. Framed in self-determination theory, this study aimed to qualitatively explore how this patient group articulate and experience different types of motivation when attempting lifestyle change. Methods: A secondary analysis of semi-structured interview data collected with 30 (n female = 18, n male = 12) adults who had been newly diagnosed with type two diabetes and were participants in the Early ACTID trial was undertaken. Deductive directed content analysis was performed using NVivo V10 and researcher triangulation to identify and describe patient experiences and narratives that reflected the motivation types outlined in selfdetermination theory and if/how these changed over time. Results: The findings revealed the diversity in motivation quality both between and within individuals over time and that patients with newly-diagnosed diabetes have multifaceted often competing motivations for lifestyle behaviour change. Applying self-determination theory, we identified that many participants reported relatively dominant controlled motivation to comply with lifestyle recommendations, avoid their non-compliance being “found out” or supress guilt following lapses in behaviour change attempts. Such narratives were accompanied by experiences of frustrating slow behaviour change progress. More autonomous motivation was expressed as something often achieved over time and reflected goals to improve health, quality of life or family time. Motivational internalisation was evident and some participants had integrated their behaviour change to a new way of life which they found resilient to common barriers. Conclusions: Motivation for lifestyle change following diagnosis with type two diabetes is complex and can be relatively low in self-determination. To achieve the patient empowerment aspirations of current national health care plans, intervention developers, and clinicians would do well to consider the quality not just quantity of their patients’ motivation.National Institute for Health Research (NIHR

Scepticism and perceived self-efficacy influence fishers’ low risk perceptions of climate change

This is the final version. Available from Elsevier via the DOI in this record. Anonymised quantitative data that support these findings are available from the author upon reasonable request, but are not held on an openly public database due to the confidentiality of the data.Climate change is impacting fisheries globally, posing both risks and opportunities to those dependent on marine resources. Understanding how fishers perceive climate change, and what factors shape these perceptions, can provide insights into behavioural intentions and support required for climate change focused strategies and management. This study interviewed demersal fishers from a south-west UK fishing port to explore: 1) the future risks fishers identified that may affect their business and wider industry; 2) fishers’ beliefs and risk perceptions relating to climate change; and 3) the factors influencing these perceptions. Fishers identified a number of environmental, socio-economic and fisheries governance risks but climate change was rarely mentioned. While fishers overall had low risk perceptions of climate change, these perceptions were heterogeneous across the sample. Climate change scepticism and a high perceived self-efficacy to adapt to climate change were associated with lower risk perceptions. These findings provide new insights into how fishers perceive climate change and, importantly, greater understanding of the possible drivers of such perceptions. Findings suggest that undertaking climate-awareness raising initiatives in isolation to support adaptation strategies could be limited in success. Instead, wider focus should be applied to removing barriers to adaptation, managing wider risks and incorporating fishers into decision making to effectively support and motivate fishers’ adaptation.Natural Environment Research Council (NERC

Individuals' Long Term Use of Cognitive Behavioural Skills to Manage their Depression: A Qualitative Study

Background: Cognitive Behavioural Therapy (CBT) aims to teach people skills to help them self-manage their depression. Trial evidence shows that CBT is an effective treatment for depression and individuals may experience benefits long-term. However, there is little research about individuals’ continued use of CBT skills once treatment has finished. Aims: To explore whether individuals who had attended at least 12 sessions of CBT continued to use and value the CBT skills they had learnt during therapy. Method: Semi-structured interviews were held with participants from the CoBalT trial who had received CBT, approximately 4 years earlier. Interviews were audio-recorded, transcribed and analysed thematically. Results: 20 participants were interviewed. Analysis of the interviews suggested that individuals who viewed CBT as a learning process, at the time of treatment, recalled and used specific skills to manage their depression once treatment had finished. In contrast, individuals who viewed CBT only as an opportunity to talk about their problems did not appear to utilize any of the CBT skills they had been taught and reported struggling to manage their depression once treatment had ended. Conclusions: Our findings suggest individuals may value and use CBT skills if they engage with CBT as a learning opportunity at the time of treatment. Our findings underline the importance of the educational model in CBT and the need to emphasize this to individuals receiving treatment

Adjusting trial results for biases in meta-analysis: combining data-based evidence on bias with detailed trial assessment.

Flaws in the conduct of randomized trials can lead to biased estimation of the intervention effect. Methods for adjustment of within-trial biases in meta-analysis include the use of empirical evidence from an external collection of meta-analyses, and the use of expert opinion informed by the assessment of detailed trial information. Our aim is to present methods to combine these two approaches to gain the advantages of both. We make use of the risk of bias information that is routinely available in Cochrane reviews, by obtaining empirical distributions for the bias associated with particular bias profiles (combinations of risk of bias judgements). We propose three methods: a formal combination of empirical evidence and opinion in a Bayesian analysis; asking experts to give an opinion on bias informed by both summary trial information and a bias distribution from the empirical evidence, either numerically or by selecting areas of the empirical distribution. The methods are demonstrated through application to two example binary outcome meta-analyses. Bias distributions based on opinion informed by trial information alone were most dispersed on average, and those based on opinions obtained by selecting areas of the empirical distribution were narrowest. Although the three methods for combining empirical evidence with opinion vary in ease and speed of implementation, they yielded similar results in the two examples

Community composition of epibenthic megafauna on the West Greenland Shelf

Epibenthic organisms are a critical component of the marine environment, functioning as ecosystem engineers, habitat and food for other organisms. Our knowledge of the diversity, complexity and sensitivities of these habitats is limited, particularly at higher latitudes and greater depths. The West Coast of Greenland is the site of a commercially important shrimp trawl fishery, but there are few published records describing the benthic community structure of the region. Here we report results from benthic camera surveys conducted at 119 sites, over 3 years, spanning 1400 km of the West Greenland continental shelf (61–725 m depth). A total of 29 classes of epibenthic taxa were identified from the images. There are significant differences of composition and diversity in sites with hard and soft substrate. Hard-substrate communities are relatively diverse with higher abundances and are characterised by sessile, attached groups such as Hydrozoa, Anthozoa, Bryozoa and Porifera. Soft-sediment sites are less diverse and dominated by Polychaeta and have specialist Malacostraca such as the commercially exploited shrimp, Pandalus borealis. Distribution patterns and variation in epibenthic megafauna are related to substrate and the environmental parameters depth, temperature and current speed. This study represents the first quantitative characterisation of epibenthic megafaunal assemblages on the West Greenland continental shelf. These data constitute an important baseline, albeit in a region heavily impacted by trawl fisheries, and demonstrate the utility of benthic photography for examining and monitoring seabed diversity and change

Improved timed-mating, non-invasive method using fewer unproven female rats with pregnancy validation via early body mass increases

For studies requiring accurate conception-timing, reliable, efficient methods of detecting oestrus reduce time and costs, whilst improving welfare. Standard methods use vaginal cytology to stage cycle, and breeders are paired–up using approximately five proven females with proven males to achieve at least one conception on a specific day. We describe an alternative, fast, consistent, non-invasive method of timed-mating using detection of lordosis behaviour in Wistar and Lister-Hooded rats that used unproven females with high success rates. Rats under reverse-lighting had body masses recorded pre-mating, day (d) 3-4, d8, d10 and d18 of pregnancy. Using only the presence of the oestrus dance to time-mate females for 24-hrs, 89% Wistar and 88% Lister-Hooded rats successfully conceived. We did not observe behavioural oestrus in Sprague-Dawleys without males present. Significant body mass increases following mating distinguished pregnant from non-pregnant rats, as early as d4 of pregnancy (10% ± 1.0 increase cf 3% ± 1.2). The pattern of increases throughout gestation was similar for all pregnant rats until late pregnancy, when there were smaller increases for primi- and multiparous rats (32% ± 2.5; 25% ± 2.4), whereas nulliparous rats had highest gains (38% ± 1.5). This method demonstrated a distinct refinement of the previous timed-mating common practice used, as disturbance of females was minimised. Only the number required of nulli-, primi- or multiparous rats were mated, and body mass increases validated pregnancy status. This new breeding-management method is now established practice for two strains of rat and resulted in a reduction in animal use

A candidate tolerance gene identified in a natural population of field voles (Microtus agrestis)

The animal immune response has hitherto been viewed primarily in the context of resistance only. However, individuals, can also employ a tolerance strategy to maintain good health in the face of on-going infection. To shed light on the genetic and physiological basis of tolerance, we use a natural population of field voles, Microtus agrestis, to search for an association between the expression of the transcription factor Gata3, previously identified as a marker of tolerance in this system, and polymorphism in 84 immune and non-immune genes. Our results show clear evidence for an association between Gata3 expression and polymorphism in the Fcer1a gene, with the explanatory power of this polymorphism being comparable to that of other non-genetic variables previously identified as important predictors of Gata3 expression. We also uncover the possible mechanism behind this association using an existing protein-protein interaction network for the mouse model rodent, Mus musculus, which we validate using our own expression network for M. agrestis. Our results suggest that the polymorphism in question may be working at the transcriptional level, leading to changes in the expression of the Th2-related genes, Tyrosine-protein kinase BTK and Tyrosine-protein kinase TXK, and hence potentially altering the strength of the Th2 response, of which Gata3 is a mediator. We believe our work has implications for both treatment and control of infectious disease