IMPARTER, Phase 1 of an intervention to improve patients' understanding of gene expression profiling tests in breast cancer.

PURPOSE: To compare participants' knowledge about gene expression profiling (GEP) tests and recurrence risks after reading an information leaflet with that following viewing of an information film. METHODS: Using a randomised cross-over design, at time-point one (T1), women aged 45-75 years without breast cancer either read leaflets or watched information films about Oncotype DX or Prosigna tests. Participants answered nine questions assessing knowledge (maximum score 18). Next-day information in the opposite modality was provided and knowledge re-assessed. Additional questions probed which format was easiest to understand, participants' preferences for film or leaflet and their reasons for these. RESULTS: 120 women participated (60 received OncotypeDX films and leaflets; 60 received the Prosigna versions). T1 mean knowledge scores were higher following film viewing (13.37) compared with that after reading leaflets (9.25) (mean difference 4.1; p < 0.0001; 95% CI 3.2, 5.0). When participants read leaflets first and subsequently viewed films, all increased their scores (mean + 6.08, from T1 of 9.25, p < 0.0001; 95% CI 5.44, 6.72). When films were viewed first, followed by leaflets, (36/60, 60%), participants' scores declined (mean-1.55 from T1 of 13.37, p < 0.001; 95% CI -2.32, -0.78). A majority of participants expressed preferences for the films (88/120, 73.3%) irrespective as to whether they described OncotypeDX or Prosigna. Reasons included the clarity, ease of understanding, visual material and reassuring voice-over. CONCLUSION: Discussions between oncologists and patients about recurrence risk results can be challenging. Information leaflets may aid understanding but often employ complex language. Information films significantly improved knowledge and were preferred by participants.

Adverse childhood experiences during childhood and academic attainment at age 7 and 11 years: an electronic birth cohort study.

OBJECTIVES: Adverse childhood experiences (ACEs) have a negative impact on childhood health, but their impact on education outcomes is less well known. We investigated whether or not ACEs were associated with reduced educational attainment at age 7 and 11 years. STUDY DESIGN: The study design used in the study is a population-based electronic cohort study. METHODS: We analysed data from a total population electronic child cohort in Wales, UK. ACEs (exposures) were living with an adult household member with any of (i) serious mental illness, (ii) common mental disorder (CMD), (iii) an alcohol problem; (iv) child victimisation, (v) death of a household member and (vi) low family income. We used multilevel logistic regression to model exposure to these ACEs and not attaining the expected level at statutory education assessments, Key Stage (KS) 1 and KS2 separately, adjusted for known confounders including perinatal, socio-economic and school factors. RESULTS: There were 107,479 and 43,648 children included in the analysis, with follow-up to 6-7 years (KS1) and 10-11 years (KS2), respectively. An increased risk of not attaining the expected level at KS1 was associated with living with adult household members with CMD (adjusted odds ratio [aOR]: 1.13 [95% confidence interval [CI]: 1.09-1.17]) or an alcohol problem (adjusted odds ratio [aOR]: 1.16 [95% confidence interval [CI]: 1.10-1.22]), childhood victimisation (adjusted odds ratio [aOR]: 1.58 [95% confidence interval [CI]: 1.37-1.82]), death of a household member (adjusted odds ratio [aOR]: 1.14 [95% confidence interval [CI]: 1.04-1.25]) and low family income (adjusted odds ratio [aOR]: 1.92 [95% confidence interval [CI]: 1.84-2.01]). Similar results were observed for KS2. Children with multiple adversities had substantially increased odds of not attaining the expected level at each educational assessment. CONCLUSION: The educational potential of many children may not be achieved due to exposure to adversity in childhood. Affected children who come in to contact with services should have relevant information shared between health and care services, and schools to initiate and facilitate a coordinated approach towards providing additional support and help for them to fulfil their educational potential, and subsequent economic and social participation.

Effect of neighbourhood deprivation and social cohesion on mental health inequality: a multilevel population-based longitudinal study.

BACKGROUND: The common mental disorders (CMDs) of anxiety and depression are the most common form of poor mental health in the general population. Evidence from the small number of previous cohort studies on the role of neighbourhood factors in mental health is inconclusive. We tested the hypothesis that high levels of neighbourhood social cohesion modify an adverse association between change in individual mental health and neighbourhood deprivation. METHOD: We carried out a longitudinal multilevel analysis using data from the Caerphilly Health and Social Needs Cohort Study with a 7-year follow-up (n = 4426; age range 18-74 years at baseline). Neighbourhood deprivation and neighbourhood social cohesion were assessed at baseline and change in mental health between follow-up and baseline was assessed using the five-item Mental Health Inventory (MHI-5). RESULTS: Residence in the most deprived neighbourhoods was negatively associated with change in mental health, after adjusting for baseline individual socio-economic risk factors and transitions in life events. This negative effect was significantly reduced in high social cohesion neighbourhoods. The predicted change in mental health score was calculated for the 10th and 90th centiles of the household low-income distribution. The difference between them was -2.8 in the low social cohesion group and 1.1 in the high cohesion group. The difference between the groups was 3.9 [95% confidence interval (CI) 0.2-7.6]. CONCLUSIONS: The public health burden of poor mental health and mental health inequality could potentially be reduced by strengthening social cohesion in deprived neighbourhoods. This offers a mechanism to address the adverse effect of neighbourhood deprivation on population mental health.

Drivers and barriers to patient participation in RCTs.

BACKGROUND: Recruitment of patients into randomised clinical trials (RCTs) is essential for treatment evaluation. Appreciation of the barriers and drivers towards participation is important for trial design, communication and information provision. METHOD: As part of an intervention to facilitate effective multidisciplinary team communication about RCTs, cancer patients completed two study-specific questionnaires following trial discussions. One questionnaire examined reasons why patients accepted or declined trial entry, the other perceptions about their health-care professionals' (HCPs) information giving. RESULTS: Questionnaires were completed by 74% (358/486) of patients approached; of these 81% (291/358) had joined an RCT, 16% (56/358) had declined and 3% (11/358) were undecided. Trial participation status of the 128 patients not returning questionnaires is unknown. Trial acceptance was not dependent on disease stage, tumour type, sex or age. Satisfaction with trial information and HCPs' communication was generally very good, irrespective of participation decisions. The primary reason given for trial acceptance was altruism (40%; 110/275), and for declining, trust in the doctor (28%; 12/43). Decliners preferred doctors to choose their treatment rather than be randomised (54% vs 39%; P<0.027). Acceptors were more likely to perceive doctors as wanting them to join trials (54% vs 30%; P<0.001). Trial type, that is, standard treatment vs novel or different durations of treatment, also influenced acceptance rates. CONCLUSION: The drivers and barriers to trial participation are partly related to trial design. Unease about randomisation and impact of duration on treatment efficacy are barriers for some. Altruism and HCPs' perceived attitudes are powerful influencing factors.

Missing at random: a stochastic process perspective.

We offer a natural and extensible measure-theoretic treatment of missingness at random. Within the standard missing-data framework, we give a novel characterization of the observed data as a stopping-set sigma algebra. We demonstrate that the usual missingness-at-random conditions are equivalent to requiring particular stochastic processes to be adapted to a set-indexed filtration. These measurability conditions ensure the usual factorization of likelihood ratios. We illustrate how the theory can be extended easily to incorporate explanatory variables, to describe longitudinal data in continuous time, and to admit more general coarsening of observations.

Clinicians' attitudes towards clinical trials of cancer therapy.

BACKGROUND: Patient accrual into cancer clinical trials remains at low levels. This survey elicited attitudes and practices of cancer clinicians towards clinical trials. METHOD: The 43-item Clinicians Attitudes to Clinical Trials Questionnaire was completed by participants in an intervention study aimed at improving multi-disciplinary involvement in randomised trials. Responses from 13 items were summed to form a research-orientation score. RESULTS: Eighty-seven clinicians (78%) returned questionnaires. Physicians, more often than surgeons, chose to prioritise prolonging a patient's life, recruited ≥50% of patients into trials and attended more research-focussed conferences. Clinicians at specialist centres were more positive about trials with no-treatment arms than those at district general hospitals, more likely to believe clinician, rather than patient reluctance to participate was the greater obstacle to trial accrual, and preferred national and international to local recognition. Clinicians belonging to breast and colorectal teams were less disappointed about not enrolling patients in trials and more accepting of no-treatment arm trials. Research orientation was higher in physicians than surgeons and higher in specialist centres than district hospitals. CONCLUSIONS: This study provides greater understanding of clinicians' attitudes to trials. Results have been used to inform training interventions for clinicians targeting the problem of low and selective accrual.

The attitudes of 1066 patients with cancer towards participation in randomised clinical trials.

BACKGROUND: barriers to randomised clinical trial (RCT) recruitment include failure to identify eligible patients, reluctance of staff to approach them and attitudes of some health-care professionals and patients. As part of a larger UK prospective study examining the communication and involvement in RCTs of 22 multidisciplinary teams in Wales, we also assessed the attitudes of patients they treat towards trials. METHODS: out of 1146 patients attending outpatient departments who were approached, 1146 (93%) completed the seven-item Attitudes to Randomised Trials Questionnaire (ARTQ), probing their general attitudes towards medical research and likely participation in a hypothetical two-arm RCT. RESULTS: randomisation initially deterred many patients from endorsing a willingness to participate. However, if information about the trial logic, voluntary nature and rights to withdraw were provided, together with further treatment details, 83% (886 out of 1066) would potentially participate. Other variables associated with a positive inclination towards participation included previous trial experience (P<0.01), male gender (P<0.01) and younger age, with patients > or =70 years less likely to consider trial entry (P<0.01). CONCLUSION: the majority of patients were receptive to RCT participation. Many of those initially disinclined because of randomisation would consider joining if given further details that form part of standard GCP consent guidelines. These data show the importance and need for clear communication and information to encourage RCT participation. Evidence-based training courses are available to assist with this.

What neuroimaging should be performed in children in whom inflicted brain injury (iBI) is suspected? A systematic review.

AIMS: To investigate the optimal neuroradiological investigation strategy to identify inflicted brain injury (iBI). MATERIALS AND METHODS: A systematic review of studies published between 1970-2008 in any language was conducted, searching 20 databases and four websites, using over 100 keywords/phrases, supplemented by hand-searching of references. All studies underwent two independent reviews (with disagreements adjudicated by a third reviewer) by trained reviewers from paediatrics, paediatric neuroradiology and related disciplines, using standardized critical appraisal tools, and strict inclusion/exclusion criteria. We included primary studies that evaluated the diagnostic yield of magnetic resonance imaging (MRI), in addition to initial computed tomography (CT), or follow-up CT or ultrasound in children with suspected iBI. RESULTS: Of the 320 studies reviewed, 18 met the inclusion criteria, reflecting data on 367 children with iBI and 12 were published since 1998. When an MRI was conducted in addition to an abnormal early CT examination, additional information was found in 25% (95% CI: 18.3-33.16%) of children. The additional findings included further subdural haematoma, subarachnoid haemorrhage, shearing injury, ischaemia, and infarction; it also contributed to dating of injuries. Diffusion-weighted imaging (DWI) further enhanced the delineation of ischaemic changes, and assisted in prognosis. Repeat CT studies varied in timing and quality, and none were compared to the addition of an early MRI/DWI. CONCLUSIONS: In an acutely ill child, the optimal imaging strategy involves initial CT, followed by early MRI and DWI if early CT examination is abnormal, or there are ongoing clinical concerns. The role of repeat CT imaging, if early MRI is performed, is unclear, as is the place for MRI/DWI if initial CT examination is normal in an otherwise well child.

Electronic Longitudinal Alcohol Study in Communities (ELAStiC) Wales - protocol for platform development.

INTRODUCTION: Excessive alcohol consumption has adverse effects on health and there is a recognised need for the longitudinal analysis of population data to improve our understanding of the patterns of alcohol use, harms to consumers and those in their immediate environment. The UK has a number of linkable, longitudinal databases that if assembled properly could support valuable research on this topic. AIMS AND OBJECTIVES: This paper describes the development of a broad set of cross-linked cohorts, e-cohorts, surveys and linked electronic healthcare records (EHRs) to construct an alcohol-specific analytical platform in the United Kingdom using datasets on the population of Wales.The objective of this paper is to provide a description of existing key datasets integrated with existing, routinely collected electronic health data on a secure platform, and relevant derived variables to enable population-based research on alcohol-related harm in Wales. We illustrate our use of these data with some exemplar research questions that are currently under investigation. METHODS: Record-linkage of routine and observational datasets. Routine data includes hospital admissions, general practice, and cohorts specific to children. Two observational studies were included. Routine socioeconomic descriptors and mortality data were also linked. CONCLUSION: We described a record-linked, population-based research protocol for alcohol related harm on a secure platform. As the datasets used here are available in many countries, ELAStiC provides a template for setting up similar initiatives in other countries. We have also defined a number of alcohol specific variables using routinely-collected available data that can be used in other epidemiological studies into alcohol related outcomes. With over 10 years of longitudinal data, it will help to understand alcohol-related disease and health trajectories across the lifespan.

Ignorability for general longitudinal data.

Likelihood factors that can be disregarded for inference are termed ignorable. We demonstrate that close ties exist between ignorability and identification of causal effects by covariate adjustment. A graphical condition, stability, plays a role analogous to that of missingness at random, but is applicable to general longitudinal data. Our formulation of ignorability does not depend on any notion of missing data, so is appealing in situations where missing data may not actually exist. Several examples illustrate how stability may be assessed.

Teams Talking Trials: results of an RCT to improve the communication of cancer teams about treatment trials.

BACKGROUND: Previous research has shown that communication between members of multidisciplinary teams (MDTs) is often suboptimal and communication about trials between MDTs and their patients is difficult. Educational interventions can help dyadic exchanges with different aspects of trial recruitment but less work has focussed on team interventions. METHODS: 22 multidisciplinary cancer teams in the UK participated in an RCT of a novel Teams Talking Trials (TTT) Workshop aimed at improving the following: awareness, involvement, communication and recruitment to cancer trials. MDTs were randomised following either 6 or 12 months of audits, which were repeated after the intervention. Audits included numbers approached about trials, team members' attitudes, involvement and awareness of their teams' trial portfolios. RESULTS: There was no significant difference in the rate of approaching patients about trials post workshop (estimated improvement 22% higher regression coefficient of 0.2, exp. (0.2)=1.22). There was improvement in team members' involvement in trials in 4 areas (p≤0.04): the pressure to enter patients into RCTs, the likelihood of a start-up meeting to discuss a newly accepted trial, the informational role played by individuals and recognition of this HCP's role by other team members. Also, confidence in communication about RCTS increased and awareness of different aspects of trial management improved on all 14 aspects (p=0.001). CONCLUSION: Attendance by teams at focussed workshops designed to enhance communication and trial recruitment improved several aspects of team functioning, but a significant impact on the number of patients approached could not be demonstrated.

Which clinical features distinguish inflicted from non-inflicted brain injury? A systematic review.

AIM: A systematic review of the scientific literature to define clinical indicators distinguishing inflicted (iBI) from non-inflicted brain injury (niBI). METHODS: An all language literature search of 20 electronic databases, websites, references and bibliographies from 1970-2008 was carried out. Relevant studies were independently reviewed by two trained reviewers, with a third review where required. Inclusion criteria included primary comparative studies of iBI and niBI in children aged <18 years, with high surety of diagnosis describing key clinical features. Multilevel logistic regression analysis was conducted, determining the positive predictive value (PPV) and odds ratios (OR) with p values for retinal haemorrhage, rib/long bone/skull fractures, apnoea, seizures and bruising to head/neck. RESULTS: 8151 studies were identified, 320 were reviewed and 14 included, representing 1655 children, 779 with iBI. Gender was not a discriminatory feature. In a child with intracranial injury, apnoea (PPV 93%, OR 17.06, p<0.001) and retinal haemorrhage (PPV 71%, OR 3.504, p = 0.03) were the features most predictive of iBI. Rib fractures (PPV 73%, OR 3.03, p = 0.13) had a similar PPV to retinal haemorrhages, but there were less data for analysis. Seizures and long bone fractures were not discriminatory, and skull fracture and head/neck bruising were more associated with niBI, although not significantly so. CONCLUSIONS: This systematic review shows that apnoea and retinal haemorrhage have a high odds ratio for association with iBI. This review identifies key features that should be recorded in the assessment of children where iBI is suspected and may help clinicians to define the likelihood of iBI.

What determines the cost-effectiveness of diabetes screening?

AIMS/HYPOTHESIS: The cost-effectiveness of screening for diabetes is unknown but has been modelled previously. None of these models has taken account of uncertainty. We aimed to describe these uncertainties in a model where the outcome was CHD risk. SUBJECTS AND METHODS: Our model used population data from the Danish Inter99 study, and simulations were run in a theoretical population of 1,000,000 individuals. CHD risk was estimated using the UK Prospective Diabetes Study (UKPDS) risk engine, and risk reduction from published randomised clinical trials. Probabilistic sensitivity analysis was used to provide confidence intervals for modelled outputs. Uncertain parameter values were independently simulated from distributions derived from existing literature and deterministic sensitivity analysis performed using multiple model runs under different strategy choices and using extreme parameter estimates. RESULTS: In the least conservative model (low costs and multiplicative risk reduction for combined treatments), the 95% confidence interval of the incremental cost-effectiveness ratio varied from pound23,300-82,000. The major contributors to this uncertainty were treatment risk reduction model parameters: the risk reduction for hypertension treatment and UKPDS risk model intercept. Overall cost-effectiveness ratio was not sensitive to decisions about which groups to screen, nor the costs of screening or treatment. It was strongly affected by assumptions about how treatments combine to reduce risk. CONCLUSIONS/INTERPRETATION: Our model suggests that there is considerable uncertainty about whether or not screening for diabetes would be cost-effective. The most important but uncertain parameter is the effect of treatment. In addition to directly influencing current policy decisions, health care modelling can identify important unknown or uncertain parameters that may be the target of future research.