Discovering biomarkers for antidepressant response:protocol from the Canadian biomarker integration network in depression (CAN-BIND) and clinical characteristics of the first patient cohort

Background: Major Depressive Disorder (MDD) is among the most prevalent and disabling medical conditions worldwide. Identification of clinical and biological markers ("biomarkers") of treatment response could personalize clinical decisions and lead to better outcomes. This paper describes the aims, design, and methods of a discovery study of biomarkers in antidepressant treatment response, conducted by the Canadian Biomarker Integration Network in Depression (CAN-BIND). The CAN-BIND research program investigates and identifies biomarkers that help to predict outcomes in patients with MDD treated with antidepressant medication. The primary objective of this initial study (known as CAN-BIND-1) is to identify individual and integrated neuroimaging, electrophysiological, molecular, and clinical predictors of response to sequential antidepressant monotherapy and adjunctive therapy in MDD. Methods: CAN-BIND-1 is a multisite initiative involving 6 academic health centres working collaboratively with other universities and research centres. In the 16-week protocol, patients with MDD are treated with a first-line antidepressant (escitalopram 10-20 mg/d) that, if clinically warranted after eight weeks, is augmented with an evidence-based, add-on medication (aripiprazole 2-10 mg/d). Comprehensive datasets are obtained using clinical rating scales; behavioural, dimensional, and functioning/quality of life measures; neurocognitive testing; genomic, genetic, and proteomic profiling from blood samples; combined structural and functional magnetic resonance imaging; and electroencephalography. De-identified data from all sites are aggregated within a secure neuroinformatics platform for data integration, management, storage, and analyses. Statistical analyses will include multivariate and machine-learning techniques to identify predictors, moderators, and mediators of treatment response. Discussion: From June 2013 to February 2015, a cohort of 134 participants (85 outpatients with MDD and 49 healthy participants) has been evaluated at baseline. The clinical characteristics of this cohort are similar to other studies of MDD. Recruitment at all sites is ongoing to a target sample of 290 participants. CAN-BIND will identify biomarkers of treatment response in MDD through extensive clinical, molecular, and imaging assessments, in order to improve treatment practice and clinical outcomes. It will also create an innovative, robust platform and database for future research. Trial registration: ClinicalTrials.gov identifier NCT01655706. Registered July 27, 2012.

Breast cancer teams:the impact of constitution, new cancer workload and methods of operation on their effectiveness

National guidance and clinical guidelines recommended multidisciplinary teams (MDTs) for cancer services in order to bring specialists in relevant disciplines together, ensure clinical decisions are fully informed, and to coordinate care effectively. However, the effectiveness of cancer teams was not previously evaluated systematically. A random sample of 72 breast cancer teams in England was studied (548 members in six core disciplines), stratified by region and caseload. Information about team constitution, processes, effectiveness, clinical performance, and members' mental well-being was gathered using appropriate instruments. Two input variables, team workload (P=0.009) and the proportion of breast care nurses (P=0.003), positively predicted overall clinical performance in multivariate analysis using a two-stage regression model. There were significant correlations between individual team inputs, team composition variables, and clinical performance. Some disciplines consistently perceived their team's effectiveness differently from the mean. Teams with shared leadership of their clinical decision-making were most effective. The mental well-being of team members appeared significantly better than in previous studies of cancer clinicians, the NHS, and the general population. This study established that team composition, working methods, and workloads are related to measures of effectiveness, including the quality of clinical care. © 2003 Cancer Research UK.

An investigation into inductive parameter learning in complex hierarchical knowledge structures representing clinical expertise

This dissertation investigates the very important and current problem of modelling human expertise. This is an apparent issue in any computer system emulating human decision making. It is prominent in Clinical Decision Support Systems (CDSS) due to the complexity of the induction process and the vast number of parameters in most cases. Other issues such as human error and missing or incomplete data present further challenges. In this thesis, the Galatean Risk Screening Tool (GRiST) is used as an example of modelling clinical expertise and parameter elicitation. The tool is a mental health clinical record management system with a top layer of decision support capabilities. It is currently being deployed by several NHS mental health trusts across the UK. The aim of the research is to investigate the problem of parameter elicitation by inducing them from real clinical data rather than from the human experts who provided the decision model. The induced parameters provide an insight into both the data relationships and how experts make decisions themselves. The outcomes help further understand human decision making and, in particular, help GRiST provide more accurate emulations of risk judgements. Although the algorithms and methods presented in this dissertation are applied to GRiST, they can be adopted for other human knowledge engineering domains.

Children's views on unlicensed/off-label paediatric prescribing and paediatric clinical trials

Objectives - To explore the views and perspectives of children on the unlicensed/off-label use of medicines in children and on the participation of children in clinical trials. Methods - Focus-group discussions, involving school children, were carried out in a range of primary and secondary schools in Northern Ireland. A purposeful sample was chosen to facilitate representation of various socioeconomic groupings. Results - A total of 123 pupils, aged from 10 to 16 years, from six schools, participated in 16 focus groups. In general, pupils viewed the unlicensed/off-label use of medicines in children as unsafe and unethical and felt it is necessary to test medicines in children to improve the availability of licensed products. The majority felt that older children should be told, and that parents should be told, about the unlicensed/off-label use of medicines in children, yet they recognised some implications of this, such as potential medication non-adherence. Conclusions - This is the first study to explore the views of healthy children on unlicensed medicine use in children. Children were able to recognise potential risks associated with the unlicensed use of medicines and felt it is necessary to test and license more medicines in children. Practice implications - Health care professionals should consider the views of children in decisions that affect their health.

The influence of patient's age on clinical decision-making about coronary heart disease in the USA and the UK

This paper examines UK and US primary care doctors' decision-making about older (aged 75 years) and midlife (aged 55 years) patients presenting with coronary heart disease (CHD). Using an analytic approach based on conceptualising clinical decision-making as a classification process, it explores the ways in which doctors' cognitive processes contribute to ageism in health-care at three key decision points during consultations. In each country, 56 randomly selected doctors were shown videotaped vignettes of actors portraying patients with CHD. The patients' ages (55 or 75 years), gender, ethnicity and social class were varied systematically. During the interviews, doctors gave free-recall accounts of their decision-making. The results do not establish that there was substantial ageism in the doctors' decisions, but rather suggest that diagnostic processes pay insufficient attention to the significance of older patients' age and its association with the likelihood of co-morbidity and atypical disease presentations. The doctors also demonstrated more limited use of 'knowledge structures' when diagnosing older than midlife patients. With respect to interventions, differences in the national health-care systems rather than patients' age accounted for the differences in doctors' decisions. US doctors were significantly more concerned about the potential for adverse outcomes if important diagnoses were untreated, while UK general practitioners cited greater difficulty in accessing diagnostic tests.

Classifying clinical decision making:a unifying approach

This is the first of two linked papers exploring decision making in nursing which integrate research evidence from different clinical and academic disciplines. Currently there are many decision-making theories, each with their own distinctive concepts and terminology, and there is a tendency for separate disciplines to view their own decision-making processes as unique. Identifying good nursing decisions and where improvements can be made is therefore problematic, and this can undermine clinical and organizational effectiveness, as well as nurses' professional status. Within the unifying framework of psychological classification, the overall aim of the two papers is to clarify and compare terms, concepts and processes identified in a diversity of decision-making theories, and to demonstrate their underlying similarities. It is argued that the range of explanations used across disciplines can usefully be re-conceptualized as classification behaviour. This paper explores problems arising from multiple theories of decision making being applied to separate clinical disciplines. Attention is given to detrimental effects on nursing practice within the context of multidisciplinary health-care organizations and the changing role of nurses. The different theories are outlined and difficulties in applying them to nursing decisions highlighted. An alternative approach based on a general model of classification is then presented in detail to introduce its terminology and the unifying framework for interpreting all types of decisions. The classification model is used to provide the context for relating alternative philosophical approaches and to define decision-making activities common to all clinical domains. This may benefit nurses by improving multidisciplinary collaboration and weakening clinical elitism.

Classifying clinical decision making:interpreting nursing intuition, heuristics and medical diagnosis

This is the second of two linked papers exploring decision making in nursing. The first paper, 'Classifying clinical decision making: a unifying approach' investigated difficulties with applying a range of decision-making theories to nursing practice. This is due to the diversity of terminology and theoretical concepts used, which militate against nurses being able to compare the outcomes of decisions analysed within different frameworks. It is therefore problematic for nurses to assess how good their decisions are, and where improvements can be made. However, despite the range of nomenclature, it was argued that there are underlying similarities between all theories of decision processes and that these should be exposed through integration within a single explanatory framework. A proposed solution was to use a general model of psychological classification to clarify and compare terms, concepts and processes identified across the different theories. The unifying framework of classification was described and this paper operationalizes it to demonstrate how different approaches to clinical decision making can be re-interpreted as classification behaviour. Particular attention is focused on classification in nursing, and on re-evaluating heuristic reasoning, which has been particularly prone to theoretical and terminological confusion. Demonstrating similarities in how different disciplines make decisions should promote improved multidisciplinary collaboration and a weakening of clinical elitism, thereby enhancing organizational effectiveness in health care and nurses' professional status. This is particularly important as nurses' roles continue to expand to embrace elements of managerial, medical and therapeutic work. Analysing nurses' decisions as classification behaviour will also enhance clinical effectiveness, and assist in making nurses' expertise more visible. In addition, the classification framework explodes the myth that intuition, traditionally associated with nurses' decision making, is less rational and scientific than other approaches.

A randomised controlled trial of the clinical effectiveness and cost-effectiveness of the levonorgestrel-releasing intrauterine system in primary care against standard treatment for menorrhagia:the ECLIPSE trial

BACKGROUND: Heavy menstrual bleeding (HMB) is a common problem, yet evidence to inform decisions about initial medical treatment is limited. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of the levonorgestrel-releasing intrauterine system (LNG-IUS) (Mirena(®), Bayer) compared with usual medical treatment, with exploration of women's perspectives on treatment. DESIGN: A pragmatic, multicentre randomised trial with an economic evaluation and a longitudinal qualitative study. SETTING: Women who presented in primary care. PARTICIPANTS: A total of 571 women with HMB. A purposeful sample of 27 women who were randomised or ineligible owing to treatment preference participated in semistructured face-to-face interviews around 2 and 12 months after commencing treatment. INTERVENTIONS: LNG-IUS or usual medical treatment (tranexamic acid, mefenamic acid, combined oestrogen-progestogen or progesterone alone). Women could subsequently swap or cease their allocated treatment. OUTCOME MEASURES: The primary outcome was the patient-reported score on the Menorrhagia Multi-Attribute Scale (MMAS) assessed over a 2-year period and then again at 5 years. Secondary outcomes included general quality of life (QoL), sexual activity, surgical intervention and safety. Data were analysed using iterative constant comparison. A state transition model-based cost-utility analysis was undertaken alongside the randomised trial. Quality-adjusted life-years (QALYs) were derived from the European Quality of Life-5 Dimensions (EQ-5D) and the Short Form questionnaire-6 Dimensions (SF-6D). The intention-to-treat analyses were reported as cost per QALY gained. Uncertainty was explored by conducting both deterministic and probabilistic sensitivity analyses. RESULTS: The MMAS total scores improved significantly in both groups at all time points, but were significantly greater for the LNG-IUS than for usual treatment [mean difference over 2 years was 13.4 points, 95% confidence interval (CI) 9.9 to 16.9 points; p < 0.001]. However, this difference between groups was reduced and no longer significant by 5 years (mean difference in scores 3.9 points, 95% CI -0.6 to 8.3 points; p = 0.09). By 5 years, only 47% of women had a LNG-IUS in place and 15% were still taking usual medical treatment. Five-year surgery rates were low, at 20%, and were similar, irrespective of initial treatments. There were no significant differences in serious adverse events between groups. Using the EQ-5D, at 2 years, the relative cost-effectiveness of the LNG-IUS compared with usual medical treatment was £1600 per QALY, which by 5 years was reduced to £114 per QALY. Using the SF-6D, usual medical treatment dominates the LNG-IUS. The qualitative findings show that women's experiences and expectations of medical treatments for HMB vary considerably and change over time. Women had high expectations of a prompt effect from medical treatments. CONCLUSIONS: The LNG-IUS, compared with usual medical therapies, resulted in greater improvement over 2 years in women's assessments of the effect of HMB on their daily routine, including work, social and family life, and psychological and physical well-being. At 5 years, the differences were no longer significant. A similar low proportion of women required surgical intervention in both groups. The LNG-IUS is cost-effective in both the short and medium term, using the method generally recommended by the National Institute for Health and Care Excellence. Using the alternative measures to value QoL will have a considerable impact on cost-effectiveness decisions. It will be important to explore the clinical and health-care trajectories of the ECLIPSE (clinical effectiveness and cost-effectiveness of levonorgestrel-releasing intrauterine system in primary care against standard treatment for menorrhagia) trial participants to 10 years, by which time half of the cohort will have reached menopause. TRIAL REGISTRATION: Current Controlled Trials ISRCTN86566246. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 88. See the NIHR Journals Library website for further project information.