Designing and evaluating complex interventions to improve health care

Complex interventions are “built up from a number of components, which may act both independently and interdependently.”1 2 Many health service activities should be considered as complex. Evaluating complex interventions can pose a considerable challenge and requires a substantial investment of time. Unless the trials illuminate processes and mechanisms they often fail to provide useful information. If the result is negative, we are left wondering whether the intervention is inherently ineffective (either because the intervention was inadequately developed or because all similar interventions are ineffective), whether it was inadequately applied or applied in an inappropriate context, or whether the trial used an inappropriate design, comparison groups or outcomes. If there is a positive effect, it can be hard to judge how the results of the trial might be applied to a different context (box 1)

Relationship of self-rated health with fatal and non-fatal outcomes in cardiovascular disease: a systematic review and meta-analysis.

BACKGROUND: People who rate their health as poor experience higher all-cause mortality. Study of disease-specific association with self-rated health might increase understanding of why this association exists. OBJECTIVES: To estimate the strength of association between self-rated health and fatal and non-fatal cardiovascular disease. METHODS: A comprehensive search of PubMed MEDLINE, EMBASE, CINAHL, BIOSIS, PsycINFO, DARE, Cochrane Library, and Web of Science was undertaken during June 2013. Two reviewers independently searched databases and selected studies. Inclusion criteria were prospective cohort studies or cohort analyses of randomised trials with baseline measurement of self-rated health with fatal or non-fatal cardiovascular outcomes. 20 studies were pooled quantitatively in different meta-analyses. Study quality was assessed using Newcastle-Ottawa scales. RESULTS: 'Poor' relative to 'excellent' self-rated health (defined by most extreme categories in each study, most often' poor' or 'very poor' and 'excellent' or 'good') was associated over a follow-up of 2.3-23 years with cardiovascular mortality in studies: where varying degrees of adjustments had been made for cardiovascular disease risk (HR 1.79 (95% CI 1.50 to 2.14); 15 studies, I2 = 71.24%), and in studies reporting outcomes in people with pre-existing cardiovascular disease or ischaemic heart disease symptoms (HR 2.42 (95% CI 1.32 to 4.44); 3 studies; I2 = 71.83%). 'Poor' relative to 'excellent' self rated health was also associated with the combined outcome of fatal and non-fatal cardiovascular events (HR 1.90 (95% CI 1.26 to 2.87); 5 studies; I2 = 68.61%), Self-rated health was not significantly associated with non-fatal cardiovascular disease outcomes (HR 1.66 (95% CI 0.96 to 2.87); 5 studies; I2 = 83.60%). CONCLUSIONS: Poor self rated health is associated with cardiovascular mortality in populations with and without prior cardiovascular disease. Those with current poor self-rated health may warrant additional input from health services to identify and address reasons for their low subjective health.This is the final published version. It is accessible from the PLOS One website at: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0103509

An explanatory model of temperature influence on flowering through whole-plant accumulation of FLOWERING LOCUS T in Arabidopsis thaliana

We assessed mechanistic temperature influence on flowering by incorporating temperature-responsive flowering mechanisms across developmental age into an existing model. Temperature influences the leaf production rate as well as expression of FLOWERING LOCUS T (FT), a photoperiodic flowering regulator that is expressed in leaves. The Arabidopsis Framework Model incorporated temperature influence on leaf growth but ignored the consequences of leaf growth on and direct temperature influence of FT expression. We measured FT production in differently aged leaves and modified the model, adding mechanistic temperature influence on FT transcription, and causing whole-plant FT to accumulate with leaf growth. Our simulations suggest that in long days, the developmental stage (leaf number) at which the reproductive transition occurs is influenced by day length and temperature through FT, while temperature influences the rate of leaf production and the time (in days) the transition occurs. Further, we demonstrate that FT is mainly produced in the first 10 leaves in the Columbia (Col-0) accession, and that FT accumulation alone cannot explain flowering in conditions in which flowering is delayed. Our simulations supported our hypotheses that: (i) temperature regulation of FT, accumulated with leaf growth, is a component of thermal time, and (ii) incorporating mechanistic temperature regulation of FT can improve model predictions when temperatures change over time

Blood glucose self-monitoring in type 2 diabetes: a randomised controlled trial

OBJECTIVES: To determine whether self-monitoring of blood glucose (SMBG), either alone or with additional instruction in incorporating the results into self-care, is more effective than usual care in improving glycaemic control in non-insulin-treated diabetes. DESIGN: An open, parallel group randomised controlled trial. SETTING: 24 general practices in Oxfordshire and 24 in South Yorkshire, UK. PARTICIPANTS: Patients with non-insulin-treated type 2 diabetes, aged > or = 25 years and with glycosylated haemoglobin (HbA1c) > or = 6.2%. INTERVENTIONS: A total of 453 patients were individually randomised to one of: (1) standardised usual care with 3-monthly HbA1c (control, n = 152); (2) blood glucose self-testing with patient training focused on clinician interpretation of results in addition to usual care (less intensive self-monitoring, n = 150); (3) SMBG with additional training of patients in interpretation and application of the results to enhance motivation and maintain adherence to a healthy lifestyle (more intensive self-monitoring, n = 151). MAIN OUTCOME MEASURES: The primary outcome was HBA1c at 12 months, and an intention-to-treat analysis, including all patients, was undertaken. Blood pressure, lipids, episodes of hypoglycaemia and quality of life, measured with the EuroQol 5 dimensions (EQ-5D), were secondary measures. An economic analysis was also carried out, and questionnaires were used to measure well-being, beliefs about use of SMBG and self-reports of medication taking, dietary and physical activities, and health-care resource use. RESULTS: The differences in 12-month HbA1c between the three groups (adjusted for baseline HbA1c) were not statistically significant (p = 0.12). The difference in unadjusted mean change in HbA1c from baseline to 12 months between the control and less intensive self-monitoring groups was -0.14% [95% confidence interval (CI) -0.35 to 0.07] and between the control and more intensive self-monitoring groups was -0.17% (95% CI -0.37 to 0.03). There was no evidence of a significantly different impact of self-monitoring on glycaemic control when comparing subgroups of patients defined by duration of diabetes, therapy, diabetes-related complications and EQ-5D score. The economic analysis suggested that SMBG resulted in extra health-care costs and was unlikely to be cost-effective if used routinely. There appeared to be an initial negative impact of SMBG on quality of life measured on the EQ-5D, and the potential additional lifetime gains in quality-adjusted life-years, resulting from the lower levels of risk factors achieved at the end of trial follow-up, were outweighed by these initial impacts for both SMBG groups compared with control. Some patients felt that SMBG was helpful, and there was evidence that those using more intensive self-monitoring perceived diabetes as having more serious consequences. Patients using SMBG were often not clear about the relationship between their behaviour and the test results. CONCLUSIONS: While the data do not exclude the possibility of a clinically important benefit for specific subgroups of patients in initiating good glycaemic control, SMBG by non-insulin-treated patients, with or without instruction in incorporating findings into self-care, did not lead to a significant improvement in glycaemic control compared with usual care monitored by HbA1c levels. There was no convincing evidence to support a recommendation for routine self-monitoring of all patients and no evidence of improved glycaemic control in predefined subgroups of patients

An explanatory model of temperature influence on flowering through whole-plant accumulation of FLOWERING LOCUS T in Arabidopsis thaliana

We assessed mechanistic temperature influence on flowering by incorporating temperature-responsive flowering mechanisms across developmental age into an existing model. Temperature influences the leaf production rate as well as expression of FLOWERING LOCUS T (FT), a photoperiodic flowering regulator that is expressed in leaves. The Arabidopsis Framework Model incorporated temperature influence on leaf growth but ignored the consequences of leaf growth on and direct temperature influence of FT expression. We measured FT production in differently aged leaves and modified the model, adding mechanistic temperature influence on FT transcription, and causing whole-plant FT to accumulate with leaf growth. Our simulations suggest that in long days, the developmental stage (leaf number) at which the reproductive transition occurs is influenced by day length and temperature through FT, while temperature influences the rate of leaf production and the time (in days) the transition occurs. Further, we demonstrate that FT is mainly produced in the first 10 leaves in the Columbia (Col-0) accession, and that FT accumulation alone cannot explain flowering in conditions in which flowering is delayed. Our simulations supported our hypotheses that: (i) temperature regulation of FT, accumulated with leaf growth, is a component of thermal time, and (ii) incorporating mechanistic temperature regulation of FT can improve model predictions when temperatures change over time

Are people with negative diabetes screening tests falsely reassured? Parallel group cohort study embedded in the ADDITION (Cambridge) randomised controlled trial

Objective To assess whether receiving a negative test result at primary care based stepwise diabetes screening results in false reassurance

Impact of an informed choice invitation on uptake of screening for diabetes in primary care (DICISION): trial protocol.

BACKGROUND: Screening invitations have traditionally been brief, providing information only about population benefits. Presenting information about the limited individual benefits and potential harms of screening to inform choice may reduce attendance, particularly in the more socially deprived. At the same time, amongst those who attend, it might increase motivation to change behavior to reduce risks. This trial assesses the impact on attendance and motivation to change behavior of an invitation that facilitates informed choices about participating in diabetes screening in general practice. Three hypotheses are tested: 1. Attendance at screening for diabetes is lower following an informed choice compared with a standard invitation. 2. There is an interaction between the type of invitation and social deprivation: attendance following an informed choice compared with a standard invitation is lower in those who are more rather than less socially deprived. 3. Amongst those who attend for screening, intentions to change behavior to reduce risks of complications in those subsequently diagnosed with diabetes are stronger following an informed choice invitation compared with a standard invitation. METHOD/DESIGN: 1500 people aged 40-69 years without known diabetes but at high risk are identified from four general practice registers in the east of England. 1200 participants are randomized by households to receive one of two invitations to attend for diabetes screening at their general practices. The intervention invitation is designed to facilitate informed choices, and comprises detailed information and a decision aid. A comparison invitation is based on those currently in use. Screening involves a finger-prick blood glucose test. The primary outcome is attendance for diabetes screening. The secondary outcome is intention to change health related behaviors in those attenders diagnosed with diabetes. A sample size of 1200 ensures 90% power to detect a 10% difference in attendance between arms, and in an estimated 780 attenders, 80% power to detect a 0.2 sd difference in intention between arms. DISCUSSION: The DICISION trial is a rigorous pragmatic denominator based clinical trial of an informed choice invitation to diabetes screening, which addresses some key limitations of previous trials.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

The ProActive trial protocol - a randomised controlled trial of the efficacy of a family-based, domiciliary intervention programme to increase physical activity among individuals at high risk of diabetes [ISRCTN61323766].

BACKGROUND: Increasing prevalence of obesity and disorders associated with sedentary living constitute a major global public health problem. While previous evaluations of interventions to increase physical activity have involved communities or individuals with established disease, less attention has been given to interventions for individuals at risk of disease. METHODS/DESIGN: ProActive aims to evaluate the efficacy of a theoretical, evidence- and family-based intervention programme to increase physical activity in a sedentary population, defined as being at-risk through having a parental family history of diabetes. Primary care diabetes or family history registers were used to recruit 365 individuals aged 30-50 years, screened for activity level. Participants were assigned by central randomisation to three intervention programmes: brief written advice (comparison group), or a psychologically based behavioural change programme, delivered either by telephone (distance group) or face-to-face in the family home over one year. The protocol-driven intervention programme is delivered by trained facilitators, and aims to support increases in physical activity through the introduction and facilitation of a range of self-regulatory skills (e.g. goal setting). The primary outcome is daytime energy expenditure and its ratio to resting energy expenditure, measured at baseline and one year using individually calibrated heart rate monitoring. Secondary measures include self-report of individual and family activity, psychological mediators of behaviour change, physiological and biochemical correlates, acceptability, and costs, measured at baseline, six months and one year. The primary intention to treat analysis will compare groups at one-year post randomisation. Estimation of the impact on diabetes incidence will be modelled using data from a parallel ten-year cohort study using similar measures. DISCUSSION: ProActive is the first efficacy trial of an intervention programme to promote physical activity in a defined high-risk group accessible through primary care. The intervention programme is based on psychological theory and evidence; it introduces and facilitates the use of self-regulatory skills to support behaviour change and maintenance. The trial addresses a range of methodological weaknesses in the field by careful specification and quality assurance of the intervention programme, precise characterisation of participants, year-long follow-up and objective measurement of physical activity. Due to report in 2005, ProActive will provide estimates of the extent to which this approach could assist at-risk groups who could benefit from changes in behaviours affecting health, and inform future pragmatic trials

Does electronic monitoring influence adherence to medication? Randomized controlled trial of measurement reactivity.

BACKGROUND: Electronic monitoring is recommended for accurate measurement of medication adherence but a possible limitation is that it may influence adherence. PURPOSE: To test the reactive effect of electronic monitoring in a randomized controlled trial. METHODS: A total of 226 adults with type 2 diabetes and HbA1c ≥58 mmol/mol were randomized to receiving their main oral glucose lowering medication in electronic containers or standard packaging. The primary outcomes were self-reported adherence measured with the MARS (Medication Adherence Report Scale; range 5-25) and HbA1c at 8 weeks. RESULTS: Non-significantly higher adherence and lower HbA1c were observed in the electronic container group (differences in means, adjusting for baseline value: MARS, 0.4 [95 % CI -0.1 to 0.8, p = 0.11]; HbA1c (mmol/mol), -1.02 [-2.73 to 0.71, p = 0.25]). CONCLUSIONS: Electronic containers may lead to a small increase in adherence but this potential limitation is outweighed by their advantages. Our findings support electronic monitoring as the method of choice in research on medication adherence. (Trial registration Current Controlled Trials ISRCT N30522359)

Protocol for SAMS (Support and Advice for Medication Study): a randomised controlled trial of an intervention to support patients with type 2 diabetes with adherence to medication.

BACKGROUND: Although some interventions have been shown to improve adherence to medication for diabetes, results are not consistent. We have developed a theory-based intervention which we will evaluate in a well characterised population to test efficacy and guide future intervention development and trial design. METHODS AND DESIGN: The SAMS (Supported Adherence to Medication Study) trial is a primary care based multi-centre randomised controlled trial among 200 patients with type 2 diabetes and an HbA1c of 7.5% or above. It is designed to evaluate the efficacy of a two-component motivational intervention based on the Theory of Planned Behaviour and volitional action planning to support medication adherence compared with standard care. The intervention is delivered by practice nurses. Nurses were trained using a workshop approach with role play and supervised using assessment of tape-recorded consultations. The trial has a two parallel groups design with an unbalanced three-to-two individual randomisation eight weeks after recruitment with twelve week follow-up. The primary outcome is medication adherence measured using an electronic medication monitor over 12 weeks and expressed as the difference between intervention and control in mean percentage of days on which the correct number of medication doses is taken. Subgroup analyses will explore impact of number of medications taken, age, HbA1c, and self-reported adherence at baseline on outcomes. The study also measures the effect of dispensing medication to trial participants packaged in the electronic medication-monitoring device compared with conventional medication packaging. This will be achieved through one-to-one randomisation at recruitment to these conditions with assessment of the difference between groups in self-report of medication adherence and change in mean HbA1c from baseline to eight weeks. Anonymised demographic data are collected on non-respondents. Central randomisation is carried out independently of trial co-ordination and practices using minimisation to adjust for selected confounders. DISCUSSION: The SAMS intervention and trial design address weaknesses of previous research by recruitment from a well-characterised population, definition of a feasible theory based intervention to support medication taking and careful measurement to estimate and interpret efficacy. The results will inform practice and the design of a cost-effectiveness trial [ISRCTN30522359].RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are