Ian Harvey

Dissemination and publication of research findings: an updated review of related biases.

OBJECTIVES To identify and appraise empirical studies on publication and related biases published since 1998; to assess methods to deal with publication and related biases; and to examine, in a random sample of published systematic reviews, measures taken to prevent, reduce and detect dissemination bias. DATA SOURCES The main literature search, in August 2008, covered the Cochrane Methodology Register Database, MEDLINE, EMBASE, AMED and CINAHL. In May 2009, PubMed, PsycINFO and OpenSIGLE were also searched. Reference lists of retrieved studies were also examined. REVIEW METHODS In Part I, studies were classified as evidence or method studies and data were extracted according to types of dissemination bias or methods for dealing with it. Evidence from empirical studies was summarised narratively. In Part II, 300 systematic reviews were randomly selected from MEDLINE and the methods used to deal with publication and related biases were assessed. RESULTS Studies with significant or positive results were more likely to be published than those with non-significant or negative results, thereby confirming findings from a previous HTA report. There was convincing evidence that outcome reporting bias exists and has an impact on the pooled summary in systematic reviews. Studies with significant results tended to be published earlier than studies with non-significant results, and empirical evidence suggests that published studies tended to report a greater treatment effect than those from the grey literature. Exclusion of non-English-language studies appeared to result in a high risk of bias in some areas of research such as complementary and alternative medicine. In a few cases, publication and related biases had a potentially detrimental impact on patients or resource use. Publication bias can be prevented before a literature review (e.g. by prospective registration of trials), or detected during a literature review (e.g. by locating unpublished studies, funnel plot and related tests, sensitivity analysis modelling), or its impact can be minimised after a literature review (e.g. by confirmatory large-scale trials, updating the systematic review). The interpretation of funnel plot and related statistical tests, often used to assess publication bias, was often too simplistic and likely misleading. More sophisticated modelling methods have not been widely used. Compared with systematic reviews published in 1996, recent reviews of health-care interventions were more likely to locate and include non-English-language studies and grey literature or unpublished studies, and to test for publication bias. CONCLUSIONS Dissemination of research findings is likely to be a biased process, although the actual impact of such bias depends on specific circumstances. The prospective registration of clinical trials and the endorsement of reporting guidelines may reduce research dissemination bias in clinical research. In systematic reviews, measures can be taken to minimise the impact of dissemination bias by systematically searching for and including relevant studies that are difficult to access. Statistical methods can be useful for sensitivity analyses. Further research is needed to develop methods for qualitatively assessing the risk of publication bias in systematic reviews, and to evaluate the effect of prospective registration of studies, open access policy and improved publication guidelines.

Systematic review of multidisciplinary interventions in heart failure

Objective: To determine the impact of multidisciplinary interventions on hospital admission and mortality in heart failure. Design: Systematic review. Thirteen databases were searched and reference lists from included trials and related reviews were checked. Trial authors were contacted if further information was required. Setting: Randomised controlled trials conducted in both hospital and community settings. Patients: Trials were included if all, or a defined subgroup of patients, had a diagnosis of heart failure. Interventions: Multidisciplinary interventions were defined as those in which heart failure management was the responsibility of a multidisciplinary team including medical input plus one or more of the following: specialist nurse, pharmacist, dietician, or social worker. Interventions were separated into four mutually exclusive groups: provision of home visits; home physiological monitoring or televideo link; telephone follow up but no home visits; and hospital or clinic interventions alone. Pharmaceutical and exercise based interventions were excluded. Main outcome measures: All cause hospital admission, all cause mortality, and heart failure hospital admission. Results: 74 trials were identified, of which 30 contained relevant data for inclusion in meta-analyses. Multidisciplinary interventions reduced all cause admission (relative risk (RR) 0.87, 95% confidence interval (CI) 0.79 to 0.95, p  =  0.002), although significant heterogeneity was found (p  =  0.002). All cause mortality was also reduced (RR 0.79, 95% CI 0.69 to 0.92, p  =  0.002) as was heart failure admission (RR 0.70, 95% CI 0.61 to 0.81, p < 0.001). These results varied little with sensitivity analyses. Conclusion: Multidisciplinary interventions for heart failure reduce both hospital admission and all cause mortality. The most effective interventions were delivered at least partly in the home.

Does home based medication review keep older people out of hospital? The HOMER randomised controlled trial.

Abstract Objective To determine whether home based medication review by pharmacists affects hospital readmission rates among older people. Design Randomised controlled trial. Setting Home based medication review after discharge from acute or community hospitals in Norfolk and Suffolk. Participants 872 patients aged over 80 recruited during an emergency admission (any cause) if returning to own home or warden controlled accommodation and taking two or more drugs daily on discharge. Intervention Two home visits by a pharmacist within two weeks and eight weeks of discharge to educate patients and carers about their drugs, remove out of date drugs, inform general practitioners of drug reactions or interactions, and inform the local pharmacist if a compliance aid is needed. Control arm received usual care. Main outcome measure Total emergency readmissions to hospital at six months. Secondary outcomes included death and quality of life measured with the EQ-5D. Results By six months 178 readmissions had occurred in the control group and 234 in the intervention group (rate ratio = 1.30, 95% confidence interval 1.07 to 1.58; P = 0.009, Poisson model). 49 deaths occurred in the intervention group compared with 63 in the control group (hazard ratio = 0.75, 0.52 to 1.10; P = 0.14). EQ-5D scores decreased (worsened) by a mean of 0.14 in the control group and 0.13 in the intervention group (difference = 0.01, -0.05 to 0.06; P = 0.84, t test). Conclusions The intervention was associated with a significantly higher rate of hospital admissions and did not significantly improve quality of life or reduce deaths. Further research is needed to explain this counterintuitive finding and to identify more effective methods of medication review.

Leukotriene Antagonists as First-Line or Add-on Asthma-Controller Therapy

BACKGROUND Most randomized trials of treatment for asthma study highly selected patients under idealized conditions. METHODS We conducted two parallel, multicenter, pragmatic trials to evaluate the real-world effectiveness of a leukotriene-receptor antagonist (LTRA) as compared with either an inhaled glucocorticoid for first-line asthma-controller therapy or a long-acting beta(2)-agonist (LABA) as add-on therapy in patients already receiving inhaled glucocorticoid therapy. Eligible primary care patients 12 to 80 years of age had impaired asthma-related quality of life (Mini Asthma Quality of Life Questionnaire [MiniAQLQ] score ≤6) or inadequate asthma control (Asthma Control Questionnaire [ACQ] score ≥1). We randomly assigned patients to 2 years of open-label therapy, under the care of their usual physician, with LTRA (148 patients) or an inhaled glucocorticoid (158 patients) in the first-line controller therapy trial and LTRA (170 patients) or LABA (182 patients) added to an inhaled glucocorticoid in the add-on therapy trial. RESULTS Mean MiniAQLQ scores increased by 0.8 to 1.0 point over a period of 2 years in both trials. At 2 months, differences in the MiniAQLQ scores between the two treatment groups met our definition of equivalence (95% confidence interval [CI] for an adjusted mean difference, -0.3 to 0.3). At 2 years, mean MiniAQLQ scores approached equivalence, with an adjusted mean difference between treatment groups of -0.11 (95% CI, -0.35 to 0.13) in the first-line controller therapy trial and of -0.11 (95% CI, -0.32 to 0.11) in the add-on therapy trial. Exacerbation rates and ACQ scores did not differ significantly between the two groups. CONCLUSIONS Study results at 2 months suggest that LTRA was equivalent to an inhaled glucocorticoid as first-line controller therapy and to LABA as add-on therapy for diverse primary care patients. Equivalence was not proved at 2 years. The interpretation of results of pragmatic research may be limited by the crossover between treatment groups and lack of a placebo group. (Funded by the National Coordinating Centre for Health Technology Assessment U.K. and others; Controlled Clinical Trials number, ISRCTN99132811.).

Physical activity and dietary behaviour in a population-based sample of British 10-year old children: the SPEEDY study (Sport, Physical activity and Eating behaviour: environmental Determinants in Young people).

BackgroundThe SPEEDY study was set up to quantify levels of physical activity (PA) and dietary habits and the association with potential correlates in 9–10 year old British school children. We present here the analyses of the PA, dietary and anthropometry data.MethodsIn a cross-sectional study of 2064 children (926 boys, 1138 girls) in Norfolk, England, we collected anthropometry data at school using standardised procedures. Body mass index (BMI) was used to define obesity status. PA was assessed with the Actigraph accelerometer over 7 days. A cut-off of ≥ 2000 activity counts was used to define minutes of moderate-to-vigorous PA (MVPA). Dietary habits were assessed using the Health Behaviour in School Children food questionnaire. Weight status was defined using published international cut-offs (Cole, 2000). Differences between groups were assessed using independent t-tests for continuous data and chi-squared tests for categorical data.ResultsValid PA data (>500 minutes per day on ≥ 3 days) was available for 1888 children. Mean (± SD) activity counts per minute among boys and girls were 716.5 ± 220.2 and 635.6 ± 210.6, respectively (p < 0.001). Boys spent an average of 84.1 ± 25.9 minutes in MVPA per day compared to 66.1 ± 20.8 among girls (p < 0.001), with an average of 69.1% of children accumulating 60 minutes each day. The proportion of children classified as overweight and obese was 15.0% and 4.1% for boys and 19.3% and 6.6% for girls, respectively (p = 0.001). Daily consumption of at least one portion of fruit and of vegetables was 56.8% and 49.9% respectively, with higher daily consumption in girls than boys and in children from higher socioeconomic backgrounds.ConclusionResults indicate that almost 70% of children meet national PA guidelines, indicating that a prevention of decline, rather than increasing physical activity levels, might be an appropriate intervention target. Promotion of daily fruit and vegetable intake in this age group is also warranted, possibly focussing on children from lower socioeconomic backgrounds.

A randomised controlled trial. Shifting boundaries of doctors and physiotherapists in orthopaedic outpatient departments

OBJECTIVE: To evaluate the effectiveness and cost effectiveness of specially trained physiotherapists in the assessment and management of defined referrals to hospital orthopaedic departments. DESIGN: Randomised controlled trial. SETTING: Orthopaedic outpatient departments in two hospitals. SUBJECTS: 481 patients with musculoskeletal problems referred for specialist orthopaedic opinion. INTERVENTIONS: Initial assessment and management undertaken by post-Fellowship junior orthopaedic surgeons, or by specially trained physiotherapists working in an extended role (orthopaedic physiotherapy specialists). MAIN OUTCOME MEASURES: Patient centred measures of pain, functional disability and perceived handicap. RESULTS: A total of 654 patients were eligible to join the trial, 481 (73.6%) gave their consent to be randomised. The two arms (doctor n = 244, physiotherapist n = 237) were similar at baseline. Baseline and follow up questionnaires were completed by 383 patients (79.6%). The mean time to follow up was 5.6 months after randomisation, with similar distributions of intervals to follow up in both arms. The only outcome for which there was a statistically or clinically important difference between arms was in a measure of patient satisfaction, which favoured the physiotherapist arm. A cost minimisation analysis showed no significant differences in direct costs to the patient or NHS primary care costs. Direct hospital costs were lower (p < 0.00001) in the physiotherapist arm (mean cost per patient = 256 Pounds, n = 232), as they were less likely to order radiographs and to refer patients for orthopaedic surgery than were the junior doctors (mean cost per patient in arm = 498 Pounds, n = 238). CONCLUSIONS: On the basis of the patient centred outcomes measured in this randomised trial, orthopaedic physiotherapy specialists are as effective as post-Fellowship junior staff and clinical assistant orthopaedic surgeons in the initial assessment and management of new referrals to outpatient orthopaedic departments, and generate lower initial direct hospital costs.

Adjusted indirect comparison may be less biased than direct comparison for evaluating new pharmaceutical interventions

OBJECTIVE To investigate discrepancies between direct comparison and adjusted indirect comparison in meta-analyses of new versus conventional pharmaceutical interventions. STUDY DESIGN AND SETTING Results of direct comparison were compared with results of adjusted indirect comparison in three meta-analyses of new versus conventional drugs. The three case studies are (1) bupropion versus nicotine replacement therapy for smoking cessation, (2) risperidone versus haloperidol for schizophrenia, and (3) fluoxetine versus imipramine for depressive disorders. RESULTS In all the three cases, effects of new drugs estimated by head-to-head trials tend to be greater than that by adjusted indirect comparisons. The observed discrepancies could not be satisfactorily explained by the play of chance or by bias and heterogeneity in adjusted indirect comparison. This observation, along with analysis of possible systematic bias in the direct comparisons, suggested that the indirect method might have produced less biased results. Simulations found that adjusted indirect comparison may counterbalance bias under certain circumstances. CONCLUSION Adjusted indirect comparison could be used to cross-examine the validity and applicability of results from head-to-head randomized trials. The hypothesis that adjusted indirect comparison may provide less biased results than head-to-head randomized trials needs to be investigated by further research.

Prevalence and risk factors for common vision problems in children: data from the ALSPAC study

Objective: To estimate the distribution and predictors of some common visual problems (strabismus, amblyopia, hypermetropia) within a population-based cohort of children at the age of 7 years. Methods: Children participating in a birth cohort study were examined by orthoptists who carried out cover/uncover, alternate cover, visual acuity and non-cycloplegic refraction tests. Prospectively collected data on potential risk factors were available from the study. Results: Data were available for 7825 seven-year-old children. 2.3% (95% CI 2.0% to 2.7%) had manifest strabismus, 3.6% (95% CI 3.3% to 4.1%) had past/present amblyopia, and 4.8% (95% CI 4.4% to 5.3%) were hypermetropic. Children from the lowest occupational social class background were 1.82 (95% CI 1.03% to 3.23%) times more likely to be hypermetropic than children from the highest social class. Amblyopia (p = 0.089) and convergent strabismus (p = 0.066) also tended to increase as social class decreased. Conclusions: Although strabismus has decreased in the UK, it and amblyopia remain common problems. Children from less advantaged backgrounds were more at risk of hypermetropia and to a lesser extent of amblyopia and convergent strabismus. Children’s eye-care services may need to take account of this socio-economic gradient in prevalence to avoid inequity in access to care.

Effectiveness of visits from community pharmacists for patients with heart failure: HeartMed randomised controlled trial

Objective To test whether a drug review and symptom self management and lifestyle advice intervention by community pharmacists could reduce hospital admissions or mortality in heart failure patients. Design Randomised controlled trial. Setting Home based intervention in heart failure patients. Participants 293 patients diagnosed with heart failure were included (149 intervention, 144 control) after an emergency admission. Intervention Two home visits by one of 17 community pharmacists within two and eight weeks of discharge. Pharmacists reviewed drugs and gave symptom self management and lifestyle advice. Controls received usual care. Main outcome measures The primary outcome was total hospital readmissions at six months. Secondary outcomes included mortality and quality of life (Minnesota living with heart failure questionnaire and EQ-5D). Results Primary outcome data were available for 291 participants (99%). 136 (91%) intervention patients received one or two visits. 134 admissions occurred in the intervention group compared with 112 in the control group (rate ratio=1.15, 95% confidence interval 0.89 to 1.48; P=0.28, Poisson model). 30 intervention patients died compared with 24 controls (hazard ratio=1.18, 0.69 to 2.03; P=0.54). Although EQ-5D scores favoured the intervention group, Minnesota living with heart failure questionnaire scores favoured controls; neither difference was statistically significant. Conclusion This community pharmacist intervention did not lead to reductions in hospital admissions in contrast to those found in trials of specialist nurse led interventions in heart failure. Given that heart failure accounts for 5% of hospital admissions, these results present a problem for policy makers who are faced with a shortage of specialist provision and have hoped that skilled community pharmacists could produce the same benefits. Trial registration number ISRCTN59427925.

Amblyopia treatment outcomes after screening before or at age 3 years: follow up from randomised trial

Abstract Objective: To assess the effectiveness of early treatment for amblyopia in children. Design: Follow up of outcomes of treatment for amblyopia in a randomised controlled trial comparing intensive orthoptic screening at 8, 12, 18, 25, 31, and 37 months (intensive group) with orthoptic screening at 37 months only (control group). Setting: Avon, southwest England. Participants: 3490 children who were part of a birth cohort study. Main outcome measures: Prevalence of amblyopia and visual acuity of the worse seeing eye at 7.5 years of age. Results: Amblyopia at 7.5 years was less prevalent in the intensive group than in the control group (0.6% v 1.8%; P=0.02). Mean visual acuities in the worse seeing eye were better for children who had been treated for amblyopia in the intensive group than for similar children in the control group (0.15 v 0.26 LogMAR units; P<0.001). A higher proportion of the children who were treated for amblyopia had been seen in a hospital eye clinic before 3 years of age in the intensive group than in the control group (48% v 13%; P=0.0002). Conclusions: The intensive screening protocol was associated with better acuity in the amblyopic eye and a lower prevalence of amblyopia at 7.5 years of age, in comparison with screening at 37 months only. These data support the hypothesis that early treatment for amblyopia leads to a better outcome than later treatment and may act as a stimulus for research into feasible screening programmes. What is already known on this topic Observational studies have produced conflicting results about whether early treatment for amblyopia gives better results than later treatment A recent systematic review highlighted the lack of high quality data available and recommended the cessation of preschool vision screening programmes This has led to fierce debate and to confusion about the provision of vision screening services What this study adds Children treated for amblyopia are four times more likely to remain amblyopic if they were screened at 37 months only than if they were screened repeatedly between 8 and 37 months Children screened early can see an average of one line more with their amblyopic eye after treatment than children screened at 37 months Early treatment is more effective than later treatment for amblyopia, supporting the principle of preschool vision screening