Catrin Tudur-Smith

Indirect Comparisons: A Review of Reporting and Methodological Quality

Background The indirect comparison of two interventions can be valuable in many situations. However, the quality of an indirect comparison will depend on several factors including the chosen methodology and validity of underlying assumptions. Published indirect comparisons are increasingly more common in the medical literature, but as yet, there are no published recommendations of how they should be reported. Our aim is to systematically review the quality of published indirect comparisons to add to existing empirical data suggesting that improvements can be made when reporting and applying indirect comparisons. Methodology/Findings Reviews applying statistical methods to indirectly compare the clinical effectiveness of two interventions using randomised controlled trials were eligible. We searched (1966–2008) Database of Abstracts and Reviews of Effects, The Cochrane library, and Medline. Full review publications were assessed for eligibility. Specific criteria to assess quality were developed and applied. Forty-three reviews were included. Adequate methodology was used to calculate the indirect comparison in 41 reviews. Nineteen reviews assessed the similarity assumption using sensitivity analysis, subgroup analysis, or meta-regression. Eleven reviews compared trial-level characteristics. Twenty-four reviews assessed statistical homogeneity. Twelve reviews investigated causes of heterogeneity. Seventeen reviews included direct and indirect evidence for the same comparison; six reviews assessed consistency. One review combined both evidence types. Twenty-five reviews urged caution in interpretation of results, and 24 reviews indicated when results were from indirect evidence by stating this term with the result. Conclusions This review shows that the underlying assumptions are not routinely explored or reported when undertaking indirect comparisons. We recommend, therefore, that the quality of indirect comparisons should be improved, in particular, by assessing assumptions and reporting the assessment methods applied. We propose that the quality criteria applied in this article may provide a basis to help review authors carry out indirect comparisons and to aid appropriate interpretation.

Advertising as a cue to consume: a systematic review and meta-analysis of the effects of acute exposure to unhealthy food and nonalcoholic beverage advertising on intake in children and adults

BACKGROUND Several studies have assessed the effects of food and nonalcoholic beverage (hereafter collectively referred to as food) advertising on food consumption, but the results of these studies have been mixed. This lack of clarity may be impeding policy action. OBJECTIVE We examined the evidence for a relation between acute exposure to experimental unhealthy food advertising and food consumption. DESIGN The study was a systematic review and meta-analysis of published studies in which advertising exposure (television or Internet) was experimentally manipulated, and food intake was measured. Five electronic databases were searched for relevant publications (SCOPUS, PsycINFO, MEDLINE, Emerald Insight, and JSTOR). An inverse variance meta-analysis was used whereby the standardized mean difference (SMD) in food intake was calculated between unhealthy food advertising and control conditions. RESULTS Twenty-two articles were eligible for inclusion. Data were available for 18 articles to be included in the meta-analysis (which provided 20 comparisons). With all available data included, the analysis indicated a small-to-moderate effect size for advertising on food consumption with participants eating more after exposure to food advertising than after control conditions (SMD: 0.37; 95% CI: 0.09; 0.65; I(2) = 98%). Subgroup analyses showed that the experiments with adult participants provided no evidence of an effect of advertising on intake (SMD: 0.00; P = 1.00; 95% CI: -0.08, 0.08; I(2) = 8%), but a significant effect of moderate size was shown for children, whereby food advertising exposure was associated with greater food intake (SMD: 0.56; P = 0.003; 95% CI: 0.18, 0.94; I(2) = 98%). CONCLUSIONS Evidence to date shows that acute exposure to food advertising increases food intake in children but not in adults. These data support public health policy action that seeks to reduce childrens exposure to unhealthy food advertising.

Will smaller plates lead to smaller waists? A systematic review and meta-analysis of the effect that experimental manipulation of dishware size has on energy consumption

It has been suggested that providing consumers with smaller dishware may prove an effective way of helping people eat less and preventing weight gain, but experimental evidence supporting this has been mixed. The objective of the present work was to examine the current evidence base for whether experimentally manipulated differences in dishware size influence food consumption. We systematically reviewed studies that experimentally manipulated the dishware size participants served themselves at a meal with and measured subsequent food intake. We used inverse variance meta‐analysis, calculating the standardized mean difference (SMD) in food intake between smaller and larger dishware size conditions. Nine experiments from eight publications were eligible for inclusion. The majority of experiments found no significance difference in food intake when participants ate from smaller vs. larger dishware. With all available data included, analysis indicated a marginal effect of dishware size on food intake, with larger dishware size associated with greater intake. However, this effect was small and there was a large amount of heterogeneity across studies (SMD: −0.18, 95% confidence interval: −0.35, 0.00, I2 = 77%). Evidence to date does not show that dishware size has a consistent effect on food intake, so recommendations surrounding the use of smaller plates/dishware to improve public health may be premature.

Seizure recurrence after antiepileptic drug withdrawal and the implications for driving: further results from the MRC Antiepileptic Drug Withdrawal Study and a systematic review

Background In the UK, patients with epilepsy in remission, who withdraw antiepileptic drug (AED) treatment, are advised not to drive during withdrawal and for 6 months thereafter, assuming the risk of recurrence in the next 12 months is below 20%. Those with a seizure recurrence currently have to be seizure-free for 12 months before returning to drive, whether treatment is restarted or not. New EU regulations recommend returning to driving 3 months after restarting treatment. Methods Regression modelling of data from the Medical Research Council AED withdrawal study was undertaken to estimate the risk of seizure recurrence in the next 12 months at various time points following: completion of drug withdrawal; AED reinstatement for those with a recurrence. A systematic review of prospective studies was also undertaken. Results Immediately following treatment withdrawal, the recurrence risk in the next 12 months was 30% (95% CI 25% to 35%) and at 3 months after withdrawal was 15% (95% CI 10% to 19%). At 3 months following the recommencement of treatment following a seizure recurrence, the risk of a seizure in the next 12 months was 26% (95% CI 17% to 35%), at 6 months 18% (95% CI 10% to 27%) and at 12 months 17% (95% CI 3% to 27%). Systematic review results were similar. Conclusion Current UK legislation concerning time off driving after withdrawing AED treatment may be too conservative. For those restarting treatment after a recurrence, current UK guidance may be too conservative but the new EU guidance too liberal.

Reporting of adverse events in randomised controlled trials of antiepileptic drugs using the CONSORT criteria for reporting harms

PURPOSE To assess the reporting of adverse events (AEs) in randomised controlled trials (RCTs) of antiepileptic drugs (AEDs) using the CONSORT statement for harms 2004, and to determine if reporting has changed since introduction of this standard. PRINCIPAL RESULTS One hundred and fifty two RCTs were included from a search of papers published between 1999 and 2008 inclusive. We identified 23 criteria in the CONSORT statements. The mean number of criteria met per trial was 11.3 (95%CI 10.6-12.0). Commercially funded studies met 12.6 and non-commercially funded met 9.4 (p<0.001). Trials recruiting adults met 12.5 and trials recruiting children met 9.3 (p<0.001). Trials published before 2004 met 11.6 and trials published after 2004 met 11.1 (p=0.53). Commercially funded trials met the majority of criteria more than non-commercially sponsored trials, particularly for definition of AEs (RR 3.15, CI 1.67-5.95) and the use of a validated dictionary of terms (RR 3.46, CI 1.41-8.44). Definitions for AEs (RR 2.32, CI 1.07-5.02) and details of analyses (RR 2.05, CI 1.01-4.15) were reported in adult trials more often than trials in children. MAJOR CONCLUSIONS Reporting of AEs in RCTs of AEDs is poor and has not improved since the publication of the CONSORT guidelines on the reporting of harms. Commercially funded trials were better reported than non-commercially funded trials and trials recruiting adults were better reported than trials recruiting children. These findings have serious implications as poor reporting precludes bias being detected and hinders adequate risk benefit analyses. Journal editors, authors and reviewers should be encouraged to follow current guidance.

Risk of recurrence after a first seizure and implications for driving: further analysis of the Multicentre study of early Epilepsy and Single Seizures.

Objective To determine for how long after a first unprovoked seizure a driver must be seizure-free before the risk of recurrence in the next 12 months falls below 20%, enabling them to regain their driving licence. Design Randomised controlled trial: Multicentre study of early Epilepsy and Single Seizures (MESS). Setting UK hospital outpatient clinics from 1 January 1993 to 31 December 2000. Participants People entered MESS if they had had one or more unprovoked seizures and both the participant and the clinician were uncertain about the need to start antiepileptic drug treatment. The subset of people used for this analysis comprised participants aged at least 16 years with a single unprovoked seizure. Main outcome measure Risk of seizure recurrence in the 12 months after a seizure-free period of 6, 12, 18, or 24 months from the date of the first (index) seizure. Regression modelling was used to investigate how antiepileptic treatment and several clinical factors influence the risk of seizure recurrence. Results At six months after the index seizure the risk of recurrence in the next 12 months for those who start antiepileptic drugs was significantly below 20% (unadjusted risk 14%, 95% confidence interval 10% to 18%). For patients who did not start treatment the risk estimate was less than 20% but the upper limit of the confidence interval was greater than 20% (18%, 13% to 23%). Multivariable analyses identified subgroups with a significantly greater than 20% risk of seizure recurrence in the 12 months after a six month seizure-free period, such as those with a remote symptomatic seizure with abnormal electroencephalogram results. Conclusion After a single unprovoked seizure this reanalysis of MESS provides estimates of seizure recurrence risks that will inform policy and guidance about regaining an ordinary driving licence. Further guidance is needed as to how such data should be utilised; in particular, whether a population approach should be taken with a focus on the unadjusted results or whether attempts should be made to individualise risk. Guidance is also required as to whether the focus should be on risk estimates only or on the confidence interval as well. If the focus is on the estimate only our unadjusted estimates suggest that treated and untreated patients are eligible to drive after being seizure-free for six months. If the focus is also on confidence intervals, direction is needed as to whether a conservative or liberal approach should be taken. Trial registration Current Controlled Trials ISRCTN98767960.

Reporting of harms data in RCTs: a systematic review of empirical assessments against the CONSORT harms extension

Objective To determine the standard of reporting of harms-related data, in randomised controlled trials (RCTs) according to the Consolidated Standards of Reporting Trials (CONSORT) statement extension for harms. Design Systematic review. Data sources The Cochrane library, Ovid MEDLINE, Scopus and ISI Web of Knowledge were searched for relevant literature. Eligibility criteria for selecting studies We included publications of studies that used the CONSORT harms extension to assess the reporting of harms in RCTs. Results We identified 7 studies which included between 10 and 205 RCTs. The clinical areas of the 7 studies were: hypertension (1), urology (1), epilepsy (1), complimentary medicine (2) and two not restricted to a clinical topic. Quality of the 7 studies was assessed by a risk of bias tool and was found to be variable. Adherence to the CONSORT harms criteria reported in the 7 studies was inadequate and variable across the items in the checklist. Adverse events are poorly defined, with 6 studies failing to exceed 50% adherence to the items in the checklist. Conclusions Readers of RCT publications need to be able to balance the trade-offs between benefits and harms of interventions. This systematic review suggests that this is compromised due to poor reporting of harms which is evident across a range of clinical areas. Improvements in quality could be achieved by wider adoption of the CONSORT harms criteria by journals reporting RCTs.

Elicitation of Expert Prior Opinion: Application to the MYPAN Trial in Childhood Polyarteritis Nodosa

Objectives Definitive sample sizes for clinical trials in rare diseases are usually infeasible. Bayesian methodology can be used to maximise what is learnt from clinical trials in these circumstances. We elicited expert prior opinion for a future Bayesian randomised controlled trial for a rare inflammatory paediatric disease, polyarteritis nodosa (MYPAN, Mycophenolate mofetil for polyarteritis nodosa). Methods A Bayesian prior elicitation meeting was convened. Opinion was sought on the probability that a patient in the MYPAN trial treated with cyclophosphamide would achieve disease remission within 6-months, and on the relative efficacies of mycophenolate mofetil and cyclophosphamide. Expert opinion was combined with previously unseen data from a recently completed randomised controlled trial in ANCA associated vasculitis. Results A pan-European group of fifteen experts participated in the elicitation meeting. Consensus expert prior opinion was that the most likely rates of disease remission within 6 months on cyclophosphamide or mycophenolate mofetil were 74% and 71%, respectively. This prior opinion will now be taken forward and will be modified to formulate a Bayesian posterior opinion once the MYPAN trial data from 40 patients randomised 1:1 to either CYC or MMF become available. Conclusions We suggest that the methodological template we propose could be applied to trial design for other rare diseases.

‘Seizure First Aid Training’ for people with epilepsy who attend emergency departments, and their family and friends: study protocol for intervention development and a pilot randomised controlled trial

Introduction People with chronic epilepsy (PWE) often make costly but clinically unnecessary emergency department (ED) visits. Offering them and their carers a self-management intervention that improves confidence and ability to manage seizures may lead to fewer visits. As no such intervention currently exists, we describe a project to develop and pilot one. Methods and analysis To develop the intervention, an existing group-based seizure management course that has been offered by the Epilepsy Society within the voluntary sector to a broader audience will be adapted. Feedback from PWE, carers and representatives from the main groups caring for PWE will help refine the course so that it addresses the needs of ED attendees. Its behaviour change potential will also be optimised. A pilot randomised controlled trial will then be completed. 80 PWE aged ≥16 who have visited the ED in the prior 12 months on ≥2 occasions, along with one of their family members or friends, will be recruited from three NHS EDs. Dyads will be randomised to receive the intervention or treatment as usual alone. The proposed primary outcome is ED use in the 12 months following randomisation. For the pilot, this will be measured using routine hospital data. Secondary outcomes will be measured by patients and carers completing questionnaires 3, 6 and 12 months postrandomisation. Rates of recruitment, retention and unblinding will be calculated, along with the ED event rate in the control group and an estimate of the interventions effect on the outcome measures. Ethics and dissemination Ethical approval: NRES Committee North West—Liverpool East (Reference number 15/NW/0225). The projects findings will provide robust evidence on the acceptability of seizure management training and on the optimal design of a future definitive trial. The findings will be published in peer-reviewed journals and presented at conferences. Trial registration number ISRCTN13 871 327.

A systematic review of placebo-controlled trials of topiramate: How useful is a multiple-indications review for evaluating the adverse events of an antiepileptic drug?

Topiramate (TPM) is an antiepileptic drug that is also used for other indications (e.g., migraine). Adverse event (AE) data from epilepsy trials could be supplemented by data from trials in other indications. Combining data across trials and indications is a novel method for evaluating AEs. We conducted a multiple‐indications review by systematically reviewing randomized placebo‐controlled trials of TPM, to compare the nervous system AEs of TPM in epilepsy with those in other indications.