Differential dropout and bias in randomised controlled trials: when it matters and when it may not.
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ABSTRACT:
SUBMITTER: Bell ML
PROVIDER: S-EPMC4688419 | biostudies-literature | 2013 Jan
REPOSITORIES: biostudies-literature
Publications
Differential dropout and bias in randomised controlled trials: when it matters and when it may not.
Bell Melanie L ML Kenward Michael G MG Fairclough Diane L DL Horton Nicholas J NJ
BMJ (Clinical research ed.) 20130121
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Project description:BackgroundClinical trials with longitudinally measured outcomes are often plagued by missing data due to patients withdrawing or dropping out from the trial before completing the measurement schedule. The reasons for dropout are sometimes clearly known and recorded during the trial, but in many instances these reasons are unknown or unclear. Often such reasons for dropout are non-ignorable. However, the standard methods for analysing longitudinal outcome data assume that missingness is non-informative and ignore the reasons for dropout, which could result in a biased comparison between the treatment groups.MethodsIn this article, as a post hoc analysis, we explore the impact of informative dropout due to competing reasons on the evaluation of treatment effect in the MAGNETIC trial, the largest randomised placebo-controlled study to date comparing the addition of nebulised magnesium sulphate to standard treatment in acute severe asthma in children. We jointly model longitudinal outcome and informative dropout process to incorporate the information regarding the reasons for dropout by treatment group.ResultsThe effect of nebulised magnesium sulphate compared with standard treatment is evaluated more accurately using a joint longitudinal-competing risk model by taking account of such complexities. The corresponding estimates indicate that the rate of dropout due to good prognosis is about twice as high in the magnesium group compared with standard treatment.ConclusionsWe emphasise the importance of identifying reasons for dropout and undertaking an appropriate statistical analysis accounting for such dropout. The joint modelling approach accounting for competing reasons for dropout is proposed as a general approach for evaluating the sensitivity of conclusions to assumptions regarding missing data in clinical trials with longitudinal outcomes.Trial registrationEudraCT number 2007-006227-12 . Registration date 18 Mar 2008.
| S-EPMC4849065 | biostudies-literature
Project description:BackgroundRandomised controlled trials (RCTs) are considered the gold standard form of evidence for assessing treatment efficacy, but many factors can influence their reliability including methodological quality, reporting quality and funding source. The aim of this study was to examine the relationship between funding source and positive outcome reporting in veterinary RCTs published in 2011 and to assess the risk of bias in the RCTs identified.MethodsA structured search of PubMed was used to identify feline, canine, equine, bovine and ovine clinical trials examining the efficacy of pharmaceutical interventions published in 2011. Funding source and outcomes were extracted from each RCT and an assessment of risk of bias made using the Cochrane risk of bias tool.ResultsLiterature searches returned 972 papers, with 86 papers (comprising 126 individual RCTs) included in the analysis. There was found to be a significantly higher proportion of positive outcomes reported in the pharmaceutical funding group (P) compared to the non-pharmaceutical (NP) and 'no funding source stated' (NF) groups (P = 56.9%, NP = 34.9%, NF = 29.1%, p < 0.05). A high proportion of trials had an unclear risk of bias across the five criteria examined.ConclusionsWe found evidence that veterinary RCTs were more likely to report positive outcomes if they have pharmaceutical industry funding or involvement. Consistently poor reporting of trials, including non-identification of funding source, was found which hinders the use of the available evidence.
| S-EPMC5557072 | biostudies-literature
Project description:Randomised controlled trials (RCT) are highly influential upon medical decisions. Thus RCTs must not distort the truth. One threat to internal trial validity is the correct prediction of future allocations (selection bias). The Berger-Exner test detects such bias but has not been widely utilized in practice. One reason for this non-utilisation may be a lack of information regarding its test accuracy. The objective of this study is to assess the accuracy of the Berger-Exner test on the basis of relevant simulations for RCTs with dichotomous outcomes.Simulated RCTs with various parameter settings were generated, using R software, and subjected to bias-free and selection bias scenarios. The effect size inflation due to bias was quantified. The test was applied in both scenarios and the pooled sensitivity and specificity, with 95% confidence intervals for alpha levels of 1%, 5%, and 20%, were computed. Summary ROC curves were generated and the relationships of parameters with test accuracy were explored.An effect size inflation of 71% - 99% was established. Test sensitivity was 1.00 (95% CI: 0.99 - 1.00) for alpha level 1%, 5%, and 20%; test specificity was 0.94 (95% CI: 0.93 - 0.96); 0.82 (95% CI: 0.80 - 0.84), and 0.56 (95% CI: 0.54 - 0.58) for alpha 1%, 5%, and 20%, respectively. Test accuracy was best with the maximal procedure used with a maximum tolerated imbalance (MTI)?= 2 as the randomisation method at alpha 1%.The results of this simulation study suggest that the Berger-Exner test is generally accurate for identifying third-order selection bias.
| S-EPMC4209086 | biostudies-other
Project description:BackgroundPoor recruitment to randomised controlled trials (RCTs) is a widespread and important problem. With poor recruitment being such an important issue with respect to the conduct of randomised trials, a systematic review of controlled trials on recruitment methods was undertaken in order to identify strategies that are effective.MethodsWe searched the register of trials in Cochrane library from 1996 to end of 2004. We also searched Web of Science for 2004. Additional trials were identified from personal knowledge. Included studies had to use random allocation and participants had to be allocated to different methods of recruitment to a 'real' randomised trial. Trials that randomised participants to 'mock' trials and trials of recruitment to non-randomised studies (e.g., case control studies) were excluded. Information on the study design, intervention and control, and number of patients recruited was extracted by the 2 authors.ResultsWe identified 14 papers describing 20 different interventions. Effective interventions included: telephone reminders; questionnaire inclusion; monetary incentives; using an 'open' rather than placebo design; and making trial materials culturally sensitive.ConclusionFew trials have been undertaken to test interventions to improve trial recruitment. There is an urgent need for more RCTs of recruitment strategies.
| S-EPMC1559709 | biostudies-literature
Project description:IntroductionBurn care represents a healthcare and economic burden to patients internationally. Choice of the most clinically effective treatment strategies requires evidence which is best obtained through high-quality randomised controlled trials (RCT). The number of published RCTs of burn care is increasing. However, trial quality and reporting standards are unclear. This study will assess the risk of bias and adequacy of reporting in recent burn care RCTs using tools endorsed by the Cochrane Collaboration.Methods and analysisA systematic literature review will be undertaken, assessing parallel group RCTs evaluating therapeutic interventions for patients with cutaneous burns. Literature searches will use Ovid Medline, Ovid Embase, Web of Science and the Cochrane Library. Separate searches for each database will include medical subject heading and free text terms including 'burn', 'scald', 'thermal injury' and 'RCT'. Two reviewers will independently assess each study for inclusion. Risk of bias (RoB) will be assessed with the revised tool (RoB 2) and reporting completeness with the CONsolidated Standards of Reporting Trials (CONSORT) 2010 guidelines. We will report a narrative synthesis of all studies, including domain specific, and overall risk of bias for the primary outcome of each trial. Inter-rater agreement for RoB 2 will be reported using Fleiss's Kappa. For adherence to the CONSORT guidelines, we will generate a completeness of reporting index for the five domains.Ethics and disseminationNo ethics approval is required because published documents will be used. Findings of the study will be disseminated in a peer-reviewed journal and presented at conferences.Prospero registration numberCRD42018111020.
| S-EPMC6937119 | biostudies-literature
Project description:ObjectiveTo assess risk of bias and to investigate methodological issues concerning the design, conduct and analysis of randomised controlled trials (RCTs) testing acupuncture for knee osteoarthritis (KOA).MethodsPubMed, EMBASE, Cochrane Central Register of Controlled Trials and four major Chinese databases were searched for RCTs that investigated the effect of acupuncture for KOA. The Cochrane tool was used to examine the risk of bias of eligible RCTs. Their methodological details were examined using a standardised and pilot-tested questionnaire of 48 items, together with the association between four predefined factors and important methodological quality indicators.ResultsA total of 248 RCTs were eligible, of which 39 (15.7%) used computer-generated randomisation sequence. Of the 31 (12.5%) trials that stated the allocation concealment, only one used central randomisation. Twenty-five (10.1%) trials mentioned that their acupuncture procedures were standardised, but only 18 (7.3%) specified how the standardisation was achieved. The great majority of trials (n=233, 94%) stated that blinding was in place, but 204 (87.6%) did not clarify who was blinded. Only 27 (10.9%) trials specified the primary outcome, for which 7 used intention-to-treat analysis. Only 17 (6.9%) trials included details on sample size calculation; none preplanned an interim analysis and associated stopping rule. In total, 46 (18.5%) trials explicitly stated that loss to follow-up occurred, but only 6 (2.4%) provided some information to deal with the issue. No trials prespecified, conducted or reported any subgroup or adjusted analysis for the primary outcome.ConclusionThe overall risk of bias was high among published RCTs testing acupuncture for KOA. Methodological limitations were present in many important aspects of design, conduct and analyses. These findings inform the development of evidence-based methodological guidance for future trials assessing the effect of acupuncture for KOA.
| S-EPMC5855180 | biostudies-literature
Project description:IntroductionIn some randomised trials, the primary interest is in the mechanisms by which an intervention exerts its effects on health outcomes. That is, clinicians and policy-makers may be interested in how the intervention works (or why it does not work) through hypothesised causal mechanisms. In this article, we highlight the value of understanding causal mechanisms in randomised trials by applying causal mediation analysis to two randomised trials of complex interventions.Main bodyIn the first example, we examine a potential mechanism by which an exercise programme for rheumatoid arthritis of the hand could improve hand function. In the second example, we explore why a rehabilitation programme for ankle fractures failed to improve lower-limb function through hypothesised mechanisms. We outline critical assumptions that are required for making valid causal inferences from these analyses, and provide results of sensitivity analyses that are used to assess the degree to which the estimated causal mediation effects could have been biased by residual confounding.ConclusionThis paper demonstrates how the application of causal mediation analyses to randomised trials can identify the mechanisms by which complex interventions exert their effects. We discuss methodological issues and assumptions that should be considered when mediation analyses of randomised trials are used to inform clinical practice and policy decisions.
| S-EPMC6708183 | biostudies-literature
Project description:Recent literature hints that outcomes of clinical trials in medicine are selectively reported. If applicable to psychotic disorders, such bias would jeopardize the reliability of randomized clinical trials (RCTs) investigating antipsychotics and thus their extrapolation to clinical practice. We therefore comprehensively examined outcome reporting bias in RCTs of antipsychotic drugs by a systematic review of prespecified outcomes on ClinicalTrials.gov records of RCTs investigating antipsychotic drugs in schizophrenia and schizoaffective disorder between 1 January 2006 and 31 December 2013. These outcomes were compared with outcomes published in scientific journals. Our primary outcome measure was concordance between prespecified and published outcomes; secondary outcome measures included outcome modifications on ClinicalTrials.gov after trial inception and the effects of funding source and directionality of results on record adherence. Of the 48 RCTs, 85% did not fully adhere to the prespecified outcomes. Discrepancies between prespecified and published outcomes were found in 23% of RCTs for primary outcomes, whereas 81% of RCTs had at least one secondary outcome non-reported, newly introduced, or changed to a primary outcome in the respective publication. In total, 14% of primary and 44% of secondary prespecified outcomes were modified after trial initiation. Neither funding source (P=0.60) nor directionality of the RCT results (P=0.10) impacted ClinicalTrials.gov record adherence. Finally, the number of published safety endpoints (N=335) exceeded the number of prespecified safety outcomes by 5.5 fold. We conclude that RCTs investigating antipsychotic drugs suffer from substantial outcome reporting bias and offer suggestions to both monitor and limit such bias in the future.
| S-EPMC5639247 | biostudies-literature
Project description:OBJECTIVE:To determine (i) the difference in the frequency of serious adverse events (SAEs) reported in trial registrations and their respective primary publications and (ii) the effect of adding SAE data from registries to a network meta-analysis (NMA) in changing the surface under the cumulative ranking (SUCRA) curve values of interventions. DESIGN:Secondary analysis of primary publications from two NMAs. ELIGIBILITY CRITERIA FOR SELECTING STUDIES:We included randomised trials published in English after 2005 that were included in two NMAs of pharmacological interventions for Alzheimer's disease and chronic obstructive pulmonary disease. DATA EXTRACTION:Two reviewers independently searched multiple international trial registries for registration status and abstracted data from the included study publications and ClinicalTrials.gov. RESULTS:Of the 203 randomised trials included, 140 (69.0%) were registered with a trial registry and 72 (35.5%) posted results in the registry. The proportion of registered trials increased over time (38.5% in 2005 vs 78.6% in 2014). Of the publications with results posted in a trial registry, 14 (19.4%) had inconsistent reporting of overall SAEs; 7 (10.4%) studies did not report SAEs in the publication but did in the registry. In the 134 randomised trials with a prespecified primary outcome in the registry, 19 studies (9.4%) had a change in the primary outcome in the publication. Adding SAEs reported in registries to the NMAs did not affect the ranking of interventions. CONCLUSION:We identified inconsistent reporting of SAEs in randomised trials that were included in two NMAs. Findings highlight the importance of including trial registries in the grey literature search and verifying safety data before incorporating it into NMAs. STUDY REGISTRATION:osf.io/mk6dr.
| S-EPMC6731894 | biostudies-literature
Project description:Objectivesto test whether an occupation-based lifestyle intervention can sustain and improve the mental well-being of adults aged 65 years or over compared to usual care, using an individually randomised controlled trial.Participants288 independently living adults aged 65 years or over, with normal cognition, were recruited from two UK sites between December 2011 and November 2015.Interventionslifestyle Matters is a National Institute for Health and Care Excellence recommended multi-component preventive intervention designed to improve the mental well-being of community living older people at risk of decline. It involves weekly group sessions over 4 months and one to one sessions.Main outcome measuresthe primary outcome was mental well-being at 6 months (mental health (MH) dimension of the SF-36). Secondary outcomes included physical health dimensions of the SF-36, extent of depression (PHQ-9), quality of life (EQ-5D) and loneliness (de Jong Gierveld Loneliness Scale), assessed at 6 and 24 months.Resultsdata on 262 (intervention = 136; usual care = 126) participants were analysed using intention to treat analysis. Mean SF-36 MH scores at 6 months differed by 2.3 points (95 CI: -1.3 to 5.9; P = 0.209) after adjustments.Conclusionsanalysis shows little evidence of clinical or cost-effectiveness in the recruited population with analysis of the primary outcome revealing that the study participants were mentally well at baseline. The results pose questions regarding how preventive interventions to promote well-being in older adults can be effectively targeted in the absence of proactive mechanisms to identify those who at risk of decline.Trial registrationISRCTN67209155.
| S-EPMC5860501 | biostudies-literature