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A novel complete-case analysis to determine statistical significance between treatments in an intention-to-treat population of randomized clinical trials involving missing data.

ABSTRACT: The application of the principle of the intention-to-treat (ITT) to the analysis of clinical trials is challenged in the presence of missing outcome data. The consequences of stopping an assigned treatment in a withdrawn subject are unknown. It is difficult to make a single assumption about missing mechanisms for all clinical trials because there are complicated reactions in the human body to drugs due to the presence of complex biological networks, leading to data missing randomly or non-randomly. Currently there is no statistical method that can tell whether a difference between two treatments in the ITT population of a randomized clinical trial with missing data is significant at a pre-specified level. Making no assumptions about the missing mechanisms, we propose a generalized complete-case (GCC) analysis based on the data of completers. An evaluation of the impact of missing data on the ITT analysis reveals that a statistically significant GCC result implies a significant treatment effect in the ITT population at a pre-specified significance level unless, relative to the comparator, the test drug is poisonous to the non-completers as documented in their medical records. Applications of the GCC analysis are illustrated using literature data, and its properties and limits are discussed.

SUBMITTER: Liu W

PROVIDER: S-EPMC5963886 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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A novel complete-case analysis to determine statistical significance between treatments in an intention-to-treat population of randomized clinical trials involving missing data.

Liu Wei W Ding Jinhui J

Statistical methods in medical research 20160525 4

The application of the principle of the intention-to-treat (ITT) to the analysis of clinical trials is challenged in the presence of missing outcome data. The consequences of stopping an assigned treatment in a withdrawn subject are unknown. It is difficult to make a single assumption about missing mechanisms for all clinical trials because there are complicated reactions in the human body to drugs due to the presence of complex biological networks, leading to data missing randomly or non-random ...[more]

PMID: 27230128

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Project description:ObjectivesTo determine the incidence and characteristics of randomised controlled trials that report using the modified intention to treat approach, and how the approach is described.DesignSystematic review.Data sourcesPubMed, Embase, Cochrane central register of controlled trials, ISI Web of Knowledge, Ovid, HighWire Press, Science-Direct, Ingenta, Medscape, BioMed Central, Springer, and Wiley, from inception to December 2006.Main outcome measuresIncidence of trials in which use of modified intention to treat was reported, and how the approach was described (classified according to the type and number of deviations from the intention to treat approach).Results475 randomised controlled trials reported use of a modified intention to treat analysis. Of these, 76 (16%) were published in five highly cited general medical journals. The incidence of all trials that reported use of modified intention to treat published in journals indexed in Medline increased from 0.006% in 1982-6 to 0.5% in 2002-6 (P<0.001 for linear trend). When the description of the modified intention to treat was examined in each trial, 192 (40%) reported one type of deviation from the intention to treat approach, 261 (55%) reported two or more types, and 22 (5%) did not describe any type. In 266 (56%) of the trials the deviation was related to the treatment received, in 196 (41%) to a post baseline assessment, in 118 (25%) to a baseline assessment, in 108 (23%) to a target condition, and in 23 (5%) to follow-up. Post-randomisation exclusions occurred in 380 (80%) trials. The results reported by 270 of the 352 (77%) superiority trials favoured the drug under investigation. All of the 123 trials using equivalence or non-inferiority methods to investigate interventions reported results that favoured their assumptions.ConclusionsRandomised controlled trials that report using a modified intention to treat are increasingly being published in the medical literature. The descriptions of such an approach were ambiguous, and may cover any type of descriptions for exclusion, such as missing data and deviation from protocol. Explicit statements about post-randomisation exclusions should replace the ambiguous terminology of modified intention to treat.

Project description:ObjectiveTo examine whether deviation from the standard intention to treat analysis has an influence on treatment effect estimates of randomised trials.DesignMeta-epidemiological study.Data sourcesMedline, via PubMed, searched between 2006 and 2010; 43 systematic reviews of interventions and 310 randomised trials were included.Eligibility criteria for selecting studiesFrom each year searched, random selection of 5% of intervention reviews with a meta-analysis that included at least one trial that deviated from the standard intention to treat approach. Basic characteristics of the systematic reviews and randomised trials were extracted. Information on the reporting of intention to treat analysis, outcome data, risk of bias items, post-randomisation exclusions, and funding were extracted from each trial. Trials were classified as: ITT (reporting the standard intention to treat approach), mITT (reporting a deviation from the standard approach), and no ITT (reporting no approach). Within each meta-analysis, treatment effects were compared between mITT and ITT trials, and between mITT and no ITT trials. The ratio of odds ratios was calculated (value <1 indicated larger treatment effects in mITT trials than in other trial categories).Results50 meta-analyses and 322 comparisons of randomised trials (from 84 ITT trials, 118 mITT trials, and 108 no ITT trials; 12 trials contributed twice to the analysis) were examined. Compared with ITT trials, mITT trials showed a larger intervention effect (pooled ratio of odds ratios 0.83 (95% confidence interval 0.71 to 0.96), P=0.01; between meta-analyses variance τ(2)=0.13). Adjustments for sample size, type of centre, funding, items of risk of bias, post-randomisation exclusions, and variance of log odds ratio yielded consistent results (0.80 (0.69 to 0.94), P=0.005; τ(2)=0.08). After exclusion of five influential studies, results remained consistent (0.85 (0.75 to 0.98); τ(2)=0.08). The comparison between mITT trials and no ITT trials showed no statistical difference between the two groups (adjusted ratio of odds ratios 0.92 (0.70 to 1.23); τ(2)=0.57).ConclusionsTrials that deviated from the intention to treat analysis showed larger intervention effects than trials that reported the standard approach. Where an intention to treat analysis is impossible to perform, authors should clearly report who is included in the analysis and attempt to perform multiple imputations.

Project description:BackgroundIn non-inferiority trials, there is a concern that intention-to-treat (ITT) analysis, by including participants who did not receive the planned interventions, may bias towards making the treatment and control arms look similar and lead to mistaken claims of non-inferiority. In contrast, per protocol (PP) analysis is viewed as less likely to make this mistake and therefore preferable in non-inferiority trials. In a systematic review of antibiotic non-inferiority trials, we compared ITT and PP analyses to determine which analysis was more conservative.MethodsIn a secondary analysis of a systematic review, we included non-inferiority trials that compared different antibiotic regimens, used absolute risk reduction (ARR) as the main outcome and reported both ITT and PP analyses. All estimates and confidence intervals (CIs) were oriented so that a negative ARR favored the control arm, and a positive ARR favored the treatment arm. We compared ITT to PP analyses results. The more conservative analysis between ITT and PP analyses was defined as the one having a more negative lower CI limit.ResultsThe analysis included 164 comparisons from 154 studies. In terms of the ARR, ITT analysis yielded the more conservative point estimate and lower CI limit in 83 (50.6%) and 92 (56.1%) comparisons respectively. The lower CI limits in ITT analysis favored the control arm more than in PP analysis (median of - 7.5% vs. -6.9%, p = 0.0402). CIs were slightly wider in ITT analyses than in PP analyses (median of 13.3% vs. 12.4%, p < 0.0001). The median success rate was 89% (interquartile range IQR 82 to 93%) in the PP population and 44% (IQR 23 to 60%) in the patients who were included in the ITT population but excluded from the PP population (p < 0.0001).ConclusionsContrary to common belief, ITT analysis was more conservative than PP analysis in the majority of antibiotic non-inferiority trials. The lower treatment success rate in the ITT analysis led to a larger variance and wider CI, resulting in a more conservative lower CI limit. ITT analysis should be mandatory and considered as either the primary or co-primary analysis for non-inferiority trials.Trial registrationPROSPERO registration number CRD42020165040 .

Project description:While journals and reporting guidelines recommend the presentation of confidence intervals, many authors adhere strictly to statistically significant testing. Our objective was to determine what proportions of not statistically significant (NSS) cardiovascular trials include potentially clinically meaningful effects in primary outcomes and if these are associated with authors' conclusions.Cardiovascular studies published in six high-impact journals between 1 January 2010 and 31 December 2014 were identified via PubMed. Two independent reviewers selected trials with major adverse cardiovascular events (stroke, myocardial infarction, or cardiovascular death) as primary outcomes and extracted data on trial characteristics, quality, and primary outcome. Potentially clinically meaningful effects were defined broadly as a relative risk point estimate ?0.94 (based on the effects of ezetimibe) and/or a lower confidence interval ?0.75 (based on the effects of statins).We identified 127 randomized trial comparisons from 3200 articles. The primary outcomes were statistically significant (SS) favoring treatment in 21% (27/127), NSS in 72% (92/127), and SS favoring control in 6% (8/127). In 61% of NSS trials (56/92), the point estimate and/or lower confidence interval included potentially meaningful effects. Both point estimate and confidence interval included potentially meaningful effects in 67% of trials (12/18) in which authors' concluded that treatment was superior, in 28% (16/58) with a neutral conclusion, and in 6% (1/16) in which authors' concluded that control was superior. In a sensitivity analysis, 26% of NSS trials would include potential meaningful effects with relative risk thresholds of point estimate ?0.85 and/or a lower confidence interval ?0.65.Point estimates and/or confidence intervals included potentially clinically meaningful effects in up to 61% of NSS cardiovascular trials. Authors' conclusions often reflect potentially meaningful results of NSS cardiovascular trials. Given the frequency of potentially clinical meaningful effects in NSS trials, authors should be encouraged to continue to look beyond significance testing to a broader interpretation of trial results.

Project description:BackgroundExtant literature suggests that a substantial portion of athletes may not report a possible concussion and that concussion knowledge is insufficient to predict concussion reporting behavior. One area that has not been explored is reporting skill; that is, mastery of the actions required to report a concussion. This study evaluated the relationship between reporting skill and reporting intention, introducing a measure of the reporting skill construct.HypothesesReporting intentions will be more closely associated with reporting skill than with concussion/symptom knowledge. The relationship between concussion (or symptom) knowledge and reporting intentions will differ by level of reporting skill.Study designRepeated cross-sectional study.Level of evidenceLevel 2.MethodsA set of items was administered to young adults aged 18 to 24 years from the Survey Sampling International panel. Exploratory/confirmatory factor analyses were conducted on 2 waves of data to develop the scale (n = 899). Hypotheses were tested using structural equation modeling on the responses from the third wave of participants (n = 406).ResultsKnowing the actions to take in reporting was more important than having knowledge of concussions or concussion symptoms. Reporting skill, not concussion or concussion symptom knowledge, was associated with higher intentions to report symptoms. Among those with higher levels of reporting skill, concussion symptom knowledge (but not general concussion knowledge) was associated with higher intentions to report symptoms.ConclusionReporting skill is an important and, until now, missing ingredient in the concussion literature and practice.Clinical relevanceIncorporating reporting skill development in concussion education and team activities to teach athletes how to report is likely to improve actual reporting intentions. While further study is needed with particular sports and additional age groups, reporting skill holds promise as a new avenue for increased concussion reporting.

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A novel complete-case analysis to determine statistical significance between treatments in an intention-to-treat population of randomized clinical trials involving missing data.

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A novel complete-case analysis to determine statistical significance between treatments in an intention-to-treat population of randomized clinical trials involving missing data.

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