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Sensitivity of adaptive enrichment trial designs to accrual rates, time to outcome measurement, and prognostic variables.

ABSTRACT: Adaptive enrichment designs involve rules for restricting enrollment to a subset of the population during the course of an ongoing trial. This can be used to target those who benefit from the experimental treatment. Trial characteristics such as the accrual rate and the prognostic value of baseline variables are typically unknown when a trial is being planned; these values are typically assumed based on information available before the trial starts. Because of the added complexity in adaptive enrichment designs compared to standard designs, it may be of special concern how sensitive the trial performance is to deviations from assumptions. Through simulation studies, we evaluate the sensitivity of Type I error, power, expected sample size, and trial duration to different design characteristics. Our simulation distributions mimic features of data from the Alzheimer's Disease Neuroimaging Initiative cohort study, and involve two subpopulations based on a genetic marker. We investigate the impact of the following design characteristics: the accrual rate, the time from enrollment to measurement of a short-term outcome and the primary outcome, and the prognostic value of baseline variables and short-term outcomes. To leverage prognostic information in baseline variables and short-term outcomes, we use a semiparametric, locally efficient estimator, and investigate its strengths and limitations compared to standard estimators. We apply information-based monitoring, and evaluate how accurately information can be estimated in an ongoing trial.

SUBMITTER: Qian T

PROVIDER: S-EPMC5898543 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Sensitivity of adaptive enrichment trial designs to accrual rates, time to outcome measurement, and prognostic variables.

Qian Tianchen T Colantuoni Elizabeth E Fisher Aaron A Rosenblum Michael M

Contemporary clinical trials communications 20170816

Adaptive enrichment designs involve rules for restricting enrollment to a subset of the population during the course of an ongoing trial. This can be used to target those who benefit from the experimental treatment. Trial characteristics such as the accrual rate and the prognostic value of baseline variables are typically unknown when a trial is being planned; these values are typically assumed based on information available before the trial starts. Because of the added complexity in adaptive en ...[more]

PMID: 29696195

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Project description:Background and aimsThe functional luminal imaging probe (FLIP) can provide measurements of lower esophageal sphincter (LES) distensibility. Studies report that use of intraoperative FLIP examination during peroral endoscopic myotomy (POEM) for achalasia is associated with treatment success, but evidence is limited and inconsistent. The main aim of the present study was to assess associations between intraoperative FLIP values and 1-year outcomes. Additionally, associations between 1-year FLIP measurements and other 1-year outcome variables were studied.MethodsWe performed a single-center prospective study of consecutive achalasia patients treated with POEM with a standardized 1-year follow-up. The inclusion period was from June 2017 to January 2020. We compared 1-year outcomes (FLIP measurement values, Eckardt score (ES), reflux esophagitis, timed barium esophagogram (TBE), and lower esophageal sphincter resting pressure (LES-rp)) in patients with and without intraoperative FLIP examination. We also assessed associations between intraoperative FLIP values, 1-year FLIP values, and other 1-year outcomes. Results are given as median (IQR), and non-parametrical statistical analyses were applied.ResultsSixty-two patients (27 females) with median age 45 years (35-54) were included. Baseline characteristics were similar in patients with (n = 32) and without (n = 30) intraoperative FLIP examination. In patients with intraoperative FLIP, ES was 2 (1-3) and LES distensibility index (DI) 3.7 (2.6-5.4) after 1 year, compared with ES 2 (1-3) and DI 4.0 (3.1-6.8)) in patients without intraoperative FLIP (ns). Intraoperative DI was not correlated with 1-year ES or DI. One-year DI correlated significantly with 1-year ES (rs - 0.42), TBE (rs - 0.34), and LES-rp (rs - 0.29).ConclusionsUse of intraoperative FLIP measurements in POEM for achalasia is not associated with improved 1-year outcome, and the clinical value of intraoperative FLIP in POEM for achalasia is questioned. Follow-up FLIP measurements are moderately associated with symptomatic outcome, and may serve as an additional diagnostic modality in post-treatment evaluation.

Project description:BackgroundTraumatic brain injuries (TBI) are associated with high risk of morbidity and mortality. Early outcome prediction in patients with TBI require reliable data input and stable prognostic models. The aim of this investigation was to analyze different CT classification systems and prognostic calculators in a representative population of TBI-patients, with known outcomes, in a neurointensive care unit (NICU), to identify the most suitable CT scoring system for continued research.Materials and methodsWe retrospectively included 158 consecutive patients with TBI admitted to the NICU at a level 1 trauma center in Sweden from 2012 to 2016. Baseline data on admission was recorded, CT scans were reviewed, and patient outcome one year after trauma was assessed according to Glasgow Outcome Scale (GOS). The Marshall classification, Rotterdam scoring system, Helsinki CT score and Stockholm CT score were tested, in addition to the IMPACT and CRASH prognostic calculators. The results were then compared with the actual outcomes.ResultsGlasgow Coma Scale score on admission was 3-8 in 38%, 9-13 in 27.2%, and 14-15 in 34.8% of the patients. GOS after one year showed good recovery in 15.8%, moderate disability in 27.2%, severe disability in 24.7%, vegetative state in 1.3% and death in 29.7%. When adding the variables from the IMPACT base model to the CT scoring systems, the Stockholm CT score yielded the strongest relationship to actual outcome. The results from the prognostic calculators IMPACT and CRASH were divided into two subgroups of mortality (percentages); ≤50% (favorable outcome) and > 50% (unfavorable outcome). This yielded favorable IMPACT and CRASH scores in 54.4 and 38.0% respectively.ConclusionThe Stockholm CT score and the Helsinki score yielded the closest relationship between the models and the actual outcomes in this consecutive patient series, representative of a NICU TBI-population. Furthermore, the Stockholm CT score yielded the strongest overall relationship when adding variables from the IMPACT base model and would be our method of choice for continued research when using any of the current available CT score models.

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Sensitivity of adaptive enrichment trial designs to accrual rates, time to outcome measurement, and prognostic variables.

Publications

Sensitivity of adaptive enrichment trial designs to accrual rates, time to outcome measurement, and prognostic variables.

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