Estimands: bringing clarity and focus to research questions in clinical trials.
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ABSTRACT:
SUBMITTER: Clark TP
PROVIDER: S-EPMC8724703 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectivesTo evaluate how often the precise research question being addressed about an intervention (the estimand) is stated or can be determined from reported methods, and to identify what types of questions are being investigated in phase 2-4 randomised trials.DesignSystematic review of the clarity of research questions being investigated in randomised trials in 2020 in six leading general medical journals.Data sourcePubMed search in February 2021.Eligibility criteria for selecting studiesPhase 2-4 randomised trials, with no restrictions on medical conditions or interventions. Cluster randomised, crossover, non-inferiority, and equivalence trials were excluded.Main outcome measuresNumber of trials that stated the precise primary question being addressed about an intervention (ie, the primary estimand), or for which the primary estimand could be determined unambiguously from the reported methods using statistical knowledge. Strategies used to handle post-randomisation events that affect the interpretation or existence of patient outcomes, such as intervention discontinuations or uses of additional drug treatments (known as intercurrent events), and the corresponding types of questions being investigated.Results255 eligible randomised trials were identified. No trials clearly stated all the attributes of the estimand. In 117 (46%) of 255 trials, the primary estimand could be determined from the reported methods. Intercurrent events were reported in 242 (95%) of 255 trials; but the handling of these could only be determined in 125 (49%) of 255 trials. Most trials that provided this information considered the occurrence of intercurrent events as irrelevant in the calculation of the treatment effect and assessed the effect of the intervention regardless (96/125, 77%)-that is, they used a treatment policy strategy. Four (4%) of 99 trials with treatment non-adherence owing to adverse events estimated the treatment effect in a hypothetical setting (ie, the effect as if participants continued treatment despite adverse events), and 19 (79%) of 24 trials where some patients died estimated the treatment effect in a hypothetical setting (ie, the effect as if participants did not die).ConclusionsThe precise research question being investigated in most trials is unclear, mainly because of a lack of clarity on the approach to handling intercurrent events. Clear reporting of estimands is necessary in trial reports so that all stakeholders, including clinicians, patients and policy makers, can make fully informed decisions about medical interventions.Systematic review registrationPROSPERO CRD42021238053.
| S-EPMC9396446 | biostudies-literature
Project description:Gray matter atrophy has been shown to be a strong correlate to clinical disability in multiple sclerosis (MS) and its most commonly used animal model, experimental autoimmune encephalomyelitis (EAE). However, the relationship between gray mater atrophy and the spinal cord pathology often observed in EAE has never been established. Here EAE was induced in Thy1.1-YFP mice and their brains imaged using in vivo magnetic resonance imaging (MRI). The brains and spinal cords were subsequently optically cleared using Clear Lipid-exchanged Acrylamide-hybridized Rigid Imaging-compatible Tissue-hYdrogel (CLARITY). Axons were followed 5mm longitudinally in three dimensions in intact spinal cords revealing that 61% of the axons exhibited a mean of 22 axonal ovoids and 8% of the axons terminating in axonal end bulbs. In the cerebral cortex, we observed a decrease in the mean number of layer V pyramidal neurons and a decrease in the mean length of the apical dendrites of the remaining neurons, compared to healthy controls. MRI analysis demonstrated decreased cortical volumes in EAE. Cross-modality correlations revealed a direct relationship between cortical volume loss and axonal end bulb number in the spinal cord, but not ovoid number. This is the first report of the use of CLARITY in an animal model of disease and the first report of the use of both CLARITY and MRI.
| S-EPMC4437539 | biostudies-literature
Project description:Cluster-randomized trials are often conducted to assess vaccine effects. Defining estimands of interest before conducting a trial is integral to the alignment between a study's objectives and the data to be collected and analyzed. This paper considers estimands and estimators for overall, indirect, and total vaccine effects in trials, where clusters of individuals are randomized to vaccine or control. The scenario is considered where individuals self-select whether to participate in the trial, and the outcome of interest is measured on all individuals in each cluster. Unlike the overall, indirect, and total effects, the direct effect of vaccination is shown in general not to be estimable without further assumptions, such as no unmeasured confounding. An illustrative example motivated by a cluster-randomized typhoid vaccine trial is provided.
| S-EPMC8273646 | biostudies-literature
Project description:Clinical trials test new ways to prevent, detect, diagnose, or treat diseases. Researchers have found that minority patients are willing to participate in clinical trials, yet these patients have barriers which hinder their access to trials.To explore African American women's participation in breast cancer clinical trials, eight focus groups were conducted with breast cancer patients, family members/care givers, religious leaders, and healthcare providers to gather information on the perspectives and opinions on the topic. The focus group conversations were transcribed, and transcripts were imported into QSR International's NVivo 10 software. The transcripts were organized into folders based on four categories. The content analysis performed was based on recordings and notes.The following themes were generated as a result of conducting these focus groups and gathering information on the perspectives and opinions about participating in clinical trials, based on the groups who participated: Promoting participation in research; Personal experience with cancer; Support and support services; Awareness, knowledge, and experience with clinical trials; Providers' roles in clinical trials.The data collected in this study present several actionable themes that, if addressed by individual researchers and the medical community at large, could increase participation in clinical trials by African American patients. They also provide a deeper and more nuanced understanding of the factors influencing African American patients' decisions around participating in clinical trials.
| S-EPMC5536902 | biostudies-other
Project description:BackgroundContextual effects (i.e., placebo response) refer to all health changes resulting from administering an apparently inactive treatment. In a randomized clinical trial (RCT), the overall treatment effect (i.e., the post-treatment effect in the intervention group) can be regarded as the true effect of the intervention plus the impact of contextual effects. This meta-research was conducted to examine the average proportion of the overall treatment effect attributable to contextual effects in RCTs across clinical conditions and treatments and explore whether it varies with trial contextual factors.MethodsData was extracted from trials included in the main meta-analysis from the latest update of the Cochrane review on "Placebo interventions for all clinical conditions" (searched from 1966 to March 2008). Only RCTs reported in English having an experimental intervention group, a placebo comparator group, and a no-treatment control group were eligible.ResultsIn total, 186 trials (16,655 patients) were included. On average, 54% (0.54, 95%CI 0.46 to 0.64) of the overall treatment effect was attributable to contextual effects. The contextual effects were higher for trials with blinded outcome assessor and concealed allocation. The contextual effects appeared to increase proportional to the placebo effect, lower mean age, and proportion of females.ConclusionApproximately half of the overall treatment effect in RCTs seems attributable to contextual effects rather than to the specific effect of treatments. As the study did not include all important contextual factors (e.g., patient-provider interaction), the true proportion of contextual effects could differ from the study's results. However, contextual effects should be considered when assessing treatment effects in clinical practice.Trial registrationPROSPERO CRD42019130257 . Registered on April 19, 2019.
| S-EPMC8314506 | biostudies-literature
Project description:X-ray crystallography is experiencing a renaissance as a method for probing the protein conformational ensemble. The inherent limitations of Bragg analysis, however, which only reveals the mean structure, have given way to a surge in interest in diffuse scattering, which is caused by structure variations. Diffuse scattering is present in all macromolecular crystallography experiments. Recent studies are shedding light on the origins of diffuse scattering in protein crystallography, and provide clues for leveraging diffuse scattering to model protein motions with atomic detail.
| S-EPMC6078797 | biostudies-literature
Project description:We present a method to evaluate the free energies of ligand binding utilizing a Monte Carlo estimation of the configuration integrals concomitant with uncertainty quantification. Ensembles for integration are built through systematically perturbing an initial ligand conformation in a rigid binding pocket, which is optimized separately prior to incorporation of the ligand. We call the procedure producing the ensembles "blurring", and it is carried out using an in-house developed code. The Boltzmann factor contribution of each pose to the configuration integral is computed and from there the free energy is obtained. Potential function uncertainties are estimated using a fragment-based error propagation method. This method has been applied to a set of small aromatic ligands complexed with T4 Lysozyme L99A mutant. Microstate energies have been determined with the force fields ff99SB and ff94, and the semiempirical method PM6DH2 in conjunction with continuum solvation models including Generalized Born (GB), the Conductor-like Screening Model (COSMO), and SMD. Of the methods studied, PM6DH2-based scoring gave binding free energy estimates, which yielded a good correlation to the experimental binding affinities (R2 = 0.7). All methods overestimated the calculated binding affinities. We trace this to insufficient sampling, the single static protein structure, and inaccuracies in the solvent models we have used in this study.
| S-EPMC4006398 | biostudies-literature
Project description:AimsCLARITY is a novel technique which enables three-dimensional visualization of immunostained tissue for the study of circuitry and spatial interactions between cells and molecules in the brain. In this study, we aimed to compare methodological differences in the application of CLARITY between rodent and large human post mortem brain samples. In addition, we aimed to investigate if this technique could be used to visualize Lewy pathology in a post mortem Parkinson's brain.MethodsRodent and human brain samples were clarified and immunostained using the passive version of the CLARITY technique. Samples were then immersed in different refractive index matching media before mounting and visualizing under a confocal microscope.ResultsWe found that tissue clearing speed using passive CLARITY differs according to species (human vs. rodents), brain region and degree of fixation (fresh vs. formalin-fixed tissues). Furthermore, there were advantages to using specific refractive index matching media. We have applied this technique and have successfully visualized Lewy body inclusions in three dimensions within the nucleus basalis of Meynert, and the spatial relationship between monoaminergic fibres and Lewy pathologies among nigrostriatal fibres in the midbrain without the need for physical serial sectioning of brain tissue.ConclusionsThe effective use of CLARITY on large samples of human tissue opens up many potential avenues for detailed pathological and morphological studies.
| S-EPMC5053282 | biostudies-literature
Project description:BackgroundClinical trials aim to draw conclusions about the effects of treatments, but a trial can address many different potential questions. For example, does the treatment work well for patients who take it as prescribed? Or does it work regardless of whether patients take it exactly as prescribed? Since different questions can lead to different conclusions on treatment benefit, it is important to clearly understand what treatment effect a trial aims to investigate-this is called the 'estimand'. Using estimands helps to ensure trials are designed and analysed to answer the questions of interest to different stakeholders, including patients and public. However, there is uncertainty about whether patients and public would like to be involved in defining estimands and how to do so. Public partners are patients and/or members of the public who are part of, or advise, the research team. We aimed to (i) co-develop a tool with public partners that helps explain what an estimand is and (ii) explore public partner's perspectives on the importance of discussing estimands during trial design.MethodsAn online consultation meeting was held with 5 public partners of mixed age, gender and ethnicities, from various regions of the UK. Public partner opinions were collected and a practical tool describing estimands, drafted before the meeting by the research team, was developed. Afterwards, the tool was refined, and additional feedback sought via email.ResultsPublic partners want to be involved in estimand discussions. They found an introductory tool, to be presented and described to them by a researcher, helpful for starting a discussion about estimands in a trial design context. They recommended storytelling, analogies and visual aids within the tool. Four topics related to public partners' involvement in defining estimands were identified: (i) the importance of addressing questions that are relevant to patients and public in trials, (ii) involving public partners early on, (iii) a need for education and communication for all stakeholders and (iv) public partners and researchers working together.ConclusionsWe co-developed a tool for researchers and public partners to use to facilitate the involvement of public partners in estimand discussions.
| S-EPMC10324181 | biostudies-literature
Project description: Not available
| S-EPMC2040461 | biostudies-literature