Imputing missing quality of life data as covariate in survival analysis of the International Breast Cancer Study Group Trials VI and VII

Quality of life (QoL) was an important endpoint in the adjuvant breast cancer trials International Breast Cancer Study Group (IBCSG) Trial VI and VII. Here, QoL was considered as a time-dependent effect. The hypothesis explored is that poorer QoL throughout the trial is associated with poorer disease-free survival (DFS) and vice-versa. Potential bias in the parameter estimates is an important concern associated with missing observations. Standard simple and multiple imputation methods were applied to missing QoL assessments before analysis in a time-dependent Cox model. There was no evidence that the patient's QoL is related to the patient's DFS

Towards the TIGER International Framework for Recommendations of Core Competencies in Health Informatics 2.0: Extending the Scope and the Roles

This paper describes the methodology and developments towards the TIGER International Recommendation Framework of Core Competencies in Health Informatics 2.0. This Framework is meant to augment the scope from nursing towards a series of six other professional roles, i.e. direct patient care, health information management, executives, chief information officers, engineers and health IT specialists and researchers and educators. Health informatics core competency areas were compiled from various sources that had integrated the literature and were grouped into consistent clusters. The relevance of these core competency areas was rated in a survey by 718 professional experts from 51 countries. Furthermore, 22 local case studies illustrated the competencies and gave insight into examples of local educational practice. The Framework contributes to the overall discourse on how to shape health informatics education to improve quality and safety of care by enabling useful and successful health information systems

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

BACKGROUND: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. METHODS: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). FINDINGS: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29-146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0- 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25-1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39-1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65-1·60]; p=0·92). INTERPRETATION: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention. FUNDING: British Heart Foundation

Influence of missing explanatory variables and longitudinal assessments in breast cancer clinical trials

Clinical trials in breast cancer assess treatment regimens based on a balance of efficacy and adverse effects. To achieve high-quality evidence for these assessments, it is important to minimise potential sources of bias. Therefore, potential bias in the parameter estimates resulting from missing observations is an important concern.In this thesis, the influence of missing data on explanatory variables in time-dependent Cox model analysis is explored, with application to breast cancer clinical trials. In particular, imputation in the context of time-dependent covariates that may be informative missing data which is described has not been studied in detail in the statistical literature. Standard imputation methods from the statistical literature are described, which involve assumptions about the missing data mechanism. Missing observations of quality of life (QoL) are imputed by standard methods before analysis of disease-free survival (DFS) and the performance of the imputation methods is considered. Then the influence of missing observations of an outcome variable assessing safety is considered. Repeated measures analysis of a safety assessment is performed. The insights into the influence of missing data could be generalised.Two clinical trials are considered; the International Breast Cancer Study Group (IBCSG) Trials VI and VII and the Herceptin Adjuvant (HERA) trial. Both investigated adjuvant treatment in breast cancer. There was no evidence in Trials VI and VII that the patient's QoL is related to the patient's DFS, though such a relationship could be masked by the missing observations. Simulation was performed in the context of a positive relationship between QoL and DFS. The simulation study suggested that the performance of the standard imputation methods was influenced by the missing data mechanism. There was no benefit from imputing LVEF values in the HERA trial. It was appropriate to perform the repeated measures analysis of LVEF values using observed LVEF values only.Clinical trials in breast cancer assess treatment regimens based on a balance of efficacy and adverse effects. To achieve high-quality evidence for these assessments, it is important to minimise potential sources of bias. Therefore, potential bias in the parameter estimates resulting from missing observations is an important concern.In this thesis, the influence of missing data on explanatory variables in time-dependent Cox model analysis is explored, with application to breast cancer clinical trials. In particular, imputation in the context of time-dependent covariates that may be informative missing data which is described has not been studied in detail in the statistical literature. Standard imputation methods from the statistical literature are described, which involve assumptions about the missing data mechanism. Missing observations of quality of life (QoL) are imputed by standard methods before analysis of disease-free survival (DFS) and the performance of the imputation methods is considered. Then the influence of missing observations of an outcome variable assessing safety is considered. Repeated measures analysis of a safety assessment is performed. The insights into the influence of missing data could be generalised.Two clinical trials are considered; the International Breast Cancer Study Group (IBCSG) Trials VI and VII and the Herceptin Adjuvant (HERA) trial. Both investigated adjuvant treatment in breast cancer. There was no evidence in Trials VI and VII that the patient's QoL is related to the patient's DFS, though such a relationship could be masked by the missing observations. Simulation was performed in the context of a positive relationship between QoL and DFS. The simulation study suggested that the performance of the standard imputation methods was influenced by the missing data mechanism. There was no benefit from imputing LVEF values in the HERA trial. It was appropriate to perform the repeated measures analysis of LVEF values using observed LVEF values only

Stand der Forschung über die Lehrerinnen- und Lehrerbildung in Grossbritannien

This paper offers an analysis of the current state of teacher education research in the United Kingdom (UK). It commences with a brief historical overview of developments over the last century. Some recent «capacity building» initiatives designed to enhance and develop teacher education research are described. There is then a focus on a particular web-based resource that draws together a significant number of publications in UK teacher education research from 2000-2008. This database is then analysed in order to identify in which journals and by which authors this work is produced. The range of methodological approaches and substantive areas of focus that appear to predominate in teacher education research in the UK are reviewed, according to categories within the database. This demonstrates that there are some very real challenges to be faced by teacher education researchers in the years ahead, similar but not identical to those faced elsewhere. (DIPF/Orig.)Der vorliegende Beitrag beschäftigt sich mit der gegenwärtigen Situation der Forschung in der Lehrerinnen- und Lehrerbildung in Großbritannien. Einleitend geben die Autoren einen kurzen historischen Überblick über die Entwicklungen des letzten Jahrhunderts, gefolgt von der Darstellung einiger jüngster Initiativen, die auf den Kapazitätenausbau in der Lehrerinnen- und Lehrerbildungforschung abzielen. Die Basis des Artikels bildet die Analyse einer einschlägigen Online-Datenbank, die eine große Anzahl wissenschaftlicher Veröffentlichungen zur Lehrerinnen- und Lehrerbildung im Vereinigten Königreich für den Zeitraum 2000-2008 abdeckt. Durch die Analyse dieser bibliografischen Datenbank wird in einem ersten Schritt ermittelt, in welcher wissenschaftlichen Zeitschrift und von welchen Autoren ein Artikel veröffentlicht wurde. Die Untersuchung soll dann zeigen, welche methodischen Ansätze und welche thematischen Schwerpunkte in der Lehrerinnen- und Lehrerbildungsforschung in Großbritannien überwiegen. Sie soll abschließend veranschaulichen, mit welchen Herausforderungen sich Forschende in der Lehrerinnen- und Lehrerbildung in den kommenden Jahren konfrontiert sehen werden. (DIPF/Orig.

Performance of standard imputation methods for missing quality of life data as covariate in survival analysis based on simulations from the International Breast Cancer Study Group Trials VI and VII*

<p>Imputation methods for missing data on a time-dependent variable within time-dependent Cox models are investigated in a simulation study. Quality of life (QoL) assessments were removed from the complete simulated datasets, which have a positive relationship between QoL and disease-free survival (DFS) and delayed chemotherapy and DFS, by missing at random and missing not at random (MNAR) mechanisms. Standard imputation methods were applied before analysis. Method performance was influenced by missing data mechanism, with one exception for simple imputation. The greatest bias occurred under MNAR and large effect sizes. It is important to carefully investigate the missing data mechanism.</p

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