ORCID Profile
0000-0001-8478-8170
Current Organisations
University of Ottawa
,
Ottawa Hospital Research Institute
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Publisher: Springer Science and Business Media LLC
Date: 06-07-2009
Abstract: Randomized clinical trials (RCTs) stopped early for benefit often receive great attention and affect clinical practice, but pose interpretational challenges for clinicians, researchers, and policy makers. Because the decision to stop the trial may arise from catching the treatment effect at a random high, truncated RCTs (tRCTs) may overestimate the true treatment effect. The St udy O f Trial P olicy Of I nterim T runcation (STOPIT-1), which systematically reviewed the epidemiology and reporting quality of tRCTs, found that such trials are becoming more common, but that reporting of stopping rules and decisions were often deficient. Most importantly, treatment effects were often implausibly large and inversely related to the number of the events accrued. The aim of STOPIT-2 is to determine the magnitude and determinants of possible bias introduced by stopping RCTs early for benefit. We will use sensitive strategies to search for systematic reviews addressing the same clinical question as each of the tRCTs identified in STOPIT-1 and in a subsequent literature search. We will check all RCTs included in each systematic review to determine their similarity to the index tRCT in terms of participants, interventions, and outcome definition, and conduct new meta-analyses addressing the outcome that led to early termination of the tRCT. For each pair of tRCT and systematic review of corresponding non-tRCTs we will estimate the ratio of relative risks, and hence estimate the degree of bias. We will use hierarchical multivariable regression to determine the factors associated with the magnitude of this ratio. Factors explored will include the presence and quality of a stopping rule, the methodological quality of the trials, and the number of total events that had occurred at the time of truncation. Finally, we will evaluate whether Bayesian methods using conservative informative priors to "regress to the mean" overoptimistic tRCTs can correct observed biases. A better understanding of the extent to which tRCTs exaggerate treatment effects and of the factors associated with the magnitude of this bias can optimize trial design and data monitoring charters, and may aid in the interpretation of the results from trials stopped early for benefit.
Publisher: Springer Science and Business Media LLC
Date: 27-04-2014
Publisher: BMJ
Date: 12-09-2018
DOI: 10.1136/BMJ.K3478
Abstract: To determine the efficacy of high dose folic acid supplementation for prevention of pre-ecl sia in women with at least one risk factor: pre-existing hypertension, prepregnancy diabetes (type 1 or 2), twin pregnancy, pre-ecl sia in a previous pregnancy, or body mass index ≥35. Randomised, phase III, double blinded international, multicentre clinical trial. 70 obstetrical centres in five countries (Argentina, Australia, Canada, Jamaica, and UK). 2464 pregnant women with at least one high risk factor for pre-ecl sia were randomised between 2011 and 2015 (1144 to the folic acid group and 1157 to the placebo group) 2301 were included in the intention to treat analyses. Eligible women were randomised to receive either daily high dose folic acid (four 1.0 mg oral tablets) or placebo from eight weeks of gestation to the end of week 16 of gestation until delivery. Clinicians, participants, adjudicators, and study staff were masked to study treatment allocation. The primary outcome was pre-ecl sia, defined as hypertension presenting after 20 weeks’ gestation with major proteinuria or HELLP syndrome (haemolysis, elevated liver enzymes, low platelets). Pre-ecl sia occurred in 169/1144 (14.8%) women in the folic acid group and 156/1157 (13.5%) in the placebo group (relative risk 1.10, 95% confidence interval 0.90 to 1.34 P=0.37). There was no evidence of differences between the groups for any other adverse maternal or neonatal outcomes. Supplementation with 4.0 mg/day folic acid beyond the first trimester does not prevent pre-ecl sia in women at high risk for this condition. Current Controlled Trials ISRCTN23781770 and ClinicalTrials.gov NCT01355159 .
Publisher: American Medical Association (AMA)
Date: 24-03-2010
Abstract: Theory and simulation suggest that randomized controlled trials (RCTs) stopped early for benefit (truncated RCTs) systematically overestimate treatment effects for the outcome that precipitated early stopping. To compare the treatment effect from truncated RCTs with that from meta-analyses of RCTs addressing the same question but not stopped early (nontruncated RCTs) and to explore factors associated with overestimates of effect. Search of MEDLINE, EMBASE, Current Contents, and full-text journal content databases to identify truncated RCTs up to January 2007 search of MEDLINE, Cochrane Database of Systematic Reviews, and Database of Abstracts of Reviews of Effects to identify systematic reviews from which in idual RCTs were extracted up to January 2008. Selected studies were RCTs reported as having stopped early for benefit and matching nontruncated RCTs from systematic reviews. Independent reviewers with medical content expertise, working blinded to trial results, judged the eligibility of the nontruncated RCTs based on their similarity to the truncated RCTs. Reviewers with methodological expertise conducted data extraction independently. The analysis included 91 truncated RCTs asking 63 different questions and 424 matching nontruncated RCTs. The pooled ratio of relative risks in truncated RCTs vs matching nontruncated RCTs was 0.71 (95% confidence interval, 0.65-0.77). This difference was independent of the presence of a statistical stopping rule and the methodological quality of the studies as assessed by allocation concealment and blinding. Large differences in treatment effect size between truncated and nontruncated RCTs (ratio of relative risks <0.75) occurred with truncated RCTs having fewer than 500 events. In 39 of the 63 questions (62%), the pooled effects of the nontruncated RCTs failed to demonstrate significant benefit. Truncated RCTs were associated with greater effect sizes than RCTs not stopped early. This difference was independent of the presence of statistical stopping rules and was greatest in smaller studies.
Publisher: JMIR Publications Inc.
Date: 07-11-2019
Abstract: ach year, half a million patients with a potential neck (c-spine) injury are transported to Ontario emergency departments (EDs). Less than 1.0% (1/100) of these patients have a neck bone fracture. Even less (1/200, 0.5%) have a spinal cord injury or nerve damage. Currently, paramedics transport all trauma victims (with or without an injury) by ambulance using a backboard, cervical collar, and head immobilizers. Importantly, prolonged immobilization is often unnecessary it causes patient discomfort and pain, decreases community access to paramedics, contributes to ED crowding, and is very costly. We therefore developed the Canadian C-Spine Rule (CCR) for alert and stable trauma patients. This decision rule helps ED physicians and triage nurses to safely and selectively remove immobilization, without x-rays and missed injury. We successfully taught Ottawa paramedics to use the CCR in the field in a single-center study. his study aimed to improve patient care and health system efficiency and outcomes by allowing paramedics to assess eligible low-risk trauma patients with the CCR and selectively transport them without immobilization to the ED. e propose a pragmatic stepped-wedge cluster randomized design with health economic evaluation, designed collaboratively with knowledge users. Our 36-month study will consist of a 12-month setup and training period (year 1), followed by the stepped-wedge trial (year 2) and a 12-month period for study completion, analyses, and knowledge translation. A total of 12 Ontario paramedic services of various sizes distributed across the province will be randomly allocated to one of three sequences. Paramedic services in each sequence will cross from the control condition (usual care) to the intervention condition (CCR implementation) at intervals of 3 months until all communities have crossed to the intervention. Data will be collected on all eligible patients in each paramedic service for a total duration of 12 months. A major strength of our design is that each community will have implemented the CCR by the end of the study. nterim results are expected in December 2019 and final results in 2020. If this multicenter trial is successful, we expect the Ontario Ministry of Health will recommend that paramedics evaluate all eligible patients with the CCR in the Province of Ontario. e conservatively estimate that in Ontario, more than 60% of all eligible trauma patients (300,000 annually) could be transported safely and comfortably, without c-spine immobilization devices. This will significantly reduce patient pain and discomfort, paramedic intervention times, and ED length of stay, thereby improving access to paramedics and ED care. This could be achieved rapidly and with lower health care costs compared with current practices (possible cost saving of Can $36 [US $25] per immobilization or Can $10,656,000 [US $7,335,231] per year). linicalTrials.gov NCT02786966 t2/show/NCT02786966. ERR1-10.2196/16966
Publisher: BMJ
Date: 2019
DOI: 10.1136/BMJOPEN-2018-024744
Abstract: Patients presenting with acute intracerebral haemorrhage are at a high risk of exhibiting haematoma expansion, a phenomenon that can significantly worsen long-term functioning. Numerous clinical and radiological factors are associated with expansion. In a bid to better select patients at increased risk of expanding, these factors have been collated together into clinical scores. Several clinical scores have been developed, but comparisons of diagnostic potential between these scores are limited and the frequency of use in clinical trial enrolment is unknown. To perform a scoping review of haematoma expansion scores and explore numerous factors such as the methodology of development and diagnostic capabilities. MEDLINE, PubMed, EMBASE, CENTRAL and ClinicalTrials.gov will be searched with assistance from an experienced information specialist. Eligible studies will involve adults presenting with spontaneous intracerebral haemorrhage who received baseline assessments, follow-up imaging and risk stratification through a haematoma expansion score. Reviewers will independently extract data from the included studies and will collect data on patient demographics and medical history, details on score development, diagnostic capabilities and usage proportions. Analysis of extracted data will focus on comparing the predictive capability of each score and similarities/differences in score development. The exact analysis technique will be dictated on the type of data extracted. Formal ethics is not required as primary data will not be collected. The findings of this study will be disseminated through conference presentations and peer-reviewed publications.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 24-08-2021
DOI: 10.1212/WNL.0000000000012393
Abstract: Hematoma expansion (HE) is commonly analyzed as a dichotomous outcome in intracerebral hemorrhage (ICH) trials. In this proof-of-concept study, we propose an HE shift analysis model as a method to improve the evaluation of candidate ICH therapies. Using data from the Antihypertensive Treatment of Acute Cerebral Hemorrhage II (ATACH-2) trial, we performed HE shift analysis in response to intensive blood pressure lowering by generating polychotomous strata based on previously established HE definitions, percentile/absolute quartiles of hematoma volume change, and quartiles of 24-hour follow-up hematoma volumes. The relationship between blood pressure treatment and HE shift was explored with proportional odds models. The primary analysis population included 863 patients. In both treatment groups, approximately one-third of patients exhibited no HE. With the use of a trichotomous HE stratification, the highest strata of ≥33% revealed a 5.8% reduction in hematoma growth for those randomized to intensive therapy (adjusted odds ratio [aOR] 0.77, 95% confidence interval [CI] 0.60–0.99). Using percentile quartiles of hematoma volume change, we observed a favorable shift to reduce growth in patients treated with intensive therapy (aOR 0.73, 95% CI 0.57–0.93). Similarly, in a tetrachotomous analysis of 24-hour follow-up hematoma volumes, shifts in the highest stratum ( .9 mL) were most notable. Our findings suggest that intensive blood pressure reduction may preferentially mitigate growth in patients at risk of high volume HE. A shift analysis model of HE provides additional insights into the biological effects of a given therapy and may be an additional way to assess hemostatic agents in future studies. ClinicalTrials.gov Identifier:NCT01176565.
Publisher: Elsevier BV
Date: 11-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-04-2023
DOI: 10.1212/WNL.0000000000206879
Abstract: There is significant heterogeneity in the reporting of outcome measures in aneurysmal subarachnoid hemorrhage (aSAH) research. The modified Rankin scale (mRS) is the most commonly reported functional outcome measure. The mRS focuses on physical disability however, many aSAH survivors experience sequalae in other domains, and the mRS may therefore not capture outcomes important to aSAH survivors. The objective of this study was to assess the clinical relevance of the mRS as a research outcome measure to people with lived aSAH experience. We conducted an international cross-sectional survey of 355 aSAH survivors, family members, and caregivers to evaluate patient-perceived outcomes in relation to the mRS. The mRS was assessed using a previously validated web-based tool. Response rate was 60% respondents from 7 continents were composed of 86% aSAH survivors and 14% family members/caregivers. Agreement between self-assessed outcome and the mRS was poor (Kappa 0.26 [CI 0.14–0.39]). Of the 172 respondents who self-assessed as having had a good aSAH outcome, 122 (71%) had a score of 0–2 on the mRS. Approximately 19% of respondents with a good outcome, based on a measured mRS score of 0–2, self-assessed as having had a poor aSAH outcome. When the mRS score was dichotomized as 0–3 corresponding to a good outcome, agreement between the score and self-assessed outcome remained poor with a Kappa score of 0.40 (CI 0.20–0.60). Approximately 30% of respondents believed that the mRS should not be used as an outcome measure in future aSAH trials. The findings suggest that there is poor agreement between aSAH survivors' self-assessed outcome, their actual mRS score, and the dichotomization of the mRS score into good oor outcomes. Patient-centered and patient-informed outcome measurement tools are needed to guide the aSAH research agenda.
Publisher: SAGE Publications
Date: 13-12-2011
Abstract: We review controversies associated with randomized controlled trials (RCTs) stopped early for apparent benefit (truncated RCTs or tRCTs) and present our groups’ perspective. Long-established theory, simulations and recent empirical evidence demonstrate that tRCTs will on average overestimate treatment effects, and this overestimation may be large, particularly when tRCTs have small number of events. Theoretical considerations and simulations demonstrate that on average, meta-analyses of RCTs with appropriate stopping rules will lead to only trivial overestimation of treatment effects. However, tRCTs will disproportionally contribute to meta-analytic estimates when tRCTs occur early in the sequence of trials with few subsequent studies, publication of nontruncated RCTs is delayed, there is publication bias, or tRCTs result in a ‘freezing’ effect in which ‘correcting’ trials are never undertaken. To avoid applying overestimates of effect to clinical decision-making, clinicians should view the results of in idual tRCTs with small s le sizes and small number of events with skepticism. Pooled effects from meta-analyses including tRCTs are likely to overestimate effect when there is a substantial difference in effect estimates between the tRCTs and the nontruncated RCTs, and in which the tRCTs have a substantial weight in the meta-analysis despite themselves having a relatively small number of events. Such circumstances call for sensitivity analyses omitting tRCTs.
Publisher: JMIR Publications Inc.
Date: 06-2020
DOI: 10.2196/16966
Abstract: Each year, half a million patients with a potential neck (c-spine) injury are transported to Ontario emergency departments (EDs). Less than 1.0% (1/100) of these patients have a neck bone fracture. Even less (1/200, 0.5%) have a spinal cord injury or nerve damage. Currently, paramedics transport all trauma victims (with or without an injury) by ambulance using a backboard, cervical collar, and head immobilizers. Importantly, prolonged immobilization is often unnecessary it causes patient discomfort and pain, decreases community access to paramedics, contributes to ED crowding, and is very costly. We therefore developed the Canadian C-Spine Rule (CCR) for alert and stable trauma patients. This decision rule helps ED physicians and triage nurses to safely and selectively remove immobilization, without x-rays and missed injury. We successfully taught Ottawa paramedics to use the CCR in the field in a single-center study. This study aimed to improve patient care and health system efficiency and outcomes by allowing paramedics to assess eligible low-risk trauma patients with the CCR and selectively transport them without immobilization to the ED. We propose a pragmatic stepped-wedge cluster randomized design with health economic evaluation, designed collaboratively with knowledge users. Our 36-month study will consist of a 12-month setup and training period (year 1), followed by the stepped-wedge trial (year 2) and a 12-month period for study completion, analyses, and knowledge translation. A total of 12 Ontario paramedic services of various sizes distributed across the province will be randomly allocated to one of three sequences. Paramedic services in each sequence will cross from the control condition (usual care) to the intervention condition (CCR implementation) at intervals of 3 months until all communities have crossed to the intervention. Data will be collected on all eligible patients in each paramedic service for a total duration of 12 months. A major strength of our design is that each community will have implemented the CCR by the end of the study. Interim results are expected in December 2019 and final results in 2020. If this multicenter trial is successful, we expect the Ontario Ministry of Health will recommend that paramedics evaluate all eligible patients with the CCR in the Province of Ontario. We conservatively estimate that in Ontario, more than 60% of all eligible trauma patients (300,000 annually) could be transported safely and comfortably, without c-spine immobilization devices. This will significantly reduce patient pain and discomfort, paramedic intervention times, and ED length of stay, thereby improving access to paramedics and ED care. This could be achieved rapidly and with lower health care costs compared with current practices (possible cost saving of Can $36 [US $25] per immobilization or Can $10,656,000 [US $7,335,231] per year). ClinicalTrials.gov NCT02786966 t2/show/NCT02786966. DERR1-10.2196/16966
No related grants have been discovered for Tim Ramsay.