Semiparametric recurrent event vs time‐to‐first‐event analyses in randomized trials: Estimands and model misspecification

2021 ◽  
Author(s):  
Yujie Zhong ◽  
Richard J. Cook
Keyword(s):  
Randomized Trials ◽  
Model Misspecification ◽  
Recurrent Event

scholarly journals Improving Precision and Power in Randomized Trials for COVID-19 Treatments Using Covariate Adjustment, for Binary, Ordinal, and Time-to-Event Outcomes

2020 ◽  
Author(s):  
David Benkeser ◽  
Iván Díaz ◽  
Alex Luedtke ◽  
Jodi Segal ◽  
Daniel Scharfstein ◽  
...  
Keyword(s):  
New York ◽  
Sample Size ◽  
Randomized Trials ◽  
Model Misspecification ◽  
Value Added ◽  
Standard Of Care ◽  
R Package ◽  
Covariate Adjustment ◽  
European Medicines Agency ◽  
Time To Event

SummaryTime is of the essence in evaluating potential drugs and biologics for the treatment and prevention of COVID-19. There are currently over 400 clinical trials (phase 2 and 3) of treatments for COVID-19 registered on clinicaltrials.gov. Covariate adjustment is a statistical analysis method with potential to improve precision and reduce the required sample size for a substantial number of these trials. Though covariate adjustment is recommended by the U.S. Food and Drug Administration and the European Medicines Agency, it is underutilized, especially for the types of outcomes (binary, ordinal and time-to-event) that are common in COVID-19 trials. To demonstrate the potential value added by covariate adjustment in this context, we simulated two-arm, randomized trials comparing a hypothetical COVID-19 treatment versus standard of care, where the primary outcome is binary, ordinal, or time-to-event. Our simulated distributions are derived from two sources: longitudinal data on over 500 patients hospitalized at Weill Cornell Medicine New York Presbyterian Hospital, and a Centers for Disease Control and Prevention (CDC) preliminary description of 2449 cases. We found substantial precision gains from using covariate adjustment-equivalent to 9-21% reductions in the required sample size to achieve a desired power-for a variety of estimands (targets of inference) when the trial sample size was at least 200. We provide an R package and practical recommendations for implementing covariate adjustment. The estimators that we consider are robust to model misspecification.

scholarly journals A Comparison of Covariate Adjustment Approaches Under Model Misspecification In Individually Randomized Trials

2022 ◽  
Author(s):  
Mia S. Tackney ◽  
Tim Morris ◽  
Ian White ◽  
Clemence Leyrat ◽  
Karla Diaz-Ordaz ◽  
...  
Keyword(s):  
Sample Size ◽  
Randomized Trials ◽  
Model Misspecification ◽  
Likelihood Estimation ◽  
Small Sample ◽  
Analysis Of Covariance ◽  
Small Samples ◽  
Linear Interaction ◽  
Inverse Probability ◽  
Omitted Covariate

Abstract Adjustment for baseline covariates in randomized trials has been shown to lead to gains in power and can protect against chance imbalances in covariates. For continuous covariates, there is a risk that the the form of the relationship between the covariate and outcome is misspecified when taking an adjusted approach. Using a simulation study focusing on small to medium-sized individually randomized trials, we explore whether a range of adjustment methods are robust to misspecification, either in the covariate-outcome relationship or through an omitted covariate-treatment interaction. Specifically, we aim to identify potential settings where G-computation, Inverse Probability of Treatment Weighting ( IPTW ), Augmented Inverse Probability of Treatment Weighting ( AIPTW ) and Targeted Maximum Likelihood Estimation ( TMLE ) offer improvement over the commonly used Analysis of Covariance ( ANCOVA ). Our simulations show that all adjustment methods are generally robust to model misspecification if adjusting for a few covariates, sample size is 100 or larger, and there are no covariate-treatment interactions. When there is a non-linear interaction of treatment with a skewed covariate and sample size is small, all adjustment methods can suffer from bias; however, methods that allow for interactions (such as G-computation with interaction and IPTW ) show improved results compared to ANCOVA . When there are a high number of covariates to adjust for, ANCOVA retains good properties while other methods suffer from under- or over-coverage. An outstanding issue for G-computation, IPTW and AIPTW in small samples is that standard errors are underestimated; development of small sample corrections is needed.

A Higher than Expected Incidence of Factor VIII Inhibitors in Multitransfused Haemophilia A Patients Treated with an Intermediate Purity Pasteurized Factor VIII Concentrate

1993 ◽  
Vol 69 (02) ◽  
pp. 115-118 ◽  
Author(s):  
Kathelijne Peerlinck ◽  
Jef Arnout ◽  
Jean Guy Gilles ◽  
Jean-Marie Saint-Remy ◽  
Jos Vermylen
Keyword(s):  
Factor Viii ◽  
Randomized Trials ◽  
Specific Factor ◽  
Factor Viii Inhibitor ◽  
Haemophilia A ◽  
Viral Inactivation ◽  
Gradual Decline ◽  
Inhibitor Level ◽  
Factor Viii Concentrates ◽  
Viii Inhibitor

SummaryIn May 1990, 218 patients with haemophilia A regularly attending the Leuven Haemophilia Center were randomly assigned to a group receiving either of two newly introduced factor VIII concentrates: factor VIII-P, an intermediate purity pasteurized concentrate, or factor VIII-SD, a high purity concentrate treated with solvent-detergent for viral inactivation.Patients were followed from May 1990 until October 1991. Between August 1991 and October 1991 a clinically important factor VIII inhibitor was detected in five out of the 109 patients receiving factor VIII-P while none of the 109 patients receiving factor VIII-SD developed such antibodies. All patients acquiring an inhibitor had previously been clinically tolerant to transfused factor VIII with 200 to more than 1,000 days of exposure to factor VIII prior to May 1990. Patients with inhibitors were transfused daily with 30 U factor VIII-SD per kg body weight, which was associated with a gradual decline of the inhibitor level. In all patients the antibodies were relatively slow-acting and predominantly directed towards the light chain of factor VIII.This study demonstrates a higher than expected incidence of factor VIII inhibitors associated with the use of a specific factor VIII concentrate in multitransfused haemophilia A patients. It indicates the usefulness of evaluating newly introduced concentrates in prospective, randomized trials.

Recurrent Stroke Risk in Pilots with Atrial Fibrillation

2020 ◽  
Vol 91 (4) ◽  
pp. 352-357
Author(s):  
Jessica Tedford ◽  
Valerie Skaggs ◽  
Ann Norris ◽  
Farhad Sahiar ◽  
Charles Mathers
Keyword(s):  
Atrial Fibrillation ◽  
General Population ◽  
Recurrent Events ◽  
Stroke Risk ◽  
Event Rate ◽  
Recurrent Stroke ◽  
Previous History ◽  
Recurrent Event ◽  
Recurrence Rates ◽  
Medical Certification

INTRODUCTION: Atrial fibrillation (AF) is one of the most common cardiac arrhythmias in the general population and is considered disqualifying aeromedically. This study is a unique examination of significant outcomes in aviators with previous history of both AF and stroke.METHODS: Pilots examined by the FAA between 2002 and 2012 who had had AF at some point during his or her medical history were reviewed, and those with an initial stroke or transient ischemic attack (TIA) during that time period were included in this study. All records were individually reviewed to determine stroke and AF history, medical certification history, and recurrent events. Variables collected included medical and behavior history, stroke type, gender, BMI, medication use, and any cardiovascular or neurological outcomes of interest. Major recurrent events included stroke, TIA, cerebrovascular accident, death, or other major events. These factors were used to calculate CHA2DS2-VASc scores.RESULTS: Of the 141 pilots selected for the study, 17.7% experienced a recurrent event. At 6 mo, the recurrent event rate was 5.0%; at 1 yr, 5.8%; at 3 yr 6.9%; and at 5 yr the recurrent event rate was 17.3%. No statistical difference between CHA2DS2-VASc scores was found as it pertained to number of recurrent events.DISCUSSION: We found no significant factors predicting risk of recurrent event and lower recurrence rates in pilots than the general population. This suggests CHA2DS2-VASc scores are not appropriate risk stratification tools in an aviation population and more research is necessary to determine risk of recurrent events in aviators with atrial fibrillation.Tedford J, Skaggs V, Norris A, Sahiar F, Mathers C. Recurrent stroke risk in pilots with atrial fibrillation. Aerosp Med Hum Perform. 2020; 91(4):352–357.

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