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Statistical considerations in the early termination of the multicenter trial of cryotherapy for retinopathy of prematurity
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Abstracts isation of the treatment effect is considered in several ways. For each parameterisation the significance level and power achieved by the triangler test are presented from simulation results.
Choosing Covariates in the Analysis of Clinical Trials Michael Beach
University of Chicago, Chicago, Illinois (S-12) It is typical in the conduct of clinical trials to measure a large number of covariates--more than can be induced in the analysis---so that some method is needed to choose among them if we are to adjust at all. One common method is to pick covariates showing the greatest disparity between the treatment and control groups. Another is to choose these strongly related to outcome, i.e., those with high influence. Canner 0981) showed that for the 2 × 2 × 2 contingency table, one can express the difference between the unadjusted test statistic, Zu, and the adjusted test statistic, ZA, as the ~ of the z-value for influence, ZI, and the z-value for disparity, ZD: Zu - ZA = Z~ × ZD/VN. Canner then suggests that choice of covariates which are both influential and disparate or those having a large product may be a useful alternative selection procedure. Different selection procedures were explored in six major clinical studies. Although the influence of the covariates was in each case small and no improvement in precision results from such adjustment, there were substantial shifts in the estimated treatment effect, leading to ambiguity in the interpretation ot the findings. Canner's work is extended to the multiple linear regression model, to generalized linear models, and to the Cox Proportional Hazards model. An extensive Monte Carlo experiment was carried out to study the performance of these three selection procedures. In many common settings covariate adjustment provides little if any advantage. Where adjustment is advantageous, that based on the product of influence and disparity can outperform selection based on either alone. Statistical Considerations in the Early Termination of the Multicenter Trial o f Cryotherapy for Retinopathy of Prematurity Robert J. H a r d y , Barry R. Davis, Betty T u n g , Earl A. P a l m e r University of Texas, Houston, Texas (13) The Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) was a randomized trial designed to test whether cryotherapy applied to one randomly selected eye when there was Stage 3 + ROP significantly decreased the incidence of an unfavorable outcome. An unfavorable outcome was defined as either retinal detachment or a retinal fold and was determined at three months post-treatment by the use of a masked photographic system. The trial was terminated on recommendation of the Data and Safety Monitoring Committee nine months before the scheduled closing date. At the time of the decision, an unfavorable outcome was significantly less frequent in the cryotherapy eyes (21.8%) as compared to the untreated eyes (43%), (chi-square = 20.5). The basic statistical method used in evaluating the significance of the p r i m a ~ outcome results was conditional power (or stochastic curtailment). This method was applied for the first time to a trial with a matched pair design. Several other issues were considered in deciding to terminate the trial including the examination of results across subgroups and clinical centers, the completeness of the follow-up, clinical assessment of outcome, and longterm consequences of the treatment.
Operational Aspects of the Early Termination of the Multicenter Trial o f Cryotherapy for Retinopathy of Prematurity Earl A. Palmer, Robert J. H a r d y , J o h n T. F l y n n , Dale L. P h e l p s , David B. Schaffer, Barry R. Davis, Richard M o w e r y , Betty T u n g , C y n t h i a Phillips Oregon Health Sciences University, Portland, Oregon (14) The Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) was a randomized trial designed to test v. hether cryotherapy applied to one randomly selected eye when there was Stage 3 + ROP significantly decreased the incidence of an unfavorable outcome. An unfavorable outcome was defined as either retinal detachment or a retinal fold and was determined at 3 month post-treatment by the use of a masked photographic system. The trial was
Abstracts isation of the treatment effect is considered in several ways. For each parameterisation the significance level and power achieved by the triangler test are presented from simulation results.
Choosing Covariates in the Analysis of Clinical Trials Michael Beach
University of Chicago, Chicago, Illinois (S-12) It is typical in the conduct of clinical trials to measure a large number of covariates--more than can be induced in the analysis---so that some method is needed to choose among them if we are to adjust at all. One common method is to pick covariates showing the greatest disparity between the treatment and control groups. Another is to choose these strongly related to outcome, i.e., those with high influence. Canner 0981) showed that for the 2 × 2 × 2 contingency table, one can express the difference between the unadjusted test statistic, Zu, and the adjusted test statistic, ZA, as the ~ of the z-value for influence, ZI, and the z-value for disparity, ZD: Zu - ZA = Z~ × ZD/VN. Canner then suggests that choice of covariates which are both influential and disparate or those having a large product may be a useful alternative selection procedure. Different selection procedures were explored in six major clinical studies. Although the influence of the covariates was in each case small and no improvement in precision results from such adjustment, there were substantial shifts in the estimated treatment effect, leading to ambiguity in the interpretation ot the findings. Canner's work is extended to the multiple linear regression model, to generalized linear models, and to the Cox Proportional Hazards model. An extensive Monte Carlo experiment was carried out to study the performance of these three selection procedures. In many common settings covariate adjustment provides little if any advantage. Where adjustment is advantageous, that based on the product of influence and disparity can outperform selection based on either alone. Statistical Considerations in the Early Termination of the Multicenter Trial o f Cryotherapy for Retinopathy of Prematurity Robert J. H a r d y , Barry R. Davis, Betty T u n g , Earl A. P a l m e r University of Texas, Houston, Texas (13) The Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) was a randomized trial designed to test whether cryotherapy applied to one randomly selected eye when there was Stage 3 + ROP significantly decreased the incidence of an unfavorable outcome. An unfavorable outcome was defined as either retinal detachment or a retinal fold and was determined at three months post-treatment by the use of a masked photographic system. The trial was terminated on recommendation of the Data and Safety Monitoring Committee nine months before the scheduled closing date. At the time of the decision, an unfavorable outcome was significantly less frequent in the cryotherapy eyes (21.8%) as compared to the untreated eyes (43%), (chi-square = 20.5). The basic statistical method used in evaluating the significance of the p r i m a ~ outcome results was conditional power (or stochastic curtailment). This method was applied for the first time to a trial with a matched pair design. Several other issues were considered in deciding to terminate the trial including the examination of results across subgroups and clinical centers, the completeness of the follow-up, clinical assessment of outcome, and longterm consequences of the treatment.
Operational Aspects of the Early Termination of the Multicenter Trial o f Cryotherapy for Retinopathy of Prematurity Earl A. Palmer, Robert J. H a r d y , J o h n T. F l y n n , Dale L. P h e l p s , David B. Schaffer, Barry R. Davis, Richard M o w e r y , Betty T u n g , C y n t h i a Phillips Oregon Health Sciences University, Portland, Oregon (14) The Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) was a randomized trial designed to test v. hether cryotherapy applied to one randomly selected eye when there was Stage 3 + ROP significantly decreased the incidence of an unfavorable outcome. An unfavorable outcome was defined as either retinal detachment or a retinal fold and was determined at 3 month post-treatment by the use of a masked photographic system. The trial was