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A quantitative study of the missing covariate bias in survival studies
Abstracts
241
number of times and the proportion of simulated values as large or larger than the value obtained for the actual data gives the p value. The PARIS II are used to illustrate the method.
A Quantitative Study of the Missing Covariate Bias in Survival Studies D a v i d Byar, C l a u d e C h a s t a n g , a n d S t e v e n Piantadosi
Clinical and Diagnostic Trials Section, National Cancer Institute, National Institutes of Health, Bethesda, MD (P74) It has recently been pointed out that failure to adjust for a prognostic factor may bias estimation of a treatment effect in nonlinear models often used to analyze randomized studies even though the omitted covariate is perfectly balanced across the treatment groups. We present simple analytic expressions that allow quantitative assessment of the bias for postulated or known effects of one or more omitted covariates when the response variable is a censored exponential survival time. Although large biases may exist if the effects of the omitted covariates are large, investigation of examples omitting several covariates whose effects are typical of those found in prognostic studies of cancer and other chronic diseases shows that in general the bias will be relatively small. The effect of censoring on this bias was at first surprising, but can be explained.
Dealing with N e w Information During an Ongoing Trial Joel Singer, M a r g a r e t V a n d e r v o o r t , a n d J o h n A. Cairns McMaster University, Hamilton, Ontario, Canada (75) How should one deal with new information from another source about a therapy that is under investigation in a randomized controlled trial (RCT)? This paper reports upon the experience of the Canadian Unstable Angina Study which examined in a 2 x 2 factorial design the effects of the antiplatelet drugs, aspirin and sulfinpyrazone, on patients hospitalized with unstable angina. Approximately 1 year before the scheduled end of this study, another group of researchers reported at a scientific meeting that they had conducted an RCT with a very similarly defined group of patients and had found aspirin to have a positive effect on the same major clinical outcomes in which we were interested. The decision that we took, to continue on with our study without examining our data, is discussed, focusing on such issues as the importance of peer review and replication, generalizability between studies, ongoing medical practice and ethical obligation to study patients. lvermectin in Onchocerciasis: Clinical Studies in West Africa M o h a m m e d A. A z i z
Merck Sharp & Dohme Research Laboratories, Rahway, NJ (76) Onchocerciasis is a significant cause of blindness in the Third World; of 40 million people infected with the parasite 10 million have serious eye disease. The currently used drugs diethylcarbamazine (DEC) and suramin are potentially seriously toxic and must be administered under medical supervision. There is real need for safe and effective chemotherapy. Ivermectin, a new antiparasitic drug, has been investigated in onchocerciasis in four West African countries-Senegal, Ghana, Mali, and Liberia. In controlled clinical studies, a small single oral dose was found superior in efficacy and safety to the present multidose regimen of DEC. Skin microfilariae (m0 in ivermectin patients decreased rapidly to near zero and remained below 10% of pretreatment in most patients for at least 6 months. This prolonged effect of ivermecfin may interfere with transmission of the disease by the black fly vector. The encouraging initial data are being confirmed in large scale studies. Community-wide single-dose ivermectin therapy compaigns against this disease in areas with minimal medical supervision may become a reality. Unique aspects of the ivermectin clinical program are discussed.
Comparison of Two Data Collection Methods Dorice M. Jasperse a n d S u s a n W. A h m e d
The EMMES Corp., Potomac, MD (77) The Mid-Atlantic Oncology Program (MAOP) compared data collected by circuit riding data managers (CDM) from the stat office with local data managers (LDM) from clinics and practices, the latter being the standard data capture method in cancer clinical trials. LDMs and CDMs filled out identical study forms, using the same patient charts, for randomly selected patients on MAOP
241
number of times and the proportion of simulated values as large or larger than the value obtained for the actual data gives the p value. The PARIS II are used to illustrate the method.
A Quantitative Study of the Missing Covariate Bias in Survival Studies D a v i d Byar, C l a u d e C h a s t a n g , a n d S t e v e n Piantadosi
Clinical and Diagnostic Trials Section, National Cancer Institute, National Institutes of Health, Bethesda, MD (P74) It has recently been pointed out that failure to adjust for a prognostic factor may bias estimation of a treatment effect in nonlinear models often used to analyze randomized studies even though the omitted covariate is perfectly balanced across the treatment groups. We present simple analytic expressions that allow quantitative assessment of the bias for postulated or known effects of one or more omitted covariates when the response variable is a censored exponential survival time. Although large biases may exist if the effects of the omitted covariates are large, investigation of examples omitting several covariates whose effects are typical of those found in prognostic studies of cancer and other chronic diseases shows that in general the bias will be relatively small. The effect of censoring on this bias was at first surprising, but can be explained.
Dealing with N e w Information During an Ongoing Trial Joel Singer, M a r g a r e t V a n d e r v o o r t , a n d J o h n A. Cairns McMaster University, Hamilton, Ontario, Canada (75) How should one deal with new information from another source about a therapy that is under investigation in a randomized controlled trial (RCT)? This paper reports upon the experience of the Canadian Unstable Angina Study which examined in a 2 x 2 factorial design the effects of the antiplatelet drugs, aspirin and sulfinpyrazone, on patients hospitalized with unstable angina. Approximately 1 year before the scheduled end of this study, another group of researchers reported at a scientific meeting that they had conducted an RCT with a very similarly defined group of patients and had found aspirin to have a positive effect on the same major clinical outcomes in which we were interested. The decision that we took, to continue on with our study without examining our data, is discussed, focusing on such issues as the importance of peer review and replication, generalizability between studies, ongoing medical practice and ethical obligation to study patients. lvermectin in Onchocerciasis: Clinical Studies in West Africa M o h a m m e d A. A z i z
Merck Sharp & Dohme Research Laboratories, Rahway, NJ (76) Onchocerciasis is a significant cause of blindness in the Third World; of 40 million people infected with the parasite 10 million have serious eye disease. The currently used drugs diethylcarbamazine (DEC) and suramin are potentially seriously toxic and must be administered under medical supervision. There is real need for safe and effective chemotherapy. Ivermectin, a new antiparasitic drug, has been investigated in onchocerciasis in four West African countries-Senegal, Ghana, Mali, and Liberia. In controlled clinical studies, a small single oral dose was found superior in efficacy and safety to the present multidose regimen of DEC. Skin microfilariae (m0 in ivermectin patients decreased rapidly to near zero and remained below 10% of pretreatment in most patients for at least 6 months. This prolonged effect of ivermecfin may interfere with transmission of the disease by the black fly vector. The encouraging initial data are being confirmed in large scale studies. Community-wide single-dose ivermectin therapy compaigns against this disease in areas with minimal medical supervision may become a reality. Unique aspects of the ivermectin clinical program are discussed.
Comparison of Two Data Collection Methods Dorice M. Jasperse a n d S u s a n W. A h m e d
The EMMES Corp., Potomac, MD (77) The Mid-Atlantic Oncology Program (MAOP) compared data collected by circuit riding data managers (CDM) from the stat office with local data managers (LDM) from clinics and practices, the latter being the standard data capture method in cancer clinical trials. LDMs and CDMs filled out identical study forms, using the same patient charts, for randomly selected patients on MAOP