Criteria for Surrogate End Points

Abstract

A surrogate end point is often used to evaluate the effects of treatments or exposures on the true end point in medical researches. Various criteria for the statistical surrogate, principal surrogate and strong surrogate have been proposed. We first illustrate that, with a surrogate end point that is defined by these criteria, it is possible that a treatment has a positive effect on the surrogate, which in turn has a positive effect on the true end point, but the treatment has a negative effect on the true end point. We define such a phenomenon as a surrogate paradox. The surrogate paradox also means that the sign of the treatment effect on the true end point is unpredictable by the effect signs of both the treatment on the surrogate and the surrogate on the true end point. Then we propose two notions for a consistent surrogate and a strictly consistent surrogate to avoid the surrogate paradox. With the causal network that was presented by Lauritzen, we discuss the conditions for a strong surrogate to be a consistent surrogate and a strictly consistent surrogate. Copyright 2007 Royal Statistical Society.

Principal Stratification -- Uses and Limitations

“…Chen et al (2007) and Ju et al (2010) note that a principal surrogate as de ned by Frangakis and Rubin (2002) does not avert the so called "surrogate paradox." That is to say, a variable S may be a principal surrogate and the treatment may have a positive effect on the surrogate and the surrogate may have a positive effect on the outcome but it may still be the case the effect of the treatment on the outcome is negative!…”

Criteria for Multiple Surrogates

“…Joffe and Greene (2009) summarized related statistical approaches and discussed the relationships among these approaches. However, the above criteria cannot avoid the surrogate paradox proposed in Chen et al (2007). The surrogate paradox means that a treatment has a positive effect on a surrogate and the surrogate has a positive effect on an endpoint, but the treatment has a negative effect on the endpoint.…”

“…The conditions can be checked empirically by observed data if the endpoint is observed in a validation study. VanderWeele (2013) extended the results of Chen et al (2007) and Ju and Geng (2010) to the cases where there is a direct effect of the treatment on the endpoint. All of these criteria are only for a single surrogate.…”

“…The surrogate paradox means that a treatment has a positive effect on a surrogate and the surrogate has a positive effect on an endpoint, but the treatment has a negative effect on the endpoint. Chen et al (2007) and Ju and Geng (2010) proposed the criteria for consistent surrogates to avoid the surrogate paradox based on the causation knowledge between the surrogate and the endpoint. Wu et al (2011) proposed sufficient conditions to predict the sign of treatment effect on the unmeasured endpoint by the sign of treatment effect on the measured surrogate based on the association knowledge between the surrogate and the endpoint.…”

Surrogate Endpoints: Application in Pediatric Clinical Trials

“…However, for a treating physician who has observed a tumor response in a specific patient and wants to know how this can predict the survival of the patient, the individual dimension will be most useful. 30,31 .…”