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Surrogacy assessment using principal stratification when surrogate and outcome measures are multivariate normal.

ABSTRACT: In clinical trials, a surrogate outcome variable (S) can be measured before the outcome of interest (T) and may provide early information regarding the treatment (Z) effect on T. Using the principal surrogacy framework introduced by Frangakis and Rubin (2002. Principal stratification in causal inference. Biometrics 58, 21-29), we consider an approach that has a causal interpretation and develop a Bayesian estimation strategy for surrogate validation when the joint distribution of potential surrogate and outcome measures is multivariate normal. From the joint conditional distribution of the potential outcomes of T, given the potential outcomes of S, we propose surrogacy validation measures from this model. As the model is not fully identifiable from the data, we propose some reasonable prior distributions and assumptions that can be placed on weakly identified parameters to aid in estimation. We explore the relationship between our surrogacy measures and the surrogacy measures proposed by Prentice (1989. Surrogate endpoints in clinical trials: definition and operational criteria. Statistics in Medicine 8, 431-440). The method is applied to data from a macular degeneration study and an ovarian cancer study.

SUBMITTER: Conlon AS

PROVIDER: S-EPMC4023321 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Surrogacy assessment using principal stratification when surrogate and outcome measures are multivariate normal.

Conlon Anna S C AS Taylor Jeremy M G JM Elliott Michael R MR

Biostatistics (Oxford, England) 20131126 2

In clinical trials, a surrogate outcome variable (S) can be measured before the outcome of interest (T) and may provide early information regarding the treatment (Z) effect on T. Using the principal surrogacy framework introduced by Frangakis and Rubin (2002. Principal stratification in causal inference. Biometrics 58, 21-29), we consider an approach that has a causal interpretation and develop a Bayesian estimation strategy for surrogate validation when the joint distribution of potential surro ...[more]

PMID: 24285772

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Project description:Because of the time and expense required to obtain clinical outcomes of interest, such as functional limitations or death, clinical trials often focus the effects of treatment on earlier and more easily obtained surrogate markers. Preliminary work to define surrogates focused on the fraction of a treatment effect "explained" by a marker in a regression model, but as notions of causality have been formalized in the statistical setting, formal definitions of high-quality surrogate markers have been developed in the causal inference framework, using either the "causal effect" or "causal association" settings. In the causal effect setting, high-quality surrogate markers have a large fraction of the total treatment effect explained by the effect of the treatment on the marker net of the treatment on the outcome. In the causal association setting, high-quality surrogate markers have large treatment effects on the outcome when there are large treatment effects on the marker, and small effects on the outcome when there are small effects on the marker. A particularly important feature of a surrogate marker is that the direction of a treatment effect be the same for both the marker and the outcome. Settings in which the marker and outcome are positively associated but the marker and outcome have beneficial and harmful or harmful and beneficial treatment effects, respectively, have been referred to as "surrogate paradoxes". If this outcome always occurs, it is not problematic; however, as correlations among the outcome, marker, and their treatment effects weaken, it may occur for some trials and not for others, leading to potentially incorrect conclusions, and real-life examples that shortened thousands of lives are unfortunately available. We propose measures for assessing the risk of the surrogate paradox using the meta-analytic causal association framework, which allows us to focus on the probability that a given treatment will yield treatment effect in different directions between the marker and the outcome, and to determine the size of a beneficial effect of the treatment on the marker required to minimize the risk of a harmful effect of the treatment on the outcome. We provide simulations and consider two applications.

Dataset Information

Surrogacy assessment using principal stratification when surrogate and outcome measures are multivariate normal.

Publications

Surrogacy assessment using principal stratification when surrogate and outcome measures are multivariate normal.

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