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A bayesian approach to surrogacy assessment using principal stratification in clinical trials.

ABSTRACT: A surrogate marker (S) is a variable that can be measured earlier and often more easily than the true endpoint (T) in a clinical trial. Most previous research has been devoted to developing surrogacy measures to quantify how well S can replace T or examining the use of S in predicting the effect of a treatment (Z). However, the research often requires one to fit models for the distribution of T given S and Z. It is well known that such models do not have causal interpretations because the models condition on a postrandomization variable S. In this article, we directly model the relationship among T, S, and Z using a potential outcomes framework introduced by Frangakis and Rubin (2002, Biometrics 58, 21-29). We propose a Bayesian estimation method to evaluate the causal probabilities associated with the cross-classification of the potential outcomes of S and T when S and T are both binary. We use a log-linear model to directly model the association between the potential outcomes of S and T through the odds ratios. The quantities derived from this approach always have causal interpretations. However, this causal model is not identifiable from the data without additional assumptions. To reduce the nonidentifiability problem and increase the precision of statistical inferences, we assume monotonicity and incorporate prior belief that is plausible in the surrogate context by using prior distributions. We also explore the relationship among the surrogacy measures based on traditional models and this counterfactual model. The method is applied to the data from a glaucoma treatment study.

SUBMITTER: Li Y

PROVIDER: S-EPMC3365598 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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A bayesian approach to surrogacy assessment using principal stratification in clinical trials.

Li Yun Y Taylor Jeremy M G JM Elliott Michael R MR

Biometrics 20090810 2

A surrogate marker (S) is a variable that can be measured earlier and often more easily than the true endpoint (T) in a clinical trial. Most previous research has been devoted to developing surrogacy measures to quantify how well S can replace T or examining the use of S in predicting the effect of a treatment (Z). However, the research often requires one to fit models for the distribution of T given S and Z. It is well known that such models do not have causal interpretations because the models ...[more]

PMID: 19673864

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Project description:Exploration of causal mechanisms is often important for researchers and policymakers to understand how an intervention works and how it can be improved. This task can be crucial in clustered encouragement designs (CED). Encouragement design studies arise frequently when the treatment cannot be enforced because of ethical or practical constrains and an encouragement intervention (information campaigns, incentives, etc) is conceived with the purpose of increasing the uptake of the treatment of interest. By design, encouragements always entail the complication of non-compliance. Encouragements can also give rise to a variety of mechanisms, particularly when encouragement is assigned at cluster level. Social interactions among units within the same cluster can result in spillover effects. Disentangling the effect of encouragement through spillover effects from that through the enhancement of the treatment would give better insight into the intervention and it could be compelling for planning the scaling-up phase of the program. Building on previous works on CEDs and non-compliance, we use the principal stratification framework to define stratum-specific causal effects, that is, effects for specific latent subpopulations, defined by the joint potential compliance statuses under both encouragement conditions. We show how the latter stratum-specific causal effects are related to the decomposition commonly used in the literature and provide flexible homogeneity assumptions under which an extrapolation across principal strata allows one to disentangle the effects. Estimation of causal estimands can be performed with Bayesian inferential methods using hierarchical models to account for clustering. We illustrate the proposed methodology by analyzing a cluster randomized experiment implemented in Zambia and designed to evaluate the impact on malaria prevalence of an agricultural loan program intended to increase the bed net coverage. Farmer households assigned to the program could take advantage of a deferred payment and a discount in the purchase of new bed nets. Our analysis shows a lack of evidence of an effect of the offering of the program to a cluster of households through spillover effects, that is through a greater bed net coverage in the neighborhood.

Project description:PurposeInter-individual variability in clinical endpoints and occurrence of potentially severe adverse effects represent an enormous challenge in drug development at all phases of (pre-)clinical research. To ensure patient safety it is important to identify adverse events or critical subgroups within the population as early as possible. Hence, a comprehensive understanding of the processes governing pharmacokinetics and pharmacodynamics is of utmost importance. In this paper we combine Bayesian statistics with detailed mechanistic physiologically-based pharmacokinetic (PBPK) models. On the example of pravastatin we demonstrate that this combination provides a powerful tool to investigate inter-individual variability in groups of patients and to identify clinically relevant homogenous subgroups in an unsupervised approach. Since PBPK models allow the identification of physiological, drug-specific and genotype-specific knowledge separately, our approach supports knowledge-based extrapolation to other drugs or populations.MethodsPBPK models are based on generic distribution models and extensive collections of physiological parameters and allow a mechanistic investigation of drug distribution and drug action. To systematically account for parameter variability within patient populations, a Bayesian-PBPK approach is developed rigorously quantifying the probability of a parameter given the amount of information contained in the measured data. Since these parameter distributions are high-dimensional, a Markov chain Monte Carlo algorithm is used, where the physiological and drug-specific parameters are considered in separate blocks.ResultsConsidering pravastatin pharmacokinetics as an application example, Bayesian-PBPK is used to investigate inter-individual variability in a cohort of 10 patients. Correlation analyses infer structural information about the PBPK model. Moreover, homogeneous subpopulations are identified a posteriori by examining the parameter distributions, which can even be assigned to a polymorphism in the hepatic organ anion transporter OATP1B1.ConclusionsThe presented Bayesian-PBPK approach systematically characterizes inter-individual variability within a population by updating prior knowledge about physiological parameters with new experimental data. Moreover, clinically relevant homogeneous subpopulations can be mechanistically identified. The large scale PBPK model separates physiological and drug-specific knowledge which allows, in combination with Bayesian approaches, the iterative assessment of specific populations by integrating information from several drugs.

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A bayesian approach to surrogacy assessment using principal stratification in clinical trials.

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A bayesian approach to surrogacy assessment using principal stratification in clinical trials.

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