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Biostatistics. 2018 Jul 1;19(3):307-324. doi: 10.1093/biostatistics/kxx037.

Evaluation and comparison of predictive individual-level general surrogates.

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Division of Clinical Research, Biostatistics Research Branch, NIAID/NIH, 5601 Fishers Lane, MSC 9820 Rockville, MD, 20892-9820 USA
Unit of Biostatistics, Institute of Environmental Medicine, Nobels väg 13, Karolinska Institutet, 17177 Stockholm, Sweden.
Department of Biostatistics, School of Public Health, University of Washington, 1705 NE Pacific Street, Seattle, 98195 WA, USA, Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., Mail Stop E5-110, Seattle, WA 98109, USA and Center for Inference and Dynamics of Infectious Diseases, 1100 Fairview Ave. N, M2-C200, Seattle, WA 98109-1024, USA.


An intermediate response measure that accurately predicts efficacy in a new setting at the individual level could be used both for prediction and personalized medical decisions. In this article, we define a predictive individual-level general surrogate (PIGS), which is an individual-level intermediate response that can be used to accurately predict individual efficacy in a new setting. While methods for evaluating trial-level general surrogates, which are predictors of trial-level efficacy, have been developed previously, few, if any, methods have been developed to evaluate individual-level general surrogates, and no methods have formalized the use of cross-validation to quantify the expected prediction error. Our proposed method uses existing methods of individual-level surrogate evaluation within a given clinical trial setting in combination with cross-validation over a set of clinical trials to evaluate surrogate quality and to estimate the absolute prediction error that is expected in a new trial setting when using a PIGS. Simulations show that our method performs well across a variety of scenarios. We use our method to evaluate and to compare candidate individual-level general surrogates over a set of multi-national trials of a pentavalent rotavirus vaccine.

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