A rank-based approach to evaluate a surrogate marker in a small sample setting.

Abstract

In clinical studies of chronic diseases, the effectiveness of an intervention is often assessed using "high cost" outcomes that require long-term patient follow-up and/or are invasive to obtain. While much progress has been made in the development of statistical methods to identify surrogate markers, that is, measurements that could replace such costly outcomes, they are generally not applicable to studies with a small sample size. These methods either rely on nonparametric smoothing which requires a relatively large sample size or rely on strict model assumptions that are unlikely to hold in practice and empirically difficult to verify with a small sample size. In this paper, we develop a novel rank-based nonparametric approach to evaluate a surrogate marker in a small sample size setting. The method developed in this paper is motivated by a small study of children with nonalcoholic fatty liver disease (NAFLD), a diagnosis for a range of liver conditions in individuals without significant history of alcohol intake. Specifically, we examine whether change in alanine aminotransferase (ALT; measured in blood) is a surrogate marker for change in NAFLD activity score (obtained by biopsy) in a trial, which compared Vitamin E ($n=50$) versus placebo ($n=46$) among children with NAFLD.