Measuring Surrogacy in Clinical Research
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Measuring Surrogacy in Clinical Research With an Application to Studying Surrogate Markers for HIV Treatment-as-Prevention Rui Zhuang1
· Ying Qing Chen2
Received: 14 October 2018 / Revised: 17 April 2019 / Accepted: 27 May 2019 © International Chinese Statistical Association 2019
Abstract In clinical research, validated surrogate markers are highly desirable in study design, monitoring, and analysis, as they do not only reduce the required sample size and follow-up duration, but also facilitate scientific discoveries. However, challenges exist to identify a reliable marker. One particular statistical challenge arises on how to measure and rank the surrogacy of potential markers quantitatively. We review the main statistical methods for evaluating surrogate markers. In addition, we suggest a new measure, the so-called population surrogacy fraction of treatment effect, or simply the ρ-measure, in the setting of clinical trials. The ρ-measure carries an appealing population impact interpretation and supplements the existing statistical measures of surrogacy by providing “absolute” information. We apply the new measure along with other prominent measures to the HIV Prevention Trial Network 052 Study, a landmark trial for HIV/AIDS treatment-as-prevention. Keywords Population attributable fraction · Proportion of treatment effect explained · Surrogate marker · Randomized trial
1 Introduction Between April 2005 and May 2015, a landmark Human Immunodeficiency Virus (HIV) prevention trial on 1763 married, serodiscordant couples, namely the HIV Prevention Trial Network (HPTN) 052 Study, was conducted in four continents, nine countries to examine whether or not treating the HIV-positive partner of a couple
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Rui Zhuang [email protected]
1
University of Washington, Seattle, WA 98195, USA
2
Vaccine and Infectious Disease Division and Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA
123
Statistics in Biosciences
when his/her CD4+ count was between 350 and 550 cells per cubic millimeter with antiretroviral therapy (ART) would prevent HIV transmission to his/her partner, compared with the standard-of-care (SOC) of treating later when the CD4+ count fell between 200 and 250 per cubic millimeter, or an indication of Acquired Immunodeficiency Disease Syndrome (AIDS) was developed [23]. As designed, there would be an 18-month enrollment period, and each enrolled couple would be followed up for at least 5 years to ensure sufficient power for the trial, given the fact that an HIV transmission event was considered “rare” in a modern clinical trial setting. Large-size long-term randomized clinical trials, like the HPTN 052 Study, can be very resource-demanding and time-consuming. Investigators are hence often motivated to find an appropriate surrogate to substitute for rare or distal clinical meaningful endpoints [31,34,73]. A surrogate endpoint is usually referring to a biomarker that predicts clinical benefits and risks reliably [24]. Hence, the terms “surrogate marker” and
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