Abstract
Background: Substantial uncertainty exists as to whether combining multiple disease-associated single nucleotide polymorphisms (SNPs) into a genotype risk score (GRS) can provide clinically useful information.
Methods: We critically evaluated the ability of a simple count GRS to predict the risk of a dichotomous outcome, under both a multiplicative (log additive) and linear additive model of combined effects. We also evaluated the ability of a count GRS to predict the level of a continuous outcome variable. We then compared the results of these simulations with the observed results of published GRS measured within multiple epidemiologic cohort studies on cancer health disparities.
Results: If the combined effect of each disease-associated SNP included in a GRS is multiplicative on the risk scale, then a count GRS score should be useful for risk stratification with as few as 10-20 SNPs. Adding additional SNPs to the GRS under this model dramatically improves risk stratification with modest gains in risk discrimination. By contrast, if the combined effect of each SNP included in a GRS is linearly additive on the risk scale, a simple count GRS is unlikely to provide clinically useful risk prediction or discrimination. Adding additional SNPs to the GRS under this model does not improve any measures of clinical utility. The combined effect of SNPs included in a GRS measured in several epidemiologic cohort studies appears to be more consistent with a linearly additive combined effect. Unlike the case for predicting a dichotomous outcome, a simple count GRS can potentially provide clinically useful information to predict the level of a continuous outcome variable under a wide variety of circumstances, even when the amount of explained variance is low.
Conclusion: A simple count GRS can provide clinically useful information to predict the level of a continuous variable under a variety of circumstances. By contrast, a count GRS is unlikely to be clinically useful for predicting the risk of a dichotomous outcome. To provide clinically useful information about the genetic risk of dichotomous outcomes, alternative methods for constructing GRS that attempt to identify and include SNPs whose combined effect is at least multiplicative are needed.
Citation Format: Wonsuk Yoo. A clinical evaluation of the clinical utility of genotype risk scores in cancer health disparities. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr B19. doi:10.1158/1538-7755.DISP13-B19
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