A better design for stratified medicine based on genomic prediction

Abstract

Genomic prediction shows promise for personalised medicine in which diagnosis and treatment are tailored to individuals based on their genetic profiles. Genomic prediction is arguably the greatest need for complex diseases and disorders for which both genetic and non-genetic factors contribute to risk. However, we have no adequate insight of the accuracy of such predictions, and how accuracy may vary between individuals or between populations. In this study, we present a theoretical framework to demonstrate that prediction accuracy can be maximised by targeting more informative individuals in a discovery set with closer relationships with the subjects, making prediction more similar to those in populations with small effective size (Ne). Increase of prediction accuracy from closer relationships is achieved under an additive model and does not rely on any interaction effects (gene x gene, gene x environment or gene x family). Using theory, simulations and real data analyses, we show that the predictive accuracy or the area under the receiver operating characteristic curve (AUC) increased exponentially with decreasing Ne. For example, with a set of realistic parameters (the sample size of discovery set N=3000 and heritability h2=0.5), AUC value approached to 0.9 (Ne=100) from 0.6 (Ne=10000), and the top percentile of the estimated genetic profile scores had 23 times higher proportion of cases than the general population (with Ne=100), which increased from 2 times higher proportion of cases (with Ne=10000). This suggests that different interventions in the top percentile risk groups maybe justified (i.e. stratified medicine). In conclusion, it is argued that there is considerable room to increase prediction accuracy for polygenic traits by using an efficient design of a smaller Ne (e.g. a design consisting of closer relationships) so that genomic prediction can be more beneficial in clinical applications in the near future.