Predictive testing for complex diseases using multiple genes: Fact or fiction?

Abstract

Purpose: There is ongoing debate about whether testing low-risk genes at multiple loci will be useful in clinical care and public health. We investigated the usefulness of multiple genetic testing using simulated data. Methods:Usefulness was evaluated by the area under the receiver-operating characteristic curve (AUC), which indicates the accuracy of genetic profiling in discriminating between future patients and nonpatients. The AUC was investigated in relation to the number of genes assumed to be involved, the risk allele frequency, the odds ratio of the risk genotypes, and to the proportion of variance explained by genetic factors as an approximation of the heritability of the disease. Results: We demonstrated that a high (AUC Ͼ 0.80) to excellent discriminative accuracy (AUC Ͼ 0.95) can be obtained by simultaneously testing multiple susceptibility genes. A higher discriminative accuracy is obtained when genetic factors play a larger role in the disease, as indicated by the proportion of explained variance.The maximum discriminative accuracy of future genetic profiling can be estimated at present from the heritability and prevalence of disease. Conclusions: Genetic profiling may have the potential to identify individuals at higher risk of disease depending on the prevalence and heritability of the disease. Genet Med 2006:8(7):395-400.

Variations in five genes and the severity of age-related macular degeneration: results from the Muenster aging and retina study

“…Model performance was evaluated using the area under the ROC curve (or c-statistics) to assess the discriminatory power of the model. 38 To account for the number of statistical comparisons performed for each SNP, we adjusted the statistical significance level to the number of AMD stages (a/n, ie, 0.05/4 ¼ 0.0125), and report exclusively 99% confidence intervals. Likewise, statistical significance of a result was accepted if the error level was less than 1%.…”

Rapid aneuploidy detection or karyotyping? Ethical reflection

“…54,55 We are only at the start of unravelling these complex interactions. 56,57 The development of automated genomics techniques has enabled scientists to quickly compare the inherited characteristics of large numbers of people. It can be used to detect subtle differences and look at them in the context of environmental factors.…”

Is the time right for translation research in genomics?

“…Typical gene discovery studies include 1,000s of patients and are able to detect variants with odds ratios as low as 1.05-1.10. Yet, also a very large number of weak susceptibility variants may further improve risk prediction [15]. Furthermore, stronger genetic effects may still be found for gene-gene and geneenvironment interactions.…”

“…From an epidemiological perspective, investigating the predictive value of a limited number of susceptibility genes with weak effects seems somewhat overoptimistic as a priori high predictive value is not expected [18]. The predictive value of genetic profiling, often investigated in terms of the discriminative accuracy indicated by the area under the receiver operating characteristic curve (AUC), is determined by the number of variants, the frequency of the risk genotypes and their strength of association to disease risk [15]. To reach appreciable predictive value for genetic profiling, we either should be able to include up to tens or hundreds of weak susceptibility genes or a few variants with strong effects as in AMD and hypertriglyceridemia [15].…”

“…The predictive value of genetic profiling, often investigated in terms of the discriminative accuracy indicated by the area under the receiver operating characteristic curve (AUC), is determined by the number of variants, the frequency of the risk genotypes and their strength of association to disease risk [15]. To reach appreciable predictive value for genetic profiling, we either should be able to include up to tens or hundreds of weak susceptibility genes or a few variants with strong effects as in AMD and hypertriglyceridemia [15]. These variants can be single gene effects, but can also be derived from gene-gene or gene-environment interactions.…”