An application of the patient rule‐induction method for evaluating the contribution of the Apolipoprotein E and Lipoprotein Lipase genes to predicting ischemic heart disease

Abstract

Different combinations of genetic and environmental risk factors are known to contribute to the complex etiology of ischemic heart disease (IHD) in different subsets of individuals. We employed the Patient Rule-Induction Method (PRIM) to select the combination of risk factors and risk factor values that identified each of 16 mutually exclusive partitions of individuals having significantly different levels of risk of IHD. PRIM balances two competing objectives: (1) finding partitions where the risk of IHD is high and (2) maximizing the number of IHD cases explained by the partitions. A sequential PRIM analysis was applied to data on the incidence of IHD collected over 8 years for a sample of 5,455 unrelated individuals from the Copenhagen City Heart Study (CCHS) to assess the added value of variation in two candidate susceptibility genes beyond the traditional, lipid and body mass index risk factors for IHD. An independent sample of 362 unrelated individuals also from the city of Copenhagen was used to test the model obtained for each of the hypothesized partitions.

Validated context-dependent associations of coronary heart disease risk with genotype variation in the chromosome 9p21 region: the Atherosclerosis Risk in Communities study

“…The PRIM is an iterative process that partitions the sample according to values (or combinations of values) of the risk factors (for more details, please see “Methods” and Fried-man and Fisher 1999; Dyson et al 2007, 2009). Using the values of the TRFs, seven unique, sequential sub-groups and a remainder subgroup were defined by the PRIM analysis of the ARIC sample (Fig.…”

“…Dyson et al (2007, 2009) have modified the PRIM algorithm, originally proposed by Friedman and Fisher (1999), to address this question. Here, our application of the PRIM treats all cases of CHD as equivalent in a cross-sectional analysis that does not consider time to event.…”

“…Sub-groups are defined to maximize θ , the relative frequency of individuals with CHD, given the partition satisfies the support parameter, β. β is the minimum proportion of individuals, among those who are not already assigned to a partition, required to create a new partition. We use a likelihood-based grid search to choose the optimum β for each PRIM application across a range of values from 0.05 to 0.50 (in increments of 0.005) (Dyson et al 2007). Only sub-groups with a statistically significant θ , tested against a theoretical null distribution derived by Dyson and Sing (in press), are retained in the peeling and pasting process.…”

Progressing From Risk Factors to Omics

“…53 Clinicians hope that genetic and metabolic pathway research will provide improved ways to identify persons with higher risk for adverse outcomes and that "not all risk factors are predictors of ischemic heart disease (or another adverse outcome) in all subsets of individuals." 54 What is the utility in genetic testing for lipid abnormalities at this time? Humphries et al 55 addressed that question for familial hypercholesterolemia in a recent publication.…”

Is Life Law-Like?

“…The degree to which phenotypes depend upon such context is not, we think, nearly sufficiently appreciated (or, perhaps, too often appreciated only in passing), but has clearly been demonstrated in the biomedical arena (Sing et al 2003(Sing et al , 2004Dyson et al 2007). Indeed, SNP alleles that are severely deleterious in one species can become normal in other species due, for example, to compensatory variation elsewhere in the genome (Kondrashov et al 2002;Gao and Zhang 2003).…”