Table 1.

Summary of the three-step candidate-pathway gene-environment interaction approach*

Analysis step	Interaction of interest	Variable of interest	Model	Specific procedures	Product
Colon cancer risk analysis steps
Step 1: Summarize gene effects	SNP-set interaction within gene	SNPs on each gene separately	Logic regression with logit link	Cross-validation to determine optimal model size	Gene-specific trees
Step 2: Summarize pathway effects	Gene-gene interaction within pathway	All GSTs on the pathway	Logic regression with logit link	Cross-validation to determine optimal model size	Pathway trees
Step 3: Test gene- environment interaction	Gene-environment interaction within pathway	a. Subpathway- specific GSTxEb. Full pathway GSTxE	Logistic regression model†	Statistical significance testing	Pathway GEIs
Colon cancer survival analysis steps
Step 1: Summarize gene effects	SNP-set interaction within gene	SNPs on each gene separately	Logic regression fitting exponential survival models	Cross-validation to determine optimal model size	Gene-specific trees
Step 2: Summarize pathway effects	Gene-gene interaction within pathway	All GSTs on the pathway	Logic regression fitting exponential survival models	Cross-validation to determine optimal model size	Pathway trees
Step 3: Test gene- environment interaction	Gene-environment interaction within pathway	a. Subpathway- specific GSTxEb. Full pathway GSTxE	Cox proportional hazards model‡	Statistical significance testing	Pathway GEIs

* GEI = gene-environment interaction; GST = gene-specific tree; GSTxE = gene-specific tree–environment interaction; SNP = single nucleotide polymorphism.

† Models adjusted for age, sex, race, study center, and pathway tree.

‡ Models adjusted for age, sex, race, study center, and pathway trees, stratified by cancer stage.