Pros and Cons of the Pathway Based Approach

The pathway-based approach is an extension of the candidate gene approach. It is hypothesis driven and uses a priori knowledge of potentially functional SNPs and gene functions. It gives a more complete picture of the roles for genes and pathways in affecting treatment response. By evaluating the combined impact of multiple polymorphisms, it may be possible to identify minor associations that would not have been detected with the candidate gene approach. By using sophisticated machine-learning and analysis tools, it may be possible to identify high-order gene-gene interaction and provide a clinically relevant prediction value based on distinct genotype profiles.

However, this approach is still limited by our current knowledge of the function of selected genes and polymorphisms. By tallying the number of adverse alleles, this approach assumes an equal weight for each allele, which may not be true for all genes and polymorphisms. It is arbitrary to assign which allele is the adverse allele because there may be no functional data to show that one specific allele is functionally inferior. The minor alleles may not necessarily result in reduced gene expression or protein function. Data analyses using machine-learning tools become more complex with increasing numbers of polymorphisms, and the analyses require larger sample sizes. Finally, the validation of identified genotype combinations by association studies is more demanding, and their biological plausibility is difficult to assess experimentally.

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