1. Confounding

Most studies have considered at least some potential confounders (e.g., age). The concept of confounding is related to the existence of a variable that is a risk factor for the disease and is associated with the genotype. If the prevalence of a certain genotype changes with age because of a survival effect, age is a confounder since it is strongly predictive of cancer onset. Often, which relevant confounders could exist in genotyping studies is difficult to hypothesize. As the genotype is fixed, confounding related to enzyme induction is irrelevant. On the other hand, in the phenotypic studies, potentially many potential confounders may affect results, e.g., cancer status, diet, exercise. These make the results of phenotypic studies all the more difficult to interpret.

2. Publication bias

Publication bias occurs when positive studies are preferentially published by scientific journals compared to negative studies and particularly to small negative studies. In the genotyping studies we are examining, all results except Duell et al.35 were small or moderately small. Curiously, the lowest ORs come from Duell et al.35 and from another relatively larger investigation, Stern et al.39 This is only a weak suggestion in favor of potential publication bias. With the increasing recognition of this problem, more negative studies are being published.

3. Other bias

One limitation of several studies is that the control group is poorly defined or clearly inadequate. For example, Shen et al.32 compared Chinese cases living in the United States with Chinese controls living in China. One study29 used cadaveric transplant donors as controls, and one used friends of the cases.26

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