Restricted cubic spline models allow for easy visualization of nonlinear relationships between an exposure and an outcome43 and 44—in this case, cigarette smoking and Barrett’s esophagus. These models were plotted using a linear scale on the x-axis (pack-years of cigarette smoking) and a logarithmic (base 10) scale on the y-axis (OR). To determine whether cigarette smoking biologically BMS-354825 cell line interacts with other exposures in relation to risk of Barrett’s esophagus, we tested

for departure from additivity. Positive departure from additivity implies that the number of cases attributable to 2 exposures in combination is larger than the sum of the numbers of cases that would be caused by each exposure separately. The covariates tested for biological interaction with ever-cigarette smoking were BMI (<27.5, ≥27.5), heartburn and regurgitation (population-based control comparisons

only), alcohol, H pylori, and nonsteroidal anti-inflammatory drugs. For each combination Selleck LGK 974 of variables, we generated 4 exposure categories; using BMI as an example: A = never-smoker, low BMI; B = smoker, low BMI; C = never-smoker, high BMI; D = smoker, high BMI. These variables were modeled in the pooled dataset of individual patient data using logistic regression adjusted for age, sex, BMI, education, and study. Assuming that the OR approximates the relative risk, the output from these models was used to estimate 3 interaction statistics: interaction contrast ratio, attributable proportion, and synergy index. 45 and 46 When the interaction contrast ratio and attributable proportion ≠ 0 and synergy index ≠ 1, there is evidence for departure from additivity (biological interaction). Interaction contrast ratio is the excess risk due to interaction relative to the risk without either exposure. Attributable proportion is the proportion of disease

attributable to interaction among individuals with both exposures. Synergy index is the ratio of the observed excess risk in individuals exposed to both factors relative to the expected excess risk, assuming that both exposures are independent risk factors (ie, under the assumption of no additive interaction). Confidence intervals for these metrics were estimated using the delta method. 45 All analyses were performed using STATA software, version 11.1 (StataCorp LP, College C225 Station, TX). All statistical tests were 2-sided and P values <0.05 were considered to be statistically significant. Descriptors of cases and controls included in the analysis are shown in Table 2. The population-based control distributions were more similar to the cases in terms of age and sex than the GERD controls, and this is because 3 of the 4 studies with population-based controls matched on these variables to the Barrett’s esophagus case group; GERD controls were matched to the Barrett’s esophagus group on age and sex in only 1 study (Table 1).