Visualization and Quantification of the Association Between Breast Cancer and Cholesterol in the All of Us Research Program

Epidemiologic evidence for the association of cholesterol and breast cancer is inconsistent. Several factors may contribute to this inconsistency, including limited sample sizes, confounding effects of antihyperlipidemic treatment, age, and body mass index, and the assumption that the association follows a simple linear function. Here, we aimed to address these factors by combining visualization and quantification a large-scale contemporary electronic health record database (the All of Us Research Program). We find clear visual and quantitative evidence that breast cancer is strongly, positively, and near-linearly associated with total cholesterol and low-density lipoprotein cholesterol, but not associated with triglycerides. The association of breast cancer with high-density lipoprotein cholesterol was non-linear and age dependent. Standardized odds ratios were 2.12 (95% confidence interval 1.9-2.48), P = 5.6 × 10⁻³¹ for total cholesterol; 1.99 (1.75-2.26), P = 2.6 × 10⁻²⁶ for low-density lipoprotein cholesterol; 1.69 (1.3-2.2), P = 9.0 × 10⁻⁵ for high-density lipoprotein cholesterol at age < 56; and 0.65 (0.55-0.78), P = 1.2 × 10⁻⁶ for high-density lipoprotein cholesterol at age ⩾ 56. The inclusion of the lipid levels measured after antihyperlipidemic treatment in the analysis results in erroneous associations. We demonstrate that the use of the logistic regression without inspecting risk variable linearity and accounting for confounding effects may lead to inconsistent results.