Supplementary Table S7. Confounding analyses for the association between the interaction of the TGF-B-Polygenic Risk Score and red meat intake in relation to colorectal cancer risk.

Supplementary Figure S3 shows participant selection flowchart for adenoma analysis. Flow diagram illustrating inclusion and exclusion of participants in the Nurses’ Health Study II to define the analytic cohort for colorectal adenoma analyses.

Supplementary Table S9 shows sensitivity analyses of colorectal cancer precursors risk with alternative dietary adjustment using red and processed meat intake.

Supplementary Table S11 shows sensitivity analyses of cumulative history of depression and risk of colorectal cancer precursors.

Supplementary Figure S1, LocusZoom plots.

Supplementary Table S17 shows sensitivity analyses of depression defined by depressive symptoms (MHI-5 score or physician-diagnosed depression) in relation to colorectal cancer precursors.

Supplementary Table S7 shows sensitivity analysis of depression and colorectal cancer precursors excluding potential mediators (BMI, diet, physical activity, sedentary behavior, smoking, and alcohol).

Mendelian randomization can reveal the etiological association between body mass index (BMI) and lung cancer. However, the associations between the trajectories of BMI and the risk of lung cancer remain inconclusive. We employed growth mixture modeling to identify trajectories of pre-diagnostic BMI in 163 545 individuals (117 445 women from the Nurses' Health Study and 46 100 men from the Health Professionals Follow-Up Study). We assessed the associations between BMI trajectories and lung cancer risk, as well as the effects within subgroups. Four trajectories were identified: normal-moderate increasing (class 1), overweight-marked increasing (class 2), overweight-obese turning (class 3), and obese-persistent (class 4). We observed a decreased risk of lung cancer in class 2 (adjusted hazard ratio [aHR], 0.53; 95% CI, 0.38-0.75; P = 2.32 ×10-4) and class 3 (aHR, 0.67; 95% CI, 0.48-0.94; P = .022). In stratification analysis, we observed that the effects of class 4 on lung cancer risk vary among histological subtypes. Additionally, within the class 1 population, the top quintile of BMI also demonstrated different effects among histological subtypes. Increasing lifetime BMI was associated with a decreased risk of lung cancer, with this association varying by histological subtypes, indicating histology-specific mechanisms in lung carcinogenesis.

Supplementary Figure S9. The combined T-cell status of precursor and carcinoma tissue categories in relation to anatomic location. (A-B) CD3+CD4+ and CD3+CD8+ T-cell densities in overall tissue regions stratified by anatomic location. (C-D) CD3+CD4+FOXP3+ and CD3+CD8+FOXP3+ T-cell densities in overall tissue regions stratified by anatomic location. P values were calculated with the Mann-Whitney U test (Wilcoxon rank-sum test) as compared to colorectal normal mucosa near precursor lesions (Normal mucosa) and carcinoma with proficient mismatch repair (pMMR). ***: P <0.0005, **: P <0.005, *: P <0.05. Abbreviations: CA, colorectal invasive carcinoma; dMMR, deficient mismatch repair; Non-serrated, non-serrated adenomas, Normal, colorectal normal mucosa near the precursor lesions; pMMR, proficient mismatch repair; Serrated without SSL, serrated lesions including hyperplastic polyp and traditional serrated adenoma; SSL, sessile serrated lesions.

Supplementary Table S3. Weights used for polygenic risk score estimation and coordinates from single nucleotide polymorphisms considered in the study.

Supplementary Table S12 shows sensitivity analysis of antidepressant use and colorectal cancer.

Supplementary Table S8 shows sensitivity analyses of colorectal cancer risk with alternative dietary adjustment using red and processed meat intake.

Antibodies and Staining Conditions for Multiplex Identification of T-cell Subsets and Epithelial Cells

OBJECTIVE:The purpose of this study was to estimate the lifetime risk of alcohol-attributable mortality and morbidity in the United States based on a person's average lifetime weekly alcohol consumption to assess the impact of per-occasion alcohol consumption on health. METHOD:Lifetime risks were estimated using a cause-specific modeling approach that combined exposure data from national health surveys, relative risks, population data from the U.S. Census Bureau, mortality data from the Centers for Disease Control and Prevention, and morbidity data from the Institute for Health Metrics and Evaluation. A narrative review assessed the health impact of per-occasion alcohol consumption on health. RESULTS:At low levels of consumption, no protective net effect of alcohol consumption on health was observed. Elevated mortality and morbidity risks were associated with alcohol consumption starting at relatively low levels. Males consuming >6.5 (95% CI [<1, 13.5]) and females consuming >7.0 (95% CI [<1, 11.5]) drinks per week had life-time alcohol-attributable mortality risks >1:1,000. At >8.5 (95% CI [2.5, 13]) drinks per week for both males and females, these risks increased to >1:100. At 14 drinks per week for males (the upper limit of the former Dietary Guidelines for males), the risk of an alcohol-caused death was 1:25 (4%). Drinking patterns also impacted risk. Above 1 drink per occasion, higher consumption was associated with progressively increased risks of breast cancer, cardiovascular disease, and injury. CONCLUSIONS:Alcohol consumption, including at what may be perceived as "moderate" levels, is associated with increased mortality and morbidity risks. These results support tightening alcohol use guidance in the United States, for both males and females, to no more than 1 drink per day.