Supplementary Online Content

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1 Supplementary Online Content Ebbing M, Bønaa KH, Nygård O, et al. Cancer incidence and mortality after treatment with folic acid and vitamin B 1. JAMA. 9;3(19): etable 1. Circulating Levels of B Vitamins and Total Homocysteine at Baseline and During Study Treatment etable. Hazard Ratios for the Primary End Points by Serum Levels of Folate and Cobalamin Measured During Study Treatment efigure. Kaplan-Meier Curves for Cancer Incidence, Cancer Mortality, and All-Cause Mortality for the Main Comparisons Through Extended Follow-Up Panel A: Cancer Incidence Folic Acid vs Non Folic Acid Groups Panel B: Cancer Incidence Vitamin B Groups vs Non Vitamin B Groups Panel C: Cancer Mortality Folic Acid vs Non Folic Acid Groups Panel D: Cancer Mortality Vitamin B Groups vs Non Vitamin B Groups Panel E: All-Cause Mortality Folic Acid vs Non Folic Acid Groups Panel F: All-Cause Mortality Vitamin B Groups vs Non Vitamin B Groups This supplementary material has been provided by the authors to give readers additional information about their work.

2 etable 1. Circulating Levels of B Vitamins and Total Homocysteine at Baseline and During Study Treatment Folic Acid + Vitamins B 1 and B (n = 17) Folic Acid + Vitamin B 1 (n = 173) Vitamin B (n = 175) Placebo (n = 171) Serum folate (ng/ml) Baseline (n = 773) 3.9 (.9) 3.9 (.7) 3. (.) 3.9 (.7).5 1- mo (n = 1) 5.3 (1.5) 9. (1.) 3. (1.) 3.9 (.5) <.1 Final study visit b (n = 557) 5.5 (17.9) 9.3 (19.) 3.7 (.).5 (3.3) <.1 Serum cobalamin (pg/ml) Baseline (n = 79) 77 () 77 (3) 77 () 7 (3) mo (n = 13) 9 (7) 3 (9) 9 (5) 1 (7) <.1 Final study visit b (n = 557) 71 (31) 7 (3) 5 (17) 73 (19) <.1 Plasma total homocysteine (µmol/l) Baseline (n = 1) 11. (.) 11.1 (.) 11. (.7) 11. (.) mo (n = 1).3 (.9). (.) 11. (.) 11.5 (.) <.1 Final study visit b (n = 55).1 (.9).3 (3.1) 11. (.) 11. (.7) <.1 Plasma pyridoxal 5 phosphate (ng/ml) Baseline (n = 7).1 (.) 7.9 (5.5).3 (.3). (5.5).7 1- mo (n = ) 7. (.9) 9.3 (.1) 9.3 (3.3) 9.3 (.3) <.1 Final study visit b (n = 59) 75.5 (.) 9. (.5) 75.3 (9.) 9.5 (.) <.1 Values are medians and interquartile ranges. SI conversion factors: To convert folate to nmol/l, multiply by.. To convert cobalamin to pmol/l, multiply by.737. To convert pyridoxal 5 phosphate to nmol/l, multiply by.. a Kruskal-Wallis test across the four intervention groups. b The final study visit occurred after median (interquartile range) 39 (1) months of in-trial follow-up. P Value a

3 etable. Hazard Ratios for the Primary End Points by Serum Levels of Folate and Cobalamin Measured During Study Treatment Cancer Incidence Cancer Mortality All-Cause Mortality Serum Level, Quartiles Folate d Total No. a No. of Events Hazard Ratio b (95% CI) P Value c No. of Events Hazard Ratio b (95% CI) P Value c No. of Events Hazard Ratio b (95% CI) Quartile ( ) (.7-1.7) (1.-1.).7 Quartile Quartile (.-1.39) ( ) ( ).9 Quartile ( ) (1.5-.3) (1.1-.9) <.1 All <.1 Cobalamin e Quartile (.91-1.) (.-1.93) ( ).7 Quartile Quartile (1.5-1.) (.9-.) (.7-1.9).55 Quartile ( ) (.95-.9) (.9-1.3).5 All P Value c Abbreviations: CI, confidence interval. SI conversion factors: To convert folate to nmol/l, multiply by.. To convert cobalamin to pmol/l, multiply by.737. a A total of 37 (93.1%) of participants had one or two measurements of serum folate and of serum cobalamin during study treatment with B vitamins or placebo. Folate and cobalamin quartiles were computed by using the mean of measurements from the study visit at 1 to months after randomization and at the final study visit median 39 months after randomization, or the actual value if only one sample was available after random treatment assignment. b Hazard ratios estimated by Cox regression, unadjusted, stratified by trial. Participants in the second serum folate quartile or cobalamin quartile during study treatment had the lowest cancer incidence, cancer mortality and all-cause mortality through extended follow-up, thus quartile was used as the reference category. c P value for difference between quartiles with quartile as reference category, or for heterogeneity across all quartiles. d For serum folate, quartile 1, 3. ng/ml; quartile, ng/ml; quartile 3, ng/ml; quartile, >7. ng/ml. e For serum cobalamin, quartile 1, 5.3 pg/ml; quartile, pg/ml; quartile 3, pg/ml; quartile, >79. pg/ml.

4 efigure. Kaplan-Meier Curves for Cancer Incidence, Cancer Mortality, and All-Cause Mortality for the Main Comparisons Through Extended Follow-Up Panel A: Cancer Incidence Folic Acid vs Non-Folic Acid Groups Panel B: Cancer incidence Vitamin B Groups vs Non-Vitamin B Groups Panel C: Cancer Mortality Folic Acid vs Non-Folic Acid Groups Panel D: Cancer Mortality Vitamin B Groups vs Non-Vitamin B Groups Panel E: All-Cause Mortality Folic Acid vs Non-Folic Acid Groups Panel F: All-Cause Mortality Vitamin B Groups vs Non-Vitamin B Groups The primary end points were cancer incidence (Panels A and B), cancer mortality (Panels C and D) and allcause mortality (Panels E and F) from randomization throughout the year 7. Non-melanoma skin cancers were not included in cancer incidence. The comparisons were between folic acid groups and non-folic acid groups (Panels A, C and E) and between vitamin B groups and non-vitamin B groups (Panels B, D and F). Folic acid groups were assigned to treatment with folic acid,. mg, and vitamin B 1,. mg, or folic acid and vitamin B 1 in combination with vitamin B, mg. Non-folic acid groups were assigned to treatment with vitamin B alone, or placebo. Vitamin B groups were assigned to treatment with vitamin B, mg alone or in combination with folic acid,. mg, and vitamin B 1,. mg. Non-vitamin B groups were assigned to treatment with folic acid and vitamin B 1, or placebo.

5 Panel A - Cancer Incidence Log-rank P =. Cumulative Incidence.5 Folic acid groups Non-folic acid groups Folic acid groups Non-folic acid groups

6 Panel B - Cancer Incidence Log-rank P =.3 Cumulative Incidence.5 Vitamin B groups Non-vitamin B groups Vitamin B groups Non-vitamin B groups

7 Panel C - Cancer Mortality Log-rank P =.1 Cumulative Mortality.5 Folic acid groups Non-folic acid groups Folic acid groups Non-folic acid groups

8 Cumulative Mortality Panel D - Cancer Mortality Log-rank P =.51.5 Non-vitamin B groups Vitamin B groups Vitamin B groups Non-vitamin B groups

9 Panel E - All-Cause Mortality.5 Log-rank P =.1. Cumulative Mortality Folic acid groups Non-folic acid groups.5 Folic acid groups Non-folic acid groups

10 Panel F - All-Cause Mortality.5 Log-rank P =.35. Cumulative Mortality Vitamin B groups Non-vitamin B groups.5 Vitamin B groups Non-vitamin B groups