Statistical analysis

In this meta-analysis, the common measure of association was OR in case-control studies, and RR in cohort studies. Results from case-control and cohort studies were separately presented. A random-effects model[20] which considers both within-and between-study variation was assigned to combine study-specific risk estimates. Several studies presented results for different sources of vitamin C intake (total, diet and supplement), and the results for total intake were included in the main analysis. Subgroup analysis were performed according to geographic area, source of control (for case-control studies), sex of subjects, years of follow-up (for cohort studies), number of events, and source of vitamin C.

Considering the distinct cutoffs across studies, we conducted a dose-response analysis with the method of Greenland and Longnecker[21] and Orsiniet al.[22]. The method requires that the number of cases and controls (or person-years) and the risk estimates with their variance for at least 3 quantitative exposure categories are known. For every study, the median/mean level of the intake for each category was assigned to each corresponding risk estimate. When the median/mean intake per category was not provided, the midpoint of the upper and lower boundaries in each category was assigned as the average intake. If the highest/lowest category was open-ended, we assumed the width of the interval to be the same as in the closest category. Because of limited number of eligible studies in case-control studies[16, 18, 23]., we only conducted the dose-response analysis for prospective cohort studies.

Heterogeneity test was performed using Q and I² statistics [24]. For the Q statistic, level of significance was set at P<0.1; and for the I², a value of <25%, 25–75% and >75% represents little/no, moderate, and considerable heterogeneity. Potential publication bias was investigated with both Begg correlation test and Egger regression test[25, 26],. All statistical analyses were performed using STATA software, version 12.0 (STATA Corp., College Station, TX, USA).