Vitamin D and cancer in Japan: “If you torture the data long enough, it will confess.”*
* Ronald Coase.
Budhathokiet al’s evaluation of the association between pre-diagnostic circulating vitamin D concentration and the subsequent risk of cancers deserves robust comment.(1)
First, using arbitrary cut-points to derive various subgroups (by quarter and by third) for vitamin D is not appropriate as there is a continuous distribution of the values with no obvious modal values.
Second, similarly for arbitrary cut-points to derive subgroups for confounding clinical variables. Moreover, a self-administered survey is a poorly reliable method for variables such as tobacco or alcohol use.
Accordingly, the sophistication of the statistical methods for adjustment contrasts with the poor quality and relevance of the data. However, the main problem is that adjustment is almost impossible: a) smokers have lower vitamin D;(2) b) vitamin D is associated with a higher risk of tobacco-related cancers.(3) Similarly, alcohol consumption, obesity, insulin resistance, type 2 diabetes have an impact on vitamin D status.(4)
In 1998, a robust prospective survey (NHANES III, n= 13,331) investigated vitamin D levels with mortality, accounting for age, sex, ethnicity, diabetes, current smoking, body mass index, physical activity, supplementation, season.(5) It revealed a small higher risk, which was not statistically significant. More recent well-designed studies are also negative as recently a nested case-control study from the Prostate, Lung, Colorectal, and Ovarian Cancer screening trial cohort which failed to show evidence that vitamin D plays a protective role.(6) In this study controls were matched to each case by age, race, sex, and month of blood draw while Budhathoki et al created complex and unvalidated quantiles to account for seasonal variability.(1)
Age-specific mortality rate of cancer is increasing in Japan. Obviously infection and tobacco use ranks first for causality; if other causes or risk factors deserve scrutiny, it must be food borne mutagenic/carcinogenic heterocyclic amines.(7)
1 Budhathoki S, Hidaka A, Yamaji T et al. Plasma 25-hydroxyvitamin D concentration and subsequent risk of total and site specific cancers in Japanese population: large case-cohort study within Japan Public Health Center-basedProspective Study cohort. BMJ 2018;360:k671.
2 Tønnesen R, Hovind PH, Jensen LT, Schwarz P. Determinants of vitamin D status in young adults: influence of lifestyle, sociodemographic and anthropometric factors. BMC Public Health 2016;16:385.
3 Afzal S, Bojesen SE, Nordestgaard BG. Low plasma 25-hydroxyvitamin D and risk of tobacco-related cancer. Clin Chem 2013;59:771-80.
4 Palaniswamy S, Hyppönen E, Williams D, Jokelainen J, Lowry E, Keinänen-Kiukaanniemi S, Herzig KH, Järvelin MR, Sebert S. Potential determinants of vitamin D in Finnish adults: a cross-sectional study from the Northern Finland birth cohort 1966. BMJ Open 2017;7: e013161.
5 Melamed ML, Michos ED, Post W, Astor B. 25-hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med 2008;168:1629-37.
6 Piper MR, Freedman DM, Robien K et al. Vitamin D-binding protein and pancreatic cancer: a nested case-control study. Am J Clin Nutr 2015;101:1206-15.
7 Nagao M, Tsugane S. Cancer in Japan: Prevalence, prevention and the role of heterocyclic amines in human carcinogenesis. Genes Environ 2016; 38: 16.
Competing interests: No competing interests