Skip to main content
SpringerLink
Log in

Predictors of 25-hydroxyvitamin D and its association with risk factors for prostate cancer: evidence from the Prostate testing for cancer and Treatment study

  • Original paper
  • Published:
Cancer Causes & Control Aims and scope Submit manuscript

Abstract

Purpose

Circulating 25-hydroxyvitamin D (25(OH)D) may protect against prostate and other cancers. Few epidemiology studies have measured 25(OH)D on all participants, weakening the evidence-base through reduced statistical power and the potential for bias. We developed a score to predict individual 25(OH)D based on potential predictors, including sun exposure, nutrient intake, and vitamin D pathway genes, providing a method of substituting missing values. We assessed the usefulness of predicted 25(OH)D by comparison with multiple imputation of 25(OH)D levels.

Methods

Amongst 1,091 controls from a population-based case–control study (ProtecT), we quantified relationships of sun exposure, demographic, clinical, anthropologic, nutrient, and genetic data with circulating 25(OH)D and constructed several prediction scores from subsets of these measures. We investigated associations of three prostate cancer risk factors (PSA level, BMI, family history of prostate cancer) with 25(OH)D levels in sensitivity analyses based upon participants with measured 25(OH)D only and based upon the addition of all participants with missing 25(OH)D levels substituted by prediction score values or by multiple imputation.

Results

Our score accounted for 27.7% of the variation in measured 25(OH)D. Associations with risk factors of prostate cancer were consistent across the different estimates of 25(OH)D. However, standard deviations for the prediction score did not incorporate extra error from prediction. Multiple imputation of missing 25(OH)D values predicted a more realistic range of 25(OH)D.

Conclusion

In epidemiological studies of cancer risk associated with vitamin D, multiple imputation of missing 25(OH)D is preferable to prediction scores, as a wider range of 25(OH)D levels are imputed and appropriate confidence intervals calculated.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Hanchette CL, Schwartz GG (1992) Geographic patterns of prostate cancer mortality. Evidence for a protective effect of ultraviolet radiation. Cancer 70(12):2861–2869

    Article  PubMed  CAS  Google Scholar 

  2. Schwartz GG, Hanchette CL (2006) UV, latitude, and spatial trends in prostate cancer mortality: all sunlight is not the same (United States). Cancer Causes Control 17(8):1091–1101

    Article  PubMed  Google Scholar 

  3. Holick MF (2004) Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr 80(6):1678S–1688S

    PubMed  CAS  Google Scholar 

  4. Gilbert R, Metcalfe C, Oliver SE, Whiteman DC, Bain C, Ness AR, Donovan J, Hamdy F, Neal DE, Lane JA, Martin RM (2009) Life course sun exposure and risk of prostate cancer: population-based nested case-control study and meta-analysis. Int J Cancer 125(6):1414–1423

    Article  PubMed  CAS  Google Scholar 

  5. World Cancer Research Fund/American Institute for Cancer R (2007) Food, nutrition, physical activity, and the prevention of cancer: a global perspective. AICR, Washington

    Google Scholar 

  6. Gilbert R, Martin RM, Beynon R, Harris R, Savovic J, Zuccolo L, Bekkering GE, Fraser WD, Sterne JAC, Metcalfe C (2011) Associations of circulating and dietary vitamin D with prostate cancer risk: a systematic review and dose-response meta-analysis. Cancer Causes Control 22:319–340

    Article  PubMed  Google Scholar 

  7. Fang F, Kasperzyk JL, Shui I, Hendrickson W, Hollis BW, Fall K, Ma J, Gaziano JM, Stampfer MJ, Mucci LA, Giovannucci E (2011) Prediagnostic plasma vitamin D metabolites and mortality among patients with prostate cancer. PLoS One 6(4):e18625 (Electronic Resource)

    Article  PubMed  CAS  Google Scholar 

  8. Janssen KJM, Donders AR, Harrell FE Jr, Vergouwe Y, Chen Q, Grobbee DE, Moons KGM (2010) Missing covariate data in medical research: to impute is better than to ignore. J Clin Epidemiol 63(7):721–727

    Article  PubMed  Google Scholar 

  9. Wood AM, White IR, Royston P (2008) How should variable selection be performed with multiply imputed data? Stat Med 27(17):3227–3246

    Article  PubMed  Google Scholar 

  10. Giovannucci E, Liu Y, Rimm EB, Hollis BW, Fuchs CS, Stampfer MJ, Willett WC (2006) Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. JNCI Cancer Spectr 98(7):451–459

    Article  CAS  Google Scholar 

  11. Lane JA, Hamdy FC, Martin RM, Turner EL, Neal DE, Donovan JL (2010) Latest results from the UK trials evaluating prostate cancer screening and treatment: the CAP and ProtecT studies. Eur J Cancer 46(17):3095–3101

    Article  PubMed  CAS  Google Scholar 

  12. Jacques PF, Felson DT, Tucker KL, Mahnken B, Wilson PW, Rosenberg IH, Rush D (1997) Plasma 25-hydroxyvitamin D and its determinants in an elderly population sample. Am J Clin Nutr 66(4):929–936

    PubMed  CAS  Google Scholar 

  13. Andersen R, Molgaard C, Skovgaard LT, Brot C, Cashman KD, Chabros E, Charzewska J, Flynn A, Jakobsen J, Karkkainen M, Kiely M, Lamberg-Allardt C, Moreiras O, Natri AM, O’Brien M, Rogalska-Niedzwiedz M, Ovesen L (2005) Teenage girls and elderly women living in northern Europe have low winter vitamin D status. Eur J Clin Nutr 59(4):533–541

    Article  PubMed  CAS  Google Scholar 

  14. van Dam RM, Snijder MB, Dekker JM, Stehouwer CDA, Bouter LM, Heine RJ, Lips P (2007) Potentially modifiable determinants of vitamin D status in an older population in the Netherlands: the Hoorn Study. Am J Clin Nutr 85(3):755–761

    PubMed  Google Scholar 

  15. Bolland MJ, Grey AB, Ames RW, Mason BH, Horne AM, Gamble GD, Reid IR (2007) The effects of seasonal variation of 25-hydroxyvitamin D and fat mass on a diagnosis of vitamin D sufficiency. Am J Clin Nutr 86(4):959–964

    PubMed  CAS  Google Scholar 

  16. Egan KM, Signorello LB, Munro HM, Hargreaves MK, Hollis BW, Blot WJ (2008) Vitamin D insufficiency among African-Americans in the southeastern United States: implications for cancer disparities (United States). Cancer Causes Control 19(5):527–535

    Article  PubMed  Google Scholar 

  17. Jacobs ET, Alberts DS, Foote JA, Green SB, Hollis BW, Yu Z, Martinez ME (2008) Vitamin D insufficiency in southern Arizona. Am J Clin Nutr 87(3):608–613

    PubMed  CAS  Google Scholar 

  18. Tseng M, Giri V, Bruner DW, Giovannucci E (2009) Prevalence and correlates of vitamin D status in African American men. BMC Public Health 9:191

    Article  PubMed  Google Scholar 

  19. Brock K, Huang WY, Fraser DR, Ke L, Tseng M, Stolzenberg-Solomon R, Peters U, Ahn J, Purdue M, Mason RS, McCarty C, Ziegler RG, Graubard B (2010) Low vitamin D status is associated with physical inactivity, obesity and low vitamin D intake in a large US sample of healthy middle-aged men and women. J Steroid Biochem Mol Biol 121(1–2):462–466

    Article  PubMed  CAS  Google Scholar 

  20. McCullough ML, Weinstein SJ, Freedman DM, Helzlsouer K, Flanders WD, Koenig K, Kolonel L, Laden F, Le Marchand L, Purdue M, Snyder K, Stevens VL, Stolzenberg-Solomon R, Virtamo J, Yang G, Yu K, Zheng W, Albanes D, Ashby J, Bertrand K, Cai H, Chen Y, Gallicchio L, Giovannucci E, Jacobs EJ, Hankinson SE, Hartge P, Hartmuller V, Harvey C, Hayes RB, Horst RL, Shu XO (2010) Correlates of circulating 25-Hydroxyvitamin D: cohort consortium vitamin D pooling project of rarer cancers. Am J Epidemiol 172(1):21–35

    Article  PubMed  Google Scholar 

  21. Iarc Working Group Reports I (2008) Vitamin D and cancer. http://comiarcfr/en/publications/pdfs-online/wrk/wrk5/Report_VitDpdf

  22. Calle EE, Kaaks R (2004) Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer 4(8):579–591

    Article  PubMed  CAS  Google Scholar 

  23. Holick MF (2004) Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am J Clin Nutr 79(3):362–371

    PubMed  CAS  Google Scholar 

  24. Pittas AG, Dawson-Hughes B (2010) Vitamin D and diabetes. J Steroid Biochem Mol Biol 121(1–2):425–429

    Article  PubMed  CAS  Google Scholar 

  25. Maynard MJ, Blane D (2009) Dietary assessment in early old age: experience from the Boyd Orr cohort. Eur J Clin Nutr 63:S58–S63

    Article  PubMed  Google Scholar 

  26. Rowlands MA, Holly JM, Gunnell D, Gilbert R, Donovan J, Lane JA, Marsden G, Collin SM, Hamdy F, Neal DE, Martin RM (2010) The relation between adiposity throughout the life course and variation in IGFs and IGFBPs: evidence from the ProtecT (Prostate testing for cancer and Treatment) study. Cancer Causes Control 21(11):1829–1842

    Article  PubMed  Google Scholar 

  27. Whiteman DC, Stickley M, Watt P, Hughes MC, Davis MB, Green AC (2006) Anatomic site, sun exposure, and risk of cutaneous melanoma. J Clin Oncol 24(19):3172–3177

    Article  PubMed  Google Scholar 

  28. Calvo MS, Whiting SJ, Barton CN (2005) Vitamin D intake: a global perspective of current status. J Nutr 135(2):310–316

    PubMed  CAS  Google Scholar 

  29. Chen L, Davey SG, Evans DM, Cox A, Lawlor DA, Donovan J, Yuan W, Day IN, Martin RM, Lane A, Rodriguez S, Davis M, Zuccolo L, Collin SM, Hamdy F, Neal D, Lewis SJ (2009) Genetic variants in the vitamin d receptor are associated with advanced prostate cancer at diagnosis: findings from the prostate testing for cancer and treatment study and a systematic review. Cancer Epidemiol Biomarkers Prev 18(11):2874–2881

    Article  PubMed  CAS  Google Scholar 

  30. McGrath JJ, Saha S, Burne THJ, Eyles DW (2010) A systematic review of the association between common single nucleotide polymorphisms and 25-hydroxyvitamin D concentrations. J Steroid Biochem Mol Biol 121(1–2):471–477

    Article  PubMed  CAS  Google Scholar 

  31. Ahn J, Albanes D, Berndt SI, Peters U, Chatterjee N, Freedman ND, Abnet CC, Huang WY, Kibel AS, Crawford ED, Weinstein SJ, Chanock SJ, Schatzkin A, Hayes RB, for the Prostate LC, Ovarian Trial Project T (2009) Vitamin D-related genes, serum vitamin D concentrations and prostate cancer risk. Carcinogenesis 30(5):769–776

    Article  PubMed  CAS  Google Scholar 

  32. Royston P (2005) Multiple imputation of missing values: update of ice. Stata J 5(4):527–536

    Google Scholar 

  33. Abayomi K, Gelman A, Levy M (2008) Diagnostics for multivariate imputations. J Royal Stat Soc Series C Appl Stat 57:273–291

    Article  Google Scholar 

  34. Stuart EA, Azur M, Frangakis C, Leaf P (2009) Multiple imputation with large data sets: a case study of the children’s mental health initiative. Am J Epidemiol 169(9):1133–1139

    Article  PubMed  Google Scholar 

  35. Royston P, Sauerbrei W (2008) Multivariable model-building: a pragmatic approach to regression analysis based on fractional polynomials for modelling continuous variables. Wiley Series in Probability and Statistics, Wiley

    Google Scholar 

  36. Heymans M, van Buuren S, Knol D, van Mechelen W, de Vet H (2007) Variable selection under multiple imputation using the bootstrap in a prognostic study. BMC Med Res Methodol 7(1):33

    Article  PubMed  Google Scholar 

  37. Royston P (2009) Multiple imputation of missing values: further update of ice, with an emphasis on categorical variables. Stata J 9(3):466–477

    Google Scholar 

  38. Carlin JB, Galati JC, Royston P (2008) A new framework for managing and analyzing multiply imputed data in Stata. Stata J 8(1):49–67

    Google Scholar 

  39. Royston P, Carlin JB, White IR (2009) Multiple imputation of missing values: new features for mim. Stata J 9(2):252–264

    Google Scholar 

  40. Royston P, Sauerbrei W (2009) Bootstrap assessment of the stability of multivariable models. Stata J 9(4):547–570

    Google Scholar 

  41. Royston P (2004) Multiple imputation of missing values. Stata J 4(3):227–241

    Google Scholar 

  42. Millen AE, Wactawski-Wende J, Pettinger M, Melamed ML, Tylavsky FA, Liu S, Robbins J, LaCroix AZ, LeBoff MS, Jackson RD (2010) Predictors of serum 25-hydroxyvitamin D concentrations among postmenopausal women: the Women’s Health Initiative Calcium plus Vitamin D Clinical Trial. Am J Clin Nutr 91(5):1324–1335

    Article  PubMed  CAS  Google Scholar 

  43. Liu E, Meigs JB, Pittas AG, Economos CD, McKeown NM, Booth SL, Jacques PF (2010) Predicted 25-hydroxyvitamin D score and incident type 2 diabetes in the Framingham Offspring Study. Am J Clin Nutr 91(6):1627–1633

    Article  PubMed  CAS  Google Scholar 

  44. Chan J, Jaceldo-Siegl K, Fraser G (2010) Determinants of serum 25 hydroxyvitamin D levels in a nationwide cohort of blacks and non-Hispanic whites. Cancer Causes Control 21(4):501–511

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This analysis was funded by the World Cancer Research Fund UK (Grant number 2006/15). RG is recipient of a Cancer Research UK Graduate Training Fellowship (C31211/A10095). The UK Department of Health funded the ProtecT study through the NIHR Health Technology Assessment programme. Freddie Hamdy, Jenny Donovan, and David Neal are NIHR Senior Investigators. The authors would like to acknowledge the provision of additional epidemiological data by the NHS R&D Directorate supported Prodigal study and the ProMPT (Prostate Mechanisms of Progression and Treatment) collaboration, which is supported by the National Cancer Research Institute (NCRI) formed by the Department of Health, the Medical Research Council and Cancer Research, UK. The authors would like to acknowledge the tremendous contribution of all members of the ProtecT study research group, and especially the following who were involved in this research (Prasad Bollina, Sue Bonnington, Lynn Bradshaw, James Catto, Debbie Cooper, Michael Davis, Liz Down, Andrew Doble, Alan Doherty, Garrett Durkan, Emma Elliott, David Gillatt, Pippa Herbert, Peter Holding, Joanne Howson, Mandy Jones, Roger Kockelbergh, Howard Kynaston, Teresa Lennon, Norma Lyons, Hing Leung, Malcolm Mason, Hilary Moody, Philip Powell, Alan Paul, Stephen Prescott, Derek Rosario, Patricia O’Sullivan, Pauline Thompson, and Sarah Tidball). They would also like to thank Gemma Marsden, who processed the blood samples at the biorepository. Department of Health disclaimer: The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Department of Health..

Conflicts of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. School of Social and Community Medicine, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol, BS8 2PS, UK

    Rebecca Gilbert, Richard M. Martin, Sarah Lewis, Jenny Donovan, J. Athene Lane & Chris Metcalfe

  2. MRC Centre for Causal Analysis in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Bristol, UK

    Richard M. Martin & Sarah Lewis

  3. Norwich Medical School, Faculty of Medicine and Health Sciences, University of East Anglia, Norwich, UK

    William D. Fraser

  4. Nuffield Department of Surgery, University of Oxford, Oxford, UK

    Freddie Hamdy

  5. Department of Oncology, University of Cambridge, Cambridge, UK

    David E. Neal

Authors
  1. Rebecca Gilbert
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Richard M. Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. William D. Fraser
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sarah Lewis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jenny Donovan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Freddie Hamdy
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. David E. Neal
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J. Athene Lane
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Chris Metcalfe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rebecca Gilbert.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 163 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gilbert, R., Martin, R.M., Fraser, W.D. et al. Predictors of 25-hydroxyvitamin D and its association with risk factors for prostate cancer: evidence from the Prostate testing for cancer and Treatment study. Cancer Causes Control 23, 575–588 (2012). https://doi.org/10.1007/s10552-012-9919-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10552-012-9919-8

Keywords

Search

Navigation