Skip to main content
×
×
Home

Controlled trials of vitamin D, causality and type 2 statistical error

  • OIiver Gillie (a1)
Abstract

Two recent studies published in The Lancet (Autier et al. (2013) Lancet Diabetes Endocrinol 2, 76–89 and Bolland et al. (2014) Lancet Diabetes Endocrinol 2, 307–320) have concluded that low levels of vitamin D are not a cause but a consequence of ill health brought about by reduced exposure to the sun, an association known as ‘reverse causality’. The scientific evidence and reasoning for these conclusions are examined here and found to be faulty. A null result in a clinical trial of vitamin D in adults need not lead to a conclusion of reverse causation when low vitamin D is found in observational studies of the same disease earlier in life. To assume an explanation of reverse causality has close similarities with type 2 statistical error.

For example, a null result in providing vitamin D for treatment of adult bones that are deformed in the pattern of the rachitic rosary would not alter the observation that lack of vitamin D can cause rickets in childhood and may have lasting consequences if not cured with vitamin D. Other examples of diseases considered on a lifetime basis from conception to adulthood are used to further illustrate the issue, which is evidently not obvious and is far from trivial.

It is concluded that deficiency of vitamin D in cohort studies, especially at critical times such as pregnancy and early life, can be the cause of a number of important diseases. Denial of the possible benefits of vitamin D, as suggested by insistent interpretation of studies with reverse causation, may lead to serious harms, some of which are listed.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Controlled trials of vitamin D, causality and type 2 statistical error
      Available formats
      ×
      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Controlled trials of vitamin D, causality and type 2 statistical error
      Available formats
      ×
      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Controlled trials of vitamin D, causality and type 2 statistical error
      Available formats
      ×
Copyright
Corresponding author
* Corresponding author: Email olivergillie@blueyonder.co.uk
References
Hide All
1. Autier, PBM, Pizot, C & Mullie, P (2013) Vitamin D status and ill health: a systematic review. Lancet Diabetes Endocrinol 2, 7689.
2. Bolland, MJ, Grey, A, Gamble, GD et al. (2014) The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis. Lancet Diabetes Endocrinol 2, 307320.
3. Anon. (2014) Vitamin D: chasing a myth? (editorial). Lancet Diabetes Endocrinol 2, 1.
4. Hossein-Nezhad, A & Holick, MF (2006) Vitamin D for health: global perspsective. Mayo Clin Proc 81, 353373.
5. Anon. (2014) Further doubt cast on benefit of vitamin D supplementation for disease prevention. Press release promoting Autier et al. (2013); available at http://www.thelancet.com/press-room
6. Anon. (2014) New analysis suggests that further trials of vitamin D have little chance of showing health benefits. Press release promoting Bolland et al. (2014); available at http://www.thelancet.com/press-room
7. Heaney, R (2014) Some guidelines for design and analysis of clinical studies of nutrient effects. Nutr Rev 72, 4854.
8. Holick, MF (2006) Resurrection of vitamin D deficiency and rickets. J Clin Invest 116, 20622072.
9. Barker, DJ & Gardner, MJ (1974) Distribution of Paget’s disease in England, Wales and Scotland and a possible relationship with vitamin D deficiency in childhood. Br J Prev Soc Med 28, 226232.
10. Guillard-Cumming, DF, Beard, DJ, Douglas, DL et al. (1985) Abnormal vitamin D metabolism in Paget’s disease of bone. Clin Endocrinol (Oxf) 22, 559566.
11. Reddy, SV (2004) Etiology of Paget’s disease and osteoclast abnormalities. J Cell Biochem 93, 688696.
12. Perry, D (2013) Unravelling the enigma of Perthes’ disease. Ann R Coll Surg Engl 95, 311316.
13. Ameri, P, Canepa, M, Milaneschi, Y et al. (2013) Relationship between vitamin D status and left ventricular geometry in a healthy population: results from the Baltimore Longitudinal Study of Aging. J Intern Med 273, 253262.
14. Assalin, HB, Rafacho, BP, dos Santos, PP et al. (2013) Impact of the length of vitamin D deficiency on cardiac remodeling. Circ Heart Fail 6, 809816.
15. Zheng, Y, Zhu, J, Zhou, M et al. (2013) Meta-analysis of long-term vitamin D supplementation on overall mortality. PLoS One 8, e82109.
16. Łuczyńska, A, Kaaks, R, Rohrmann, S et al. (2013) Plasma 25-hydroxyvitamin D concentration and lymphoma risk: results of the European Prospective Investigation into Cancer and Nutrition. Am J Clin Nutr 98, 827838.
17. Ottaggio, L, Zunino, A, Maric, I et al. (2008) The presence of high-risk chromosome aberrations in chronic lymphocytic leukaemia does not correlate with centrosome aberrations. Hematol Oncol Clin North Am 26, 3942.
18. Pepper, C, Thomas, A, Hoy, T et al. (2003) The vitamin D3 analog EB1089 induces apoptosis via a p53-independent mechanism involving p38 MAP kinase activation and suppression of ERK activity in B-cell chronic lymphocytic leukemia cells in vitro . Blood 101, 24542460.
19. Pierrot-Deseilligny, C & Sounerbielle, JC (2013) Contribution of vitamin D insufficiency to the pathogenesis of multiple sclerosis. Ther Adv Neurol Disord 6, 81116.
20. DeLuca, GC, Kolasinski, J, Ramagopalan, SV et al. (2013) Review: the role of vitamin D in nervous system health and disease. Neuropathol Appl Neurobiol 39, 458484.
21. Tulic, MK, Andrews, D, Crook, ML et al. (2012) Changes in thymic regulatory T-cell maturation from birth to puberty: differences in atopic children. J Allergy Clin Immunol 129, 199206.
22. Ramagopalan, SV, Maugeri, NJ, Handunnetthi, L et al. (2009) Expression of the multiple sclerosis-associated MHC class II allele HLA-DRB1*1501 is regulated by vitamin D. PLoS Genet 5, e1000369.
23. Derakhshandi, H, Etemadifar, M, Feizi, A et al. (2013) Preventive effect of vitamin D3 supplementation on conversion of optic neuritis to clinically definite multiple sclerosis: a double blind, randomized, placebo-controlled pilot clinical trial. Acta Neurol Belg 113, 257263.
24. Ramagopalan, SV, Maugeri, NJ, Handunnetthi, L et al. (2013) Hospital admissions for vitamin D related conditions and subsequent immune-mediated disease: record-linkage studies. BMC Med 11, 171.
25. Disanto, G, Chaplin, G, Morahan, JM et al. (2012) Month of birth, vitamin D and risk of immune mediated disease: a case control study. BMC Med 10, 69.
26. Disanto, G, Morahan, JM, Lacey, MV et al. (2012) Seasonal distribution of psychiatric births in England. PLoS One 7, e34866.
27. Grant, WB & Soles, CM (2009) Epidemiologic evidence supporting the role of maternal vitamin D deficiency as a risk factor for the development of infantile autism. Dermato-endocrinology 1, 223228.
28. Gibney, SM & Drexhage, HA (2013) Evidence for a dysregulated immune system in the etiology of psychiatric disorders. J Neuroimmune Pharmacol 8, 900920.
29. Boucher, B (2011) Vitamin D insufficiency and diabetes risks. Current Drug Targets 12, 6187.
30. Hypponen, E, Laara, E, Reunanen, A et al. (2001) Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 358, 15001503.
31. Byar, DP, Simon, RM, Friedewald, WT et al. (1976) Randomized clinical trials. Perspectives on some recent ideas. N Engl J Med 95, 7480.
32. Ross, A, Manson, J, Abrams, S et al. (2011) The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab 96, 5358.
33. Holick, MF, Binkley, NC, Bischoff-Ferrari, HA et al. (2011) Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 96, 19111930.
34. Pilz, S, Tomaschitz, A, Drechsler, M et al. (2011) Vitamin D, cardiovascular disease and mortality. Clin Endocrinol (Oxf) 75, 575584.
35. Zittermann, A, Gummert, JF & Borgermann, J (2009) Vitamin D deficiency and mortality. Curr Opin Clin Nutr Metab Care 12, 634639.
36. Zittermann, A & Grant, WB (2009) 25-Hydroxyvitamin D levels and all-cause mortality. Arch Intern Med 169, 10751076, author reply 1076.
37. Autier, P & Gandini, S (2007) Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. Arch Intern Med 167, 17301737.
38. Grant, W (2011) An estimate of the global reduction in mortality rates through doubling vitamin D levels. Eur J Clin Nutr 65, 10161026.
39. Coussens, AK, Wilkinson, RA, Hanifa, Y et al. (2012) Vitamin D accelerates resolution of inflammatory responses during tuberculosis treatment. Proc Natl Acad Sci USA 109, 1544915454.
40. Martineau, A (2013) Vitamin D: an adjunct to antiretroviral therapy? J Infect Dis 207, 373375.
41. Camargo, CA Jr, Ganmas, D, Lindsay Frazier, A et al. (2012) Randomized trial of vitamin D supplementation and risk of acute respiratory tract infection in Mongolia. Pediatrics 130, 561567.
42. Urashima, M, Segawa, T, Okazaki, M et al. (2010) Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. Am J Clin Nutr 91, 12551260.
43. Berlanga-Taylor, A & Ramagopalan, S (2013) Vitamin D and multiple sclerosis: what is the clinial impact? Expert Opin Diagn 7, 227229.
44. Aghajafari, F, Nagulesapillai, T, Ronksley, P et al. (2013) Association between maternal serum 25-hydroxyvitamin D level and pregnancy and neonatal outcomes: systematic review and meta-analysis of observational studies. BMJ 346, f1169.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Public Health Nutrition
  • ISSN: 1368-9800
  • EISSN: 1475-2727
  • URL: /core/journals/public-health-nutrition
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×

Keywords

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed