Unmeasured confounding: exercise example

Can you really sit on your couch, pop vitamin D pills, and shave seconds off your 5k? Touted as a miracle cure-all, vitamin D is claimed to slash cancer and infection risks while boosting mood, cognition, and athletic performance. But does upping your vitamin D really make you healthier and happier? In this episode, we’ll follow the epidemiologic evidence—from clues in petri dishes through randomized trials. Along our journey, we’ll encounter chocolate-fueled Nobel Prizes, rock stars, pasty Brits, and a tangled mess of promiscuous variables.

Statistical topics

• ecological studies
• ecological fallacy
• correlation is not causation
• observational studies
• statistical adjustment
• confounding
• randomized trials
• factorial design
• post-hoc analyses
• subgroup analyses

Methodologic morals

• “Variables with too many entanglements make observational studies a fool’s game.”
• “If your intervention works only when you torture your data, it’s probably a false confession.”

Citations

Garland CF, Garland FC. Do sunlight and vitamin D reduce the likelihood of colon cancer? Int J Epidemiol. 1980;9:227-31.

Messerli FH. Chocolate consumption, cognitive function, and Nobel laureates. N Engl J Med. 2012;367:1562-64.

Holick, MF. The Vitamin D Solution: A 3-Step Strategy to Cure Our Most Common Health Problems. Penguin Publishing Group, 2011. 

McMillan A. Can vitamin D boost your fitness routine? Dec 18, 2018.

Marawan A, Kurbanova N, Qayyum R. Association between serum vitamin D levels and cardiorespiratory fitness in the adult population of the USA. Eur J Prev Cardiol. 2019;26:750-55.

Vitamin D levels in the blood linked to cardiorespiratory fitness. European Society of Cardiology. Oct 30, 2018.

Jones AM, Kirby BS, Clark IE, et al. Physiological demands of running at 2-hour marathon race pace. J Appl Physiol. 2021;130:369-79.

Manson JE, Bassuk SS, Lee IM, et al. The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Contemp Clin Trials. 2012;33:159-71.

Manson JE, Cook NR, Lee IM, et al. Vitamin D supplements and prevention of cancer and cardiovascular disease. NEJM. 2019;380:33-44.

Lee KL, McNeer JF, Starmer CF, et al. Clinical judgment and statistics: lessons from a simulated randomized trial in coronary artery disease. Circulation. 1980; 61:508-15.

Wood S. VITAL: No Benefits to Vitamin D and Omega-3s in Reducing Major CV Events, Cancer. TCTMD.com. Nov 10, 2018.

Neale RE, Baxter C, Romero BD, et al. The D-Health Trial: a randomised controlled trial of the effect of vitamin D on mortality. Lancet Diabetes Endocrinol. 2022;10:120-28.

Okereke OI, Reynolds CF, Mischoulon D, et al. Effect of Long-term Vitamin D3 Supplementation vs Placebo on Risk of Depression or Clinically Relevant Depressive Symptoms and on Change in Mood Scores: A Randomized Clinical Trial. JAMA. 2020;324:471-80.

LeBoff MS, Murata EM, Cook NR, et al. VITamin D and OmegA-3 TriaL (VITAL): Effects of Vitamin D Supplements on Risk of Falls in the US Population. J Clin Endocrinol Metab. 2020;105:2929-38.

Albert CM, Cook NR, Pester J, et al. Effect of Marine Omega-3 Fatty Acid and Vitamin D Supplementation on Incident Atrial Fibrillation: A Randomized Clinical Trial. JAMA. 2021;325:1061-73.

Rist PM, Buring JE, Cook NR, et al. Effect of Vitamin D and/or Marine n-3 Fatty Acid Supplementation on Changes in Migraine Frequency and Severity. Am J Med. 2021;134:756-62.

Christen WG, Cook NR, Manson JE, et al. Effect of Vitamin D and ω-3 Fatty Acid Supplementation on Risk of Age-Related Macular Degeneration: An Ancillary Study of the VITAL Randomized Clinical Trial. JAMA Ophthalmol. 2020;138:1280-89.

MacFarlane LA, Cook NR, Kim E, et al. The Effects of Vitamin D and Marine Omega-3 Fatty Acid Supplementation on Chronic Knee Pain in Older US Adults: Results From a Randomized Trial. Arthritis Rheumatol. 2020 Nov;72(11):1836-1844.

Chou SH, Murata EM, Yu C, et al. Effects of Vitamin D3 Supplementation on Body Composition in the VITamin D and OmegA-3 TriaL (VITAL). J Clin Endocrinol Metab. 2021;106:1377-88.

Kang JH, Vyas CM, Okereke OI, et al. Effect of vitamin D on cognitive decline: results from two ancillary studies of the VITAL randomized trial. Sci Rep. 2021;11:23253.

Rist PM, Buring JE, Cook NR, et al. Effect of vitamin D and/or omega‐3 fatty acid supplementation on stroke outcomes: A randomized trial. Eur J Neurol. 2021;28:809-15.

Hahn J, Cook NR, Alexander EK, et al. Vitamin D and marine omega 3 fatty acid supplementation and incident autoimmune disease: VITAL randomized controlled trial. BMJ. 2022;376:e066452

LeBoff MS, Chou SH, Murata EM, et al. Effects of Supplemental Vitamin D on Bone Health Outcomes in Women and Men in the VITamin D and OmegA-3 TriaL (VITAL). J Bone Miner Res. 2020;35:883-93.

LeBoff MS, Chou SH, Ratliff KA, et al. Supplemental vitamin D and incident fractures in midlife and older adults. NEJM. 2022;387:299-309.

Kolata G. Study finds another condition that vitamin D pills do not help. The New York Times. July 27, 2022

Jolliffe DA, Holt H, Greenig M, et al. Effect of a test-and-treat approach to vitamin D supplementa...