On the Nature of Evidence and ‘Proving’ Causality: Smoking and Lung Cancer vs. Sun Exposure, Vitamin D and Multiple Sclerosis

Abstract

If environmental exposures are shown to cause an adverse health outcome, reducing exposure should reduce the disease risk. Links between exposures and outcomes are typically based on ‘associations’ derived from observational studies, and causality may not be clear. Randomized controlled trials to ‘prove’ causality are often not feasible or ethical. Here the history of evidence that tobacco smoking causes lung cancer—from observational studies—is compared to that of low sun exposure and/or low vitamin D status as causal risk factors for the autoimmune disease, multiple sclerosis (MS). Evidence derives from in vitro and animal studies, as well as ecological, case-control and cohort studies, in order of increasing strength. For smoking and lung cancer, the associations are strong, consistent, and biologically plausible—the evidence is coherent or ‘in harmony’. For low sun exposure/vitamin D as risk factors for MS, the evidence is weaker, with smaller effect sizes, but coherent across a range of sources of evidence, and biologically plausible. The association is less direct—smoking is directly toxic and carcinogenic to the lung, but sun exposure/vitamin D modulate the immune system, which in turn may reduce the risk of immune attack on self-proteins in the central nervous system. Opinion about whether there is sufficient evidence to conclude that low sun exposure/vitamin D increase the risk of multiple sclerosis, is divided. General public health advice to receive sufficient sun exposure to avoid vitamin D deficiency (<50 nmol/L) should also ensure any benefits for multiple sclerosis, but must be tempered against the risk of skin cancers.

Environmental and genetic risk factors for MS: an integrated review

“…Within White populations, the dose–response relationship is inconsistent; for example, both threshold (e.g. protective only at 25OHD levels >99 nmol/L or increased risk only for the lowest quintile of 25OHD) and linear effects are described . These inconsistent associations may be because few studies have accounted for sun exposure.…”

The Determinants of Economic Freedom: A Survey

“…To underscore this, consider that at the time of tobacco litigation in the United States and its concurrent public debate, the quality of much of the evidence showing a link between tobacco use and cancer was “merely” observational (Ong and Glantz ; Samet and Burke ; c.f. Lucas and Rodney Harris ). To claim that quasi‐experimental methodology is the minimal quality of identification that one should accept for social scientific research is to repudiate the rationale for the broad conclusions of that public debate.…”

A Narrative Review of the Evidence for Variations in Serum 25-Hydroxyvitamin D Concentration Thresholds for Optimal Health

“…Many types of studies are used to help determine whether a factor modifies disease risks (incidence, survival, and/or mortality rates). A typical evidence pyramid published in 2018 showed a hierarchy with in vitro studies at the bottom, progressing upward with animal, ecological, cross-sectional, case-control studies, and randomized controlled trials (RCTs) with meta-analyses of RCTs at its apex [ 114 ]. Although this pyramid is appropriate for pharmaceutical drugs, it has various limitations when applied to nutrients.…”