Correlation without a cause: an epidemiological odyssey

Background: In the 1980s debate intensified over whether there was a protective effect
of high-density lipoprotein cholesterol (HDL-C) or an adverse effect of triglycerides on
coronary heart disease (CHD) risk. In a 1991 paper reprinted in the IJE we suggested that
the high degree of correlation between the two, together with plausible levels of measurement error, made it unlikely that conventional epidemiological approaches could
contribute to causal understanding. The consensus that HDL-C was protective, popularly
reified in the notion of ‘good cholesterol’, strengthened over subsequent years.
Reviewing the biostatistical and epidemiological literature from before and after 1991 we
suggest that within the observational epidemiology pantheon only Mendelian randomization studies—that began to appear at the same time as the initial negative randomized
controlled trials—made a meaningful contribution. It is sobering to realize that many
issues that appear suitable targets for epidemiological investigation are simply refractory
to conventional approaches. The discipline should surely revisit this and other highprofile cases of consequential epidemiological failure—such as that with respect to vitamin E supplementation and CHD risk—rather than pass them over in silence.