26 May 2016 10:00am

Heritability, OPERA and ICE FALCON: thoughts on causation, and causes of variation in (some aspect of a) disease


Heritability, as a measure of (relative) variation in genetic causes, has been well-defined for a continuous trait for nearly a century, with wise caveats from its inventor, R.A. Fisher. Extension of this concept to a binary trait by invoking an unmeasured ‘liability’ construct has been widely used, even for genome-wide association studies, yet I will show that it is meaningless and does not mean what I think its users intend it to mean, let alone justify the ‘message’ they convey. OPERA (Odds PER Adjusted standard deviation) is a way of determining the extent to which a risk factor differentiates cases from controls for continuous, binary and other quantitative traits, that takes into account other factors implicit in study design and analysis. The increased risk of having an affected MZ twin is a better measure of the potential of genetic factors to ‘explain’ variation in disease incidence across the population than ‘heritability’. ICE FALCON (Inference about Causation from Examination of FAmiliaL CONfounding) is a way of testing the null hypothesis of no direct causation using data on exposure and outcome from pairs of individuals who are correlated in their exposure, such as twin pairs. This work intends to reorientate twin research away from naïve and misunderstood concepts of ‘nature versus nurture’ so as to inform 21st century health and medical research in novel and insightful ways not possible otherwise.