Oedipus's dilemma

I love Greek mythology, and of all myths, Oedipus is probably the one that fascinates me the most. Nothing to do with the fact that it's become a psychiatric hallmark. I love this myth because it always makes me wonder: if somebody came to you and told you they knew with absolute certainty your future (how many years you'll live, what you'll accomplish, etc.), would you want to know? It's a paradox, because that knowledge would affect the future course of action you choose. Think about Laius: he fulfilled his destiny exactly because of the actions he took in order to avoid his destiny. Predestination paradoxes have been used forever in all mythologies, and even these days -- can you think of at least a novel or a movie where it's been used?

I'm rambling, but I actually have a point for this post, I promise.

As you know, nobody's going to come and offer to tell you your exact destiny. But, they might offer to type your entire genome. And from that, they may argue they can tell you the exact risk you have of developing certain diseases. In fact, some of you may already have opted to have their entire genome typed. Such services have become more affordable, accurate, and efficient in just a handful of years. The benefits are numerous: drug therapy could be genetically targeted, and just by looking at your DNA your doctor could already know which drugs will be more effective and which could instead have adverse effects. Assessing one's risk for cancer, diabetes, or other diseases can be a good motivator to a healthier lifestyle and open up preventive treatment choices.

So, where's the catch?

The catch is that, as a new study on Science Translational Medicine shows [1], sequencing the entire genome doesn't tell us the whole story. In fact, in many cases, it doesn't tell us much at all.

Roberts et al. argue that the risk we need to be able to assess should be pretty strong in order to make preventive measures effective. For example, currently the general population risk of developing breast cancer within a woman's lifetime is 12%, obviously too low for women to opt for a preventive mastectomy. However, if a woman learned that her risk was 90%, she might reconsider. Any preventive measure carries consequences, and therefore, the risk reduction it ensures should be pretty strong in order to establish clinical utility.

After setting a meaningful risk threshold, Roberts et al. collected genetic data from numerous homozygous twin registries and cohorts. (Little pet peeve of mine: couldn't find the exact number of pairs they had in the study, it's probably in the supplemental material, but I find sample size important enough to expect it in the main text). They then developed a mathematical model to estimate the maximum capacity of whole-genome sequencing to predict the risk for 24 common diseases, including autoimmune diseases, cancer, cardiovascular diseases, genito-urinary diseases, neurological diseases, and obesity-associated diseases. The idea behind the mathematical model is to assess the risk increment of an individual with a disease-associated genotype compared to someone with no genetic risk at all. Since homozygous twins have nearly identical genomes, you would expect their genetic risks to have a nearly identical outcome.

"The general public does not appear to be aware that, despite their very similar height and appearance, monozygotic twins in general do not always develop or die from the same maladies. This basic observation, that monozygotic twins of a pair are not always afflicted by the same maladies, combined with extensive epidemiologic studies of twins and statistical modeling, allows us to estimate upper and lower bounds of the predictive value of whole-genome sequencing."

Using their model, the researchers showed that most individuals would show a risk predisposition to at least one of the 24 diseases tested. At the same time, they would test negative for most diseases. What does this mean? It means that we cannot predict the risk allele distribution of the actual population, and most often genetic testing will only say that individual X has the same risk of developing disease Y as the general population -- hardly enough to make whole genome testing surpass the clinical utility threshold.

"Thus, our results suggest that genetic testing, at its best, will not be the dominant determinant of patient care and will not be a substitute for preventative medicine strategies incorporating routine checkups and risk management based on the history, physical status, and life-style of the patient."

[1] Nicholas J. Roberts, Joshua T. Vogelstein, Giovanni Parmigiani, Kenneth W. Kinzler, Bert Vogelstein1 and, & Victor E. Velculescu (2012). The Predictive Capacity of Personal Genome Sequencing Sci Transl Med 4, 133ra58 DOI: 10.1126/scitranslmed.3003380