UPFRONT

Punctuating Equilibrium

Peter K. Kaiser, MD

Nothing is more dangerous than a dogmatic world view — nothing more constraining, more blinding to innovation, more destructive of openness to novelty.

— Stephen Jay Gould

I love this quote from one of my college professors, known for his theory of “punctuated equilibrium,” a departure from the traditional theory of the day. In punctuated equilibrium, species generally undergo minimal change for many years before a sudden event leads to a large change. In many ways, science works in this manner, with sudden leaps in knowledge resulting in entirely new levels of understanding.

According to the Guidelines for Genetic Testing from the AAO, “until clinical trials can demonstrate that AMD patients with specific genotypes benefit from specific types of therapy or exam regimens, ophthalmologists should refrain from ordering such testing for AMD patients, or patients with a family history of AMD.”

This is a reasonable stance because no FDA-approved treatments for dry AMD exist, and patients with AMD know they have it. But we also know that lifestyle modifications, especially early in life, may reduce the risk, even with a genetic predisposition.

So a 30-year-old, chain-smoking, overweight son of a patient with wet AMD certainly knows he’s at risk, but a genetic test quantifying his risk may be enough for him to “treat” himself by stopping smoking, improving his diet, and exercising more. While not FDA-approved, this “treatment” will indeed reduce his risk of AMD.

Because the AREDS formulation worked in average study patients enrolled in AREDS and wasn’t based on genotype, the AAO statement was reasonable. But the unintended consequence was the loss of reimbursement for genotyping patients, shutting down the widespread use of the test and preventing us from making the scientific leaps Professor Gould described. Without widespread genotyping, making scientific discoveries in this field is possible in certain academic institutions and will likely occur at a very slow pace.

This issue was highlighted at the recent ASRS meeting in Toronto, where a presentation showed that certain genotypes in the AREDS study benefited from taking zinc, while others were actually harmed and had a higher risk of progressing to advanced AMD when taking the AREDS formulation.

This is a huge departure from the conclusions of both the original AREDS study and the recent AREDS2 study, and if true, we have some of our patients on the wrong vitamin formulation. The only way to find out is with a genetic test that is not covered by Medicare. We can’t determine this fact by clinical examination alone.

So as retina specialists, we must now decide whether we believe the findings of this study, which will be difficult to replicate because randomizing the required number of patients to zinc or no-zinc is unlikely, as is asking our patients to pay for a test that the AAO doesn’t recommend. Or do we follow the AAO guidelines and hope the findings of the paper are wrong? How this will play out is going to very interesting.