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In the news: Genetic Tests Don't Predict Response to Supplementation in AMD

Results from independent analyses of the Age-related Eye Disease Study (AREDS) indicate that no genetic testing is needed before offering zinc and antioxidants to AMD patients who meet the criteria for AREDS supplementation (1). These results appeared online Oct 9th, ahead of print in the journal Ophthalmology.

Genetics & AREDS Supplements: The Controversy

Whether or not genotyping should be considered for AMD patients who are eligible for AREDS supplementation has been controversial. In brief, Awh et al. have reported an adverse interaction between CFH risk alleles and high dose zinc in analyses of AREDS data, concluding that patients with certain genotypes should receive antioxidants alone.

In contrast, reanalysis by the original AREDS authors Chew et al, failed to find that genotype predicts treatment effect, and concluded that combined zinc and antioxidants reduced the rate of AMD progression across all genotype groups.

To help resolve this debate, the Office of Intramural
Research at the NIH asked three separate bio-statistical groups to reexamine the data used by Awh et al. and Chew et al. to determine whether genotype predicts response to supplements in AMD. Data from both groups were provided to biostatisticians at Duke University, MD Anderson Cancer Center, and Memorial Sloan Kettering Cancer Center, all of whom remained anonymous to Awh, Chew, and their colleagues.

Participants and Methods

The population of interest was genotyped AREDS participants with AMD worse than category 1. Though the data provided by the Awh and Chew groups did not overlap perfectly, the same CFH and ARMS2 single nucleotide polymorphisms were measured by both groups in a dataset involving 879 participants.

Each statistical group took a separate but complementary approach. The MD Anderson Cancer Center group focused on checking data and evaluating the concordance between different data sets.

The Duke University group’s role was to replicate the key findings of Awh et al concerning interactions between genotype and outcome. The Sloan Kettering group took a blank slate approach, using all baseline data, including both clinical variables and genotype data, to determine whether benefit from treatment could be predicted.

Results

• Errors were found in the data used to support the claim of genotype-treatment interaction.
• Though evidence was found that high-risk patients had more to gain from treatment, analysis of all 11 of the genotypes examined by Awh et al. showed no significant interactions after adjusting for multiple testing.
• Even when assuming that interactions did in fact exist, the statisticians found no evidence to support the claim that supplementation leads to a large increase in risk of advanced AMD in some genotype sub-groups.

Conclusion

All three statistical groups concluded that genotyping of CFH and ARMS2 to guide AREDS supplement choice for the prevention of AMD progression is unwarranted.

Comments

One issue raised by the authors of this paper is the lack of adjustment for multiple testing by Awh et al - a fundamental and uncontroversial aspect of statistical methodology, especially when analyzing genetic data.

Notably, the authors also remind us of a well-accepted principle: conclusions based upon retrospective analysis of a single study require validation in a prospective study. Those who advocate genetic testing would do well to collect and analyze new data because currently “we do not have good reason to believe that genotyping will do more good than harm,” according to this study’s authors.

References

1. Assel MJ, et al. Genetic polymorphisms of CFH and ARMS2 do not predict response to antioxidants and zinc in patients with age-related macular degeneration. Ophthalmol. Epub ahead of print, Oct 9, 2017.