Density Complex Ocular Traits Figure 1. Scatter plot showing the density (number of distinct traits per patient) of the 10 complex ocular traits listed in Table 1 versus age for all 100 patients. A, The plotted points are the observed data and the line depicts the modeled relationship between age and density. B, The modeled probability of patients having AMD and glaucoma as a function of age using the logistic regression model. doi:10.1371/journal.pone.0002510.g001 Additional concerns in the use of case-control studies are the potential for selection bias and the possibility of confounding due to unmeasured differences between case and control status that are associated with genetic exposures. One manner is which this could arise might be from referral patterns to the specific physicians from which the case or control subjects are being collected. Thus, an additional benefit of documentation of secondary complex traits affecting the eye would be to account for such effects using standard statistical techniques. At this time it is largely unknown if this type of confounding exists in genetic association studies of ophthalmic or other traits. Thus, our identification of association between vitreomacular traction and AMD is of particular interest. The observation that patients with vitreomacular traction were less likely to have AMD, was unexpected because previous studies have suggested it might be a risk factor for exudative AMD [11,13,29]. Our observation likely is due to referral biases, where patients with vitreomacular traction who also had AMD were not referred for surgical management. Even though the examiner of the 100 consecutive subjects in this study routinely documents all ocular traits including the ten in Table 1, we recognize that traits are missed due to the distractions that occur in a busy clinic. Thus, our estimate of the density of common complex traits is very likely under-estimated. Prospective examination with photographic documentation and quantitative Table 3. Odds-ratio for association between genotypes and traits that might be detected with a power of 0.8 at the specified minor allele frequency. Complex ocular trait* Number with trait Number without trait Odds-ratio** at a minor allele frequency of 0.1 *** Odds-ratio at a minor allele frequency of 0.2*** Odds-ratio at a minor allele frequency of 0.4*** 0.001 0.00001 0.001 0.00001 0.001 0.00001 ABMD Fuchs Cataract PXE Glaucoma PVD AMD VMT RVO Retinal tears 20 140 1920 60 240 1080 1080 400 140 100 1980 1860 80 1940 1760 920 920 1600 1860 1900 *Abbreviations and definitions are given in Table 1. **Power was estimated assuming a log-additive genetic model, significance levels of 0.05, 0.001, and 0.00001, complete linkage disequilibrium between the single nucleotide polymorphism (SNP) studied and the genetic variant underlying the association, and the population prevalence estimates shown in Table 1. ***The three significance levels, namely 0.05, 0.001, and 0.00001, refer to testing one variant, multiple variants in a single gene, and variants across the genome, respectively. doi:10.1371/journal.pone.0002510.t003 PLoS ONE | www.plosone.org 4 June 2008 | Volume 3 | Issue 6 | e2510 0.05 3.25 1.70 2.25 2.10 1.55 1.35 1.35 1.45 1.70 1.80 5.20 2.10 3.60 2.80 1.80 1.60 1.55 1.65 2.05 2.30 7.90 2.60 5.80 3.60 2.10 1.80 1.70 1.90 2.45 2.80 0.05 2.70 1.50 1.80 1.80 1.40 1.25 1.25 1.35 1.50 1.60 4.10 1.80 2.45 2.35 1.60 1.40 1.40 1.50 1.80 2.00 6.10 2.10 3.25 2.90 1.80 1.55 1.50 1.65 2.10 2.35 0.05 2.50 1.45 1.60 1.70 1.35 1.20 1.20 1.25 1.45 1.50 4.00 1.70 2.15 2.15 1.50 1.30 1.30 1.40 1.70 1.85 6.30 1.95 2.50 2.70 1.70 1.45 1.40 1.55 1.95 2.15