Qiao Fan

A Comparison of Sevelamer and Calcium-Based Phosphate Binders on Mortality, Hospitalization, and Morbidity in Hemodialysis: A Secondary Analysis of the Dialysis Clinical Outcomes Revisited (DCOR) Randomized Trial Using Claims Data

BACKGROUND The Dialysis Clinical Outcomes Revisited (DCOR) trial, a large, randomized, multicenter, open-label study, compared effects of sevelamer with calcium-based phosphate binders on mortality and hospitalization in hemodialysis patients. Many patients were lost to follow-up, precluding intent-to-treat analysis by using prospective data collection. STUDY DESIGN Preplanned secondary analysis, intent-to-treat design for all outcomes, using Centers for Medicare & Medicaid Services (CMS) data. SETTING & PARTICIPANTS Participants were 18 years or older and on hemodialysis therapy for more than 3 months, with Medicare as primary payor. The trial was completed at the end of 2004. INTERVENTION Sevelamer, calcium-based phosphate binders. OUTCOMES Mortality, morbidity, and hospitalization end points. MEASUREMENTS DCOR subjects were linked to the CMS End-Stage Renal Disease database. Outcomes were evaluated through the CMS End-Stage Renal Disease enrollment and claims database; baseline characteristics and comorbid conditions were evaluated using CMS and case-report data. RESULTS Groups were well balanced except for a greater percentage of calcium-group patients with atherosclerotic heart disease. Analyses were adjusted by using 10 baseline characteristics. All-cause (17.7 versus 17.4 deaths/100 patient-years; P = 0.8 unadjusted; P = 0.9 adjusted) and cardiovascular mortality (9.0 versus 8.2 deaths/100 patient-years; P = 0.3 unadjusted; P = 0.4 adjusted) did not differ significantly between treatment groups. First hospitalization, cause-specific multiple hospitalizations, first morbidity, and multiple morbidity rates also did not differ significantly. Multiple all-cause hospitalization rate (1.7 versus 1.9 admissions/patient-year; P = 0.03 unadjusted; P = 0.02 adjusted) and hospital days (12.3 versus 13.9 days/patient-year; P = 0.05 unadjusted; P = 0.03 adjusted) were lower in the sevelamer group. LIMITATIONS Outcome parameters and cardiovascular comorbidity assessments were derived from Medicare claims data; only subjects with Medicare-as-primary-payor status were included in hospitalization and morbidity analyses. CONCLUSIONS In this secondary analysis, treatment with sevelamer versus calcium-based binders did not affect overall mortality (primary outcome), cause-specific mortality, morbidity, or first or cause-specific hospitalization (secondary outcomes), but there was evidence for a beneficial effect on multiple all-cause hospitalizations and hospital days (secondary outcomes).

Genome-wide association studies reveal genetic variants in CTNND2 for high myopia in Singapore Chinese

OBJECTIVE To determine susceptibility genes for high myopia in Singaporean Chinese. DESIGN A meta-analysis of 2 genome-wide association (GWA) datasets in Chinese and a follow-up replication cohort in Japanese. PARTICIPANTS AND CONTROLS Two independent datasets of Singaporean Chinese individuals aged 10 to 12 years (Singapore Cohort Study of the Risk factors for Myopia [SCORM]: cases = 65, controls = 238) and more than 21 years (Singapore Prospective Study Program [SP2]: cases = 222, controls = 435) for GWA studies, and a Japanese dataset aged more than 20 years (cases = 959, controls = 2128) for replication. METHODS Genomic DNA samples from SCORM and SP2 were genotyped using various Illumina Beadarray platforms (>HumanHap 500). Single-locus association tests were conducted for each dataset with meta-analysis using pooled z-scores. The top-ranked genetic markers were examined for replication in the Japanese dataset. Fisher P was calculated for the combined analysis of all 3 cohorts. MAIN OUTCOME MEASURES High myopia, defined by spherical equivalent (SE) ≤ -6.00 diopters (D); controls defined by SE between -0.50 and +1.00 D. RESULTS Two SNPs (rs12716080 and rs6885224) in the gene CTNND2 on chromosome 5p15 ranked top in the meta-analysis of our Chinese datasets (meta P = 1.14 × 10(-5) and meta P = 1.51 × 10(-5), respectively) with strong supporting evidence in each individual dataset analysis (max P = 1.85 × 10(-4) in SCORM: max P = 8.8 × 10(-3) in SP2). Evidence of replication was observed in the Japanese dataset for rs6885224 (P = 0.035, meta P of 3 datasets: 7.84 × 10(-6)). CONCLUSIONS This study identified a strong association of CTNND2 for high myopia in Asian datasets. The CTNND2 gene maps to a known high myopia linkage region on chromosome 5p15.

Application of advanced statistics in ophthalmology.

Statistics is an integral part of research in ophthalmology. The application of appropriate statistical strategies allows clinicians to realize the full potential in analyzing data from paired ocular measurements, longitudinal design, and genome-wide association study (GWAS). The increasing popularity of longitudinal follow-up in either clinical or epidemiologic study demands advanced statistical methodologies. This article describes robust statistical models that can cope with correlated components for both paired-eye data and repeated measurements over time. Also highlight are the statistical challenges and corresponding strategies available for testing multiple hypotheses with paired-eye data in GWAS, which has been the subject of intense interest for the past 5 years within the ophthalmology community in investigating the genetic etiology of eye disorders.

Genetic Variants on Chromosome 1q41 Influence Ocular Axial Length and High Myopia

As one of the leading causes of visual impairment and blindness, myopia poses a significant public health burden in Asia. The primary determinant of myopia is an elongated ocular axial length (AL). Here we report a meta-analysis of three genome-wide association studies on AL conducted in 1,860 Chinese adults, 929 Chinese children, and 2,155 Malay adults. We identified a genetic locus on chromosome 1q41 harboring the zinc-finger 11B pseudogene ZC3H11B showing genome-wide significant association with AL variation (rs4373767, β = −0.16 mm per minor allele, Pmeta = 2.69×10−10). The minor C allele of rs4373767 was also observed to significantly associate with decreased susceptibility to high myopia (per-allele odds ratio (OR) = 0.75, 95% CI: 0.68–0.84, Pmeta = 4.38×10−7) in 1,118 highly myopic cases and 5,433 controls. ZC3H11B and two neighboring genes SLC30A10 and LYPLAL1 were expressed in the human neural retina, retinal pigment epithelium, and sclera. In an experimental myopia mouse model, we observed significant alterations to gene and protein expression in the retina and sclera of the unilateral induced myopic eyes for the murine genes ZC3H11A, SLC30A10, and LYPLAL1. This supports the likely role of genetic variants at chromosome 1q41 in influencing AL variation and high myopia.

Cycloplegic refraction in preschool children: comparisons between the hand-held autorefractor, table-mounted autorefractor and retinoscopy.

Aims:  It is common for refraction to be measured using different testing methods in children, with much debate still ongoing on the preferred method. Therefore, we compared cycloplegic refraction measurements using three objective methods in a large cohort of children.

Association of variants in FRAP1 and PDGFRA with corneal curvature in Asian populations from Singapore

Corneal curvature (CC) is a key determinant of major eye diseases, such as keratoconus, myopia and corneal astigmatism. No prior studies have discovered the genes for CC. Here we report the findings from four genome-wide association studies of CC in 10 008 samples from three population groups in Singapore. Our discovery phase surveyed 2867 Chinese and 3072 Malays, allowing us to identify two loci that were associated with CC variation: FRAP1 on chromosome 1p36.2 and PDGFRA on chromosome 4q12. These findings were subsequently replicated in a validation study involving an additional 2953 Asian Indians and a further collection of 1116 Chinese children. The effect sizes of the identified variants were consistent across all four cohorts, with seven single nucleotide polymorphisms (SNPs) in FRAP1 (lead SNP: rs17036350, meta P-value = 4.06 × 10(-13)) and six SNPs in PDGFRA (lead SNP: rs2114039, meta P-value = 1.33 × 10(-9)) attaining genome-wide significance in the SNP-based meta-analysis of the four studies. This is the first genome-wide survey of CC variation and we have identified two implicated loci in three genetically diverse Asian populations, suggesting the presence of common genetic etiology across multiple populations.

Genome-Wide Meta-Analysis of Five Asian Cohorts Identifies PDGFRA as a Susceptibility Locus for Corneal Astigmatism

Corneal astigmatism refers to refractive abnormalities and irregularities in the curvature of the cornea, and this interferes with light being accurately focused at a single point in the eye. This ametropic condition is highly prevalent, influences visual acuity, and is a highly heritable trait. There is currently a paucity of research in the genetic etiology of corneal astigmatism. Here we report the results from five genome-wide association studies of corneal astigmatism across three Asian populations, with an initial discovery set of 4,254 Chinese and Malay individuals consisting of 2,249 cases and 2,005 controls. Replication was obtained from three surveys comprising of 2,139 Indians, an additional 929 Chinese children, and an independent 397 Chinese family trios. Variants in PDGFRA on chromosome 4q12 (lead SNP: rs7677751, allelic odds ratio = 1.26 (95% CI: 1.16–1.36), P meta = 7.87×10−9) were identified to be significantly associated with corneal astigmatism, exhibiting consistent effect sizes across all five cohorts. This highlights the potential role of variants in PDGFRA in the genetic etiology of corneal astigmatism across diverse Asian populations.

New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics

Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increased risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup-disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed so far. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a. In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk.

Education influences the association between genetic variants and refractive error: a meta-analysis of five Singapore studies

Refractive error is a complex ocular trait governed by both genetic and environmental factors and possibly their interplay. Thus far, data on the interaction between genetic variants and environmental risk factors for refractive errors are largely lacking. By using findings from recent genome-wide association studies, we investigated whether the main environmental factor, education, modifies the effect of 40 single nucleotide polymorphisms on refractive error among 8461 adults from five studies including ethnic Chinese, Malay and Indian residents of Singapore. Three genetic loci SHISA6-DNAH9, GJD2 and ZMAT4-SFRP1 exhibited a strong association with myopic refractive error in individuals with higher secondary or university education (SHISA6-DNAH9: rs2969180 A allele, β = -0.33 D, P = 3.6 × 10(-6); GJD2: rs524952 A allele, β = -0.31 D, P = 1.68 × 10(-5); ZMAT4-SFRP1: rs2137277 A allele, β = -0.47 D, P = 1.68 × 10(-4)), whereas the association at these loci was non-significant or of borderline significance in those with lower secondary education or below (P for interaction: 3.82 × 10(-3)-4.78 × 10(-4)). The evidence for interaction was strengthened when combining the genetic effects of these three loci (P for interaction = 4.40 × 10(-8)), and significant interactions with education were also observed for axial length and myopia. Our study shows that low level of education may attenuate the effect of risk alleles on myopia. These findings further underline the role of gene-environment interactions in the pathophysiology of myopia.

Testability of Vision and Refraction in Preschoolers: The Strabismus, Amblyopia, and Refractive Error Study in Singaporean Children

PURPOSE To determine the testability of several vision and refraction tests in preschool-aged children. DESIGN Population-based study of Chinese preschool-aged children in Singapore. METHODS One thousand five hundred and forty-two Singaporean Chinese children aged 6 to 72 months were recruited through door-to-door screening of government-subsidized apartments in Singapore. Trained eye professionals administered all tests, including monocular logarithm of the minimum angle of resolution visual acuity with the Sheridan Gardiner chart, monocular Ishihara color testing (Richmond Products Inc, Albuquerque, New Mexico, USA), biometric measurements using IOLMaster (Carl Zeiss, Jena, Germany), and Randot stereoacuity (Stereo Optical Co, Chicago, Illinois, USA) for children 30 to younger than 72 months. Cycloplegic refraction and keratometry measurements also were determined using a table-mounted autorefractor (Canon Autorefractor RK-F1; Canon, Tokyo, Japan) in children 24 to younger than 72 months. RESULTS Testabilities were 84.8% for visual acuity (40.7% for age 30 to < 36 months, 70.8% for age 36 to < 42 months, 86.7% for age 42 to < 48 months, 94.8 for age 48 to < 54 months, 98.6 for age 54 to < 66 months, and 98.7% for age 66 to < 72 months), 81.1% for the Ishihara color test, 82.2% for Randot stereoacuity, 62.2% for table mounted autorefraction, and 91.7% for IOLMaster. All testabilities significantly increased with age (P < .0001). Girls had higher testability rates than boys for the autorefraction and Randot stereoacuity tests (P = .036 and .008, respectively). CONCLUSIONS The vision and refraction tests were testable in a high proportion of preschool-aged Chinese Singaporeans. Preschool children in older age groups are likely to complete these tests successfully, with important implications for determining age limits for screening in the community and clinic.