Extremely Discordant Sib-Pair Study Design to Determine Risk Factorsfor Neovascular Age-Related Macular Degeneration

DeAngelis, Margaret M.; Lane, Anne Marie; Shah, Chirag P.; Ott, Jürg; Dryja, Thaddeus P.; Miller, Joan W.

doi:10.1001/archopht.122.4.575

Cited by 46 publications

(45 citation statements)

References 15 publications

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“…A multi-factor model was then constructed using risk factors that were suggestive of association with need for laser treatment, defined as P < 0.1 in the single factor analysis. In order to create the most parsimonious statistical model predictive of the need for laser treatment of ROP, a second multifactor model was constructed using risk factors that remained significant after the initial multifactor model, as performed in previous epidemiologic papers 19. The Students’ t -test was used to determine if there was a significant difference in mean birth weight between the natural conception and ART groups, and the Mann–Whitney U test was used to analyze mean gestational ages between infants requiring laser in the two groups.…”

Section: Methodsmentioning

confidence: 99%

Association between assisted reproductive technology and advanced retinopathy of prematurity

Chan¹,

Yonekawa²,

Morrison³

et al. 2010

OPTH

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PurposeTo investigate the associations between assisted reproductive technology (ART) and severe retinopathy of prematurity (ROP) requiring treatment.MethodsRetrospective analyses of inborn preterm infants screened for severe ROP at the Weill Cornell Medical Center Neonatal Intensive Care Unit at the New York-Presbyterian Hospital by single factor logistic regression and multifactor models.ResultsOf 399 ethnically diverse infants, 253 were conceived naturally and 146 by ART. Eight (3.16%) patients conceived naturally, and 11 (7.53%) with ART required laser treatment. In multifactor analyses, significant risks for severe ROP requiring treatment included both gestational age (odds ratio [OR] 0.34; 95% confidence interval [CI] 0.23–0.52; P < 0.001) and ART ([OR] 4.70; [CI], 1.52–4.57; P = 0.007).ConclusionsART is associated with severe ROP requiring treatment in this cohort. This is the first report that demonstrates a statistically significant association between ART and severe ROP requiring treatment in infants in the US.

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Section: Methodsmentioning

confidence: 99%

Association between assisted reproductive technology and advanced retinopathy of prematurity

Chan¹,

Yonekawa²,

Morrison³

et al. 2010

OPTH

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“…20 In brief, index patients with neovascular AMD were recruited from the Retina Service of the Massachusetts Eye and Ear Infirmary and Associated Retina Consultants at the Beaumont Hospital. All index patients were 50 years or older and had the neovascular form of AMD in at least one eye, defined by subretinal hemorrhage, fibrosis, or fluorescein angiographic presence of neovascularization documented at the time of or before enrollment in the study.…”

Section: Patient Populationmentioning

confidence: 99%

Alleles in the HtrA Serine Peptidase 1 Gene Alter the Risk of Neovascular Age-Related Macular Degeneration

DeAngelis

Adams

et al. 2008

Ophthalmology

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Objective-To examine if the genes encoding the pleckstrin homology domain-containing protein gene (PLEKHA1), hypothetical LOC387715/ARMS2 gene, and HtrA serine peptidase 1 gene (HTRA1) located on the long arm of chromosome 10 (10q26 region) confer risk for neovascular age-related macular degeneration (AMD) in an independent or interactive manner when controlling for complement factor H gene (CFH) genotype and smoking exposure.Design-Retrospective matched-pair case-control study.Participants-Hospital clinic-based sample of 134 unrelated patients with neovascular AMD who have a sibling with normal maculae (268 subjects).Methods-Disease status was ascertained by at least 2 investigators by review of fundus photographs and/or fluorescein angiography according to the Age-Related Eye Disease Study grading scale. If necessary, a home retinal examination was performed (n = 6). A combination of direct sequencing and analysis of 8 highly polymorphic microsatellite markers was used to genotype 33 megabases of the 10q26 region on leukocyte DNA. Smoking history was obtained via a standardized questionnaire and measured in pack-years. The family-based association test, haplotype analysis, multiple conditional logistic regression, and linkage analysis were used to determine significant associations. Main Outcome Measure-Neovascular AMD status.Results-Of the 23 variants we identified in the 10q26 region, 6 were significant. Four of the 6 were novel and included 2 genotypes that reduced risk of AMD. Many single-nucleotide polymorphisms (SNPs), including the previously reported variants rs10490924 (hypothetical NIH Public Access Author ManuscriptOphthalmology. Author manuscript; available in PMC 2014 November 24. Published in final edited form as:Ophthalmology. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptLOC387715/ARMS2) and rs11200638 (HTRA1), defined 2 significant haplotypes associated with increased risk of neovascular AMD. The coding HTRA1 SNP rs2293870, not part of the significant haplotypes containing rs10490924 and rs11200638, showed as strong an association with increased susceptibility to neovascular AMD. Linkage analysis supported our findings of SNP association (P<10 −15 ). No significant interactions were found between any of the SNPs in the 10q26 and smoking or between these SNPs and CFH genotype.Conclusions-Independent of CFH genotype or smoking history, an individual's risk of AMD could be increased or decreased, depending on their genotype or haplotype in the 10q26 region.Neovascular age-related macular degeneration (AMD) is characterized by the growth of abnormal new blood vessels beneath the retina that can cause severe and rapid vision loss due to hemorrhage and exudation. It is this more advanced form that is responsible for the majority of debilitating vision loss due to AMD. In the United States, it is predicted that about 3 million individuals over the age of 50 will have advanced AMD in at least one eye by 2020. 1Current diagnostic methods focus on the detection of ne...

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“…This paper addresses three features related to the design of studies using DNA sequencing to study rare variants: the samples used for variant discovery, selection of specific genes and variants for follow-up, and replication of putative genotype-phenotype relationships in independent samples. We focus on one widely discussed design feature: the ascertainment of samples from the extremes of a population distribution [Ahituv et al, 2007;Bell et al, 2007;Cohen et al, 2004;DeAngelis et al, 2004;Kryukov et al, 2009;Mohammadi et al, 2009;Nebert 2000;PerezGracia et al, 2002;Zhang, 1995, 1996;Romeo et al, 2007] (previously referred to as ''selective genotyping'') [Lander and Botstein, 1989;Van Gestel et al, 2000]. Intuitively, ascertainment of samples from the extremes of phenotype should enrich for the burden of alleles influencing a trait, thus improving power to discover risk variants and to detect their association to phenotype.…”

Section: Introductionmentioning

confidence: 99%

Power in the phenotypic extremes: a simulation study of power in discovery and replication of rare variants

Guey

Kravić

Melander

et al. 2011

Genetic Epidemiology

107

104

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Next-generation sequencing technologies are making it possible to study the role of rare variants in human disease. Many studies balance statistical power with cost-effectiveness by (a) sampling from phenotypic extremes and (b) utilizing a two-stage design. Two-stage designs include a broad-based discovery phase and selection of a subset of potential causal genes/variants to be further examined in independent samples. We evaluate three parameters: first, the gain in statistical power due to extreme sampling to discover causal variants; second, the informativeness of initial (Phase I) association statistics to select genes/variants for follow-up; third, the impact of extreme and random sampling in (Phase 2) replication. We present a quantitative method to select individuals from the phenotypic extremes of a binary trait, and simulate disease association studies under a variety of sample sizes and sampling schemes. First, we find that while studies sampling from extremes have excellent power to discover rare variants, they have limited power to associate them to phenotype—suggesting high false-negative rates for upcoming studies. Second, consistent with previous studies, we find that the effect sizes estimated in these studies are expected to be systematically larger compared with the overall population effect size; in a well-cited lipids study, we estimate the reported effect to be twofold larger. Third, replication studies require large samples from the general population to have sufficient power; extreme sampling could reduce the required sample size as much as fourfold. Our observations offer practical guidance for the design and interpretation of studies that utilize extreme sampling.

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Extremely Discordant Sib-Pair Study Design to Determine Risk Factorsfor Neovascular Age-Related Macular Degeneration

Cited by 46 publications

References 15 publications

Association between assisted reproductive technology and advanced retinopathy of prematurity

Association between assisted reproductive technology and advanced retinopathy of prematurity

Alleles in the HtrA Serine Peptidase 1 Gene Alter the Risk of Neovascular Age-Related Macular Degeneration

Power in the phenotypic extremes: a simulation study of power in discovery and replication of rare variants

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