scholarly journals Improved Score Statistics for Meta-analysis in Single-variant and Gene-level Association Studies

2017 ◽  
Author(s):  
Jingjing Yang ◽  
Sai Chen ◽  
Gonçalo Abecasis ◽  
Keyword(s):  
Power Loss ◽  
Association Studies ◽  
Meta Analysis ◽  
Genetic Association Studies ◽  
Age Related Macular Degeneration ◽  
Joint Analysis ◽  
Analysis Methods ◽  
Age Related ◽  
Score Statistics ◽  
Gene Level

AbstractMeta-analysis is now an essential tool for genetic association studies, allowing these to combine large studies and greatly accelerating the pace of genetic discovery. Although the standard meta-analysis methods perform equivalently as the more cumbersome joint analysis under ideal settings, they result in substantial power loss under unbalanced settings with various case-control ratios. Here, we investigate why the standard meta-analysis methods lose power under unbalanced settings, and further propose a novel meta-analysis method that performs as efficiently as joint analysis under general settings. Our proposed method can accurately approximate the score statistics obtainable by joint analysis, for both linear and logistic regression models, with and without covariates. In addition, we propose a novel approach to adjust for population stratification by correcting for known population structures through minor allele frequencies (MAFs). In the simulated gene-level association studies under unbalanced settings, our method recovered up to 85% power loss caused by the standard method. We further showed the power gain of our method in gene-level association studies with 26 unbalanced real studies of Age-related Macular Degeneration (AMD). In addition, we took the meta-analysis of three studies of type 2 diabetes (T2D) as an example to discuss the challenges of meta-analyzing multi-ethnic samples. In summary, we propose improved single-variant score statistics in meta-analysis, requiring “accurate” population-specific MAFs for multi-ethnic studies. These improved score statistics can be used to construct both single-variant and gene-level association studies, providing a useful framework for ensuring well-powered, convenient, cross-study analyses.

scholarly journals A Validated Phenotyping Algorithm for Genetic Association Studies in Age-related Macular Degeneration

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Joseph M. Simonett ◽  
Mahsa A. Sohrab ◽  
Jennifer Pacheco ◽  
Loren L. Armstrong ◽  
Margarita Rzhetskaya ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Genetic Association ◽  
Association Studies ◽  
Genetic Association Studies ◽  
Age Related Macular Degeneration ◽  
Age Related

scholarly journals Big DNA as a tool to dissect an age-related macular degeneration-associated haplotype

2018 ◽  
Author(s):  
Jon M Laurent ◽  
Xin Fu ◽  
Sergei German ◽  
Matthew T Maurano ◽  
Kang Zhang ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Association Studies ◽  
Genetic Association Studies ◽  
Cell Types ◽  
Difficult Problem ◽  
Age Related Macular Degeneration ◽  
Functional Sites ◽  
Functional Variants ◽  
Age Related ◽  
Aging Populations

AbstractAge-related Macular Degeneration (AMD) is a leading cause of blindness in the developed world, especially in aging populations, and is therefore an important target for new therapeutic development. Recently, there have been several studies demonstrating strong associations between AMD and sites of heritable genetic variation at multiple loci, including a highly significant association at 10q26. The 10q26 risk region contains two genes, HTRA1 and ARMS2, both of which have been separately implicated as causative for the disease, as well as dozens of sites of non-coding variation. To date, no studies have successfully pinpointed which of these variant sites are functional in AMD, nor definitively identified which genes in the region are targets of such regulatory variation. In order to efficiently decipher which sites are functional in AMD phenotypes, we describe a general framework for combinatorial assembly of large ‘synthetic haplotypes’ along with delivery to relevant disease cell types for downstream functional analysis. We demonstrate the successful and highly efficient assembly of a first-draft 119kb wild-type ‘assemblon’ covering the HTRA1/ARMS2 risk region. We further propose the parallelized assembly of a library of combinatorial variant synthetic haplotypes covering the region, delivery and analysis of which will identify functional sites and their effects, leading to an improved understanding of AMD development. We anticipate that the methodology proposed here is highly generalizable towards the difficult problem of identifying truly functional variants from those discovered via GWAS or other genetic association studies.

Potentiality of Risk SNPs identification Based on GSP Theory

2020 ◽  
Vol 15 ◽  
Author(s):  
Hengyi Zhang ◽  
Qinli Zhang
Keyword(s):  
Association Studies ◽  
Experimental Results ◽  
Age Related Macular Degeneration ◽  
Joint Analysis ◽  
Genome Wide Association Studies ◽  
Lasso Regression ◽  
Chi Square ◽  
Age Related ◽  
Chi Square Test ◽  
Risk Snps

Background: A large number of studies have shown that susceptibility to diseases may be related to some Single Nucleotide Polymorphisms (SNPs). Therefore, the location of SNPs associated with diseases in genes can help us understand the genetic mechanism of disease, intervene in risk SNPs and prevent some genetic diseases/ Method: Based on Graph Signal Processing (GSP) theory, a novel method is proposed to locate the risk SNPs in this paper. The proposed method first builds the graph signal model of all SNP loci, and then realizes the location of abnormal SNPs (risk SNPs) based on the joint analysis of vertex domain and frequency domain of graph Results: The experimental results on synthetic datasets show that our method outperforms many existing methods, including BOOST, SNPHarvester, SNPRule, Random Forest (RF), Chi-square Test and LASSO regression in terms of power. The experimental results on two real Genome-Wide Association Studies (GWAS) datasets, Age-related Macular Degeneration (AMD) and Genetic Disease A (GDA), show that our method not only finds the risk SNPs found by several state-of-the-art methods, including RF, Chi-square Test and LASSO regression, but also discovers three potential risk SNPs. Conclusion: Our method is suitable and effective for the identification of risk SNPs in GWAS.

scholarly journals Improved score statistics for meta-analysis in single-variant and gene-level association studies

2018 ◽  
Vol 42 (4) ◽  
pp. 333-343 ◽  
Author(s):  
Jingjing Yang ◽  
Sai Chen ◽  
Gonçalo Abecasis ◽  
Keyword(s):  
Association Studies ◽  
Meta Analysis ◽  
Score Statistics ◽  
Gene Level

scholarly journals Comparative efficacy and safety of different regimens of ranibizumab for neovascular age-related macular degeneration: a network meta-analysis of randomised controlled trials

BMJ Open ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. e040906
Author(s):  
Xinyu Zhao ◽  
Lihui Meng ◽  
Youxin Chen
Keyword(s):  
Adverse Events ◽  
Macular Degeneration ◽  
Randomised Controlled Trials ◽  
Meta Analysis ◽  
Age Related Macular Degeneration ◽  
Controlled Trials ◽  
Cochrane Central Register ◽  
Efficacy And Safety ◽  
Age Related ◽  
Randomised Controlled

ObjectiveTo give a comprehensive efficacy and safety ranking of different therapeutic regimens of ranibizumab for neovascular age-related macular degeneration (nAMD).DesignA systematic review and network meta-analysis.MethodsThe PubMed, Embase, Cochrane Central Register of Controlled Trials, and other clinical trial registries were searched up to 1 October 2019 to identify related randomised controlled trials (RCT) of different regimens of ranibizumab for nAMD. The primary efficacy outcome was the changes of best-corrected visual acuity (BCVA) at 1 year, the primary safety outcome was the incidence of severe ocular adverse events. Secondary outcomes such as changes of central retinal thickness (CRT) were evaluated. We estimated the standardised mean difference (SMD), ORs, 95% CIs, the surface under the cumulative ranking curves and the mean ranks for each outcome using network meta-analyses with random effects by Stata 14.0.ResultsWe identified 26 RCTs involving 10 821 patients with nAMD randomly assigned to 21 different therapeutic regimens of ranibizumab or sham treatment. Ranibizumab 0.5 mg (treat and extend, T&E) is most effective in terms of changes of BCVA (letters, SMD=21.41, 95% CI 19.86 to 22.95) and three or more lines of BCVA improvement (OR=2.83, 95% CI 1.27 to 4.38). However, it could not significantly reduce retreatment times compared with monthly injection (SMD=−0.94, 95% CI −2.26 to 0.39). Ranibizumab 0.5 mg (3+pro re nata)+non-steroidal anti-inflammatory drugs (NSAIDs) is most effective in reducing CRT and port delivery system of ranibizumab (100 mg/mL) could reduce the number of retreatment most significantly. All regimes have no more risk of severe ocular complications (including vitreous haemorrhage, rhegmatogenous retinal detachment, endophthalmitis, retinal tear and retinal pigment epithelium tear) or cardiocerebral vascular complications.ConclusionsRanibizumab 0.5 mg (T&E) is most effective in improving the visual outcome. The administration of topical NSAIDs could achieve additional efficacy in CRT reduction and visual improvement. Both interventions had acceptable risks of adverse events.

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