scholarly journals Simulation and Sensitivity Analysis and Cross-Validation, Demonstrating the Utility of Genteract GxE Discovery methods

2020 ◽  
Author(s):  
Brody Holohan ◽  
Raphael Laderman

AbstractGene-environment interactions are at the heart of why many complex traits are not fully heritable, and why prediction of disease incidence and individual response to environmental changes based on genetics has been underwhelming in utility. Understanding these interactions is the primary limiting factor for the application of personalized medicine, but current methods are not well suited for dealing with complex traits that pose both a dimensionality and sparse data problem to unsupervised analysis methods. Genteract has developed a proprietary analytical technique that allows for detection and interpretation of GxEs regarding specific pairs of a single phenotype with a single environmental factor; these methods allow us to develop a platform that can be used to predict how individuals will respond to changes in their environment based on their genetics. To validate the methods we performed two types of testing: cross-validation against a dataset of clinical study results, and application of the methods in a simulated dataset. These tests enable a greater understanding of the methods’ utility, statistical power and predictive capabilities.

2016 ◽  
Author(s):  
Danny S. Park ◽  
Itamar Eskin ◽  
Eun Yong Kang ◽  
Eric R. Gamazon ◽  
Celeste Eng ◽  
...  

IAbstractBackground:Epistasis and gene-environment interactions are known to contribute significantly to variation of complex phenotypes in model organisms. However, their identification in human association studies remains challenging for myriad reasons. In the case of epistatic interactions, the large number of potential interacting sets of genes presents computational, multiple hypothesis correction, and other statistical power issues. In the case of gene-environment interactions, the lack of consistently measured environmental covariates in most disease studies precludes searching for interactions and creates difficulties for replicating studies.Results:In this work, we develop a new statistical approach to address these issues that leverages genetic ancestry in admixed populations. We applied our method to gene expression and methylation data from African American and Latino admixed individuals respectively, identifying nine interactions that were significant at p < 5×10−8, we show that two of the interactions in methylation data replicate, and the remaining six are significantly enriched for low p-values (p < 1.8×10−6).Conclusion:We show that genetic ancestry can be a useful proxy for unknown and unmeasured covariates in the search for interaction effects. These results have important implications for our understanding of the genetic architecture of complex traits.


Author(s):  
Andrey Ziyatdinov ◽  
Jihye Kim ◽  
Dmitry Prokopenko ◽  
Florian Privé ◽  
Fabien Laporte ◽  
...  

Abstract The effective sample size (ESS) is a metric used to summarize in a single term the amount of correlation in a sample. It is of particular interest when predicting the statistical power of genome-wide association studies (GWAS) based on linear mixed models. Here, we introduce an analytical form of the ESS for mixed-model GWAS of quantitative traits and relate it to empirical estimators recently proposed. Using our framework, we derived approximations of the ESS for analyses of related and unrelated samples and for both marginal genetic and gene-environment interaction tests. We conducted simulations to validate our approximations and to provide a quantitative perspective on the statistical power of various scenarios, including power loss due to family relatedness and power gains due to conditioning on the polygenic signal. Our analyses also demonstrate that the power of gene-environment interaction GWAS in related individuals strongly depends on the family structure and exposure distribution. Finally, we performed a series of mixed-model GWAS on data from the UK Biobank and confirmed the simulation results. We notably found that the expected power drop due to family relatedness in the UK Biobank is negligible.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Chao-Yu Guo ◽  
Reng-Hong Wang ◽  
Hsin-Chou Yang

AbstractAfter the genome-wide association studies (GWAS) era, whole-genome sequencing is highly engaged in identifying the association of complex traits with rare variations. A score-based variance-component test has been proposed to identify common and rare genetic variants associated with complex traits while quickly adjusting for covariates. Such kernel score statistic allows for familial dependencies and adjusts for random confounding effects. However, the etiology of complex traits may involve the effects of genetic and environmental factors and the complex interactions between genes and the environment. Therefore, in this research, a novel method is proposed to detect gene and gene-environment interactions in a complex family-based association study with various correlated structures. We also developed an R function for the Fast Gene-Environment Sequence Kernel Association Test (FGE-SKAT), which is freely available as supplementary material for easy GWAS implementation to unveil such family-based joint effects. Simulation studies confirmed the validity of the new strategy and the superior statistical power. The FGE-SKAT was applied to the whole genome sequence data provided by Genetic Analysis Workshop 18 (GAW18) and discovered concordant and discordant regions compared to the methods without considering gene by environment interactions.


Biostatistics ◽  
2017 ◽  
Vol 18 (3) ◽  
pp. 477-494 ◽  
Author(s):  
Jakub Pecanka ◽  
Marianne A. Jonker ◽  
Zoltan Bochdanovits ◽  
Aad W. Van Der Vaart ◽  

Summary For over a decade functional gene-to-gene interaction (epistasis) has been suspected to be a determinant in the “missing heritability” of complex traits. However, searching for epistasis on the genome-wide scale has been challenging due to the prohibitively large number of tests which result in a serious loss of statistical power as well as computational challenges. In this article, we propose a two-stage method applicable to existing case-control data sets, which aims to lessen both of these problems by pre-assessing whether a candidate pair of genetic loci is involved in epistasis before it is actually tested for interaction with respect to a complex phenotype. The pre-assessment is based on a two-locus genotype independence test performed in the sample of cases. Only the pairs of loci that exhibit non-equilibrium frequencies are analyzed via a logistic regression score test, thereby reducing the multiple testing burden. Since only the computationally simple independence tests are performed for all pairs of loci while the more demanding score tests are restricted to the most promising pairs, genome-wide association study (GWAS) for epistasis becomes feasible. By design our method provides strong control of the type I error. Its favourable power properties especially under the practically relevant misspecification of the interaction model are illustrated. Ready-to-use software is available. Using the method we analyzed Parkinson’s disease in four cohorts and identified possible interactions within several SNP pairs in multiple cohorts.


2015 ◽  
Vol 46 (4) ◽  
pp. 759-770 ◽  
Author(s):  
N. Mullins ◽  
R. A. Power ◽  
H. L. Fisher ◽  
K. B. Hanscombe ◽  
J. Euesden ◽  
...  

BackgroundMajor depressive disorder (MDD) is a common and disabling condition with well-established heritability and environmental risk factors. Gene–environment interaction studies in MDD have typically investigated candidate genes, though the disorder is known to be highly polygenic. This study aims to test for interaction between polygenic risk and stressful life events (SLEs) or childhood trauma (CT) in the aetiology of MDD.MethodThe RADIANT UK sample consists of 1605 MDD cases and 1064 controls with SLE data, and a subset of 240 cases and 272 controls with CT data. Polygenic risk scores (PRS) were constructed using results from a mega-analysis on MDD by the Psychiatric Genomics Consortium. PRS and environmental factors were tested for association with case/control status and for interaction between them.ResultsPRS significantly predicted depression, explaining 1.1% of variance in phenotype (p= 1.9 × 10−6). SLEs and CT were also associated with MDD status (p= 2.19 × 10−4andp= 5.12 × 10−20, respectively). No interactions were found between PRS and SLEs. Significant PRSxCT interactions were found (p= 0.002), but showed an inverse association with MDD status, as cases who experienced more severe CT tended to have a lower PRS than other cases or controls. This relationship between PRS and CT was not observed in independent replication samples.ConclusionsCT is a strong risk factor for MDD but may have greater effect in individuals with lower genetic liability for the disorder. Including environmental risk along with genetics is important in studying the aetiology of MDD and PRS provide a useful approach to investigating gene–environment interactions in complex traits.


2003 ◽  
Vol 54 (3) ◽  
pp. 211 ◽  
Author(s):  
Rex Oram ◽  
Greg Lodge

Current trends in grass cultivar development are reviewed, with respect to the range of species involved, and the objectives and methodology within each species. Extrapolations and predictions are made about future directions and methodologies. It is assumed that selection will necessarily cater for the following environmental changes: (1) higher year-round temperatures, higher variability of rainfall incidence, and lower total winter and spring rainfall along the south of the continent; (2) higher nutrient and lime inputs as land utilisation intensifies; and (3) the grazing management requirements of the important pasture components will be increasingly defined and met in practice.The 'big four' species, perennial ryegrass, phalaris, cocksfoot and tall fescue, will continue to be the most widely sown species in temperate regions for many decades, with the latter 3 increasing most in area and genetic differentiation. However, species diversification will continue, especially with native grasses, legumes, and shrubs from fertile regions of Australia and exotics from little-explored parts of the world, such as South Africa, western North and South America, coastal Caucasus, and Iraq–Iran. By contrast, the recent high rate of species diversification in the tropics and subtropics will probably give way to a much lower rate of cultivar development by refinement and diversification within the established species. Domestication of native grasses will continue for amenity, recreational, land protection, and grazing purposes. As seed harvesting technologies and ecological knowledge improve, natural stands will become increasingly important as local sources of seed. It is suggested that many native grasses have been greatly changed by natural selection so as to withstand strong competition from introduced species under conditions of higher soil fertility and grazing pressure. Conversely, some introduced species are being selected consciously and naturally to persist in regions with irregular rainfall and less fertile soils. Therefore, the distinction between native and introduced grasses may be disappearing, and many populations of native species could now be as foreign to the habitats of pre-European settlement as are populations of introduced species that have been evolving here for 50–200 years. Methods used for genetic improvement will continue to be selection among both overseas accessions and the many native and introduced populations that have responded to natural selection in Australia. As well, there will be deliberate recurrent crossing and selection programs in both native and introduced species for specific purposes and environments. Increasingly, molecular biology methods will complement traditional ones, at first by the provision of DNA markers to assist the selection of complex traits, and for proving distinctness to obtain Plant Breeders' Rights for new cultivars. Later, genetic engineering will be used to manipulate nutritive value, resistance to fungal and viral diseases, and breeding systems, especially cytoplasmic male sterility and apomixis, to utilise heterosis in hybrid cultivars of grasses, particularly for dairying and intensive meat production.Areas where the practice and management of grass breeding and selection programs could be improved are highlighted throughout the review, and reiterated in a concluding statement. Most problems appear to stem from inadequate training in population ecology, population genetics, evolution, and quantitative inheritance.


Author(s):  
S. Mirzaee ◽  
M. Motagh ◽  
H. Arefi ◽  
M. Nooryazdan

Due to its special imaging characteristics, Synthetic Aperture Radar (SAR) has become an important source of information for a variety of remote sensing applications dealing with environmental changes. SAR images contain information about both phase and intensity in different polarization modes, making them sensitive to geometrical structure and physical properties of the targets such as dielectric and plant water content. In this study we investigate multi temporal changes occurring to different crop types due to phenological changes using high-resolution TerraSAR-X imagers. The dataset includes 17 dual-polarimetry TSX data acquired from June 2012 to August 2013 in Lorestan province, Iran. Several features are extracted from polarized data and classified using support vector machine (SVM) classifier. Training samples and different features employed in classification are also assessed in the study. Results show a satisfactory accuracy for classification which is about 0.91 in kappa coefficient.


Stroke ◽  
2020 ◽  
Vol 51 (11) ◽  
pp. 3392-3405 ◽  
Author(s):  
Ralph L. Sacco

Numerous epidemiological studies have demonstrated stroke disparities across race and ethnic groups. The goal of the NOMAS (Northern Manhattan Study) was to evaluate race and ethnic differences in stroke within a community with 3 different race-ethnic groups. Starting as a population-based incidence and case-control study, the study evolved into a cohort study. Results from NOMAS have demonstrated differences in stroke incidence, subtypes, risk factors, and outcomes. Disparities in ideal cardiovascular health can help explain many differences in stroke incidence and call for tailored risk factor modification through innovative portals to shift more diverse subjects to ideal cardiovascular health. The results of NOMAS and multiple other studies have provided foundational data to support interventions. Conceptual models to address health disparities have called for moving from detecting disparities in disease incidence, to determining the underlying causes of disparities and developing interventions, and then to testing interventions in human populations. Further actions to address race and ethnic stroke disparities are needed including innovative risk factor interventions, stroke awareness campaigns, quality improvement programs, workforce diversification, and accelerating policy changes.


2021 ◽  
pp. bjophthalmol-2021-319067
Author(s):  
Felix Friedrich Reichel ◽  
Stylianos Michalakis ◽  
Barbara Wilhelm ◽  
Ditta Zobor ◽  
Regine Muehlfriedel ◽  
...  

AimsTo determine long-term safety and efficacy outcomes of a subretinal gene therapy for CNGA3-associated achromatopsia. We present data from an open-label, nonrandomised controlled trial (NCT02610582).MethodsDetails of the study design have been previously described. Briefly, nine patients were treated in three escalating dose groups with subretinal AAV8.CNGA3 gene therapy between November 2015 and October 2016. After the first year, patients were seen on a yearly basis. Safety assessment constituted the primary endpoint. On a secondary level, multiple functional tests were carried out to determine efficacy of the therapy.ResultsNo adverse or serious adverse events deemed related to the study drug occurred after year 1. Safety of the therapy, as the primary endpoint of this trial, can, therefore, be confirmed. The functional benefits that were noted in the treated eye at year 1 were persistent throughout the following visits at years 2 and 3. While functional improvement in the treated eye reached statistical significance for some secondary endpoints, for most endpoints, this was not the case when the treated eye was compared with the untreated fellow eye.ConclusionThe results demonstrate a very good safety profile of the therapy even at the highest dose administered. The small sample size limits the statistical power of efficacy analyses. However, trial results inform on the most promising design and endpoints for future clinical trials. Such trials have to determine whether treatment of younger patients results in greater functional gains by avoiding amblyopia as a potential limiting factor.


2004 ◽  
Vol 87 (1) ◽  
pp. 15-32 ◽  
Author(s):  
Kenneth J. Kopecky ◽  
Scott Davis ◽  
Thomas E. Hamilton ◽  
Mark S. Saporito ◽  
Lynn E. Onstad

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