Robust joint score tests in the application of DNA methylation data analysis

Li, Xuan; Fu, Yuejiao; Wang, Xiaogang; Qiu, Weiliang

doi:10.1186/s12859-018-2185-3

Cited by 4 publications

(3 citation statements)

References 21 publications

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“…The results revealed that GSDMD was not detected in the normal glial cells, but glioma tissues were detected with medium or low staining ( Figure 1 B,C). In addition, it is well known that methylation is an important regulatory factor in gene expression [ 25 ]. Then, we further analyzed the GSDMD methylation in GBM primary tumors and normal tissues from the TCGA database, while data for LGG are not available.…”

Section: Resultsmentioning

confidence: 99%

Gasdermin D Plays an Oncogenic Role in Glioma and Correlates to an Immunosuppressive Microenvironment

Jiang

Wei

et al. 2023

Biomolecules

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Background: Understanding the molecular mechanisms driving oncogenic processes in glioma is important in order to develop efficient treatments. Recent studies have proposed gasdermin D (GSDMD) as a newly discovered pyroptosis executive protein associated with tumorigenesis. However, the precise effect of GSDMD on glioma progression remains unknown. Methods: The expression levels of GSDMD in 931 glioma and 1157 normal control tissues were collected. A series of bioinformatic approaches and in vivo and in vitro experiments were used to investigate the roles and mechanisms of GDSMD in glioma. Results: Significant upregulation of GSDMD was detected in glioma tissues compared to normal brain tissues. Patients with glioma and higher GSDMD levels had shorter overall survival, and the Cox regression analysis revealed that GSDMD was an independent risk factor. In addition, upregulation of GSDMD was associated with higher tumor mutation burden and PD-1/PD-L1 expression. Immune infiltration and single-cell analyses indicated that GSDMD was positively associated with an immunosuppressive microenvironment with more infiltrated macrophages and cancer-associated fibroblasts. Furthermore, the in vitro and in vivo experiments revealed that GSDMD knockdown inhibited glioma proliferation, migration, and growth in vivo. Conclusion: Our analyses revealed a relatively comprehensive understanding of the oncogenic role of GSDMD in glioma. GSDMD is a promising prognostic biomarker and a potential target for glioma treatment.

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Section: Resultsmentioning

confidence: 99%

Gasdermin D Plays an Oncogenic Role in Glioma and Correlates to an Immunosuppressive Microenvironment

Jiang

Wei

et al. 2023

Biomolecules

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“…Since this test can be re-formulated in a regression framework [14,15], it can be extended to continuous exposures. Methods for jointly testing mean and variability have also been proposed [7,[14][15][16][17][18][19], although these approaches are either limited by sensitivity to distributional assumptions or are restricted to binary exposures.…”

Section: Introductionmentioning

confidence: 99%

A robust mean and variance test with application to high-dimensional phenotypes

et al. 2021

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Most studies of continuous health-related outcomes examine differences in mean levels (location) of the outcome by exposure. However, identifying effects on the variability (scale) of an outcome, and combining tests of mean and variability (location-and-scale), could provide additional insights into biological mechanisms. A joint test could improve power for studies of high-dimensional phenotypes, such as epigenome-wide association studies of DNA methylation at CpG sites. One possible cause of heterogeneity of variance is a variable interacting with exposure in its effect on outcome, so a joint test of mean and variability could help in the identification of effect modifiers. Here, we review a scale test, based on the Brown-Forsythe test, for analysing variability of a continuous outcome with respect to both categorical and continuous exposures, and develop a novel joint location-and-scale score (JLSsc) test. These tests were compared to alternatives in simulations and used to test associations of mean and variability of DNA methylation with gender and gestational age using data from the Accessible Resource for Integrated Epigenomics Studies (ARIES). In simulations, the Brown-Forsythe and JLSsc tests retained correct type I error rates when the outcome was not normally distributed in contrast to the other approaches tested which all had inflated type I error rates. These tests also identified > 7500 CpG sites for which either mean or variability in cord blood methylation differed according to gender or gestational age. The Brown-Forsythe test and JLSsc are robust tests that can be used to detect associations not solely driven by a mean effect.

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“…Since this test can be re-formulated in a regression framework 10,11 , it can be extended to continuous exposures. Methods for jointly testing mean and variability have also been proposed 4,10,11,12,13,14,15 , although these approaches are either limited by sensitivity to distributional assumptions or are restricted to binary exposures.…”

Section: Introductionmentioning

confidence: 99%

A robust mean and variance test with application to high-dimensional phenotypes

Staley

Windmeijer

Suderman

et al. 2020

Preprint

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BackgroundMost studies of high-dimensional phenotypes focus on assessing differences in mean levels (location) of the phenotype by exposure, e.g. epigenome-wide association studies of the effect of exposure on mean DNA methylation at CpG sites. However, identifying effects on the variability (scale) of these outcomes could provide additional insights into biological mechanisms.MethodsWe introduce a scale test, based on the Brown-Forsythe test, for analysing phenotype variability for both categorical and continuous exposures. We also present a novel joint location-and-scale score test (JLSsc). These tests were compared to the equivalent likelihood-ratio tests and alternative approaches in simulations and used to test associations of mean and variability of DNA methylation with gender and gestational age using data from the Accessible Resource for Integrated Epigenomics Studies (ARIES).ResultsThe extended Brown-Forsythe test and JLSsc had good statistical properties for both categorical and continuous exposures, without requiring transformation of the methylation levels. All of the other methods assessed had inflated type I error using the raw methylation levels. In ARIES, JLSsc identified 7228 and 340 CpG sites (240 CpGs were associated with methylation variability differences between males and females using the extended Brown-Forsythe test) that were associated with either mean or variability in gender and gestational age in cord blood, respectively.ConclusionsThe extended Brown-Forsythe test and JLSsc are robust tests of variability and combined mean and variability effects, respectively. These tests can be used to detect associations not solely driven by a mean effect of the exposure on the outcome.

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Robust joint score tests in the application of DNA methylation data analysis

Cited by 4 publications

References 21 publications

Gasdermin D Plays an Oncogenic Role in Glioma and Correlates to an Immunosuppressive Microenvironment

Gasdermin D Plays an Oncogenic Role in Glioma and Correlates to an Immunosuppressive Microenvironment

A robust mean and variance test with application to high-dimensional phenotypes

A robust mean and variance test with application to high-dimensional phenotypes

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