Identifying differentially expressed genes  using
false discovery rate controlling procedures

Reiner, Anat; Yekutieli, Daniel; Benjamini, Yoav

doi:10.1093/bioinformatics/btf877

Cited by 1,570 publications

(1,212 citation statements)

References 18 publications

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“…After data pre-processing using within-array global loess normalization, the empirical eBayes method in Limma, which computes moderated t-statistics, moderated F-statistics, and log-odds of differential expression, was applied to identify the significance of differential expression in each culture condition. Adjustment for multiple testing was carried out using the false discovery rate (FDR) method [71] in Limma. Significant changes in gene expression were limited to p < 0.05.…”

Section: Methodsmentioning

confidence: 99%

Transcriptome analysis of porcine PBMCs after in vitro stimulation by LPS or PMA/ionomycin using an expression array targeting the pig immune response

et al. 2010

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BackgroundDesigning sustainable animal production systems that better balance productivity and resistance to disease is a major concern. In order to address questions related to immunity and resistance to disease in pig, it is necessary to increase knowledge on its immune system and to produce efficient tools dedicated to this species.ResultsA long-oligonucleotide-based chip referred to as SLA-RI/NRSP8-13K was produced by combining a generic set with a newly designed SLA-RI set that targets all annotated loci of the pig major histocompatibility complex (MHC) region (SLA complex) in both orientations as well as immunity genes outside the SLA complex.The chip was used to study the immune response of pigs following stimulation of porcine peripheral blood mononuclear cells (PBMCs) with lipopolysaccharide (LPS) or a mixture of phorbol myristate acetate (PMA) and ionomycin for 24 hours. Transcriptome analysis revealed that ten times more genes were differentially expressed after PMA/ionomycin stimulation than after LPS stimulation. LPS stimulation induced a general inflammation response with over-expression of SAA1, pro-inflammatory chemokines IL8, CCL2, CXCL5, CXCL3, CXCL2 and CCL8 as well as genes related to oxidative processes (SOD2) and calcium pathways (S100A9 and S100A12). PMA/ionomycin stimulation induced a stronger up-regulation of T cell activation than of B cell activation with dominance toward a Th1 response, including IL2, CD69 and TNFRSF9 (tumor necrosis factor receptor superfamily, member 9) genes. In addition, a very intense repression of THBS1 (thrombospondin 1) was observed. Repression of MHC class I genes was observed after PMA/ionomycin stimulation despite an up-regulation of the gene cascade involved in peptide processing. Repression of MHC class II genes was observed after both stimulations. Our results provide preliminary data suggesting that antisense transcripts mapping to the SLA complex may have a role during immune response.ConclusionThe SLA-RI/NRSP8-13K chip was found to accurately decipher two distinct immune response activations of PBMCs indicating that it constitutes a valuable tool to further study immunity and resistance to disease in pig. The transcriptome analysis revealed specific and common features of the immune responses depending on the stimulation agent that increase knowledge on pig immunity.

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Section: Methodsmentioning

confidence: 99%

Transcriptome analysis of porcine PBMCs after in vitro stimulation by LPS or PMA/ionomycin using an expression array targeting the pig immune response

et al. 2010

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“…Migration time and ion signal intensity (amplitude) were normalized using internal polypeptide standards [45], [46]. For the identification of potential biomarkers, the reported p-values were calculated using the Wilcoxon Rank-Sum test followed by adjustment for multiple testing using the method described by Benjamini and Hochberg [47]. Disease-specific polypeptide patterns were generated using SVM based MosaCluster software [48].…”

Section: Methodsmentioning

confidence: 99%

A Distinct Urinary Biomarker Pattern Characteristic of Female Fabry Patients That Mirrors Response to Enzyme Replacement Therapy

et al. 2011

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Female patients affected by Fabry disease, an X-linked lysosomal storage disorder, exhibit a wide spectrum of symptoms, which renders diagnosis, and treatment decisions challenging. No diagnostic test, other than sequencing of the alpha-galactosidase A gene, is available and no biomarker has been proven useful to screen for the disease, predict disease course and monitor response to enzyme replacement therapy. Here, we used urine proteomic analysis based on capillary electrophoresis coupled to mass spectrometry and identified a biomarker profile in adult female Fabry patients. Urine samples were taken from 35 treatment-naïve female Fabry patients and were compared to 89 age-matched healthy controls. We found a diagnostic biomarker pattern that exhibited 88.2% sensitivity and 97.8% specificity when tested in an independent validation cohort consisting of 17 treatment-naïve Fabry patients and 45 controls. The model remained highly specific when applied to additional control patients with a variety of other renal, metabolic and cardiovascular diseases. Several of the 64 identified diagnostic biomarkers showed correlations with measures of disease severity. Notably, most biomarkers responded to enzyme replacement therapy, and 8 of 11 treated patients scored negative for Fabry disease in the diagnostic model. In conclusion, we defined a urinary biomarker model that seems to be of diagnostic use for Fabry disease in female patients and may be used to monitor response to enzyme replacement therapy.

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“…All analyses were performed using StatView, version 5.0 (SAS Institute, Cary, NC). Benjamini and Hochberg post hoc correction for multiple comparisons was applied to reduce falsepositive results (25).…”

Section: Analysis Of Tendon Biomechanicsmentioning

confidence: 99%

Modulation of aggrecan and ADAMTS expression in ovine tendinopathy induced by altered strain

Smith

Sakurai

Smith

et al. 2008

Arthritis & Rheumatism

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Objective. To evaluate histologic, immunohistochemical, and molecular changes in tendon induced by altered strain in a large-animal model.Methods. A full-thickness partial-width laceration of the infraspinatus tendon was created in 5 sheep, while 5 sham-operated sheep were used as controls. Sheep were killed after 4 weeks, and 4 differentially stressed tendon regions (tensile or near bone attachment from overstressed or stress-deprived halves) were evaluated for histopathology, proteoglycan (PG) accumulation, and characterization of glycosaminoglycans and aggrecan catabolites. Gene expression of matrix components, enzymes, and inhibitors was analyzed by reverse transcriptase-polymerase chain reaction.Results. Histopathologic changes were detected in both overstressed and stress-deprived tensile tendon, but only in stress-deprived tendon near bone. In overstressed and stress-deprived tensile tendon, levels of keratan sulfate, chondroitin 4-sulfate, and chondroitin 6-sulfate were increased. In overstressed tensile tendon, levels of ADAMTS-generated aggrecan catabolites were increased. There was increased matrix metalloproteinase 13 (MMP-13) and decreased fibromodulin and decorin expression in all regions. Increased MMP-1, MMP-9, MMP-14, and ADAMTS-1 expression, and decreased type II collagen expression were restricted to stress-deprived tendon. In stress-deprived boneattachment regions, messenger RNA (mRNA) for aggrecan was decreased, and ADAMTS was increased. In overstressed tensile tendon, aggrecan mRNA was increased, and ADAMTS was decreased.Conclusion. The distinct molecular changes in adjacent tissue implicate altered strain rather than humoral factors in controlling abnormal tenocyte metabolism, and highlight the importance of regional sampling. Tendon abnormalities induced by increased strain are accompanied by increased aggrecan, decreased ADAMTS, and low PG expression, which may negatively impact the structural integrity of the tissue and predispose to rupture.Injuries of the shoulder due to overuse are increasingly prevalent in both the sporting arena and the workplace. Occupational injury of the shoulder is second only to neck and low back pain in the frequency of consultation by general practitioners, with the most common injury involving the rotator cuff. (1,2) The prevalence of rotator cuff conditions increases with age, from 30-50% in the seventh decade of life to a staggering 70-80% by the ninth (3,4). Although most cases are treated conservatively, many patients undergo surgical repair with a prolonged convalescence. There are no drugs to specifically treat disorders of the rotator cuff or other tendons, and many surgical repairs fail within 12 months (5). Lack of knowledge of the fundamental mechanisms that underlie tendon breakdown results in limited and inadequate management options for tendon disorders.

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Identifying differentially expressed genes using false discovery rate controlling procedures

Abstract: An R program that adjusts p-values using FDR controlling procedures is freely available over the Internet at www.math.tau.ac.il/~ybenja.

Cited by 1,570 publications

References 18 publications

Transcriptome analysis of porcine PBMCs after in vitro stimulation by LPS or PMA/ionomycin using an expression array targeting the pig immune response

Transcriptome analysis of porcine PBMCs after in vitro stimulation by LPS or PMA/ionomycin using an expression array targeting the pig immune response

A Distinct Urinary Biomarker Pattern Characteristic of Female Fabry Patients That Mirrors Response to Enzyme Replacement Therapy

Modulation of aggrecan and ADAMTS expression in ovine tendinopathy induced by altered strain

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