Discovery proteomics and nonparametric modeling pipeline in the development of a candidate biomarker panel for dengue hemorrhagic fever.
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ABSTRACT:
SUBMITTER: Brasier AR
PROVIDER: S-EPMC3590808 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Dengue serotype 3 viruses were isolated from patients in Brazil from 2002 through 2004. On the basis of phylogenetic analyses, these isolates were assigned genotype 1. This genotype had never been reported in South America before. Its appearance indicates a major risk factor for dengue epidemics and severe disease.
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Project description:BackgroundGenetic risk factors for dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) and dengue fever (DF) are limited, in particular there are sparse data on genetic risk across diverse populations.MethodsWe conducted a genome-wide association study (GWAS) in a derivation and validation sample of 7, 460 participants of Latin American, South Asian, and South East Asian ancestries. We then developed a weighted polygenic risk score (PRS) for each participant in each of the validation cohorts of the three ancestries to predict the risk of DHF/DSS compared to DF, DHF/DSS compared to controls, and, DF compared to controls.FindingsThe risk of DHF/DSS was significantly increased, odds ratio [OR] 1.84 (95%CI 1.47 to 2.31) (195 SNPs), compared to DF, fourth PRS quartile versus first quartile, in the validation cohort. The risk of DHF/DSS compared to controls was increased (OR=3.94; 95% CI 2.84 to 5.45) (278 SNPs), as was the risk of DF compared to controls (OR=1.97; 95%CI 1.63 to 2.39) (251 SNPs). Risk increased in a dose-dependent manner with increase in quartiles of PRS across comparisons. Significant associations persisted for PRS built within ancestries and applied to the same or different ancestries as well as for PRS built for one outcome (DHF/DSS or DF) and applied to the other.InterpretationThere is a strong genetic effect that predisposes to risk of DHF/DSS and DF. The genetic risk for DHF/DSS is higher than that for DF when compared to controls, and this effect persists across multiple ancestries.
| S-EPMC6940652 | biostudies-literature
Project description:Mass spectrometry (MS)-based label-free proteomics offers an unbiased approach to screen biomarkers related to disease progression and therapy-resistance of breast cancer on the global scale. However, multi-step sample preparation can introduce large variation in generated data, while inappropriate statistical methods will lead to false positive hits. All these issues have hampered the identification of reliable protein markers. A workflow, which integrates reproducible and robust sample preparation and data handling methods, is highly desirable in clinical proteomics investigations. Here we describe a label-free tissue proteomics pipeline, which encompasses laser capture microdissection (LCM) followed by nanoscale liquid chromatography and high resolution MS. This pipeline routinely identifies on average ?10,000 peptides corresponding to ?1,800 proteins from sub-microgram amounts of protein extracted from ?4,000 LCM breast cancer epithelial cells. Highly reproducible abundance data were generated from different technical and biological replicates. As a proof-of-principle, comparative proteome analysis was performed on estrogen receptor ? positive or negative (ER+/-) samples, and commonly known differentially expressed proteins related to ER expression in breast cancer were identified. Therefore, we show that our tissue proteomics pipeline is robust and applicable for the identification of breast cancer specific protein markers.
| S-EPMC3428526 | biostudies-literature
Project description:BackgroundMost patients with dengue experience mild disease, dengue fever (DF), while few develop the life-threatening diseases dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). No laboratory tests predict DHF or DSS. We evaluated whether the serum chymase level can predict DHF or DSS in adult and pediatric patients and the influence of preexisting conditions (PECs) on chymase levels.MethodsSerum chymase levels were measured in patients presenting with undifferentiated fever to hospitals in Colombo District, Sri Lanka. The value of serum the chymase concentration and clinical signs and symptoms as predictors of DHF and/or DSS was evaluated by multivariate analysis. We assessed the influence of age, PECs, and day after fever onset on the robustness of the chymase level as a biomarker for DHF and/or DSS.ResultsAn elevated chymase level in acute phase blood samples was highly indicative of later diagnosis of DHF or DSS for pediatric and adult patients with dengue. No recorded PECs prevented an increase in the chymase level during DHF. However, certain PECs (obesity and cardiac or lung-associated diseases) resulted in a concomitant increase in chymase levels among adult patients with DHF.ConclusionsThese results show that patients with acute dengue who present with high levels of serum chymase consistently are at greater risk of DHF. The chymase level is a robust prognostic biomarker of severe dengue for adult and pediatric patients.
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Project description:Dengue fever (DF) and dengue hemorrhagic fever (DHF) are recurrent diseases that are widespread in the tropics. Here, we identified candidate genes associated with these diseases by performing integrated analyses of DF (GSE51808) and DHF (GSE18090) microarray datasets in the Gene Expression Omnibus (GEO). In all, we identified 7635 differentially expressed genes (DEGs) in DF and 8147 DEGs in DHF as compared to healthy controls (P < 0.05). In addition, we discovered 215 differentially expressed long non-coding RNAs (DElncRNAs) in DF and 225 DElncRNAs in DHF. There were 1256 common DEGs and eight common DElncRNAs in DHF vs DF, DHF vs normal control, and DF vs normal control groups. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that signal transduction (false discovery rate = 8.33E-10), 'toxoplasmosis', and 'protein processing in endoplasmic reticulum' were significantly enriched pathways for common DEGs. We conclude that the MAGED1,STAT1, and IL12A genes may play crucial roles in DF and DHF, and suggest that our findings may facilitate the identification of biomarkers and the development of new drug design strategies for DF and DHF treatment.
| S-EPMC6396354 | biostudies-literature
Project description:There is a pressing and continued need for improved predictive power in preclinical pharmaceutical toxicology assessment as substantial numbers of drugs are still removed from the market, or from late-stage development, because of unanticipated issues of toxicity. In recent years a number of consortia have been formed with a view to integrating -omics molecular profiling strategies to increase the sensitivity and predictive power of preclinical toxicology evaluation. In this study we report on the LC-MS based proteomic analysis of the effects of the hepatotoxic compound EMD 335823 on liver from rats using an integrated discovery to targeted proteomics approach. This compound was one of a larger panel studied by a variety of molecular profiling techniques as part of the InnoMed PredTox Consortium. Label-free LC-MS analysis of hepatotoxicant EMD 335823 treated animals revealed only moderate correlation of individual protein expression with changes in mRNA expression observed by transcriptomic analysis of the same liver samples. Significantly however, analysis of the protein and transcript changes at the pathway level revealed they were in good agreement. This higher level analysis was also consistent with the previously suspected PPARα activity of the compound. Subsequently, a panel of potential biomarkers of liver toxicity was assembled from the label-free LC-MS proteomics discovery data, the previously acquired transcriptomics data and selected candidates identified from the literature. We developed and then deployed optimized selected reaction monitoring assays to undertake multiplexed measurement of 48 putative toxicity biomarkers in liver tissue. The development of the selected reaction monitoring assays was facilitated by the construction of a peptide MS/MS spectral library from pooled control and treated rat liver lysate using peptide fractionation by strong cation exchange and off-gel electrophoresis coupled to LC-MS/MS. After iterative optimization and quality control of the selected reaction monitoring assay panel, quantitative measurements of 48 putative biomarkers in the liver of EMD 335823 treated rats were carried out and this revealed that the panel is highly enriched for proteins modulated significantly on drug treatment/hepatotoxic insult. This proof-of-principle study provides a roadmap for future large scale pre-clinical toxicology biomarker verification studies whereby putative toxicity biomarkers assembled from multiple disparate sources can be evaluated at medium-high throughput by targeted MS.
| S-EPMC3412970 | biostudies-literature
Project description:To identify genes associated with the clinical presentation of dengue, 50 cases of probable or possible dengue hemorrhagic fever (DHF), 236 dengue fever (DF), and 236 asymptomatic infections were genotyped for 593 single-nucleotide polymorphisms (SNPs) in 56 genes across the type 1 interferon (IFN) response pathway as well as other important candidate genes. By single locus analysis comparing DHF with DF, 11 of the 51 markers with P<0.05 were in the JAK1 gene. Five markers were significantly associated by false discovery rate criteria (q<0.20 when P<6 × 10(-4)). The JAK1 SNPs showed differential distribution by ethnicity and ancestry consistent with epidemiologic observations in the Americas. The association remained significant after controlling for ancestry and income. No association was observed with markers in the gene encoding CD209 (DC-SIGN). An association between DHF and JAK1 polymorphisms is in agreement with expression profiles showing generalized decreased type 1 IFN-stimulated gene expression in these patients.
| S-EPMC2950898 | biostudies-literature
Project description:Cytokines play important roles in the physiopathology of dengue infection; therefore, the suppressors of cytokine signaling (socs) that control the type and timing of cytokine functions could be involved in the origin of immune alterations in dengue.To explore the association of cytokine and socs levels with disease severity in dengue patients.Blood samples of 48 patients with confirmed dengue infection were analyzed. Amounts of interleukins IL-2, IL-4, IL-6, and IL-10, interferon- (IFN-) γ, and tumor necrosis factor- (TNF-) α were quantified by flow cytometry, and the relative expression of socs1 and socs3 mRNA was quantified by real-time RT-PCR.Increased levels of IL-10 and socs3 and lower expression of socs1 were found in patients with dengue hemorrhagic fever (DHF) with respect to those with dengue fever (DF) (p < 0.05). Negative correlations were found between socs1 and both IL-10 and socs3 (p < 0.01). The cutoff values of socs3 (>199.8-fold), socs1 (<1.94-fold), and IL-10 (>134 pg/ml) have the highest sensitivity and specificity to discriminate between DF and DHF.Simultaneous changes in IL-10 and socs1/socs3 could be used as prognostic biomarkers of dengue severity.
| S-EPMC5554562 | biostudies-other
Project description:BACKGROUND: Dengue virus (DENV) infection is the most common arthropod-borne viral disease in man and there are approximately 100 million infections annually. Despite the global burden of DENV infections many important questions regarding DENV pathogenesis remain unaddressed due to the lack of appropriate animal models of infection and disease. A major problem is the fact that no non-human species naturally develop disease similar to human dengue fever (DF) or dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Apart from other risk factors for severe dengue such as host genetics and secondary infection with a heterologous DENV, virus virulence is a risk factor that is not well characterized. RESULTS: Three clinical DENV-1 isolates from Cambodian patients experiencing the various forms of dengue disease (DF, DHF, and DSS) were inoculated in BALB/c mice at three different concentrations. The DENV-1 isolates had different organ and cell tropism and replication kinetics. The DENV-1 isolate from a DSS patient infected the largest number of mice and was primarily neurotropic. In contrast, the DENV-1 isolates from milder clinical dengue cases infected predominantly lungs and liver, and to a lesser extent brain. In addition, infection with the DENV isolate derived from a DSS patient persisted for more than two weeks in a majority of mice compared to the other DENV-1 isolates that peaked during the first week. CONCLUSIONS: These results confirm the in vitro findings of the same DENV-1 isolates, that showed that the isolate derived from a DSS patient can be distinguished based on phenotypic characteristics that differ from the isolates derived from a DF and DHF case 1. We observed in this study that the DSS virus isolate persist longer in vivo with extensive neuroinvasion in contrast to the other DENV-1 isolates originating in milder human cases. Genomic characterization of the three clinical isolates identified six amino acid substitutions unique for the DSS isolates that were located both in structural genes (M and E) and in non-structural genes (NS1, NS3, and NS5). The characterization of these clinically distinct DENV-1 isolates highlight that DENVs within the same genotype may have different in vivo phenotypes. HIGHLIGHTS: • Clinical DENV-1 isolates have different organ tropism in BALB/c mice.• The isolate from a DSS patient is primarily neurotropic compared to the other isolates.• The DENV-1 isolates have different in vivo replication kinetics.• The isolate from a DSS patient persists longer compared to the other isolates.• These phenotypic differences confirm our earlier in vitro findings with the same DENV-1 isolates. Thus, DENVs within the same serotype and genotype may differ enough to affect clinical conditions in vivo.
| S-EPMC3170302 | biostudies-literature
Project description:BACKGROUND: Dengue is the most prevalent mosquito-borne virus, and potentially fatal dengue hemorrhagic fever (DHF) occurs mainly in secondary infections. It recently was hypothesized that, due to the presence of cross-immunity, the relationship between the incidence of DHF and transmission intensity may be negative at areas of intense transmission. We tested this hypothesis empirically, using vector abundance as a surrogate of transmission intensity. METHODOLOGY/PRINCIPAL FINDINGS: House Index (HI), which is defined as the percentage of households infested with vector larvae/pupae, was obtained from surveys conducted on one million houses in Thailand, between 2002 and 2004. First, the utility of HI as a surrogate of transmission intensity was confirmed because HI was correlated negatively with mean age of DHF in the population. Next, the relationship between DHF incidence and HI was investigated. DHF incidence increased only up to an HI of about 30, but declined thereafter. Reduction of HI from the currently maximal level to 30 would increase the incidence by more than 40%. Simulations, which implemented a recently proposed model for cross-immunity, generated results that resembled actual epidemiological data. It was predicted that cross-immunity generates a wide variation in incidence, thereby obscuring the relationship between incidence and transmission intensity. The relationship would become obvious only if data collected over a long duration (e.g., >10 years) was averaged. CONCLUSION: The negative relationship between DHF incidence and dengue transmission intensity implies that in regions of intense transmission, insufficient reduction of vector abundance may increase long-term DHF incidence. Further studies of a duration much longer than the present study, are warranted.
| S-EPMC2442222 | biostudies-other