Human Disease Risk Research Articles

Identification of exon skipping events associated with Alzheimer\u2019s disease in the human hippocampus

BackgroundAt least 90% of human genes are alternatively spliced. Alternative splicing has an important function regulating gene expression and miss-splicing can contribute to risk for human diseases, including Alzheimer’s disease (AD).MethodsWe developed a splicing decision model as a molecular mechanism to identify functional exon skipping events and genetic variation affecting alternative splicing on a genome-wide scale by integrating genomics, transcriptomics, and neuroimaging data in a systems biology approach. In this study, we analyzed RNA-Seq data of hippocampus brain tissue from Alzheimer’s disease (AD; n = 24) and cognitively normal elderly controls (CN; n = 50) and identified three exon skipping events in two genes (RELN and NOS1) as significantly associated with AD (corrected p-value < 0.05 and fold change > 1.5). Next, we identified single-nucleotide polymorphisms (SNPs) affecting exon skipping events using the splicing decision model and then performed an association analysis of SNPs potentially affecting three exon skipping events with a global cortical measure of amyloid-β deposition measured by [18F] Florbetapir position emission tomography (PET) scan as an AD-related quantitative phenotype. A whole-brain voxel-based analysis was also performed.ResultsTwo exons in RELN and one exon in NOS1 showed significantly lower expression levels in the AD participants compared to CN participants, suggesting that the exons tend to be skipped more in AD. We also showed the loss of the core protein structure due to the skipped exons using the protein 3D structure analysis. The targeted SNP-based association analysis identified one intronic SNP (rs362771) adjacent to the skipped exon 24 in RELN as significantly associated with cortical amyloid-β levels (corrected p-value < 0.05). This SNP is within the splicing regulatory element, i.e., intronic splicing enhancer. The minor allele of rs362771 conferred decreases in cortical amyloid-β levels in the right temporal and bilateral parietal lobes.ConclusionsOur results suggest that exon skipping events and splicing-affecting SNPs in the human hippocampus may contribute to AD pathogenesis. Integration of multiple omics and neuroimaging data provides insights into possible mechanisms underlying AD pathophysiology through exon skipping and may help identify novel therapeutic targets.

Antioxidants, its role in preventing free radicals and infectious diseases in human body

Abstract Recent research on herbal field reports various ailments associated with free radicals. The risk of ailments because of oxidative stress increases due to undesirable way of life, exposure of natural and synthetic chemicals, cigarette smoking, medications, stress and so on. Cancer prevention agents are the substances which can search free radicals and help diminish the frequency of oxidative pressure induced harm. The main sources of antioxidants are vitamins, fruits, minerals, plants and vegetables. The functions of antioxidants are to neutralize the effect of reactive oxygen species (ROS) and prevent various diseases such as cancer, diabetes and cardiovascular diseases. The presence of antioxidants can be evaluated by various methods but the cheapest and easiest available methods are 1, 1-diphenyl-2-picrylhydrazyl (DPPH), total antioxidants capacity (TAC), total phenolic contents (TPC), reducing power (RP) and ferric reducing antioxidant potential (FRAP) methods. This review generally discusses the information related to the antioxidants and their role in changing the free radicals into neutral or less reactive species. It also discusses the role of antioxidant enrich sources in decreasing the risk of different human diseases. Keywords: Antioxidants; Free radicals; Oxidation; Prevention; Species http://dx.doi.org/10.19045/bspab.2018.700197

Sympatric Ixodes-tick species: pattern of distribution and pathogen transmission within wild rodent populations

The generalist tick Ixodes ricinus is the most important vector for tick-borne pathogens (TBP), including Borrelia burgdorferi sensu lato, in Europe. However, the involvement of other sympatric Ixodes ticks, such as the specialist vole tick I. trianguliceps, in the enzootic circulations of TBP remains unclear. We studied the distribution of I. ricinus and I. trianguliceps in Central Finland and estimated the TBP infection likelihood in the most common rodent host in relation with the abundance of the two tick species. Ixodes trianguliceps was encountered in all 16 study sites whereas I. ricinus was frequently observed only at a quarter of the study sites. The abundance of I. ricinus was positively associated with open water coverage and human population density around the study sites. Borrelia burgdorferi s. l.-infected rodents were found only in sites where I. ricinus was abundant, whereas the occurrence of other TBP was independent of I. ricinus presence. These results suggest that I. trianguliceps is not sufficient, at least alone, in maintaining the circulation of B. burgdorferi s. l. in wild hosts. In addition, anthropogenic factors might affect the distribution of I. ricinus ticks and, hence, their pathogens, thus shaping the landscape of tick-borne disease risk for humans.

Adipocyte Size Evaluation Based on Photoacoustic Spectral Analysis Combined with Deep Learning Method

Adipocyte size, i.e., the cell area of adipose tissue, is correlated directly with metabolic disease risk in obese humans. This study proposes an approach of processing the photoacoustic (PA) signal power spectrum using a deep learning method to evaluate adipocyte size in human adipose tissue. This approach has the potential to provide noninvasive assessment of adipose tissue dysfunction, replacing traditional invasive methods of evaluating adipose tissue via biopsy and histopathology. A deep neural network with fully connected layers was used to fit the relationship between PA spectrum and average adipocyte size. Experiments on human adipose tissue specimens were performed, and the optimal parameters of the deep learning method were applied to establish the relationship between the PA spectrum and average adipocyte size. By studying different spectral bands in the entire spectral range using the deep network, a spectral band mostly sensitive to the adipocyte size was identified. A method of combining all frequency components of PA spectrum was tested to achieve a more accurate evaluation.

Impact of Genetic Polymorphisms on Human Immune Cell Gene Expression

While many genetic variants have been associated with risk for human diseases, how these variants affect gene expression in various cell types remains largely unknown. To address this gap, the DICE (database of immune cell expression, expression quantitative trait loci [eQTLs], and epigenomics) project was established. Considering all human immune cell types and conditions studied, we identified cis-eQTLs for a total of 12,254 unique genes, which represent 61% of all protein-coding genes expressed in these cell types. Strikingly, a large fraction (41%) of these genes showed a strong cis-association with genotype only in a single cell type. We also found that biological sex is associated with major differences in immune cell gene expression in a highly cell-specific manner. These datasets will help reveal the effects of disease risk-associated genetic polymorphisms on specific immune cell types, providing mechanistic insights into how they might influence pathogenesis (https://dice-database.org).

In This Issue

HomeCirculation ResearchVol. 123, No. 10In This Issue Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBIn This Issue Ruth Williams Ruth WilliamsRuth Williams Search for more papers by this author Originally published25 Oct 2018https://doi.org/10.1161/RES.0000000000000238Circulation Research. 2018;123:1103is related toLack of Cardiac Improvement After Cardiosphere-Derived Cell Transplantation in Aging Mouse Heartsis related toTranscriptome Analysis Reveals Nonfoamy Rather Than Foamy Plaque Macrophages Are Proinflammatory in Atherosclerotic Murine ModelsMicrobial Transplantation With Human Gut Commensals Containing CutC Is Sufficient to Transmit Enhanced Platelet Reactivity and Thrombosis PotentialTranscriptome of Atherosclerotic Macrophages (p 1127)Download figureDownload PowerPointNonfoamy plaque macrophages are more proinflammatory than their foamy counterparts, report Kim et al.Atherosclerosis is characterized by the deposition of fat and the accumulation of immune cells such as macrophages in the vessel wall. These macrophages phagocytose the lipid particles and ultimately turn into fat-filled foam cells. Given this central role of macrophages in atherosclerosis, Kim and colleagues wanted to investigate their characteristics more thoroughly. To that end, they developed a new flow-cytometry technique that could distinguish between nonfoamy plaque macrophages (those that have accumulated little to no lipids) and fully lipid-laden foamy cells. They separated these two populations of macrophages by differences in their granularity and fluorescent labeling by the lipid probe BODIPY493/503, and compared their transcriptomes. They found that nonfoamy macrophages tended to express high levels of proinflammatory genes, while foamy macrophages had high levels of genes involved in lipid processing and as well as the resolution of inflammation. The team also confirmed the results obtained with mouse cells in human plaque macrophages, showing that the nonfoamy cell population was markedly proinflammatory.CDC Transplantation in Aging Mouse Hearts (p e21)Download figureDownload PowerPointCardiosphere-derived cells do not improve heart function in aged mice, say Zhao et al.Several clinical and preclinical studies are currently evaluating the potential of different cell types for promoting the repair and regeneration of injured and aged heart tissue. Of the candidate cells under consideration, cardiosphere-derived cells (CDCs), which are balls of cells that form during ex vivo culture of myocardial tissue, have been shown capable of differentiating into all three major cell types of the heart: cardiac myocytes, endothelium, and smooth muscle cells. Although recent work has shown that in aged rats CDCs can improve myocardial performance, Zhao and colleagues now report that this result is not reproducible in aged mice, where intramyocardial injections of CDCs provided no perceivable benefits over control treatments. To test the effects of CDCs, Zhao et al injected these cells in the left ventricles of nineteen 21-month-old mice. A separate group of 15 mice received control injections of phosphate-buffered saline. A month after these treatments, there was no difference between these two groups in terms of their left ventricle function, exercise capacity, or other markers of myocardial health. In view of the inconsistent results obtained with CDCs, the authors advise that further preclinical evaluation with these cells may be required to determine their efficacy.Microbial Transplantation Confers Thrombosis Risk (p 1164)Download figureDownload PowerPointGut microbes containing the gene cutC confer thrombosis risk, report Skye et al.Transfer of gut microbes from one organism to another can, in some cases, lead to the transfer of phenotypes, such as disease susceptibility. It is thought that the metabolites produced by the microbes somehow affect host physiology. Indeed, one such bacterial metabolite—trimethylamine N-oxide (TMAO)—has been linked to an increase in platelet reactivity, thrombosis risk, and cardiovascular disease risk in animal models and humans. The microbial gene responsible for the production of TMA (which gets converted to TMAO in the host liver) has been identified, but whether the presence of this gene—cutC—in human microbial specimens is sufficient to affect thrombosis has not been demonstrated. Skye and colleagues now show that mice that received an oral dose of a defined set of human gut microbes—all of which lacked cutC—did not exhibit increased platelet activation and thrombosis, while the addition of just one species containing cutC to that microbial set heightened platelet aggregation in the recipient mice. Together, these results provide further evidence that microbial TMA is linked to thrombosis risk and suggest that targeting cutC or TMA may be a novel avenue for preventing or treating cardiovascular disease. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesLack of Cardiac Improvement After Cardiosphere-Derived Cell Transplantation in Aging Mouse HeartsZhen-Ao Zhao, et al. Circulation Research. 2018;123:e21-e31Transcriptome Analysis Reveals Nonfoamy Rather Than Foamy Plaque Macrophages Are Proinflammatory in Atherosclerotic Murine ModelsKyeongdae Kim, et al. Circulation Research. 2018;123:1127-1142Microbial Transplantation With Human Gut Commensals Containing CutC Is Sufficient to Transmit Enhanced Platelet Reactivity and Thrombosis PotentialSarah M. Skye, et al. Circulation Research. 2018;123:1164-1176 October 26, 2018Vol 123, Issue 10 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000238 Originally publishedOctober 25, 2018 PDF download Advertisement

Current Therapies Focused on High-Density Lipoproteins Associated with Cardiovascular Disease.

High-density lipoproteins (HDL) comprise a heterogeneous family of lipoprotein particles divided into subclasses that are determined by density, size and surface charge as well as protein composition. Epidemiological studies have suggested an inverse correlation between High-density lipoprotein-cholesterol (HDL-C) levels and the risk of cardiovascular diseases and atherosclerosis. HDLs promote reverse cholesterol transport (RCT) and have several atheroprotective functions such as anti-inflammation, anti-thrombosis, and anti-oxidation. HDLs are considered to be atheroprotective because they are associated in serum with paraoxonases (PONs) which protect HDL from oxidation. Polyphenol consumption reduces the risk of chronic diseases in humans. Polyphenols increase the binding of HDL to PON1, increasing the catalytic activity of PON1. This review summarizes the evidence currently available regarding pharmacological and alternative treatments aimed at improving the functionality of HDL-C. Information on the effectiveness of the treatments has contributed to the understanding of the molecular mechanisms that regulate plasma levels of HDL-C, thereby promoting the development of more effective treatment of cardiovascular diseases. For that purpose, Scopus and Medline databases were searched to identify the publications investigating the impact of current therapies focused on high-density lipoproteins.

Association of single-nucleotide polymorphisms of the KEAP1 gene with the risk of various human diseases and its functional impact using in silico analysis.

Keap1, Kelch-like erythroid derived Cap 'n' collar homology (ECH) associated protein 1 is a highly redox-sensitive member of the BTB-Kelch substrate adaptor protein which acts as a major upstream regulator of Nrf2 (Nuclear factor erythroid 2-related factor 2) by Cul3 ubiquitin E3 ligase complex, leading to its proteasomal degradation. Oxidative and electrophilic stresses impair the structural integrity of Keap1-Cul3 ubiquitin E3 ligase complex resulting in the dissociation of Nrf2-Keap1 binding and nuclear accumulation of Nrf2. Studies on tissue-specific Keap1 null mutation have demonstrated the important roles of Keap1 mediated Nrf2 degradation. An increasing body of evidence suggests that loss of functional mutation in Keap1 arbitrates constitutive activation and expression of Nrf2 which in turn provokes the chemotherapeutic resistance in various diseases. The current review addresses the genetic aspects of KEAP1 including somatic mutations and in silico functional profiling of human disease-associated and polymorphic amino acid substitutions.

Broad, Multi-Year Sampling Effort Highlights Complex Dynamics of the Tick-Borne PathogenEhrlichia chaffeensis(Rickettsiales: Anaplasmatacae)

Ehrlichia chaffeensis (Rickettsiales: Anaplasmatacae), an understudied bacterial pathogen emerging in the eastern United States, is increasing throughout the range of its vector, the lone star tick [Amblyomma americanum, L. (Acari: Ixodidae)]. To mitigate human disease risk, we must understand what factors drive E. chaffeensis prevalence. Here, we report patterns of E. chaffeensis prevalence in southeastern Virginia across 4 yr and ask how seasonal weather patterns affect variation in rates of E. chaffeensis occurrence. We collected A. americanum nymphs at 130 plots across southeastern Virginia in 2012, 2013, 2015, and 2016, and used polymerase chain reaction and gel electrophoresis to test for the presence of E. chaffeensis DNA. Prevalence estimates varied among years, ranging from 0.9% to 3.7%, and persistence of E. chaffeensis occurrence varied across space, with some sites never testing positive, and one site testing positive every year. Using generalized linear mixed-effects models, we related E. chaffeensis occurrence to temperature, humidity, vapor-pressure deficit, and precipitation during seasons up to 21 mo prior to sampling. Surprisingly, all support was lent to a positive effect of temperature during the previous fall and winter (i.e., prior to the nymphs' hatching), which we hypothesize to influence reservoir host population dynamics through changes to mortality or natality. Although further work is necessary to truly elucidate the mechanisms at play, our study shows E. chaffeensis distribution to be very dynamic across multiple dimensions, demanding broad concerted monitoring efforts that can consider both space and time.

Role of Selenium Intake for Risk and Development of Hyperthyroidism

To investigate the importance of dietary selenium (Se) for hyperthyroidism. We performed a more in-depth analysis of a large cross-sectional study of 6152 participants from two counties within the Shaanxi Province, China. These counties are characterized by different habitual Se intake. We investigated the effects of a different dietary Se supply (0.02, 0.18, 0.6, or 2.0 ppm Se) on disease development in a mouse model of Graves disease (GD). The cross-sectional study revealed a comparable prevalence of hyperthyroidism, irrespective of Se intake, in both counties. However, an unexpected sex-specific difference was noted, and Se deficiency might constitute a risk factor for hyperthyroidism, especially in males. In a mouse model, pathological thyroid morphology was affected, and greater Se intake exerted some protecting effects on the pathological distortion. Circulating thyroid hormone levels, malondialdehyde concentrations, total antioxidant capacity, and the titer of GD-causing TSH receptor autoantibodies were not affected by Se. Expression analysis of the transcripts in the spleen indicated regulatory effects on genes implicated in the immune response, erythropoiesis, and oxygen status. However, the humoral immune response, including the CD4/CD8 or T-helper 1/T-helper 2 cell ratio and the concentration of regulatory T cells, was similar between the experimental groups, despite the difference in Se intake. Our data have highlighted a sexual dimorphism for the interaction of Se and thyroid disease risk in humans, with indications of a local protective effects of Se on thyroid gland integrity, which appears not to be reflected in the circulating biomarkers tested.

Parasitic interactions among Trypanosoma cruzi, triatomine vectors, domestic animals, and wildlife in Big Bend National Park along the Texas-Mexico border

National parks attract millions of visitors each year. Park visitors, employees, and pets are at risk of infection with various zoonotic pathogens, including Trypanosoma cruzi, causative agent of Chagas disease. Big Bend National Park is located along the Texas-Mexico border in a region with endemic triatomine insects- vectors of T. cruzi- yet the degree to which the parasite is transmitted in this region is unknown. We collected triatomines for T. cruzi detection and discrete typing unit (DTU) determination, and conducted blood meal analyses to determine recent hosts. As an index of domestic/peridomestic transmission, we tested residential dogs in the Park for exposure to T. cruzi. From 2015 to 2017, 461 triatomines of three species—Triatoma rubida, Triatoma gerstaeckeri, and Triatoma protracta—were collected in and around the Park. Adult triatomine encounters peaked in June of each year (52.8% of collections). We detected an overall infection prevalence of 23.1% in adult triatomines (n = 320) and 4.2% in nymph triatomines (n = 24). DTU TcI was the only T. cruzi strain detected. Of 89 triatomines subjected to blood meal analyses, vertebrate host DNA was successfully amplified from 42 (47.2%); blood meal sources included humans, domestic animals, and avian and mammalian wildlife species. Tested dogs were considered positive if reactive on at least two independent serologic assays; we found 28.6% seroprevalence in 14 dogs. These findings reveal interactions between infected triatomines, humans, dogs, and wildlife in and around Big Bend National Park, with potential risk of human disease.

Ecological niche modelling and predicted geographic distribution of Lutzomyia cruzi, vector of Leishmania infantum in South America.

In some transmission foci of Leishmania infantum in Brazil, Lutzomyia cruzi could be considered the main vector of this pathogen. In addition, L. cruzi is a permissive vector of L. amazonensis. Its geographical distribution seems to be restricted and limited to Cerrado and Pantanal biomes, which includes some areas in Brazil and Bolivia. Considering that predicting the distribution of the species involved in transmission cycles is an effective approach for assessing human disease risk, this study aims to predict the spatial distribution of L. cruzi using a multiscale ecological niche model based in both climate and habitat variables. Ecological niche modelling was used to identify areas in South America that are environmentally suitable for this particular vector species, but its presence is not recorded. Vector occurrence records were compiled from the literature, museum collections and Brazilian Health Departments. Bioclimatic variables, altitude, and land use and cover were used as predictors in five ecological niche model algorithms: BIOCLIM, generalised linear model (logistic regression), maximum entropy, random forests, and support vector machines. The vector occurs in areas where annual mean temperature values range from 21.76°C to 26.58°C, and annual total precipitation varies from 1005 mm and 2048 mm. Urban areas were most present around capture locations. The potential distribution area of L. cruzi according to the final ecological niche model spans Brazil and Bolivia in patches of suitable habitats inside a larger climatically favourable area. The bigger portion of this suitable area is located at Brazilian States of Mato Grosso do Sul and Mato Grosso. Our findings identified environmentally suitable areas for L. cruzi in regions without its known occurrence, so further field sampling of sand flies is recommended, especially in southern Goiás State, Mato Grosso do Sul (borders with Mato Grosso, São Paulo and Minas Gerais); and in Bolivian departments Santa Cruz and El Beni.

Toxocara eggs in public places worldwide - A systematic review and meta-analysis

Toxocariasis is a neglected tropical disease of humans. Although many studies have indicated or shown that environmental contamination with Toxocara species eggs is a major risk factor for toxocariasis in humans, there has been no comprehensive analysis of published data or information. Here, we conducted the first systematic review and meta-analysis of current literature to assess the global prevalence of Toxocara eggs in public places (including beaches, parks and playgrounds). We conducted searches of the PubMed, Embase, Scopus and Science Direct databases for relevant studies published until 20 April 2018, and assessed the prevalence rates of Toxocara eggs in public places. We used the random effects model to calculate pooled prevalence estimates, with 95% confidence intervals (CIs), and analysed data in relation to WHO geographical regions. Subgroup analysis and meta-regressions regarding the geographical and environmental variables were also performed. Of 2384 publications identified, 109 studies that tested 42,797 soil samples in 40 countries were included in the meta-analysis. The pooled global prevalence of Toxocara eggs in public places was 21% (95% CI, 16–27%; 13,895/42,797). The estimated prevalence rates in the different WHO regions ranged from 13% to 35%: Western Pacific (35%; 95% CI, 15–58%), Africa (27%; 95% CI, 11–47%), South America (25%; 95% CI, 13–33%), South-East Asia (21%; 95% CI, 3–49%), Middle East and North Africa (18%; 95% CI, 11–24%), Europe (18%; 95% CI, 14–22%), and North and Central Americas (13%; 95% CI, 8–23%). A high prevalence was significantly associated with high geographical longitude (P = 0.04), low latitude (P = 0.02) and high relative environmental humidity (P = 0.04). This meta-analysis of data from published records indicates that public places are often heavily contaminated with eggs of Toxocara. This finding calls for measures to reduce the potential risk of infection and disease in humans.

ANRIL: A lncRNA at the CDKN2A/B Locus With Roles in Cancer and Metabolic Disease.

The CDKN2A/B genomic locus is associated with risk of human cancers and metabolic disease. Although the locus contains several important protein-coding genes, studies suggest disease roles for a lesser-known antisense lncRNA encoded at this locus, called ANRIL. ANRIL is a complex gene containing at least 21 exons in simians, with many reported linear and circular isoforms. Like other genes, abundance of ANRIL is regulated by epigenetics, classic transcription regulation, splicing, and post-transcriptional influences such as RNA stability and microRNAs. Known molecular functions of ANRIL include in cis and in trans gene regulation through chromatin modification complexes, and influence over microRNA signaling networks. Polymorphisms at the ANRIL gene are linked to risk for many different cancers, as well as risk of atherosclerotic cardiovascular disease, bone mass, obesity and type 2 diabetes. A broad array of variable reported impacts of polymorphisms on ANRIL abundance, splicing and function suggests that ANRIL has cell-type and context-dependent regulation and actions. In cancer cells, ANRIL gain of function increases proliferation, metastasis, cell survival and epithelial-mesenchymal transformation, whereas ANRIL loss of function decreases tumor size and growth, invasion and metastasis, and increases apoptosis and senescence. In metabolic disease, polymorphisms at the ANRIL gene are linked to risk of type 2 diabetes, coronary artery disease, coronary artery calcium score, myocardial infarction, and stroke. Intriguingly, with the exception of one polymorphism in exon 2 of ANRIL, the single nucleotide polymorphisms (SNPs) associated with atherosclerosis and diabetes are non-overlapping. Evidence suggests that ANRIL gain of function increases atherosclerosis; in diabetes, a risk-SNP reduced the pancreatic beta cell proliferation index. Studies are limited by the uncertain relevance of rodent models to ANRIL studies, since most ANRIL exons do not exist in mouse. Diverse cell-type-dependent results suggest it is necessary to perform studies in the relevant primary human tissue for each disease. Much remains to be learned about the biology of ANRIL in human health and disease; this research area may lead to insight into disease mechanisms and therapeutic approaches.

Conditional Regression Based on a Multivariate Zero-Inflated Logistic-Normal Model for Microbiome Relative Abundance Data.

The human microbiome plays critical roles in human health and has been linked to many diseases. While advanced sequencing technologies can characterize the composition of the microbiome in unprecedented detail, it remains challenging to disentangle the complex interplay between human microbiome and disease risk factors due to the complicated nature of microbiome data. Excessive numbers e f zero values, high dimensionality, the hierarchical phylogenetic tree and compositional structure are compounded and consequently make existing methods inadequate to appropriately address these issues. We propose a multivariate two-part zero-inflated logistic normal (MZILN) model to analyze the association of disease risk factors with individual microbial taxa and overall microbial community composition. This approach can naturally handle excessive numbers e f zeros and the compositional data structure with the discrete part and the logistic-normal part e f the model. For parameter estimation, an estimating equations approach is employed that enables us to address the complex inter-taxa correlation structure induced by the hierarchical phylogenetic tree structure and the compositional data structure. This model is able to incorporate standard regularization approaches to deal with high dimensionality. Simulation shews that our model outperforms existing methods. Our approach is also compared to ethers using the analysis of real microbiome data.

An interactome perturbation framework prioritizes damaging missense mutations for developmental disorders.

Identifying disease-associated missense mutations remains a challenge, especially in large-scale sequencing studies. Here we establish an experimentally and computationally integrated approach to investigate the functional impact of missense mutations in the context of the human interactome network and test our approach by analyzing ~2,000 de novo missense mutations found in autism subjects and their unaffected siblings. Interaction-disrupting de novo missense mutations are more common in autism probands, principally affect hub proteins, and disrupt a significantly higher fraction of hub interactions than in unaffected siblings. Moreover, they tend to disrupt interactions involving genes previously implicated in autism, providing complementary evidence that strengthens previously identified associations and enhances the discovery of new ones. Importantly, by analyzing de novo missense mutation data from six disorders, we demonstrate that our interactome perturbation approach offers a generalizable framework for identifying and prioritizing missense mutations that contribute to the risk of human disease.

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

BackgroundRecently differential variability has been showed to be valuable in evaluating the association of DNA methylation to the risks of complex human diseases. The statistical tests based on both differential methylation level and differential variability can be more powerful than those based only on differential methylation level. Anh and Wang (2013) proposed a joint score test (AW) to simultaneously detect for differential methylation and differential variability. However, AW’s method seems to be quite conservative and has not been fully compared with existing joint tests.ResultsWe proposed three improved joint score tests, namely iAW.Lev, iAW.BF, and iAW.TM, and have made extensive comparisons with the joint likelihood ratio test (jointLRT), the Kolmogorov-Smirnov (KS) test, and the AW test. Systematic simulation studies showed that: 1) the three improved tests performed better (i.e., having larger power, while keeping nominal Type I error rates) than the other three tests for data with outliers and having different variances between cases and controls; 2) for data from normal distributions, the three improved tests had slightly lower power than jointLRT and AW. The analyses of two Illumina HumanMethylation27 data sets GSE37020 and GSE20080 and one Illumina Infinium MethylationEPIC data set GSE107080 demonstrated that three improved tests had higher true validation rates than those from jointLRT, KS, and AW.ConclusionsThe three proposed joint score tests are robust against the violation of normality assumption and presence of outlying observations in comparison with other three existing tests. Among the three proposed tests, iAW.BF seems to be the most robust and effective one for all simulated scenarios and also in real data analyses.

Efficacy of Recombinase Polymerase Amplification to Diagnose Trypanosoma cruzi Infection in Dogs with Cardiac Alterations from an Endemic Area of Mexico.

Chagas disease is a lingering Public Health problem in Latin America with ∼5.7 million people infected with Trypanosoma cruzi. Transmission is still taking place in most countries of the Americas, including the United States. Dogs are frequently infected with T. cruzi and its high infection prevalence is associated with increased risk of Chagas disease in humans. The city of Mérida in the Yucatan peninsula is endemic for Chagas disease and canines are frequently infected with T. cruzi. The objective of this study was to evaluate the performance of a qualitative point of care (POC) molecular test (RPA-LF, recombinase polymerase amplification-lateral flow) developed in our laboratory for identifying infected dogs. We used retrospective samples of dogs that came for consultation because of cardiac alterations and proved to be infected with T. cruzi as determined by enzyme-linked immunosorbent assay (ELISA), Western blot, and quantitative PCR (qPCR). The analytical sensitivity indicated that RPA-LF amplified T. cruzi DNA in samples containing almost equal to one to two parasites per reaction. Serial twofold dilutions of T. cruzi epimastigotes showed that the test had 95% (19/20) repeatability at concentrations of two parasites per reaction. The test showed no cross reactivity with human DNA or other protozoan parasites (Trypanosoma rangeli, Leishmania spp., and Plasmodium spp.). RPA-LF had the capacity to amplify all discrete typing units (DTUs I-VI) of T. cruzi that circulate in domestic or extradomestic environments. The RPA-LF had 93.2% (95% confidence interval 87.2-98.1) sensitivity and excellent agreement with qPCR used as gold standard (Cohen's Kappa test = 0.963). ELISA was positive in 96.6% (85/88) of dogs, which together with the molecular tests confirmed the frequent contact with infected triatomine bugs in the city of Mérida. These preliminary results on the diagnostic efficacy of the RPA-LF deserve further large-scale field testing of this POC test for T. cruzi infection in endemic areas.

MACARON: a python framework to identify and re-annotate multi-base affected codons in whole genome/exome sequence data.

Predicted deleteriousness of coding variants is a frequently used criterion to filter out variants detected in next-generation sequencing projects and to select candidates impacting on the risk of human diseases. Most available dedicated tools implement a base-to-base annotation approach that could be biased in presence of several variants in the same genetic codon. We here proposed the MACARON program that, from a standard VCF file, identifies, re-annotates and predicts the amino acid change resulting from multiple single nucleotide variants (SNVs) within the same genetic codon. Applied to the whole exome dataset of 573 individuals, MACARON identifies 114 situations where multiple SNVs within a genetic codon induce an amino acid change that is different from those predicted by standard single SNV annotation tool. Such events are not uncommon and deserve to be studied in sequencing projects with inconclusive findings. MACARON is written in python with codes available on the GENMED website (www.genmed.fr). Supplementary data are available at Bioinformatics online.

Agricultural land use and infectious disease risks in southeast Asia: a systematic review and meta analyses

BackgroundAgricultural land use and land-use change activities are a major contributor to biodiversity loss, pollution, and carbon emissions. Evidence from multiple studies also implicates agricultural activities as a factor underlying a range of human infectious disease risks. However, these links have not been systematically assessed or quantified, hindering efforts to incorporate human health effects into land-use decision and policy making. In this study, we test and quantify the association between exposure to agricultural land use and human infectious disease risks, focusing on the highly diverse yet tractable example of southeast Asia. MethodsWe systematically reviewed English peer-reviewed publications from PubMed, EMBASE, Medline, Global Health, Google Scholar, and Web of Science databases between April 24, and Sept 10, 2017. Only studies done in southeast Asia testing the association between land use or changes in land use and infectious disease prevalence or incidence in human beings were included. We extracted crude and adjusted odds ratios (ORs) from the original studies, and for studies that did not present ORs, we calculated crude ORs provided sufficient data were available. We did a meta-analysis with mutually exclusive estimates using a random effects logistic regression model, with heterogeneity of effects addressed using prespecified subgroup analysis, the I2 test for heterogeneity and the Cochrane Q test. We assessed publication bias using funnel plots, a linear regression test, and the trim and fill method, and explored the effect of potential unmeasured confounders with an E-value analysis. The primary outcome was risk of infection in people who worked in agriculture or lived in an agricultural setting. FindingsOf 15 476 unique citations generated from our literature search, 37 articles were included in our meta-analysis. Our results showed that people who live or work in or near agricultural land are more likely to be infected with a pathogen than controls (OR 1·54, 95% CI 1·30–1·83, p<0·0001, E=2·16). Significant between-study heterogeneity was found, thereby warranting the use of subgroup analysis (land-use types and disease categories). No evidence of significant publication or measured or unmeasured confounder bias was detected. InterpretationThe results suggest that agricultural land use consistently exacerbates human infectious disease risks in southeast Asia, highlighting a clear need to consider human health effects of agricultural land use and land-use change policies alongside effects and benefits in other sectors. Although responses clearly vary by land-use and disease types, generalisable results from this and further studies could help identify co-management opportunities for health and the environment. FundingHS has received funding from the Grantham Institute and Commonwealth Scientific and Industrial Research Organisation (CSIRO). PH has received funding from the Natural Environment Research Council.