Haplotype frequency estimation error analysis in the presence of missing genotype data

BACKGROUND: Increasingly researchers are turning to the use of haplotype analysis as a tool in population studies, the investigation of linkage disequilibrium, and candidate gene analysis. When the phase of the data is unknown, computational methods, in particular those employing the Expectation-Maximisation (EM) algorithm, are frequently used for estimating the phase and frequency of the underlying haplotypes. These methods have proved very successful, predicting the phase-known frequencies from data for which the phase is unknown with a high degree of accuracy. Recently there has been much speculation as to the effect of unknown, or missing allelic data – a common phenomenon even with modern automated DNA analysis techniques – on the performance of EM-based methods. To this end an EM-based program, modified to accommodate missing data, has been developed, incorporating non-parametric bootstrapping for the calculation of accurate confidence intervals. RESULTS: Here we present the results of the analyses of various data sets in which randomly selected known alleles have been relabelled as missing. Remarkably, we find that the absence of up to 30% of the data in both biallelic and multiallelic data sets with moderate to strong levels of linkage disequilibrium can be tolerated. Additionally, the frequencies of haplotypes which predominate in the complete data analysis remain essentially the same after the addition of the random noise caused by missing data. CONCLUSIONS: These findings have important implications for the area of data gathering. It may be concluded that small levels of drop out in the data do not affect the overall accuracy of haplotype analysis perceptibly, and that, given recent findings on the effect of inaccurate data, ambiguous data points are best treated as unknown

Transcriptome Analysis of CD4+ T Cells in Coeliac Disease Reveals Imprint of BACH2 and IFNγ Regulation

peer-reviewedData Availability: The raw sequencing reads (FASTQ files) and sequence read counts mapped to UCSC hg19 for each of the 74 transcriptomes sequenced in this study have been deposited at Gene Expression Omnibus (GEO) accession GSE69549.This project was funded by Science Foundation Ireland Grant number 09/IN.1/B2640 to RM.Genetic studies have to date identified 43 genome wide significant coeliac disease susceptibility (CD) loci comprising over 70 candidate genes. However, how altered regulation of such disease associated genes contributes to CD pathogenesis remains to be elucidated. Recently there has been considerable emphasis on characterising cell type specific and stimulus dependent genetic variants. Therefore in this study we used RNA sequencing to profile over 70 transcriptomes of CD4+ T cells, a cell type crucial for CD pathogenesis, in both stimulated and resting samples from individuals with CD and unaffected controls. We identified extensive transcriptional changes across all conditions, with the previously established CD gene IFNy the most strongly up-regulated gene (log2 fold change 4.6; Padjusted = 2.40x10-11) in CD4+ T cells from CD patients compared to controls. We show a significant correlation of differentially expressed genes with genetic studies of the disease to date (Padjusted = 0.002), and 21 CD candidate susceptibility genes are differentially expressed under one or more of the conditions used in this study. Pathway analysis revealed significant enrichment of immune related processes. Co-expression network analysis identified several modules of coordinately expressed CD genes. Two modules were particularly highly enriched for differentially expressed genes (P</iframe

Reflections on the process of using systematic review techniques to evaluate the literature regarding the neurotoxicity of low level exposure to organophosphate pesticides

We undertook a systematic review (incorporating meta-analysis) of the literature concerning the neurotoxicity of cumulative low level occupational exposure to organophosphate pesticides, which was published online by the journal Critical Reviews in Toxicology in 2012. As far as we are aware, we were the first research team to attempt quantitative evaluation of study findings on this topic, using meta-analysis. We wish to encourage others to apply systematic review techniques in chemical risk assessment to reduce bias, increase transparency and better inform public policy. We thought it would be useful to share our experience of undertaking a systematic review in the hope of dispelling misconceptions about the complexity, time and resource issues involved along with the view that meta-analysis is meaningless when studies are not homogeneous. In this commentary paper we reflect on aspects of the process which were relatively straightforward; aspects which were more challenging; the advantages of using systematic review techniques; and the advantages and limitations of using statistical techniques such as meta-analysis in this context

Neurobehavioral problems following low-level exposure to organophosphate pesticides: a systematic and meta-analytic review

Meta-analysis was carried out to determine the neurotoxic effects of long-term exposure to low levels of organophosphates (OPs) in occupational settings. Concern about the effects of OPs on human health has been growing as they are increasingly used throughout the world for a variety of agricultural, industrial and domestic purposes. The neurotoxic effects of acute poisoning are well established but the possibility that low-level exposure causes ill health is controversial. It is important to get a clear answer to this question as more individuals are at risk of low-level exposure than acute poisoning. Although a number of reviews on this topic have been published in the past, authors have come to conflicting conclusions. To date, none of these reviews have attempted quantitative evaluation of study findings using meta-analysis. This paper reviews the available evidence concerning the neurotoxicity of low-level occupational exposure to OPs and goes on to report the results of a meta-analysis of 14 studies which fulfilled criteria for this type of statistical analysis (means and standard deviations of dependant variables reported). Data were assimilated from more than 1600 participants. The majority of well designed studies found a significant association between low-level exposure to OPs and impaired neurobehavioral function which is consistent, small to moderate in magnitude and concerned primarily with cognitive functions such as psychomotor speed, executive function, visuospatial ability, working and visual memory. Unresolved issues in the literature which should become the focus of further studies are highlighted and discussed

Diagnosis and management of schistosomiasis

The authors’ studies on schistosomiasis have received financial support from various sources including: the UNICEF/UNDP/World Bank/WHO Special Program for Research and Training in Tropical Diseases; the National Health and Medical Research Council of Australia; the Wellcome Trust (UK); the Sandler Foundation (USA); the Dana Foundation (USA); and the National Institute of Allergy and Infectious Diseases

Oriental schistosomiasis with neurological complications: case report

We describe a case of cerebral schistosomiasis, caused by Asian (oriental) Schistosoma japonicum trematode blood flukes, in a young Chinese patient and its management. We also provide a brief update for physicians on the clinical features, diagnosis and treatment of schistosomiasis, with particular emphasis on neuroschistosomiasis, the most severe clinical outcome associated with this parasitic infection

Two-year impact of praziquantel treatment for Schistosoma japonicum infection in China: re-infection, subclinical disease and fibrosis marker measurements

We studied a community cohort of 193 individuals exposed to endemic Schistosoma japonicum infection in the Dongting Lake region of China to assess subclinical morbidity and the 2-year benefit of curative therapy (praziquantel) administered in 1996. Prevalence and intensity of S. japonicum infection before treatment were 28% and 192 eggs per gram faeces (epg), respectively. Two years after cure, 22% of the cohort were reinfected, but with a lighter intensity (67 epg). Sixty-four subjects (37%) showed significant improvement in ultrasound parenchyma images after treatment and 51 subjects (54%) showed significant improvement of periportal fibrosis. Left-lobe enlargement also reversed (P 0·05). The serum levels of laminin and collagen IV associated with reinfection and intensity and hyaluronic acid levels correlated with ultrasound findings (P < 0·01). Overall, treatment induced a marked decrease in subclinical hepatosplenic morbidity attributable to S. japonicum although low-intensity re-infection after treatment remained relatively frequent. Stratified analysis and logistic models evaluated potential confounding factors for assessment of treatment effects on hepatic fibrosis. S. japonicum infection and moderate-heavy alcohol intake interacted: improvement in parenchymal morbidity was impeded among drinkers (P < 0·05). Chemotherapy focused on at-risk residents controls prevalent subclinical hepatic fibrosis but re-infection indicates the need for complementary control strategie

Septic shock is correlated with asymmetrical dimethyl arginine levels, which may be influenced by a polymorphism in the dimethylarginine dimethylaminohydrolase II gene: a prospective observational study

INTRODUCTION: Asymmetrical dimethyl arginine (ADMA) is an endogenous non-selective inhibitor of nitric oxide synthase that may influence the severity of organ failure and the occurrence of shock secondary to an infectious insult. Levels may be genetically determined by a promoter polymorphism in a regulatory gene encoding dimethylarginine dimethylaminohydrolase II (DDAH II), which functions by metabolising ADMA to citrulline. The aim of this study was to examine the association between ADMA levels and the severity of organ failure and shock in severe sepsis and also to assess the influence of a promoter polymorphism in DDAH II on ADMA levels. METHODS: A prospective observational study was designed, and 47 intensive care unit (ICU) patients with severe sepsis and 10 healthy controls were enrolled. Serum ADMA and IL-6 were assayed on admission to the ICU and seven days later. Allelic variation for a polymorphism at position -449 in the DDAH II gene was assessed in each patient. Clinical and demographic details were also collected. RESULTS: On day 1 more ADMA was detectable in the ICU group than in the control group (p = 0.005). Levels subsequently increased during the first week in ICU (p = 0.001). ADMA levels were associated with vasopressor requirements on day one (p = 0.001). ADMA levels and Sequential Organ Failure Assessment scores were directly associated on day one (p = 0.0001) and day seven (p = 0.002). The degree of acidaemia and lactaemia was directly correlated with ADMA levels at both time points (p < 0.01). On day seven, IL-6 was directly correlated with ADMA levels (p = 0.006). The variant allele with G at position -449 in the DDAH II gene was associated with increased ADMA concentrations at both time points (p < 0.05). CONCLUSION: Severity of organ failure, inflammation and presence of early shock in severe sepsis are associated with increased ADMA levels. ADMA concentrations may be influenced by a polymorphism in the DDAH II gene