A note on the use of the generalized odds ratio in meta-analysis of association studies involving bi- and tri-allelic polymorphisms

<p>Abstract</p> <p>Background</p> <p>The generalized odds ratio (GOR) was recently suggested as a genetic model-free measure for association studies. However, its properties were not extensively investigated. We used Monte Carlo simulations to investigate type-I error rates, power and bias in both effect size and between-study variance estimates of meta-analyses using the GOR as a summary effect, and compared these results to those obtained by usual approaches of model specification. We further applied the GOR in a real meta-analysis of three genome-wide association studies in Alzheimer's disease.</p> <p>Findings</p> <p>For bi-allelic polymorphisms, the GOR performs virtually identical to a standard multiplicative model of analysis (e.g. per-allele odds ratio) for variants acting multiplicatively, but augments slightly the power to detect variants with a dominant mode of action, while reducing the probability to detect recessive variants. Although there were differences among the GOR and usual approaches in terms of bias and type-I error rates, both simulation- and real data-based results provided little indication that these differences will be substantial in practice for meta-analyses involving bi-allelic polymorphisms. However, the use of the GOR may be slightly more powerful for the synthesis of data from tri-allelic variants, particularly when susceptibility alleles are less common in the populations (≤10%). This gain in power may depend on knowledge of the direction of the effects.</p> <p>Conclusions</p> <p>For the synthesis of data from bi-allelic variants, the GOR may be regarded as a multiplicative-like model of analysis. The use of the GOR may be slightly more powerful in the tri-allelic case, particularly when susceptibility alleles are less common in the populations.</p

A rare genomic duplication in 2p14 underlies autosomal dominant hearing loss DFNA58

Here we define a ~ 200Kb genomic duplication in 2p14 as the genetic signature that segregates with post-lingual progressive sensorineural autosomal dominant hearing loss in 20 affected individuals from the DFNA58 family, first reported in 2009. The duplication includes two entire genes, PLEK and CNRIP1, and the first exon of PPP3R1 (protein-coding), in addition to four uncharacterized long noncoding (lnc) RNA genes and part of a novel protein-coding gene. Quantitative analysis of mRNA expression in blood samples revealed selective overexpression of CNRIP1 and of two lncRNA genes (LOC107985892 and LOC102724389) in all affected members tested, but not in unaffected ones. Qualitative analysis of mRNA expression identified also fusion transcripts involving parts of PPP3R1, CNRIP1 and an intergenic region between PLEK and CNRIP1, in the blood of all carriers of the duplication, but were heterogeneous in nature. By in situ hybridization and immunofluorescence, we showed that Cnrip1, Plek and Ppp3r1 genes are all expressed in the adult mouse cochlea including the spiral ganglion neurons, suggesting changes in expression levels of these genes in the hearing organ could underlie the DFNA58 form of deafness. Our study highlights the value of studying rare genomic events leading to hearing loss such as copy number variations. Further studies will be required to determine which of these genes, either coding proteins or non-coding RNAs, is or are responsible for DFNA58 hearing loss

Stroke Correlates in Chagasic and Non-Chagasic Cardiomyopathies

BACKGROUND: Aging and migration have brought changes to the epidemiology and stroke has been shown to be independently associated with Chagas disease. We studied stroke correlates in cardiomyopathy patients with focus on the chagasic etiology. METHODOLOGY/PRINCIPAL FINDINGS: We performed a cross-sectional review of medical records of 790 patients with a cardiomyopathy. Patients with chagasic (329) and non-chagasic (461) cardiomyopathies were compared. There were 108 stroke cases, significantly more frequent in the Chagas group (17.3% versus 11.1%; p<0.01). Chagasic etiology (odds ratio [OR], 1.79), pacemaker (OR, 2.49), atrial fibrillation (OR, 3.03) and coronary artery disease (OR, 1.92) were stroke predictors in a multivariable analysis of the entire cohort. In a second step, the population was split into those with or without a Chagas-related cardiomyopathy. Univariable post-stratification stroke predictors in the Chagas cohort were pacemaker (OR, 2.73), and coronary artery disease (CAD) (OR, 2.58); while atrial fibrillation (OR, 2.98), age over 55 (OR, 2.92), hypertension (OR, 2.62) and coronary artery disease (OR, 1.94) did so in the non-Chagas cohort. Chagasic stroke patients presented a very high frequency of individuals without any vascular risk factors (40.4%; OR, 4.8). In a post-stratification logistic regression model, stroke remained associated with pacemaker (OR, 2.72) and coronary artery disease (OR, 2.60) in 322 chagasic patients, and with age over 55 (OR, 2.38), atrial fibrillation (OR 3.25) and hypertension (OR 2.12; p = 0.052) in 444 non-chagasic patients. CONCLUSIONS/SIGNIFICANCE: Chagas cardiomyopathy presented both a higher frequency of stroke and an independent association with it. There was a high frequency of strokes without any vascular risk factors in the Chagas as opposed to the non-Chagas cohort. Pacemaker rhythm and CAD were independently associated with stroke in the Chagas group while age over 55 years, hypertension and atrial fibrillation did so in the non-Chagas cardiomyopathies

Evidence That Lipopolisaccharide May Contribute to the Cytokine Storm and Cellular Activation in Patients with Visceral Leishmaniasis

Visceral leishmaniasis (VL) affects organs rich in lymphocytes, being characterized by intense Leishmania-induced T-cell depletion and reduction in other hematopoietic cells. In other infectious and non-infectious diseases in which the immune system is affected, such as HIV-AIDS and inflammatory bowel disease, damage to gut-associated lymphocyte tissues occurs, enabling luminal bacteria to enter into the circulation. Lipopolisaccharide (LPS) is a bacterial product that stimulates macrophages, leading to the production of pro-inflammatory cytokines and other soluble factors such as MIF, which in turn activate lymphocytes. Continuous and exaggerated stimulation causes exhaustion of the T-cell compartment, contributing to immunosuppression

Between-day reliability of electromechanical delay of selected neck muscles during performance of maximal isometric efforts

<p>Abstract</p> <p>Background</p> <p>The purpose of this study was to assess the between-day reliability of the electromechanical delay (EMD) of selected neck muscles during the performance of maximal isometric contractions in five different directions.</p> <p>Methods</p> <p>Twenty-one physically active males participated in two testing sessions separated by seven to eight days. Using a custom-made fixed frame dynamometer, cervical force and surface electromyography (EMG) were recorded bilaterally from the splenius capitis, upper trapezius and sternocleidomastoid muscles during the performance of efforts in extension, flexion, left and right lateral bending, and protraction. The EMD was extracted using the Teager-Kaiser Energy Operator. Reliability indices calculated for each muscle in each testing direction were: the difference in scores between the two testing sessions and corresponding 95% confidence intervals, the standard error of measurement (SEM) and intra-class correlation coefficients (ICC).</p> <p>Results</p> <p>EMD values showed no evidence of systematic difference between the two testing sessions across all muscles and testing directions. The SEM for extension, flexion and lateral bending efforts ranged between 2.5 ms to 4.8 ms, indicating a good level of measurement precision. For protraction, SEM values were higher and considered to be imprecise for research and clinical purposes. ICC values for all muscles across all testing directions ranged from 0.23 to 0.79.</p> <p>Conclusion</p> <p>EMD of selected neck muscles can be measured with sufficient precision for the assessment of neck muscle function in an athletic population in the majority of directions tested.</p

Cost-effectiveness analysis of PCR for the rapid diagnosis of pulmonary tuberculosis

<p>Abstract</p> <p>Background</p> <p>Tuberculosis is one of the most prominent health problems in the world, causing 1.75 million deaths each year. Rapid clinical diagnosis is important in patients who have co-morbidities such as Human Immunodeficiency Virus (HIV) infection. Direct microscopy has low sensitivity and culture takes 3 to 6 weeks <abbrgrp><abbr bid="B1">1</abbr><abbr bid="B2">2</abbr><abbr bid="B3">3</abbr></abbrgrp>. Therefore, new tools for TB diagnosis are necessary, especially in health settings with a high prevalence of HIV/TB co-infection.</p> <p>Methods</p> <p>In a public reference TB/HIV hospital in Brazil, we compared the cost-effectiveness of diagnostic strategies for diagnosis of pulmonary TB: Acid fast bacilli smear microscopy by Ziehl-Neelsen staining (AFB smear) plus culture and AFB smear plus colorimetric test (PCR dot-blot).</p> <p>From May 2003 to May 2004, sputum was collected consecutively from PTB suspects attending the Parthenon Reference Hospital. Sputum samples were examined by AFB smear, culture, and PCR dot-blot. The gold standard was a positive culture combined with the definition of clinical PTB. Cost analysis included health services and patient costs.</p> <p>Results</p> <p>The AFB smear plus PCR dot-blot require the lowest laboratory investment for equipment (US$20,000). The total screening costs are 3.8 times for AFB smear plus culture versus for AFB smear plus PCR dot blot costs (US$ 5,635,760 versus US$1,498, 660). Costs per correctly diagnosed case were US$ 50,773 and US$13,749 for AFB smear plus culture and AFB smear plus PCR dot-blot, respectively. AFB smear plus PCR dot-blot was more cost-effective than AFB smear plus culture, when the cost of treating all correctly diagnosed cases was considered. The cost of returning patients, which are not treated due to a negative result, to the health service, was higher in AFB smear plus culture than for AFB smear plus PCR dot-blot, US$ 374,778,045 and US$ 110,849,055, respectively.</p> <p>Conclusion</p> <p>AFB smear associated with PCR dot-blot associated has the potential to be a cost-effective tool in the fight against PTB for patients attended in the TB/HIV reference hospital.</p