On modeling locus heterogeneity using mixture distributions

BACKGROUND: Locus heterogeneity poses a major difficulty in mapping genes that influence complex genetic traits. A widely used approach to deal with this problem involves modeling linkage data in terms of finite mixture distributions. In its simplest setup, also known as the admixture approach, a single parameter is used to model the probability that the disease-causing gene of a family is linked to a reference marker. This parameter is usually interpreted as the overall proportion of linked families. RESULTS: In this article, we address two issues regarding the admixture approach. First, we tackle the question of whether the single parameter of linked proportion is well defined in general. By formulating the likelihood under a classification scheme based on distributions, we show that such a parameter is meaningful only when a certain well-characterized condition is met. Second, we study a condition given in the literature for validating the admixture approach. A counter example is constructed to illustrate that the condition does not necessarily lead to valid estimates. CONCLUSIONS: Estimators from the admixture approach may be inconsistent. This holds even if a condition given in the literature to validate the approach is satisfied

A new Bayesian approach incorporating covariate information for heterogeneity and its comparison with HLOD

We consider a new Bayesian approach for heterogeneity that can take into account categorical covariates, if available. We use the Genetic Analysis Workshop 14 simulated data to first compare the Bayesian approach with the heterogeneity LOD, when no covariate information is used. We find that the former is more powerful, while the two approaches have comparable false-positive rates. We then include informative covariates in the Bayesian approach and find that it tends to give more precise interval estimates of the disease gene location than when covariates are not included. We had knowledge of the simulation models at the time we performed the analyses

Retrospective review of maternal deaths and maternal near misses due to major obstetric haemorrhage at a tertiary care centre in India

Background: Maternal near miss (MNM) is now widely accepted as a better indicator of maternal health than maternal death and reflects the quality of obstetric care in a particular institution.Methods: This is a retrospective study conducted at Lady Hardinge Medical College and Smt. Sucheta Kriplani  Hospital over a period of 12 months (April 2016-March 2017), of  all cases of maternal death and near miss maternal deaths due to major obstetric haemorrhage(MOH).Results: During the period reviewed, there were 13,083 deliveries, 12,958 live births and 37 maternal deaths. There were 30 cases of near miss maternal deaths and 2 maternal mortalities due to MOH. The mortality index was 6.25%. Severe maternal outcome ratio (SMOR) was  2.46.Among the near miss cases (n=30), morbidly adherent placenta was the cause in 26.6% of cases(n=8), postpartum hemorrhage in 23% of cases(n=7); rupture uterus in 13% cases(n=4); massive abruption in 13% of cases(n=4) and placenta praevia with antepartum haemorrhage in 3% of cases(n=1). Early obstetric haemorrhage due to ruptured ectopic pregnancy and incomplete abortion resulted in MNM in 16% (n=5) and 3.3% (n=1) cases respectively.It was observed that in 40% (n=12) of MNM cases (8 cases of morbidly adherent placenta plus 4 cases of rupture uterus), previous cesarean section was the single most important causative factor  for the morbidity of the patient.Conclusions: Reduction in cesarean section rates is imperative to reduce morbidity and mortality associated with MOH.

Linkage analysis of the simulated data – evaluations and comparisons of methods

The goal of this study is to evaluate, compare, and contrast several standard and new linkage analysis methods. First, we compare a recently proposed confidence set approach with MAPMAKER/SIBS. Then, we evaluate a new Bayesian approach that accounts for heterogeneity. Finally, the newly developed software SIMPLE is compared with GENEHUNTER. We apply these methods to several replicates of the Genetic Analysis Workshop 13 simulated data to assess their ability to detect the high blood pressure genes on chromosome 21, whose positions were known to us prior to the analyses. In contrast to the standard methods, most of the new approaches are able to identify at least one of the disease genes in all the replicates considered

Assessment of the pharmacokinetics, safety, and tolerability of levothyroxine sodium in healthy Indian volunteers

Background: Few studies have assessed the pharmacokinetics of various marketed formulations of levothyroxine available in the Indian market. Here, we assessed the pharmacokinetics and safety of Thyronorm® 100 in healthy Indian volunteers.Methods: The primary and secondary objectives were to determine the pharmacokinetic profile and to monitor safety and tolerability of 600 µg of levothyroxine, respectively. Eligible subjects received a single oral dose of 6×100 µg of levothyroxine, and pharmacokinetic profiles were monitored up to 432 hours post-dose. Safety assessments included exposure of study drug and incidence of adverse events (AEs) and serious AEs. The mean plasma concentration of LT4 versus time profile was presented on both untransformed and log-transformed scales.Results: Of 20 enrolled subjects, 1 was discontinued due to an AE of pain, unrelated to study drug. The mean [standard deviation (SD)] age and body mass index of subjects were 35.7 (6.33) years and 25.0 (3.0) kg/m2, respectively. Following baseline correction, the mean maximum observed drug concentration (Cmax) and area under the plasma concentration-time curve measured to the last quantifiable concentration (AUC0-t) of free thyroxine were found to be 68.4 (12.09) ng/ml and 6760.0 (2065.05) ng×hr/ml, respectively, with an elimination half-life (t1/2) of 205.6 (180.26) hrs and a residual area of 24.6%. The median time to first observed maximum drug concentration (Tmax) was 2.5 (1.5-2.5) hrs.Conclusions: These parameters were in accordance with those of other marketed formulations and confirmed the pharmacokinetics and safety of Thyronorm® 100 in healthy volunteers from India

Rheology Based Design of Shear Thickening Fluid for Soft Body Armor Applications

The ballistic resistance of high-strength fabrics improves upon impregnation with Shear Thickening Fluids (STFs). The performance of such STF treated fabrics depends on the rheological properties of the STF which in turn are governed by the physicochemical properties of the STF. The present study utilizes rheological characterization of shear thickening silica-polyethylene glycol dispersions (of different material configurations in terms of packing fraction, particle size and continuous phase viscosity) to assess their performance and obtain the best STF material configuration for ballistic body armor applications based on the design criteria proposed herein. The ballistic performance assessment results showed that the STFs with high packing fractions which thicken discontinuously, are highly effective compared to the continuously shear thickening fluids. Furthermore, the use of smaller particle size dispersed phase in the STF formulation was determined to be economical. Also, the use of lower molecular weight dispersion medium was suggested as it allows for a broader working temperature range of the STF. Additionally, the technological issues associated with the development and the practical application of STF-Armor were addressed