A note on the empirical Bayes heterogeneity variance estimator in meta-analysis

This paper focuses on the empirical Bayes (EB) or Mandel-Paule estimator of the heterogeneity variance in meta-analysis, which was discussed by Morris and proposed in earlier publications by Mandel and Paule in an inter-laboratory context. The relationship of the EB estimator to other heterogeneity variance estimators typically used in meta-analysis is explored, and approximate variance estimators for the EB estimate of the heterogeneity variance are proposed based on the M-estimation method. Statistical inference for the overall treatment effect using the EB estimator and the proposed standard errors is discussed using two example data sets from meta-analysis applications.     

Impact of a Spatial Repellent on Malaria Incidence in Two Villages in Sumba,Indonesia

A randomized, double-blinded, placebo-controlled study was conducted to examine the effect of spatial repellent (SR) in households at risk of malaria in Indonesia. Following presumptive radical cure for malaria in 180 adult men representing sentinels of new infection in four clusters within two villages, all households were given either metofluthrin or placebo mosquito coils. Weekly blood smear screening and human-landing mosquito catches were done throughout the 6 months intervention. Malaria infections occurred in 61 subjects living in placebo households and 31 subjects living in SR coil households, suggesting a 52% protective effect of SR. Likewise, anopheles indoor human landing rates were 32% lower in homes receiving SR coils. Differences in the malaria attack rate between SR- and placebo-treated homes was significant when not accounting for the effects of clustering. When the analysis was adjusted for intra-cluster correlation, the differences between SR- and placebo-treated homes were not statistically significant. The findings provide evidence of SR public health benefit and support a larger trial statistically powered to detect those effects.     

Novel retinal findings in β-thalassemia major: older age and higher ferritin level as the risk factors

Graefe's Archive for Clinical and Experimental Ophthalmology - To investigate retinal changes in β-thalassemia major patients and identify their association with systemic risk factors. In...     

A note on variance estimation in random effects meta-regression

For random effects meta-regression inference, variance estimation for the parameter estimates is discussed. Because estimated weights are used for meta-regression analysis in practice, the assumed or estimated covariance matrix used in meta-regression is not strictly correct, due to possible errors in estimating the weights. Therefore, this note investigates the use of a robust variance estimation approach for obtaining variances of the parameter estimates in random effects meta-regression inference. This method treats the assumed covariance matrix of the effect measure variables as a working covariance matrix. Using an example of meta-analysis data from clinical trials of a vaccine, the robust variance estimation approach is illustrated in comparison with two other methods of variance estimation. A simulation study is presented, comparing the three methods of variance estimation in terms of bias and coverage probability. We find that, despite the seeming suitability of the robust estimator for random effects meta-regression, the improved variance estimator of Knapp and Hartung (2003) yields the best performance among the three estimators, and thus may provide the best protection against errors in the estimated weights.     

Exact unconditional tests for testing non-inferiority in matched-pairs design

The problem of testing non-inferiority in a 2 x 2 matched-pairs sample is considered. Two exact unconditional tests based on the standard and the confidence interval p-values are proposed. Although tests of non-inferiority have two nuisance parameters under the null hypothesis, the exact tests are defined by reducing the dimension of nuisance parameter space from two to one using the monotonicity of the distribution. The exact sizes and powers of these tests and the existing asymptotic test are considered. The exact tests are found to be accurate in view of their size property. In addition, the exact test based on the confidence interval p-value is more powerful than the other exact test. It is shown that the asymptotic test is inaccurate, that is, its size exceeds the claimed nominal level alpha. Therefore, it recommends a cautious approach in use of the asymptotic test for the problem of testing non-inferiority, particularly when sample sizes are small or moderately large.     

Sphingosine modulates myocyte electrophysiology, induces negative inotropy, and decreases survival after myocardial ischemia.

Contractility studies in isolated feline myocytes have demonstrated that sphingosine, a metabolite stimulated by tumor necrosis factor (TNF) binding, decreases intracellular calcium release and depresses inotropic activity. This study investigated the electrophysiologic effects of sphingosine in isolated cat myocytes as well as the cardiodynamic consequence of TNF, sphingosine, and its metabolic precursors in vivo. In cat myocytes, sphingosine markedly decreased action potential duration, lowered action potential plateau, and inhibited L-type calcium current (I(Ca-L)). After administration of TNF, sphingomyelin, C2-ceramide, or sphingosine, only C2-ceramide and sphingosine depressed cardiac function in normal rats. Negative inotropic effects of C2-ceramide were attenuated by N-oleoylethanolamine (NOE), a ceramidase inhibitor that blocks sphingosine formation. Rats pretreated with NOE before undergoing 30 min of acute regional myocardial ischemia followed by 150 min of reperfusion exhibited improved survival. Most deaths could be attributed to acute pump failure accompanied by bradycardia. Myocardial infarct size and peak serum TNF were not different between NOE- and vehicle-treated groups (3,908 +/- 1097 pg/ml and 3,027 +/- 846 pg/ml, respectively). These results indicate that sphingosine exerts direct inhibitory effects on the action potential and I(Ca-L) in isolated feline myocytes, consistent with previously reported sphingosine activity on I(Ca-L) in isolated rat myocytes. The in vivo study suggests that reducing sphingosine production with N-oleoylethanolamine attenuates cardiodepression and can improve overall survival after ischemic injury. Clearly, agents that modulate sphingosine production limit cardiodepression and may provide a therapeutic benefit in clinical conditions of myocardial inflammatory injury.     

Correlation between repair patch ligation and nucleosome rearrangement in human cells treated with bleomycin, UV radiation or methyl methanesulfonate.

We have examined ligation and nucleosome rearrangement of repair patches in chromatin of human fibroblasts damaged with bleomycin (BLM), UV radiation and methyl methanesulfonate (MMS) to follow completion of excision repair involving different combinations of repair enzymes. Conditions were used that allowed analysis of the correlation between these two events over a large range (i.e. from 5% to greater than 99% ligated). Cells exposed to BLM were reversibly permeabilized with L-alpha-lysophosphatidylcholine and pulse-labeled with either [3H]dTTP or [3H]dThd to label selectively cells that 'reseal their membranes' at different rates. A striking difference is observed in the rates of ligation of these nascent repair patches, in that those labeled with [3H]dTTP are ligated much slower (25-50% unligated after 24 h) than those labeled with [3H]dThd (less than 5% unligated after 6 h). The nuclease sensitivity of [3H]dTTP-labeled patches also decreases more slowly, indicating that the rate of nucleosome rearrangement decreases compared to that of repair patches labeled with [3H]dThd. The rates of repair patch ligation and loss of nuclease sensitivity were also modulated in intact cells exposed to UV radiation or MMS by treatment with aphidicolin and/or hydroxyurea. A plot of relative nuclease sensitivity versus fraction of ligated repair patches yields an overall linear correlation of greater than 0.8 in each case, indicating that these two features of nascent repair patches are 'moderately coupled' events. These results support the idea that ligation of repair patches is a prerequisite for nucleosome rearrangement following three different modes of excision repair.