A Robust Method for Large‐Scale Multiple Hypotheses Testing

When drawing large‐scale simultaneous inference, such as in genomics and imaging problems, multiplicity adjustments should be made, since, otherwise, one would be faced with an inflated type I error. Numerous methods are available to estimate the proportion of true null hypotheses π₀, among a large number of hypotheses tested. Many methods implicitly assume that the π₀ is large, that is, close to 1. However, in practice, mid‐range π₀ values are frequently encountered and many of the widely used methods tend to produce highly variable or biased estimates of π₀. As a remedy in such situations, we propose a hierarchical Bayesian model that produces an estimator of π₀ that exhibits considerably less bias and is more stable. Simulation studies seem indicative of good method performance even when low‐to‐moderate correlation exists among test statistics. Method performance is assessed in simulated settings and its practical usefulness is illustrated in an application to a type II diabetes study.     

An investigation into the antimicrobial effects of adrenomedullin on members of the skin, oral, respiratory tract and gut microflora

Adrenomedullin, a novel vasoactive peptide, is known to be expressed by many surface epithelial cells and it was postulated that this peptide may have a protective role. The objective of the study was to assess the antimicrobial activity of adrenomedullin against members of the human skin, oral, respiratory tract and gut microflora using disc diffusion and broth microdilution assays. All strains of bacteria screened in an agar diffusion assay were sensitive; gram-positive and gram-negative bacteria were equally susceptible. No activity against the yeast Candida albicans was observed. In a broth microdilution assay, minimum inhibitory and minimum bacteriocidal concentrations ranged from 7.75 x 10(-1) to 12.5 microg ml(-1) and 0.003 to > 25.0 microg ml(-1), respectively. We propose an antimicrobial role for adrenomedullin. participating in the prevention of local infection, thus contributing to host defence systems.     

Estimations of the efficacy and reliability of paternity assignments from DNA microsatellite analysis of multiple-sire matings

It is important for bovine DNA testing laboratories to provide the cattle industry with accurate estimates of the efficacy and reliability of DNA tests offered so that end users of this technology can adequately assess the cost-benefits of testing. To address these issues for bovine paternity testing, paternity exclusion probability estimates were obtained from breed panel data and were predictive of the efficacy of the DNA tests used in 39 multiple-sire mating groups, involving 5960 calves and 505 bulls. Paternity testing of these mating groups has demonstrated that the majority involve a variable proportion of unknown sires and this impacts on the reliability of sire allocation. Mathematical models based on binomial or beta-binomial probability distributions were used to estimate the reliability of single-sire allocations from multiple-sire matings involving unknown sires. Reliability of 98-99% is achieved when the exclusion probability is 0.99 or greater, after allowing for up to 20% unknown sires. When the exclusion probability drops below 0.90 and there are 20% unknown sires, the reliability is poor, bringing into question the benefits of testing. This highlights the need for DNA testing laboratories to offer paternity tests with an exclusion power of at least 99%.     

Comparative Study of Agar Diffusion Test and the NCCLS Macrobroth Method for In Vitro Susceptibility Testing of Candida spp.

We performed a prospective double-blind study to evaluate the correlation between inhibition zones obtained by a disk-diffusion test, using Neo-sensitabs of fluconazole (Rosco Diagnostica), and the MICs generated by the NCCLS macrobroth dilution assay. Eighty clinical isolates, representing 5 of the clinically relevant species of Candida, were tested simultaneously by both methods. A clear inverse correlation was found between the results obtained by both tests (r = −0.69). In addition, there was high degree of agreement between methods in the identification of susceptible isolates. However, the resistance definition by disk-diffusion test had a positive predictive value of only 17%. Our data support the hypothesis that Rosco Fluconazole Neo-sensitabs have potential as a screening test for the identification of Candida isolates susceptible to fluconazole. Resistant isolates should be further investigated by standardized broth procedures. This revised version was published online in June 2006 with corrections to the Cover Date.     

The measurement of force/velocity relationships of fresh and fatigued human adductor pollicis muscle

The purpose of the study was to obtain force/velocity relationships for electrically stimulated (80 Hz) human adductor pollicis muscle (n = 6) and to quantify the effects of fatigue. There are two major problems of studying human muscle in situ; the first is the contribution of the series elastic component, and the second is a loss of force consequent upon the extent of loaded shortening. These problems were tackled in two ways. Records obtained from isokinetic releases from maximal isometric tetani showed a late linear phase of force decline, and this was extrapolated back to the time of release to obtain measures of instantaneous force. This method gave usable data up to velocities of shortening equivalent to approximately one-third of maximal velocity. An alternative procedure (short activation, SA) allowed the muscle to begin shortening when isometric force reached a value that could be sustained during shortening (essentially an isotonic protocol). At low velocities both protocols gave very similar data (r2 = 0.96), but for high velocities only the SA procedure could be used. Results obtained using the SA protocol in fresh muscle were compared to those for muscle that had been fatigued by 25 s of ischaemic isometric contractions, induced by electrical stimulation at the ulnar nerve. Fatigue resulted in a decrease of isometric force [to 69 (3)%], an increase in half-relaxation time [to 431 (10)%], and decreases in maximal shortening velocity [to 77 (8)%] and power [to 42 (5)%]. These are the first data for human skeletal muscle to show convincingly that during acute fatigue, power is reduced as a consequence of both the loss of force and slowing of the contractile speed.     

Robustness of group testing in the estimation of proportions

In binomial group testing, unlike one-at-a-time testing, the test unit consists of a group of individuals, and each group is declared to be defective or nondefective. A defective group is one that is presumed to include one or more defective (e.g., infected, positive) individuals and a nondefective group to contain only nondefective individuals. The usual binomial model considers the individuals being grouped as independent and identically distributed Bernoulli random variables. Under the binomial model and presuming that groups are tested and classified without error, it has been shown that, when the proportion of defective individuals is low, group testing is often preferable to individual testing for identifying infected individuals and for estimating proportions of defectives. We discuss the robustness of group testing for estimating proportions when the underlying assumptions of (i) no testing errors and (ii) independent individuals are violated. To evaluate the effect of these model violations, two dilution-effect models and a serial correlation model are considered. Group testing proved to be quite robust to serial correlation. In the presence of a dilution effect, smaller group sizes should be used, but most of the benefits of group testing can still be realized.     

Robustness of the latent variable model for correlated binary data

The marginal regression model offers a useful alternative to conditional approaches to analyzing binary data (Liang, Zeger, and Qaqish, 1992, Journal of the Royal Statistical Society, Series B 54, 3-40). Instead of modelling the binary data directly as do Liang and Zeger (1986, Biometrika 73, 13-22), the parametric marginal regression model developed by Qu et al. (1992, Biometrics 48, 1095-1102) assumes that there is an underlying multivariate normal vector that gives rise to the observed correlated binary outcomes. Although this parametric approach provides a flexible way to model different within-cluster correlation structures and does not restrict the parameter space, it is of interest to know how robust the parameter estimates are with respect to choices of the latent distribution. We first extend the latent modelling to include multivariate t-distributed latent vectors and assess the robustness in this class of distributions. Then we show through a simulation that the parameter estimates are robust with respect to the latent distribution even if latent distribution is skewed. In addtion to this empirical evidence for robustness, we show through the iterative algorithm that the robustness of the regression coefficents with respect to misspecifications of covariance structure in Liang and Zeger's model in fact indicates robustness with respect to underlying distributional assumptions of the latent vector in the latent variable model.     

ZK-I菌发酵液中抗真菌活性化合物的纯化与部分特性研究

芽孢杆菌属(Bacillus sp．)菌株ZK-I对甜瓜疫霉病、棉花枯萎病等多种作物真菌病害以及啤酒酵母都有很强的抑制作用。报道了ZK-I菌发酵液中抗真菌化合物的分离纯化及其部分特性。该菌株发酵液经过酸沉淀、正相硅胶层析以及C_(18)相硅胶层析等步骤,得到四个化合物,经HPLC检测均为单峰,通过质谱测定分子量并结合高效液相检测结果确定它们为同系物,其中A为捷安肽素A,并推测其余化合物为捷安肽素A的结构类似物。     

Antibiotic activity and structural analysis of the scorpion-derived antimicrobial peptide IsCT and its analogs

IsCT is a non-cell-selective antimicrobial peptide isolated from the scorpion Opisthacanthus madagascariensis that has potent cytolytic activity against both mammalian and bacterial cells. To investigate the structure-activity relationships of IsCT and to design novel peptide antibiotics with bacterial cell selectivity, we synthesized several analogs of IsCT and determined their three-dimensional structures in solution by 2D-NMR spectroscopy. IsCT has a linear alpha-helical structure from Gly3 to Phe13, and [K7]-IsCT has a linear alpha-helical structure from Leu2 to Phe13. [K7, P8, K11]-IsCT, which has a bend in its middle region, exhibited the highest antibacterial activity without hemolytic activity, suggesting that its proline-induced bend is an important determinant of this selectivity. Tryptophan fluorescence showed that the high selectivity of [K7, P8, K11]-IsCT toward bacterial cells is closely correlated with its highly selective interaction with negatively charged phospholipids. Its potent activity against antibiotic-resistant bacteria suggests that [K7, P8, K11]-IsCT may serve as a promising lead candidate in the development of new peptide antibiotics.