Meta‐Analysis of Diagnostic Test Accuracy Studies with Multiple Thresholds using Survival Methods

Diagnostic tests play an important role in clinical practice. The objective of a diagnostic test accuracy study is to compare an experimental diagnostic test with a reference standard. The majority of these studies dichotomize test results into two categories: negative and positive. But often the underlying test results may be categorized into more than two, ordered, categories. This article concerns the situation where multiple studies have evaluated the same diagnostic test with the same multiple thresholds in a population of non‐diseased and diseased individuals. Recently, bivariate meta‐analysis has been proposed for the pooling of sensitivity and specificity, which are likely to be negatively correlated within studies. These ideas have been extended to the situation of diagnostic tests with multiple thresholds, leading to a multinomial model with multivariate normal between‐study variation. This approach is efficient, but computer‐intensive and its convergence is highly dependent on starting values. Moreover, monotonicity of the sensitivities/specificities for increasing thresholds is not guaranteed. Here, we propose a Poisson‐correlated gamma frailty model, previously applied to a seemingly quite different situation, meta‐analysis of paired survival curves. Since the approach is based on hazards, it guarantees monotonicity of the sensitivities/specificities for increasing thresholds. The approach is less efficient than the multinomial/normal approach. On the other hand, the Poisson‐correlated gamma frailty model makes no assumptions on the relationship between sensitivity and specificity, gives consistent results, appears to be quite robust against different between‐study variation models, and is computationally very fast and reliable with regard to the overall sensitivities/specificities.     

Interactions in a tritrophic acarine predator– prey metapopulation system: prey location and distance moved by Phytoseiulus persimilis (Acari: Phytoseiidae)

The between-plant movement of the predatory mite Phytoseiulus persimilis was studied in a greenhouse. The aims were to determine the distance moved by P. persimilis and the response of the predator to the location of a plant infested with two-spotted spider mite, Tetranychus urticae. In addition, we tested whether the predator exhibits random movement between plants or whether its dispersal is oriented. We found that a high proportion of the predators released on a central plant were able to reach plants at the periphery provided the plants were connected to the central plant with 'bridges'. The results further showed that P. persimilis does not disperse randomly to the surrounding plants. The distribution of immigrants was influenced by the position of an infested plant in the neighbourhood, but light/shadow effects in the greenhouse may also influence the choice of direction. The likely implications of the findings for biological control are discussed. © Rapid Science Ltd. 1998     

Structure–function relationships of four compression wood types: micromechanical properties at the tissue and fibre level

The mechanisms behind compressive stress generation in gymnosperms are not yet fully understood. Investigating the structure–function relationships at the tissue and cell level, however, can provide new insights. Severe compression wood of all species lacks a S3 layer, has a high microfibril angle in the S2 layer and a high lignin content. Additionally, special features like helical cavities or spiral thickenings appear, which are not well understood in terms of their mechanical relevance, but need to be examined with regard to evolutionary trends in compression wood development. Thin compression wood foils and isolated tracheids of four gymnosperm species [Ginkgo biloba L., Taxus baccata L., Juniperus virginiana L., Picea abies (L.) Karst.] were investigated. The tracheids were isolated mechanically by peeling them out of the solid wood using fine tweezers. In contrast to chemical macerations, the cell wall components remained in their original condition. Tensile properties of tissue foils and tracheids were measured in a microtensile apparatus under wet conditions. Our results clearly show an evolutionary trend to a much more flexible compression wood. An interpretation with respect to compressive stress generation is discussed.     

Weak phylogenetic effects on ecological niches of Sylvia warblers

To understand the evolution of ecological niches it is important to know whether niche evolution is constrained by phylogeny. We approached this question for Sylvia warblers by testing if closely related species are more similar in 20 ecologically relevant morphological traits than distantly related species. Phylogenetic relatedness was quantified using a molecular phylogeny based on the mitochondrial cytochrome b gene. By Principal Component Analysis (PCA) two major niche axes were extracted. We tested the individual ecomorphological traits and the positions of the species on the PCA axes for phylogenetic effects using Mantel tests. The results demonstrated small but significant phylogenetic effects only for the length of the middle toe, a trait probably correlated with locomotion. In general, however, phylogenetic effects were very weak. This suggests that ecological niches in passerine birds have the potential to evolve rapidly and are not subject to major phylogenetic constraints.     

Testing the link between the latitudinal gradient in species richness and rates of molecular evolution

Numerous hypotheses have been proposed to explain latitudinal gradients in species richness, but all are subject to ongoing debate. Here we examine Rohde's (1978, 1992) hypothesis, which proposes that climatic conditions at low latitudes lead to elevated rates of speciation. This hypothesis predicts that rates of molecular evolution should increase towards lower latitudes, but this prediction has never been tested. We discuss potential links between rates of molecular evolution and latitudinal diversity gradients, and present the first test of latitudinal variation in rates of molecular evolution. Using 45 phylogenetically independent, latitudinally separated pairs of bird species and higher taxa, we compare rates of evolution of two mitochondrial genes and DNA-DNA hybridization distances. We find no support for an effect of latitude on rate of molecular evolution. This result casts doubt on the generality of a key component of Rohde's hypothesis linking climate and speciation.     

Testing for spatial correlation in nonstationary binary data, with application to aberrant crypt foci in colon carcinogenesis

In an experiment to understand colon carcinogenesis, all animals were exposed to a carcinogen, with half the animals also being exposed to radiation. Spatially, we measured the existence of what are referred to as aberrant crypt foci (ACF), namely, morphologically changed colonic crypts that are known to be precursors of colon cancer development. The biological question of interest is whether the locations of these ACFs are spatially correlated: if so, this indicates that damage to the colon due to carcinogens and radiation is localized. Statistically, the data take the form of binary outcomes (corresponding to the existence of an ACF) on a regular grid. We develop score-type methods based upon the Matern and conditionally autoregressive (CAR) correlation models to test for the spatial correlation in such data, while allowing for nonstationarity. Because of a technical peculiarity of the score-type test, we also develop robust versions of the method. The methods are compared to a generalization of Moran's test for continuous outcomes, and are shown via simulation to have the potential for increased power. When applied to our data, the methods indicate the existence of spatial correlation, and hence indicate localization of damage.     

Exact log-rank tests for unequal follow-up

The asymptotic log-rank and generalized Wilcoxon tests are the standard procedures for comparing samples of possibly censored survival times. For comparison of samples of very different sizes, an exact test is available that is based on a complete permutation of log-rank or Wilcoxon scores. While the asymptotic tests do not keep their nominal sizes if sample sizes differ substantially, the exact complete permutation test requires equal follow-up of the samples. Therefore, we have developed and present two new exact tests also suitable for unequal follow-up. The first of these is an exact analogue of the asymptotic log-rank test and conditions on observed risk sets, whereas the second approach permutes survival times while conditioning on the realized follow-up in each group. In an empirical study, we compare the new procedures with the asymptotic log-rank test, the exact complete permutation test, and an earlier proposed approach that equalizes the follow-up distributions using artificial censoring. Results confirm highly satisfactory performance of the exact procedure conditioning on realized follow-up, particularly in case of unequal follow-up. The advantage of this test over other options of analysis is finally exemplified in the analysis of a breast cancer study.     

Statistical analysis of noninferiority trials with a rate ratio in small-sample matched-pair designs

Testing of noninferiority has become increasingly important in modern medicine as a means of comparing a new test procedure to a currently available test procedure. Asymptotic methods have recently been developed for analyzing noninferiority trials using rate ratios under the matched-pair design. In small samples, however, the performance of these asymptotic methods may not be reliable, and they are not recommended. In this article, we investigate alternative methods that are desirable for assessing noninferiority trials, using the rate ratio measure under small-sample matched-pair designs. In particular, we propose an exact and an approximate exact unconditional test, along with the corresponding confidence intervals based on the score statistic. The exact unconditional method guarantees the type I error rate will not exceed the nominal level. It is recommended for when strict control of type I error (protection against any inflated risk of accepting inferior treatments) is required. However, the exact method tends to be overly conservative (thus, less powerful) and computationally demanding. Via empirical studies, we demonstrate that the approximate exact score method, which is computationally simple to implement, controls the type I error rate reasonably well and has high power for hypothesis testing. On balance, the approximate exact method offers a very good alternative for analyzing correlated binary data from matched-pair designs with small sample sizes. We illustrate these methods using two real examples taken from a crossover study of soft lenses and a Pneumocystis carinii pneumonia study. We contrast the methods with a hypothetical example.     

Comparative Molecular Evolution of Primary (<Emphasis Type="BoldItalic">Buchnera</Emphasis>) and Secondary Symbionts of Aphids Based on Two Protein-Coding Genes

A+T content, phylogenetic relationships, codon usage, evolutionary rates, and ratio of synonymous versus non-synonymous substitutions have been studied in partial sequences of the atpD and aroQ/pheA genes of primary (Buchnera) and secondary symbionts of aphids and a set of selected non-symbiotic bacteria, belonging to the five subdivisions of the Proteobacteria. Compared to the homologous genes of the last group, both genes belonging to Buchnera behave in a similar way, showing a higher A+T content, forming a monophyletic group, a loss in codon bias, especially in third base position, an evolutionary acceleration and an increase in the number of non-synonymous substitutions, confirming previous results reported elsewhere for other genes. When available, these properties have been partly observed with the secondary symbionts, but with values that are intermediate between Buchnera and free living Proteobacteria. They show high A+T content, but not as high as Buchnera, a non-solved phylogenetic position between Buchnera, and the other γ-Proteobacteria, a loss in codon bias, again not as high as in Buchnera and a significant evolutionary acceleration in the case of the three atpD genes, but not when considering aroQ/pheA genes. These results give support to the hypothesis that they are symbionts at different stages of the symbiotic accommodation to the host.