Improved two‐stage group sequential procedures for testing a secondary endpoint after the primary endpoint achieves significance

In two‐stage group sequential trials with a primary and a secondary endpoint, the overall type I error rate for the primary endpoint is often controlled by an α‐level boundary, such as an O'Brien‐Fleming or Pocock boundary. Following a hierarchical testing sequence, the secondary endpoint is tested only if the primary endpoint achieves statistical significance either at an interim analysis or at the final analysis. To control the type I error rate for the secondary endpoint, this is tested using a Bonferroni procedure or any α‐level group sequential method. In comparison with marginal testing, there is an overall power loss for the test of the secondary endpoint since a claim of a positive result depends on the significance of the primary endpoint in the hierarchical testing sequence. We propose two group sequential testing procedures with improved secondary power: the improved Bonferroni procedure and the improved Pocock procedure. The proposed procedures use the correlation between the interim and final statistics for the secondary endpoint while applying graphical approaches to transfer the significance level from the primary endpoint to the secondary endpoint. The procedures control the familywise error rate (FWER) strongly by construction and this is confirmed via simulation. We also compare the proposed procedures with other commonly used group sequential procedures in terms of control of the FWER and the power of rejecting the secondary hypothesis. An example is provided to illustrate the procedures.     

Anatomically-based skeletal coordinate systems for use with impact biomechanics data intended for anthropomorphic test device development

Post-mortem human subjects (PMHS) are frequently used to characterize biomechanical response and injury tolerance of humans to various types of loading by means of instrumentation installed directly on the skeleton. Data extracted from such tests are often used to develop and validate anthropomorphic test devices (ATDs), which function as human surrogates in tests for injury assessment. Given that the location and orientation of installed instrumentation differs between subjects, nominally similar measurements made on different PMHS must be transformed to standardized, skeletal-based local coordinate systems (LCS) before appropriate data comparisons can be made. Standardized PMHS LCS that correspond to ATD instrumentation locations and orientations have not previously been published. This paper introduces anatomically-defined PMHS LCS for body regions in which kinematic measurements are made using ATDs. These LCS include the head, sternum, single vertebrae, pelvis, femurs (distal and proximal), and tibiae (distal and proximal) based upon skeletal landmarks extracted from whole body CT scans. The proposed LCS provide a means to standardize the reporting of PMHS data, and facilitate both the comparison of PMHS impact data across institutions and the application of PMHS data to the development and validation of ATDs.     

Climate oscillations and species interactions: large‐scale congruence but regional differences in the phylogeographic structures of an alpine plant and its monophagous insect

Aim To predict the fate of alpine interactions involving specialized species, using a monophagous beetle and its host plant as a case study. Location The Alps. Methods We investigated genetic structuring of the herbivorous beetle Oreina gloriosa and its specific host‐plant Peucedanum ostruthium. We used genome fingerprinting (in the insect and the plant) and sequence data (in the insect) to compare the distribution of the main gene pools in the two associated species and to estimate divergence time in the insect, a proxy for the temporal origin of the interaction. We quantified the similarity in spatial genetic structures by performing a Procrustes analysis, a tool from shape theory. Finally, we simulated recolonization of an empty space analogous to the deglaciated Alps just after ice retreat by two lineages from two species showing unbalanced dependence, to examine how timing of the recolonization process, as well as dispersal capacities of associated species, could explain the observed pattern. Results Contrasting with expectations based on their asymmetrical dependence, patterns in the beetle and plant were congruent at a large scale. Exceptions occurred at a regional scale in areas of admixture, matching known suture zones in Alpine plants. Simulations using a lattice‐based model suggested these empirical patterns arose during or soon after recolonization, long after the estimated origin of the interaction c. 0.5 million years ago. Main conclusions Species‐specific interactions are scarce in alpine habitats because glacial cycles have limited the opportunities for co‐evolution. Their fate, however, remains uncertain under climate change. Here we show that whereas most dispersal routes are paralleled at a large scale, regional incongruence implies that the destinies of the species might differ under changing climate. This may be a consequence of the host dependence of the beetle, which locally limits the establishment of dispersing insects.     

<Emphasis Type="Italic">In vitro</Emphasis> selection and regeneration of chrysanthemum (<Emphasis Type="Italic">Dendranthema grandiflorum</Emphasis> Tzelev) plants resistant to culture filtrate of <Emphasis Type="Italic">Septoria obesa</Emphasis> Syd

Callus cultures derived from leaf segments of chrysanthemum cultivar ‘Snow Ball’ which was susceptible to Septoria obesa were successfully used for in vitro selection for resistance to this pathogenic fungus. Resistant cell lines were selected by culturing callus on growth medium containing various concentrations of S. obesa filtrate. Resistant calluses obtained after two cycles (30 d each cycle) of selection were used for plant regeneration. About 30% of the plants regenerated from the resistant calluses and 70–80% of the plants raised from cuttings had acquired considerable resistance against the pathogen in the field. No phenotypic variation was observed in the selected regenerates.     

Exact Test Procedures for Generalized Kendall Correlation Coefficients

An exact test of KENDALL'S tau is presented, useful in small samples when the asymptotic test may not be adequate. The procedure is proposed especially for situations when ties and/or censored observations are present in the variables to be analyzed by KENDALL'S tau. The paper describes generalizations of the procedure, presents calculated examples and offers a computer program, which facilitates the usage of the proposed procedure.     

Nuclear corrosion monitoring—

Nuclear corrosion technique has been developed for the assay of various heavy metals released through corrosion and abrasion into electrolytes from various biomaterials like amalgams, chromium— cobalt and gold alloys, steel, and titanium. Application of the technique in measurement of selective release rates under static or dynamic conditions, i.e., during cyclic loading, is discussed. The elements chromium, cobalt, copper, gold, iron, mercury, molybdenum, silver, titanium, and zinc have been quantitatively assessed. In vivo corrosion measurements are further included. By combining the present nuclear tracer technique with ESCA technique, knowledge about reaction mechanisms occurring at the interface solid/liquid is obtained. Exposure of humans to various heavy metals from biomaterials, e.g., dental materials, can be estimated using the NCM technique. The technique also has a potential for selective release measurements of several nuclides possessing suitable radioanalytical properties from other types of alloys immersed in various liquid environments.     

The tortoise beetle Physonota maculiventris (Chrysomelidae: Cassidinae) is suitable for release against the weedy Mexican sunflower Tithonia diversifolia (Asteraceae) in South Africa

The biology and host range of the defoliating beetle Physonota maculiventris Boheman (Chrysomelidae: Cassidinae) were studied in quarantine to determine its suitability for release as a biological control agent against Mexican sunflower, Tithonia diversifolia (Hemsl.) A. Gray (Asteraceae), in South Africa. Females laid 5.25?±?0.25 (mean?±?SE) egg batches during their lifetimes, with each batch consisting of approximately 33 eggs. Larvae were highly gregarious as early instars and both larvae and adults fed voraciously, often defoliating the plants completely. The life cycle of the beetle was completed in 67.5?±?7.5 days under quarantine conditions. Among the 58 test plant species subjected to no-choice tests, P. maculiventris developed successfully on T. diversifolia and some sunflower (Helianthus annuus L.) cultivars. However, only minor damage was recorded on non-target species, notably the exotic weed Xanthium strumarium L. and some H. annuus cultivars. Also, survival to adulthood was considerably lower on sunflower cultivars than on the target weed during these tests. During choice tests, P. maculiventris oviposited and developed successfully on T. diversifolia only, with only minor feeding damage on some H. annuus cultivars, suggesting that the beetle’s field host range will be confined to the target weed. Risk analysis also showed that P. maculiventris presents an extremely low risk to non-target plant species (e.g. within the tribe Heliantheae and other close relatives). The study concluded that P. maculiventris is safe for release in South Africa and an application for its release is being considered by the relevant South African regulatory authorities.     

Primary HPV testing: a proposal for co‐testing in initial rounds of screening to optimise sensitivity of cervical cancer screening

As explained by Kitchener in a previous issue of Cytopathology (2015; 26 :4‐6), primary human papillomavirus (HPV) testing is likely to be introduced in the UK for all women aged 25–64 years following pilot site studies already in place. This will be necessary when the prevalence of cervical cancer and its precursors declines when vaccination takes effect but there is a risk in abandoning cytology as a primary test: a risk that would be most apparent in the present unvaccinated population in which the prevalence of cervical cancer and its precursors is exceptionally high. HPV testing is more sensitive than cytology but has a significant false‐negative rate that could be detrimental to a successful screening programme if introduced without cytology backup. Accurate cytology would be needed for triage and could be compromised if HPV‐negative tests were excluded from examination. This article proposes a compromise: cytology and HPV co‐testing for the first two screening tests to optimise the sensitivity of the test as a whole. Registrations of invasive and in situ carcinoma of the uterine cervix in England indicate that the prevalence of the disease is highest in young women in the early rounds of screening. Calculations of the likely impact on the workload of this proposal have been based on a service evaluation of 295 cytology tests received at St Thomas’ Hospital, which suggests that the volume of cytology tests would be reduced by approximately 60% compared with 80% for primary HPV testing alone. This proposal should be debated openly before irrevocable changes are made to a skilled workforce.