Adaptive seamless clinical trials using early outcomes for treatment or subgroup selection: Methods,simulation model and their implementation in R

Adaptive seamless designs combine confirmatory testing, a domain of phase III trials, with features such as treatment or subgroup selection, typically associated with phase II trials. They promise to increase the efficiency of development programmes of new drugs, for example, in terms of sample size and/or development time. It is well acknowledged that adaptive designs are more involved from a logistical perspective and require more upfront planning, often in the form of extensive simulation studies, than conventional approaches. Here, we present a framework for adaptive treatment and subgroup selection using the same notation, which links the somewhat disparate literature on treatment selection on one side and on subgroup selection on the other. Furthermore, we introduce a flexible and efficient simulation model that serves both designs. As primary endpoints often take a long time to observe, interim analyses are frequently informed by early outcomes. Therefore, all methods presented accommodate interim analyses informed by either the primary outcome or an early outcome. The R package asd , previously developed to simulate designs with treatment selection, was extended to include subgroup selection (so-called adaptive enrichment designs). Here, we describe the functionality of the R package asd and use it to present some worked-up examples motivated by clinical trials in chronic obstructive pulmonary disease and oncology. The examples both illustrate various features of the R package and provide insights into the operating characteristics of adaptive seamless studies.     

Mycorrhizal preference promotes habitat invasion by a native Australian orchid: Microtis media

Background and Aims

Mycorrhizal specialization has been shown to limit recruitment capacity in orchids, but an increasing number of orchids are being documented as invasive or weed-like. The reasons for this proliferation were examined by investigating mycorrhizal fungi and edaphic correlates of Microtis media, an Australian terrestrial orchid that is an aggressive ecosystem and horticultural weed.

Methods

Molecular identification of fungi cultivated from M. media pelotons, symbiotic in vitro M. media seed germination assays, ex situ fungal baiting of M. media and co-occurring orchid taxa (Caladenia arenicola, Pterostylis sanguinea and Diuris magnifica) and soil physical and chemical analyses were undertaken.

Key Results

It was found that: (1) M. media associates with a broad taxonomic spectrum of mycobionts including Piriformospora indica, Sebacina vermifera, Tulasnella calospora and Ceratobasidium sp.; (2) germination efficacy of mycorrhizal isolates was greater for fungi isolated from plants in disturbed than in natural habitats; (3) a higher percentage of M. media seeds germinate than D. magnifica, P. sanguinea or C. arenicola seeds when incubated with soil from M. media roots; and (4) M. media–mycorrhizal fungal associations show an unusual breadth of habitat tolerance, especially for soil phosphorus (P) fertility.

Conclusions

The findings in M. media support the idea that invasive terrestrial orchids may associate with a diversity of fungi that are widespread and common, enhance seed germination in the host plant but not co-occurring orchid species and tolerate a range of habitats. These traits may provide the weedy orchid with a competitive advantage over co-occurring orchid species. If so, invasive orchids are likely to become more broadly distributed and increasingly colonize novel habitats.     

Consistent and variable leaf anatomical characters in Carex (Cyperaceae)

The anatomy and morphology of leaves in Carex have the potential to be taxonomically useful. However, studies on the variability of leaf characteristics in the genus are sparse. Researchers therefore risk using leaf anatomical characters without the knowledge of whether they are consistent in a species. We examined 22 qualitative and seven quantitative leaf anatomy characters from transverse leaf sections to test their consistency across 11 Carex spp. The characters were clearly described and primarily microscopic. Some characters were found to exhibit high levels of intraspecific variation, whereas other characters exhibited high levels of consistency in a species, including the shape of the leaf section, the density of papillae and the size of epidermal cells. Caution must be applied when choosing leaf anatomy to delimit taxa because of the intraspecific variability found in some characters, but sufficient numbers of invariant characters exist to provide useful taxonomic separation. © 2013 The Linnean Society of London, Botanical Journal of the Linnean Society, 2013, 172 , 371–384.     

Can temperate insects take the heat? A case study of the physiological and behavioural responses in a common ant, Iridomyrmex purpureus (Formicidae), with potential climate change

Insects in temperate regions are predicted to be at low risk of climate change relative to tropical species. However, these assumptions have generally been poorly examined in all regions, and such forecasting fails to account for microclimatic variation and behavioural optimisation. Here, we test how a population of the dominant ant species, Iridomyrmex purpureus, from temperate Australia responds to thermal stress. We show that ants regularly forage for short periods (minutes) at soil temperatures well above their upper thermal limits (upper lethal temperature = 45.8 ± 1.3 °C; CT_max = 46.1 °C) determined over slightly longer periods (hours) and do not show any signs of a classic thermal performance curve in voluntary locomotion across soil surface temperatures of 18.6–57°C (equating to a body temperature of 24.5–43.1 °C). Although ants were present all year round, and dynamically altered several aspects of their thermal biology to cope with low temperatures and seasonal variation, temperature-dependence of running speed remained invariant and ants were unable to elevate high temperature tolerance using plastic responses. Measurements of microclimate temperature were higher than ant body temperatures during the hottest part of the day, but exhibited a stronger relationship with each other than air temperatures from the closest weather station. Generally close associations of ant activity and performance with microclimatic conditions, possibly to maximise foraging times, suggest I. purpureus displays highly opportunistic thermal responses and readily adjusts behaviour to cope with high trail temperatures. Increasing frequency or duration of high temperatures is therefore likely to result in an immediate reduction in foraging efficiency. In summary, these results suggest that (1) soil-dwelling temperate insect populations may be at higher risks of thermal stress with increased frequency or duration of high temperatures resulting from climate change than previously thought, however, behavioural cues may be able to compensate to some extent; and (2) indices of climate change-related thermal stress, warming tolerance and thermal safety margin, are strongly influenced by the scale of climate metrics employed.     

PATTERNS OF OSSIFICATION IN SOUTHERN VERSUS NORTHERN PLACENTAL MAMMALS

Consensus on placental mammal phylogeny is fairly recent compared to that for vertebrates as a whole. A stable phylogenetic hypothesis enables investigation into the possibility that placental clades differ from one another in terms of their development. Here, we focus on the sequence of skeletal ossification as a possible source of developmental distinctiveness in “northern” (Laurasiatheria and Euarchontoglires) versus “southern” (Afrotheria and Xenarthra) placental clades. We contribute data on cranial and postcranial ossification events during growth in Afrotheria, including elephants, hyraxes, golden moles, tenrecs, sengis, and aardvarks. We use three different techniques to quantify sequence heterochrony: continuous method, sequence‐ANOVA (analysis of variance) and event‐paring/Parsimov. We show that afrotherians significantly differ from other placentals by an early ossification of the orbitosphenoid and caudal vertebrae. Our analysis also suggests that both southern placental groups show a greater degree of developmental variability; however, they rarely seem to vary in the same direction, especially regarding the shifts that differ statistically. The latter observation is inconsistent with the Atlantogenata hypothesis in which afrotherians are considered as the sister clade of xenarthrans. Interestingly, ancestral nodes for Laurasiatheria and Euarchontoglires show very similar trends and our results suggest that developmental homogeneity in some ossification sequences may be restricted to northern placental mammals (Boreoeutheria).     

Reducing infectivity of HIV upon exposure to surfaces coated with N,N‐dodecyl,methyl‐polyethylenimine

The infectivity of high‐titer, cell‐free HIV in culture media and human milk is rapidly reduced upon exposure to polyethylene slides painted with the linear hydrophobic polycation N,N‐dodecyl,methyl‐polyethylenimine (DMPEI). Accompanying viral p24 protein and free viral RNA analysis of solutions exposed to DMPEI‐coated surfaces suggests that virion attachment to the polycationic surface and its subsequent inactivation are the likely mechanism of this phenomenon. Biotechnol. Bioeng. 2013; 110: 2058–2062. © 2013 Wiley Periodicals, Inc.     

Global mapping of infectious disease

The primary aim of this review was to evaluate the state of knowledge of the geographical distribution of all infectious diseases of clinical significance to humans. A systematic review was conducted to enumerate cartographic progress, with respect to the data available for mapping and the methods currently applied. The results helped define the minimum information requirements for mapping infectious disease occurrence, and a quantitative framework for assessing the mapping opportunities for all infectious diseases. This revealed that of 355 infectious diseases identified, 174 (49%) have a strong rationale for mapping and of these only 7 (4%) had been comprehensively mapped. A variety of ambitions, such as the quantification of the global burden of infectious disease, international biosurveillance, assessing the likelihood of infectious disease outbreaks and exploring the propensity for infectious disease evolution and emergence, are limited by these omissions. An overview of the factors hindering progress in disease cartography is provided. It is argued that rapid improvement in the landscape of infectious diseases mapping can be made by embracing non-conventional data sources, automation of geo-positioning and mapping procedures enabled by machine learning and information technology, respectively, in addition to harnessing labour of the volunteer ‘cognitive surplus’ through crowdsourcing.     

On the genetic diversity of spiny mice (genus Acomys) and gerbils (genus Gerbillus) in the Arabian Peninsula

Using non-destructive sampling we provide further genetic characterisations for spiny mice (Acomys dimidiatus/cahirinus) and gerbils (Gerbillus sp.) in three regions in Saudi Arabia. All individuals were sequenced for a fragment of the cytochrome b gene, and compared against available conspecifics and closely related taxa. We confirm the existence of a second Acomys dimidiatus/cahirinus lineage specific to the Arabian Peninsula as seen previously. The Arabian Gerbillus nanus is shown to group with Middle Eastern rather than African conspecifics. A second cryptic Gerbillus lineage was also sampled across multiple locations, which may be an uncharacterised G. dasyurus.     

Oligarchies in Amazonian tree communities: a ten‐year review

This paper revisits various hypotheses about oligarchic patterns in Amazonian tree communities put forward by Pitman et al. (2001) . Together, these hypotheses predict that most lowland sites in the Amazon are located within large patches of relatively homogeneous edaphic and other environmental conditions, where an oligarchy of common, frequent tree species accounts for a majority of trees. To assess the degree to which these hypotheses have been corroborated or refuted over the last ten years, we reviewed > 200 studies published since 2001. We found overwhelming support for the hypo thesis that large‐scale oligarchies of common and frequent species are a common feature of Amazonian tree communities. At least 22 studies have documented oligarchies in Amazonian woody plant communities to date, and no studies have looked for oligarchies as defined by Pitman et al. (2001) and failed to find them. We argue that six publications that offer critiques of the oligarchy hypothesis do not constitute valid tests. The other hypotheses in Pitman et al. (2001) – one regarding the specific oligarchic taxa that dominate forests near the eastern base of the Andes and one that attempts to explain why oligarchic species exist – are less well supported by the literature, in large part because they have not been subjected to many tests. We discuss links between these hypotheses and other well‐known patterns and hypotheses in ecology (the abundance–occupancy relationship, the Janzen–Connell hypothesis, the niche‐environment hypothesis, and the niche breadth hypothesis), and provide additional detail to facilitate rigorous tests in the future. The paper concludes by presenting remote sensing evidence that large patches of relatively homogeneous environmental conditions account for most of the upland forest landscape across Amazonian Peru.