Integrated evaluation of targeted and non-targeted therapies in a network meta-analysis

Individualized therapies for patients with biomarkers are moving more and more into the focus of research interest when developing new treatments. Hereby, the term individualized (or targeted) therapy denotes a treatment specifically developed for biomarker-positive patients. A network meta-analysis model for a binary endpoint combining the evidence for a targeted therapy from individual patient data with the evidence for a non-targeted therapy from aggregate data is presented and investigated. The biomarker status of the patients is either available at patient-level in individual patient data or at study-level in aggregate data. Both types of biomarker information have to be included. The evidence synthesis model follows a Bayesian approach and applies a meta-regression to the studies with aggregate data. In a simulation study, we address three treatment arms, one of them investigating a targeted therapy. The bias and the root-mean-square error of the treatment effect estimate for the subgroup of biomarker-positive patients based on studies with aggregate data are investigated. Thereby, the meta-regression approach is compared to approaches applying alternative solutions. The regression approach has a surprisingly small bias even in the presence of few studies. By contrast, the root-mean-square error is relatively greater. An illustrative example is provided demonstrating implementation of the presented network meta-analysis model in a clinical setting.     

Relative efficiency of using summary versus individual data in random-effects meta-analysis

Meta-analysis is a statistical methodology for combining information from diverse sources so that a more reliable and efficient conclusion can be reached. It can be conducted by either synthesizing study-level summary statistics or drawing inference from an overarching model for individual participant data (IPD) if available. The latter is often viewed as the “gold standard.” For random-effects models, however, it remains not fully understood whether the use of IPD indeed gains efficiency over summary statistics. In this paper, we examine the relative efficiency of the two methods under a general likelihood inference setting. We show theoretically and numerically that summary-statistics-based analysis is at most as efficient as IPD analysis, provided that the random effects follow the Gaussian distribution, and maximum likelihood estimation is used to obtain summary statistics. More specifically, (i) the two methods are equivalent in an asymptotic sense; and (ii) summary-statistics-based inference can incur an appreciable loss of efficiency if the sample sizes are not sufficiently large. Our results are established under the assumption that the between-study heterogeneity parameter remains constant regardless of the sample sizes, which is different from a previous study. Our findings are confirmed by the analyses of simulated data sets and a real-world study of alcohol interventions.     

Seasonal and diel plasticity of song type use in individual ovenbirds (Seiurus aurocapilla)

Animal communication is an important aspect of ecology across taxa, and there is a growing area of research that examines how animals plastically adjust their signals to account for both abiotic and biotic factors. Song type use and the temporal plasticity of song have been described in many bird species, but as of yet, few studies have examined how song type use may change across both seasonal and diel timeframes, and no studies have considered individual-level variation in plasticity. Using a hierarchical framework, we examined temporal patterns of primary and flight song use in ovenbirds (Seiurus aurocapilla; N = 21 individuals). We recorded ovenbird songs (N = 99,259) with autonomous recorders over 24-hr periods once per week across a breeding season near Sault Ste. Marie, Canada. As predicted, the occurrence and frequency of both song types significantly decreased over the season and showed temporal separation over diel periods. Primary songs peaked at dawn and declined throughout the day, while flight songs peaked at dusk and night. Our results support that primary songs have multiple functions as they remained more frequent during dawn and morning across the breeding season, while flight songs likely serve an intersexual function as they decreased similarly for all diel periods as mating opportunities decreased. Individuals were consistent in how frequently they sang their primary songs, but not their flight songs, suggesting that flight songs are more plastically expressed. We highlight the importance of examining plasticity in animal communication at the individual level as we show that males significantly differed in both their song behaviours (random intercepts) and the seasonal plasticity (random slopes) in these behaviours. Integrating themes such as song type use, temporal plasticity, and individual variation will be important for examining the evolutionary mechanisms that shape animal communication systems.     

Microsatellite markers uncover cryptic species of Odontotermes (Termitoidae: Termitidae) from Peninsular Malaysia

Termites from the genus Odontotermes are known to contain numerous species complexes that are difficult to tell apart morphologically or with mitochondrial DNA sequences. We developed markers for one such cryptic species complex, that is, Odontotermes srinakarinensis sp. nov. from Maxwell Hill Forest Reserve (Perak, Malaysia), and characterised them using a sample of 41 termite workers from three voucher samples from the same area. We then genotyped 150 termite individuals from 23 voucher samples/colonies of this species complex from several sites in Peninsular Malaysia. We analysed their population by constructing dendograms from the proportion of shared-alleles between individuals and genetic distances between colonies; additionally, we examined the Bayesian clustering pattern of their genotype data. All methods of analysis indicated that there were two distinct clusters within our data set. After the morphologies of specimens from each cluster were reexamined, we were able to separate the two species morphologically and found that a single diagnostic character found on the mandibles of its soldiers could be used to separate the two species quite accurately. The additional species in the clade was identified as Odontotermes denticulatus after it was matched to type specimens at the NHM London and Cambridge Museum of Zoology.     

Genes alternations with exposure time of environmental factors

A theoretical model discussing the environmental factors (EFs) effect of exposure time on genes, which leads to human diseases, is presented using multi-logistic model. The advantages and limitations of this model are discussed in terms of its usefulness for simulating genetic samples. It has been shown that EFs affect genes with the same degree both at high exposure level, low exposure time and at low exposure level, high exposure time.     

Shift Work and Inter‐Individual Differences in Sleep and Sleepiness

Inter‐individual differences in tolerance for shift work have been studied primarily in terms of external factors affecting alertness on the job or the ability to rest and sleep while at home. However, there is increasing evidence that neurobiological factors play a role as well, particularly the major processes involved in the regulation of sleep and wakefulness. These include a sleep homeostatic process seeking to balance wakefulness and sleep and a circadian process seeking to promote wakefulness during the day and sleep during the night. Shift work is associated with a temporal misalignment of these two endogenous processes. During nightwork, this misalignment makes it difficult to stay awake during the nightshift and sleep during the day. However, inter‐individual variability in the processes involved in sleep/wake regulation is substantial. Recent studies have demonstrated the existence of inter‐individual differences in vulnerability to cognitive deficits from sleep loss. Moreover, these inter‐individual differences were shown to constitute a trait. Interestingly, self‐evaluations of sleepiness did not correspond well with the trait inter‐individual variability in objective levels of performance impairment during sleep deprivation. Perhaps because of this discrepancy, in operational settings, the inter‐individual differences in vulnerability to sleep loss do not appear to be limited due to self‐selection mechanisms. Indeed, even among a highly select group of active‐duty jet fighter pilots flying a series of simulated night missions, systematic inter‐individual differences in performance impairment from sleep loss were still observed. There are significant personal and economic consequences to human error and accidents caused by performance deficits due to sleep loss. It is important, therefore, to study the inter‐individual differences in the regulation of sleep and wakefulness in the work environment so that cognitive impairment during shift work may be better anticipated and prevented.     

Relatedness and resource diversity interact to influence the intensity of competition

When resource competition occurs between close relatives, the negative effects of competition are potentially amplified. However, kin selection theory predicts that natural selection should promote the evolution of mechanisms that minimize the intensity of competition between kin. Experimental tests of these hypotheses are mixed, however. Moreover, there is little consensus regarding the generality of either outcome, suggesting that the conditions important in determining the effects of competition between kin are likely complex and not fully understood. We performed two experiments using spadefoot toad tadpoles (Spea multiplicata) to evaluate the hypothesis that individuals can minimize the negative effects of exploitative competition by using alternative resources when competing with close relatives. Supporting our hypothesis, we found that only when individuals had access to alternative resources were the negative effects of competition between siblings less than between unrelated competitors. We suggest that mechanisms to lessen kin competition may be more likely to evolve in environments where alternative resources are available, and that selection to minimize exploitative competition between kin may promote the evolution of resource polyphenism. © 2013 The Linnean Society of London, Biological Journal of the Linnean Society, 2013, 110 , 689–695.     

Finding your mate in a seabird colony: contrasting strategies of the Guillemot Uria aalge and King Penguin Aptenodytes patagonicus

Capsule King Penguins recognize their mates by voice, but Guillemots do not need acoustic cues even though their calls show individual variation.

Aims To determine whether the structure of Guillemot calls could allow individual recognition, as with King Penguin, and whether acoustic cues are used to locate mates among a dense mass of conspecifics at a colony.

Methods Observations were made on breeding Guillemots and King Penguins. Calls made by birds returning to their mates were recorded, the signals digitized and the calls analysed. Calls were later played back to the mates of the birds concerned and the effects noted on both them and their neighbours.

Results Both Guillemots and King Penguins emitted calls on return to the breeding site which contained individual signatures and were therefore potentially usable for mate recognition. In King Penguins, auditory recognition was essential for finding a mate, whereas in Guillemots most of the arriving birds located their mate in a dense crowd of conspecifics without the help of acoustic signals. Guillemots could differentiate neighbours from strangers without auditory cues.

Conclusion Calls are essential for the successful identification of mates by King Penguins but not by Guillemots.     

EVOLUTIONARY CONSTRAINTS AND THE MAINTENANCE OF INDIVIDUAL SPECIALIZATION THROUGHOUT SUCCESSION

Constraints on life‐history traits, with their close links to fitness, are widely invoked as limits to niche expansion at most organizational levels. Theoretically, such constraints can maintain individual specialization by preventing adaptation to all niches available, but empirical evidence of them remains elusive for natural populations. This problem may be compounded by a tendency to seek constraints involving multiple traits, neglecting their added potential to manifest in trait expression across environments (i.e., within reaction norms). By replicating genotypes of a colonial marine invertebrate across successional stages in its local community, and taking a holistic approach to the analysis of ensuing reaction norms for fitness, we show the potential for individual specialization to be maintained by genetic constraints associated with these norms, which limit the potential for fitness at one successional stage to improve without loss of fitness at others. Our study provides new insight into the evolutionary maintenance of individual specialization in natural populations and reinforces the importance of reaction norms for studying this phenomenon.