A note on nonparametric quantile inference for competing risks and more complex multistate models

Nonparametric quantile inference for competing risks has recentlybeen studied by Peng & Fine (2007). Their key result establishesuniform consistency and weak convergence of the inverse of theAalen–Johansen estimator of the cumulative incidence function,using the representation of the cumulative incidence estimatoras a sum of independent and identically distributed random variables.The limit process is of a form similar to that of the standardsurvival result, but with the cause-specific hazard of interestreplacing the all-causes hazard. We show that this fact is nota coincidence, but can be derived from a general Hadamard differentiationresult. We discuss a simplified proof and extensions of theapproach to more complex multistate models. As a further consequence,we find that the bootstrap works.     

Smoothed quantile regression analysis of competing risks

Censored quantile regression models, which offer great flexibility in assessing covariate effects on event times, have attracted considerable research interest. In this study, we consider flexible estimation and inference procedures for competing risks quantile regression, which not only provides meaningful interpretations by using cumulative incidence quantiles but also extends the conventional accelerated failure time model by relaxing some of the stringent model assumptions, such as global linearity and unconditional independence. Current method for censored quantile regressions often involves the minimization of the L₁‐type convex function or solving the nonsmoothed estimating equations. This approach could lead to multiple roots in practical settings, particularly with multiple covariates. Moreover, variance estimation involves an unknown error distribution and most methods rely on computationally intensive resampling techniques such as bootstrapping. We consider the induced smoothing procedure for censored quantile regressions to the competing risks setting. The proposed procedure permits the fast and accurate computation of quantile regression parameter estimates and standard variances by using conventional numerical methods such as the Newton–Raphson algorithm. Numerical studies show that the proposed estimators perform well and the resulting inference is reliable in practical settings. The method is finally applied to data from a soft tissue sarcoma study.     

Recent advances in lactoferrin research and development during the past two years (2007–2009): in lieu of a preface of the special issue lactoferrin

This is a short preface of this Special Issue Lactoferrin, it described the major points of key reporters in ‘The 9th International Conference on LF Structure, Function and Applications’ in Beijing in late Autumn 2009, and the major articles published in this issue. A panaroma and the lastest advances of lactoferrin R&D during past two years (2007–2009) was tried to extract.     

Gene frequency-based estimation of natural outcrossing in opium poppy (<Emphasis Type="Italic">Papaver somniferum</Emphasis> L.)

Mating systems are generally thought to be important factors in determining the amount and nature of genetic variability in a population. Nearly 1,000 individuals at a single location (Lucknow) and over two years were crossed and subsequently scored for selfing versus outcrossing in 9–10 monohybrid populations of opium poppy (Papaver somniferum). Three different alleles of two marker loci (two—R/r and P/p—for anthocyanin locus and B/b for capsule size locus) were used to determine the male gametes that had effected fertilizations in F₂ recessives (rr, pp and bb). The estimates of the gene frequency-based outcrossing parameter (α) were found to vary with year, cross and marker locus used (α range: 7.21–71.03%). Study of the two dihybrid crosses concerning the two marker loci simultaneously, further confirmed that outcrossing at the R/r or P/p locus was significantly greater than that at the B/b locus. The nature of the outcrossing was, in general, nonrandom. In this species, in general, selfing predominated, with one exception in respect of monohybrid crosses involving the purple form of anthocyanin locus, in which outcrossing predominated.     

Introducing inter-individual growth variability in the assessment of a cephalopod population: application to the English Channel squid Loligo forbesi

A new approach is presented here to better take into account inter-individual growth variability in age-structured models used for stock assessment. Cohort analysis requires knowledge of the age structure of the catch, generally derived from an age–length key and length-structure information. Age distribution at length is estimated by applying conditional quantile regression to a data set of lengths and ages estimated from calcareous parts. A “stochastic” age–length key that describes the probability of age-at-length is applied to the English Channel squid Loligo forbesi. Age distribution at length from quantile regression proved to be considerably less biased than that resulting from both polymodal decomposition (PD) and two separate slicing methods. Both catch-at-age and stock size were underestimated using classical methods. Estimations of fishing mortalities from classical methods were higher causing underestimation in yield simulations. Quantile regression offers a more complete statistical analysis of the stochastic relationships among random variables than mean regression and PD.     

Fractional Calculus in Biomechanics: A 3D Viscoelastic Model Using Regularized Fractional Derivative Kernels with Application to the Human Calcaneal Fat Pad

A viscoelastic model of the K-BKZ (Kaye, Technical Report 134, College of Aeronautics, Cranfield 1962; Bernstein et al., Trans Soc Rheol 7: 391–410, 1963) type is developed for isotropic biological tissues and applied to the fat pad of the human heel. To facilitate this pursuit, a class of elastic solids is introduced through a novel strain-energy function whose elements possess strong ellipticity, and therefore lead to stable material models. This elastic potential – via the K-BKZ hypothesis – also produces the tensorial structure of the viscoelastic model. Candidate sets of functions are proposed for the elastic and viscoelastic material functions present in the model, including two functions whose origins lie in the fractional calculus. The Akaike information criterion is used to perform multi-model inference, enabling an objective selection to be made as to the best material function from within a candidate set.Dedicated to Prof. Ronald L. Bagley.     

The ‘requirement of total evidence’ and its role in phylogenetic systematics

The question of whether or not to partition data for the purposes of inferring phylogenetic hypotheses remains controversial. Opinions have been especially divided since Kluge's (1989, Systematic Zoology 38, 7–25) claim that data partitioning violates the requirement of total evidence (RTE). Unfortunately, advocacy for or against the RTE has not been based on accurate portrayals of the requirement. The RTE is a basic maxim for non-deductive inference, stipulating that evidence must be considered if it has relevance to an inference. Evidence is relevant if it has a positive or negative effect on a given conclusion. In the case of ℈partitioned’ phylogenetic inferences, the RTE is violated, and the basis for rational belief in any conclusion is compromised, unless it is shown that the partitions are evidentially irrelevant to one another. The goal of phylogenetic systematics is to hypothesize past causal conditions to account for observed shared similarities among two or more species. Such inferences are non-deductive, necessitating consideration of the RTE. Some phylogeneticists claim the parsimony criterion as justification for the RTE. There is no relation between the two – parsimony is a relation between a hypothesis and causal question(s). Parsimony does not dictate the content of premises prior to an inference. ℈Taxonomic congruence,’ ℈supertrees,’ and ℈conditional combination’ methods violate the RTE. Taxonomic congruence and supertree methods also fail to achieve the intended goal of phylogenetic inference, such that ℈consensus trees’ and ℈supertrees’ lack an empirical basis. ℈Conditional combination’ is problematic because hypotheses derived from partitioned data cannot be compared – a causal hypothesis inferred to account for a set of effects only has relevance to those effects, not any comparative relevance to other causal hypotheses. A similar problem arises in the comparisons of hypotheses derived from different causal theories.     

Quantifying Medicinal Plant Knowledge among Non–Specialist Antanosy Villagers in Southern Madagascar

Quantifying Medicinal Plant Knowledge among Non–Specialist Antanosy Villagers in Southern Madagascar. Medicinal plant knowledge among non–specialist Antanosy villagers of southeastern Madagascar was investigated in a two–stage study. First, free–listing was used to collect the names of medicinal plants most familiar to local people. Data were organized by habitat and frequency into a short list of the 42 most frequently listed plants by habitat. A second group of interviewees were asked to name health conditions that could be treated with plants on the short list. Age, gender, and dwelling proximity to the forest were tested across the general habitat in which medicinal plants were found: in or near the village, in disturbed buffer areas between the village and the forest, or in the forest itself. Neither age nor gender was significant in free–listing. Naming health conditions treated with specific plants showed that knowledge increases with age and that for all but the oldest age group, women knew more plant uses than men. Women knew more plants from the village and buffer areas, and fewer from the forest than men. The proximity of the home to the forest had no influence on medicinal plant knowledge. The non–specialists interviewed named an average of 14 medicinal plants and most knew an average of 37 uses for 9 of the 42 most common medicinal plants. The most common conditions for people knew of plant treatments were stomach ache, babies’ fevers, and several unlisted conditions. Both exotic and endemic plant species were known to the non–specialists indicating that medicinal plant knowledge is being sustained and adapted to changes affecting both the people and their environment.     

The Exact Distribution of Divergence Times

The recent work of Haubold and Wiehe (Mol. Biol. Evol. 18:1157–1160, 2001) considered statistical inference of the divergence time. However, there appears to be a fundamental flaw in the paper since it treated the divergence time as a random variable and not as a parameter. In this note, we derive a valid statistical inference for the divergence time. We derive an estimator for the divergence time as well as explicit expressions for its the probability density function, cumulative distribution function and the means. We also provide a 5-line computer program for computing the associated confidence intervals. We expect that the results presented could be useful for statistical modeling of divergence times.     

An enhanced quantile approach for assessing differential gene expressions

Summary .   Due to the small number of replicates in typical gene microarray experiments, the performance of statistical inference is often unsatisfactory without some form of information-sharing across genes. In this article, we propose an enhanced quantile rank score test (EQRS) for detecting differential expression in GeneChip studies by analyzing the quantiles of gene intensity distributions through probe-level measurements. A measure of sign correlation, δ, plays an important role in the rank score tests. By sharing information across genes, we develop a calibrated estimate of δ, which reduces the variability at small sample sizes. We compare the EQRS test with four other approaches for determining differential expression: the gene-specific quantile rank score test, the quantile rank score test assuming a common δ, a modified t -test using summarized probe-set-level intensities, and the Mack–Skillings rank test on probe-level data. The proposed EQRS is shown to be favorable for preserving false discovery rates and for being robust against outlying arrays. In addition, we demonstrate the merits of the proposed approach using a GeneChip study comparing gene expression in the livers of mice exposed to chronic intermittent hypoxia and of those exposed to intermittent room air.     

Comments on ‘Is Partial Coherence a Viable Technique for Identifying Generators of Neural Oscillations?’

To aid prospective neural connectivity inference analysts and hoping to preclude misconception spread, we exploit the didatic value of some of the issues raised by Albo et al. (Biol Cybern 90: 318–326, 2004) who claim that signal-to-noise ratio (SNR) values can lead to mistakes in structural inference when using partial coherence in connection to Gersch’s 1970 method for spotting signal sources (Gersch in Math Biosci 14: 177– 196, 1972). We show theoretically that Gersch’s method is able only to spot which measurement of some common underlying factor has the least amount of additive noise and that this has nothing to do with any reasonable notion of ‘causality’ as suggested by Albo et al. (Biol Cybern 90: 318–326, 2004). We also show that despite the inherent structural ambiguity of the model used by Albo et al. (Biol Cybern 90: 318–326, 2004) to back their claim, its data can nonetheless furnish the correct time precedence hierarchy between the activities in its measured structures, both when simple (correlation) and more sophisticated methods are used (partial directed coherence) (Baccala and Sameshima in Biol Cybern 84:463–474, 2001a) in a true depiction of time series causality.     

Prediction of parathyroid hormone signalling potency using SVMs

Parathyroid hormone is the most important endocrine regulator of calcium concentration. Its N-terminal fragment (1–34) has sufficient activity for biological function. Recently, site-directed mutagenesis studies demonstrated that substitutions at several positions within shorter analogues (1–14) can enhance the bioactivity to greater than that of PTH (1–34). However, designing the optimal sequence combination is not simple due to complex combinatorial problems. In this study, support vector machines were introduced to predict the biological activity of modified PTH (1–14) analogues using mono-substituted experimental data and to analyze the key physicochemical properties at each position that correlated with bioactivity. This systematic approach can reduce the time and effort needed to obtain desirable molecules by bench experiments and provide useful information in the design of simpler activating molecules.     

Casares’ map function: no need for a ‘corrected’ Haldane’s map function

A genetic map function M(d) = RF provides a mapping from the additive genetic distance d to the non-additive recombination fraction RF between a given pair of loci, where the recombination fraction is the proportion of gametes that are recombinant between the two loci. Genetic map functions are needed because in most experiments all we can directly observe are the recombination events. However, since a recombination event is only observed if there are an odd number of crossovers between the two loci, recombination fractions are not additive. One of the most widely used map functions is Haldane’s map function, which is derived under the assumptions of no chiasma and no chromatid interference, and has been in widespread use since 1919. However, Casares recently proposed a ‘corrected’ Haldane’s map function – we show here that this ‘corrected’ map function is not correct due to faulty assumptions and mistakes in its derivation.     

Plant regeneration of mangosteen via nodular callus formation

Nodular callus was induced at a high frequency on young purple red, 5–15 mm long laminae taken from in vitro grown plants of mangosteen. The optimal medium was composed of Murashige and Skoog (MS) nutrients supplemented with 2.22 μM benzyladenine (BA), 2.25 μM thidiazuron (TDZ), 500 mg l^-1 polyvinylpyrrolidone (PVP 360 000) and 3% sucrose. A multiplication rate of two–three was obtained by subculture of the nodular callus at 3–4-week intervals. Plantlet regeneration from the nodules was achieved by transfer to woody plant medium (WPM) with 500 mg l^-1 PVP, 0.4 μM BA and 3% sucrose and overlaying with half strength liquid MS containing 0.32 μM naphthaleneacetic acid (NAA), 0.13 μM BA and 3% sucrose. Elongated shoots were rooted to 100% when wounded at the base of shoot, dipped in 4.4 mM indolebutyric acid (IBA) solution in the dark for 15 min and cultured on WPM supplemented with 1.11 μM BA, 0.25% activated charcoal, 34.5 μM phloroglucinol (PG) and 3% sucrose. This revised version was published online in June 2006 with corrections to the Cover Date.     

Activated omentum becomes rich in factors that promote healing and tissue regeneration

In order to study the mechanism by which an omental pedicle promotes healing when applied to an injured site, we injected a foreign body into the abdominal cavity to activate the omentum. One week after the injection, we isolated the omentum and measured blood vessel density, blood content, growth and angiogenesis factors (VEGF and others), chemotactic factors (SDF-1α), and progenitor cells (CXCR-4, WT-1). We found that the native omentum, which consisted mostly of adipose tissue, expanded the mass of its non-adipose part (milky spots) 15– to 20-fold. VEGF and other growth factors increased by two– to four-fold, blood vessel density by three-fold, and blood content by two-fold. The activated omentum also showed increases in SDF-1α, CXCR-4, and WT-1 cells (factors and cells positively associated with tissue regeneration). Thus, we propose that an omentum activated by a foreign body (or by injury) greatly expands its milky-spot tissue and becomes rich in growth factors and progenitor cells that facilitate the healing and regeneration of injured tissue. This work was partly supported by a grant (no. 2000–241 to A.K.S.) from the Juvenile Diabetes Foundation International.     

Carbon dioxide exchange in a cool-temperate evergreen coniferous forest over complex topography in Japan during two years with contrasting climates

We investigated carbon dioxide (CO₂) exchange and its environmental response during two years with contrasting climate (2006 and 2007) in a cool-temperate mixed evergreen coniferous forest dominated by Japanese cedar (Cryptomeria japonica) and Japanese cypress (Chamaecyparis obtusa). The study, which was conducted in a mountainous region of central Japan, used the eddy-covariance technique. Our results (crosschecked using the common u _* approach and van Gorsel’s alternative approach) showed that annual gross primary production (GPP) and ecosystem respiration (RE) were at least 6% higher in the dry year than in the wet year, whereas net ecosystem exchange (NEE) was similar in both years. Without soil water stress, strong light stress or seasonality of plant area index during most of the study period, the forest had high metabolic activity. GPP and RE differed greatly between the two years, especially in spring (April–May) and summer (July–September), respectively. The spring GPP difference (>20%) was influenced by different winter air temperatures and snow melt timing, which controlled photosynthetic capacity in spring, and by different spring light intensities. The annual NEE differed depending on the evaluation method used, but the mean 2-year NEE estimated by the u _* threshold approach [−3.39 ± 0.11 (SD) MgC ha⁻¹ year⁻¹] appears more reasonable in comparison with results from other forests.     

Regression on Quantile Residual Life

Summary A time‐specific log‐linear regression method on quantile residual lifetime is proposed. Under the proposed regression model, any quantile of a time‐to‐event distribution among survivors beyond a certain time point is associated with selected covariates under right censoring. Consistency and asymptotic normality of the regression estimator are established. An asymptotic test statistic is proposed to evaluate the covariate effects on the quantile residual lifetimes at a specific time point. Evaluation of the test statistic does not require estimation of the variance–covariance matrix of the regression estimators, which involves the probability density function of the survival distribution with censoring. Simulation studies are performed to assess finite sample properties of the regression parameter estimator and test statistic. The new regression method is applied to a breast cancer data set with long‐term follow‐up to estimate the patients' median residual lifetimes, adjusting for important prognostic factors.     

Structure of the pore-helix of the hERG K<Superscript>+</Superscript> channel

The hERG K⁺ channel undergoes rapid inactivation that is mediated by ‘collapse’ of the selectivity filter, thereby preventing ion conduction. Previous studies have suggested that the pore-helix of hERG may be up to seven residues longer than that predicted by homology with channels with known crystal structures. In the present work, we determined structural features of a peptide from the pore loop region of hERG (residues 600–642) in both sodium dodecyl sulfate (SDS) and dodecyl phosphocholine (DPC) micelles using NMR spectroscopy. A complete structure calculation was done for the peptide in DPC, and the localization of residues inside the micelles were analysed by using a water-soluble paramagnetic reagent with both DPC and SDS micelles. The pore-helix in the hERG peptide was only two–four residues longer at the N-terminus, compared with the pore helices seen in the crystal structures of other K⁺ channels, rather than the seven residues suggested from previous NMR studies. The helix in the peptide spanned the same residues in both micellar environments despite a difference in the localization inside the respective micelles. To determine if the extension of the length of the helix was affected by the hydrophobic environment in the two types of micelles, we compared NMR and X-ray crystallography results from a homologous peptide from the voltage gated potassium channel, KcsA.     

Development and characterization of microsatellite markers for Psychotria tenuinervis (Rubiaceae), a shrub species from the Atlantic forest, and primers transferability from Coffea

The shrub species Psychotria tenuinervis (Rubiaceae) is native to the Brazilian Atlantic forest and is largely found within natural and disturbed forest fragments. Aiming to develop studies on population genetic structure of forest fragment species, eigth microsatellite markers were developed for P. tenuinervis. Also, 15 loci already developed for Coffea (Rubiaceae) were tested for transferability to this species. We utilized 45 individuals from natural populations of three different fragments-anthropic edge, interior fragment and natural edge, within the Brazilian Atlantic forest. The average number of alleles per locus was 2.5 (two–four alleles/locus). These loci will be useful for future population genetic studies aiming to the conservation and management of this species.     

Successful eradication of invasive rodents from a small island through pulsed baiting inside covered stations

We show the results of an eradication campaign against Rattus rattus developed in Rey Francisco Island (12 ha), Chafarinas islands, southwestern Mediterranean. Rat population size was estimated by snap trapping in up to 93.47 ind./ha and a trapping index of 9.58 captures/100 traps-night. We think that population was underestimated because of the number of traps found strung but without capture. Several products were tested in order to define the method of eradication. In 1992, we selected a second generation anticoagulant, pelleted brodifacoum 50 ppm into 5 l plastic containers as baiting stations. Bait consumption reached zero after three pulses, and intensive searching of tracks and signals were unsuccessful. After more than two years of absence of signals and sightings, in 1995, rat scats were observed in Rey Francisco, and the population rose dizzily. After several snap-trapping sessions in 1996, 1997 and 1999, when trapping success reached 37 captures/100 trap-nights, a new campaign started in autumn–winter 1999–2000 using flocoumafen 50 ppm inside 180 baiting stations. Eradication occurred with a very low risk for non-target fauna, setting less than 1 kg/ha of bait each time. Monitoring, both with snap traps and baiting at a lower intensity assures the absence of reinvasion. This revised version was published online in July 2006 with corrections to the Cover Date.