Robust Inference for Univariate Proportional Hazards Frailty Regression Models

We consider a class of semiparametric regression models which are one-parameter extensions of the Cox [J. Roy. Statist. Soc. Ser. B 34 (1972) 187-220] model for right-censored univariate failure times. These models assume that the hazard given the covariates and a random frailty unique to each individual has the proportional hazards form multiplied by the frailty. The frailty is assumed to have mean 1 within a known one-parameter family of distributions. Inference is based on a nonparametric likelihood. The behavior of the likelihood maximizer is studied under general conditions where the fitted model may be misspecified. The joint estimator of the regression and frailty parameters as well as the baseline hazard is shown to be uniformly consistent for the pseudo-value maximizing the asymptotic limit of the likelihood. Appropriately standardized, the estimator converges weakly to a Gaussian process. When the model is correctly specified, the procedure is semiparametric efficient, achieving the semiparametric information bound for all parameter components. It is also proved that the bootstrap gives valid inferences for all parameters, even under misspecification. We demonstrate analytically the importance of the robust inference in several examples. In a randomized clinical trial, a valid test of the treatment effect is possible when other prognostic factors and the frailty distribution are both misspecified. Under certain conditions on the covariates, the ratios of the regression parameters are still identifiable. The practical utility of the procedure is illustrated on a non-Hodgkin's lymphoma dataset.Comment: Published by the Institute of Mathematical Statistics (http://www.imstat.org) in the Annals of Statistics (http://www.imstat.org/aos/) at http://dx.doi.org/10.1214/00905360400000053

Monitoring and Management of Childhood Asthma in Asian Countries

BACKGROUND: A recent study by the International Study of Asthma and Allergies in Childhood has shown that asthma symptom prevalence is still increasing in parts of Asia. As such, it is important to know how well asthma is being managed. Practices of physicians in India, China, Sri Lanka, Australia, Singapore, Indonesia, Philippines, and Taiwan in monitoring and treating childhood asthma were examined. METHODS: A 6-page standardized questionnaire was sent to physicians via post. The questionnaire is made up of 3 parts, including (1) methods of monitoring of childhood asthma, (2) practices in managing acute asthma exacerbations, and (3) choice of therapy in maintenance treatment. RESULTS: Our study reflects mostly the practices of physicians who practice in urban regions. Of respondents, 41.4% were general pediatricians, whereas 26.3% were general practitioners. A small fraction of physicians used score cards or diaries to monitor asthma, ranging from 0% (Philippines and Australia) to 15.9% (India). Only 8.1% (Sri Lanka) to 52.0% (Australia) use either a peak flow meter and/or spirometry to monitor asthma. However, for frequency of use, 35% (China) to 94% (Indonesia) never or seldom make use of a peak flow meter, and 33% (China) to 97.6% (Indonesia) never or seldom use spirometry for monitoring. Most physicians treat acute asthma appropriately with short-acting bronchodilators. For maintenance treatment, an inhaled corticosteroid was the most frequently chosen first-choice therapy. However, a significant fraction of physicians chose a long-acting β-agonist monotherapy as a first-choice treatment for asthma maintenance. For infants, the percentage ranged from 1.4% (Australia) to 76.3% (Indonesia); in preschoolers, 1.8% (Australia) to 43.3% (Indonesia); and in older children, 0% (Philippines) to 28.8% (Indonesia). These results may be related to the overall affluence of each nation. CONCLUSIONS: There is much room for improvement in increasing physicians' awareness to guidelines for more effective management of pediatric asthma in Southeast Asia, especially regarding the high use of long-acting β-agonist monotherapy, even in young children

Pareto versus lognormal: a maximum entropy test

It is commonly found that distributions that seem to be lognormal over a broad range change to a power-law (Pareto) distribution for the last few percentiles. The distributions of many physical, natural, and social events (earthquake size, species abundance, income and wealth, as well as file, city, and firm sizes) display this structure. We present a test for the occurrence of power-law tails in statistical distributions based on maximum entropy. This methodology allows one to identify the true data-generating processes even in the case when it is neither lognormal nor Pareto. The maximum entropy approach is then compared with other widely used methods and applied to different levels of aggregation of complex systems. Our results provide support for the theory that distributions with lognormal body and Pareto tail can be generated as mixtures of lognormally distributed units

Psychotherapy mediated by remote communication technologies: a meta-analytic review

Reproduced with permission of the publisher. © 2008 Bee et al; licensee BioMed Central Ltd. The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-244X/8/60. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background Access to psychotherapy is limited by psychopathology (e.g. agoraphobia), physical disability, occupational or social constraints and/or residency in under-served areas. For these populations, interventions delivered via remote communication technologies (e.g. telephone, internet) may be more appropriate. However, there are concerns that such delivery may influence the therapeutic relationship and thus reduce therapy effectiveness. This review aimed to determine the clinical effectiveness of remotely communicated, therapist-delivered psychotherapy. Methods Systematic review (including electronic database searching and correspondence with authors) of randomised trials of individual remote psychotherapy. Electronic databases searched included MEDLINE (1966–2006), PsycInfo (1967–2006), EMBASE (1980–2006) and CINAHL databases (1982–2006). The Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDAN-CTR). All searches were conducted to include studies with a publication date to July 2006. Results Thirteen studies were identified, ten assessing psychotherapy by telephone, two by internet and one by videoconference. Pooled effect sizes for remote therapy versus control conditions were 0.44 for depression (95%CI 0.29 to 0.59, 7 comparisons, n = 726) and 1.15 for anxiety-related disorders (95%CI 0.81 to 1.49, 3 comparisons, n = 168). There were few comparisons of remote versus face-to-face psychotherapy. Conclusion Remote therapy has the potential to overcome some of the barriers to conventional psychological therapy services. Telephone-based interventions are a particularly popular research focus and as a means of therapeutic communication may confer specific advantages in terms of their widespread availability and ease of operation. However, the available evidence is limited in quantity and quality. More rigorous trials are required to confirm these preliminary estimates of effectiveness. Future research priorities should include overcoming the methodological shortcomings of published work by conducting large-scale trials that incorporate both clinical outcome and more process-orientated measures

The Mersey Estuary : sediment geochemistry

This report describes a study of the geochemistry of the Mersey estuary carried out between April 2000 and December 2002. The study was the first in a new programme of surveys of the geochemistry of major British estuaries aimed at enhancing our knowledge and understanding of the distribution of contaminants in estuarine sediments. The report first summarises the physical setting, historical development, geology, hydrography and bathymetry of the Mersey estuary and its catchment. Details of the sampling and analytical programmes are then given followed by a discussion of the sedimentology and geochemistry. The chemistry of the water column and suspended particulate matter have not been studied, the chief concern being with the geochemistry of the surface and near-surface sediments of the Mersey estuary and an examination of their likely sources and present state of contamination

Incidence of fatal food anaphylaxis in people with food allergy: a systematic review and meta-analysis

BACKGROUND: Food allergy is a common cause of anaphylaxis, but the incidence of fatal food anaphylaxis is not known. The aim of this study was to estimate the incidence of fatal food anaphylaxis for people with food allergy and relate this to other mortality risks in the general population. METHODS: We undertook a systematic review and meta-analysis, using the generic inverse variance method. Two authors selected studies by consensus, independently extracted data and assessed the quality of included studies using the Newcastle-Ottawa assessment scale. We searched Medline, Embase, PsychInfo, CINAHL, Web of Science, LILACS or AMED, between January 1946 and September 2012, and recent conference abstracts. We included registries, databases or cohort studies which described the number of fatal food anaphylaxis cases in a defined population and time period and applied an assumed population prevalence rate of food allergy. RESULTS: We included data from 13 studies describing 240 fatal food anaphylaxis episodes over an estimated 165 million food-allergic person-years. Study quality was mixed, and there was high heterogeneity between study results, possibly due to variation in food allergy prevalence and data collection methods. In food-allergic people, fatal food anaphylaxis has an incidence rate of 1.81 per million person-years (95%CI 0.94, 3.45; range 0.63, 6.68). In sensitivity analysis with different estimated food allergy prevalence, the incidence varied from 1.35 to 2.71 per million person-years. At age 0–19, the incidence rate is 3.25 (1.73, 6.10; range 0.94, 15.75; sensitivity analysis 1.18–6.13). The incidence of fatal food anaphylaxis in food-allergic people is lower than accidental death in the general European population. CONCLUSION: Fatal food anaphylaxis for a food-allergic person is rarer than accidental death in the general population

Growth performance, carcass characteristics and meat quality of group-penned surgically castrated, immunocastrated (Improvac®) and entire male pigs and individually penned entire male pigs

The objective of the study was to compare growth performance, carcass characteristics, meat quality and fatty acid composition of the adipose tissue of group-penned barrows, immunocastrated boars and entire males. Furthermore, the effect of housing of entire males on the aforementioned parameters was evaluated. At 55.2 days of age, 52 Swiss Large White pigs were blocked by litter and assigned by BW to four experimental groups: barrows (C), immunocastrated boars (IC), entire males (EMG) reared in group pens and entire males (EMP) reared in individual pens. In experiment 1, the effects of the method of castration were investigated (experimental groups C, IC and EMG). In experiment 2, the effects of housing on entire male pigs were evaluated (experimental groups EMG and EMP). All pigs had ad libitum access to standard diets from weaning to 107 kg BW. The two vaccinations (Improvac®) were applied to the IC pigs at an average BW of 22.6 and 73.0 kg. In experiment 1, average daily gain (ADG) did not (P > 0.05) differ among the experimental groups. However, EMG consumed less feed and had a better feed-conversion ratio than C (P 0.05) differ between EMP and EMG. However, EMP pigs consumed more feed than EMG pigs and had a poorer feed efficiency (P < 0.01 for each). In conclusion, EMG pigs had a better feed efficiency than IC pigs and their carcasses were leaner, but the risk of boar tainted pork was elevated. Group-housing negatively affected average daily feed intake but not ADG of entire males. At the moment, immunocastration offers a good approach to avoid castration and minimize the risk of boar tain

Hydrolysable tannin-based diet rich in gallotannins has a minimal impact on pig performance but significantly reduces salivary and bulbo-urethral gland size

Tannins have long been considered ‘anti-nutritional’ factors in monogastric nutrition, shown to reduce feed intake and palatability. However, recent studies revealed that compared to condensed tannins, hydrolysable tannins (HT) appear to have far less impact on growth performance but may be inhibitory to the total activity of caecal bacteria. This in turn could reduce microbial synthesis of skatole and indole in the hindgut of entire males (EM). Thus, the objective of this study was to determine the impact of a group of dietary HT on growth performance, carcass traits and boar taint compounds of group housed EM. For the study, 36 Swiss Large White boars were assigned within litter to three treatment groups. Boars were offered ad libitum one of three finisher diets supplemented with 0 (C), 15 (T15) or 30 g/kg (T30) of HT from d 105 to 165 of age. Growth performance, carcass characteristics, boar taint compounds in the adipose tissue and CYP2E1, CYP1A2, and CYP2A19 gene expression in the liver was assessed. Compared to C, feed efficiency but not daily gain and daily feed intake was lower (P < 0.05) in T15 and T30 boars. Except for the percent carcass weight loss during cooling, which tended (P < 0.10) to be greater in T30 than C and T15, carcass characteristics were not affected by the diets. In line with the numerically lower androstenone level, bulbo-urethral and salivary glands of T30 boars were lighter (P < 0.05) than of T15 with intermediate values for C. Indole level was lower (P < 0.05) in the adipose tissue of T30 than C pigs with intermediate levels in T15. Skatole levels tended (P < 0.10) to be lower in T30 and C than T15 pigs. Hepatic gene expression of CYP isoenzymes did not differ between treatment groups but was negatively correlated (P < 0.05) with androstenone (CYP2E1 and CYP1A2), skatole (CYP2E1, CYP2A) and indole (CYP2A) level. In line with the numerically highest androstenone and skatole concentrations, boar taint odour but not flavour was detected by the panelists in loins from T15 compared with loins from C and T30 boars. These results provide evidence that HT affected metabolism of indolic compounds and androstenone and that they affected the development of accessory sex glands. However, the effects were too small to be detected by sensory evaluation

A high-throughput in vivo micronucleus assay for genome instability screening in mice.

We describe a sensitive, robust, high-throughput method for quantifying the formation of micronuclei, markers of genome instability, in mouse erythrocytes. Micronuclei are whole chromosomes or chromosome segments that have been separated from the nucleus. Other methods of detection rely on labor-intensive, microscopy-based techniques. Here we describe a 2-d, 96-well plate-based flow cytometric method of micronucleus scoring that is simple enough for a research technician experienced in flow cytometry to perform. The assay detects low levels of genome instability that cannot be readily identified by classic phenotyping, using 25 μl of blood. By using this assay, we have screened >10,000 blood samples and discovered novel genes that contribute to vertebrate genome maintenance, as well as novel disease models and mechanisms of genome instability disorders. We discuss experimental design considerations, including statistical power calculation, we provide troubleshooting tips and we discuss factors that contribute to a false-positive increase in the number of micronucleated red blood cells and to experimental variability.Acknowledgments We thank M. Hitcham and N. Harman for assistance with blood collections, W. Cheng for assistance with flow cytometry during high-throughput screening and K. Dry for comments on the manuscript. R.E.M. is supported by Cancer Research UK (CRUK; project grant C20510/A12401). D.J.A. is supported by CRUK. D.J.A. and B.L.N. are supported by the Wellcome Trust. Research in the Jackson Laboratory is funded by CRUK program grant no. C6/A11224, the European Research Council and the European Community Seventh Framework Programme grant agreement no. HEALTH-F2-2010-259893 (DDResponse). Core funding is provided by CRUK (C6946/A14492) and the Wellcome Trust (WT092096). S.P.J. receives his salary from the University of Cambridge, UK, supplemented by CRUK. G.B. is funded by CRUK program grant no. C6/A11224.This is the accepted manuscript for a paper published in Nature Protocols 10, 205–215 (2015) doi:10.1038/nprot.2015.010, Published online 31 December 201

Performances, meat quality and boar taint of castrates and entire male pigs fed a standard and a raw potato starch-enriched diet

In Europe there is increasing concern about the common practice of surgical castration of piglets without anaesthesia. One possible alternative to completely avoid castration is entire male pig production. Thus, the objective of the study was to compare the growth performance, carcass characteristics, organ weights, meat quality traits, fat score and boar taint compounds in the adipose tissue of group-penned entire male pigs and castrates. Furthermore, the effect of raw potato starch (RPS) fed for 7 days prior to slaughter was determined. Pigs (n = 36) were blocked by BW into 12 blocks (3 littermates/block) and assigned to three experimental groups: surgical castrates (C); entire males (EM); and entire males offered RPS (30 g RPS/100 g diet) for 7 days prior to slaughter (EM+). Pigs had ad libitum access to the feed from 22 to 107 kg, individual feed intake was recorded daily and BW once a week. Entire males grew slower (EM: 771, EM+: 776 v. C: 830 g/day; P 0.05) differ among experimental groups but the adipose tissue was more unsaturated in entire males than in C as indicated by the higher fat scores (EM: 69.1, EM+: 67.2 v. C: 63.6; P < 0.01). Feeding RPS reduced (P = 0.04) the skatole tissue concentrations (expressed in μg/g lipid) in EM+ (0.22) compared to EM (0.85), whereas androstenone and indole levels were not (P 0.60) affected (EM: 1.7 and 0.10, EM+: 2.0 and 0.09, respectively). Although the current results confirmed the high efficiency of entire males compared to castrates, the observed high androstenone levels represent a major challenge to implement entire males productio