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On the evolution of statistical methods as applied to clinical trials.

This paper describes how statistical methods have evolved in parallel with activities associated with randomized control trials. In particular we emphasize the pivotal role of two papers published in British Journal of Cancer, and the paper describing the Cox proportional hazards model. In addition, the importance of early papers on estimating the sample size required for trials is highlighted. Later developments including the increasing roles for competing risks, multilevel modelling and Bayesian methodologies are described. The interplay between computer software and statistical methodological developments is stressed. Finally some future directions are indicated.

Humans↗

Parallelising a model of bacterial interaction and evolution.

Large simulations of bacterial colonies require huge amounts of computational time, the only way to achieve the necessary level of performance is with parallel computers and a suitably designed implementation that maps the problem onto the hardware. For real problems this mapping can be a non-trivial problem requiring careful consideration of the constraints in both the system being modelled and the hardware that executes that model. Here we describe an implementation of a system for modelling bacterial evolution that encompasses many physical scales. This system is composed entirely of individual entities all playing out a complex series of interactions. These individuals exist at the scale of the population of bacterial and at the gene product scale. This paper reports that it is possible to map a dynamic problem such as this onto fixed resources, for the most part making use of implicit multiplexing of resources provided by the OS and partitioning the problem to reduce communication time. Through this an efficient simulation can be created, making maximal use of the available hardware without constraining the model to require excessively specific resources.

Bacterial Physiological Phenomena↗

Maximum-likelihood methods for phylogeny estimation.

Maximum-likelihood (ML) estimation of phylogenies has reached a rather high level of sophistication because of algorithmic advances, improvements in models of sequence evolution, and improvements in statistical approaches and application of cluster computing. Here, I provide a brief basic background in application of the general principle of ML estimation to phylogenetics and provide an example of selecting among a nested set of ML models using a dynamic approach to hierarchical likelihood-ratio tests. I focus attention on PAUP* because it provides unique ease of switching among alternative optimality criteria (e.g., minimum evolution, parsimony, and ML). Further, examples of parametric bootstrap tests are provided that demonstrate statistical tests of phylogenetic hypotheses and model adequacy, in an absolute rather than relative sense. The increasing availability of clustered, parallelized computation makes use of such parametric approaches feasible.

Algorithms↗

Role of new allergens and of allergens consumption in the increased incidence of food sensitizations in France.

Food allergy is a group of distinct clinico-pathological entities that have an immunological basis in common, and in which an abnormal or exaggerated immunological response to a specific food leads to disease. Some clinical pictures involving multiple organ system (anaphylaxis) are potentially fatal. The data on the incidence, prevalence, mortality rate and food products involved in food-induced anaphylaxis and the evolution of food sensitization compared with changes in eating habits are not very reliable. In the present study we analysed, over a period of 9 years (1984-1992), a group of 580 patients with pathological reactions to foods, 60 of which presented severe, near-fatal reactions. We sought the etiologic components and food sensitization in comparison with the principal tendencies of food consumption in France. Food products most frequently incriminated in anaphylactic reactions are not of a primary nutritional importance: celery (30%), crustaceans (17%), fish (13%), peanuts (12%), mango (6%), mustard (3%), but they are often hidden allergens in commercial foods. The sensitization to food products in the group of 580 patients reveals, in decreasing order of frequency: wheat (39%), peanuts (37%), crab (34%), celery (30%), soy (30%). Compared with previous data, the frequency of sensitization to different foods has changed; for instance, the sensitizations to wheat, soy, peanuts, celery, mustard, rice, are definitely increasing. The increased consumption and more attentive clinical research may be the reasons for this evolution. For products such as egg and pork, the data are stable and parallel with consumption, whilst for other products like milk and other dairy products, the increased consumption is accompanied by a decrease of the incidence of sensitization. The reactivity to some allergens may be affected by the way of preparing the food.

Adolescent↗

Expression and purification of histidine-tagged bacteriophage T7 DNA polymerase.

The formation of inclusion bodies is a frequent consequence of high-level production of foreign protein in the cytoplasm of Escherichia coli. This phenomenon is also observed with bacteriophage T7 gene 5 protein, the phage-encoded subunit of T7 DNA polymerase, if expression is based on the T5 promoter/lac operator transcription-translation system present in a vector with ColE1 origin of replication. To avoid tedious procedures for recovering protein from insoluble aggregates, we studied the expression of T7 gene 5 protein using a series of E. coli strains, and optimized the yield of soluble, histidine-tagged (His-tagged) protein by varying the respective growth conditions (temperature, amount of inducer isopropyl-beta-d-thiogalactopyranoside, and presence of organic osmolytes). Although the expression levels in three different strains (BL21, SG13009, and XL1-Blue) were almost comparable with a given set of growth conditions, the yields of soluble protein differed markedly. The largest quantities of soluble, His-tagged T7 gene 5 protein were achieved using "cloning strain" XL1-Blue which benefitted significantly from the presence of sorbitol and glycine betaine-in contrast to the expression strains BL21 and SG13009. Purification of His-tagged T7 gene 5 protein was achieved using single-step metal-affinity chromatography that yielded large amounts of highly active polymerase (97% homogeneity). The application of this expression/purification approach represents not only a useful method to purify large quantities of T7 DNA polymerase for structural investigations but also, provides a fast and efficient protocol for the parallel purification of T7 DNA polymerase variants, e.g., for automated screenings or directed evolution experiments.

Bacteriophage T7↗

Risk factors associated with an outbreak of dengue fever in a favela in Fortaleza, north-east Brazil.

To increase the effectiveness of ongoing anti-dengue control measures, we conducted a case-control study in a favela in Fortaleza (north-east Brazil) during an outbreak of dengue fever. Cases were defined according to the national guidelines for dengue control as well as based on the detection of IgM-dengue antibodies, and 34 cases and 34 controls were investigated. Significant risk factors were: living in a street perpendicular to the beach on which the favela is situated (P < 0.0001), an interval > 30 days since the last visit of the vector control agent (P=0.001), receptacles in the garden or courtyard (P=0.001), plants with temporary water pools on the property, gutter to collect rainwater, uncovered water storage container (all P=0.02), and no waste collection (P=0.03). Socio-economic variables were not associated with dengue fever. The probable starting point of the epidemic was an uncovered water tank on the roof of the house adjacent to the index case. From there, the outbreak spread uphill parallel to the prevailing direction of the wind. Thus, the chronological and spatial evolution of the epidemic could have been forecast after the first cases had occurred. This example of investigative epidemiology in an operational setting shows that targeted intervention leading to increased effectiveness of control measures is possible.

Adolescent↗

DNA hybridization for assessment of response of Plasmodium falciparum to chloroquine therapy.

We studied the accuracy of PFR1-AP, a synthetic DNA hybridization probe conjugated to alkaline phosphatase, in monitoring Plasmodium falciparum parasitemia during in vivo drug susceptibility surveys. Duplicate blood samples were collected from six children enrolled in a 14-day in vivo chloroquine study in Rwanda. Results obtained by microscopic examination of Giemsa-stained thick blood smears and by DNA hybridization were compared. Both techniques successfully monitored an infection with chloroquine-susceptible parasites and infections exhibiting various levels of resistance to treatment. For each patient, temporal evolution of the microscopic parasite counts and the DNA hybridization signals were closely parallel, although a wide range of rapidly changing levels of parasitemia occurred through the course of the study. This suggests that DNA hybridization assay using PFR1-AP detects P. falciparum parasites sensitively and specifically and is a valuable tool for drug resistance surveys.

Animals↗

Evolution of biliary secretion during bile diversion in normal and two-thirds hepatectomized rats.

The effect of the interruption of the enterohepatic circulation on bile production in anesthetized rats both before and after two thirds partial hepatectomy (PH) was studied. Both in the control animals and in the different periods after PH, interruption of the enterohepatic circulation led to significant decreases in bile flow and bile acid and sodium output. The evolution of choleresis in all the experimental groups was seen to follow a parallel course to that of sodium output and showed qualitative and quantitative discrepancies with the behavior of bile acid output. The cumulative secretion of bile acids expressed per 100 g of body weight was comparable in the controls and at 384 h after PH, though only in the former did the bile acid circulating pool size seem to be depleted. This depletion was more delayed than that described for conscious nonfasting rats. At 96 and 384 h after PH both cumulative bile flow and cumulative sodium secretion expressed per gram of liver were greater than those of the control animals. The choleretic capacity of the bile acids and the bile acid independent fraction of bile flow were significantly modified in the different posthepatectomy periods.

Animals↗

Solar spectral irradiometer for validation of remotely sensed hyperspectral data.

A new solar spectral irradiometer that operates in the visible and near-infrared spectral ranges has been developed. This instrument takes advantage of a new concept optical head that collects the light that impinges on a hemispheric surface, thus improving the instrument angular response with respect to traditional devices. The technical characteristics of the instrument are investigated and detailed, and its radiometric calibration, performed by means of a Langley-like method, is discussed. A new simplified theoretical model that accounts for the diffuse irradiance observed in an optically thin plane-parallel atmosphere has been developed to improve the fit of the irradiance diurnal evolution. An alternative polynomial parametric representation of monochromatic diffuse irradiance evolution has been attempted, but satisfactory results were not obtained from the fitting of experimental data. The new instrument could be useful to carry out remote-sensing validation campaigns.

Journal Article↗

The emerging problem of nonalcoholic steatohepatitis (NASH).

Nonalcoholic steatohepatitis (NASH) is an increasing recognized form of chronic liver condition affecting both children and adults within the wide spectrum of fatty liver diseases. Recently NASH has been often associated with insulin resistance and has shown potential harmful evolution towards end-stage liver disease. Its incidence and prevalence is increasing, paralleling the rise in obesity and diabetes mellitus in Western Countries. Once all the other causes of persistent elevation of serum transaminase levels are excluded, the diagnosis of NASH can be only confirmed by liver histology. Non-invasive diagnostic tools, however, are awaited to allow the follow-up of patients at higher risk for major liver dysfunction. This article focus on current thoughts on the natural history and clinical presentation of NASH and describes current trends in the diagnosis and treatment of this emerging condition.

Diet↗

[Health measurement: theoretical and methodologic perspectives].

The present article consists of a revision of the different ways health has been measured and was ordered according to the historic evolution of the health concept and conditions. The development of health measures has paralleled the changes occurred in the epidemiologic profiles and the many refinements in the conceptualization and interpretation of health. Along the years, the meaning of health has become increasingly wider. Initially, only infectious diseases were considered; later, degenerative processes were included. Nowadays, health is viewed as multifactorial and as a reflection of the life style and conditions. This essay contains a description of the theoretical postulates upon which the different health measures are based, their strategies and some of their limitations. It is divided into five main sections: morbidity, disability, and mortality indicators; measures of the health of the populations; sociomedical indicators, including measures of physical and mental health, as well as of the social component of health, positive health indicators and, finally a revision of measures of health need. It is of the utmost importance to be aware of the perspective used in the different public health research efforts since it has direct repercussions for the planning and evaluation of the health services and, in particular, for the quality of health care.

Persons with Disabilities↗

On the role of the notochord in somite formation and the possible evolutionary significance of the concomitant cell re-orientation.

Homoplastic grafts of re-orientated unsegmented paraxial mesoderm transplanted from stage 20 Xenopus embryos into host embryos of the same age resulted in segmentation and the formation of somites in the same axis as if they had been left in situ. Because grafts transplanted with various orientations came under the stretching effect of the notochord in different directions but never the less maintained their original pattern and direction of segmentation, it would appear that the notochord has no effect on somite formation which thus emerges as an autonomous process independent of the elongation of the embryo. The re-alignment of cells which occurs as the somites are formed and which, in normal unimpeded development, results in the long axis of the cells lying parallel to that of the notochord, is considered in the light of the evolution of sinusoid locomotion and it is suggested that it may be the primary process with the formation of somite blocks as one of its consequences.

Animals↗

Amino acid sequence of phospholipase A2-alpha from the venom of Crotalus adamanteus. A new classification of phospholipases A2 based upon structural determinants.

The complete amino acid sequence of Crotalus adamanteus venom phospholipase A2-alpha has been determined by analysis of the five tryptic peptides from the citraconylated, reduced, and S-[14C]carboxamidomethylated enzyme. Earlier studies (Tsao, F. H. C., Keim, P. S., and Heinrikson, R. L. (1975) Arch. Biochem. Biophys. 167, 706) provided the information necessary to align the tryptic fragments so that secondary cleavage procedures to establish overlaps were unnecessary. The subunit in the phospholipase A2-alpha dimer is a single polypeptide chain containing 122 amino acids and seven disulfide bonds. The histidine residue implicated in the active site of mammalian phospholipases is at position 47 in the C. adamanteus enzyme and is located in a domain of the molecule which is highly homologous in sequence with corresponding regions of phospholipases from a variety of venom and pancreatic sources. Comparative sequence analysis has revealed insights with regard to the function and evolution of phospholipases A2. Primary structural relationships observed among the snake venom enzymes parallel the phylogenetic classification of the venomous reptiles from which they were derived. It is proposed that phospholipases A2 of this general type be divided into two groups depending upon the presence or absence of distinctive structural features elucidated in this study.

Amino Acid Sequence↗

Mosaics of islet-1-expressing amacrine cells assembled by short-range cellular interactions.

The nervous system has a modular architecture with neurons of the same type commonly organized in nonrandom arrays or mosaics. Modularity is essential to parallel processing of sensory information and has provided a key element for brain evolution, but we still know very little of the way neuronal mosaics form during development. Here we have identified the immature elements of two retinal mosaics, the choline acetyltransferase (ChAT) amacrine cells, by their early expression of the homeodomain protein Islet-1, and we show that spatial ordering is an intrinsic property of the two Islet-1 mosaics, dynamically maintained while new elements are inserted into the mosaics. Migrating Islet-1 cells do not show this spatial ordering, indicating that they must move tangentially as they enter the mosaic, under the action of local mechanisms. Clonal territory analysis in X-inactivation transgenic mice confirms the lateral displacement of ChAT amacrine cells away from their clonal columns of origin, and mathematical models show how short-range cellular interactions can guide the assemblage of these mosaics via a simple biological rule.

Animals↗

The basic depression ratio of the host: the evolution of host resistance to microparasites.

The basic reproduction ratio R0 occupies a central position in the theory of host pathogen interactions. However, this quantity stresses the role of the pathogen. This paper proposes an additional, more host-centred char acterization using the basic depression ratio D0. This quantity is the number of host individuals per infected by which the infected host population is depressed below its uninfected level. This paper shows that a baseline criterion for the evolution of host resistance to microparasites is that resistance evolves to minimize D0. This parallels the result for pathogen virulence where R0 is maximized. The tension between these two criteria is noted. The framework established allows a discussion of trade-offs between aspects of the pathogen-free host biology and the host pathogen interaction. For certain linear and convex trade-offs it is shown that the strain with the lowest transmission parameter beta wins (despite the fact that it has the lowest intrinsic birth rate a). For corresponding concave trade-offs, either the strain with minimum beta and a or the strain with maximum beta and a wins. Finally the connection with the techniques of adaptive dynamics is made. Evolutionary singular points are shown to occur at extrema of D0. The evolutionary attainment of the results is discussed.

Adaptation, Physiological↗

Earliest presence of humans in northeast Asia.

The timing of the earliest habitation and oldest stone technologies in different regions of the world remains a contentious topic in the study of human evolution. Here we contribute to this debate with detailed magnetostratigraphic results on two exposed parallel sections of lacustrine sediments at Xiaochangliang in the Nihewan Basin, north China; these results place stringent controls on the age of Palaeolithic stone artifacts that were originally reported over two decades ago. Our palaeomagnetic findings indicate that the artifact layer resides in a reverse polarity magnetozone bounded by the Olduvai and Jaramillo subchrons. Coupled with an estimated rate of sedimentation, these findings constrain the layer's age to roughly 1.36 million years ago. This result represents the age of the oldest known stone assemblage comprising recognizable types of Palaeolithic tool in east Asia, and the earliest definite occupation in this region as far north as 40 degrees N.

Animals↗

[Immunologic research in pediatrics].

The child, in his ontogenesis, repeats the phylogenetic evolution of the immune processes. The immunologic maturation gradually appears, the process having a definite duration. The immunologic maturation seems to be parallel to the maturation of other physiological processes. The immune system of the child is different from that of the adult, and the development features of his immune reactivity will give a specific evolution to his morbid manifestations.

Antibody Formation↗

Bias in the introduction of variation as an orienting factor in evolution.

According to New Synthesis doctrine, the direction of evolution is determined by selection and not by "internal causes" that act by way of propensities of variation. This doctrine rests on the theoretical claim that because mutation rates are small in comparison to selection coefficients, mutation is powerless to overcome opposing selection. Using a simple population-genetic model, this claim is shown to depend on assuming the prior availability of variation, so that mutation may act only as a "pressure" on the frequencies of existing alleles, and not as the evolutionary process that introduces novelty. As shown here, mutational bias in the introduction of novelty can strongly influence the course of evolution, even when mutation rates are small in comparison to selection coefficients. Recognizing this mode of causation provides a distinct mechanistic basis for an "internalist" approach to determining the contribution of mutational and developmental factors to evolutionary phenomena such as homoplasy, parallelism, and directionality.

Alleles↗