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Results for “Observer Variation”

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PubMed1994

The case for case-mix adjustment in practice profiling. When good apples look bad.

OBJECTIVE: To assess the influence of patient characteristics on practice profiling. Using the example of specialty referrals by primary care physicians, we evaluated the impact of adjusting for patient characteristics (age/sex vs case mix) on the estimation of practice variation, the identification of outlier practices, and the evaluation of potential predictors of variation. DESIGN AND SETTING: We applied several measurement strategies to a retrospective cohort of patients (N = 37,830) within 52 physician practices in a large staff-model health maintenance organization during a 1-year period. OUTCOME MEASURES: We calculated unadjusted referral rates and adjusted standardized referral ratios for each physician. Using these, we determined coefficients of variation and statistical "outlier status." RESULTS: Adjustment for patient characteristics decreased the observed variation in referral profiles, with a decrease of more than 50% in the coefficient of variation. Three quarters of the physicians identified as statistical outliers with use of an age/sex-adjusted measure were no longer identified as such with use of an case-mix-adjusted measure. Several key predictors of unadjusted referral rate (including physician age, practice tenure, site of practice, and extent of laboratory test ordering) dropped out of regression models when the outcome variable was adjusted for patient characteristics. CONCLUSION: Failure to adjust for case mix in physician practice profiles may lead to overestimates of variation and misidentification of outliers. To the extent that unadjusted practice profiles are used for decisions about education, sanctions, or employment, physicians may be subject to inequitable decisions and actions. Misinformation about the causes and extent of practice variation may also lead to misdirection of scarce resources for quality improvement efforts.

Age Factors↗

PubMed1989

Variation in buoyant density of whole cells and isolated cell walls of Streptococcus faecium (ATCC 9790).

The buoyant density of whole cells of Streptococcus faecium varies with growth rate and during the cell cycle. Two possible explanations for this were explored: (i) the density of cell walls may vary, and (ii) the proportions of wall and cytoplasm may vary. We tested the first possibility by isolating walls from chilled, unfixed populations of S. faecium cells and fractionating them on Percoll density gradients. Mean cell wall density averaged 4% less than whole-cell density and did not vary significantly with growth rate. In addition, walls isolated from heavy and light fractions of a population of cells did not differ significantly in density. Thus, variation in the density of isolated cell walls could not account for the observed variation in whole-cell density within or between populations. Using previously published measurements of the physical dimensions of S. faecium cells, we also found that the relative proportions of wall and cytoplasm (see the second possibility above) could not account for the observed changes in whole-cell buoyant density.

Cell Wall↗

PubMed1998

Heterogeneity of microsatellite mutations within and between loci, and implications for human demographic histories.

Microsatellites have been widely used to reconstruct human evolution. However, the efficient use of these markers relies on information regarding the process producing the observed variation. Here, we present a novel approach to the locus-by-locus characterization of this process. By analyzing somatic mutations in cancer patients, we estimated the distributions of mutation size for each of 20 loci. The same loci were then typed in three ethnically diverse population samples. The generalized stepwise mutation model was used to test the predicted relationship between population and mutation parameters under two demographic scenarios: constant population size and rapid expansion. The agreement between the observed and expected relationship between population and mutation parameters, even when the latter are estimated in cancer patients, confirms that somatic mutations may be useful for investigating the process underlying population variation. Estimated distributions of mutation size differ substantially amongst loci, and mutations of more than one repeat unit are common. A new statistic, the normalized population variance, is introduced for multilocus estimation of demographic parameters, and for testing demographic scenarios. The observed population variation is not consistent with a constant population size. Time estimates of the putative population expansion are in agreement with those obtained by other methods.

Adenocarcinoma↗

PubMed2002

Polymorphism and evolution in the constant region of the T-cell receptor beta chain in an advanced teleost fish.

Sequence, PCR and Southern data are presented as evidence that, as in mammals, two gene loci encode C regions of the TCR beta chain in the bicolor damselfish, Stegastes partitus. The loci are distinguished by an insertion of ten amino acids in the c-d loop at one locus and by a high interlocus divergence of the third intron and fourth exon sequences. Unlike their mammalian counterparts, the damselfish TCRBC genes encode highly polymorphic regions. None of the eight complete cDNA or four partial genomic DNA sequences presented from a single animal are identical; and three of the four animals examined are heterozygous at both loci, suggesting high heterozygosity in the damselfish population. Coding regions of the eight cDNA clones differ by up to 12% at the DNA level and 23% at the amino acid level. Polymorphism is concentrated primarily in the less evolutionarily conserved regions, suggesting that this variation may be selectively neutral. However, a comparison of the variation between synonymous and non-synonymous sites suggests that at least a portion of the observed variation results from selection. As in mammals, a gradient of sequence homogenization between the two loci is observed. Data presented here suggest that both interlocus homogenization and the sharing of polymorphic segments are likely achieved by partial gene conversion.

Amino Acid Sequence↗

PubMed1999

Pharmacokinetics of intravenous and oral L-arginine in normal volunteers.

AIMS: Recent studies in patients with cardiovascular diseases suggest potential for the use of orally administered L-arginine, the precursor of nitric oxide, as a therapeutic agent. This crossover study was designed to examine the pharmacokinetics of single i.v. and oral doses of L-arginine in healthy volunteers (n = 10). METHODS: A preliminary control study (n = 12) was performed to assess the variation in plasma L-arginine concentrations when ingesting a normal diet. The observed variation was taken into account when interpreting the pharmacokinetic data obtained after exogenous administration. RESULTS: The mean baseline plasma concentration of L-arginine in the control study was 15.1+/-2.6 microg ml(-1). After intravenous administration (30 g over 30 min), the plasma concentration reached 1390+/-596 microg ml(-1). The disappearance of l-arginine appeared biphasic, with an initial rapid disappearance due to concentration-dependent renal clearance followed by a slower fall in plasma concentrations due to nonrenal elimination. The peak concentration after oral administration (10 g) was 50.0+/-13.4 microg ml(-1), occurring 1 h after administration. Renal elimination was not observed after oral administration of this dose. The absolute bioavailability of a single oral 10 g dose of L-arginine is approximately 20%. CONCLUSIONS: This study provides basic knowledge of L-arginine pharmacokinetics in healthy humans. Intravenous and oral administrations show at minimum a biphasic pattern. Further studies will assess whether a similar profile is observed when the drug is administered to patients.

Administration, Oral↗

PubMed2006

Variations on a theme: sources of heterogeneity in the form of the interspecific relationship between abundance and distribution.

1. A positive interspecific relationship between abundance and distribution is widely considered to be one of the most general patterns in ecology. However, the relationship appears to vary considerably across assemblages, from significant positive to significant negative correlations and all shades in between. 2. This variation has led to the suggestion that the abundance-distribution relationship has multiple forms, with the corollary that different patterns may inform about, or have different, causes. However, this variation has never been formally quantified, nor has it been determined whether the observed variation is indicative of sampling error in estimating a single effect or of real heterogeneity in such relationships. Here, we use the meta-analytical approach to assess variation in abundance-distribution relationships, and to test different hypotheses for it. 3. Analysis of 279 relationships found a mean effect size of 0.655, which was both highly significantly different from zero and indicative of a strong positive association between abundance and distribution. However, effect sizes were highly heterogeneous, supporting the contention that this relationship does indeed have multiple forms. 4. Most notably, relationships vary significantly in strength across realms, with the strongest in the marine and intertidal, intermediate relationships for terrestrial and parasitic assemblages, and the weakest relationships in freshwater systems. Effect sizes in all of the aquatic realms are homogeneous, suggesting that realm is an important source of the heterogeneity observed across all studies. We posit that this may be because the different spatial structure of the environment in each realm affects the opportunity for the dispersal of individuals between sites. 5. Some of the remaining heterogeneity in effect sizes for terrestrial assemblages could be explained by partitioning assemblages by habitat, scale, biogeographical region and taxon, but considerable heterogeneity in effect sizes for terrestrial and parasitic assemblages remained unexplained.

Amphibians↗

PubMed2004

Benthic diatom community response to environmental variables and metal concentrations in a contaminated bay adjacent to Casey Station, Antarctica.

This study examined the effects of anthropogenic contaminants and environmental variables on the composition of benthic diatom communities within a contaminated bay adjacent to an abandoned waste disposal site in Antarctica. The combination of geographical, environmental and chemical data included in the study explained all of the variation observed within the diatom communities. The chemical data, particularly metal concentrations, explained 45.9% of variation in the diatom communities, once the effects of grain-size and spatial structure had been excluded. Of the metals, tin explained the greatest proportion of variation in the diatom communities (28%). Tin was very highly correlated (R2>0.95) with several other variables (copper, iron, lead, and sum of metals), all of which explained similarly high proportions of total variation. Grain-size data explained 23% of variation once the effects of spatial structure and the chemical data had been excluded. The pure spatial component explained only 1.8% of the total variance. The study demonstrates that much of the compositional variability observed in the bay can be explained by concentrations of metal contaminants.

Antarctic Regions↗

PubMed2004

Haplotypes of the alpha-1 antitrypsin gene in healthy controls and Z deficiency patients.

Alpha-1 antitrypsin (AAT; HUGO symbol, SERPINA1) is one of the major serine protease inhibitors (serpins) in human plasma. Deficiency of AAT is a recognised risk factor for chronic obstructive pulmonary disease (COPD), attributed to uninhibited neutrophil elastase released into the lung tissue during inflammatory states. In this study we used sequencing to screen the exonic regions, 5' and 3' flanking sequence of the AAT gene in order to generate a high density map of single nucleotide polymorphisms (SNPs). 16 SNPs were identified throughout AAT. Haplotypes based on SNPs with a minor allele frequency of > or =5% were estimated using genotypic information from 225 healthy control individuals and 41 AAT deficient Pi-ZZ individuals. AAT shows a large amount of variation in the control population, with 17 haplotypes accounting for 88% of the observed variation. The haplotype distribution of the common deficiency Pi-Z variant of AAT was significantly different when compared to the normal variants. In addition to the haplotype information, we present evidence for a functional effect of a SNP in intron 1.

Cell Line↗

PubMed1990

Topographic variations in W-cell input to cat superior colliculus.

Most of the retinal input to the cat's superior colliculus (SC) arises from W-cells of the contralateral eye and terminates just below the tectal surface. The goal of this study was to determine whether the strength of this input is uniform over the collicular map or, instead, exhibits topographic variations as has been reported for the retinotectal Y-cell projection (McIlwain and Lufkin 1976). Monosynaptic inputs from the principal W-cell projection mediate the late negative potential (LNP), a collicular field potential that can be evoked by shocks to the optic pathway. We assumed that the amplitude of the potential provided a measure of the strength of the W-cell input to the upper superficial gray layer. Using a fixed stimulus, we measured the maximal amplitude of the LNP at 90 topographically identified tectal sites in 5 cats. The amplitude of the LNP varied as much as 5-fold over the SC and was systematically related to the azimuthal position of the recording site. LNP amplitudes were consistently smallest in the representation of the area centralis and vertical meridian and largest in the representations of the contralateral hemifield periphery and the ipsilateral hemifield. There was little systematic variation in LNP amplitude as a function of elevation in the map. The observed variations did not result from non-uniform activation of retinal afferents or drift in properties of the recording electrodes, stimuli, or preparation. The results suggest that the principal W-cell input to the SC is weaker in the representation of the area centralis than elsewhere in the map.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗

PubMed1996

[Monitoring of the activities of low-threshold access structures for drug users in Switzerland: distribution of sterile injection equipment, results for 1993 and various cantonal examples].

In Switzerland numerous structures distribute or sell sterile injecting equipment for i.v. drug users, low threshold centres (LTC's) being the major provider. A national survey of these centres was initiated by the UEPP in january 1993, in the context of the global evaluation of the new set of the federal measures to reduce the problems related to illegal drug use. This article concentrates mainly on the results of the monitoring activity of the LTC's, which in 1993 distributed 7.1 millions syringes. This important offer is not, however, uniform across the different regions of the country. Some examples of regional variations are presented, as are fluctuations of demand in many LTC's. The observed variations can be correlated with season (increased demand in summer), but also with the development of LTC's (opening /closing down of centre, change in the structure, opening hours, etc.) and with external events (policy, increased pressure from police, etc.). This type of monitoring is useful not only for researchers in the field of drug addiction and prevention of HIV/AIDS, but also for decision makers and actors in the field of public health. The recommendations based on the first three years of this monitoring suggest that efforts to prevent sexual transmission of HIV among i.v. drug users should be reinforced as well as measures to supply sterile injecting equipment and condoms at low threshold level must be continued and further developed.

Community Health Services↗

PubMed1998

Limited flexibility of the inter-protofilament bonds in microtubules assembled from pure tubulin.

The superposition of the regular arrangement of tubulin subunits in microtubules gives rise to moiré patterns in cryo-electron micrographs. The moiré period can be predicted from the dimensions of the tubulin subunits and their arrangement in the surface lattice. Although the average experimental moiré period is usually in good agreement with the theoretical one, there is variation both within and between microtubules. In this study, we addressed the origin of this variability. We examined different possibilities, including artefacts induced by the preparation of the vitrified samples, and variations of the parameters that describe the microtubule surface lattice. We show that neither flattening nor bending of the microtubules, nor changes in the subunit dimensions, can account for the moiré period variations observed in 12 and 14 protofilament microtubules. These can be interpreted as slight variations, in the range -0.5 A to +0.9 A, of the lateral interactions between tubulin subunits in adjacent protofilaments. These results indicate that the inter-protofilament bonds are precisely maintained in microtubules assembled in vitro from pure tubulin. The fact that the moiré period is not affected by bending indicates that the local interactions between tubulin subunits are sufficiently stiff to accommodate large deformations of the microtubule wall.

Animals↗

PubMed1983

Circadian and genetic influences on tissue sensitivity and sleep time to ethanol in LS and SS mice.

Circadian variations in response to ethanol were studied in long-sleep (LS) and short-sleep (SS) mice. Each LS animal received a 2.5 g/kg intraperitoneal ethanol injection, while the SS animals were injected with 4.1 or 5.0 g/kg. Different groups of mice were assessed for sleep time, waking blood alcohol concentration (BAC), and waking brain ethanol concentration (BREC) at 03.00, 09.00, 15.00, or 21.00 hr. Sleep times, waking BACs, and waking BRECs showed circadian variations in the LS mice. SS animals given the 4.1 g/kg dose showed circadian variations for waking BAC and waking BREC, but not for sleep time. The observed variations in the physiological parameters for these animals may have been confounded by a short sleep time so that they reflected circadian variations in drug absorption and/or distribution rather than in CNS sensitivity. SS mice given the 5.0 g/kg dose slept longer than those given the 4.1 g/kg dose and did not show circadian variations for sleep time, waking BAC, or waking BREC. These results suggest both circadian and genetic influences on tissue sensitivity to ethanol.

Animals↗

PubMed1996

Quality control of HIV cultures in a clinical retrovirology laboratory.

The culture of primary HIV isolates requires fresh phytohemagglutinin (PHA) stimulated peripheral blood mononuclear cells (PBMC) from seronegative donors. The variation inherent in donor cells, obtained from many different individuals, might affect the likelihood of virus isolation. We developed a quality control (QC) procedure which could determine quantitatively the susceptibility of random donor cells to HIV infection. The QC reagents consisted of cells and supernatants infected with a syncytium-inducing clinical isolate of HIV. Six 5-fold dilutions of QC cells (starting at 1000 cells) and supernatant (starting at a 1:200 dilution) were cultured in parallel with 1 x 10(6) 2-3-day-old PHA stimulated donor cells. After 7 or 14 days the resulting culture supernatant was tested for syncytia formation with MT-2 cells. A total of 127 sequential donors were tested over an 11 month period. All but one donor PBMC preparation was capable of being infected by the QC reagents (and this particular donor was permissive for several other primary isolates). The standard variation observed among all cultures was about one 5-fold dilution. The coefficient of variation ranged from 10.7 to 17.3%. These results suggest that the mononuclear cells from most, if not all, individuals are permissive for HIV to approximately the same level. Other quality control measures used in the laboratory are described.

Cell Line↗

PubMed1995

The genetic diversity and epizootiology of infectious hematopoietic necrosis virus.

Infectious hematopoietic necrosis virus (IHNV) is a rhabdovirus which causes a serious disease in salmonid fish. The T1 ribonuclease fingerprinting method was used to compare the RNA genomes of 26 isolates of IHNV recovered from sockeye salmon (Oncorhynchus nerka), chinook salmon (O. tshawytscha), and steelhead trout (O. mykiss) throughout the enzootic portion of western North America. Most of the isolates analyzed in this study were from a single year (1987) to limit time of isolation as a source of genetic variation. In addition, isolates from different years collected at three sites were analyzed to investigate genetic drift or evolution of IHNV within specific locations. All of the isolates examined by T1 fingerprint analysis contained less than a 50% variation in spot location and were represented by a single fingerprint group. The observed variation was estimated to correspond to less than 5% variation in the nucleic acid sequence. However, sufficient variation was detected to separate the isolates into four subgroups which appeared to correlate to different geographic regions. Host species appeared not to be a significant source of variation. The evolutionary and epizootiologic significance of these findings and their relationship to other evidence of genetic variation in IHNV isolates are discussed.

Animals↗

PubMed1992

Effect of attachment factors (pili plus Opa) on Neisseria gonorrhoeae invasion of human fallopian tube tissue in vitro: quantitation by computerized image analysis.

Pili (P) and opacity-associated proteins (Opa) facilitate Neisseria gonorrhoeae attachment to human fallopian tube epithelium. Subsequent effects on invasion are unproven. Computerized image analysis was used to study the effects of attachment factors on invasion by comparing a P+Opa+ variant to a P-Opa- variant of strain R10 in the fallopian tube organ culture model. Gonococci in sections of infected fallopian tube tissue were identified with FITC-labelled monoclonal anti-gonococcal antibodies. Nomarski DIC microscopy was used to establish anatomic boundaries that excluded extracellular gonococci from invasion measurements. The area of intracellular fluorescence served as an index of gonococcal invasion. With conservative criteria to exclude extracellular gonococci, the per cent of the intracellular area occupied by fluorescent P+Opa+ gonococci was 18% compared to 4.7% for the P-Opa- variant (P < 0.001). Data suggest that P+Opa+ organisms invaded deeper than P-Opa- microbes over the same time period (P = 0.029). Intra-observer variation in invasion measurements was not significant (P > or = 0.85), and inter-observer correlation was high (correlation coefficient = 0.96). Computerized image analysis is a rapid, reliable means of quantifying gonococcal invasion of fallopian tube epithelium. We conclude that gonococcal attachment factors can facilitate events which enhance gonococcal invasion of fallopian tube epithelium.

Antigens, Bacterial↗

PubMed2002

Hidden evolution: progress and limitations in detecting multifarious natural selection.

From illustrative examples of research on the best-studied group of species to date, Drosophila melanogaster and its closest relatives, we argue that selection is multifarious, but often hidden. Selective fixation of new, highly advantageous alleles is the most parsimonious explanation for a typical pattern of molecular variation observed in genomic regions characterized by very low recombination: drastically reduced DNA sequence variation within species and typical levels of sequence divergence among species. At the same time, the identity of the gene (or genes) influenced by selection is not just difficult to discern; it may be impossible. Studies of the genetic basis of reproductive isolation demonstrate that, although the D. melanogaster complex species appear virtually identical, dozens of currently unidentified genes contribute to hybrid sterility. We argue that these findings are best explained by selectively-driven functional divergence and demonstrate the multifarious nature of selection. Although multifarious selection certainly occurs, the exact characters responsible for differences in survival and reproductive success are unknown. We do not see these inherent limits as a cause for despair or a problem for evolutionary biology. Instead, we hope to raise awareness of these complexities of evolution by highlighting both the progress and the limitations of characterizing multifarious natural selection.

Alcohol Dehydrogenase↗

PubMed1991

Intraspecific variation in population gene diversity and effective population size correlates with the mating system in plants.

Published data on allele frequencies at isozyme loci in inbreeding and outbreeding plant species were analyzed to examine intraspecific variation in gene diversity and effective population size (Ne). Compared with outbreeders, inbreeding species showed markedly greater variation among populations in average values of Nei's gene diversity statistic. Effective population size was estimated by assuming that the variation observed at isozyme loci is selectively neutral. Inbreeding species showed greater levels of variation in Ne than did outbreeders, although the upper range of Ne was similar in the two classes of species. The results suggest that there may be considerable genetic variation and potential for evolutionary change in some but not all populations of inbreeders. Moreover, these findings are important with respect to the conservation of genetic resources. In particular, that the amount of intraspecific variation in population genetic diversity and Ne differs between inbreeding and outbreeding species should be taken into account in sampling efforts designed to optimize the diversity of germplasm collections.

Journal Article↗

PubMed2000

Antigenic and genetic stability of bovine immunodeficiency virus during long-term persistence in cattle experimentally infected with the BIV(R29) isolate.

Experimental infection of cattle with bovine immunodeficiency virus (BIV) is characterized by persistent, low levels of virus replication in the absence of clinical disease. A virus neutralization (VN) assay was developed to examine the role of VN antibodies in controlling virus replication in cattle experimentally infected with the BIV(R29) isolate of BIV. All animals developed VN antibody, but there was no correlation between VN titres and restriction of virus replication in vivo. BIV infection did not induce high-titred, cross-neutralizing antibody and there was no evidence for antigenic variation through more than 4 years in vivo. Genetic comparisons among the BIV(R29) inoculum virus and viruses isolated from infected animals identified only limited genetic variation during 4 years in vivo. Moreover, there was no evidence that the observed variation was due to selection. Analyses of genetic diversity in the virus stock used for inoculation indicated a fairly homogeneous population. In the absence of high levels of virus replication and overt clinical disease, there appeared to be little selection of virus variants, resulting in antigenic and genetic stability of BIV(R29) during long-term, persistent infection.

Amino Acid Sequence↗