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Mathematical derivative applied to international normalised ratio and analytical variations in oral anticoagulant therapy control.

A reliable prothrombin time (PT) testing and a careful drug dosage can prevent thrombotic or bleeding complications of the oral anticoagulant therapy. The international normalised ratio (INR) as PT standardisation introduced an analytical variation that increases with higher PT measures and higher international sensitivity index (ISI) values. Our study was conducted to investigate the INR accuracy through the mathematical derivative application to reduce the analytical component of the INR uncertainty. The evaluation of accuracy among four different systems (prothrombin activity percent, PT seconds, PT ratio and INR) was determined by the simulation of a systematic error. Plasma samples were diluted 1:2; then they were compared observed with the expected values. We analysed the calculation system of the INR through the mathematical derivative in 87 PT ratio measurements. The analytical incidence of thromboplastin ISI was performed through an elaboration of INR mathematical derivative considering 10 different ISI values ranging from 1.1 to 2. The data expressed as PT ratios revealed a lower systematic error propagation suggesting that a linear system is more accurate. According to the calculation formula of INR, analytical variability increases with the PT measurements, then with the intensity of anticoagulation. Mathematical derivative suggests that the INR uncertainty due to the ISI can be reduced using a thromboplastin reagent with a low ISI or with ISI close to 1.

Administration, Oral↗

Spectrophotometric determination of sorbic and benzoic acids in fruit juices by a net analyte signal-based method with selection of the wavelength range to avoid non-modelled interferences.

Sorbic (SOR) and benzoic (BEN) acids were determined in fruit juice samples by using a net analyte signal-based methodology named HLA/GO (an hybrid linear analysis presented by Goicoechea and Olivieri) applied to spectroscopic signals. The calibration set was built with several fruit juices in order to take into account the natural variability and concentrations of both analytes covering the range usually present in commercial samples. Relative errors of prediction (REP %) of 3.6 and 5.2% were calculated for SOR and BEN respectively. Several figures of merit were calculated-sensitivity, selectivity, analytical sensitivity, and limit of detection. The method is quantitative, with reasonably good recoveries and excellent precision (less than 1%). Wavelength selection was applied, based on the concept of net analyte signal regression, and it allowed us to improve the method performance in samples containing non-modelled interferences, e.g. fruit juices different to those used to build the calibration model.

Benzoates↗

Oral contraceptives and breast cancer: review of the epidemiologic literature.

Oral contraceptives have caused little or no overall increase in risk of breast cancer in women in developed countries, even in long-term users or after more than two decades since initial exposure. Limited evidence suggests a possible small increase in risk in users of oral contraceptives in developing countries, and further studies of breast cancer and oral contraceptives in low risk populations are warranted. Oral contraceptives may enhance risk of breast cancer in young women with a history of benign breast disease, and this possibility should also be investigated further. Multiple investigations have fairly consistently shown risk of breast cancer in women under age 45 years to be increased slightly in long-term users of oral contraceptives. Further studies should be conducted to elucidate the mechanism of this apparent phenomenon.

Breast Neoplasms↗

Functional assay to measure yessotoxins in contaminated mussel samples.

Yessotoxin (YTX) treatment of MCF-7 cells results in the accumulation of a 100-kDa fragment of E-cadherin (ECRA(100)) without a parallel loss of the intact protein in cytosoluble extracts. As a consequence, concentration-dependent increases in the total immunoreactivity detectable by anti-E-cadherin antibodies relative to controls (RTI) and in the relative immunoreactivity of ECRA(100) (RI) are observed. These responses have been exploited to develop a functional assay to measure YTX in samples from contaminated mussels by a three-step procedure, consisting of (i) treatment of MCF-7 cells with YTX standard in the concentration range 0-1nM and of unknown samples; (ii) preparation of cellular extracts, fractionation of proteins by polyacrylamide gel electrophoresis under denaturing conditions, and immunoblotting with anti-E-cadherin antibodies, followed by densitometric analyses of autoradiographies and calculation of RI of ECRA(100) and of RTI of the samples; and (iii) interpolation of the YTX concentrations in unknown samples on standard curves, by the RI of ECRA(100) and the RTI of the samples. The procedure has been used to measure yessotoxins in contaminated mussel samples, and the results obtained show that this functional assay is very sensitive (limit of detection of about 100ng equivalent YTX/g of digestive gland), and robust, as (i) it is insensitive to matrix effects in the range of toxin concentrations relevant for risk assessment to protect humans from exposure to YTX, (ii) calculations are based on a molecular parameter (the RI of ECRA(100)) which is not affected by errors in sample preparation, (iii) it can be performed by the use of antibodies commercially available from different companies, and (iv) it does not show an absolute need of calibration by a pure standard within each assay.

Animals↗

Comparison of microarray designs for class comparison and class discovery.

MOTIVATION: Two-color microarray experiments in which an aliquot derived from a common RNA sample is placed on each array are called reference designs. Traditionally, microarray experiments have used reference designs, but designs without a reference have recently been proposed as alternatives. RESULTS: We develop a statistical model that distinguishes the different levels of variation typically present in cancer data, including biological variation among RNA samples, experimental error and variation attributable to phenotype. Within the context of this model, we examine the reference design and two designs which do not use a reference, the balanced block design and the loop design, focusing particularly on efficiency of estimates and the performance of cluster analysis. We calculate the relative efficiency of designs when there are a fixed number of arrays available, and when there are a fixed number of samples available. Monte Carlo simulation is used to compare the designs when the objective is class discovery based on cluster analysis of the samples. The number of discrepancies between the estimated clusters and the true clusters were significantly smaller for the reference design than for the loop design. The efficiency of the reference design relative to the loop and block designs depends on the relation between inter- and intra-sample variance. These results suggest that if cluster analysis is a major goal of the experiment, then a reference design is preferable. If identification of differentially expressed genes is the main concern, then design selection may involve a consideration of several factors.

Algorithms↗

The determination of Papanicolaou smear adequacy using a semiquantitative method to evaluate cellularity.

To examine the influence of sample cellularity and the presence of endocervical columnar cells on the detection of cervical dysplasia, Papanicolaou (Pap) smears taken from patients with biopsy-proven CIN II and III were analyzed retrospectively. Adequacy was semiquantitated by dividing each smear into 15 equal areas using a lined template and assigning an adequacy index (AI) of 0 to 15. The total false-negative (FN) rate was 15.8 percent, with 6.1% representing interpretive error and 9.7% representing sampling error. For FN slides truly lacking abnormal cells, the average AI was significantly lower than that of true positives (TP), even when endocervical columnar cells were present. The entire group was then blindly re-evaluated using a subjective application of the Bethesda System, classifying slides as satisfactory, less than optimal, and unsatisfactory. Although correlation of AI with the rapid Bethesda System categorization was imperfect, the exclusion of less than optimal and unsatisfactory smears also lowered the FN rate, but less effectively. An AI scoring technique, therefore, may be useful in the routine evaluation of Pap smear adequacy.

Carcinoma, Squamous Cell↗

Screening for congenital hypothyroidism in France. Misdiagnosed cases: collaborative study of screening centres in France.

Misdiagnosed cases of congenital-hypothyroidism (CH) during the first 9 years of the French screening program were analysed. A total of 50 cases were missed (3% of total diagnosed) which represents a severe failure of the system. Failures were caused by technical errors of sample collection or TSH assay (n = 27) or due to normal TSH (n = 22) or T4 (n = 1) concentrations in the newborn blood specimens. We conclude that screening methods should be improved and that physicians should remain alert to clinical signs of hypothyroidism.

Congenital Hypothyroidism↗

Identification of the major sources of error in estrogen receptor measurements for individual laboratories using both tissue and cytosol samples.

The major sources of error between laboratories performing estrogen receptor measurements in tissue samples were identified for 17 participating laboratories in a trial conducted by the Australasian Quality Assurance programme. Both tissue and cytosol samples were provided, and the In-House assays were compared with the ER-EIA kit (Abbott Laboratories, U.S.A.) as a reference assay. For both the In-House and Abbott assays, tissue samples resulted in a between laboratory CV of about 55% and a within laboratory CV of about 30%. In contrast to tissue samples, the between laboratory CV for cytosol samples was reduced to 41% for the In-House assays and to 33% for the Abbott assay, whereas the within laboratory CV was reduced to 10% for both types of assay. The different methods of tissue homogenization by themselves were not found to be sources of error, and protein extraction efficiency from tissue was strongly correlated with protein measurement (P less than 0.0005). The major sources of error due to protein measurement, cytosol preparation, In-House and Abbott assays were evaluated for individual laboratories. The results indicated absence of any major sources of error for four laboratories, while one, two and three or more sources were indicated for seven, three and three laboratories respectively. The conclusion that about half the participants need to improve their ER assays was confirmed by three independent reviews. Furthermore, the trial demonstrated that tissue samples are essential as quality assurance material for a realistic assessment of ER assays in biopsy specimens.

Animals↗

Toward a global phylogeny of the Brassicaceae.

The Brassicaceae is a large plant family (338 genera and 3,700 species) of major scientific and economic importance. The taxonomy of this group has been plagued by convergent evolution in nearly every morphological feature used to define tribes and genera. Phylogenetic analysis of 746 nrDNA internal transcribed spacer (ITS) sequences, representing 24 of the 25 currently recognized tribes, 146 genera, and 461 species of Brassicaceae, produced the most comprehensive, single-locus-based phylogenetic analysis of the family published to date. Novel approaches to nrDNA ITS analysis and extensive taxonomic sampling offered a test of monophyly for a large complement of the currently recognized tribes and genera of Brassicaceae. In the most comprehensive analysis, tribes Alysseae, Anchonieae plus Hesperideae, Boechereae, Cardamineae, Eutremeae, Halimolobeae, Iberideae, Noccaeeae, Physarieae, Schizopetaleae, Smelowskieae, and Thlaspideae were all monophyletic. Several broadly defined genera (e.g., Draba and Smelowskia) were supported as monophyletic, whereas others (e.g., Sisymbrium and Alyssum) were clearly polyphyletic. Analyses of ITS data identified several problematic sequences attributable to errors in sample identification or database submission. Results from parsimony ratchet and Bayesian analyses recovered little support for the backbone of the phylogeny, suggesting that many lineages of Brassicaceae have undergone rapid radiations that may ultimately be difficult to resolve with any single locus. However, the development of a preliminary supermatrix including the combination of 10 loci for 65 species provides an initial estimate of intertribal relations and suggests that broad application of such a method will provide greater understanding of relationships in the family.

Animals↗

Test of significant differences with a priori probability in microarray experiments.

A traditional method for comparing two expression levels of genes in microarray experiments is the two-sample t-test. Because of the difficulty in using a large number of microarrays, an alternative method is required which can provide a reliable judgment of the comparison from a small number of replicates, even from a single pair of control and treatment. We present a method for detecting the changes in the gene expression levels under two different conditions in microarray experiments. Our method targets a single experiment for each condition, while retaining the statistical advantages of the t-test. The new proposals are: 1) standard deviation (SD) estimates of the expression levels which are an indicator for significant differences are given a priori as a function of the expression levels; 2) the limit of detection (LOD) for the expression levels is used to eliminate the majority of genes expressed at extremely low levels. The a priori SD estimates are obtained from six replicates under a fixed condition and are shown to be the approximate, but proper description of the expression uncertainty covering diverse conditions (e.g., different samples (human and rat) and different DNA chips). The LOD is defined as three times blank SD according to the IUPAC recommendation. A cell line (HL60) which will undergo macrophage differentiation on treatment with 12-O-tetradecanoylphorbol 13-acetate (TPA) is taken as an example. Our method is compared with the t-test for the data on duplicate TPA experiments and the former alone is evaluated with the data on a single TPA experiment. The errors from sample preparation and instrumental analysis are discussed.

Animals↗

Effect of color on judgments of food aroma and flavour intensity in young and elderly adults.

The hypothesis was tested that subjects' judgments of food aroma and flavour strength will be increasingly influenced by food color as the chemosensory differences between foods become less apparent. Elderly (n = 24) and young (n = 22) adults were presented with pairs of food samples and instructed to indicate which sample had the more intense aroma or flavor. The chemosensory discriminations varied in difficulty, and the color of the food pairs was also manipulated so that either they were similarly colored, or the color strength differed so that it was either positively or inversely correlated with flavour strength. Overall, the results failed to support the hypothesis that color alters the perceived intensity of the food aroma or flavor. There was a weak trend toward a greater number of errors among sample pairs that varied in color, especially when color strength was inversely related to flavor strength. Elderly and young adult groups did not differ in chemosensory ability or in their responses to food color differences, although the elderly adults were significantly more certain of the accuracy of their chemosensory judgments.

Adult↗

[Effective renal plasma flow with I-131-hipuran: evaluation of a method with four extractions].

The aim of this work was to evaluate a method for the estimation of the effective renal plasma flow (ERPF) using sodium 131I-o-hippurate (OIH) by means the bicompartmental analysis of the radioactive concentration of 4 plasma samples, analyzing the error obtained respecting to the multi-sample method and comparing it with those obtained with other simplified methods. We calculated the ERPF from 62 patients using the multi-sample method as standard, the method based in a single sample at 44 minutes p.i., a method based in 2 samples from the first exponential, 4 methods based in 2 samples from the second exponential, one method based in 3 samples and 5 methods based in 4 samples (2 from the first exponential and 2 from the second exponential). Each simplified method was compared to the standard method and their absolute error (AE) and standard estimation error (SEE) were calculated. The method based in the 4 samples withdrawn at 4, 10, 30 and 60 minutes p.i. was the best of them with a correlation factor with the standard equal to 0.997, an EA that ranged from -63 ml/min to 49 ml/min (mean: -4 ml/min) and a SEE of 19.5 ml/min.

Body Fluid Compartments↗

Possibility for error in FDA diffusion assays.

Computational procedures specified for the FDA single-dose diffusion assay for antibiotics may cause substantial error in estimated sample potency. An unrecognized mistake in reference solution concentration is the source of error. It is caused by correcting responses from standard and sample plates differently. The error can be avoided by correcting both standard and sample responses to the observed reference response.

Anti-Bacterial Agents↗

An examination of the morpheme BE in children with specific language impairment: the role of contractibility and grammatical form class.

This study examined the production of the morpheme BE, focusing on the influence of contractibility, the relationship between copula and auxiliary forms, and the occurrence of non-omission errors. Language samples collected from children with SU and from normal language learners at equivalent MLU levels were analyzed. Three levels of contractibility were examined: contractible, syntactically uncontractible, and phonetically uncontractible. Contractible contexts were produced significantly more accurately than uncontractible contexts by both groups. There was no difference between the two forms of uncontractibility. Furthermore, there were no significant interactions between language status and contractibility, suggesting that contractibility influenced both groups equally. Copula forms were produced more consistently than auxiliary. There was no interaction between BE type and language status. The groups did not differ in proportion or type of non-omission error. The results are discussed in relation to accounts of morphological deficits in SU.

Child↗

How the probability of a false positive affects the value of DNA evidence.

Errors in sample handling or test interpretation may cause false positives in forensic DNA testing. This article uses a Bayesian model to show how the potential for a false positive affects the evidentiary value of DNA evidence and the sufficiency of DNA evidence to meet traditional legal standards for conviction. The Bayesian analysis is contrasted with the "false positive fallacy," an intuitively appealing but erroneous alternative interpretation. The findings show the importance of having accurate information about both the random match probability and the false positive probability when evaluating DNA evidence. It is argued that ignoring or underestimating the potential for a false positive can lead to serious errors of interpretation, particularly when the suspect is identified through a "DNA dragnet" or database search, and that ignorance of the true rate of error creates an important element of uncertainty about the value of DNA evidence.

Bayes Theorem↗

[Hyperprolactinaemia--pitfalls in PRL assessment].

Prolactin (PRL) is one of the most commonly assessed hormones, and hyperprolactinaemia seems to be often endocrine disorder. Hyperprolactinaemia is not a disease, but only a symptom indicating relevant medical conditions to be diagnosed and properly treated. Laboratory findings should be always cautiously interpreted with reference to clinical context. Possible problems could be evoked by errors during sampling and assessment itself. While interpreting laboratory results, one have to pay attention on pulsate secretion profile of PRL (within hours), and shows marked diurnal cycle (with maximum during sleep period). PRL level depends also on emotional status (stress amplifies PRL secretion), and also on dietary habits and stimulants. Lastly, a growing body of evidence proven that in some cases elevated PRL level could be caused by presence of polymeric form of PRL--so called "macroprolactin". This form has diminished receptor-binding specificity and weak, if any, biological effect while immunoreactivity is preserved. In clinical practice, in cases of macroprolactinaemia high level of circulating hormone does not correlate with slight, if even, clinical symptoms. To avoid errors in prolactin assessment blood should be drawn fasting, preferentially in series or during dynamic test after dopaminergic blockade with metoclopramide. Interpretation must parallel include clinical data. It is essential that PRL level is proportional to pituitary lactotroph tumor size. Extremely high PRL concentration could exceed technical capability of laboratory equipment and remain underestimated, or even undiagnosed. Beneath presented algorithm could be useful in planning diagnostic and therapeutic procedures.

Algorithms↗

DNA measurement errors with a scanning microdensitometer in cytologic and histologic samples of breast cancers.

The influence of various DNA measurement errors using a commercially available scanning microdensitometer was evaluated on Feulgen-stained cytologic and histologic samples prepared from paraffin blocks containing invasive ductal breast cancers. The overall average total measurement error was 5.5% for the cytologic specimens and 10.9% for the 4 micron histologic sections. Components of the error included microscopic adjustment variation and focussing errors (3.5% and 1.1%, respectively, for both cytologic and histologic samples) and background intensity estimation errors (3.0% for the cytologic samples and 10.0% for the histologic samples). Measurements of the integrated optical density had a minimal error of 0.5% and an average error of 1.0%. Limitations due to the histologic architecture and/or heterogeneous cell population gave rise to large differences in the selection of nuclei when differently sized scanning masks were used. To improve the reproducibility, masks used should be based on the individual cell size, and background intensity values should be carefully estimated in the vicinity of the selected cells. Overall, the cytologic tumor samples were preferable to the histologic samples for static DNA measurements. It was easier to select cells suitable for measurement in the cytologic samples, and the cytologic measurements were less time consuming and produced a smaller measurement error.

Breast Neoplasms↗

Acoustic absorption measurement of human hair and skin within the audible frequency range.

Utilizing the two-microphone impedance tube method, the acoustic absorption of human skin and hair is measured in the frequency range 1-6 kHz. Various locations on a number of human subjects are measured to determine if the presence of bone or an air pocket affects the acoustic absorption of human skin. The absorption coefficient of human hair is also measured. Additional techniques are utilized to minimize errors due to sample mounting methods. Techniques are employed to minimize potential errors in sensor and sample locations. The results of these measurements are compared to relevant historical papers on similar investigations. Results for skin measurements compare well with previous work. Measured hair absorption data do not agree with previous work in the area but do coincide with expected trends, which previous works do not.

Absorption↗