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Multiprogram characterization of laboratory bias, precision, and total error. Proposal for improved assessment with shared external and expanded internal (regional) quality control pools.

We establish that, for the analytes aspartate aminotransferase, glucose, phosphorus, and potassium, there is significant correlation between laboratory performance as determined by College of American Pathologists-sponsored external (Surveys) and expanded internal (regional) quality control (Quality Assurance Service) programs. However, relatively low parametric and nonparametric correlation coefficients and significant departure of linear regression slopes from unity reflect major differences in the calculated parameters of absolute bias, precision, and total error obtained through internal and external quality control. Significantly better performance in both Surveys and the Quality Assurance Service was documented for laboratories participating in the College of American Pathologists Laboratory Accreditation Program. Multiple descriptors of laboratory quality, as indicated here, are superior in describing laboratory performance to proficiency testing alone. As a bridge between external and internal quality control, shared pools of quality control materials are described for use as unknown Survey challenges and subsequent distribution for regional quality control. Such programs, which can be configured to serve thousands of laboratories, could offer cost savings, better quality assurance, and improved characterization of laboratory performance by minimizing interprogram differences in control matrix and method classification and providing greater reliability of target values.

Academies and Institutes↗

SUPERFICIAL--surface mapping of proteins via structure-based peptide library design.

BACKGROUND: The determination of protein surfaces and the detection of binding sites are essential to our understanding of protein-protein interactions. Such binding sites can be characterised as linear and non-linear, the non-linear sites being prevailant. Conventional mapping techniques with arrays of synthetic peptides have limitations with regard to the location of discontinuous or non-linear binding sites of proteins. RESULTS: We present a structure-based approach to the design of peptide libraries that mimic the whole surface or a particular region of a protein. Neighbouring sequence segments are linked by short spacers to conserve local conformation. To this end, we have developed SUPERFICIAL, a program that uses protein structures as input and generates library proposals consisting of linear and non-linear peptides. This process can be influenced by a graphical user interface at different stages, from the surface computation up to the definition of spatial regions. CONCLUSION: Based on 3D structures, SUPERFICIAL may help to negotiate some of the existing limitations, since binding sites consisting of several linear pieces can now be detected.

Binding Sites↗

Predictors of human gestational length.

OBJECTIVES: Our objective was to identify statistically significant variables that determine the length of human gestation. STUDY DESIGN: Multiple linear regression was used to analyze 9355 observations from the Delivery Interview Program, a cross-sectional study conducted from 1977 through 1980 at the Boston Hospital for Women (now called the Brigham and Women's Hospital). RESULTS: Maternal parity, age, and race were found to be the most important variables determining the length of human gestation. Multiparous women, women aged < 19 or > 34 years, and black women were found to have shorter gestations than primiparous women, women aged 19 to 34 years, or white women. CONCLUSION: By means of our linear model the length of pregnancy for women with different risk factors can be estimated more precisely than Naegele's rule allows.

Adult↗

Attributes of curriculum athletic training programs related to the passing rate of first-time certification examinees.

The purpose of this study was twofold: (1) to identify attributes of athletic training programs that have been accredited by the Commission on Accreditation of Allied Health Education Programs (CAAHEP) as they relate to outcomes of their students on the National Athletic Training Association Board of Certification (NATABOC) examination and (2) to determine the most effective curriculum in preparing candidates for the examination. For all subjects, the following survey information was assessed: the seven domains (competencies), number of clinical rotation sites, grade point average requirement, faculty responsibilities, faculty terminal degrees, faculty K-12 experience, association with allied health schools, capstone course availability, and course examination similarities. Fifty-four subjects, representing 60% of all of the program directors of CAAHEP accredited athletic training programs, responded in this study. Data were analyzed using a general linear model procedure and regression analyses. Even domains of athletic training, variety of rotation sites, clinical responsibility of faculty, faculty terminal degrees, and faculty K-12 school experience significantly affected the passing rate of first time certification examinees. Grade point average requirement, allied health school association, course examination format, and capstone course were not related significantly to the passing rate of first-time certification examinees. The most effective curricular model included the seven domains of athletic training, faculty clinical responsibilities, and faculty K-12 work experience as related to the passing rate. Emphasizing the domains of athletic training (competencies), having a variety of rotation sites, separating clinical and academic responsibilities for faculty, and having faculty with terminal degrees and less public school experience increase the passing rate of first-time NATABOC examinees. The most effective curricular model in affecting passing rate, according to this study, includes emphasizing the seven domains of athletic training (competencies), separating clinical and academic responsibilities of faculty, and not focusing on hiring faculty with K-12 work experience. Although this article focuses primarily on athletic training education, we believe that this study can be used as a model to evaluate educational programs in other allied health, competency-based educational programs.

Allied Health Personnel↗

Optimal discrimination and classification of neuronal action potential waveforms from multiunit, multichannel recordings using software-based linear filters.

We describe advanced protocols for the discrimination and classification of neuronal spike waveforms within multichannel electrophysiological recordings. The programs are capable of detecting and classifying the spikes from multiple, simultaneously active neurons, even in situations where there is a high degree of spike waveform superposition on the recording channels. The protocols are based on the derivation of an optimal linear filter for each individual neuron. Each filter is tuned to selectively respond to the spike waveform generated by the corresponding neuron, and to attenuate noise and the spike waveforms from all other neurons. The protocol is essentially an extension of earlier work [1], [13], [18]. However, the protocols extend the power and utility of the original implementations in two significant respects. First, a general single-pass automatic template estimation algorithm was derived and implemented. Second, the filters were implemented within a software environment providing a greatly enhanced functional organization and user interface. The utility of the analysis approach was demonstrated on samples of multiunit electrophysiological recordings from the cricket abdominal nerve cord.

Action Potentials↗

Detection of linear and nonlinear dependencies in time series using the method of surrogate data in S-PLUS.

A general implementation of the method of surrogate data in the S programming language for use with the S-PLUS statistical package is presented. We illustrate the application of the S functions to testing hypotheses about a human heart rate time series and demonstrate that there is evidence for both linear and nonlinear dependencies. We expect these S functions will be useful for the application of the method of surrogate data to the analysis of biomedical time series using the S-PLUS statistical software package.

Data Interpretation, Statistical↗

[Delays and treatment interruptions: difficulties in administering radiotherapy in an ideal time-period].

Prescribed total radiation dose should be administered within in a specific time-frame and delays in commencing treatment and/or unplanned interruptions in radiation delivery are unacceptable because, in certain cancer sites, treatment-time prolongation can have a deleterious effect on local tumour control, and on patient outcomes. The present review evaluated the causes of initial treatment delays as well as interruptions in the scheduled radiotherapy. The literature search highlighted a significant concern in avoiding treatment-time prolongation in head and neck, cervix, breast and lung cancer. Among the causes involved in delay in radiotherapy commencement factors such as waiting lists, lack of material and human resources, and an increase complexity in planning, simulation and verification are highlighted. Most authors recommend radiotherapy commencement as soon as possible in radical (exclusive irradiation with active tumour present) and palliative situations with a maximum delay of no more than 6 to 8 weeks in the case of adjuvant radiotherapy (post-resection) programs. Interruptions during the course of treatment include: planned unit maintenance and servicing, acute patient toxicity or unexpected malfunction of linear accelerators; this last feature has the most deleterious effect on patients as well as radiotherapy practitioners. Interruptions that impact on the programmed time-course for radiotherapy needs to be compensated-for so as assure the biological equivalence in treatment efficacy with respect to cancer site and stage.

Humans↗

Clinical application and dosimetric calibration procedure of the superficial and orthovoltage therapy unit Therapax DXT300.

AIMS AND BACKGROUND: The aim of this study was to configure a new superficial and orthovoltage therapy unit for clinical use and discuss the clinical indications for this kind of energy. There is renewed interest in radiotherapy using photon beams in the range from 40 to 300 kVp, in particular for the treatment of non-neoplastic diseases and superficial lesions. This is due to the fact that the latest units are of good quality, relatively cheap and reliable in comparison with alternative equipment. It is therefore necessary to document the steps involved in the clinical application of this therapeutic equipment. METHODS: The calibration procedure for a new superficial/orthovoltage therapy unit, Therapax DXT300 (Pantak, USA), installed at the Radiotherapy Department of the Mauriziano Hospital in Turin, was carried out by measurement of beam quality (half-value layer, HVL), percentage depth dose (PDD), profiles, internal dosimetry system, dose rate calibration and output factors. The Therapax DXT300 can be programmed to stop treatment either by time or dose, like a linear accelerator. It is equipped with one adjustable collimator (2 x 2 divided by 20 x 20 cm2) for orthovoltage therapy (focus skin distance, FSD = 50 cm) and six fixed applicators for superficial and orthovoltage therapy (FSD = 30 and 50 cm, respectively). Up to eight combinations of generating potential, tube current and added beam filter can be set. RESULTS: In the range of accelerating potentials from 40 to 300 kVp the Therapax provides beams with HVL ranging from 1.48 mm Al to 3.68 mm Cu. As regards the PDD curves, a slight difference between PDD values has been observed with potentials ranging from 200 to 300 kVp. The beam symmetry and flatness are almost the same in Y and X plane directions for accelerating potentials of less than 200 kVp. At higher kVp values these parameters are significantly worse in the anode-cathode axis direction, because the useful X-ray beam is extracted perpendicular to the anode-cathode axis direction: as the energy increases, the bremsstrahlung becomes more forward directed, resulting in a higher dose rate on the anode side. CONCLUSION: The present paper suggests a methodological approach for the clinical application of an orthovoltage/superficial therapy unit and discusses its current indications. It is necessary to maintain the performance of the equipment within predefined limits in order to meet the requirements of an efficient quality assurance program. This unit is particularly useful in the treatment of superficial lesions and non-neoplastic diseases and in palliative care (eg for bone metastases).

Calibration↗

Simulation of laboratory errors and their effects on interlaboratory quality-control programs.

The random errors in an analytical method are additive and can be classified into analytical response-dependent and -independent terms. Non-random errors, caused by systematic faults in the analytical procedure, are not always distriguishable from the random errors, but some cases of non-linear assay response and unsuitable standardisation can be studied usefully in models without random error. Interlaboratory quality control programs cannot distinguish systematic and random error until the pattern of results on a number of specimens, or pairs of specimens, can be studied. In this case linear regression analysis is a powerful method for distinguishing different forms of error especially when response-dependent random errors do not predominate. The range of concentrations used for regression whould be as wide as that in which quantitative distinctions are used in clincal diagnosis and treatment. Preliminary reports, of the results on which the regression analysis is based, are most suitably presented on Youden diagrams with paired specimens.

Analysis of Variance↗

A linear-time algorithm for the perfect phylogeny haplotyping (PPH) problem.

Since the introduction of the Perfect Phylogeny Haplotyping (PPH) Problem in RECOMB 2002 (Gusfield, 2002), the problem of finding a linear-time (deterministic, worst-case) solution for it has remained open, despite broad interest in the PPH problem and a series of papers on various aspects of it. In this paper, we solve the open problem, giving a practical, deterministic linear-time algorithm based on a simple data structure and simple operations on it. The method is straightforward to program and has been fully implemented. Simulations show that it is much faster in practice than prior nonlinear methods. The value of a linear-time solution to the PPH problem is partly conceptual and partly for use in the inner loop of algorithms for more complex problems, where the PPH problem must be solved repeatedly.

Algorithms↗

Three-dimensional endorectal ultrasound using a new freehand software program: results in 35 patients with rectal cancer.

BACKGROUND AND STUDY AIMS: This paper describes experience in the staging of rectal cancer using a new software program for three-dimensional endoscopic ultrasonography (EUS) that works without electromagnetic sensors and can be used even with electronic radial or linear rectal probes. MATERIALS AND METHODS: From May 2003 to March 2004, 35 three-dimensional endorectal ultrasound (ERUS) examinations were carried out using this program. The indication for ERUS was local staging of rectal cancer in all cases. The three-dimensional software imaging program forms part of a new ultrasound scanning system (Hitachi 6500 or 8000) and allows reconstruction of the two-dimensional EUS images in six different scans. RESULTS: Thirty-five rectal cancers were assessed using two-dimensional and three-dimensional EUS. Using two-dimensional imaging, it was not possible to assess precisely the degree of involvement of the mesorectum (more or less than 50%). No differences were evident with three-dimensional EUS for superficial tumors (T1 and T2N0), but in six of 15 patients classified as having T3N0 lesions, three-dimensional EUS revealed malignant lymph nodes, a finding that was confirmed surgically in five of the six cases. Three-dimensional EUS also made it possible to assess the degree of infiltration of the mesorectum precisely in all cases, demonstrating complete invasion of the mesorectum in eight cases. These findings were confirmed in all cases by the surgical data. Two-dimensional EUS correctly assessed 25 of the 35 rectal tumors (71.4%) in relation to the T and N classifications, and three-dimensional EUS increased this figure to 31 correct evaluations out of 35 (88.6%). CONCLUSION: Three-dimensional ERUS is easy to carry out using this new software program. There is no need for an external sensor mounted at the tip of the probe, and manipulation of the rectal probe is facilitated. Three-dimensional ERUS can be carried out using linear and radial electronic probes with the same ultrasound equipment. Three-dimensional ERUS allows more precise staging of lesions and better definition of the mesorectal margins, and this has a direct impact on therapeutic decision-making in patients with rectal cancer.

Endosonography↗

Molecular dynamics simulations of conformational behavior of linear RGD peptidomimetics and cyclic prodrugs in aqueous and octane solutions.

Conformations available to a class of cyclic prodrugs and corresponding linear RGD peptidomimetics were explored using 1 ns length molecular dynamics simulations performed with the program CHARMM. Water and octane, modeled explicitly, were used as solvents to mimic the change of the environment experienced by the solutes upon partition from water to membrane in the trans-cellular transport process. In water, the linear peptidomimetics tended to populate extended-like structures, characterized by strong favorable interactions with solvent and low intrinsic stability. In these extended conformations the charged termini are able to assume large distances, above 15 A for the longest systems. These linear peptidomimetics have been found to exhibit the highest potency in experimental studies, in accord with the trends experimentally observed for RGD peptides. In contrast, in octane compact conformers of the linear peptidomimetics were favored, with all charged groups aggregated and shielded from solvent, exhibiting high intrinsic stability and weak solute-solvent interactions. Our calculations predict a large unfavorable energy change for transferring the linear systems from water to octane, in agreement with experimental findings that these compounds are not transported via the trans-cellular pathway. The cyclic prodrugs did not exhibit major structural differences between the simulations in water and octane, adopting turn-like conformations in both solvents. The limited response of the cyclic structures to changes in the environment leads to energies of transfer from water to octane that are also unfavorable, but much less so than for the linear molecules. This effect is in accord with the observed enhanced passive trans-cellular transport of the cyclic prodrugs.

Amino Acid Sequence↗

Application of the four-parameter logistic model to bioassay: comparison with slope ratio and parallel line models.

Bioassays with a quantitative response showing a sigmoid log-dose relationship can be analysed by fitting a non-linear dose-response model directly to the data. It is demonstrated that the four-parameter logistic model, previously applied to immunoassay (Healy 1972), is applicable to the free fat cell bioassay of insulin (Moody, Stan, Stan and Gliemann 1974). It is shown that the standard slope ratio and parallel line models for bioassay can be considered as approximations to the logistic in the extreme dose regions, while the parallel line model can be expected to fit in the middle region. The full statistical analysis of the four-parameter logistic model applied to a general assay design is described. An APL computer program has been developed to facilitate the calculations, which include non-linear curve-fitting, tests of goodness of fit and parallelity, as well as point and interval estimates of the relative potency. Examples of free fat cell bioassays of insulin that have been analysed according to these methods are given. Efficient estimation of the potency calls for concentrating the doses in the region with the steepest slope of the dose-response curve. With respect to testing the parallelity and to allow for assay-to-assay variability and unpredictable potencies, it may be preferable to use an assay design with doses distributed over a wide range and to apply a dose-response model which, like the four-parameter logistic, is capable of fitting over the whole feasible dose range.

Biological Assay↗

Simple and choice reaction time methods in the study of motor programming.

In an extensive series of experiments Sternberg, Monsell, Knoll, and Wright (1978) reported that simple RT increased as a linear function of the number of items to be pronounced or typed. The present experiments replicate a portion of these results, but show that the effect is less general than may have been supposed. Since the effect does not occur in every case in which a response programming interpretation would predict it, this interpretation must be rejected. This conclusion is consistent with the viewpoint that response programming should be investigated in a choice- rather than simple-RT paradigm. In this view, motivated subjects can program responses in advance of the simple-RT interval because the particular response to be made has been precued. Effects of response parameters which are observed for motivated subjects in the simple-RT paradigm, such as those reported by Sternberg et al. (1978), should be attributed to processes other than programming motor responses.

Journal Article↗

Effectiveness of personal protective equipment: relevance of dermal and inhalation exposure to chlorpyrifos among pest control operators.

This study assessed the effectiveness of a custom fit personal protective equipment (PPE) program aimed at reducing occupational exposure to pesticides. The intervention study was carried out on 15 pest control operators (PCOs) during mixing/loading and application of chlorpyrifos. Each worker was measured twice; first while the worker used PPE as normal (baseline measurement), and second after making some adjustments to the PPE (postintervention measurement). The applied intervention consisted of a tight-fitting, full-face respirator, fit-testing, long gloves, chemical-proof boots, a Tyvek hood, and an instruction video that was shown prior to putting on the PPE. A comprehensive evaluation program was used for the within-subject comparisons, including assessment of potential dermal exposure, actual dermal exposure, inhalation exposure, and internal dose as measured by the urinary metabolite 3,5,6-trichloro-2-pyridinol (TCP). The PPE program resulted in a significant increase in fit factors from a mean of 670 to 132,000. Actual dermal exposure levels decreased on average by fourfold after implementation of the PPE program (baseline AM = 132.1 microg; postintervention AM = 32.6 microg). The TCP levels in urine collected 24-32 hours after spray activities were lower in the postintervention data set (AM = 21.2 microg TCP/g creatinine vs. AM = 13.9 microg TCP/g creatinine). However, it is impossible to attribute these differences totally to the PPE program since workers had significant and varying urinary TCP levels before onset of spraying activities. Linear regression models showed that dermal exposure was only a predictive parameter for TCP levels in urine in the baseline data set. Although the results should be interpreted cautiously this study suggests a protective effect of the evaluated PPE program.

Administration, Cutaneous↗

Teaching and social support: effects on knowledge, attitudes, and behaviors to prevent low back injuries in industry.

An educational program designed to reduce low back injuries was modeled after several well-known back schools and taught to postal workers in a randomized trial of about 4,000 workers. Physical therapists taught 3 hours of class sessions, including knowledge, skills, and individual work station assessment, to small groups of workers and supervisors, with reinforcement every 6 months afterward. At 2 1/2 years, a random sample of 209 workers was surveyed for program impact on intermediate outcomes. We observed increased knowledge among experimental unit workers, but no significant improvements in behaviors associated with back health or in proportion of workers with tired backs. Experimental unit workers who had received training by the time of the survey were less likely to report helping/reinforcement for healthy behaviors than controls or untrained experimental unit workers. The program might have led trained workers to perceive a lack of support and reinforcement for back safety among coworkers and supervisors by sensitizing them to what is possible and raising expectations. There appeared to be group social effects in the dissemination of knowledge and perhaps of helpful behaviors; however, it is apparent that worker social support for change in health behaviors is a complex phenomenon that cannot always be relied upon to enhance program goals.

Back↗

Analysis program based on finite element method, MULTI(FEM), for evaluation of dose-dependent local disposition of drug in liver.

A curve-fitting program based on the Finite Element Method, MULTI(FEM), was developed to model nonlinear local disposition of a drug in the liver under non-steady-state conditions. The program was written in FORTRAN on an IBM-compatible personal computer. The validity of MULTI(FEM) was confirmed by analyzing the outflow kinetics of oxacillin (a model drug) following a pulse input to isolated, perfused rat livers, according to both linear and nonlinear dispersion models. Four dose levels (300, 1000, 3000, and 5000 microg) of oxacillin were administered to observe the dose-dependency in the hepatic local disposition. First, the individual outflow time-profiles at the same dose were averaged, and the average time-profile was analyzed by MULTI(FEM) based on linear dispersion models to yield a single curve fit. The fitted parameters at each dose level were compared with parameters estimated using MULTI(FILT), a program based on fast inverse Laplace transform, to analyze linear pharmacokinetics. The estimated parameters by MULTI(FEM) were in good agreement with those by MULTI(FILT). The apparent elimination rate constant (ke) decreased with an increase in dose, whereas other parameters showed no discernible dependency on an increase of dose. Second, the average outflow time-profiles at the four dose levels were simultaneously analyzed by MULTI(FEM) based on dispersion models featuring Michaelis-Menten elimination. The outflow time-profiles of oxacillin were well approximated by a two-compartment dispersion model with central Michaelis-Menten elimination. The maximum elimination rate constant (Vmax) and the Michaelis constant (Km) were estimated to be 1520 microg/mL/min and 41.3 microg/mL, respectively. Thus, the capability of MULTI(FEM) was demonstrated in evaluating capacity-limited local disposition in the liver.

Animals↗

The estimation of population pharmacokinetic parameters using an EM algorithm.

An EM algorithm was used to analyse data arising from non-linear mixed-effects models. The fixed parameters were determined by maximum likelihood using simplex minimization, and the random effects were estimated using the EM algorithm after linearization with respect to the random effects. Applications to a simple linear model and population pharmacokinetics are described. The use of posterior parameter estimates to investigate covariate relationships is briefly described. The implementation of the estimation-maximization (EM) algorithm described here has proved in practice to be robust but slow. We intend to use a Newton-Raphson minimization routine in place of the simplex method to hasten convergence. The alternative linearization of the non-linear mixed effects model suggested by Lindstrom and Bates (Biometrics 46 (1990) 673-687) is much more unstable than the usual linearization, especially during the initial iterations. In the case of indomethacin the two linearizations produced very similar results. The individual posterior parameter estimates provided by the program are very useful for the detection of covariate relationships in population pharmacokinetic studies. In addition, the posterior means can be used in the estimation of pharmacokinetic-pharmacodynamic relationships from sparse pharmacokinetic data where individual modelling is impossible.

Algorithms↗