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Patient registration and treatment allocation in multicenter clinical trials using a FAX-OCR system.

This article describes the design and results of implementation of an automated patient registration and treatment allocation system (RETAS) used in multicenter clinical trials. RETAS was developed using a FAX-OCR system by which handwritten Japanese and English characters, as well as numericals and forms with check boxes, are sent from participating institutions by Fax, processed using an optical character reader, and then transmitted to a host computer at a statistical center. Based on the facsimile data, RETAS can automatically review eligibility, collect patient identification data and provide a randomized treatment allocation. RETAS permits uninterrupted, unattended operation at a statistical center, 24 hours a day, 7 days a week. Therefore, it drastically decreases the workload of personnel at the statistical center needed to support central telephone registration coverage. Consequently, staff members are free to focus on patient registration, treatment allocation, and follow-up of patients. The treatment allocation procedure in this system is based on Pocock and Simon's minimization method combined with Zelen's method for institution balancing. By this system it was possible to balance treatment numbers for each level of various prognostic factors over an entire trial and, at the same time, balance the allocation of treatments within an institution. The system currently supports the protocol of a clinical trial for Adjuvant Chemo-Endocrine Therapy for Breast Cancer in West Japan.

Computer Systems↗

Calculation of electric fields and currents induced in a millimeter-resolution human model at 60 Hz using the FDTD method.

The finite-difference time-domain (FDTD) method has previously been used to calculate induced currents in anatomically based models of the human body at frequencies ranging from 20 to 915 MHz and resolutions down to about 1.25 cm. Calculations at lower frequencies and higher resolutions have been precluded by the huge number of time steps that would be needed in these simulations. This paper describes a method used to overcome this problem and efficiently calculate induced currents in an MRI-based, 6-mm-resolution model of the human under a high-voltage transmission line. This model is significantly higher resolution than the 1.31-cm-resolution model previously used; therefore, it can be used to pinpoint locations of peak current densities in the body. Proposed safety guidelines would allow external electric fields of 10 kV/m and 25 kV/m for exposure to 60 Hz fields of the general public and workers, respectively. For this external electric field exposure of 10 kV/m, local induced current densities as high as 20 mA/m2 are found in the head and trunk with even higher values (above 150 mA/m2) in the legs. These currents are considerably higher than the 4 or even 10 mA/m2 that have been suggested in the various safety guidelines, thus indicating an inconsistency in the proposed guidelines. In addition, several ratios of E/H typical of power line exposures were examined, and it was found that the vertical electric field couples strongly to the body, whereas the horizontal magnetic field does not.

Computer Simulation↗

Selective stabilization of muscle innervation during development: a mathematical model.

The biochemical model presented concerns a critical step of the development of skeletal muscle innervation. After invasion of the muscle by exploratory motor axons, several nerve terminals converge from different motoneurons onto each muscle fibre at a single endplate. During the following weeks the redundant innervation disappears: a single nerve ending per muscle fibre becomes stabilized. The model is based on the assumption that the numbers of motoneurons and of muscle fibres remain constant during this evolution and that the selective stabilization of the adult connectivity results from the competition of the active nerve terminals for a postsynaptic retrograde factor mu. At the peak of the multiple innervation, the synthesis of mu by the muscle fiber stops, possibly as a consequence of muscle electrical and/or mechanical activity. The stock of mu becomes limited; a retrograde trans-synaptic diffusion of mu from the muscle to the nerve endings takes place. Within each nerve ending, mu enters into a chemical autocatalytic reaction which results in the production of a presynaptic stabilization factor s. The nerve impulses reaching the nerve terminal initiate this reaction. Any given nerve terminal become stabilized when the concentration of s reaches a threshold value. The mathematical analysis of the model shows that there exists a unique solution which is physically acceptable. Its application and computer simulation predict that only one nerve terminal becomes stabilized per muscle fibre. The model accounts for the experimental observations that the reduction in size of the motor units is not necessarily accompanied by a reduction in the variability of their size. The model also accounts for the acceleration or delay in regression which follows modifications of the chronic activity of the nerve endings and for the variability of the pattern of innervation observed in isogenic organisms. Plausible biochemical hypotheses concerning the factors engaged in the "selective stabilization" of the nerve-endings are discussed.

Animals↗

Neural cross-correlation and signal decorrelation: insights into coding of auditory space.

The auditory systems of humans and many other species use the difference in the time of arrival of acoustic signals at the two ears to compute the lateral position of sound sources. This computation is assumed to initially occur in an assembly of neurons organized along a frequency-by-delay surface. Mathematically, the computations are equivalent to a two-dimensional cross-correlation of the input signals at the two ears, with the position of the peak activity along this surface designating the position of the source in space. In this study, partially correlated signals to the two ears are used to probe the mechanisms for encoding spatial cues in stationary or dynamic (moving) signals. It is demonstrated that a cross-correlation model of the auditory periphery coupled with statistical decision theory can predict the patterns of performance by human subjects for both stationary and motion stimuli as a function of stimulus decorrelation. Implications of these findings for the existence of a unique cortical motion system are discussed.

Acoustic Stimulation↗

[Importance of mathematical analysis of the retinal image in diabetic retinopathy].

The authors test whether for evaluation of the severity of diabetic retinopathy it is possible to use the method of computer assisted mathematical processing of the retinal image. This method is based on the identification of vascular endings in the visualized part of the retina. It is assumed that with the severity of the finding the number of vascular endings increases in conjunction with the process of neogenesis. For assessment of the number of vascular endings the authors use the Adaptive Contrast Control (ACC) method. By a special procedure the vascular endings are identified and their number is assessed in the investigated area of the retina. The method makes it possible to assess in addition to the number of vascular endings also the total length of the vessels, their volume, surface, area they cover and the histogram of the diameter of the vessels. The authors examined 19 patients (38 eyes) with a quite normal finding on the retina. The mean age of the group was 37.3 years. Moreover they examined 10 patients (20 eyes) with middle advanced and advanced non-proliferative diabetic retinopathy and 10 patients (20 eyes) with risk proliferative diabetic retinopathy. In every patient a standard digital photograph of the fundus of both eyes size "tif" was made and each picture was subjected to mathematical analysis. The group of patients was divided into three sub-groups (patients with a normal finding, a non-proliferative finding and a finding of proliferative diabetic retinopathy). In the conclusion the authors provide evidence that with increasing severity of the finding on the retina also the number of vascular endings increases.

Adolescent↗

[Comparing two groups of patients].

In medical research, comparing two groups of patients occurs frequently. The basic principles of comparison and the usual statistical tests--according to the types of variables and the choices of sampling methods--are presented. Elements needed for the computation of the size of a comparative study are given.

Humans↗

Accuracy and precision for analytical results.

Unknown amounts of drug from plasma samples are determined from inverse prediction of a calibration line. A statistician's criteria for accuracy and three methods for computing precision are given.

Blood Chemical Analysis↗

User-friendly and versatile software for analysis of protein hydrophobicity.

We have developed a simple and flexible program to analyze regional hydrophobicity of a protein from its amino acid (aa) sequence. This program runs as a Microsoft Excel document into which aa sequence can be copied from any Windows-compatible or Macintosh word processor. The program returns the hydrophobicity index of each aa residue and other analyses that can be used to predict transmembrane domains, amphiphilic alpha helices and putative antigenic epitopes in a protein using established algorithms. The program can also be easily modified to test user-defined algorithms and to accommodate non-conventional aa residues or ambiguities in the aa sequence. Simple modification of the program allows direct use of nucleic acid sequence information for various analyses. Graphic visualization of the results is readily achieved using the graphics function of Microsoft Excel. Alternatively, the data can be imported into other graphics software for preparation of publication-quality figures. By running as a document in Microsoft Excel, which can be found in virtually all personal computers, this program provides easy access even to the computer novice.

Amino Acid Sequence↗

An introduction to Bayesian hierarchical models with an application in the theory of signal detection.

Although many nonlinear models of cognition have been proposed in the past 50 years, there has been little consideration of corresponding statistical techniques for their analysis. In analyses with nonlinear models, unmodeled variability from the selection of items or participants may lead to asymptotically biased estimation. This asymptotic bias, in turn, renders inference problematic. We show, for example, that a signal detection analysis of recognition memory data leads to asymptotic underestimation of sensitivity. To eliminate asymptotic bias, we advocate hierarchical models in which participant variability, item variability, and measurement error are modeled simultaneously. By accounting for multiple sources of variability, hierarchical models yield consistent and accurate estimates of participant and item effects in recognition memory. This article is written in tutorial format; we provide an introduction to Bayesian statistics, hierarchical modeling, and Markov chain Monte Carlo computational techniques.

Bayes Theorem↗

Advanced statistics: bootstrapping confidence intervals for statistics with "difficult" distributions.

The use of confidence intervals in reporting results of research has increased dramatically and is now required or highly recommended by editors of many scientific journals. Many resources describe methods for computing confidence intervals for statistics with mathematically simple distributions. Computing confidence intervals for descriptive statistics with distributions that are difficult to represent mathematically is more challenging. The bootstrap is a computationally intensive statistical technique that allows the researcher to make inferences from data without making strong distributional assumptions about the data or the statistic being calculated. This allows the researcher to estimate confidence intervals for statistics that do not have simple sampling distributions (e.g., the median). The purposes of this article are to describe the concept of bootstrapping, to demonstrate how to estimate confidence intervals for the median and the Spearman rank correlation coefficient for non-normally-distributed data from a recent clinical study using two commonly used statistical software packages (SAS and Stata), and to discuss specific limitations of the bootstrap.

Confidence Intervals↗

Decrements in volume of anterior ventromedial temporal lobe and olfactory dysfunction in schizophrenia.

CONTEXT: Patients with schizophrenia exhibit olfactory deficits, but it is unclear whether these represent a specific abnormality. The link between olfactory impairments and regional brain abnormalities has yet to be established. OBJECTIVES: To determine whether patients with schizophrenia exhibit volumetric deficits in the anterior ventromedial temporal lobe, the target for neuronal inputs from the olfactory bulb, and whether these are related to olfactory performance deficits. DESIGN: A cohort study of patients and healthy control subjects who underwent both 1-mm spoiled-gradient echo magnetic resonance imaging and behavioral tests of olfaction and memory. SETTING: Schizophrenia Research Center at the University of Pennsylvania, Philadelphia. PARTICIPANTS: Fifty-two patients with a DSM-IV diagnosis of schizophrenia and 38 healthy control subjects. Individuals were excluded for history of head trauma, significant substance abuse, and medical conditions affecting brain function or olfactory capacity. MAIN OUTCOME MEASURES: Gray matter volumes of the left and right temporal poles and the perirhinal and entorhinal cortexes; olfactory threshold detection sensitivity and identification test scores; composite indexes of verbal and spatial memory ability. RESULTS: Patients had reduced volumes, relative to cranial size, in left (P =.003) and right (P =.01) perirhinal and left (P =.002) and right (P =.002) entorhinal cortexes, but not in the temporal pole. Perirhinal, but not entorhinal, cortical volume decrement was associated with decreased olfactory threshold sensitivity. Neither region was associated with impaired memory performance. CONCLUSIONS: Patients with schizophrenia have reduced cortical volumes in brain regions that receive afferents directly from the olfactory bulb. Behavioral olfactory deficits are related to structural brain abnormalities in these regions.

Adolescent↗

Statistical geometry approach to the study of functional effects of human nonsynonymous SNPs.

The ability to predict the effect of nonsynonymous SNPs (nsSNPs) on protein function is important for the success of genetic disease association studies. Here we present a statistical geometry approach to nsSNP classification based on Delaunay tessellation, whereby the impact of nsSNPs on protein function is correlated with the change in the four-body statistical potential (DeltaQ) of the protein caused by the amino acid substitution. We observed that the DeltaQ of polymorphic proteins with disease-associated nsSNPs (daSNPs) was on average significantly lower than the DeltaQ of the proteins with neutral SNPs (ntSNPs). Clustering amino acid substitutions into conservative and nonconservative groups, and using a three-letter alphabet based on side-chain polarity showed significantly lower DeltaQ in nonconservative changes to daSNPs and when hydrophobic residues were substituted by charged or by polar residues. We also found that the daSNPs in the protein core caused much lower DeltaQ than surface daSNPs. This approach demonstrates a strong correlation between the computed DeltaQ and SNP classification. Integration of our approach with the existing models will help achieve a more precise recognition of nsSNPs that underlie polygenic diseases. All of the programs were written in Java and are available from the authors upon request.

Amino Acid Substitution↗

A reduced representation of proteins for use in restraint satisfaction calculations.

A reduced representation of proteins has been developed for use in restraint satisfaction calculations with dynamic simulated annealing. Each amino acid residue is represented by up to four spherical virtual atoms. The virtual bonds and excluded volume of these atoms has been parameterized by analysis of 83 protein structures determined at high resolution by X-ray crystallography. The use of the new representation in NOE distance restraint satisfaction has been compared with the standard all-atom representation for the determination of the structures of crambin, echistatin, and protein G. Using the reduced representation, there is a 30-fold decrease in the computer time needed for generating a single structure, and up to a 20-fold decrease in the time taken to produce an acceptable structure compared to using the all-atom representation. The root mean square deviation between the mean structure obtained with all-atom and reduced representations is between 1.5 and 1.7 A for C alpha atoms. The new representation is adequate for describing the "low-resolution" features of protein structure such as the general fold and the positions of secondary structure elements. It can also provide an initial structure for more detailed refinement with the full all-atom representation.

Computer Simulation↗

Interfacing U.S. census map files with statistical graphics software: application and use in epidemiology.

In 1990, the United States Bureau of the Census released detailed geographic map files known as TIGER/Line (Topologically Integrated Geographic Encoding and Referencing). The TIGER files, accessible through purchase or federal repository libraries, contain 24 billion characters of data describing various geographic features including coastlines, hydrography, transportation networks, political boundaries, etc. for the entire United States. Many of these physical features are of potential interest in epidemiological case studies. Unfortunately, the TIGER data base only provides raw alphanumeric data; no utility software, graphical or otherwise, is included. Recently, the S statistical software package has been extended to include a map display function. The map function augments S's high-level approach towards statistical analysis and graphical display of data. Coupling this statistical software with the map data base developed for U.S. Census data collection will facilitate epidemiological research. We discuss the technical background necessary to utilize the TIGER data base for mapping with S. Two types of S maps, segment-based and polygon-based, are discussed along with methods to construct them from TIGER data. Polygon-based maps are useful for displaying regional statistical data, such as disease rates or incidence at the census tract level. Segment-based maps are easier to assemble and are appropriate when the data are not regionalized. Census tract data of AIDS incidence in San Francisco and lung cancer case locations relative to petrochemical refinery sites in Contra Costa County are used to illustrate the methods and potential uses of interfacing the TIGER data base with S.

Acquired Immunodeficiency Syndrome↗