Improving model robustness with bootstrapping -- application to optimal discriminant analysis for ordinal responses (ODAO).

OBJECTIVE: Recent results published by Coste et al. in discriminant analysis with ordinal responses showed the superiority of optimal discriminating analysis for ordinal responses (ODAO) both in terms of classification and simplicity of implementation compared to classic methods (Fisher's discrimination, logistic regression) applied to medical data (prognostics of burns) and to simulated data. Nevertheless, the solutions obtained by ODAO may be sensitive to re-sampling (i.e the estimated coefficients by ODAO may show excessive sensitivity to the training sample). This study proposes some solutions to control the fluctuations of sampling and to ensure model stability. METHODS: We used intensive computational methods and bootstrapping, at the outset of model building in order to reduce the sampling variability of estimated coefficients. Thus, the estimation of the coefficients was not based on the minimization of a classification criterion of the training sample, but on the minimization of an aggregate criterion of bootstrapped replications of a classification criterion. Five aggregate criteria were studied. RESULTS: The improvement in terms of robustness appeared in 30% of the test cases with moderate training sample size and 55% of those with small training sample size. CONCLUSION: Simulated test cases showed that bootstrapping can help construct more robust models in difficult classification situations and small training samples which are particularly frequent.

Distance mapping of protein-binding sites using spin-labeled oligosaccharide ligands.

The binding of a nitroxide spin-labeled analog of N-acetyllactosamine to galectin-3, a mammalian lectin of 26 kD size, is studied to map the binding sites of this small oligosaccharide on the protein surface. Perturbation of intensities of cross-peaks in the (15)N heteronuclear single quantum coherence (HSQC) spectrum of full-length galectin-3 owing to the bound spin label is used qualitatively to identify protein residues proximate to the binding site for N-acetyllactosamine. A protocol for converting intensity measurements to a more quantitative determination of distances between discrete protein amide protons and the bound spin label is then described. This protocol is discussed as part of a drug design strategy in which subsequent perturbation of chemical shifts of distance mapped amide cross-peaks can be used effectively to screen a library of compounds for other ligands that bind to the target protein at distances suitable for chemical linkage to the primary ligand. This approach is novel in that it bypasses the need for structure determination and resonance assignment of the target protein.

The effect of captopril on thallium 201 myocardial perfusion in systemic sclerosis.

In systemic sclerosis, abnormalities of myocardial perfusion are common and may be caused by a disturbance of the coronary microcirculation. We evaluated the long-term effect of captopril (75 to 150 mg per day) on thallium 201 myocardial perfusion in 12 normotensive patients with systemic sclerosis. Captopril significantly decreased the mean (+/- SD) number of segments with thallium 201 myocardial perfusion defects (6.5 +/- 1.9 at baseline and 4.4 +/- 2.7 after 1 year of treatment with captopril; p less than 0.02) and increased the mean global thallium score (9.6 +/- 1.7 at baseline and 11.4 +/- 2.1 after captopril; p less than 0.05). In a control group of eight normotensive patients with systemic sclerosis who did not receive captopril, no significant modification in thallium results occurred. Side effects with captopril included hypotension (six patients), taste disturbances (one patient), and skin rash (one patient). These side effects subsided when the dosage was reduced. These findings demonstrate that captopril improves thallium 201 myocardial perfusion in patients with systemic sclerosis and may therefore have a beneficial effect on scleroderma myocardial disease.

Automated comparison of scintigraphic images.

New algorithms for automated comparison of scintigraphic images have been developed and are described here. The first step presented here is the registration of the images, performed by optimizing, with respect to the registration parameters (two translational shifts, one angle of rotation, the two parameters of a linear transformation of the gray levels), the stochastic sign change (SSC) criterion. The optimization of this criterion is demonstrated to be efficiently performed using the adaptative random search strategy; a more limited but less time-consuming method is also presented. The second step described is the point-by-point comparison of the registered images. The pixel-by-pixel application of Poisson variable statistical tests permits the generation of the significant image differences. From such images it is possible to detect modifications which escape visual inspection. Examples of applications are given in controlled and routine conditions. These algorithms are useful for the processing of many investigations and are proposed for implementation on all nuclear medicine data processing systems.

An automated method for the normalization of scintigraphic images.

The computer comparison of two images of the same organ requires normalization of the images. We propose an iterative, automated method of normalization that is highly insensitive to structural modifications in the images. The normalization factor is calculated by maximizing the number of sign changes in the scanned subtraction image with a unidimensionnal optimization method. This algorithm is efficient, computationally cheap, and can be implemented on most nuclear medicine data-processing systems.

Anti-histone reactivity in systemic lupus erythematosus sera: a disease activity index linked to the presence of DNA:anti-DNA immune complexes.

This study shows that purified murine monoclonal anti-DNA antibodies and human polyclonal anti-DNA antibodies (from systemic lupus erythematosus--SLE--patients), preincubated with DNA, acquire anti-histone reactivity. Conversely, DNAse I treatment of SLE patients' antibodies with anti-histone activity abolishes such activity. It has previously been demonstrated that anti-DNA antibodies bind to the cell membrane and recognize cell-surface polypeptides that have been identified with histones by partial sequencing. In a series of 33 sera from patients with clinically active disease and 29 sera from patients in clinical remission, positivity of an immunoblot analysis detecting antibodies against these polypeptides was associated with clinical activity of SLE (sensitivity, 0.88; specificity, 0.90). Anti-histone reactivity detected by ELISA appeared to be also a good marker of SLE activity (sensitivity, 0.64; specificity, 0.54). As expected, anti-native DNA antibody positivity and lowered complement dosage were also associated with clinical activity (sensitivity, 0.79 and 0.63, respectively; specificity, 0.48 and 0.93, respectively). Since anti-histone reactivity reflects, at least partly, the presence of anti-DNA antibodies complexed to DNA, which could bind to cell-membrane determinants, and is associated with disease clinical activity, it is suggested that this mechanism can contribute to explain the pathogenicity of anti-DNA antibodies.

Predicting mortality in adult burned patients: methodological aspects of the construction and validation of a composite ratio scale.

This article describes the methodology of construction and validation of a composite measurement scale (CMS) to predict the risk of death for burned patients, with severity of burn considered as a continuous phenomenon. Three large data sets of burned patients hospitalized in France were analyzed. Logistic regression was used to construct a prognostic model, based on age and initial evaluation of total body surface area burned. The resulting model appears to be a valid clinical tool for predicting the risk of death. In addition, the devised CMS has satisfactory content and construct validity and reliability, and provides a high measurement level (logistic ratio level). Moreover, its simplicity of use (the score is integer based) is appropriate for the daily activities of burn unit physicians, emergency medical technicians, and public health professionals.

Prognostic factors of invasive pulmonary aspergillosis in leukemic patients.

The study objective was to identify prognostic factors associated with survival in patients treated for acute leukemias who developed invasive aspergillosis (IA) during induction therapy. This retrospective analysis involved 21 patients treated in two hematologic centers over a six-year period. All were treated in protective isolated rooms with high-dose amphotericin B as soon as fungal infection was suspected. Ten (45%) of the twenty-one patients died. There was no statistical difference between the patients who survived and those who died in relation to the mean time of onset of IA or the total and mean daily dose of amphotericin B. On the other hand a favourable outcome correlated strongly with complete leukemic remission (p < 0.0001): all but one of the patients with objective residual leukemia died of IA, whereas all those who achieved complete hematological remission survived. In conclusion, it seems that the main vital prognostic factor in these leukemic patients with IA was the achievement of complete remission. We were unable to control IA in 10 of 11 patients with refractory leukemia, regardless of neutropenic status, despite early administration of high-dose amphotericin B. All the patients who achieved complete remission were successfully treated with amphotericin B.

A French version of the Sickness Impact Profile (SIP): stages in the cross cultural validation of a generic quality of life scale.

The Sickness Impact Profile is a quality of life scale developed in the United States which is now widely used in clinical trials in chronic conditions such as chronic obstructive lung disease, angina, rheumatoid arthritis, chronic pain, psoriasis, inflammatory bowel disease and cancer. Validated generic scales permit cross cultural comparisons within disease processes in clinical trials. As a simple, direct translation of a scale is inadequate, we have created a French version of the original US version of the Sickness Impact Profile. The first phase was qualitative. A first French translation of the original US version was back translated into English by three independent translators. A second French version resulted from a consensus reached by a panel of lay subjects and health professionals after comparing the original US version, the first French version and the three back translations. This second version was tested with a group of 40 healthy volunteers. This qualitative phase resulted in a French Test Version with content and face validity. The quantitative phase assessed the equivalence of the rank order of each item, by sub scale, in the US version with that of the French Test Version, ie the rank of the French item was comparable (+/- 2) to the rank of the corresponding US item. The French Test Version was tested with 47 healthy subjects. Of the 136 items of the Sickness Impact Profile, 13 were retranslated to create a final French version. This was similarly tested on ten healthy subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Automated correction of patient motion and gray values prior to subtraction in digitized angiography.

This paper deals with an automated method for the simultaneous correction of patient motion and gray values prior to subtraction in digitized angiography. The algorithm consists of maximizing the deterministic sign change (DSC) criterion with respect to three registration parameters (two translational shifts and one constant value added to the pixel values of the image with contrast medium). This method is proved to be very efficient to correct for patient motion artifacts and is computationally cheap. Its main advantage is to permit the use of regions of interest which include vascular structures for the registration procedure. This method can be proposed for a routine use on every commercial digitized angiographic system.

Comments about the coincident bit counting (CBC) criterion for image registration.

In a paper recently published (ibid., vol.12, p. 30-8, 1993), Chiang and Sullivan compare a new criterion for image registration called CBC (coincident bit counting) with two criteria that the authors proposed some years ago, namely SSC and DSC (stochastic and deterministic sign change criteria). The authors' nonparametric approach was demonstrated to outperform the conventional image registration criteria for robust registration in the fact that the value of their similarity measure did not take the specific pixel values into account. In light of this observation, Chiang and Sullivan have built the CBC criterion. The CBC method compares the number of coincident bits between the corresponding pixels in two different frames for a fixed amount of displacement. While the authors consider that the CBC is of interest and deserves to be studied, they feel that the comparison made by Chiang and Sullivan was not entirely accurate. Here the authors comment on this comparison and suggest possible further studies.

Color quantitation through image processing in dermatology.

Classical color models and their applications to computer vision are reviewed. The performances of color quantitation from digitized images are compared with those derived from a chromameter. The color quantitation obtained from either digitized color slides or directly digitized images is proved to be more efficient than the conventional visual assessment of observers. A methodology is proposed for determining the specific color indices which are needed in dermatology. An application of this methodology is developed for designing a blanching quantitation index in order to replace the visual assessment during McKenzie tests.

Assessment of healing kinetics through true color image processing.

A quantitative method of skin healing assessment using true color image processing is presented. The method was developed during a clinical trial using healthy volunteers, the goal of which was to study a drug for accelerating healing. Photographic images of the skin were sequentially acquired between day 1 and day 12 after pure painless epidermal wounds. The images were digitized in controlled conditions using a color video camera connected to a computer system. A color threshold based segmentation was developed to provide an operator-independent delineation of the wound. Two healing indexes were built measuring, the wound area and the wound color. The method was implemented in a software system allowing a fully automated determination of the healing indexes. The method provides a new quantitative global assessment of healing kinetics. It is noninvasive and well suited for multicentric clinical trials.

An automated system for the registration and comparison of photographic images in medicine.

A system is presented for digitization and automated comparison of photographic images of patients obtained at different times using a high-precision video camera. The images can be acquired either directly or from slides. The two images to be compared are registered using a complex geometrical and gray-level registration model including six parameters (planar, translation, rotation, magnification, linear transformation of the gray levels). The values of the registration parameters are automatically calculated by maximizing an integer similarity measure selected for robustness. The optimization of this function with respect to the registration parameters is performed using an adaptive random search strategy. The analysis of the differences between the registered images can be carried out through visual inspection of the subtraction image in which artifacts due to remaining infrapixel shifts have been suppressed.

Electronic prescribing for the elderly: will it improve medication usage?

Drug treatment of the elderly is problematic for various reasons. These include the risks of drug interactions, contraindications, incorrect dose and adverse events. Electronic prescribing is a promising tool which should help solve many of the problems associated with the use of medications in the elderly by providing information on drug selection, prescription checks, and information about drugs and prescriptions. Nevertheless, electronic prescribing must be improved by providing a user-friendly interface, structured drug data-bases, and the capacity to generate both criticism and suggestions, if it is to progressively replace pen and paper in the drug prescription process.

Cost-related information to be provided by computerised drug-prescription systems to promote cost-effective prescribing.

Drug prescriptions are a source of steadily increasing healthcare expenditure in most developed countries. As the use of Computerised Drug Prescription Systems (CDPS) increase both in hospital and community-care settings, the potential of such systems to promote cost-effective prescribing and help contain prescription costs should be considered. This article describes the cost-related information that could be provided by a CDPS, namely decision-support information to be provided on-line during the prescription entry, and retrospective information made available by processing stored prescription records. The review also describes design and specification requirements for building a cost-information module that can be used in various health-delivery systems. These are: (i) adequate and well-organised data; (ii) pertinent background knowledge of the domain; and (iii) algorithms that allow adaptation to site-specific features. The propositions expounded in this article result from a part of the work performed during the Optimisation of Drug Prescription using Advanced Informatics (OPADE) European project.

Enzymic synthesis of oligosaccharides terminating in the tumor-associated sialyl-Lewis-a determinant.

The isomeric sialyl-Lea-terminating pentasaccharide derivatives, alpha-Neup5Ac-(2----3)-beta-D-Galp-(1----3)-[alpha-L-Fucp-(1 ----4)]-beta- D-GlcpNAc-(1----3)-beta-D-Galp-O(CH2)8COOMe and alpha-Neup5Ac-(2----3)-beta-D-Galp-(1----3)-[alpha-L-Fucp-(1 ----4)]- beta-D-GlcpNAc-(1----6)-beta-D-Galp-O(CH2)8COOMe, have been prepared by the action in sequence of a porcine submaxillary (2----3)-alpha-sialyltransferase and a human-milk (1----3/4)-alpha-fucosyltransferase on the chemically synthesized trisaccharides beta-D-Galp-(1----3)-beta-D-GlcpNAc-(1----3)- and -(1----6)-beta-D-Galp- O(CH2)8COOMe, respectively.

Chemoenzymic synthesis of sialylated and fucosylated oligosaccharides having an N-acetyllactosaminyl core.

Several sialylated and fucosylated oligosaccharides, based upon the N-acetyllactosaminyl core structure, have been synthesized from a single trisaccharide glycoside, beta-D-GlcNAc-(1-->3)-beta-D-Gal-(1-->4)-beta-D-GlcNAc-OCH2(CH2)++ +7CO2CH3, by the sequential use of several glycosyltransferases and one sialidase. In these chemoenzymic syntheses, selective internal monofucosylation of a dimeric N-acetyl-lactosaminyl tetrasaccharide is achieved via two routes. It is demonstrated that the pentasaccharide beta-D-Gal-(1-->4)-beta-D-GlcNAc-(1-->3)-beta-D-Gal-(1-->4)-[alpha- L-Fuc-(1-->3)]-beta-D-GlcNAc-OCH2(CH2)7-CO2CH3 is an acceptor for the rat liver beta-D-Gal-(1-->3/4)-D-Glc-NAc alpha 2,3- and beta-D-Gal-(1-->4)-D-GlcNAc alpha 2,6-sialyltransferases. Among the structures obtained is the terminal hexasaccharide of the CD-65/VIM-2 epitope.

Use of human-milk fucosyltransferase in the chemoenzymic synthesis of analogues of the sialyl Lewis(a) and sialyl Lewis(x) tetrasaccharides modified at the C-2 position of the reducing unit.

Two series of trisaccharides, having the formulas alpha-Neu5Ac-(2-->3)-beta-D-Gal-(1-->4)-beta-D-GlcZ-OR and alpha-Neu5Ac-(2-->3)-beta-D-Gal-(1-->3)-beta-D-GlcZ-OR [R = (CH2)8CO2CH3] respectively, in which the 2-deoxy substituent Z is azido, amino, propionamido, or acetamido, were prepared by chemical synthesis. Both types of modified trisaccharides are acceptors for a fucosyltransferase preparation obtained from human milk. Preparative fucosylations using this enzyme provided analogues of the sialyl Lewis(x) and sialyl Lewis(a) tetrasaccharide structures, which have been proposed to be ligands for cell-adhesion molecules. These syntheses further demonstrate the utility of glycosyltransferases in the preparation of oligosaccharide analogues.

Five specificity patterns of (1----3)-alpha-L-fucosyltransferase activity defined by use of synthetic oligosaccharide acceptors. Differential expression of the enzymes during human embryonic development and in adult tissues.

The use of synthetic trisaccharides as acceptors led to the definition of five main (1----3)-alpha-L-fucosyltransferase activity patterns in human adult tissues: (I). Myeliod cells, granulocytes, monocytes, and lymphoblasts, transfer an alpha-L-fucopyranosyl group to O-3 of a 2-acetamido-2-deoxy-D-glucosyl residue of H blood-group Type 2 oligosaccharide [alpha-L-Fucp-(1----2)-beta-D-Galp-(1----4)-beta-D-GlcpNAc----R] with Mn2+ as activator. (II) Brain has the same acceptor specificity pattern as myeloid cells, but can also use Co2+ as activator. (III) Plasma and liver transfer an alpha-L-furopyranosyl group to H blood-group Type 2 and to sialyl-N-acetyllactosamine [alpha-NeuAc-(2----3)-beta-D-Galp-(1----4)-beta-D-GlcpNAc----R]. (IV) Intestine, gall bladder, kidney, and milk have the same activity as (III), but also transfer an alpha-L-fucopyranosyl group to O-4 of a 2-acetamido-2-deoxy-D-glucose residue of H blood-group Type 1 [alpha-L-Fucp-(1----2)-beta-D-Galp-(1----3)-beta-D-GlcpNAc----R] and sialyl Type 1 [alpha-NeuAc-(1----3)-beta-D-Galp-(1----3)-beta-D-GlcpNAc----R]. (V) Stomach mucosa is not able to use sialyl-N-acetyllactosamine, but can transfer an alpha-L-fucopyranosyl group to the other Type 1 and Type 2 acceptors. Unlike in adult tissue, a single myeloid-like pattern of (1----3)-alpha-L-fucosyltransferase activity was found at early stages of development in all tissues tested. This embryonic enzyme is later progressively replaced by enzymes or mixtures of enzymes having the corresponding adult patterns of enzyme expression. All lymphoblastoid cell lines and half of the tumor epithelial cell lines tested expressed the myeloid-like pattern of enzyme found in normal embryonic tissues. The remaining tumor epithelial cell lines expressed different forms of (1----3/4)-alpha-L-fucosyltransferase acceptor specificity patterns.