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PubMed2005

Robust estimating functions and bias correction for longitudinal data analysis.

Robust methods are useful in making reliable statistical inferences when there are small deviations from the model assumptions. The widely used method of the generalized estimating equations can be "robustified" by replacing the standardized residuals with the M-residuals. If the Pearson residuals are assumed to be unbiased from zero, parameter estimators from the robust approach are asymptotically biased when error distributions are not symmetric. We propose a distribution-free method for correcting this bias. Our extensive numerical studies show that the proposed method can reduce the bias substantially. Examples are given for illustration.

Age Factors↗
PubMed1994

The pharmacokinetics of propofol in children using three different data analysis approaches.

BACKGROUND: Accurate dosing of propofol in children requires accurate knowledge of propofol pharmacokinetics in this population. Improvement in pharmacokinetic accuracy may depend on the incorporation of individual patient factors into the pharmacokinetic model or the use of population approaches to estimating the pharmacokinetic parameters. We investigated whether incorporating individual subject covariates (e.g., age, weight, and gender) into the pharmacokinetic model improved the accuracy. We also investigated whether the use of a mixed-effects population model (e.g., the computer program NONMEM) improved the accuracy of the pharmacokinetic model beyond the accuracy obtained with models estimated using two simple approaches. METHODS: We studied 53 healthy, unpremedicated children (28 boys and 25 girls) ranging from 3 to 11 yr of age. Twenty children only received an initial loading dose of 3 mg/kg intravenous propofol. In the remaining 33 children, an initial intravenous propofol dose of 3.5 mg/kg was followed by a propofol maintenance infusion. Six hundred fifty-eight venous plasma samples were gathered and assayed for propofol concentrations. Three different regression techniques were used to analyze the pharmacokinetics: the "standard two-stage" approach, the "naive pooled-data" approach, and the nonlinear mixed-effects modeling approach (as implemented in NONMEM). In both the pooled-data and mixed-effects approaches, individual covariates (age, weight, height, body surface area, and gender) were added to the model to examine whether they improved the quality of the fit. Accuracy of the model was measured by the ability of the model to describe the observed concentrations. RESULTS: The pharmacokinetics of propofol in children were best described by a three-compartment pharmacokinetic model. There were no appreciable differences among the pharmacokinetics estimated using the two-stage, pooled-data, and mixed-effects approaches. Weight was a significant covariate, and the weight-proportional model was supported by all three regression approaches. The pharmacokinetic parameters of the weight-proportional pharmacokinetic model (pooled-data approach) were: central compartment (V1) = 0.52 1 x kg-1; rapid-distribution compartment (V2) = 1.01 x kg-1; slow-distribution compartment (V3) = 8.2 1 x kg-1; metabolic clearance (Cl1) = 34 ml.kg-1 x min-1; rapid-distribution clearance (Cl2) = 58 ml.kg-1 x min-1; and slow-distribution clearance (Cl3) = 26 ml.kg-1 x min-1. The inclusion of age as an additional covariate of V2 statistically improved the model, but the actual improvement in the fit was small. CONCLUSIONS: The pharmacokinetics of propofol in children are well described by a standard three-compartment pharmacokinetic model. Weight-adjusting the volumes and clearances significantly improved the accuracy of the pharmacokinetics. Adjusting the pharmacokinetics for inclusion of additional patient covariates or using a mixed-effects model did not further improve the ability of the pharmacokinetic parameters to describe the observations.

Child↗
PubMed1999

Food-induced esterase electromorphs in Carinarion spp. and their effects on taxonomic data analysis (Gastropoda, Pulmonata, Arionidae).

Nonspecific esterases (EST) are often used to measure genetic variation, yet they may be influenced by environmental factors such as food, climate and age. This may produce misleading similarity indices and genetic diversity estimates (i.e., clone or strain diversities in uniparental organisms). Therefore, polyacrylamide gel electrophoresis (PAGE) and isoelectric focusing (IEF) were used to investigate environmental effects on the EST variation in natural Carinarion populations, as well as in 45 individuals that were raised individually on carrots to produce offspring by selfing. Food effects on EST profiles in these progenies were examined by raising them on different food items (lettuce, nettle, or paper). Our results indicated that: (i) Arion (Carinarion) fasciatus and A. (C.) silvaticus show species-specific EST profiles, (ii) A. fasciatus-like outcrossers most probably are conspecific with A. fasciatus s.s., (iii) not all EST variation has a Mendelian basis since lettuce and nettle altered EST profiles, and (iv) food effects on EST profiles differed strongly between individuals. Although food-induced EST profiles did not affect taxonomic interpretations, they did inflate genetic diversity estimates and thus provided misleading population-genetic data.

Animals↗
PubMed1975

Organization of a breast tumour clinic and aspects of data analysis of a clinical material.

With the aim of making it easier for patients with tumours or suspected tumours of the breast to obtain adequate medical advice and treatment, a special breast tumour clinic was established at the Department of Surgery of the University Hospital in Uppsala for women resident in the county of Uppsala. The waiting time was less than one week. In addition to palpation, fine-needle biopsy with cytological examination, mammography and xeroradiography were performed. Close co-operation between a few doctors responsible for the various diagnostic units made it possible to give the patients quick service and contributed to an efficient use of the diagnostic resources. The clinic functioned mainly within the framework of the existing medical care facilities and did not act as a screening project. Over a period of 15 months, 1244 women were examined. 116 had breast cancer, and 5 of these tumours were occult. A comparatively low mean tumour size and a low frequency of lymph node metastases would seem to indicate that the patients came under medical care at a relatively early stage. For recording of the case histories and examination findings, special medical records permitting data processing were used. This has facilitated follow-up of the patients, special checks on certain patient groups, statistical analyses and prospective investigations. We consider that, for the patient, a clinic of this kind offers considerable psychological and financial benefits, and that for the health service as a whole it means increased efficiency and a lower cost per patient. It seems probable that both the patient's and the doctor's delay are reduced.

Adult↗
PubMed2000

Emergence of item response modeling in instrument development and data analysis.

In summary, readers are encouraged to read carefully the IRT articles in this special issue. They provide theoretical as well as practical arguments in favor of using IRT models in the health outcomes measurement field. At the same time, readers should be aware that the IRT field is complex and software is limited and, in my judgment, not very user friendly (although some packages are better than others). In addition, sample sizes will often need to be larger than in classical measurement, at least with the more general IRT models, and applications are rarely straightforward. Considerable practical experience is needed to ensure successful applications of IRT in the development and validation of instruments for health outcomes measurement.

Data Interpretation, Statistical↗
PubMed2006

Intensity range based quantitative FRET data analysis to localize protein molecules in live cell nuclei.

Förster (fluorescence) resonance energy transfer (FRET) is an ideal technique to estimate the distance between interacting protein molecules in live specimens using intensity-based microscopy. The spectral overlap of donor and acceptor- essential for FRET-also generates a contamination of the FRET signal. There are a number of algorithms available to remove this spectral bleedthrough (SBT) contamination and in this paper we compare two popular algorithms to estimate the SBT element and to calculate a more precise level of energy transfer efficiency, and with that a more accurate distance estimate.

Algorithms↗
PubMed2006

Annual prevalence of diagnosed schizophrenia in the USA: a claims data analysis approach.

BACKGROUND: Schizophrenia is a debilitating chronic mental illness. However, the annual prevalence of schizophrenia is not well understood because of under-representation of schizophrenia patients in epidemiological surveys. This study used multiple administrative claims databases to estimate the annual prevalence of diagnosed schizophrenia in the USA. METHOD: The annual prevalence of diagnosed schizophrenia in the USA was estimated for different health insurance coverage groups. The prevalence for privately insured individuals was calculated from an administrative claims database of approximately 3 million privately insured beneficiaries covering the period 1999-2003. The prevalence for Medicaid enrollees was calculated from California Medicaid claims covering the period 2000-2002. The prevalence for Medicare and Medicaid/Medicare dual eligibles was estimated using a combination of both databases. Published statistics were used to estimate the prevalence of schizophrenia in the uninsured and veteran populations and to weight the prevalence rates obtained to the population of the USA. RESULTS: The 12-month prevalence of diagnosed schizophrenia in the USA in 2002 was estimated at 5.1 per 1000 lives. The Medicaid population was identified with the highest prevalence rate among the populations studied. Sensitivity analyses taking into consideration the Veterans Affairs population only changed the estimate slightly to 5.3 per 1000 lives. CONCLUSION: Analyses of administrative claims data contribute to the understanding of the prevalence of diagnosed schizophrenia.

Adolescent↗
PubMed1995

Spatial data analysis in the quantitative assessment of cerebral white matter pathology on MRI in HIV infection.

This study was carried out using MRI (proton density--and T2-weighted) on 16 HIV-negative controls, 9 symptom-free HIV-positive patients and 25 with CDC IV HIV disease. The studies from this last group had previously been allocated by a radiologist to the following categories: 8 with focal mass lesions and normal-appearing white matter; 9 with diffuse encephalopathy (high signal on T2-weighted images, affecting most or all of the white matter) and 8 with patchy encephalopathy (high signal affecting only one or two areas within the white matter). Moran's I, a statistic of spatial autocorrelation, was calculated for the grey-scale values of a sampled pixel array from a central white matter region of each of the images. All values of Moran's I calculated in this study showed a large positive excess over the expected value under randomisation, indicating highly significant positive auto-correlation in the spatial arrangement of the grey-scale values. On T2-weighted images a statistically significant increase in the mean value of Moran's I, compared with controls, was found in the diffuse encephalopathy group, indicating that quantifiable changes in the spatial autocorrelation of pixel data can be related to recognised qualitative changes in the appearance of white matter in subjects with HIV disease. A lesser, but significant, rise in the mean value of Moran's I was also found in the focal mass lesion group, suggesting that changes in spatial autocorrelation may indicate pathological change in advance of qualitative MRI changes.

AIDS Dementia Complex↗
PubMedDate not supplied

Using situation analysis data to assess the functioning of family planning clinics in Nigeria, Tanzania, and Zimbabwe.

Situation analyses conducted in Nigeria. Tanzania, and Zimbabwe have revealed problems in the functioning of many of the subsystems of family planning service delivery, namely in supplies of commodities; in facilities and equipment; in staffing and training; in information, education, and communication; and in record keeping. Although a clear pattern of clinic use exists, in that only a few service-delivery points provide contraceptive services to the majority of new family planning acceptors in the three countries, an attempt to explain how clinics with more clients differ from those that are visited less frequently revealed only a weak association between subsystem functioning and use.

Bias↗
PubMedDate not supplied

[An evaluation of the reparative regeneration of maxillary defects based on neutron activation analysis data (experimental research)].

The major mineral components and electrolytes (K, P, Mg, Na, Cl, Mn, Fe, Co, Zn, Br, Sr) of the maxillary lamellar bone tissue and of the reparative regenerate were examined over the course of healing of maxillary nasofrontal artificial defects of various sizes (5 X 20, 7 X 20, 10 X 20 mm) perforating the nasal cavity. Check-ups carried out in 3, 4, and 8 mos after surgery have shown no osteal joining of the maxillary defect. The level of ossification by the 8th month of the follow-up, as evidenced by the content of the major osteotropic elements, just a little surpasses 50-70% of the normal value.

Animals↗
PubMed1989

Graphical and statistical approaches to data analysis for in situ hybridization.

Quantification of gene expression in a morphological context is an invaluable tool for neurobiological investigation. The ability to measure the quantity of specific mRNA molecules at the level of the single neuron permits one to monitor the modulation of complex cell synthetic activity of intact neuron populations. The cells of interest can be contiguous or dispersed in functionally significant patterns throughout a broad anatomical region of the brain. The application of quantitative in situ hybridization is technically difficult and labor intensive. Nevertheless, it has great utility for investigating gene expression from a structural perspective. (1) In situ hybridization permits one to ask questions concerning the anatomical pattern of neuronal gene expression. (2) It permits analyses concerning the initiation of expression, cell location, cell type, and alterations of level of expression within a spatial and temporal context. (3) In cases where blotting methods suggest a message exists at low copy, in situ hybridization permits queries at the single-cell level. For example, in situ hybridization can determine if very few cells are expressing the gene product or if many neurons dispersed throughout a brain region exhibit low mRNA copy number/cell. Quantitative analyses also allow detailed investigation of cell response to physiologically meaningful stimulation. Our application of statistical and numerical methods is a demonstration of the utility of probabilistic models; the mixture distribution accounted for data from both labeled and unlabeled sources. In agreement with many previous investigations, grain density over an unlabeled uniform source (oxytocinergic cells) was suitably described by the Poisson distribution. The population of labeled vasopressinergic cells, however, was best described by the negative binomial distribution. Previous investigations from different fields of biology show that the negative binomial can be used to describe many biological phenomena, and this distribution was considered in at least two previous investigations to evaluate autoradiographic data which did not fit the Poisson function. From a theoretical perspective, the probabilistic relationship between beta-particle decay (a Poisson function) and the distribution of message levels among individual neurons in a cell group (gamma distribution) prompts consideration of the negative binomial. For both data sets the observed variances were larger than the mean, and the labeled portion of the data sets exhibited positive skewness.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

DREAM: a shell-like software system for medical data analysis and decision support.

A software system was designed whose aim is to support everyday scientific research of physicians in different fields of medicine. DREAM is a shell-like tool which can be customized embedding in it the desirable structure of a particular medical problem. Various basic statistical analyses are provided along with the decision support capabilities. The decision aid is proposed in two steps--feature selection and classifier design. Genetic algorithm is implemented as the feature selection procedure. The classifier design option includes crisp and fuzzy k-Nearest Neighbors rule and a two-level classification scheme based on majority rule on the votes of several first-level k-Nearest Neighbors classifiers. The system's performance is illustrated with a database from aviation medicine.

Aerospace Medicine↗
PubMed1988

Evaluation of enzyme-linked immunosorbent assays: a method of data analysis.

Diagnostic tests are usually evaluated in terms of simple qualitative measures of sensitivity and specificity. When comparing different quantitative assays such as ELISAs, it is often more useful to deal with actual values (sample optical density/cut-off optical density ratio (OD ratio] rather than the qualitative relationship to the cut-off, i.e. positive or negative. This allows for a statistical approach to the questions of sensitivity and specificity. The National HIV Reference Laboratory of Australia has developed an approach for determining statistical estimates of sensitivity and specificity in terms of delta (delta). Delta is defined as the distance of the mean OD ratio of the sample population from the cut-off measured in standard deviation units. This paper discusses the derivation of this measurement and its usefulness when evaluating ELISA tests.

Data Interpretation, Statistical↗
PubMed2004

Virtual-SAGE: a new approach to EST data analysis.

We present a computer program, termed V-SAGE (Virtual-SAGE), designed to facilitate the analysis of gene expression profiles by combining elements of SAGE (Serial Analysis of Gene Expression) with high-throughput EST analysis. The program re-iteratively correlates sequence tags adjacent to poly(A) tail sequence strings with a second or several tags located within the cDNA adjacent to the recognition sequences of frequently-cutting endonucleases. By recording tags and their distance, the program generates an expression profile from large numbers of sequences, groups sequences according to tags, and identifies alternatively spliced transcripts as well as transcripts that are characterized by 3'-UTR sequences of different length. We discuss the application of V-SAGE to a collection of corn root segment transcripts.

Algorithms↗
PubMed1999

Crystallization and preliminary diffraction data analysis of both single and pseudo-merohedrally twinned crystals of rubredoxin oxygen oxidoreductase from Desulfovibrio gigas.

Crystals of rubredoxin oxygen oxidoreductase have been obtained and characterized. They belong to space group P2(1)2(1)2, with unit-cell dimensions a = 88.24 (15), b = 101.25 (7), c = 90.80 (3) A. The homodimer (86 kDa) in the asymmetric unit is related by a non-crystallographic twofold rotation axis parallel to the ab 'diagonal' direction, as shown by the self-rotation maximum in the section with chi = 180 degrees. This pseudo-crystallographic symmetry element was also found to be the twinning axis of pseudo-merohedrally twinned crystals, leading to apparent pseudo-tetragonal P42(1)2 crystal symmetry.

Cold Temperature↗
PubMed2004

Monocyte activation test for pro-inflammatory and pyrogenic contaminants of parenteral drugs: test design and data analysis.

An optimised test designed for an in vitro monocyte activation test for pro-inflammatory and pyrogenic contaminants of parenteral drugs is described, together with ways to address the inherent variability of such assays in which cells are cultured using 96-well plates. The test preparation is cultured with peripheral blood mononuclear cells (PBMNC) and the contaminants in the test article stimulate the release from the cells of the endogenous pyrogenic cytokine interleukin-6 (IL-6). The test system is in use within the pharmaceutical industry and at a national control authority for detecting pro-inflammatory and pyrogenic contaminants, including 'rabbit-negative' and 'LAL-negative' non-endotoxin pyrogens. Products tested include small molecules, biologicals and vaccines. The PBMNC/IL-6 monocyte activation test has been approved by the US FDA as an 'end-product release test' and also is being used for in-process testing.

Cell Culture Techniques↗
PubMed2006

Identification of PSME3 as a novel serum tumor marker for colorectal cancer by combining two-dimensional polyacrylamide gel electrophoresis with a strictly mass spectrometry-based approach for data analysis.

The purpose of this study was to identify and validate novel serological protein biomarkers of human colorectal cancer (CRC). Proteins from matched CRC and adjacent normal tissue samples were resolved by two-dimensional gel electrophoresis. From each gel all spots were excised, and enveloped proteins were identified by MS. By comparison of the resulting protein profiles, dysregulated proteins can be identified. A list of all identified proteins and validation of five exemplarily selected proteins, elevated in CRC was reported previously (Roessler, M., Rollinger, W., Palme, S., Hagmann, M. L., Berndt, P., Engel, A. M., Schneidinger, B., Pfeffer, M., Andres, H., Karl, J., Bodenmuller, H., Ruschoff, J., Henkel, T., Rohr, G., Rossol, S., Rosch, W., Langen, H., Zolg, W., and Tacke, M. (2005) Identification of nicotinamide N-methyltransferase as a novel serum tumor marker for colorectal cancer. Clin. Cancer Res. 11, 6550-6557). Here we describe identification and initial validation of another potential marker protein for CRC. Comparison of tissue protein profiles revealed strong elevation of proteasome activator complex subunit 3 (PSME3) expression in CRC tissue. This dysregulation was not detectable based on the spot pattern. The PSME3-containing spot on tumor gels showed no visible difference to the corresponding spot on matched control gels. MS analysis revealed the presence of two proteins, PSME3 and annexin 4 (ANXA4) in one and the same spot on tumor gels, whereas the matched spot contained only one protein, ANXA4, on control gels. Therefore, dysregulation of PSME3 was masked by ANXA4 and could only be recognized by MS-based analysis but not by image analysis. To validate this finding, antibody to PSME3 was developed, and up-regulation in CRC was confirmed by Western blot analysis and immunohistochemistry. Finally by developing a highly sensitive immunoassay, PSME3 could be detected in human sera and was significantly elevated in CRC patients compared with healthy donors and patients with benign bowel disease. We propose that PSME3 be considered a novel serum tumor marker for CRC that may have significance in the detection and in the management of patients with this disease. Further studies are needed to fully assess the potential clinical value of this marker candidate.

Amino Acid Sequence↗
PubMed2001

Clinical measurement, artifact, and data analysis in dioptric power space.

It appears now to be recognized that traditional clinical representations of astigmatic power, including sphere, cylinder, and axis, in particular, do not lend themselves directly to satisfactory quantitative analysis. For purposes of analysis, the clinical representations need first to be transformed into representations in dioptric power space. It turns out, however, that characteristics of the clinical measurements carried over into dioptric power space can be a source of spurious conclusions reached in such studies. The source of the problem lies in the nature of sphere, cylinder, and axis and in the discreteness (multiples of 0.25 D, usually, in sphere and cylinder and 1 or 5 degrees in axis) of the clinical measurements. As a consequence, scatter plots of clinical measurements in dioptric power space may show patterns and structures, including clusters, arcs, and moiré effects. All the structures are artifacts of the discreteness in sphere, cylinder, and axis; they have no other physical basis. Furthermore, the clinical measurements can show departures from normality that are also purely artifact. By learning to recognize artifact in the scatter plots, the researcher can overcome some of the problems. But because of the assumption of normality underlying many statistical procedures, the problem of distortions in the distributions remains. The distortions may weaken the confidence with which inferences can be made or even lead to erroneous conclusions. The purpose of this paper is to draw attention to the problems of artifact in analyses of clinical data and to suggest ways of overcoming it or avoiding it at least in part.

Artifacts↗