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PubMed2006

Unconditional analyses can increase efficiency in assessing gene-environment interaction of the case-combined-control design.

BACKGROUND: A design combining both related and unrelated controls, named the case-combined-control design, was recently proposed to increase the power for detecting gene-environment (GxE) interaction. Under a conditional analytic approach, the case-combined-control design appeared to be more efficient and feasible than a classical case-control study for detecting interaction involving rare events. METHODS: We now propose an unconditional analytic strategy to further increase the power for detecting gene-environment (GxE) interactions. This strategy allows the estimation of GxE interaction and exposure (E) main effects under certain assumptions (e.g. no correlation in E between siblings and the same exposure frequency in both control groups). Only the genetic (G) main effect cannot be estimated because it is biased. RESULTS: Using simulations, we show that unconditional logistic regression analysis is often more efficient than conditional analysis for detecting GxE interaction, particularly for a rare gene and strong effects. The unconditional analysis is also at least as efficient as the conditional analysis when the gene is common and the main and joint effects of E and G are small. CONCLUSIONS: Under the required assumptions, the unconditional analysis retains more information than does the conditional analysis for which only discordant case-control pairs are informative leading to more precise estimates of the odds ratios.

Case-Control Studies↗
PubMed2001

Variations of the asset prices.

The empirical established non-Gaussian behavior of asset price fluctuations is studied using an analytical approach. The analysis is based on a nonlinear Fokker-Planck equation with a self-organized feedback-coupling term, devised as a fundamental model for price dynamics. The evidence, and the analytical form of the memory term, are discussed in the context of statistical physics. It will be suggested that the memory term in leading order offers a power law dependence with an exponent straight theta. The stationary solution of the probability density leads asymptotically to a truncated Lévy distribution, the characteristic exponent beta of which is related to the exponent straight theta by beta=3/theta-1. The empirical data can be reproduced by theta approximately 5/4.

Journal Article↗
PubMed1985

Comparison of analytical predictions and verification flight test results for the performance of the Spacelab environmental control and life support subsystem as obtained during the 1st mission.

The environmental control and life support subsystem (ECLS) of the Spacelab module provides various functions which can be assigned to its various branches as follows: Thermal insulation from the external environment is achieved by the passive thermal control subsystem (PTCS). Rejection of the heat produced by the Spacelab subsystem equipment and by the various experiments is the task of the active thermal control subsystem (ATCS). Life support in the form of cabin air ventilation, oxygen/carbon dioxide partial pressure control; total pressure and air temperature/humidity control is achieved by the life support subsystem (LSS). In the first part of the paper a brief description of the various elements and loops forming the Spacelab ECLS will be given by discussing the PTCS, ATCS and LSS in some detail. Objective of the verification flight test program--as implied in the title already--is the verification of major requirements the ECLS has to comply with. Those requirements will then be comprehensively discussed in the second part of the paper. A description of the analytical approach is given in the third part of the paper. However, only those areas will be addressed which were included in the verification flight test program. A brief description of the flight instrumentation, the data transmission and collection follows then in the fourth part of the paper. In the fifth part of the paper the approach to select and compile flight test data obtained during the first mission (Shuttle flight STS 9) from November 28 till December 8, 1983 is illustrated. Flight test data are compared with the analytical predictions in form of examples. In the sixth and last portion of the paper the actual/measured performance is compared with the requirements, and conclusions are drawn with respect to comprehensiveness/accuracy of the flight test verification and the compliance of the Spacelab actual performance with the requirements.

Air Conditioning↗
PubMed1998

[Diagnostic use of oxygen consumption and gas exchange in exercise testing].

The interpretation of cardio-pulmonary exercise testing is usually performed on successive decisional organigrams which are based on the normality of two initial main branchpoints i.e., Vo2max and ventilatory threshold (VThr). This didactic approach leads however to a simplistic approach of exercise pathophysiology because the answer to the two original branchpoints (Vo2max and VThr) is mainly binary whereas the physiological meaning of these two parameters is multifactorial. Thus, we propose a methodic analytical approach which allows to integrate step by step the various informations concerning aerobic capacity, ventilatory and cardiocirculatory responses, and acidobasic status. After a purely descriptive analysis of data , a first synthesis describes the physiopathological behaviour during exercise and states the specificity of these informations excluding usual confounding factors. The comparison between the functional data and the clinical informations allows to propose some physiopathological hypothesis by confronting several complementary approaches: physiological, physiopathological and clinical ones. This method seems to be more adapted to the clinical diagnostic use of such a physiological investigation because it is sensitive, reproducible but not specific.

Data Interpretation, Statistical↗
PubMed2003

Alternative statistical approaches to identifying dementia in a community-dwelling sample.

Little attention has been paid to examining the extent to which alternative statistical models may facilitate identification of persons with dementia. Using a sub-sample of the Duke Established Populations for Epidemiologic Studies of the Elderly, two analytical approaches were compared: logistic regression (which focuses on identifying specific characteristics predictive here of dementia), and recursive partitioning methods using tree-based models (which permit identification of the characteristics of those groups with high dementing disorder). In the stepwise multiple logistic regression model which included as potential predictors, gender, age, history of chronic health conditions, scales of basic and instrumental activities of daily living (IADL), and cognitive status, only IADL and cognitive status were significant predictors, with cognitive status the single most important factor. The classification tree approach, which permits identification of the characteristics of those groups with particularly high dementia rates, identified cognitive status as the most important criterion for dementia (as did logistic regression analysis). Among those without cognitive impairment, older age was a risk factor, confirming findings consistently reported in the literature. Among the cognitively impaired, IADL was an important risk factor. Those with five or more IADL problems were further classified into two risk groups, based on number of ADL problems. While classification tree analysis encourages identification of groups at risk, logistic regression encourages targeting of specific characteristics.

Activities of Daily Living↗
PubMed2006

An integrated approach to identify spatiotemporal and individual-level determinants of animal home range size.

Animal home range use is a central focus of ecological research. However, how and why home range size varies between individuals is not well studied or understood for most species. We develop a hierarchical analytical approach--using generalized linear mixed-effects modeling of time series of home range sizes--that allows variance in home range size to be decomposed into components due to variation in temporal, spatial, and individual-level processes, also facilitating intra- and interspecific comparative analyses. We applied the approach to data from a roe deer population radiotracked in central Italy. Over multiple timescales, temporal variation is explained by photoperiod and climate and spatial variation by the distribution of habitat types and spatial variance in radiotracking error. Differences between individuals explained a substantial amount of variance in home range size, but only a relatively minor part was explained by the individual attributes of sex and age. We conclude that the choice of temporal scale at which data are collected and the definition of home range can significantly influence biological inference. We suggest that the appropriate choice of scale and definition requires a good understanding of the ecology and life history of the study species. Our findings contrast with several common assumptions about roe deer behavior.

Age Factors↗
PubMed1975

An epidemiological model of the natural history of a disease within a multilevel care system.

Detailed epidemiological data on the entire course and treatment of illnesses requiring a variety of forms of management and various levels of institutionalization are scarce, probably due to the difficulty of assembling such data from a multiplicity of sources, particularly within complex and fragmented health care delivery systems. This paper described several analytic approaches to, and applications of, such a body of data, taken from a retrospective cohort study of 552 fractured hip cases incident in one year in an upstate New York county. Examples of six analytic applications of the data are presented, and emphasis is placed on the potential for practical use of some of the results.

Adolescent↗
PubMed1996

Information theoretic analysis of dynamical encoding by four identified primary sensory interneurons in the cricket cercal system.

1. The stimulus/response properties of four identified primary sensory interneurons in the cricket cercal sensory system were studied using electrophysiological techniques. These four cells are thought to represent a functionally discrete subunit of the cercal system: they are the only cells that encode information about stimulus direction to higher centers for low intensity stimuli. Previous studies characterized the quantity of information encoded by these cells about the direction of air currents in the horizontal plane. In the experiments reported here, we characterized the quantity and quality of information encoded in the cells' elicited responses about the dynamics of air current waveforms presented at their optimal stimulus directions. The total sample set included 22 cells. 2. This characterization was achieved by determining the cells' frequency sensitivities and encoding accuracy using the methods of stochastic systems analysis and information theory. The specific approach used for the analysis was the "stimulus reconstruction" technique in which a functional expansion was derived to transform the observed spike train responses into the optimal estimate (i.e., "reconstruction") of the actual stimulus. A novel derivation of the crucial equations is presented. The reverse approach is compared with the more traditional forward analysis, in which an expansion is derived that transforms the stimulus to a prediction of the spike train response. Important aspects of the application of these analytical approaches are considered. 3. All four interneurons were found to have identical frequency tuning, as assessed by the accuracy with which different frequency components of stimulus waveforms could be reconstructed with a linear expansion. The interneurons encoded significant information about stimulus frequencies between 5 and 80 Hz, which peak sensitivities at approximately 15 Hz. 4. All four interneurons were found to have identical stimulus/response latencies. The mean latency between a stimulus component and the corresponding elicited spike was 17 ms. All four interneurons also had identical integration times. The integration time, measured by the duration of stimulus, which could affect the probability of spiking, was approximately 50 ms. 5. The accuracy of the encoding can be expressed as a signal-to-noise ratio, where the noise is a scaled difference between the original signal and the best estimate of the signal. Peak signal-to-noise ratios of approximately 1 were obtained for the cells across all stimulus power levels, using only the linear expansion term. Analysis of the data indicated that the consideration of second-order nonlinear transformations of the stimulus would not have increased the calculated encoding accuracy. 6. The encoding accuracy also can be expressed in the information theoretic units of bits/second, which characterizes the information transmission rate of the cell. Bits/second values varied between 10 and 80 for the 22 different cells in our experimental set. The information rate values were highly correlated with the mean spike rates of the interneurons, but were not correlated with the stimulus power levels. However, normalizing the absolute information rates by the mean spike rate in each case yielded a measure of bits/spike that was remarkably invariant across all experiments. The measured bits/spike rate was approximately 1 for all experiments. This result is discussed in the context of recent theoretical studies on optimal encoding. 7. Although the dynamic sensitivities of the four interneurons were identical, their directional sensitivities are known to be orthogonal. Thus the cells are complementary to one another from a functional standpoint: whereas a particular cell will be insensitive to air currents from some directions, one or more of the other three cells will be sensitive to stimuli from those directions...

Action Potentials↗
PubMed2000

[Evaluation of professional practices].

Concepts and methods in professional practices evaluation are often confused. After a description of the classical conceptual framework, we present these methods in an approach in which practice is the principal result to be measured. Thus it makes it possible to apply the traditional epidemiological concepts to the evaluation of the professional practices with their three traditional fields: 1) In the descriptive approach, cross-sectional practice studies allow an observation and description of the usual behaviors, possibly compared to references. The methodological constraints are the same as which of descriptive epidemiological studies; 2) In the analytical approach, factors associated with practice - simple or conformed to criteria - are evidenced on a representative sample; 3) In the evaluative approach of practices improvement, the objectives are the assessment of formative, organizational or structural interventions, aiming at modifying practices. Three types of studies are to be used: quasi experimental in which clinical audit is the reference method in the field of medical care. The six main steps of clinical audit are described; experimental, based on the community randomized trial scheme, which have the advantage to provide results that can be immediately generalized; observational in which no control on the implementation of intervention is done. "Here and else" and "before and after" studies are used. To be effective for evaluation of professional practice, theses methods must come within the scope of a favorable institutional context.

Epidemiologic Methods↗
PubMed2002

Independent component analysis of fMRI data in the complex domain.

In BOLD fMRI a series of MR images is acquired and examined for task-related amplitude changes. These functional changes are small, so it is important to maximize detection efficiency. Virtually all fMRI processing strategies utilize magnitude information and ignore the phase, resulting in an unnecessary loss of efficiency. As the optimum way to model the phase information is not clear, a flexible modeling technique is useful. To analyze complex data sets, independent component analysis (ICA), a data-driven approach, is proposed. In ICA, the data are modeled as spatially independent components multiplied by their respective time-courses. There are thus three possible approaches: 1) the time-courses can be complex-valued, 2) the images can be complex-valued, or 3) both the time-courses and the images can be complex-valued. These analytic approaches are applied to data from a visual stimulation paradigm, and results from three complex analysis models are presented and compared with magnitude-only results. Using the criterion of the number of contiguous activated voxels at a given threshold, an average of 12-23% more voxels are detected by complex-valued ICA estimation at a threshold of /Z/ > 2.5. Additionally, preliminary results from the complex models reveal a phase modulation similar to the magnitude time-course in some voxels, and oppositely modulated in other voxels.

Brain↗
PubMed2006

Analysis of Amaryllidaceae alkaloids from Narcissus by GC-MS and capillary electrophoresis.

Amaryllidaceae are known as ornamental plants, furthermore some species of this family contain galanthamine, an acetylcholinesterase inhibitor approved for the treatment of Alzheimer's disease, and other alkaloids with interesting pharmacological activity. In the present work, the quali- and quantitative analysis of Amaryllidaceae-type alkaloids in the bulbs of Narcissus species is presented using different analytical approaches. Extracts of Narcissus pseudonarcissus cv. Carlton and Narcissus jonquilla Quail, were first examined by GC-MS using a Rtx-5 MS (programmed temperature) and the major alkaloids were identified. Together with galanthamine, high contents of haemanthamine, were found. Galanthamine was reliably quantified by GC-MS, whereas haemanthamine partly decomposed under the GC conditions, thus alternative analytical methods were investigated. Firstly, reversed-phase HPLC-ESI-MS was applied to identify and isolate at semipreparative levels haemanthamine. The compound was fully characterized by MS/MS and (1)H NMR and then used as a reference substance. The quantitation of both galanthamine and haemanthamine was then accomplished by capillary electrophoresis with spectrophotometric detection. A non-aqueous (NACE) approach was selected in order to use a running buffer fully compatible with samples in organic solvent. In particular, a mixture methanol-acetonitrile (75:25, v/v) containing ammonium acetate (90 mM) was used as a background electrolyte. The same analytical sample was subjected to GC-MS and NACE analysis; the different selectivity displayed by these techniques allowed different separation profiles that can be useful in phytochemical characterization of the extracts. The GC-MS and NACE methods were validated and applied to the quantitation of galanthamine (GC-MS and NACE) and haemanthamine (NACE) in bulbs of N. jonquilla.

Amaryllidaceae Alkaloids↗
PubMed2002

Different lenses, improved outcomes: a new approach to the analysis and design of healthcare information systems.

Healthcare systems are complex sociotechnical systems in which many information system innovations fail because of problems in planning or design. One of the reasons for this is that traditional analysis methods were designed for stable, relatively simple systems and single users. New analytical approaches are needed that can encompass the complexity of changing systems and multiple, interacting users. The author suggests that integrating two seemingly disparate approaches may be helpful in achieving successful designs for the complexities of healthcare systems. The first is derived from Carper's four ways of knowing; the second is Cognitive Work Analysis (CWA). The utility of the approach is demonstrated via a case study.

Hemodynamics↗
PubMed1999

Recommended approaches for the laboratory measurement of homocysteine in the diagnosis and monitoring of patients with hyperhomocysteinaemia.

Several recent studies have indicated that an increased concentration of plasma homocysteine is an independent risk factor for the premature development of vascular disease. These important findings emphasize the need for careful selection of an appropriate analytical approach to diagnose and treat individuals who may be at risk. We compared the results obtained from the measurement of plasma total homocysteine (free + protein-bound fractions) by high-performance liquid chromatography (HPLC) with the measurement of plasma free homocystine (free fraction) by conventional ion-exchange chromatography in 10 patients with inherited defects of homocysteine metabolism and 13 obligate heterozygote individuals. This study can be used to formulate recommendations on the appropriate use of these assays in different clinical circumstances. Our results show that the concentration of total plasma homocysteine must exceed 60 mumol/L before plasma free homocystine becomes detectable by conventional ion-exchange chromatography. Similarly, assessment of the urinary excretion of homocysteine in these patients indicates that it may not become consistently detectable by conventional ion-exchange chromatography or HPLC until plasma total homocysteine exceeds 150 mumol/L. On this basis, while most patients with classical homocystinuria would be detected by analysis of plasma using conventional ion-exchange chromatography or by measurement of of the urinary homocysteine excretion, occasional patients would be missed. When monitoring patients receiving treatment for classical homocystinuria, in whom metabolic control is good, and when investigating individuals with a suspected inherited defect of cobalamin or folate metabolism, a method which measures plasma total homocysteine should be used. The identification of moderate hyperhomocysteinaemia of undefined cause investigated in relation to a history of early vacsular disease can only be identified by this approach.

Adolescent↗
PubMed1992

Measurement of muscle protein fractional synthetic rate by capillary gas chromatography/combustion isotope ratio mass spectrometry.

The measurement of skeletal muscle protein fractional synthetic rate using an infusion of (1-13C)leucine and measuring the isotopic abundance of the tracer in skeletal muscle protein by preparative gas chromatography (GC)/ninhydrin isotope ratio mass spectrometry (IRMS) is laborious and subject to errors owing to contamination by 12C. The purpose of this study was to compare muscle (13C)leucine enrichment measured with the conventional preparative GC/ninhydrin IRMS approach to a new, continuous-flow technique using capillary GC/combustion IRMS. Quadriceps muscles were removed from four Sprague-Dawley rats after each was infused at a different rate with (1-13C)leucine for 6-8 h. Muscle leucine enrichment (at. % excess) measured by both methods differed by less than 4%, except at low (13C)leucine enrichments (less than 0.03 at. % excess). In addition, capillary GC/combustion IRMS was used to assess muscle (13C)leucine enrichment and fractional muscle protein synthesis rate in ten normal young men and women infused with (1,2-13C2)leucine for 12-14 h. This approach reduced the variability of the isotope abundance measure and gave estimates of muscle protein synthesis rate (0.050 +/- 0.011% h-1 (mean +/- SEM); range = 0.023-0.147% h-1) that agree with published values determined using the standard analytical approach. The measurement of (13C)leucine enrichment from skeletal muscle protein by capillary GC/combustion IRMS provides a simple, acceptable and practical alternative to preparative GC/ninhydrin IRMS.

Adult↗
PubMed2002

Assessment of hair loss: clinical relevance of hair growth evaluation methods.

This review on hair growth measurement methods focuses on human scalp hair in the context of clinically relevant assessment of hair loss. This phenomenon is the end result of a complex combination of events closely associated with hair cycling followed by defective hair replacement. The methodological spectrum ranges from the most to the least invasive approach. All of the measurement methods referred to are critically reviewed, with their stronger and weaker aspects, in view of their potential application in the skin and hair clinic. The existence of recently developed highly resolutive noninvasive analytical methods capable of exploring almost every aspect of the dynamics of this growth and loss phenomenon allowed calibration of more global scoring method. From this review, the author concludes that a combination of a highly resolutive analytical approach with a global calibrated method seems advisable in the context of the monitoring of hair growth changes for better or worse, i.e. scalp hair growth or hair loss in the hair clinic.

Alopecia↗
PubMed1996

Direct identification of naturally processed autoantigen-derived peptides bound to HLA-DR15.

Biochemical analysis of HLA class II-associated peptides from antigen-pulsed cells is a potentially useful approach to the analysis of antigen processing and presentation because it examines directly which antigen-derived peptides are presented. This is especially advantageous in the analysis of self-antigen presentation where conventional approaches utilizing antigen-specific T cells may be biased by the presence of self-tolerance. However, successful biochemical analysis has been reported for only one exogenous antigen and no autoantigens. We have used a novel analytical approach coupling biochemical data with the reported properties of class II-associated peptides to characterize the peptides derived from a clinically relevant autoantigen presented on the disease-associated class II type. Incubating the target of autoimmune attack in patients with Goodpasture's disease, the 230-amino acid NC1 domain of the alpha3 chain of type IV collagen (Goodpasture antigen, alpha3(IV)NC1), with human B cells homozygous for HLA-DR15, the allele carried by 80% of patients, we find that alpha3(IV)NC1 is presented as at least two sets of three to five peptides centered on common core sequences (nested sets). Synthetic peptides containing these core sequences bind to HLA-DR15 with intermediate affinity (IC50, 1.1-6 microM).

Amino Acid Sequence↗
PubMed2004

An integrated approach to the meta-analysis of genetic association studies using Mendelian randomization.

A natural randomization process, sometimes called Mendelian randomization, occurs at conception to determine a person's genotype. By combining information from genotype-disease and genotype-phenotype studies, it is possible to use this Mendelian randomization to derive an estimate of the association between phenotype (risk factor) and disease that is free of the confounding and reverse causation typical of classical epidemiology. When one is synthesizing evidence, studies evaluating genotype-phenotype associations, studies evaluating genotype-disease associations, and studies evaluating both are encountered, and methods should be used that allow for this structure. Plotting the log odds ratio of genotype-disease against the mean genotype-phenotype difference may help investigators detect departures from the assumptions underlying Mendelian randomization. Testing for differences between studies reporting on only the genotype-phenotype or genotype-disease association and those reporting on both associations may help in detecting reporting bias. This integrated approach to the meta-analysis of genotype-phenotype and genotype-disease studies is illustrated here using the example of the methylenetetrahydrofolate reductase (MTHFR) gene, homocysteine level, and coronary heart disease. An integrated meta-analytical approach may increase the precision of this estimate and provide information on the assumptions underlying Mendelian randomization. Serious biases may arise if the assumptions behind the analysis based on Mendelian randomization are not met.

Confidence Intervals↗
PubMed1997

p53 and K-ras mutational genotyping in pulmonary carcinosarcoma, spindle cell carcinoma, and pulmonary blastoma: implications for histogenesis.

In an attempt to understand the molecular pathogenesis of biphasic pulmonary neoplasms, the authors studied 25 cases of carcinosarcoma, spindle cell carcinoma, and pulmonary blastoma using a combined immunohistochemical and topographic genotyping approach for the presence of p53 abnormalities within the different epithelial and mesenchymal components of these tumors. Genotyping involved a search for point mutational damage in p53 exons 5-8, which was correlated with p53 immunoreactivity. This analytical approach demonstrated p53 missense point mutations in four of nine cases of spindle cell carcinoma with a 100% concordance rate between p53 immunopositivity and the presence of DNA mutational damage. One of six carcinosarcomas, heterologous in type, exhibited a p53 mutation. The concordance rate among carcinosarcomas was also 100%. However, the concordance rate among classic biphasic pulmonary blastomas was only 43%, with one of seven cases demonstrating a p53 mutation by DNA genotyping. The lack of concordance in pulmonary blastomas was possibly due to the existence of genotypically distinct subsets of tumor cells likely bearing mutations among largely nonmutated cells. In a similar fashion, among three well-differentiated fetal type adenocarcinomas, no p53 mutations were detected despite the presence of focal p53 immunopositivity in one of the cases. No K-ras mutations were detected in any of the 25 tumors examined. Monoclonal histogenesis from a single totipotential cell in a subset of these neoplasms (six of 22 cases) was supported by the finding of p53 overexpression and identical p53 mutational genotype in both the epithelial and spindle elements of the tumors. Furthermore, the finding of a small percentage of p53-positive tumor cells within one or both components suggests late acquisition of p53 mutational change in a subset of pulmonary blastomas.

Aged↗