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At least 127 records · Page 7Linked to original sources
PubMed1995

Analytical approaches relating genetic evolutionary pathways to prognostic factors.

Human solid tumors accumulate multiple genetic abnormalities as they progress to advanced stages. Multiparameter flow cytometry measurements of individual cells within each tumor may be useful in describing the genetic pathways taken by individual tumors during the course of their genetic evolution. In this paper, we analyzed correlated cell-by-cell measurements of cell DNA content, HER-2/neu protein content, and ras protein content obtained by multiparameter flow cytometry studies of primary breast cancers from 92 patients. These laboratory findings were correlated with established clinical prognostic factors for each patient at the time of diagnosis, using a stepwise multiple analysis of variance (MANOVA). The stepwise MANOVA successively splits a group of patients into two mutually exclusive dissimilar groups, selecting the clinical prognostic factor that is most effective in doing so. Using this criterion, formation of the first three groups that were judged most dissimilar on the cytometry parameters was based on the number of positive nodes at the time of diagnosis. We show that ploidy, HER-2/neu protein content, and ras protein content, as measured by multiple parameter flow cytometry, are correlated with nodal status and other known clinical prognostic factors. The cell-by-cell multiparameter data suggest that for some individual tumors there are multiple genetic evolutionary pathways. Multiple genetic evolutionary pathways are also suggested by the MANOVA analysis. Focusing on the identification and analysis of genetic evolutionary pathways within individual tumors and across patients appears to offer a promising approach for defining the prognosis of early cancers.

Aged↗
PubMed1999

Expression of delta F508 cystic fibrosis transmembrane conductance regulator protein and related chloride transport properties in the gallbladder epithelium from cystic fibrosis patients.

Cystic fibrosis transmembrane conductance regulator (CFTR), the cystic fibrosis (CF) gene product, functions as an adenosine 3', 5'-cyclic monophosphate (cAMP)-regulated chloride channel in the apical membrane of biliary epithelial cells, including gallbladder epithelial cells. It has been shown that triangle upF508, the most common CF mutation, impedes CFTR trafficking to the apical surface of epithelial cells. To elucidate the mechanisms of CF biliary disease, we examined structural features, CFTR expression, and chloride transport properties in gallbladder epithelial cells from nine triangle upF508 homozygous liver transplant recipients. Three CF patients had microgallbladders, characterized by severe histological abnormalities. Microgallbladder epithelial cells displayed aberrant immunolocalization of CFTR and of other normally apical proteins in the lateral domain of their plasma membrane and in their cytoplasm. This pattern was mimicked by chronic cholecystitis in non-CF patients. In the 6 remaining CF patients, CFTR was predominantly apical in the gallbladder epithelium, consistent with the detection of a fully glycosylated form by Western blot. In CF as compared with non-CF gallbladder epithelial cells in primary culture, chloride efflux was lower in response to cAMP and tended to be higher in response to exogenous adenosine 5'-triphosphate (ATP). The CF cells exhibited a residual cAMP-dependent chloride secretion that was inversely correlated with ATP-induced chloride secretion, and almost completely blunted in the cells derived from microgallbladders. Our results suggest that epithelial structural alterations aggravate triangle upF508 CFTR mislocalization in the gallbladder epithelium. The associated decrease in residual cAMP-dependent chloride secretion may contribute to biliary damage despite the up-regulation of alternative chloride transport pathways.

Adolescent↗
PubMedDate not supplied

An analytic approach to quantifying pain scores.

Statistical problems in clinical trials frequently involve fitting regression lines when the underlying data are categorical or ordinal response variables. Usually an ad hoc a priori quantification is used to assign values to these ordinal responses. For pain intensity data collected in analgesic trials, the usual approach is to set none equal to 0, mild equal to 1, moderate equal to 2, and severe equal to 3. While this scheme has been generally accepted, on the basis that for similar clinical trials reasonably similar results are obtained by different investigators, concern exists that the distances between pain scores are probably not equal. A method is presented for quantifying categorical responses so that the resulting scores maximize the simultaneous fit of the dose-response regression lines. The optimal scores derived by this technique may then be used in a bioassay analysis to estimate the relative potency of 2 compounds. As illustrative examples, this method was applied to data from 2 clinical trials and the results were compared to the usual method.

Analysis of Variance↗
PubMed2002

(2)H- and (13)C-labelled tracers compared for kinetic studies of ascorbic acid metabolism in man: a factor analytical approach.

A recent report that a (13)C stable isotope method can be used to measure the kinetics of ascorbic acid uptake and distribution in man has raised some interesting questions with regard to the physiological interpretation of the data obtained, in particular the sizes of the ascorbate distribution spaces. In order to prove that this result is not a function of the label used we have compared the behaviour of two different tracers to see if they are likely to give comparable results for the kinetic parameters. Volunteers received an oral dose of ascorbic acid, half of which was labelled with (2)H, and half of which was labelled with (13)C. Blood samples were taken over the course of the next 48 h, and ascorbic acid mass spectra measured by gas chromatography/mass spectrometry (GC/MS). Principal component analysis was used to investigate the number of factors required to explain the total variations observed in the ratios of the molecular isotopomer cluster over the time course of the experiment. Theoretical cracking patterns were then used as test vectors in target transformation and as the basis for subsequent combination to determine tracer/tracee ratios. Two factors were found sufficient to account for the observed cracking pattern variations within experimental error. These were identified as (1) the spectrum of unlabelled (endogenous) ascorbic acid, and (2) a linear combination of the spectra of the two labelled species used. The absence of a third factor in the decomposition indicates that there is no difference in the behaviour of the (13)C- and (2)H-labelled tracers. Target testing allowed the tracer/tracee ratios to be determined using calculated cracking patterns, and produced equivalent results to conventional methods. Our experience in this work indicates that factor analysis has a useful place in many kinetic studies of this kind, either with one or many labelled species.

Administration, Oral↗
PubMed1993

Combining independent studies of a diagnostic test into a summary ROC curve: data-analytic approaches and some additional considerations.

We consider how to combine several independent studies of the same diagnostic test, where each study reports an estimated false positive rate (FPR) and an estimated true positive rate (TPR). We propose constructing a summary receiver operating characteristic (ROC) curve by the following steps. (i) Convert each FPR to its logistic transform U and each TPR to its logistic transform V after increasing each observed frequency by adding 1/2. (ii) For each study calculate D = V - U, which is the log odds ratio of TPR and FPR, and S = V + U, an implied function of test threshold; then plot each study's point (Si, Di). (iii) Fit a robust-resistant regression line to these points (or an equally weighted least-squares regression line), with V - U as the dependent variable. (iv) Back-transform the line to ROC space. To avoid model-dependent extrapolation from irrelevant regions of ROC space we propose defining a priori a value of FPR so large that the test simply would not be used at that FPR, and a value of TPR so low that the test would not be used at that TPR. Then (a) only data points lying in the thus defined north-west rectangle of the unit square are used in the data analysis, and (b) the estimated summary ROC is depicted only within that subregion of the unit square. We illustrate the methods using simulated and real data sets, and we point to ways of comparing different tests and of taking into account the effects of covariates.

Carcinoma, Non-Small-Cell Lung↗
PubMedDate not supplied

A data-analytic approach for estimating lead time and screening benefit based on survival curves in randomized cancer screening trials.

Screening tests are used frequently for control of diseases such as cancer. The increased survival time of screen-detected cases over those that are detected clinically may be due in part to 'lead time', or the length of time by which the disease is diagnosed earlier by screening in the presence or absence of any real extension in survival time. A realistic evaluation of screening needs to assess the true benefit of screening; that is, the length of time by which survival has been extended, beyond merely the time of the advanced diagnosis. The comparison of survival measured from time of entry between cases in a screening arm and in a control arm in randomized studies avoids the lead time bias. If the effects of average lead time and average benefit on survival are additive, these effects can be estimated by recognizing that (a) the difference in survival curves since time of diagnosis confounds benefit and lead time, but (b) the difference in survival curves since time of start of study involves benefit only. The method is evaluated on simulated data for its accuracy and may be used on data from randomized studies.

Bias↗
PubMed1985

Evoked potential latencies as a function of contrast: a system analytical approach.

That the latency of the pattern evoked potential (EP) increases as the stimulus contrast decreases can be understood as the result of, first, a low-pass filtering process of the (contrast) signal followed by, second, and nonlinear 'threshold' stage. We show here that by using this simple concept it is possible to estimate the shape of the 'unit step' response of the low-pass filter with the latency vs. contrast data. We show also that the step responses calculated from several subjects are in reasonable agreement if they are normalized with using the subjects' own contrast thresholds. Within experimental error, the response of a filter consisting of four low-pass first-order stages with a 10.5 Hz cut-off frequency gives a reasonable fit to our own data and to that of one other study (Musselwhite and Jeffreys, 1982).

Differential Threshold↗
PubMed1993

Biological monitoring of acrylonitrile exposure through a new analytical approach to hemoglobin and plasma protein adducts and urinary metabolites in rats and humans.

A new, simple and fast procedure of measuring acrylonitrile (ACN) in ACN derived mercapturic acids such as S-(2-cyanoethyl)-L-cysteine(CyEC), and in hemoglobin (Hb) and plasma protein adducts and urinary metabolites in rats and humans exposed to ACN was developed. ACN in mercapturic acids or proteins was analyzed by capillary gas chromatography (GC) by liberating ACN at a high-temperature in the injector port of GC with or without oxidizing sulfur atoms of the ACN-bound cysteines into sulfoxide form by hydrogen peroxide in vitro. At 350 degrees C, more than 90% of ACN in authentic CyEC was recovered by this method. Increasing a single ip dose of ACN from 5 to 50 mg/kg produced proportional increases in ACN bound to Hb 24 hr after the treatment. The alkylation of plasma protein with ACN was about 1/10 as low as that of Hb. After repeated daily ip doses of 1-10 mg/kg, ACN in Hb decreased with a half-life of about 9 days. ACN was also detected in the blood of workers exposed to ACN for 1 to 10 years at a Siberian synthetic rubber factory.

Acetylcysteine↗
PubMed1992

Life-style and substance use among male African-American urban adolescents: a cluster analytic approach.

Cluster analyzed four variables: school attendance, employment, church attendance, and delinquency, to develop life-style profiles. Data from 218 African-American urban adolescents were used in the study. Five meaningful clusters were retained and subjected to criterion validity analyses using measures of spirituality, participation in a voluntary organization, self-esteem, and friend's substance use. The five clusters were then compared on cigarette, alcohol, marijuana, and hard drug use. The results suggest that a life-style that includes an adaptive compensatory behavior component may be more adaptive than a life-style that does not include compensatory behavior. For example, youths who left high school before graduation but were involved in church reported less alcohol and substance use than youths who left school and were not involved in any meaningful instrumental activity. Implications for intervention and future research on high-risk behaviors are discussed.

Adolescent↗
PubMed1990

Heart rate variability in diabetic patients during orthostatic load--a spectral analytic approach.

Spectral analysis of heart rate variability (HRV) was used to assess the autonomic nervous control of cardiac function during orthostatic load in insulin-dependent diabetic patients and healthy subjects. The diabetic patients were divided into three groups: diabetics without neuropathy (group 1), diabetics with peripheral neuropathy (group 2), and diabetics with peripheral and autonomic neuropathy (group 3). Resting mid-frequency (MF, 0.05-0.15 Hz) and respiration-related (RF, power around respiration rate) HRV were significantly lower in group 2 and 3 diabetics than in controls, indicating a reduced parasympathetic nervous system influence on the heart. Standing MF and RF spectral power data were significantly lower in all diabetic groups than in controls, suggesting marked alterations in the autonomic cardiovascular control during a mild physical load not only in symptomatic diabetics but also in patients with no signs and symptoms of neuropathy. The difference between supine and standing MF power, an estimate of beta-adrenergic influence on the heart, was significantly lower in all diabetic subject groups studied than in controls. This suggests a reduced sympathetic nervous system influence on the heart in diabetic patients. Our data suggest that computerized spectral analysis of HRV during orthostatic load seems to be a very sensitive method of evaluating of the autonomic nervous systems influence on the heart in patients suffering from diabetes mellitus.

Adult↗
PubMedDate not supplied

Analytical approach to mathematical modelling of the isometric contraction of the hypertrophied myocardium.

It is attempted on the basis of the Hill two-element model to simulate mathematically the rising phase of the isometric mechanogram in the pressure-hypertrophied rat myocardium (Goldblatt II). The evaluation is based on the experimentally determined force-velocity relation as well as on the characteristic of the series-elastic stiffness. The changes in the isometric mechanogram of the hypertrophied heart muscle observed in the experiment can be mathematically predicted solely by means of the alterations in the force-velocity relationships induced by the hypertrophy, whereby the characteristic of the series-elastic stiffness is considered to be unchanged.

Cardiomegaly↗
PubMed1995

A path-analytical approach to differentiate between direct and indirect drug effects on negative symptoms in schizophrenic patients. A re-evaluation of the North American risperidone study.

The hypothesis that differences in drug effects of risperidone and haloperidol on negative symptoms in schizophrenia are secondary to effects on positive, extrapyramidal, and depressive symptoms was investigated by means of an analysis of the data from the USA-Canada risperidone double-blind randomized clinical trial of 523 chronic schizophrenic patients. Regression analyses in the total sample and within treatment groups confirmed a strong relationship between changes in negative symptoms and the other variables studied (R2 = 0.50-0.51, p < 0.001). Only depressive symptoms did not contribute significantly to these results (p > 0.10). Path analysis showed that the greater mean change (p < 0.05) of negative symptoms with risperidone compared to haloperidol could not be fully explained by correlations with favourable effects on positive and extrapyramidal symptoms. The relationship between shift in extrapyramidal symptoms and shift in negative symptoms failed to reach statistical significance; however, there was a clear tendency in the expected direction in both treatment groups.

Antipsychotic Agents↗