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PubMed1998

Model-based, goal-oriented, individualised drug therapy. Linkage of population modelling, new 'multiple model' dosage design, bayesian feedback and individualised target goals.

This article examines the use of population pharmacokinetic models to store experiences about drugs in patients and to apply that experience to the care of new patients. Population models are the Bayesian prior. For truly individualised therapy, it is necessary first to select a specific target goal, such as a desired serum or peripheral compartment concentration, and then to develop the dosage regimen individualised to best hit that target in that patient. One must monitor the behaviour of the drug by measuring serum concentrations or other responses, hopefully obtained at optimally chosen times, not only to see the raw results, but to also make an individualised (Bayesian posterior) model of how the drug is behaving in that patient. Only then can one see the relationship between the dose and the absorption, distribution, effect and elimination of the drug, and the patient's clinical sensitivity to it; one must always look at the patient. Only by looking at both the patient and the model can it be judged whether the target goal was correct or needs to be changed. The adjusted dosage regimen is again developed to hit that target most precisely starting with the very next dose, not just for some future steady state. Nonparametric population models have discrete, not continuous, parameter distributions. These lead naturally into the multiple model method of dosage design, specifically to hit a desired target with the greatest possible precision for whatever past experience and present data are available on that drug--a new feature for this goal-oriented, model-based, individualised drug therapy. As clinical versions of this new approach become available from several centers, it should lead to further improvements in patient care, especially for bacterial and viral infections, cardiovascular therapy, and cancer and transplant situations.

Anti-Arrhythmia Agents↗

PubMed1998

Ethylene oxide-protein adduct formation in humans: influence of glutathione-S-transferase polymorphisms.

OBJECTIVE: The influence of the polymorphic human glutathione-S-transferase (GST) T1 and M1 genotypes (classified as "conjugators" and "nonconjugators") on the biological effects of nonoccupational ethylene oxide exposure as reflected by the formation of globin N2-hydroxyethylvaline adducts was investigated. Specific attention was paid to smoking as a potential source of exposure. A total of 27 Caucasian subjects, including 10 women and 17 men, participated in the study. Volunteers were grouped as smokers, i.e., 6 subjects (5 male, 1 female), and nonsmokers, i.e., 21 subjects (12 male, 9 female). The regular cigarette consumption in the smoker group ranged from 10 to 25 cigarettes/day. METHODS: The amount of N2-hydroxyethylvaline (HEV) bound to the N-terminal valine in human globin was determined following a procedure described by Bader and co-workers and the Deutsche Forschungsgemeinschaft. The GST genotypes were determined by a polymerase chain reaction (PCR) analysis outlined by Bell and colleagues (with beta-globin serving as an internal standard) and Kempkes and co-workers (coamplification of the GSTT1 fragment). RESULTS: The median level of HEV detected in the smoker group was 280 pmol/g globin as compared with the median value of 50 pmol/g globin recorded for the nonsmokers, indicating that ethylene oxide intake from cigarettes may result in a approximately 5-fold higher overall HEV level in smokers in comparison with nonsmoking individuals. No dose-effect correlation was observed between daily cigarette consumption and the resulting HEV levels. Moreover, the individual GSTT1 or GSTM1 genotype did not influence the HEV level in smokers. The subgroup of nonsmoking GSTT1 conjugators revealed a median HEV value of 46 pmol/g globin as compared with the median value of 92 pmol/g globin found in the nonconjugator subgroup. Subjects with the GSTM1 gene had a median HEV value of 55 pmol/g globin, whereas subjects with the gene deletion had a median HEV value of 44 pmol/g globin. The 2-fold increase in the median HEV value detected in GSTT1 non-conjugators as compared with GSTTI conjugators indicates an influence of GSTT1 on the globin HEV levels. This hypothesis was found to be significant in the nonparametric Mann-Whitney U-test for independent samples (P < 0.002, two-sided). The same test was applied to evaluate the influence of GSTM1 on the globin HEV levels. No significant influence was observed (P > 0.10; two-sided). CONCLUSIONS: This result is in accordance with the finding that ethylene oxide is a substrate for GSTT1 but not for GSTM1. In addition, this study demonstrates a clear influence of genetically determined GSTT1 status on biological effects, e.g., protein adduct formation after non-occupational ethylene oxide exposure. In smokers, however, a modulating influence of GSTT1 status was not observed.

Case-Control Studies↗

PubMed2002

Projection pursuit nonparametric regression applied to field counts of the aphid Macrosiphum euphorbiae (Homoptera: Aphididae) on tomato crops in greenhouses.

The number of plants that sampling requires in aphid population studies often exceeds one hundred. Thus, only quick and nondestructive methods can be used to sample this pest in a reasonable time interval. We propose a visual method for estimating the density of the aphid Macrosiphum euphorbiae (Thomas) on tomato plants reared in greenhouses. After approximately 1min of visual observation plants can be assigned to abundance classes, the boundaries of which are roughly the powers of square root 10. Precise counts were collected simultaneously on sets of reference plants from the same greenhouse. Projection pursuit nonparametric regression was then used to provide unbiased estimates of aphid densities from the abundance classes and several easily gathered explanatory variables. The robustness of the method was evaluated by testing the models on the complementary data sets from plants in which the aphid densities were precisely counted. In both single and twin-row cultural conditions, for the reference and complementary data sets, the order of magnitude of the error was less than one class rank per plant. The investigation time was reduced by approximately 10-fold compared with the exact counting method. This easy-to-teach field method could be useful in large-scale population surveys and for optimizing integrated pest management strategies.

Animals↗

PubMed1998

Time series analysis of Aplysia total motion activity.

We rely on various nonparametric time series techniques to quantify several autocorrelated Aplysia total motion activity series. The effect of light on total motion activity has been removed. A general model will be proposed for total motion activity, which is found to display a circadian rhythm, and the toxic effect of PCBs on total motion activity will be assessed. No underlying assumptions are made about the form of the circadian rhythm. Several types of circadian total motion activity patterns are discovered. We form the hypothesis that different data series may be separated into three distinct groups of common patterns of circadian total motion activity. We also investigate if in fact only a single innate oscillator regulates total motion activity.

Animals↗

PubMed2006

Effects of staining and bleaching on color change of dental composite resins.

STATEMENT OF PROBLEM: Discoloration of resin-based composites by colored solutions is a common problem. The use of bleaching agents for discolored natural teeth is becoming increasingly popular. It is not clear if bleaching agents can remove the stain from composite resins. PURPOSE: The purpose of this study was to investigate the effects of 2 staining solutions and 3 bleaching systems on the color changes of 2 dental composite resins. MATERIAL AND METHODS: Forty-five disk-shaped specimens (9 x 2.5 mm) of each of 2 composite resins, Filtek Supreme (FS) and Esthet X (EX), were prepared. The specimens were then divided into 3 groups of 15 specimens each and immersed in 2 staining solutions (coffee or red wine) or distilled water (control) for 3 hours daily over a 40-day test period. The 3 groups were then divided into 3 subgroups (n = 5), and 3 bleaching agents (Crest Night Effects, Colgate Simply White Night, or Opalescence Quick) were applied to the surface of the specimens over a 14-day period. Color of the specimens was measured with a spectrophotometer using CIELAB color space relative to CIE standard illuminant D55 at baseline, after staining, and after bleaching. The color differences (deltaE(ab)*) between the 3 measurements were calculated. The value deltaE(ab)* = 3.3 was used as an acceptable value in subjective visual evaluations. Analysis of variance and nonparametric analysis (Kruskal-Wallis test and Mann-Whitney test) were used to analyze the data. RESULTS: After staining, FS had more color change than EX and was more affected by the wine solution. After bleaching, the color of both EX and FS specimens returned to the baseline. The color differences between bleaching and baseline were less than value deltaE(ab)* = 3.3 for all groups. CONCLUSION: The nanocomposite (FS) changed color more than the microhybrid composite (EX) as a result of staining in coffee or red wine solutions. After bleaching, discoloration was removed completely from the composite resins tested.

Analysis of Variance↗

PubMed2000

Splitting schizophrenia: periodic catatonia-susceptibility locus on chromosome 15q15.

The nature of subtypes in schizophrenia and the meaning of heterogeneity in schizophrenia have been considered a principal controversy in psychiatric research. We addressed these issues in periodic catatonia, a clinical entity derived from Leonhard's classification of schizophrenias, in a genomewide linkage scan. Periodic catatonia is characterized by qualitative psychomotor disturbances during acute psychotic outbursts and by long-term outcome. On the basis of our previous findings of a lifetime morbidity risk of 26.9% of periodic catatonia in first-degree relatives, we conducted a genome scan in 12 multiplex pedigrees with 135 individuals, using 356 markers with an average spacing of 11 cM. In nonparametric multipoint linkage analyses (by GENEHUNTER-PLUS), significant evidence for linkage was obtained on chromosome 15q15 (P = 2.6 x 10(-5); nonparametric LOD score [LOD*] 3.57). A further locus on chromosome 22q13 with suggestive evidence for linkage (P = 1.8 x 10(-3); LOD* 1.85) was detected, which indicated genetic heterogeneity. Parametric linkage analysis under an autosomal dominant model (affecteds-only analysis) provided independent confirmation of nonparametric linkage results, with maximum LOD scores 2.75 (recombination fraction [theta].04; two-point analysis) and 2.89 (theta =.029; four-point analysis), at the chromosome 15q candidate region. Splitting the complex group of schizophrenias on the basis of clinical observation and genetic analysis, we identified periodic catatonia as a valid nosological entity. Our findings provide evidence that periodic catatonia is associated with a major disease locus, which maps to chromosome 15q15.

Catatonia↗

PubMed1996

Probability of heterosexual transmission of HIV: relationship to the number of unprotected sexual contacts. European Study Group in Heterosexual Transmission of HIV.

The objective of this study was to investigate the relationship between the number of unprotected heterosexual contacts with an HIV-infected person and the probability of HIV transmission. Data from a European study involving 563 heterosexual partners of HIV-infected subjects were analyzed. The number of unprotected contacts could be estimated for 525 couples (377 with male index case, 148 with female index case) from the reported frequency of unprotected contacts and an estimate of the length of the period during which transmission could have occurred. Nonparametric (isotonic regression) and parametric (Bernoulli model) analyses were performed on data at study entry and on follow-up data (121 couples). The nonparametric analysis resulted in several exposure groups, with the proportion of infected partners increasing with the number of contacts. For example, the percentage of female partners infected ranged from 10%, among those with < 10 unprotected contacts with an infected male, to 23% after 2,000 unprotected contacts. The parametric estimates of (assumed constant) per-contact infectivity were higher for male-to-female than for female-to-male transmission, but not significantly so. However, in comparison with nonparametric estimates, the model assuming constant infectivity appears to seriously underestimate the risk after very few contacts and to seriously overestimate the risk associated with a large number of contacts. Our results suggest that the association between the number of unprotected sexual contacts and the probability of infection is weak and highly inconsistent with constant per-contact infectivity. Probable explanations for these findings include large variability in infectivity between couples and within individuals over time. Estimates based on partner study data under the hypothesis of constant infectivity can, therefore, be highly misleading at a public health level, particularly when extrapolated to multiple casual contacts.

Disease Transmission, Infectious↗

PubMedDate not supplied

Correlation between clinical scoring of secondary caries at crown margins and histologically assessed extent of the lesions.

PURPOSE: The aim of this study was to propose a new clinical diagnostic rating index for secondary caries lesions at crown margins and to correlate this index with histologic evaluations. MATERIALS AND METHODS: Based on criteria for the evaluation of root caries, a modification of secondary caries lesions at the crown margin (SC index) was applied; the lesion characteristics were described as SCO to SC4. A total of 16 crowned teeth exhibiting secondary caries were randomly selected. The teeth were rated and grouped according to their clinical SC grades (SC1 to SC4). After embedding in Technovit, the teeth were serially sectioned and histologic caries scores were given for each section. RESULTS: Fifty-two percent of the prepared margins were in cementum/dentin. Crown margins with no caries lesions were mainly found in teeth clinically rated as SC1 and exhibiting localized discolorations, whereas deep lesions were found histologically at teeth rated SC4. The nonparametric test according to Spearman's rank correlation coefficient (rho) confirmed a highly significant correlation between the clinical SC index and the histologic evaluation (rho = 0.87, 95% confidence interval = 0.67 to 0.96, P < 0.01). SC1 discolorations overestimate caries lesions, whereas SC2 and SC4 lesions are well correlated to the percentage of histologically evaluated caries extension into all sections of a tooth. Lesions rated SC3 demonstrated a high variability of caries penetration into the dentin. CONCLUSION: The depth of discolorations and circular lesions is clinically not well predictable. Clinical diagnosis for localized superficial caries and deep caries lesions at the crown margin correlated well with the histologic caries rating.

Adult↗

PubMed2004

A nonparametric elicitation of the equity-efficiency trade-off in cost-utility analysis.

We performed an empirical elicitation of the equity-efficiency trade-off in cost-utility analysis using the rank-dependent quality-adjusted life-year (QALY) model, a model that includes as special cases many of the social welfare functions that have been proposed in the literature. Our elicitation method corrects for utility curvature and, therefore, our estimated equity weights are not affected by diminishing marginal utility. We observed a preference for equality in the allocation of health. The data suggest that the elicited equity weights were jointly determined by preferences for equality and by insensitivity to group size. A procedure is proposed to correct the equity weights for insensitivity to group size. Finally, we give an illustration how our method can be implemented in health policy.

Adolescent↗

PubMed2007

Usefulness of texture analysis for computerized classification of breast lesions on mammograms.

This work presents the usefulness of texture features in the classification of breast lesions in 5,518 images of regions of interest, which were obtained from the Digital Database for Screening Mammography that included microcalcifications, masses, and normal cases. Sixteen texture features were used, i.e., 13 were based on the spatial gray-level dependence matrix and 3 on the wavelet transform. The nonparametric K-NN classifier was used in the classification stage. The results obtained from receiver operating characteristic analysis indicated that the texture features can be used for separating normal regions and lesions with masses and microcalcifications, yielding the area under the curve (AUC) values of 0.957 and 0.859, respectively. However, the texture features were not very effective for distinguishing between malignant and benign lesions because the AUC was 0.617 for masses and 0.607 for microcalcifications. The study showed that the texture features can be used for the detection of suspicious regions in mammograms.

Breast Neoplasms↗

PubMed2002

Effects of rotary instruments and ultrasonic irrigation on debris and smear layer scores: a scanning electron microscopic study.

AIM: This study evaluated debris and smear layer scores after two types of instruments manufactured from different alloys were used to ultrasonically activate irrigants during canal preparation. The influence of two rotary preparation techniques on cleanliness of the shaped canals was also studied. METHODOLOGY: Apical stops were prepared to size 45 in 42 single-canalled extracted premolars and canines, which were divided into six equal groups. Groups 1, 2 and 3 were prepared by ProFile.04 (PF) while groups 4, 5 and 6 were prepared by Lightspeed (LS). All groups were irrigated using 5.25% NaOCl and 17% EDTA. Irrigants in groups 2 and 5 were ultrasonically activated using a size 15 steel K-file and by a blunt flexible nickel-titanium wire in groups 3 and 6. Groups 1 and 4 served as negative controls. Roots were split and canal walls examined at 15x, 200x and 400x magnification in an SEM. Smear layer and debris scores were recorded at 3, 6 and 9 mm levels using a 5-step scoring scale and a 200- micro m grid. Means were tested for significance using nonparametric Mann-Whitney U and Kruskal-Wallis tests. RESULTS: Debris and smear layer scores for the six groups varied from 1.98 +/- 1.04 to 3.47 +/- 0.97 and from 1.37 +/- 0.4 to 2.36 +/- 0.99, respectively. Although all groups had significantly higher smear layer and debris scores at the 3 mm levels compared to the 9 mm levels (P < 0.05), no significant differences were recorded due to the ultrasonic energy transmitted by the two alloys. CONCLUSION: Ultrasonically activated irrigants did not reduce debris or smear layer scores. This finding was not influenced by the material nor by the design of the instrument used to transmit ultrasonic activation.

Dental Instruments↗

PubMed2000

Graphical exploration of covariate effects on survival data through nonparametric quantile curves.

Kaplan-Meier curves provide an effective means of presenting the distributional pattern in a sample of survival data. However, in order to assess the effect of a covariate, a standard scatterplot is often difficult to interpret because of the presence of censored observations. Several authors have proposed a running median as an effective way of indicating the effect of a covariate. This article proposes a form of kernel estimation, employing double smoothing, that can be applied in a simple and efficient manner to construct an estimator of a percentile of the survival distribution as a function of one or two covariates. Permutations and bootstrap samples can be used to construct reference bands that help identify whether particular features of the estimates indicate real features of the underlying curve or whether this may be due simply to random variation. The techniques are illustrated on data from a study of kidney transplant patients.

Biometry↗

PubMed2002

Comparison of three methods for estimating the standard error of the area under the curve in ROC analysis of quantitative data.

RATIONALE AND OBJECTIVES: Several methods have been proposed for estimating the standard error (SE) of the area under the curve (AUC) in receiver operating characteristic analysis. The authors examined the validity of three methods--the LABROC procedure, exponential approximation, and the method of DeLong et al (purely nonparametric)--for estimating the SE of the AUC in receiver operating characteristic analysis of quantitative diagnostic data. MATERIALS AND METHODS: The authors conducted a broad numerical investigation to assess how to estimate the SE of AUC in various configurations of binormal and nonbinormal pairs of distributions, in which one or both pair members were mixtures of Gaussian distributions (the samples included 100 in the diseased group and 100 in the nondiseased group). RESULTS: The authors found that exponential approximation of the SE of AUC slightly underestimates the observed SE of a nonparametric estimate of the AUC when the ratio of the standard deviation of distributions for diseased to nondiseased populations was greater than 2. With binormal data the observed SE tended to be smaller with the LABROC procedure (semiparametric) than with the method of DeLong et al, but the LABROC procedure yields more conservative estimates of SE with nonbinormal data. In particular, with bimodal data it often produces a more conservative (ie, larger) estimate of the actual (observed) fluctuation. CONCLUSION: Overall, the LABROC procedure and the method of DeLong et al yielded very close estimates of the SE of AUC, even with data generated from a nonbinormal model. The choice between these two methods can be based on users' preferences and practicality.

Area Under Curve↗

PubMed1999

Methods for detecting and estimating population threshold concentrations for air pollution-related mortality with exposure measurement error.

The association between daily fluctuations in ambient particulate matter and daily variations in nonaccidental mortality have been extensively investigated. Although it is now widely recognized that such an association exists, the form of the concentration-response model is still in question. Linear, no threshold and linear threshold models have been most commonly examined. In this paper we considered methods to detect and estimate threshold concentrations using time series data of daily mortality rates and air pollution concentrations. Because exposure is measured with error, we also considered the influence of measurement error in distinguishing between these two completing model specifications. The methods were illustrated on a 15-year daily time series of nonaccidental mortality and particulate air pollution data in Toronto, Canada. Nonparametric smoothed representations of the association between mortality and air pollution were adequate to graphically distinguish between these two forms. Weighted nonlinear regression methods for relative risk models were adequate to give nearly unbiased estimates of threshold concentrations even under conditions of extreme exposure measurement error. The uncertainty in the threshold estimates increased with the degree of exposure error. Regression models incorporating threshold concentrations could be clearly distinguished from linear relative risk models in the presence of exposure measurement error. The assumption of a linear model given that a threshold model was the correct form usually resulted in overestimates in the number of averted premature deaths, except for low threshold concentrations and large measurement error.

Air Pollutants↗

PubMed2005

Nonparametric tests for differential gene expression and interaction effects in multi-factorial microarray experiments.

BACKGROUND: Numerous nonparametric approaches have been proposed in literature to detect differential gene expression in the setting of two user-defined groups. However, there is a lack of nonparametric procedures to analyze microarray data with multiple factors attributing to the gene expression. Furthermore, incorporating interaction effects in the analysis of microarray data has long been of great interest to biological scientists, little of which has been investigated in the nonparametric framework. RESULTS: In this paper, we propose a set of nonparametric tests to detect treatment effects, clinical covariate effects, and interaction effects for multifactorial microarray data. When the distribution of expression data is skewed or heavy-tailed, the rank tests are substantially more powerful than the competing parametric F tests. On the other hand, in the case of light or medium-tailed distributions, the rank tests appear to be marginally less powerful than the parametric competitors. CONCLUSION: The proposed rank tests enable us to detect differential gene expression and establish interaction effects for microarray data with various non-normally distributed expression measurements across genome. In the presence of outliers, they are advantageous alternative approaches to the existing parametric F tests due to the robustness feature.

Animals↗

PubMed1996

A descriptive tool to characterize nonlinear kinetics, with applications to meperidine and lidocaine.

We describe an explorative data analysis tool which can detect and describe the presence of nonlinearities in multiple dose kinetics studies. The method is nonparametric (i.e. not dependent on modeling assumptions), uses regression to estimate the functions representing the kinetics, and makes the detection of nonlinearity a part of the model selection process. Flexible functions (splines) are used to describe the kinetics corresponding to the lowest given dose, and to describe the (possible) departure of the kinetics corresponding to higher doses from the reference kinetics. The estimated kinetics and departures can be examined to offer possible insight into the nature of the nonlinearity. The methodology is applied to the analysis of meperidine and lidocaine kinetics through the lungs and the heart. We find that the lung kinetics of lidocaine and meperidine are linear. However their myocardial kinetics are complex and nonlinear.

Animals↗

PubMed2006

Evaluating the performance of species richness estimators: sensitivity to sample grain size.

1. Fifteen species richness estimators (three asymptotic based on species accumulation curves, 11 nonparametric, and one based in the species-area relationship) were compared by examining their performance in estimating the total species richness of epigean arthropods in the Azorean Laurisilva forests. Data obtained with standardized sampling of 78 transects in natural forest remnants of five islands were aggregated in seven different grains (i.e. ways of defining a single sample): islands, natural areas, transects, pairs of traps, traps, database records and individuals to assess the effect of using different sampling units on species richness estimations. 2. Estimated species richness scores depended both on the estimator considered and on the grain size used to aggregate data. However, several estimators (ACE, Chao 1, Jackknifel and 2 and Bootstrap) were precise in spite of grain variations. Weibull and several recent estimators [proposed by Rosenzweig et al. (Conservation Biology, 2003, 17, 864-874), and Ugland et al. (Journal of Animal Ecology, 2003, 72, 888-897)] performed poorly. 3. Estimations developed using the smaller grain sizes (pair of traps, traps, records and individuals) presented similar scores in a number of estimators (the above-mentioned plus ICE, Chao2, Michaelis-Menten, Negative Exponential and Clench). The estimations from those four sample sizes were also highly correlated. 4. Contrary to other studies, we conclude that most species richness estimators may be useful in biodiversity studies. Owing to their inherent formulas, several nonparametric and asymptotic estimators present insensitivity to differences in the way the samples are aggregated. Thus, they could be used to compare species richness scores obtained from different sampling strategies. Our results also point out that species richness estimations coming from small grain sizes can be directly compared and other estimators could give more precise results in those cases. We propose a decision framework based on our results and on the literature to assess which estimator should be used to compare species richness scores of different sites, depending on the grain size of the original data, and of the kind of data available (species occurrence or abundance data).

Animals↗

PubMed2005

Recognition memory and introspective remember/know judgments: evidence for the influence of distractor plausibility on "remembering" and a caution about purportedly nonparametric measures.

One popular technique in the study of human recognition memory involves the elicitation of remember and know judgments and the attribution of those judgments to qualitative states of memory retrieval. An alternative view, reviewed here, implicates quantitative, but not qualitative, differences in evidence as the basis for those two judgments. That theory makes two clear and testable predictions: that of criterion shifts in "remembering" and that of isodiscriminability across different response sets. In this experiment, the makeup of the distractor set in a recognition test is shown to influence overall recognition criterion and also rates of "remember" responses. The second portion of the article demonstrates how A' is a poor choice of a measure to test the prediction of isodiscriminability. When this measure is corrected (Equation 7) to make it more consistent with current knowledge about the receiver-operating characteristic in recognition memory, it reveals that there is no difference in discriminability between "remember" and all positive responses.

Cognition↗