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PubMed1998

Recent developments in computer-assisted analysis of mixtures.

This paper reviews recent developments in the area of computer-assisted analysis of mixture distributions (C.A.MAN). Given a biometric situation of interest in which, under homogeneity assumptions, a certain parametric density occurs, such as the Poisson, the binomial, the geometric, the normal, and so forth, then it is argued that this situation can easily be enlarged to allow a variation of the scalar parameter in the population. This situation is called unobserved heterogeneity. This naturally leads to a specific form of nonparametric mixture distribution that can then be assumed to be the standard model in the biometric application of interest (since it also incorporates the homogeneous situations as a special case). Besides developments in theory and algorithms, the work focuses on developments in biometric applications such as meta-analysis, fertility studies, estimation of prevalence under clustering, and estimation of the distribution function of survival time under interval censoring. The approach is nonparametric for the mixing distribution, including leaving the number of components (subpopulations) of the mixing distribution unknown.

Animals↗

PubMed1997

Covariate effects on linkage and association using a general pair method.

The "general pair method" (GPM) is a nonparametric, identity-by-state (IBS) method of assessing linkage between a chromosomal marker and a binary phenotype. It is applicable to any pedigree structure, and uses marker information from affected as well as unaffected individuals. Results obtained here from nuclear families (Problem 2A) are contrasted with those from extended pedigrees (Problem 2B). Test statistics for chromosomal linkage between each marker and disease status are contrasted with tests for "direct association" which test the hypothesis that a particular allele is associated disease status across all pedigrees. A novel extension of the GPM is presented here for testing whether the strength of linkage (and/or association) depends on the levels of a covariate (i.e., dependency on gender, age, the levels of the "environmental factor," or the levels of the "quantitative phenotypes" supplied). The GPM is seen to have some power to detect major gene 1 on chromosome 5, and major gene 3 on chromosome 4. The gender interaction effects proved too small to detect. No direct associations are found.

Analysis of Variance↗

PubMed2003

A genomewide scan for age-related macular degeneration provides evidence for linkage to several chromosomal regions.

We report the results of a genomewide scan for age-related macular degeneration (AMD) in 158 multiplex families. AMD classification was based on fundus photography and was assigned a grade ranging from 1 (no disease) to 5 (exudative disease). Genotyping was performed by the National Heart, Lung, and Blood Institute Mammalian Genotyping Service at Marshfield (404 short tandem repeat markers). The sample included 158 families with two or more siblings with AMD, 490 affected individuals, 101 unaffected individuals, and 38 whose affection status was unknown. Relative pairs included 511 affected sibling, 28 avuncular, 53 cousin, 7 grandparent-grandchild, and 9 grand-avuncular pairs. Two-point parametric and multipoint parametric and nonparametric analyses were performed. Maximum two-point LOD scores of 1.0-2.0 were found for markers on chromosomes 1, 2, 8, 10, 14, 15, and 22. Multipoint analyses were consistent with the two-point results for chromosomes 1, 2, 8, 10, and 22 and provided evidence for additional linkage regions on chromosomes 3, 6, 8, 12, 16, and X. Our signals on chromosomes 1q, 6p, and 10q are consistent with some other previously published results. Significant linkage to AMD was found for one marker on chromosome 2, two adjacent markers on chromosome 3, two adjacent markers on chromosome 6, and seven contiguous markers on chromosome 8, with empirical P values of .00001. The consistency of many of the other signals across both two-point and multipoint, as well as parametric and nonparametric, analyses indicate several other regions worthy of follow-up.

Aging↗

PubMed2003

Nonparametric longitudinal allele-sharing model.

Basically no methods are available for the analysis of quantitative traits in longitudinal genetic epidemiological studies. We introduce a nonparametric factorial design for longitudinal data on independent sib pairs, modelling the phenotypic quadratic differences as the dependent variable. Factors are the number of alleles shared identically by descent (IBD) and the age categories at which the dependent variable is measured, allowing for dependence due to age. To identify a linked marker a rank statistic tests the influence of IBD group on phenotypic quadratic differences. No assumptions are made on normality or variances of the dependent variable. We apply our method to 71 sib pairs from the Framingham Heart Study data provided at the Genetic Analysis Workshop 13. For all 15 available markers on chromosome 17 we analyzed the influence on systolic blood pressure. In addition, different selection strategies to sample from the whole data are discussed.

Adult↗

PubMed1997

Pharmacokinetic modelling of intravenous tobramycin in adolescent and adult patients with cystic fibrosis using the nonparametric expectation maximization (NPEM) algorithm.

The availability of personal computer programs for individualizing drug dosage regimens has stimulated the interest in modelling population pharmacokinetics. Data from 82 adolescent and adult patients with cystic fibrosis (CF) who were treated with intravenous tobramycin because of an exacerbation of their pulmonary infection were analysed with a non-parametric expectation maximization (NPEM) algorithm. This algorithm estimates the entire discrete joint probability density of the pharmacokinetic parameters. It also provides traditional parametric statistics such as the means, standard deviation, median, covariances and correlations among the various parameters. It also provides graphic-2- and 3-dimensional representations of the marginal densities of the parameters investigated. Several models for intravenous tobramycin in adolescent and adult patients with CF were compared. Covariates were total body weight (for the volume of distribution) and creatinine clearance (for the total body clearance and elimination rate). Because of lack of data on patients with poor renal function, restricted models with non-renal clearance and the non-renal elimination rate constant fixed at literature values of 0.15 L/h and 0.01 h-1 were also included. In this population, intravenous tobramycin could be best described by median (+/-dispersion factor) volume of distribution per unit of total body weight of 0.28 +/- 0.05 L/kg, elimination rate constant of 0.25 +/- 0.10 h-1 and elimination rate constant per unit of creatinine clearance of 0.0008 +/- 0.0009 h-1/(ml/min/1.73 m2). Analysis of populations of increasing size showed that using a restricted model with a non-renal elimination rate constant fixed at 0.01 h-1, a model based on a population of only 10 to 20 patients, contained parameter values similar to those of the entire population and, using the full model, a larger population (at least 40 patients) was needed.

Adolescent↗

PubMed2000

Fitting nonlinear and constrained generalized estimating equations with optimization software.

In this article, we present an estimation approach for solving nonlinear constrained generalized estimating equations that can be implemented using object-oriented software for nonlinear programming, such as nlminb in Splus or fmincon and lsqnonlin in Matlab. We show how standard estimating equation theory includes this method as a special case so that our estimates, when unconstrained, will remain consistent and asymptotically normal. To illustrate this method, we fit a nonlinear dose-response model with nonnegative mixed bound constraints to clustered binary data from a developmental toxicity study. Satisfactory confidence intervals are found using a nonparametric bootstrap method when a common correlation coefficient is assumed for all the dose groups and for some of the dose-specific groups.

Animals↗

PubMed1996

Relationships between running economy and temporal EMG characteristics of bi-articular leg muscles.

Relationships between running economy (RE; submaximal VO(2) for a given running speed) and the temporal EMG characteristics of bi-articular leg muscles were quantified in a group of well-trained runners. Nine subjects completed three test sessions: a determination of maximal aerobic demand (VO(2)max); an accommodation session at the experimental speed of 4.13 m.s(-1) and a session during which EMG and RE data were collected simultaneously at the experimental speed of 4.13 m.s(-1) Measures of muscle onset, on-time durations, and on-time coactivation durations were calculated from the following muscles: rectus femoris, medial hamstrings, lateral hamstrings, and gastrocnemius. Nonparametric correlations between RE and EMG characteristics displayed both positive and negative relationships and exhibited a wide range of values. Two EMG measures were significantly correlated (r > 0.67) with RE. Earlier onset of rectus femoris during swing phase and a shorter duration of hamstring - gastrocnemius coactivation during swing were associated with more economical runners. Although not statistically significant, correlation coefficients calculated for measures of coactivation during stance and RE ranged from -0.42 to -0.65. This trend indicates that individuals who exhibited a greater amount of coactivation between bi-articular muscles during the stance phase of the running cycle tended to be more economical. These relationships suggest different activation patterns in bi-articular muscles between economical and uneconomical runners.

Adult↗

PubMed2000

Panel reactive antibodies in women with ovarian cancer undergoing high-dose chemotherapy with peripheral stem cell rescue: a case control study.

High-dose chemotherapy with stem cell support is associated with a period of profound thrombocytopenia. During periods of thrombocytopenia, alloreactive antibodies can limit the effectiveness of platelet transfusion. In this institution, women undergoing high-dose chemotherapy with stem cell support for treatment of their ovarian cancer seemed to have a high incidence of panel reactive antibodies (PRA). To evaluate this further, a case-control study was performed comparing pretransplant PRA values in 22 consecutive women undergoing high-dose chemotherapy as intensification therapy for their ovarian cancer and a control group of 51 women receiving similar or identical therapy for their breast cancer. Parity was similar in both groups. Nonparametric t-test comparison of the two groups demonstrated a significantly higher PRA value in women with ovarian cancer compared to those with breast cancer (p = 0.032). Platelet transfusions were more common in women with ovarian cancer as compared to those with breast cancer (5.45/pt and 4.79/pt), although this difference did not reach statistical significance. This finding suggests that alloimmunization may be a more frequent problem in patients with ovarian cancer than in women with breast cancer.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2001

Nonparametric test for doubly interval-censored failure time data.

This paper considers comparison of discrete failure time distributions when the survival time of interest measures elapsed time between two related events and observations on the occurrences of both events could be interval-censored. This kind of data is often referred to as doubly interval-censored failure time data. If the occurrence of the first event defining the survival time can be exactly observed, the data are usually referred to as interval-censored data. For the comparison problem based on interval-censored failure time data, Sun (1996) proposed a nonparametric test procedure. In this paper we generalize the procedure given in Sun (1996) to doubly interval-censored data case and the generalized test is evaluated by simulations.

Cohort Studies↗

PubMed1999

Complementary nonparametric analysis of covariance for logistic regression in a randomized clinical trial setting.

In the randomized clinical trial setting, controlling for covariates is expected to produce variance reduction for the treatment parameter estimate and to adjust for random imbalances of covariates between the treatment groups. However, for the logistic regression model, variance reduction is not obviously obtained. This can lead to concerns about the assumptions of the logistic model. We introduce a complementary nonparametric method for covariate adjustment. It provides results that are usually compatible with expectations for analysis of covariance. The only assumptions required are based on randomization and sampling arguments. The resulting treatment parameter is a (unconditional) population average log-odds ratio that has been adjusted for random imbalance of covariates. Data from a randomized clinical trial are used to compare results from the traditional maximum likelihood logistic method with those from the nonparametric logistic method. We examine treatment parameter estimates, corresponding standard errors, and significance levels in models with and without covariate adjustment. In addition, we discuss differences between unconditional population average treatment parameters and conditional subpopulation average treatment parameters. Additional features of the nonparametric method, including stratified (multicenter) and multivariate (multivisit) analyses, are illustrated. Extensions of this methodology to the proportional odds model are also made.

Humans↗

PubMed2000

[The regression model and the nonlinear autoregressive processes].

In this article we review different regression models with fixed and random effects. We consider the usual methods, parametric and nonparametric, for the estimation in these models. We also see how the estimation in the autoregressive nonlinear model can be deduced of the regression, if the model satisfies some mixing conditions.

Nonlinear Dynamics↗

PubMed1999

Nonparametric step-down test procedures for finding minimum effective dose.

Nonparametric versions of normal theory step-down multiple-test procedures for inferring minimum effective dose (see Tamhane et al. (1)) were developed and studied by Monte Carlo simulation. Two types of step-down testing procedures were examined. For both procedures, pairwise, linear, or Helmert contrasts of mean ranks were studied. All nonparametric step-down procedures controlled familywise error rate under normal, double exponential, and exponential distributions. Specific recommendations based on power and bias comparisons of nonparametric methods among themselves, with Shirley's (2) test, and with parametric step-down multiple-test procedures are given.

Computer Simulation↗

PubMed2005

Relations of gestational length and timing and type of incomplete pregnancy to ovarian cancer risk.

While the protective nature of parity with respect to ovarian cancer has been well documented, whether a history of incomplete pregnancy affects ovarian cancer risk is uncertain. Data collected from 739 epithelial ovarian cancer cases and 1,313 community controls in the Delaware Valley from 1994 to 1998 were used to evaluate the relation between gestational length and timing of first induced or spontaneous abortion and ovarian cancer risk. Incomplete pregnancy was not associated with ovarian cancer among nulliparous women or among ever-pregnant women either before or after adjustment for relevant confounders (for nulliparous women, odds ratio (OR) = 1.12, 95% confidence interval (CI): 0.66, 1.89; for ever-pregnant women, OR = 0.95, 95% CI: 0.76, 1.18). Among unigravid women, one full-term pregnancy was more protective than an incomplete pregnancy (adjusted OR = 0.29, 95% CI: 0.15, 0.57). These results were independent of the type of pregnancy loss. Among ever-pregnant women, a spontaneous abortion before a first birth provided significant protection (adjusted OR = 0.47, 95% CI: 0.30, 0.75), while no significant effect was found for an induced abortion prior to a first birth (adjusted OR = 0.80, 95% CI: 0.44, 1.47). These data do not support an independent association between incomplete pregnancies, either spontaneous or induced, and ovarian cancer risk.

Abortion, Induced↗

PubMed2005

A conditional nonparametric test for comparing two areas under the ROC curves from a paired design.

RATIONALE AND OBJECTIVES: To develop a conditional nonparametric procedure for comparing two correlated areas under receiver operating characteristic (ROC) curves (AUC). MATERIALS AND METHODS: A nonparametric conditional test to compare areas under two ROC curves was developed using the distribution of the elements of the nonparametric AUC estimators in a permutation space. The conditioning is made on the observed discordances between the relative orderings of ratings of the normal and abnormal cases for the two modalities taken over all possible pairs. The type I error of the procedure was verified using computer simulations. The power of the test was compared with an existing unconditional procedure on simulated datasets from binormal distributions as well as from a mixture of binormal distributions of ratings. RESULTS: The proposed test is conservative for low sample sizes, large AUC, and high correlation between modalities. It possesses a reasonable type I error for sample sizes as low as 20 actually positive and 20 actually negative cases. In plausible situations in which the sample in observer performance studies can not be monotonically transformed into a binormal distribution, this approach may have modest power advantages over the conventional nonparametric test. CONCLUSION: The conditional nonparametric test presented here is an alternative approach to existing unconditional procedures and may offer advantages in certain types of observer performance studies.

Area Under Curve↗

PubMed2000

Comparative blood flow study of arteriovenous fistulae in canine femoral arteries: modified latero-lateral and end-lateral techniques.

The aim of this study was to evaluate the blood flow of an arteriovenous fistula comparing the modified latero-lateral (LLM) and end-lateral (TL) techniques in canine femoral arteries. Ten mongrel dogs were submitted to 2 arteriovenous fistulae each, with a LLM on one side and a TL procedure on the other side. Cranial and caudal average blood flow as well as average venous flow were measured by an electronic fluxometer 15, 20, and 25 min after surgery. Mann-Whitney, Friedman, and Wilcoxon nonparametric tests were used for data analysis (alpha </= 0,05). Femoral artery flow, cranial to the fistula, was increased 5(1/2) times in both groups. In the femoral artery caudal to the fistula, the flow in the majority of the animals was reversed 1.3 times using the TL technique and 2 times using the LLM technique. The average flow in the cranial vein was statistically different with an improved flow of 7.4 times versus 6.8 times for the LLM technique. These results suggest that LLM arteriovenous fistula in dogs leads to a larger venous flow than in the TL arteriovenous fistula and the reverse caudal arterial flow in the latero-lateral technique. The flow behavior (laminar or turbulent) in the 2 types of arteriovenous fistula was studied in terms of singular head loss.

Anastomosis, Surgical↗

PubMed1997

Choice of student's t- or Wilcoxon-based confidence intervals for assessment of average bioequivalence.

An open question in the analysis of average bioequivalence is whether the nonparametric (Wilcoxon) or parametric (t) approaches to two one-sided tests is preferable. Previous work has made particular distributional assumptions as to the distribution of AUC and C(max). Instead, we simulate data according to a pharmacokinetic model for an immediate-release formulation. We find that both approaches have estimated level consistent with the nominal 5%. The only concern is a possible anticonservativeness of the parametric approach for C(max). Further, the nonparametric approach is consistently less powerful than the parametric for the cases studied.

Area Under Curve↗

PubMed2004

Nonparametric estimation of the effects of quantitative trait loci.

Interval mapping of quantitative trait loci from breeding experiments plays an important role in understanding the mechanisms of disease, both in humans and other organisms. Standard approaches to estimation involve parametric assumptions for the component distributions and may be sensitive to model misspecification. Some nonparametric tests have been studied. However, nonparametric estimation of the phenotypic distributions has not been considered in the genetics literature, even though such methods might provide essential nonparametric summaries for comparing different loci. We develop a sufficient condition for identifiability of the phenotypic distributions. Simple nonparametric estimators for the distributions are proposed for uncensored and right censored data. They have a closed form and their small and large sample properties are readily established. Their practical utility as numerical summaries which complement nonparametric tests is demonstrated on two recent genetics examples.

Animals↗

PubMed2004

Influence of cavity configuration on microleakage around Class V restorations bonded with seven self-etching adhesives.

PURPOSE: The purpose of this study was to evaluate microleakage around Class V resin composite restorations with different cavity configurations, bonded with one of seven self-etching materials or with an adhesive using the total-etch technique. MATERIALS AND METHODS: Ninety-six human molars and premolars were randomly assigned to eight groups and bonded with one of seven self-etching adhesives--Prompt-L-Pop (3M ESPE, St. Paul, MN, USA), Adper Prompt-L-Pop (3M ESPE), Clearfil SE Bond (Kuraray Medical, Okayama, Japan), Prime & Bond NT/NRC (Dentsply DeTrey, Konstanz, Germany), Xeno III (Dentsply DeTrey), One-Up Bond (Tokuyama Dental, Tokuyama, Japan), AdheSE (Ivoclar Vivadent, Schaan, Liechtenstein)-or with Prime & Bond NT (Dentsply DeTrey) using a separate total-etch technique. Cavities were cut in both the lingual and buccal surfaces and were approximately 3 mm mesiodistally, 1.5 mm deep, and 2.0 mm occlusogingivally. Selected at random, box-shaped cavities were cut on one side and V-shaped cavities were cut on the contralateral side. After bonding, the cavities were incrementally filled with a microhybrid composite (Tetric Ceram, Ivoclar Vivadent), cured, and immediately polished with Sof-Lex (3M ESPE) disks. The teeth were thermocycled, and the specimens were examined for microleakage using Procion Brilliant Red (ICI, Slough, UK) as a marker. RESULTS: Comparisons of both gingival and enamel margins within each of the groups showed no significant difference owing to configuration factor (C-factor; p > .5 in all cases, calculated with Kruskal-Wallis nonparametric analysis of variance [ANOVA]) and Dunn's multiple comparison test). All groups showed microleakage at the gingival margins irrespective of C-factor or bonding agent (box-shaped cavities, p = .8862; V-shaped cavities, p = .9623; using the ANOVA). Microleakage was not observed at all enamel margins regardless of C-factor or bonding agent, and there were no significant differences between the groups (box-shaped cavities, p = .9869; V-shaped cavities, p = .9550; using the Kruskal-Wallis nonparametric ANOVA).

Adolescent↗