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Expressing estimators of expected quality adjusted survival as functions of Nelson-Aalen estimators.

Quality adjusted survival has been increasingly advocated in clinical trials to be assessed as a synthesis of survival and quality of life. We investigate nonparametric estimation of its expectation for a general multistate process with incomplete follow-up data. Upon establishing a representation of expected quality adjusted survival through marginal distributions of a set of defined events, we propose two estimators for expected quality adjusted survival. Expressed as functions of Nelson-Aalen estimators, the two estimators are strongly consistent and asymptotically normal. We derive their asymptotic variances and propose sample-based variance estimates, along with evaluation of asymptotic relative efficiency. Monte Carlo studies show that these estimation procedures perform well for practical sample sizes. We illustrate the methods using data from a national, multicenter AIDS clinical trial.

Acquired Immunodeficiency Syndrome↗

Performance of the nonparametric linkage analysis using GENEHUNTER for a complicated genetic disease.

The nonparametric linkage (NPL) analysis of the GENEHUNTER program was applied to one set of the simulated data of Problem 2, GAW11. We conducted a straightforward screening of the genome to evaluate the performance of the NPL test, with respect to its ability to detect linkage on specific disease loci. Our findings indicate that disease genes were detected with relatively good power, despite the presence of a complex inheritance pattern. We found that the NPL test varies depending on penetrance rates and gene frequencies, however, we conclude that it is a useful tool for linkage analysis.

Alleles↗

Prospective analysis of sinus symptoms and correlation with paranasal computed tomography scan.

OBJECTIVES: We designed a prospective study to determine whether there is a correlation between the severity of sinus symptoms and the severity of computed tomography (CT) scan evidence of rhinosinusitis. METHODS: Acute and chronic rhinosinusitis patients rated their symptoms and had a CT scan of the sinuses taken the same day. A Likert severity scale and standardized CT scoring system were used. Data were analyzed by nonparametric methods with Kendall's rank correlation coefficient. RESULTS: The severity of 5 symptoms correlated with severity of disease on CT scan. Headache and facial pain or pressure had no correlation. CONCLUSION: The certainty of a clinical diagnosis of rhinosinusitis requiring treatment is enhanced in patients with high symptom severity scores for fatigue, sleep disturbance, nasal discharge, nasal blockage, or decreased sense of smell. Isolated headache and facial pain or pressure are less reliable predictors of CT scan findings supporting the diagnosis rhinosinusitis.

Acute Disease↗

Analysis of chromosome 1q42.2-43 in 152 families with high risk of prostate cancer.

One hundred fifty-two families with prostate cancer were analyzed for linkage to markers spanning a 20-cM region of 1q42.2-43, the location of a putative prostate cancer-susceptibility locus (PCAP). No significant evidence for linkage was found, by use of both parametric and nonparametric tests, in our total data set, which included 522 genotyped affected men. Rejection of linkage may reflect locus heterogeneity or the confounding effects of sporadic disease in older-onset cases; therefore, pedigrees were stratified into homogeneous subsets based on mean age at diagnosis of prostate cancer and number of affected men. Analyses of these subsets also detected no significant evidence for linkage, although LOD scores were positive at higher recombination fractions, which is consistent with the presence of a small proportion of families with linkage. The most suggestive evidence of linkage was in families with at least five affected men (nonparametric linkage score of 1.2; P=.1). If heterogeneity is assumed, an estimated 4%-9% of these 152 families may show linkage in this region. We conclude that the putative PCAP locus does not account for a large proportion of these families with prostate cancer, although the linkage of a small subset is compatible with these data.

Age Factors↗

Bayesian estimation in animal breeding using the Dirichlet process prior for correlated random effects.

In the case of the mixed linear model the random effects are usually assumed to be normally distributed in both the Bayesian and classical frameworks. In this paper, the Dirichlet process prior was used to provide nonparametric Bayesian estimates for correlated random effects. This goal was achieved by providing a Gibbs sampler algorithm that allows these correlated random effects to have a nonparametric prior distribution. A sampling based method is illustrated. This method which is employed by transforming the genetic covariance matrix to an identity matrix so that the random effects are uncorrelated, is an extension of the theory and the results of previous researchers. Also by using Gibbs sampling and data augmentation a simulation procedure was derived for estimating the precision parameter M associated with the Dirichlet process prior. All needed conditional posterior distributions are given. To illustrate the application, data from the Elsenburg Dormer sheep stud were analysed. A total of 3325 weaning weight records from the progeny of 101 sires were used.

Algorithms↗

A comparison in association and linkage genome-wide scans for alcoholism susceptibility genes using single-nucleotide polymorphisms.

We conducted genome-wide linkage scans using both microsatellite and single-nucleotide polymorphism (SNP) markers. Regions showing the strongest evidence of linkage to alcoholism susceptibility genes were identified. Haplotype analyses using a sliding-window approach for SNPs in these regions were performed. In addition, we performed a genome-wide association scan using SNP data. SNPs in these regions with evidence of association (P <or= 0.0001) were identified. We found that the general patterns for nonparametric linkage (NPL) scores from SNP and microsatellite genome scans are fairly consistent; however, the peaks of the NPL scores are mostly higher in the SNP-based scan than those using microsatellite markers, which might be located at different regions. Furthermore, SNPs identified from linkage screens were not so strongly associated with alcoholism (the most significant SNP had a p-value of 0.030) as those identified from association genomic screening (the most significant SNP had a p-value of 2.0 x 10(-8)).

Alcoholism↗

Significance of experts' overall ratings for medical student competence in relation to history-taking.

CONTEXT AND OBJECTIVE: Overall ratings (ORs) of competence, given by expert physicians, are increasingly used in clinical skills assessments. Nevertheless, the influence of specific components of competence on ORs is incompletely understood. The aim here was to investigate whether ORs for medical student history-taking competence are influenced by performance relating to communication skills, completeness of questioning and asking contentdriven key questions. DESIGN AND SETTING: Descriptive, quantitative study at Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo. METHODS: Thirty-six medical students were examined in a 15-station high-stake objective structured clinical examination (OSCE). At four stations devoted to history-taking, examiners filled out checklists covering the components investigated and independently rated students overall performance using a five-point scale from 1 (poor) to 5 (excellent). Physician ratings were aggregated for each student. Nonparametric correlations were made between ORs. RESULTS: ORs presented significant correlations with checklist scores (Spearmans rs = 0.38; p = 0.02) and OSCE general results (rs = 0.52; p < 0.001). Scores for "communication skills" tended to correlate with ORs (rs = 0.31), but without reaching significance (p = 0.06). Neither the scores for "completeness" (rs = 0.26; p = 0.11) nor those for "asking key questions" (rs = 0.07; p = 0.60) correlated with ORs. CONCLUSIONS: Experts overall ratings for medical student competence regarding history-taking is likely to encompass a particular dimension, since ratings were only weakly influenced by specific components of performance.

Adult↗

The affective dimension of low-back pain: its influence on the outcome of back school.

OBJECTIVE: Back School is a rehabilitation treatment for back pain that requires patients to understand an educational message and motivate themselves to modify their behavior to prevent relapses. In examining failed cases, the question arose as to whether the failures could be attributed to affective dimensions of pain that could be reducing tolerance to the pain itself and jeopardizing patients' compliance. We studied the role of the affective component of back pain in Back School failures to see whether this component can be used to predict the treatment's negative results and whether it can be conditioned by the treatment itself. DESIGN: Inception cohort. SETTING: Forty-two subjects with low back pain were treated with Back School at our rehabilitation department. MAIN OUTCOME MEASURES: Evaluation was carried out before Back School treatment and after 2 months, through functional clinical examination and Short Form-McGill Pain Questionnaire (affective and sensory pain indexes). RESULTS: As outcome of the treatment, we considered the modification of spontaneous and evoked pain and the motility of the spine. Unexpectedly, the nonparametric tests did not show a significant correlation between the affective indicators before and after the treatment. As expected, the two dimensions of pain, affective and sensory, are significantly related to each other, both before and after treatment, but this correlation increases after treatment (from r = .50 to r = 88). CONCLUSIONS: The initial hypothesis was not proven. These results show that high affective scores before Back School do not influence the success of the treatment and that the Back School itself is able to modify both the sensorial and affective pain descriptors.

Adult↗

A Bayesian mixture model for partitioning gene expression data.

In recent years there has been great interest in making inference for gene expression data collected over time. In this article, we describe a Bayesian hierarchical mixture model for partitioning such data. While conventional approaches cluster the observed data, we assume a nonparametric, random walk model, and partition on the basis of the parameters of this model. The model is flexible and can be tuned to the specific context, respects the order of observations within each curve, acknowledges measurement error, and allows prior knowledge on parameters to be incorporated. The number of partitions may also be treated as unknown, and inferred from the data, in which case computation is carried out via a birth-death Markov chain Monte Carlo algorithm. We first examine the behavior of the model on simulated data, along with a comparison with more conventional approaches, and then analyze meiotic expression data collected over time on fission yeast genes.

Bayes Theorem↗

A robust approach to reference interval estimation and evaluation.

We propose a new methodology for the estimation of reference intervals for data sets with small numbers of observations or for those with substantial numbers of outliers. We propose a prediction interval that uses robust estimates of location and scale. The SAS software can be readily modified to do these calculations. We compared four reference interval procedures (nonparametric, transformed, robust with a nonparametric lower limit, and transformed robust) for sample sizes of 20, 40, 60, 80, 100, and 120 from chi 2 distributions of 1, 4, 7, and 10 df. chi 2 distributions were chosen because they simulate the skewness of distributions often found in clinical chemistry populations. We used the root mean square error as the measure of performance and used computer simulation to calculate this measure. The robust estimator showed the best performance for small sample sizes. As the sample size increased, the performance values converged. The robust method for calculating upper reference interval values yields reasonable results. In two examples using real data for haptoglobin and glucose, the robust estimator provides slightly smaller upper reference limits than the other procedures. Lastly, the robust estimator was compared with the other procedures in a population where 5% of the values were multiplied by a factor of 5. The reference intervals were calculated with and without outlier detection. In this case, the robust approach consistently yielded upper reference interval values that were closer to those of the true underlying distributions. We propose that robust statistical analysis can be of great use for determinations of reference intervals from limited or possibly unreliable data.

Aged↗

Efficacy of various concentrations of citric acid at different pH values for smear layer removal.

OBJECTIVE: The efficacy of various concentrations of citric acid at different pH values for the removal of the superficial smear layer from dentinal surfaces was examined through the use of scanning electron microscopy. Study design Fifty extracted teeth were irrigated with sodium hypochlorite (NaOCl) during instrumentation. Citric acid solutions at 50%, 25%, 10%, and 5% (wt/vol) concentrations were prepared. In addition, similar solutions of citric acid were buffered to pH 6. Citric acid solutions with original and buffered pH values were used as final rinses. Bidistilled water and NaOCl were used as controls. The data were analyzed by using nonparametric Kruskal-Wallis and Mann-Whitney U tests. RESULTS: Lower concentrations with lower pH values removed smear layer more efficiently than the ones with higher pH values (P <.05), whereas no significant differences for higher concentrations were detected between low and high pH values. However, more destruction of peritubular dentin was observed at higher concentrations with low pH values. CONCLUSION: Within the limits of this study, lower concentrations of citric acid with its original pH were found to be as effective as higher concentrations in the removal of superficial smear layer.

Buffers↗

Genomewide scan in families with schizophrenia from the founder population of Afrikaners reveals evidence for linkage and uniparental disomy on chromosome 1.

We report on our initial genetic linkage studies of schizophrenia in the genetically isolated population of the Afrikaners from South Africa. A 10-cM genomewide scan was performed on 143 small families, 34 of which were informative for linkage. Using both nonparametric and parametric linkage analyses, we obtained evidence for a small number of disease loci on chromosomes 1, 9, and 13. These results suggest that few genes of substantial effect exist for schizophrenia in the Afrikaner population, consistent with our previous genealogical tracing studies. The locus on chromosome 1 reached genomewide significance levels (nonparametric LOD score of 3.30 at marker D1S1612, corresponding to an empirical P value of.012) and represents a novel susceptibility locus for schizophrenia. In addition to providing evidence for linkage for chromosome 1, we also identified a proband with a uniparental disomy (UPD) of the entire chromosome 1. This is the first time a UPD has been described in a patient with schizophrenia, lending further support to involvement of chromosome 1 in schizophrenia susceptibility in the Afrikaners.

Chromosome Mapping↗

25-hydroxyvitamin D deficiency in renal transplant recipients.

CONTEXT: Bone disease after kidney transplantation is a common problem. The serum levels of the active vitamin D metabolite 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D] have been studied extensively. In contrast, there has not been much concern about the serum levels of 25-hydroxyvitamin D(3) [25(OH)D]. However, it is well recognized that serum levels of 1,25(OH)(2)D are often normal in vitamin D-deficient patients. Moreover, inadequate serum 25(OH)D may limit the extrarenal production of 1,25(OH)(2)D that could lead to increased risk of many chronic diseases. OBJECTIVE: We analyzed whether renal transplant patients were at a higher risk of 25(OH)D deficiency because of the consequence of their need to protect themselves from sun exposure. DESIGN, SETTING, AND PATIENTS: We hypothesized that renal transplant recipients are at high risk to develop 25(OH)D deficiency. Serum 25(OH)D levels were analyzed in renal transplant patients with adequate renal function and in an age- and gender-matched control group (n = 31) at the end of winter. All renal transplant patients practiced solar UV-protection after transplantation. 25(OH)D levels were compared using a nonparametrical test (Wilcoxon rank sum test). RESULTS: Serum 25(OH)D levels were significantly lower in renal transplant patients compared with controls (P = 0.007). Geometric mean (with 95% confidence interval) in renal transplant patients was 10.9 ng/ml (8.2-14.3) compared with 20.0 ng/ml (15.7-25.5) in the control group. CONCLUSIONS: Renal transplant recipients are at high risk to develop 25(OH)D deficiency. Treatment with vitamin D is recommended to correct their vitamin D deficiency, which may help protect them from serious vitamin D deficiency-related health problems that include an increased risk for internal malignancies.

Adult↗

Testing for trend with count data.

Among the tests that can be used to detect dose-related trends in count data from toxicological studies are nonparametric tests such as the Jonckheere-Terpstra and likelihood-based tests, for example, based on a Poisson model. This paper was motivated by a data set of tumor counts in which conflicting conclusions were obtained using these two tests. To define situations where one test may be preferable, we compared the small and large sample performance of these two tests as well as a robust and conditional version of the likelihood-based test in the absence and presence of a dose-related trend for both Poisson and overdispersed Poisson data. Based on our results, we suggest using the Poisson test when little overdispersion is present in the data. For more overdispersed data, we recommend using the robust Poisson test for highly discrete data (response rate lower than 2-3) and the robust Poisson test or the Jonckheere-Terpstra test for moderately discrete or continuous data (average responses larger than 2 or 3). We also studied the effects of dose metameter misspecification. A clear effect on efficiency was seen when the 'wrong' dose metameter was used to compute the test statistic. In general, unless there is strong reason to do otherwise, we recommend the use of equally spaced dose levels when applying the Poisson or robust Poisson test for trend.

Animals↗

Linkage analysis of a complex pedigree with severe bipolar disorder, using a Markov chain Monte Carlo method.

Recently developed algorithms permit nonparametric linkage analysis of large, complex pedigrees with multiple inbreeding loops. We have used one such algorithm, implemented in the package SimWalk2, to reanalyze previously published genome-screen data from a Costa Rican kindred segregating for severe bipolar disorder. Our results are consistent with previous linkage findings on chromosome 18 and suggest a new locus on chromosome 5 that was not identified using traditional linkage analysis.

Algorithms↗

A nonparametric quantification of neural response field structures.

The response fields of higher cortical neurons are usually approximated with smooth mathematical functions for the purpose of population parameterization or theoretical modeling. We used instead two nonparametric methods (principal component analysis and independent component analysis), which provided a basis for the response field clustering. Although both methods performed satisfactorily, the principal component analysis space is more straightforward to calculate. It also gave a clear preference toward the smallest number of functional response field classes. Clustering was performed with both K-means and superparamagnetic clustering algorithms with similar results. We also show that the shapes of the eigenvectors remain consistent regardless of the response field data sets size. This finding reflects the fact that the response fields were generated by the same neural network and encode the same underlying process.

Brain Mapping↗

Modeling the surround of MT cells and their selectivity for surface orientation in depth specified by motion.

The projective transformation onto the retina loses the explicit 3D shape description of a moving object. Theoretical studies show that the reconstruction of 3D shape from 2D motion information (shape from motion, SFM) is feasible provided that the first- and second-order directional derivatives of the 2D velocity field are available. Experimental recordings have revealed that the receptive fields of the majority of the cells in macaque area middle temporal (MT) display an antagonistic (suppressive) surround and that a sizable portion of these surrounds are asymmetrical. This has led to the conjecture that these cells provide a local measure for the directional derivatives of the 2D velocity field. In this article, we adopt a nonparametric and biologically plausible approach to modeling the role played by the MT surrounds in the recovery of the orientation in depth (the slant and tilt) of a moving (translating) plane. A three-layered neural network is trained to represent the slant and tilt from the projected motion vectors. The hidden units of the network have speed-tuning characteristics and represent the MT model neurons with their surrounds. We conjecture that the MT surround results from lateral inhibitory connections with other MT cells and that populations of these cells, with different surround types, code linearly for slant and tilt of translating planes.

Animals↗

Bounding causal effects under uncontrolled confounding using counterfactuals.

Common sensitivity analysis methods for unmeasured confounders provide a corrected point estimate of causal effect for each specified set of unknown parameter values. This article reviews alternative methods for generating deterministic nonparametric bounds on the magnitude of the causal effect using linear programming methods and potential outcomes models. The bounds are generated using only the observed table. We then demonstrate how these bound widths may be reduced through assumptions regarding the potential outcomes under various exposure regimens. We illustrate this linear programming approach using data from the Cooperative Cardiovascular Project. These bounds on causal effect under uncontrolled confounding complement standard sensitivity analyses by providing a range within which the causal effect must lie given the validity of the assumptions.

Adrenergic beta-Antagonists↗