Drawbacks to Integer Scoring for Ordered Categorical Data

Linear rank tests are widely used when testing for independence against stochastic order in a 2 x J contingency table with two treatments and J ordered outcome levels. For this purpose, numerical scores are assigned, possibly by default, to the J outcome levels. When the choice of scores is not apparent, integer (equally spaced) scores are often assigned. We show that this practice generally leads to unnecessarily conservative tests. The use of slightly perturbed scores will result in a less conservative and uniformly more powerful test.     

Assessing Toxicities in a Clinical Trial: Bayesian Inference for Ordinal Data Nested within Categories

Summary This article addresses modeling and inference for ordinal outcomes nested within categorical responses. We propose a mixture of normal distributions for latent variables associated with the ordinal data. This mixture model allows us to fix without loss of generality the cutpoint parameters that link the latent variable with the observed ordinal outcome. Moreover, the mixture model is shown to be more flexible in estimating cell probabilities when compared to the traditional Bayesian ordinal probit regression model with random cutpoint parameters. We extend our model to take into account possible dependence among the outcomes in different categories. We apply the model to a randomized phase III study to compare treatments on the basis of toxicities recorded by type of toxicity and grade within type. The data include the different (categorical) toxicity types exhibited in each patient. Each type of toxicity has an (ordinal) grade associated to it. The dependence among the different types of toxicity exhibited by the same patient is modeled by introducing patient‐specific random effects.     

A Selection and Testing Procedure for Comparing Several Experimental Treatments with a Control

We consider a selection and testing procedure for comparing k experimental treatments with a control treatment where the treatments are assumed to be normally distributed with unknown means and a common, unknown variance. Stein‐type sampling is used in the selection phase to screen for an experimental treatment that exhibits evidence of being better than the control treatment and each of the other experimental treatments, where better is defined in terms of the largest mean. In the testing phase, the best experimental treatment is compared to the control using a hypothesis test. If no experimental treatment indicates that it is an improvement over the control during the selection phase, our procedure allows for early termination. We provide definitions of level and power appropriate for our hybrid procedure and compute procedure parameters required to implement our procedure.     

High-dose continuous venous infusion of interleukin-2: Influence of dose and infusion rate on tumoricidal function and lymphocyte subsets

Previous clinical studies have demonstrated a dose-response relationship between enhancement of certain immune parameters and interleukin-2 (IL-2) dose in trials with low dosages of the cytokine. This has not been demonstrated for high-dose (greater than 18×10⁶ IU/m² per day) IL-2. We completed phase II trials of sustained administration of indomethacin and ranitidine with IL-2 given as a continuous infusion over 5 days for three courses. Peripheral blood mononuclear cells, both fresh and cultured in vitro with IL-2 or IL-2 and indomethacin, were tested for tumoricidal function against K562 and Daudi targets; these results were then correlated with actual delivered dose and mean infusion rate per course. Similar correlations were calculated between delivered dose or infusion rate and absolute and proportional counts of lymphocyte subsets as determined by flow cytometry. No enhancement of in vitro tumoricidal function with either increasing delivered dose or increasing infusion rate was seen. No consistent pattern of correlation was found between the absolute counts of lymphocyte subsets after each course of IL-2 with delivered dose or infusion rate. The percent rise in absolute counts of selected T- and NK-cell subsets at the end of course 1 compared with baseline values correlated positively with infusion rate; however, a similar correlation between the infusion rate and an increase in lymphocyte tumoricidal function was lacking. Little evidence was found for improved tumoricidal function of mononuclear cells or consistent enhancement of lymphocyte subset counts in patients able to tolerate doses of IL-2 beyond 18×10⁶ IU/m² per day in a 5-day continuous infusion schedule.Presented in part at the Twenty-eighth Annual Meeting of the American Society of Clinical Oncology, May 17–19, 1992, San Diego, Calif.     

Size and Power of Test Statistics for Gene Correlation in 2 × 2 Contingency Tables

Monte Carlo simulation of size and power of two proposed tests for linkage disequilibrium between two genes each with two alleles were investigated. Results were compared with two commonly used statistics, the correlation coefficient r and the log-odds ratio tests. Depending on the sign of the linkage disequilibrium, the new tests were found to be more powerful than either of the correlation or log-odds ratio tests. However, on average (positive and negative linkage disequilibrium) the Chi-square test using the correlation coefficient was to a small extent more powerful than the other tests.     

Utility‐Based Optimization of Combination Therapy Using Ordinal Toxicity and Efficacy in Phase I/II Trials

Summary An outcome‐adaptive Bayesian design is proposed for choosing the optimal dose pair of a chemotherapeutic agent and a biological agent used in combination in a phase I/II clinical trial. Patient outcome is characterized as a vector of two ordinal variables accounting for toxicity and treatment efficacy. A generalization of the Aranda‐Ordaz model (1981, Biometrika 68 , 357–363) is used for the marginal outcome probabilities as functions of a dose pair, and a Gaussian copula is assumed to obtain joint distributions. Numerical utilities of all elementary patient outcomes, allowing the possibility that efficacy is inevaluable due to severe toxicity, are obtained using an elicitation method aimed to establish consensus among the physicians planning the trial. For each successive patient cohort, a dose pair is chosen to maximize the posterior mean utility. The method is illustrated by a trial in bladder cancer, including simulation studies of the method's sensitivity to prior parameters, the numerical utilities, correlation between the outcomes, sample size, cohort size, and starting dose pair.     

The Relative Power of Two Asymptotic Multivariate Tests for Homogeneity in a Contingency Table

In a three way contingency table two multivariate tests for homogeneity have been proposed by the author (1983) a the “catanova” test, which is a trace “metric” test and b the “multinova” test which is determinant based. Both tests are asymptotically distributed as chi-square. In this paper, the power values of the tests are compared and conditions are given for preference of each test.     

One Degree of Freedom for Non-Additivity in a Contingency Table and Its Multivariate Extension

The paper develops a chi-square test with one degree of freedom for row-column interaction in a contingency table. Use is made of the JOHNSON-GRAYBILL [1972] model which is herein generalized to a twoway multiple response situation. Some of the merits of the new test over the better-known tests for the same hypothesis are discussed.     

A Coefficient of Agreement Adjusted for Bias in Paired Ordered Categorical Data

The quality of ordered categorical recordings is determined from repeated measurements on the same subject in order to assess the level of agreement between raters, scales or occasions. The presented rating-invariant method for ordered categorical data provides means of analysing the quality of single-item rating scales, irrespective of the number of possible response values and the marginal distributions. Marginal heterogeneity implies systematic disagreement, so-called bias. An augmented ranking approach is the basis for the separation of inter-rater disagreement into systematic and random components. Correlation between pairs of augmented rank values provides a measure of agreement to the best common ordering of paired classifications, given inter-rater bias. The essential differences in interpretation and applicability of the proposed coefficient of agreement and the Spearman rank-order correlation for ordered categorical data are discussed.     

Nonparametric Analysis of Ordered Categorical Data in Designs with Longitudinal Observations and Small Sample Sizes

For designs with longitudinal observations of ordered categorical data, a nonparametric model is considered where treatment effects and interactions are defined by means of the marginal distributions. These treatment effects are estimated consistently by ranking methods. The hypotheses in this nonparametric setup are formulated by means of the distribution functions. The asymptotic distribution of the estimators for the nonparametric effects are given under the hypotheses. For small samples, a rather accurate approximation is suggested. A clinical trial with ordered categorical data is used to motivate the ideas and to explain the procedures which are extensions of the Wilcoxon‐Mann‐Whitney test to factorial designs with longitudinal observations. The application of the procedures requires only some trivial regularity assumptions.     

A randomized, placebo-controlled, double-blind trial of supplemental docosahexaenoic acid on cognitive processing speed and executive function in females of reproductive age with phenylketonuria: A pilot study

Low blood docosahexaenoic acid (DHA) is reported in patients with phenylketonuria (PKU); however, the functional implications in adolescents and adults are unknown. This pilot study investigated the effect of supplemental DHA on cognitive performance in 33 females with PKU ages 12–47 years. Participants were randomly assigned to receive DHA (10 mg/kg/day) or placebo for 4.5 months. Performance on cognitive processing speed and executive functioning tasks was evaluated at baseline and follow up. Intention-to-treat and per protocol analyses were performed. At follow up, biomarkers of DHA status were significantly higher in the DHA-supplemented group. Performance on the cognitive tasks and reported treatment-related adverse events did not differ. While no evidence of cognitive effect was seen, a larger sample size is needed to be conclusive, which may not be feasible in this population. Supplementation was a safe and effective way to increase biomarkers of DHA status (www.clinicaltrials.gov; Identifier: NCT00892554).     

A Nonparametric Test for Ordered Alternatives in Two-Way Layouts with Censored Data

A nonparametric test is presented to test for ordered alternatives of the treatment effects when the data follow a two-way layout. The observations are subject to arbitrary right censorship. The test is similar to the one developed by Hettmansperger and Norton (1987) for uncensored observations.     

Stem cell application for osteoarthritis in the knee joint: A minireview

Knee osteoarthritis is a chronic, indolent disease that will affect an ever increasing number of patients, especially the elderly and the obese. It is characterized by degeneration of the cartilage substance inside the knee which leads to pain, stiffness and tenderness. By some estimations in 2030, only in the United States, this medical condition will burden 67 million people. While conventional treatments like physiotherapy or drugs offer temporary relief of clinical symptoms, restoration of normal cartilage function has been difficult to achieve. Moreover, in severe cases of knee osteoarthritis total knee replacement may be required. Total knee replacements come together with high effort and costs and are not always successful. The aim of this review is to outline the latest advances in stem cell therapy for knee osteoarthritis as well as highlight some of the advantages of stem cell therapy over traditional approaches aimed at restoration of cartilage function in the knee. In addition to the latest advances in the field, challenges associated with stem cell therapy regarding knee cartilage regeneration and chondrogenesis in vitro and in vivo are also outlined and analyzed. Furthermore, based on their critical assessment of the present academic literature the authors of this review share their vision about the future of stem cell applications in the treatment of knee osteoarthritis.     

A Test Procedure of Equivalence in Ordinal Data with Matched‐Pairs

There are many epidemiologic studies or clinical trials, in which we may wish to establish an equivalence rather than to detect a difference between the distributions of responses. In this paper, we develop test procedures to detect equivalence with respect to the tail marginal distributions and the marginal proportions when the underlying data are on an ordinal scale with matched pairs. We include a numerical example concerning the unaided distance vision of two eyes over 7477 women to illustrate the practical usefulness of the proposed procedure. Finally, we include a brief discussion on the relation between the test procedures developed here and an asymptotic interval estimator proposed elsewhere for the simple difference in dichotomous data with matched‐pairs.     

Applications of an efficient method for comparing immunogold labelling patterns in the same sets of compartments in different groups of cells

Quantitative immunoelectron microscopy often involves determining the distributions of gold label in different intracellular compartments and then drawing comparisons between compartments in the same sample of cells or between experimental groups of cells. In the case of within-group comparisons, recent developments in the estimation of relative labelling index and labelling density make it possible to test whether or not particular compartments are preferentially labelled. These methods are ideally suited to analysing gold label restricted to volume (organelle) or surface (membrane) compartments but may be modified to analyse label localised in mixtures of both. Here, a simple and efficient approach to drawing between-group comparisons for label associated with organelles and/or membranes is presented. The method relies on multistage random sampling of specimens (via blocks and microscopic fields) followed by simply counting gold particles associated with different compartments. The distributions of raw gold counts in different groups are then compared by contingency table analysis with statistical degrees of freedom for chi-squared values being determined by the number of compartments and the number of experimental groups of cells. Compartmental chi-squared values making substantial contributions to the total chi-squared values then identify where the main between-group differences reside. The method requires no information about compartment size (for example, organelle profile area or membrane trace length) and does not even depend critically on standardising between-group magnification. Its application is illustrated using datasets from immunolabelling studies designed to localise the KDEL receptor, phosphatidyl-inositol 4,5-bisphosphate, GLUT4 and rab4 at the electron microscopic level.     

A single blind, placebo controlled, across groups dose escalation study of the safety, tolerability, pharmacokinetics and pharmacodynamics of the melatonin analog beta-methyl-6-chloromelatonin

Clinical investigation of melatonin agonists has been hampered by side effects such as hypothermia, hypotension and bradycardia. The availability of a melatonin agonist devoid of these side effects would improve our understanding of the mechanisms by which melatonin agonists affect sleep. This study investigated the pharmacokinetics, pharmacodynamics and safety of the melatonin agonist beta-methyl-6-chloromelatonin at doses up to 100 mg in healthy volunteers. The design was a single blind, across subjects, placebo controlled, group wise dose escalation using doses of 20, 35, 50 and 100 mg beta-methyl-6-chloromelatonin. Eight subjects received one dose of study drug or placebo. Pharmacokinetic analysis showed a consistent Tmax across all doses with a mean of 1.12 +/- 0.11 hr for all groups (mean +/- SD). The half-life was also consistent across dose, with a mean of 1.04 +/- 0.04 hr. Maximum plasma concentrations increased with increasing dose with values of 44.83 +/- 29.79, 100.3 +/- 41.08, 79.84 +/- 26.36 and 410.3 +/- 129.4 ng/ml at doses of 20, 35, 50 and 100 mg, respectively. Area under the curve showed similar increases. No consistent changes in vital signs occurred as a function of dose or time after study drug. The incidence of all adverse events, the severity of the event or the event's relationship to treatment did not increase with higher doses of beta-methyl-6-chloromelatonin. Sleepiness was reported after all doses of beta-methyl-6-chloromelatonin. beta-methyl-6-chloromelatonin appears safe and well tolerated at doses up to 100 mg. These doses are not associated with hypothermia, bradycardia or hypotension. A melatonin agonist lacking these side effects should allow investigation of the direct soporific effects of melatonin agonists.