A. John Petkau

Exposure of chronic obstructive pulmonary disease patients to particles: respiratory and cardiovascular health effects.

To examine hypotheses regarding air pollution health effects, we conducted an exploratory study to evaluate relationships between personal and ambient concentrations of particles with measures of cardiopulmonary health in a sample of patients with chronic obstructive pulmonary disease (COPD). Sixteen currently non-smoking COPD patients (mean age=74) residing in Vancouver were equipped with a particle (PM2.5) monitor for seven 24-h periods. Subjects underwent ambulatory heart monitoring, had their lung function and blood pressure (BP) measured, and recorded symptoms and medication use. Ambient PM2.5, PM10, sulfate, and gaseous pollutant concentrations were monitored at five sites within the study area. Although no associations between air pollution and lung function were statistically significant, an estimated effect of 3% and 1% declines in daily FEV1 change (ΔFEV1) for each 10 μg/m3 increase in ambient PM10 and PM2.5, respectively, was observed. Increases of 1 μg/m3 in personal or ambient sulfate were associated with 1.0% and 0.3% declines in ΔFEV1, respectively. Weak associations were observed between particle concentrations and increased supraventricular ectopic heartbeats and with decreased systolic BP. No consistent associations were observed between any particle metric and diastolic BP, heart rate, or heart rate variability (r-MSSD or SDNN), symptom severity, or bronchodilator use. Of the pollutants measured, ambient PM10 was most consistently associated with health parameters; the use of personal exposures did not improve the strength of any associations or lead to increased effect estimates.

A Comparison of n Estimators for the Binomial Distribution

Abstract Estimating the number, n, of trials, given a sequence of independent success counts obtained by replicating the n-trial experiment is less studied and a considerably harder problem than estimating p for the binomial distribution. Both the method of moments and the maximum likelihood estimators of n are considered. When p is unknown and small, while n is large, both estimators become highly unstable. Stabilized versions of these estimators are proposed, and their performance is described in terms of results obtained by simulation.

A role for natural killer cells in the immunopathogenesis of multiple sclerosis

Seventeen relapsing-remitting (R/R) multiple sclerosis (MS) patients and age/sex matched controls were studied every 6 weeks for 2 years. Disease activity, determined both clinically and by serial MRI, was correlated with natural killer (NK) cell functional activity (FA) and phenotype. Mean NK cell FA is significantly lower in MS patients, compared to controls (P < 0.001), while variability around the means is significantly greater (P < 0.01). The spectrum of mean NK cell FA, observed in the patient cohort, along with cyclical nature of the FA and phenotype over time, observed in both patients and controls, may begin to explain the discrepant results reported in previous studies. In R/R MS, there is a significant correlation between reductions (valleys) in NK cell FA and the development of active lesions on MRI, new (P < 0.001) or enlarging (P = 0.05). More importantly, a significant number of active lesions, new (P = 0.01) and enlarging (P = 0.02), are preceded by a reduction in NK cell FA. The correlation between the onset of clinical attacks and valleys of NK cell FA is also significant (P = 0.002). When taken together, the results suggest that reductions (valleys) in NK cell FA represent periods of susceptibility for the development of active lesions on MRI and clinical attacks. A significant positive correlation is also identified between mean NK cell FA for each R/R MS patient and total number of active MRI lesions developed by that patient over the 2 years (P = 0.001). The results would suggest that R/R MS patients with a higher mean NK cell FA are at greater risk for the development of active lesions. These results support the proposal that NK cells may play a role in the immunopathogenesis of R/R MS.

Longitudinal analyses of the effects of neutralizing antibodies on interferon beta-1b in relapsing-remitting multiple sclerosis

We have analysed data on exacerbation rates, Expanded Disability Status Scale (EDSS) scores, and lesion burdens using the results of two neutralizing antibody (NA B) assays (C PE and MxA) from the pivotal relapsing-remitting multiple sclerosis (MS) trial of interferon beta-1b (IFNB) with a longitudinal appro ach, where the influence of NA Bs in individual patients is assessed by comparing responses during NAB- positive and NA B-negative periods. There are apparent influences on exacerbation rate related to dose of IFNB, titer level, and duration of positivity. With the MxA assay, exacerbation rates after switching to NA B-positive status are estimated to be 28% higher [95% confidence interval (CI): (-15%, 92%)] and -2% higher [95% CI: (-21%, 21%)] on the low- and high-dose IFNB arms, respectively. When compared with all NA B-negative periods, exacerbation rates during NA B-positive periods are estimated to be 29% higher [95% C I: (0%, 67%)] and 18% higher [95% CI: (0%, 40%)] on the low- and high-dose IFNB arms, respectively. When NA B-positive patients again become NA B-negative, no evidence of increased exacerbation rates could then be demonstrated. More detailed exploratory analyses indicate that the effects are most evident in the approximately 20% of patients developing high titers. In these patients, the influence of NABs may be self-limited, as titers often diminish or NA Bs become undetectable with time.

Role of androgens in women's sexual dysfunction

Objective: Although suspected, androgen deficit in women with sexual dysfunction has never been established. Given that serum testosterone levels are of limited value, we sought to compare total androgen activity in women with and without hypoactive sexual desire disorder (HSDD). Intracellular production in target tissues is the major source of testosterone in older women and can now be measured. Androgen metabolites, specifically androsterone glucuronide (ADT-G), reflect intracellular and ovarian sources of testosterone. Thus, we predicted significantly lowered levels of metabolites in women with sexual dysfunction. Methods: A detailed assessment of the sexual function of women without depression, without serious relationship discord, or receiving medications affecting sexual function included 121 women with HSDD and 124 sexually healthy community controls. Sexual function was assessed using structured interviews, validated questionnaires, and steroid analysis-mass spectrometry levels of ADT-G, testosterone, and precursor hormones. Results: No group differences in serum levels of testosterone or ADT-G were found. Significantly lower levels of two precursor hormones, dehydroepiandrosterone sulfate and androstene-3&bgr;,17&bgr;-diol, were found in women with sexual dysfunction (P = 0.006 and P = 0.020, respectively). The variability of metabolite and precursor levels was substantial for all women. Conclusions: Significantly lower levels of the two precursor steroids dehydroepiandrosterone sulfate and androstene-3&bgr;,17&bgr;-diol but not the major androgen metabolite ADT-G were found in women with HSDD. Although the significance of the former awaits further study, androgen deficiency in women with HSDD was not confirmed. Given the unknown long-term effects of testosterone supplementation, women receiving testosterone therapy should be informed that a deficit of testosterone activity in women with HSDD has not been identified.

Regression of new gadolinium enhancing lesion activity in relapsing-remitting multiple sclerosis

Background: Contrast enhancing lesions (CEL) is a common endpoint in multiple sclerosis (MS) clinical trials. To minimize sample size or placebo exposure, a crossover design without a concurrent control group is attractive. Natural regression may confound this strategy. We assessed the degree of regression in monthly new gadolinium activity in relapsing-remitting (RR) placebo patients. Methods: A post hoc analysis was performed on 65 RRMS placebo patients in the Prevention of Relapses and disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis (PRISMS) trial. Patients were originally selected for relapses but not preselected for MRI activity. Eleven MRI scans were taken at screening, baseline, and months 1 through 9. Monthly new CEL rates were examined using a random effects Poisson model. Patients were analyzed as a single group and by screening CEL count level subgroups: no, low, and high (0, 1 to 3, >3 CEL). Results: A total of 32, 19, and 14 patients had no, low, and high CEL counts at screening. The monthly new CEL rates (95% CI) of all patients at baseline, months 1 to 3, 4 to 6, and 7 to 9 were 2.0 (1.3, 2.9), 1.8 (1.3, 2.5), 1.4 (1.0, 2.0), and 1.2 (0.8, 1.7). Compared to baseline, the rate decreased by 10%, 27%, and 39%. The monthly rate of the no subgroup remained stable. The rates for both the low and high subgroups decreased by 4%, 29%, and 48% at months 1 to 3, 4 to 6, and 7 to 9 compared to baseline. Conclusions: Placebo relapsing-remitting multiple sclerosis patients experience a decline of new gadolinium activity over 9 months. A crossover design without a concurrent comparison group may overestimate the treatment effect. GLOSSARY: CEL = contrast enhancing lesions; MS = multiple sclerosis; PRISMS = Prevention of Relapses and disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis; RR = relapsing-remitting.

Sequential Medical Trials for Comparing an Experimental with a Standard Treatment

Abstract The Bayes sequential solution for a particular formulation of the problem of comparing an experimental with a standard treatment in the context of medical trials is determined. For large horizon size, this solution is represented as the solution of a free-boundary problem which also arises as the solution of a related Wiener-process problem. The nature of the solution of this related problem and the approximation to the medical-trials problem provided by this related problem are examined. Suboptimal procedures are evaluated and one of these, a Wald-type sequential procedure, is found to be surprisingly efficient.

Statistical approaches to assessing the effects of neutralizing antibodies IFNβ-1b in the pivotal trial of relapsing-remitting multiple sclerosis

Carefully conducted large-scale clinical trials have provided strong evidence that type I interferons favorably influence clinical and MRI outcomes in patients with multiple sclerosis. Some patients develop neutralizing antibodies (NAbs) to these treatments, reflecting an immune system response. The clinical significance of these NAbs has been uncertain because titers vary widely, and even highly elevated NAb titers decrease to undetectable levels in some patients. Whether NAbs decrease the efficacy of these treatments is a critically important scientific question. We argue that a longitudinal data analysis is the most appropriate approach to address this question.

A longitudinal model for magnetic resonance imaging lesion count data in multiple sclerosis patients

Magnetic resonance imaging (MRI) data are routinely collected at multiple time points during phase 2 clinical trials in multiple sclerosis. However, these data are typically summarized into a single response for each patient before analysis. Models based on these summary statistics do not allow the exploration of the trade-off between numbers of patients and numbers of scans per patient or the development of optimal schedules for MRI scanning. To address these limitations, in this paper, we develop a longitudinal model to describe one MRI outcome: the number of lesions observed on an individual MRI scan. We motivate our choice of a mixed hidden Markov model based both on novel graphical diagnostic methods applied to five real data sets and on conceptual considerations. Using this model, we compare the performance of a number of different tests of treatment effect. These include standard parametric and nonparametric tests, as well as tests based on the new model. We conduct an extensive simulation study using data generated from the longitudinal model to investigate the parameters that affect test performance and to assess size and power. We determine that the parameters of the hidden Markov chain do not substantially affect the performance of the tests. Furthermore, we describe conditions under which likelihood ratio tests based on the longitudinal model appreciably outperform the standard tests based on summary statistics. These results establish that the new model is a valuable practical tool for designing and analyzing multiple sclerosis clinical trials.

The effect of truncation on a sequential test for the drift of brownian motion

Lerche (1986) investigated a sequential testing problem concerned with deciding the sign of a normal mean. He demonstrated that a parabolic boundary which corresponds to