Personalized activity index, a new safety monitoring tool for multiple sclerosis clinical trials.

BACKGROUND: An abnormal increase of contrast-enhancing lesion (CEL) counts on frequent MRIs is interpreted as a signal of potential worsening in multiple sclerosis (MS) clinical trials. We demonstrate the utility of the MR personalized activity index (MR-pax) to identify such increases. METHODS: We analyzed a previous Phase II study in relapsing patients (n = 167) with MRIs at screening, baseline and months 1-6. We performed five consecutive reviews at 90-day intervals. At each review, we evaluate the MR-pax for each patient and also identify those who meet the rule-of-five (an ad-hoc guideline currently in use). To evaluate its clinical relevance, we assess the relation between having a small MR-pax (≤0.05; indicating an unexpected CEL increase) and relapse status in the 12 weeks post-review. RESULTS: Of the 399 patient reviews, 35 cases met the rule-of-five; 35 had an MR-pax ≤ 0.05; 18 met both criteria. The proportions experiencing clinical relapse are 63% among those meeting the rule-of-five, 61% among those with MR-pax ≤0.05, and 83% for those meeting both criteria, more than double the rate of those meeting neither criterion (40%). CONCLUSION: A guideline combining this new personalized index and the existing threshold-based criterion is able to better identify patients with a higher risk of experiencing relapses.

Further investigation of safety monitoring guidelines based on magnetic resonance imaging lesion activity in multiple sclerosis clinical trials.

We assess two modified guidelines for monitoring patient safety in multiple sclerosis (MS) trials. These guidelines flag patients with an increase in contrast enhancing lesion (CEL) count above a threshold over the CEL level 1-2 months earlier. We compare the new guidelines to the original guideline where the threshold is set according to the baseline by applying the guidelines to two previous studies. The odds ratios of a subsequent clinical relapse associated with meeting the CEL threshold based on the modified guidelines are similar to those based on the original guideline. There is a need for patient and cohort specific monitoring procedures.

MRI-based clinical trials in relapsing-remitting MS: new sample size calculations based on a longitudinal model.

BACKGROUND: Sample sizes for magnetic resonance imaging (MRI)-based clinical trials in multiple sclerosis (MS) generally assume that lesion counts are reasonably described by the negative binomial (NB) model. OBJECTIVE: This study aimed to assess the appropriateness of the NB model for lesion count data and to provide sample sizes for placebo-controlled, MRI-based clinical trials in relapsing-remitting MS using a more realistic model. METHODS: The fit of the NB model in each arm of five MS clinical trials was assessed using Pearson's chi-squared statistic. Required sample sizes associated with various tests of treatment effect were estimated by simulating data from a new, longitudinal model for repeated lesion count data on individual patients. RESULTS: Evidence (p < 0.05) against the NB model was found in at least one arm of four of the five trials. If a trial is designed using this model but the resulting clinical data do not follow its assumptions then this trial can be seriously under-powered for assessing differences in mean lesion counts. CONCLUSION: Sample sizes based on the longitudinal model are more realistic and often smaller than those previously reported using the NB model.

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.

Evaluation of safety monitoring guidelines based on MRI lesion activity in multiple sclerosis.

OBJECTIVE: We evaluate variants of a commonly used data safety monitoring guideline in clinical trials in multiple sclerosis (MS) that flags patients who, at a follow-up visit, have 5 or more contrast-enhancing lesions (CELs) above their baseline count. METHODS: We apply the guideline to a relapsing cohort and a secondary progressive cohort. We assess the number of patients that meet the guideline and describe the characteristics of these patients; we also examine the value of the guideline in predicting relapse occurrence in the 28 days following that MRI. These analyses were repeated for thresholds varying from 1 to 10 CELs above baseline. RESULTS: Between 4% and 6% of patients met the threshold of 5 in both cohorts; patients with higher baseline counts and higher T2 lesion burden were more apt to meet the threshold. After adjustment for other covariates, the odds ratio (OR) of relapse associated with meeting the threshold is significant (p < 0.05) or near significant (0.05 ≤ p < 0.10) for thresholds between 5 and 8 for the relapsing cohort, but not for the secondary progressive cohort. Across thresholds, the adjusted OR is consistently greater than 1, and there is an increasing trend as the threshold increases from 1 to 7. CONCLUSIONS: A guideline based on crossing a threshold CEL count above baseline may be valuable in monitoring patient safety. Further study should be conducted using different datasets to assess the generalizability of these results.

Predictors of sexual desire disorders in women.

INTRODUCTION: A historic belief was that testosterone was the "hormone of desire." However, recent data, which show either minimal or no significant correlation between testosterone levels and women's sexual desire, suggest that nonhormonal variables may play a key role. AIM: To compare women with hypoactive sexual desire disorder (HSDD) and those with the recently proposed more symptomatic desire disorder, Sexual Desire/Interest Disorder (SDID), on the relative contribution of hormonal vs. nonhormonal variables. METHODS: Women with HSDD (N = 58, mean age 52.5) or SDID (N = 52, mean age 50.9) participated in a biopsychosocial assessment in which six nonhormonal domains were evaluated for the degree of involvement in the current low desire complaints. Participants provided a serum sample of hormones analyzed by gas chromatography-mass spectrometry or liquid chromatography/mass spectrometry/mass spectrometry. MAIN OUTCOME MEASURES: Logistic regression was used to assess the ability of variables (nonhormonal: history of sexual abuse, developmental history, psychosexual history, psychiatric status, medical history, and sexual/relationship-related factors; hormonal: dehydroepiandrosterone [DHEA], 5-diol, 4-dione, testosterone, 5-α-dihydrotestosterone, androsterone glucuronide, 3α-diol-3G, 3α-diol-17G, and DHEA-S; and demographic: age, relationship length) to predict group membership. RESULTS: Women with SDID had significantly lower sexual desire and arousal scores, but the groups did not differ on relationship satisfaction or mood. Addition of the hormonal variables to the two demographic variables (age, relationship length) did not significantly increase predictive capability. However, the addition of the six nonhormonal variables to these two sets of predictors significantly increased ability to predict group status. Developmental history, psychiatric history, and psychosexual history added significantly to the predictive capability provided by the basic model when examined individually. CONCLUSIONS: Nonhormonal variables added significant predictive capability to the basic model, highlighting the importance of their assessment clinically where women commonly have SDID in addition to HSDD, and emphasizing the importance of addressing psychological factors in treatment.

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-3ß,17ß-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-3ß,17ß-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.

Does MRI lesion activity regress in secondary progressive multiple sclerosis?

BACKGROUND: The rate of new contrast-enhancing lesions (CELs) on monthly magnetic resonance imaging (MRI) scans has been shown to decrease over a 9-month period in placebo-treated patients with relapsing-remitting (RR) multiple sclerosis (RRMS). OBJECTIVE: We examined this phenomenon in placebo-treated secondary progressive MS (SPMS) patients. METHODS: Patients were chosen from two clinical trials. Monthly scans were taken at screening, baseline and months 1-9 for Cohort-1 and months 1-6 for Cohort-2. We examined the monthly new CEL rates according to initial CEL level: 0, 1-3, >3 CELs at screening, and presence and absence of pre-study relapses. RESULTS: Respectively, 59, 21 and 14 of the 94 Cohort-1 patients, and 36, 17 and 9 of the 62 Cohort-2 patients had 0, 1-3 and >3 initial CELs. For Cohort-1, the monthly new CEL rates did not change during follow-up, regardless of initial CEL level. For Cohort-2, the monthly rate was unchanged in the 0 initial CEL subgroup, but decreased 33% (95% confidence interval: 8%, 52%) from months 1-3 to months 4-6 in the other two subgroups. For the combined cohorts, a decreasing rate was observed in the 12 patients with >3 initial CELs and pre-study relapses. CONCLUSIONS: The short-term trend of new CEL activity in placebo-treated SPMS patients may vary across cohorts.

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.

The impact of ongoing illicit drug use on methadone adherence in illicit drug users receiving treatment for HIV in a directly observed therapy program.

INTRODUCTION: Studies evaluating the effectiveness of opioid agonist therapy programs typically evaluate drug abstinence or treatment retention as their primary outcomes. However, in many circumstances (e.g. directly observed therapy (DOT) programs within methadone maintenance programs), methadone adherence is an extremely relevant clinical outcome. We sought to evaluate the impact of ongoing illicit drug use on methadone adherence within a DOT program for the treatment of HIV-infection. METHODS: Patients were enrolled in a DOT program, where methadone and HIV medication are co-administered by a community pharmacist. Drug use (amphetamines, benzodiazepines, cocaine, and opiates) was assessed by repeated urinalysis results. Methadone adherence was calculated as the fraction of days methadone was administered. RESULTS: Ongoing drug use, and poly-substance use was common, with only 4 of 60 patients abstaining from all illicit drug use. Overall methadone adherence was 84.5%. Amphetamine use (without benzodiazepine and cocaine use), benzodiazepine use (without amphetamines) and higher methadone doses were associated with higher methadone adherence. When patients used benzodiazepines or cocaine, any positive effect associated with amphetamine use was negated. In addition, opiate use was associated with decreased methadone adherence. DISCUSSION: The effect of many illicit drugs on methadone adherence may differ from reports using other treatment outcomes.

Application of hidden Markov models to multiple sclerosis lesion count data.

This paper is motivated by the work of Albert et al. who consider lesion count data observed on multiple sclerosis patients, and develop models for each patient's data individually. From a medical perspective, adequate models for such data are important both for describing the behaviour of lesions over time, and for designing efficient clinical trials. In this paper, we discuss some issues surrounding the hidden Markov model proposed by these authors. We describe an efficient estimation method and propose some extensions to the original model. Our examples illustrate the need for models which describe all patients' data simultaneously, while allowing for inter-patient heterogeneity.

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 (NAB) assays (CPE and MxA) from the pivotal relapsing-remitting multiple sclerosis (MS) trial of interferon beta-1b (IFNB) with a longitudinal approach, where the influence of NABs in individual patients is assessed by comparing responses during NAB-positive and NAB-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 NAB-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 NAB-negative periods, exacerbation rates during NAB-positive periods are estimated to be 29% higher [95% CI: (0%, 67%)] and 18% higher [95% CI: (0%, 40%)] on the low- and high-dose IFNB arms, respectively. When NAB-positive patients again become NAB-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 NABs become undetectable with time.

Statistical approaches to assessing the effects of neutralizing antibodies: IFNbeta-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.

Exposure misclassification and threshold concentrations in time series analyses of air pollution health effects.

Linear, no-threshold relationships are typically reported for time series studies of air pollution and mortality. Since regulatory standards and economic valuations typically assume some threshold level, we evaluated the fundamental question of the impact of exposure misclassification on the persistence of underlying personal-level thresholds when personal data are aggregated to the population level in the assessment of exposure-response relationships. As an example, we measured personal exposures to two particle metrics, PM2.5 and sulfate (SO4(2-)), for a sample of lung disease patients and compared these with exposures estimated from ambient measurements Previous work has shown that ambient:personal correlations for PM2.5 are much lower than for SO4(2-), suggesting that ambient PM2.5 measurements misclassify exposures to PM2.5. We then developed a method by which the measured:estimated exposure relationships for these patients were used to simulate personal exposures for a larger population and then to estimate individual-level mortality risks under different threshold assumptions. These individual risks were combined to obtain the population risk of death, thereby exhibiting the prominence (and the value) of the threshold in the relationship between risk and estimated exposure. Our results indicated that for poorly classified exposures (PM2.5 in this example) population-level thresholds were apparent at lower ambient concentrations than specified common personal thresholds, while for well-classified exposures (e.g., SO4(2-)), the apparent thresholds were similar to these underlying personal thresholds. These results demonstrate that surrogate metrics that are not highly correlated with personal exposures obscure the presence of thresholds in epidemiological studies of larger populations, while exposure indicators that are highly correlated with personal exposures can accurately reflect underlying personal thresholds.

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 (PM(2.5)) 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 PM(2.5), PM(10), 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 FEV(1) change (DeltaFEV(1)) for each 10 microg/m(3) increase in ambient PM(10) and PM(2.5), respectively, was observed. Increases of 1 microg/m(3) in personal or ambient sulfate were associated with 1.0% and 0.3% declines in DeltaFEV(1), 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 PM(10) 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.

Exposure of chronic obstructive pulmonary disease patients to particulate matter: relationships between personal and ambient air concentrations.

Mot time-series studies of particulate air pollution and acute health outcomes assess exposure of the study population using fixed-site outdoor measurements. To address the issue of exposure misclassification, we evaluate the relationship between ambient particle concentrations and personal exposures of a population expected to be at risk of particle health effects. Sampling was conducted within the Vancouver metropolitan area during April-September 1998. Sixteen subjects (non-smoking, ages 54-86) with physician-diagnosed chronic obstructive pulmonary disease (COPD) wore personal PM2.5 monitors for seven 24-hr periods, randomly spaced approximately 1.5 weeks apart. Time-activity logs and dwelling characteristics data were also obtained for each subject. Daily 24-hr ambient PM10 and PM2.5 concentrations were measured at five fixed sites spaced throughout the study region. SO4(2-), which is found almost exclusively in the fine particle fraction and which does not have major indoor sources, was measured in all PM2.5 samples as an indicator of accumulation mode particulate matter of ambient origin. The mean personal and ambient PM2.5 concentrations were 18 micrograms/m3 and 11 micrograms/m3, respectively. In analyses relating personal and ambient measurements, ambient concentrations were expressed either as an average of the values obtained from five ambient monitoring sites for each day of personal sampling, or as the concentration obtained at the ambient site closest to each subject's home. The mean personal to ambient concentration ratio of all samples was 1.75 (range = 0.24 to 10.60) for PM2.5, and 0.75 (range = 0.09 to 1.42) for SO4(2-). Regression analyses were conducted for each subject separately and on pooled data. The median correlation (Pearson's r) between personal and average ambient PM2.5 concentrations was 0.48 (range = -0.68 to 0.83). Using SO4(2-) as the exposure metric, the median r between personal and average ambient concentrations was 0.96 (range = 0.66 to 1.0). Use of the closest ambient site did not improve the median correlation of the group for either PM2.5 or SO4(2-). All pooled analyses resulted in lower correlation coefficients than the median correlation coefficient of individual regressions. Personal SO4(2-) was more highly correlated with all ambient measures than PM2.5. Inclusion of time-activity and dwelling characteristics data did not result in a useful predictive regression model for PM2.5 personal exposure, but improved the model fit from simply regressing against ambient concentration (R2 = 0.27). The model for SO4(2-) was predictive (R2 = 0.82), as personal exposures were largely explained by ambient levels. These results indicate a relatively low correlation between personal exposure and ambient PM2.5 that is not improved by assigning exposure to the closest ambient monitor. The correlation between personal exposure and ambient concentration is high, however, when using SO4(2-), an indicator of accumulation mode particulate matter of ambient origin.

Natural killer cells in relapsing-remitting MS: effect of treatment with interferon beta-1B.

OBJECTIVE: To determine the effect of treatment with interferon beta-1b (IFN-beta) on natural killer (NK) cell function and phenotype in relapsing-remitting MS (RRMS) patients, and their relationship to disease activity assessed both clinically and with serial MRI. BACKGROUND: NK cells may play a role in the immunopathogenesis of MS. Previously the authors reported a positive relationship between mean NK cell functional activity (FA) and total number of active lesions on MRI in a serial study of RRMS. Cycles in NK cell FA over time created a series of peaks and valleys, and a significant relationship has been identified between the valleys and the appearance of active lesions on MRI or onset of clinical attacks. The development of valleys in NK cell FA before the appearance of active lesions on MRI was statistically significant. METHODS: The authors studied the effect of alternate-day therapy with 8.0 mIU (high dose [HD]) or 1.6 mIU (low dose [LD]) IFN-beta on NK cell FA, assessed by an in vitro 51Cr release K-562 target cell assay, and phenotype determination in RRMS patients. RESULTS: Treatment with HD IFN-beta results in an inverse relationship between mean NK cell FA and total number of active lesions on MRI over 2 years. A stronger inverse relationship was found in those patients who did not develop neutralizing antibodies to IFN (HD-) compared with a positive relationship in those who did (HD +). Treatment with IFN-beta did not affect the cyclic nature of NK cell FA, mean NK cell FA, variability around the mean, mean length of the cycle, time spent in valleys and peaks, or the significant relationship between the appearance of active lesions on MRI/onset of clinical attacks and valleys in NK cell FA. In contrast, treatment with HD but not LD IFN-beta did result in a significant reduction in CD57+ (a cell surface marker for subsets of NK cells) peripheral blood lymphocytes (PBL) compared with placebo. This effect, which originated largely from the HD- group of patients, developed shortly after treatment was initiated and was maintained throughout the study. CONCLUSIONS: RRMS patients with higher mean NK cell FA may be not only at greater risk for the development of active lesions but also may be more likely to respond to IFN-beta. Development of neutralizing antibodies to IFN-beta could interfere with this effect. This effect may be mediated through an action on a CD57+ subset of PBL.

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.

Surveillance of clustering near point sources.

Health authorities are often alerted to suspected cancer clusters near the vicinity of potential point sources by members of the public. A surveillance system, where administrative regions around the potential point sources are regularly monitored for high disease rates, would allow for responses which are easier to obtain, timelier, and less expensive than individual thorough investigations. The monitoring could be done by using the so-called 'focused' tests for detecting disease clustering. However, these tests, generally designed to detect clusters of a fixed size around the foci, are not particularly effective when dealing with administrative regions with substantial differences in populations. In this work, an approach which overcomes the problem to a certain extent is described. Here the selected cluster sizes are based on the populations of the administrative regions under examination. The approach is used to investigate whether cancer clustering appears in the vicinity of the pulp and paper mills in British Columbia for the years 1983-1989. The results indicate that the approach performs reasonably well in identifying cancer sites for which elevated risks have also been suggested in the epidemiologic literature. Consequently, this methodology could be utilized to provide guidance for further investigation even in the absence of local reports. Similarly, it could be readily utilized to provide timely responses to local reports.