Modeling repeated measurement data for occupational exposure assessment and epidemiology

Repeated measurements designs, occur frequently in the assessment of exposure to toxic chemicals. This thesis deals with the possibilities of using mixed effects models for occupational exposure assessment and in the analysis of exposure response relationships. The model enables simultaneous estimation of both the variance components of exposure (between- and within-subject) and the unbiased regression coefficients for determinants of exposure. Implications are relevant to grouping strategies, hazard control , risk assessment and over-exposure assessment. In an Israeli cohort of industry workers sampled over a year, the geometric standard deviations representing variation of exposure between workers (after adjustment for agent and factory) and within workers were 3.1 and 3.0, respectively. These values may be used, as crude estimates of exposure variability to obtain an interval estimate of mean exposure. In studies among Dutch rubber manifactoring workers exposed to inhalable particulate and rubber fumes and pig farmers exposed to bacterial endotoxins, exposure determinants reduced the random between-worker variance estimators between 59-100%. Interestingly, the random within-worker variability was reduced only in the pig farmer data set, by 25%, when specific work activities that varied over time were accounted for. Results of linear regression and mixed models were compared. In rubber manufacturing, coefficients were similar, but fewer factors affecting exposure were statistically significant due to the high correlation between repeated measurements. In a cohort of benzene-workers, both time related factors and a non-time related factor (e.g. job task) were found to affect the mean exposure significantly. The random between workers variance was highly affected by job task. Time related factors (warm month, pay day, day of the week), were found to be responsible for the high random within-worker variance, which was more than two times higher than the between-worker variance. Grouping strategies in occupational health should result in a small between-worker variance. The within-worker variance often varies greatly. Consequently, in simulated data based on real data we found that it is common to obtain a zero or negative ANOVA estimate of the between-worker variance. We evaluated an approach proposed earlier to use an upper confidence bound when the estimate is negative, and found that this method has three main disadvantages: the estimator can remain negative , performs poorly with two repeated measures per worker, and the method can be extremely sensitive to small changes in the data. Our alternative estimator incorporates "plugging in" of an estimator in which the observed mean squares replaces the expected values and this offers a solution to these problems. Exposure assessment plays an important role in a valid exposure-response evaluation in epidemiology. In a study among Dutch bakers mixed modeling was used in two procedures: firstly to estimate exposure based on specific exposure detreminants, and secondly for exposure-response relationship where the estimated variance components were used as a scaling factor to avoid possible exposure-respons attenuation. The shape of the relationship between sensitization and exposure, was found to be a quadratic function

Effect of gait speed on gait rhythmicity in Parkinson's disease: variability of stride time and swing time respond differently

BACKGROUND: The ability to maintain a steady gait rhythm is impaired in patients with Parkinson's disease (PD). This aspect of locomotor dyscontrol, which likely reflects impaired automaticity in PD, can be quantified by measuring the stride-to-stride variability of gait timing. Previous work has shown an increase in both the variability of the stride time and swing time in PD, but the origins of these changes are not fully understood. Patients with PD also generally walk with a reduced gait speed, a potential confounder of the observed changes in variability. The purpose of the present study was to examine the relationship between walking speed and gait variability. METHODS: Stride time variability and swing time variability were measured in 36 patients with PD (Hoehn and Yahr stage 2–2.5) and 30 healthy controls who walked on a treadmill at four different speeds: 1) Comfortable walking speed (CWS), 2) 80% of CWS 3) 90% of CWS, and 4) 110% of CWS. In addition, we studied the effects of walking slowly on level ground, both with and without a walker. RESULTS: Consistent with previous findings, increased variability of stride time and swing time was observed in the patients with PD in CWS, compared to controls. In both groups, there was a small but significant association between treadmill gait speed and stride time variability such that higher speeds were associated with lower (better) values of stride time variability (p = 0.0002). In contrast, swing time variability did not change in response to changes in gait speed. Similar results were observed with walking on level ground. CONCLUSION: The present results demonstrate that swing time variability is independent of gait speed, at least over the range studied, and therefore, that it may be used as a speed-independent marker of rhythmicity and gait steadiness. Since walking speed did not affect stride time variability and swing time variability in the same way, it appears that these two aspects of gait rhythmicity are not entirely controlled by the same mechanisms. The present findings also suggest that the increased gait variability in PD is disease-related, and not simply a consequence of bradykinesia

Effect of Rivastigmine on Mobility of Patients with Higher-Level Gait Disorder: A Pilot Exploratory Study

Background: Higher-level gait disorder (HLGD) in older adults is characterized by postural instability, stepping dysrhythmicity, recurrent falls and progressive immobility. Cognitive impairments are frequently associated with HLGD. Objectives: The aim of this study was to compare gait and cognitive performance before and after the use of rivastigmine in patients with HLGD, free from cognitive impairment or Parkinsonism. Methods: Fifteen non-demented patients with HLGD (age 79.2 ± 5.9 years; 11 women; Mini-Mental State Examination [MMSE] 28.3 ± 1.4) received escalating doses of rivastigmine for 12 weeks in an open-label, pilot study. They were assessed before and after treatment (week 0 and week 12), and after a 4-week washout period (week 16). Assessments included the Mindstreams computerized neuropsychological battery, Activities-specific Balance Confidence Scale, State-Trait Anxiety Inventory, Geriatric Depression Scale, Timed Up and Go (TUG) test, gait speed and stride time variability. One-way multiple analysis of variance tests for repeated measures were used, and Pillai’s trace test was considered as robust to investigate significant differences. Results: The mean dose of rivastigmine during the 8–12 week period was 5.1 ± 2.3 mg/day. A positive effect was observed on the Mindstreams memory subscale and anxiety scores [Pillai’s trace: F(6,724) = 0.508, p = 0.010; and F(7,792) = 0.545, p = 0.006, respectively, over the course of the study] as well as on mobility (TUG test) [Pillai’s trace: F(4,863) = 0.448; p = 0.028], whereas gait speed and stride time variability did not change. Conclusions: The use of relatively low-dose rivastigmine did not affect gait speed and stride time variability; however, the general mobility and anxiety were improved. These preliminary results warrant a larger, randomized, placebo-controlled study

Simulated Pain and Cervical Motion in Patients with Chronic Disorders of the Cervical Spine

The primary objective of the present study was to determine how simulated severe cervical pain affects cervical motion in patients suffering from two distinct chronic cervical disorders: whiplash (n=25) and degenerative changes (n=25). The second objective was to derive an index that would allow the differentiation of maximal from submaximal performances of cervical range of motion. Patients first performed maximal movement of the head (maximal effort) in each of the six primary directions and then repeated the test as if they were suffering from a much more intense level of pain (submaximal effort). All measurements were repeated within four to seven days. In both groups, there was significant compression of cervical motion during the submaximal effort. This compression was also highly stable on a test-retest basis. In both groups, a significantly higher average coefficient of variation was associated with the imagined pain and it was significantly different between the two clinical groups. In the whiplash group, a logistic regression model allowed the derivation of coefficient of variation-based cutoff scores that might, at selected levels of probability and an individual level, identify chronic whiplash patients who intentionally magnify their motion restriction using pain as a cue. However, the relatively small and very stable compression of cervical motion under pain simulation supports the view that the likelihood that chronic whiplash patients are magnifying their restriction of cervical range of motion using pain as a cue is very low

Parkinson’s Disease Prevalence and Proximity to Agricultural Cultivated Fields

The risk for developing Parkinson’s disease (PD) is a combination of multiple environmental and genetic factors. The Negev (Southern Israel) contains approximately 252.5 km2 of agricultural cultivated fields (ACF). We aimed to estimate the prevalence and incidence of PD and to examine possible geographical clustering and associations with agricultural exposures. We screened all “Clalit” Health Services members in the Negev (70% of the population) between the years 2000 and 2012. Individual demographic, clinical, and medication prescription data were available. We used a refined medication tracer algorithm to identify PD patients. We used mixed Poisson models to calculate the smoothed standardized incidence rates (SIRs) for each locality. We identified ACF and calculate the size and distance of the fields from each locality. We identified 3,792 cases of PD. SIRs were higher than expected in Jewish rural localities (median SIR [95% CI]: 1.41 [1.28; 1.53] in 2001–2004, 1.62 [1.48; 1.76] in 2005–2008, and 1.57 [1.44; 1.80] in 2009–2012). Highest SIR was observed in localities located in proximity to large ACF (SIR 1.54, 95% CI 1.32; 1.79). In conclusion, in this population based study we found that PD SIRs were higher than expected in rural localities. Furthermore, it appears that proximity to ACF and the field size contribute to PD risk

Exploratory Spatial Data Analysis of Congenital Malformations (CM) in Israel, 2000–2006

Congenital Malformations (CM) impose a heavy burden on families and society. Identification of spatial patterns of CM is useful for understanding the epidemiology of this public health issue. In Israel, about 1,000,000 births and 25,000 CM cases at 37 groups were geocoded during 2000–2006. These were geo-analyzed using global-Moran’s-I statistics. Eight groups demonstrated geospatial heterogeneity and were further analyzed at both the census tract (Local Indicator of Spatial Association (LISA) and hot spot analyses) and street levels (spatial scan statistics with two population threshold sizes). The positional definition of results is further discussed in relevance to possible exposure to teratogenic sources in the region. Limitations of data and methods used are presented as well

Increased Incidence of Campylobacter spp. Infection and High Rates among Children, Israel

During 1999–2010, the annual incidence of Campylobacter spp. infection in Israel increased from 31.04 to 90.99 cases/100,000 population, a yearly increase of 10.24%. Children 26-fold higher than for the 30–<50 age group

Statin adherence and the risk of Parkinson's disease: A population-based cohort study.

While experimental data provided some compelling evidence on the benefits of statins on dopaminergic neurons, observational studies reported conflicting results regarding the potential of statins to effect the risk of Parkinson's disease (PD).To evaluate the association between changes in statin adherence over time and PD risk.A population-based cohort of new statin users (ages 40-79, years 1999-2012) was derived from a large Israeli healthcare services organization. Data included history of statin purchases and low density lipoprotein cholesterol (LDL-C) levels. Personal statin adherence was measured annually by the proportion of days covered (PDC). PD was detected employing a drug-tracer approach. Stratified (by sex, LDL-C levels at baseline and age) Cox proportional hazards models with time-dependent covariates were used to compute adjusted Hazard Ratio (HR) with 95%CI.The cohort included 232,877 individuals, 49.3% men. Mean age at first statin purchase was 56.5 (±9.8) years for men and 58.7 (±9.2) years for women. PDC distribution for the whole follow up period differed between men and women: medians 58.3% and 54.1% respectively. During a mean follow up of 7.6 (±3.4) years, 2,550 (1.1%) PD cases were identified. In a 1-year lagged analysis, we found no association between annual statin adherence and PD risk in all age-groups regardless of statin type and potency. Age-pooled HR (95%CI) for men and women with LDL-C levels at baseline ≤160mg/dL were: 0.99 (0.99-1.01), 1.01 (1.00-1.02); and for men and women with LDL-C >160mg/dL levels: 0.99 (0.98-1.01), 0.97 (0.98-1.01).Our findings suggest that statin adherence over time does not affect PD risk. Future studies should use large-scale cohorts and refining assessments of long-term profiles in statin adherence