Childhood leukemia is the most common malignant disease in children, followed by childhood CNS/brain tumors. [1, 2] Both diseases have been recognized for a long time but little is known about the etiology of childhood leukemia and primary CNS/brain tumors.

The aims of this project were to evaluate: 1) the association of several perinatal factors with childhood leukemia as well as with CNS/brain tumors; 2) the relationships between childhood leukemia and child's and parental race, Hispanic ethnicity and socio-economic status (SES) at individual and census levels; 3) factors associated with residential mobility in childhood leukemia cases.

We conducted a large registry-based study in California using California birth and cancer registries to obtain information on childhood leukemia and CNS/brain tumor cases and controls. Information on case's diagnosis, histological subtypes, age at diagnosis, sex, and diagnosis address was obtained from California cancer registry; information on perinatal factors (birth weight, gestational age, birth order, parental age at birth, maternal complications during pregnancy, abnormal condition of a newborn), socio-demographic factors (date of birth, sex, race and ethnicity of parents and child, parental education, sources of payment for delivery, birth address) were obtained from the birth registry.

We linked California cancer and birth registries to obtain information on 5788 cases of childhood leukemia and 3308 cases of CNS/brain tumors and their 5788 and 3308 controls matched on age and sex (1:1). To address at least partially the problem with misclassification we categorized birth weight, gestational age, parental age, child and parental race and Hispanic ethnicity, individual level proxies for and census-based SES in several ways. For all analyses we used conditional logistic regression, with adjustment for potential confounders.

Our results for childhood leukemia and perinatal factors indicate that high birth weight and LGA were associated with increased risk and SGA with decreased risk of total childhood leukemia and ALL, being first-born was associated with decreased risk of AML, and advanced paternal age was associated with increased risk of ALL. Our results for CNS/brain tumors and perinatal factors suggest that maternal genital herpes, blood and immunological disorders during pregnancy and newborn CNS abnormalities were associated with increased risk of CNS tumors. Maternal infections during pregnancy were associated with decreased risk of CNS tumors. Factors associated with childhood leukemia and CNS tumors varied by subtype, an indicator of different etiology for different subtypes.

We noted that Black children had decreased risk (ref. - White) and Hispanic children (ref. non-Hispanic) had increased risk of total childhood leukemia and ALL. Asian race was associated with increased risk of AML. These differences in the incidence of childhood leukemia indicate that some genetic and/or environmental/cultural (e.g., diet or lifestyle) factors are involved in etiology of childhood leukemia.

We found no evidence to support the suggestion that SES, as measured by variety of proxies is a determinant of childhood leukemia and of its both subtypes. It is likely that results of many previous studies that found an association between childhood leukemia and SES were largely influenced by selection or ecological bias.

The results of this study indicate that childhood leukemia cases in California are residentially very mobile, with 58% of them moving between birth and diagnosis. The residential mobility of childhood leukemia cases notably varied by time interval between birth and diagnosis, child's race/ethnicity, maternal age at birth, census-based SES, and the source of payment for delivery; it varied less by the distance to the nearest power line. Our results suggest that even if information on the residential mobility of subjects is unavailable, it might be possible and important to look at the distribution of factors that could be associated with residential mobility.

Previous studies have observed consistent associations between magnetic fields exposure and childhood leukemia, and in children living close to high voltage overhead power lines. Biologic plausibility, changes over time and other methodologic issues connected with observed associations with magnetic fields exposure suggests that certain factors such as other associated exposures, confounding or interaction effects may play a role in observed childhood leukemia associations. In the US, high voltage overhead power lines are located in right-of-ways (ROW), which are often locations additionally for commercial plant nurseries, a potential source of chronic pesticide exposures due to their close proximity to residencies. Pesticides are substances that are utilized to mitigate, repel, or kill unwanted pests. Pesticides are a potential childhood leukemia risk factor, due to their ability to cause molecular changes that are associated with cancer development.

We performed a large California state-wide records-based case-control study that consisted of childhood leukemia cases younger than 16 years of age that were diagnosed in California (1988-2008) obtained from the California Cancer Registry (CCR) and controls obtained from the California Birth Registry (CBR). Controls were randomly matched to cases based on their date of birth (� 6 months) and sex. We obtained commercial plant nursery and pesticide use information from the California Department of Food and Agriculture (CDFA) and the California Department of Pesticide Regulation (CDPR). We utilized CDFA reported locations for commercial plant nursery businesses that were classified as “producers,” which are plant nurseries that grow and sell a total of $1,000 or more of nursery stock annually. Additionally, we obtained Pesticide Use Reports (PUR) for pesticide applications that occurred at plant nurseries prior to 1990; for 1990 and onward, when more detailed pesticide information was available, we obtained pesticide applications for nursery plants grown in containers from the CDPR. Plant nurseries, pesticide applications and subject residences were then mapped with Geographic Information System (GIS) and then augmented with historic aerial satellite images to improve the obtained native data resolution of plant nursery/pesticide exposure information. Due to the unique size and shape footprint of plant nurseries, we selected subjects that resided within 600 m of a nursery for more detailed assessment. Additionally, many plant nurseries are located underneath high voltage power lines, therefore we selected subjects that resided within 2000 m of such power lines to ensure that we captured all nurseries in proximity to these power lines. We observed that subjects that resided very close to commercial plant nurseries had elevated childhood leukemia risks. Subjects that resided within 75 m of a plant nursery had increased risk of childhood leukemia (OR 2.40, 95% CI 0.99-5.82); this increased risk was stronger for the acute lymphocytic leukemia subtype (OR 3.09, 95% CI 1.14-8.34).

We then explored the potential relationship of commercial outdoor plant nurseries as a confounder or effect modifier for observed childhood leukemia associations with magnetic fields exposure due to high voltage power lines. Power line information was based on GIS data from electric power companies, aerial satellite images and in-person site visits. Associations with childhood leukemia and calculated fields (OR 1.51, 95% CI 0.70-3.23) slightly attenuated after controlling for commercial outdoor plant nursery proximity (OR 1.43, 95% CI 0.65-3.16) or restricting analysis to study subjects residing far away (>300 m) from plant nurseries (OR 1.43, 95% CI 0.79-2.60); similar associations were observed between proximity to high voltage power lines and childhood leukemia after controlling and restricting subjects based on their proximity to plant nurseries. Observed associations for childhood leukemia and proximity to commercial plant nurseries remained elevated after excluding study subjects exposed to high calculated fields (OR 2.16, 95% CI 0.82-5.67) or close power line proximity (OR 2.15, 95% CI 0.82-5.64). Childhood leukemia associations with plant nurseries did not materially change after controlling for calculated fields or power line proximity. Our findings suggest that close residential proximity to plant nurseries is an independent risk factor and that plant nurseries do not explain observed childhood leukemia relationships with magnetic fields exposure or close power line proximity.

Finally, we followed up our study by examining childhood leukemia relationships with more detailed pesticide exposures, including specific intended pesticide use, pesticide chemical classes and active pesticide ingredients. Elevated childhood leukemia risks were observed for exposure to several active pesticide ingredients: permethrin (odds ratio (OR) 1.49, 95% confidence interval (CI) (0.83-2.67), chlorpyrifos (OR 1.29, 95% CI 0.89-1.87), dimethoate (OR 1.79, 95% CI 0.85-3.76), mancozeb (OR 1.41, 95% CI 0.85-2.33), oxyfluorfen (OR 1.41, 95% CI 0.75-2.66), oryzalin (OR 1.60, 95% CI 0.97-2.63), and pendimethalin (OR 1.82, 95% CI 0.81-1.25). Additionally, rodenticide (OR 1.42, 95% CI 0.78-2.66) and molluscicide (OR 1.22, 95% CI 0.82-1.81) exposure had elevated childhood leukemia risks. Observed childhood leukemia associations with calculated fields or power line proximity did not materially change after controlling for pesticide exposure. Our findings suggest that pesticide exposure is an independent risk factor for childhood leukemia and that pesticide exposure does not explain observed childhood leukemia associations with high magnetic fields exposure or nearby power line proximity.

Background: Studying risk factors of rare outcomes can be difficult as single studies tend to have few exposed cases, resulting in rather wide confidence intervals. Therefore, combination of multiple studies is usually necessary to draw a conclusion. Pooling of individual patient data (IPD) is considered the gold standard due to increased statistical power through large sample sizes and other advantages. However, present pooling is limited to studies of the same designs, which does not make full use of existing data.

Objectives: To generalize pooling to studies of different designs (including cohort study, case control study, nested case control study and matched case control study), by incorporating simulation of the association of extremely low frequency magnetic field (ELF-MF) and childhood leukemia.

Method: I first simulated large cohort and case control samples based on parameters extracted from both the literature and existing large cohort and case control datasets, which included ELF-MF exposure prevalence, childhood leukemia incidence rate, prevalence of confounders including age, gender, race and SES. Then I combined these simulated data using three different methods: two stage meta-analysis, one stage pooling and two stage meta-analysis with pooling.

Results: Estimates from three synthesis methods were close to the causal estimate and there was no obvious trend of overestimation or underestimation. One stage pooling seemed to have the worst efficiency with the widest 95%CI but the difference was not significant.

Conclusion: The performance of three synthesis methods in the study was not certain. Further simulations with varying parameters and possible mathematical derivations are needed to assess why and when these methods lead to different effect estimates.

Keywords: Individual patient data (IPD), meta-analysis, pooling, simulation with R, Extremely Low Frequency Magnetic Field (ELF-MF), childhood leukemia

This dissertation examines the association of neurodegenerative diseases and electric occupations and evaluates electric shocks and magnetic fields exposures. First, we conducted a meta-analysis of occupational electromagnetic fields (MF) and neurodegenerative diseases (NDD) to systematically explore methodological differences between studies. Second, we developed an electric shocks job exposure matrix (JEM) to characterize occupations exposed to electric shocks. Finally, we examined the association between occupational electric shocks, MF and amyotrophic lateral sclerosis (ALS) mortality.

We conducted a meta-analysis of epidemiologic studies on occupational MF exposure and NDD. We found weak associations of occupational MF exposures with both AD and MND, but not with Parkinson's disease, dementia, and multiple sclerosis. Risk of developing MND was associated with electric occupations, while AD risk was associated with estimated MF levels. Nonetheless, there is extensive result variation related to aspects of study design, with dissimilarity in this variation across diseases. Our results do not support MF as the explanation for the observed electric occupation and MND association. Misclassification of disease, particularly for AD, and imprecise exposure assessment affected most studies.

To evaluate a consistent association between jobs in "electric" occupations and ALS, we developed a comprehensive JEM that includes electric shocks and MF. Electric shocks were based on two data sources along with expert judgment. Main occupational groups experiencing the electric shocks were precision production, craft and repair occupations. Specific jobs with high electric shock exposure were electrical apprentices, mechanic and repairer helpers, hoist and winch operators and electrical power installers. Examples of job titles with low electric-shock exposures were administrative support occupations, data-key entry operators, and waiters and waitresses.

The relationship between occupational electric shocks, MF and ALS was investigated using cases identified in 1991-1999 U.S. mortality data. For each ALS death, 10 sex-, age-, year- and region-matched controls were selected. We linked the usual occupation reported on the death certificate to a JEM with electric shocks and MF. Increased odds ratios were observed for ALS among those in electric occupations (OR=1.23, 95% confidence interval (CI): 1.04, 1.47). For electric shocks, ALS mortality odds ratios were 0.73 (95% CI: 0.67, 0.79) for high exposure and 0.90 (95% CI: 0.84, 0.97) for medium exposure compared to low exposure. For MF, ALS mortality odds ratios were 1.09 (95% CI: 1.00, 1.19) for high exposure and 1.09 (95% CI: 0.96, 1.23) for medium exposure as compared to low. However, ALS mortality increased only in electric occupations with medium and low electric shocks exposures. Current results support an association between electric occupations and ALS, but provide no evidence that this association is explained by occupational exposure to electric shocks or MF.

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Mortality is high among incident hemodialysis patients especially during the first several months after initiation of dialysis and can be influenced by many factors. Age, vascular access, co-morbid conditions, serum levels of albumin, and dialysis modality may affect survival. We attempted to identify factors that influence survival of incident hemodialysis patients and to determine if changes in clinical practices could improve survival. We hypothesized that patients surviving at least 24 months differ in their characteristics from those who died and so indentifying those differences and making changes may improve survival in all hemodilaysis patients.

Standardized mortality ratios (SMR) were calculated for each of the first 24 months on dialysis to determine the temporal pattern of mortality. Cox proportional hazard models were fitted to examine mortality at several a priory determined time periods for each predictor using case-mix adjustments. The associations between all-cause mortality and combined serum levels of albumin and nPCR were studied for each of first 8 quarters on dialysis. Changes in serum albumin and nPCR levels from the prior quarter were examined separately. Finally, marginal structural models (MSM) were fitted to analyze the association between mortality and dialysis modality during 24 months of treatment. Inverse probability weights were created to account for time varying confounding of quarterly measured laboratory values and changes in dialysis modality over the first 8 quarters.

SMRs were the highest during the 3-6 months after starting dialysis. Use of central venous catheters and low levels of serum albumin at the time of dialysis initiation were associated with all-cause and infection-related mortality during the first 24 months of treatment. Volume overload was associated with cardio-vascular mortality especially in non-hypoalbuminemic patients. Decrease in albumin and nPCR was associated with mortality during 24 months on dialysis. Patients on peritoneal dialysis showed better survival compared to hemodialysis patients after adjusting for modality changes by using MSMs. Patients who changed modalities at least once showed a survival advantage over those who remained on initial modality during 24 months of dialysis treatment.

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