ClustR: A Space-Time Cluster Analysis R Package for Individual-level Data.

BACKGROUND: Until recently, large individual-level longitudinal data were unavailable to investigate clusters of disease, driving a need for suitable statistical tools. We introduce a robust, efficient, intuitive R package, ClustR, for space-time cluster analysis of individual-level data. METHODS: We developed ClustR and evaluated the tool using a simulated dataset mirroring the population of California with constructed clusters. We assessed Cluster's performance under various conditions and compared it with another space-time clustering algorithm: SaTScan. RESULTS: ClustR mostly exhibited high sensitivity for urban clusters and low sensitivity for rural clusters. Specificity was generally high. Compared with SaTScan, ClustR ran faster and demonstrated similar sensitivity, but had lower specificity. Select cluster types were detected better by ClustR than SaTScan and vice versa. CONCLUSION: ClustR is a user-friendly, publicly available tool designed to perform efficient cluster analysis on individual-level data, filling a gap among current tools. ClustR and SaTScan exhibited different strengths and may be useful in conjunction.

Spatial-Temporal Cluster Analysis of Childhood Cancer in California.

BACKGROUND: The observance of nonrandom space-time groupings of childhood cancer has been a concern of health professionals and the general public for decades. Many childhood cancers are suspected to have initiated in utero; therefore, we examined the spatial-temporal randomness of the birthplace of children who later developed cancer. METHODS: We performed a space-time cluster analysis using birth addresses of 5,896 cases and 23,369 population-based, age-, sex-, and race/ethnicity-matched controls in California from 1997 to 2007, evaluating 20 types of childhood cancer and three a priori designated subgroups of childhood acute lymphoblastic leukemia (ALL). We analyzed data using a newly designed semiparametric analysis program, ClustR, and a common algorithm, SaTScan. RESULTS: We observed evidence for nonrandom space-time clustering for ALL diagnosed at 2-6 years of age in the South San Francisco Bay Area (ClustR P = 0.04, SaTScan P = 0.07), and malignant gonadal germ cell tumors in a region of Los Angeles (ClustR P = 0.03, SaTScan P = 0.06). ClustR did not identify evidence of clustering for other childhood cancers, although SaTScan suggested some clustering for Hodgkin lymphoma (P = 0.09), astrocytoma (P = 0.06), and retinoblastoma (P = 0.06). CONCLUSIONS: Our study provides evidence that childhood ALL diagnosed at 2-6 years and malignant gonadal germ cell tumors sporadically occurs in nonrandom space-time clusters. Further research is warranted to identify epidemiologic features that may inform the underlying etiology.

Allergies and Childhood Acute Lymphoblastic Leukemia: A Case-Control Study and Meta-analysis.

Background: Allergic disease is suspected to play a role in the development of childhood acute lymphoblastic leukemia (ALL). Studies conducted over the last several decades have yielded mixed results.Methods: We examined the association between allergy, a common immune-mediated disorder, and ALL in the California Childhood Leukemia Study (CCLS), a case-control study of 977 children diagnosed with ALL and 1,037 matched controls (1995-2015). History of allergies in the first year of life was obtained from interviews, mainly reported by mothers. Logistic regression analyses were conducted to estimate ORs and 95% confidence intervals (CIs), controlling for birth order, daycare attendance, and mode of delivery. In addition, we conducted meta-analyses with data from the CCLS and 12 published studies and employed a new method to estimate between-study heterogeneity (R_b).Results: Overall, no associations were observed between childhood ALL risk and specific allergy phenotypes or any allergy, as a group. However, having any allergy was associated with an increased risk of ALL among the youngest study participants. In the meta-analysis random-effects models, reduced odds of ALL were associated with hay fever (metaOR = 0.65; 95% CI, 0.47-0.90); however, restricting the analysis to studies that used medical records for assessment of allergy or recently published studies led to null or attenuated results.Conclusions: Overall, our findings do not support a clear association between allergy and childhood ALL.Impact: The degree to which epidemiologic studies can inform the relationship between allergies and risk of childhood ALL is limited by R_b. Cancer Epidemiol Biomarkers Prev; 27(10); 1142-50. ©2018 AACR.

Correlates of Prenatal and Early-Life Tobacco Smoke Exposure and Frequency of Common Gene Deletions in Childhood Acute Lymphoblastic Leukemia.

Tobacco smoke exposure has been associated with risk of childhood acute lymphoblastic leukemia (ALL). Understanding the relationship between tobacco exposures and specific mutations may yield etiologic insights. We carried out a case-only analysis to explore whether prenatal and early-life tobacco smoke exposure influences the formation of leukemogenic genomic deletions. Somatic copy number of 8 genes frequently deleted in ALL (CDKN2A, ETV6, IKZF1, PAX5, RB1, BTG1, PAR1 region, and EBF1) was assessed in 559 pretreatment tumor samples from the California Childhood Leukemia Study. Parent and child's passive tobacco exposure was assessed using interview-assisted questionnaires as well as DNA methylation in aryl-hydrocarbon receptor repressor (AHRR), a sentinel epigenetic biomarker of exposure to maternal smoking during pregnancy. Multivariable Poisson regressions were used to test the association between the smoking exposures and total number of deletions. Deletion burden varied by subtype, with a lower frequency in high-hyperdiploid and higher frequency in ETV6-RUNX1 fusion ALL. The total number of deletions per case was positively associated with tobacco smoke exposure, in particular for maternal ever-smoking (ratio of means, RM, 1.31; 95% CI, 1.08-1.59), maternal smoking during pregnancy (RM, 1.48; 95% CI, 1.12-1.94), and during breastfeeding (RM, 2.11; 95% CI, 1.48-3.02). The magnitude of association with maternal ever-smoking was stronger in male children compared with females (Pinteraction = 0.04). The total number of deletions was also associated with DNA methylation at the AHRR epigenetic biomarker (RM, 1.32; 95% CI, 1.02-1.69). Our results suggest that prenatal and early-life tobacco smoke exposure increase the frequency of somatic deletions in children who develop ALL. Cancer Res; 77(7); 1674-83. ©2017 AACR.

Home remodeling and risk of childhood leukemia.

PURPOSE: We investigated the relationship between the risk of childhood leukemia and home remodeling, a surrogate for indoor chemical exposures. METHODS: We collected information on remodeling activities carried out between birth and diagnosis in homes of 609 acute lymphoblastic leukemia (ALL) cases, 89 acute myeloid leukemia (AML) cases, and 893 matched controls participating in the California Childhood Leukemia Study (1995-2008). We used multivariable logistic regression to estimate the risk of ALL and AML associated with six remodeling activities: construction, painting, recarpeting, reflooring, roofing, and weatherproofing. Models were adjusted for age, sex, Hispanic ethnicity, race, household annual income, and residential mobility. RESULTS: Construction in the home between birth and diagnosis was associated with a significant increase in ALL risk (odds ratio [OR]: 1.52, 95% confidence interval [CI]: 1.14-2.02) and a nonsignificant increase in AML risk (OR: 1.75, 95% CI: 0.98-3.15). No other remodeling activities were associated with ALL or AML risk in the main analysis. When stratifying by Hispanic ethnicity, a positive relationship between ALL risk and painting was evident in Hispanic children (OR: 1.47, 95% CI: 1.04-2.07). CONCLUSIONS: Specific home remodeling activities appeared to be associated with increased risk of childhood ALL.

A Revised Approach for the Detection of Sight-Threatening Diabetic Macular Edema.

IMPORTANCE: Diabetic macular edema is one of the leading causes of vision loss among working-age adults in the United States. Telemedicine screening programs and epidemiological studies rely on monoscopic fundus photography for the detection of clinically significant macular edema (CSME). Improving the accuracy of detecting CSME from monoscopic images could be valuable while recognizing the limitations of such detection in an era of optical coherence tomography detection of diabetic macular edema. OBJECTIVE: To evaluate the screening test accuracy of radially arranged sectors affected by hard exudates in the detection of CSME. DESIGN, SETTING, AND PARTICIPANTS: This investigation was a cross-sectional study of CSME grading in monoscopic images using a sectors approach. The Early Treatment Diabetic Retinopathy Study criteria were used to confirm the presence of CSME by the following 2 methods: stereoscopic fundus photography (method 1) and dilated biomicroscopy in combination with optical coherence tomography (method 2). Participants were recruited at a university-based practice between June 14, 2014, and December 28, 2015. MAIN OUTCOMES AND MEASURES: Area under the receiver operating characteristic curve, sensitivity, specificity, positive predictive value, and negative predictive value. RESULTS: A total of 207 eyes from an ethnically/racially diverse group of 207 patients (mean [SD] age, 53.6 [10.8] years; 58.9% [122 of 207] female) were included in the analysis. Twelve eyes (5.8%) were diagnosed as having CSME based on method 1. The intermethod and intergrader agreement for CSME diagnosis and sector count was substantial (κ range, 0.66 [95% CI, 0.47-0.85] to 0.75 [95% CI, 0.53-0.97]; P < .001 for all). Area under the receiver operating characteristic curve was 93.2% (95% CI, 84.2%-100%) when evaluating a sectors approach against method 1 as a reference test and offered up to an 8.6% (95% CI, 3.0%-14.3%) increase in specificity compared with the existing methods of detection. The positive predictive value was 33.3% (95% CI, 25.6%-45.5%), and the negative predictive value was 98.1% (95% CI, 96.9%-100%). The results were similar when comparing a sectors approach with method 2 as a reference test. CONCLUSIONS AND RELEVANCE: A sectors approach shows good screening test characteristics for the detection of CSME. Its implementation in the existing telemedicine programs would require minimal resources. This approach will have the greatest effect in a setting where implementation of optical coherence tomography, a more objective and sensitive way to detect retinal thickening, is not feasible. The proposed method also may be easily incorporated in the automated diabetic retinopathy detection algorithms.

Maternal diet quality before pregnancy and risk of childhood leukaemia.

Previous studies on maternal nutrition and childhood leukaemia risk have focused on the role of specific nutrients such as folate and have not considered broader measures of diet quality, which may better capture intake of diverse nutrients known to impact fetal development. We examined the relationship between maternal diet quality before pregnancy, as summarised by a diet quality index, and risk of childhood acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML) in a case-control study in California. Dietary intake in the year before pregnancy was assessed using FFQ in 681 ALL cases, 103 AML cases and 1076 matched controls. Conditional logistic regression was used to estimate OR and 95 % CI for diet quality continuous score and quartiles (Q1-Q4). Higher maternal diet quality score was associated with reduced risk of ALL (OR 0·66; 95 % CI 0·47, 0·93 for Q4 v. Q1) and possibly AML (OR 0·42; 95 % CI 0·15, 1·15 for Q4 v. Q1). No single index component appeared to account for the association. The association of maternal diet quality with risk of ALL was stronger in children diagnosed under the age of 5 years and in children of women who did not report using vitamin supplements before pregnancy. These findings suggest that the joint effects of many dietary components may be important in influencing childhood leukaemia risk.

A task-based assessment of parental occupational exposure to organic solvents and other compounds and the risk of childhood leukemia in California.

PURPOSE: Data on parental occupational exposures and risk of childhood leukemia lack specificity. Using 19 task-based job modules, we examined the relationship between occupational exposure to organic solvents and other compounds and the risk of leukemia in children. METHODS: Latino (48%) and non-Latino (52%) children with acute lymphoblastic leukemia (ALL; n=670), acute myeloid leukemia (AML; n=104), and controls (n=1021) were enrolled in a study in California (2000-2008). Logistic regression models were used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for socio-demographic factors. RESULTS: Among children with non-Latino fathers, none of the exposures evaluated were associated with risks of ALL and AML. In contrast, exposure to any organic solvents in Latino fathers was associated with an increased risk of childhood ALL (OR=1.48; 95% CI: 1.01-2.16); in multivariable analyses, the OR for chlorinated hydrocarbons was 2.28 (95% CI: 0.97-5.37) while the ORs were close to one for aromatic hydrocarbons, glycol ethers, and other hydrocarbon mixtures. We also observed an increased risk of ALL with exposure to combustion exhaust/polycyclic aromatic hydrocarbons (PAHs) (ORs=1.70; 95% CI: 1.16-2.57, and 1.46; 95% CI: 0.94-2.26 with and without adjustment for chlorinated hydrocarbons, respectively). Moderately elevated risks of ALL were seen with exposure to metals, paints, and wood dust, although not statistically significant. An increased risk was reported for asbestos based on small numbers of exposed Latino fathers. No associations were reported between maternal exposures to any exposures and childhood ALL and AML. CONCLUSIONS: Our data support associations between paternal occupational exposures to chlorinated hydrocarbons, combustion exhaust, metals, and possibly asbestos and the risk of ALL in the children of Latino fathers only.

Parental Tobacco Smoking and Acute Myeloid Leukemia: The Childhood Leukemia International Consortium.

The association between tobacco smoke and acute myeloid leukemia (AML) is well established in adults but not in children. Individual-level data on parental cigarette smoking were obtained from 12 case-control studies from the Childhood Leukemia International Consortium (CLIC, 1974-2012), including 1,330 AML cases diagnosed at age <15 years and 13,169 controls. We conducted pooled analyses of CLIC studies, as well as meta-analyses of CLIC and non-CLIC studies. Overall, maternal smoking before, during, or after pregnancy was not associated with childhood AML; there was a suggestion, however, that smoking during pregnancy was associated with an increased risk in Hispanics (odds ratio = 2.08, 95% confidence interval (CI): 1.20, 3.61) but not in other ethnic groups. By contrast, the odds ratios for paternal lifetime smoking were 1.34 (95% CI: 1.11, 1.62) and 1.18 (95% CI: 0.92, 1.51) in pooled and meta-analyses, respectively. Overall, increased risks from 1.2- to 1.3-fold were observed for pre- and postnatal smoking (P < 0.05), with higher risks reported for heavy smokers. Associations with paternal smoking varied by histological type. Our analyses suggest an association between paternal smoking and childhood AML. The association with maternal smoking appears limited to Hispanic children, raising questions about ethnic differences in tobacco-related exposures and biological mechanisms, as well as study-specific biases.

Maternal prenatal intake of one-carbon metabolism nutrients and risk of childhood leukemia.

PURPOSE: Folate, vitamins B12 and B6, riboflavin, and methionine are critical nutrients for the one-carbon metabolism cycle involved in DNA synthesis and epigenetic processes. We examined the association between maternal intake of these nutrients before pregnancy and risk of childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) in a matched case-control study. METHODS: Maternal dietary intake and vitamin supplement use in the year before pregnancy was assessed by food frequency questionnaire for 681 ALL cases, 103 AML cases, and 1076 controls. Principal component analysis was used to construct a variable representing combined nutrient intake, and conditional logistic regression estimated the odds ratio (OR) and 95% confidence interval (CI) for the association of ALL and AML with the principal component and each nutrient. RESULTS: Higher maternal intake of one-carbon metabolism nutrients from food and supplements combined was associated with reduced risk of ALL (OR for one-unit change in the principal component = 0.91, CI 0.84-0.99) and possibly AML (OR for the principal component = 0.83, CI 0.66-1.04). When analyzed separately, intake of supplements high in these nutrients was associated with a reduced risk of ALL in children of Hispanic women only. CONCLUSIONS: In conclusion, these data suggest that higher maternal intake of one-carbon metabolism nutrients may reduce risk of childhood leukemia.

Tobacco Smoke and Ras Mutations Among Latino and Non-Latino Children with Acute Lymphoblastic Leukemia.

BACKGROUND AND AIMS: Childhood acute lymphoblastic leukemia (ALL) is a biologically heterogeneous disease, and mutations in the KRAS and NRAS oncogenes are present at diagnosis in about one-fifth of cases. Ras mutations were previously associated with environmental exposures in leukemias as well as in many other cancer types. This study examined whether Ras mutation could define a unique etiologic group of childhood ALL associated with tobacco smoke, a well-established mutagen and carcinogen. METHODS: We included 670 children with ALL enrolled in a case-control study in California (1995-2013), including 50.6% Latinos. Parental and child exposure to tobacco smoke was obtained from interviews. Sanger sequencing was used to detect the common KRAS and NRAS hotspot mutations in diagnostic bone marrow DNA. ALL cases were also characterized for common chromosome abnormalities. In case-case analyses, logistic regression analyses were used to estimate odds ratios to describe the association between tobacco smoke exposure and childhood ALL with Ras mutations. RESULTS: KRAS or NRAS mutations were detected in ∼18% of children diagnosed with ALL. Ras mutations were more common among Latino cases compared with non-Latino whites and in high-hyperdiploid ALL. No associations were observed between parental smoking or child's passive exposure to smoke and Ras positive ALL. CONCLUSIONS: The apparent lack of association between tobacco smoke and Ras mutation in childhood ALL suggests that Ras mutations do not specifically define a tobacco-related etiologic pathway. Reasons for racial and ethnic differences in ALL are not well understood and could reflect differences in etiology that warrant further examination.

Ocular Surface Cooling Corresponds to Tear Film Thinning and Breakup.

PURPOSE: To investigate the relationship between ocular surface temperature (OST) and tear film thinning and breakup. METHODS: Simultaneous imaging of OST and fluorescein tear thinning and breakup (FTBU) was performed on 20 subjects. Subjects were asked to open their eyes and refrain from blinking for as long as they could during testing. Ocular surface temperature was measured using an infrared thermographic camera (FLIR A655sc) and rates of ocular surface cooling (OSC) were analyzed using commercially available software. A method was developed to quantify the rate of FTBU formation using image-processing software. RESULTS: Areas of FTBU and regions of OSC were observed to be colocalized, with localized cooling preceding the formation of FTBU. The rates of OSC and FTBU formation were positively correlated (r = 0.74). A second-order polynomial model accurately describes the physiological relationship between the area of FTBU and OST (p < 0.001). A linear approximation provides a more clinically interpretable rate of FTBU formation with decreasing OST (p < 0.001), while still retaining high R. CONCLUSIONS: The results suggest a direct relationship between FTBU formation and OSC. That cooling of the ocular surface precedes FTBU formation implies a process of evaporation contributing to tear film thinning and breakup. Our study suggests that measuring the OSC rate could be an indirect assessment of tear evaporation and could contribute to the management of evaporative dry eye.

Maternal supplementation with folic acid and other vitamins and risk of leukemia in offspring: a Childhood Leukemia International Consortium study.

BACKGROUND: Maternal prenatal supplementation with folic acid and other vitamins has been inconsistently associated with a reduced risk of childhood acute lymphoblastic leukemia (ALL). Little is known regarding the association with acute myeloid leukemia (AML), a rarer subtype. METHODS: We obtained original data on prenatal use of folic acid and vitamins from 12 case-control studies participating in the Childhood Leukemia International Consortium (enrollment period: 1980-2012), including 6,963 cases of ALL, 585 cases of AML, and 11,635 controls. Logistic regression was used to estimate pooled odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for child's age, sex, ethnicity, parental education, and study center. RESULTS: Maternal supplements taken any time before conception or during pregnancy were associated with a reduced risk of childhood ALL; odds ratios were 0.85 (95% CI = 0.78-0.92) for vitamin use and 0.80 (0.71-0.89) for folic acid use. The reduced risk was more pronounced in children whose parents' education was below the highest category. The analyses for AML led to somewhat unstable estimates; ORs were 0.92 (0.75-1.14) and 0.68 (0.48-0.96) for prenatal vitamins and folic acid, respectively. There was no strong evidence that risks of either types of leukemia varied by period of supplementation (preconception, pregnancy, or trimester). CONCLUSIONS: Our results, based on the largest number of childhood leukemia cases to date, suggest that maternal prenatal use of vitamins and folic acid reduces the risk of both ALL and AML and that the observed association with ALL varied by parental education, a surrogate for lifestyle and sociodemographic characteristics.

Potential role of selection bias in the association between childhood leukemia and residential magnetic fields exposure: a population-based assessment.

PURPOSE: Data from the Northern California Childhood Leukemia Study (NCCLS) were used to assess whether selection bias may explain the association between residential magnetic fields (assessed by wire codes) and childhood leukemia as previously observed in case-control studies. METHODS: Wiring codes were calculated for participating cases, n=310; and non-participating cases, n=66; as well as for three control groups: first-choice participating, n=174; first-choice non-participating, n=252; and replacement (non-first choice participating controls), n=220. RESULTS: Participating controls tended to be of higher socioeconomic status than non-participating controls, and lower socioeconomic status was related to higher wire-codes. The odds ratio (OR) for developing childhood leukemia associated with high wire-codes was 1.18 (95% CI: 0.85, 1.64) when all cases were compared to all first-choice controls (participating and non-participating). The OR for developing childhood leukemia in the high current category was 1.43 (95% CI: 0.91, 2.26) when participating cases were compared to first-choice participating controls, but no associations were observed when participating cases were compared to non-participating controls (OR=1.06, 95% CI: 0.71, 1.57) or to replacement controls (OR=1.06, 95% CI: 0.71, 1.60). CONCLUSIONS: The observed risk estimates vary by type of control group, and no statistically significant association between wire codes and childhood leukemia is observed in the California population participating in the NCCLS.

Mode of delivery and risk of childhood leukemia.

BACKGROUND: Childhood infection and immune response have long been suspected in the etiology of childhood leukemia, specifically acute lymphoblastic leukemia (ALL). Normal primary inoculation of the core human microbiome is circumvented by cesarean section (CS) delivery, which is a proposed modulator of both immune response and early-life infection. METHODS: In this study, we examined CS delivery and the risk of childhood leukemia using data from the California Childhood Leukemia Study (CCLS) case-control study and additive logistic regression models. RESULTS: We observed no association between CS and acute myelogenous leukemia [OR, 0.96; 95% confidence interval (CI), 0.52-1.55]. We observed a suggestive association for ALL and CS (OR, 1.22; 95% CI, 0.97-1.54). When examining common ALL (cALL), defined as ALL with expression of CD10 and CD19 surface antigens and diagnosis occurring between 2 and 5.9 years of age, we found a significant association with CS (OR, 1.44; 95% CI, 1.0-2.06). ALL subjects that are not cALL showed a similar risk as ALL overall (OR, 1.15; 95% CI, 0.91-1.44). Because of previous findings suggesting effect modification, we stratified cALL subjects by Hispanic status. Although we observed no relationship for CS in non-Hispanics (OR, 1.14; 95% CI, 0.72-1.79), we did observe a strong association between cALL and CS in Hispanics (OR, 2.34; 95% CI, 1.23-4.46). CONCLUSION: Within the CCLS, CS delivery seems to be associated with cALL and Hispanic subjects may be driving the association. IMPACT: Further research combined with investigations into response to early infection and the microbiome is warranted.

Socioeconomic status and lung cancer: unraveling the contribution of genetic admixture.

OBJECTIVES: We examined the relationship between genetic ancestry, socioeconomic status (SES), and lung cancer among African Americans and Latinos. METHODS: We evaluated SES and genetic ancestry in a Northern California lung cancer case-control study (1998-2003) of African Americans and Latinos. Lung cancer case and control participants were frequency matched on age, gender, and race/ethnicity. We assessed case-control differences in individual admixture proportions using the 2-sample t test and analysis of covariance. Logistic regression models examined associations among genetic ancestry, socioeconomic characteristics, and lung cancer. RESULTS: Decreased Amerindian ancestry was associated with higher education among Latino control participants and greater African ancestry was associated with decreased education among African lung cancer case participants. Education was associated with lung cancer among both Latinos and African Americans, independent of smoking, ancestry, age, and gender. Genetic ancestry was not associated with lung cancer among African Americans. CONCLUSIONS: Findings suggest that socioeconomic factors may have a greater impact than genetic ancestry on lung cancer among African Americans. The genetic heterogeneity and recent dynamic migration and acculturation of Latinos complicate recruitment; thus, epidemiological analyses and findings should be interpreted cautiously.

Tobacco smoke exposure and the risk of childhood acute lymphoblastic and myeloid leukemias by cytogenetic subtype.

BACKGROUND: Tobacco smoke contains carcinogens known to damage somatic and germ cells. We investigated the effect of tobacco smoke on the risk of childhood acute lymphoblastic leukemia (ALL) and myeloid leukemia (AML), especially subtypes of prenatal origin such as ALL with translocation t(12;21) or high-hyperdiploidy (51-67 chromosomes). METHODS: We collected information on exposures to tobacco smoking before conception, during pregnancy, and after birth in 767 ALL cases, 135 AML cases, and 1,139 controls (1996-2008). Among cases, chromosome translocations, deletions, or aneuploidy were identified by conventional karyotype and fluorescence in situ hybridization. RESULTS: Multivariable regression analyses for ALL and AML overall showed no definite evidence of associations with self-reported (yes/no) parental prenatal active smoking and child's passive smoking. However, children with history of paternal prenatal smoking combined with postnatal passive smoking had a 1.5-fold increased risk of ALL [95% confidence interval (CI), 1.01-2.23], compared to those without smoking history (ORs for pre- or postnatal smoking only were close to one). This joint effect was seen for B-cell precursor ALL with t(12;21) (OR = 2.08; 95% CI, 1.04-4.16), but not high hyperdiploid B-cell ALL. Similarly, child's passive smoking was associated with an elevated risk of AML with chromosome structural changes (OR = 2.76; 95% CI, 1.01-7.58), but not aneuploidy. CONCLUSIONS: Our data suggest that exposure to tobacco smoking was associated with increased risks of childhood ALL and AML; and risks varied by timing of exposure (before and/or after birth) and cytogenetic subtype, based on imprecise estimates. IMPACT: Parents should limit exposures to tobacco smoke before and after the child's birth.

Exposure to herbicides in house dust and risk of childhood acute lymphoblastic leukemia.

We examine the association between exposure to herbicides and childhood acute lymphoblastic leukemia (ALL). Dust samples were collected from homes of 269 ALL cases and 333 healthy controls (<8 years of age at diagnosis/reference date and residing in same home since diagnosis/reference date) in California, using a high-volume surface sampler or household vacuum bags. Amounts of agricultural or professional herbicides (alachlor, metolachlor, bromoxynil, bromoxynil octanoate, pebulate, butylate, prometryn, simazine, ethalfluralin, and pendimethalin) and residential herbicides (cyanazine, trifluralin, 2-methyl-4-chlorophenoxyacetic acid (MCPA), mecoprop, 2,4-dichlorophenoxyacetic acid (2,4-D), chlorthal, and dicamba) were measured. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by logistic regression. Models included the herbicide of interest, age, sex, race/ethnicity, household income, year and season of dust sampling, neighborhood type, and residence type. The risk of childhood ALL was associated with dust levels of chlorthal; compared to homes with no detections, ORs for the first, second, and third tertiles were 1.49 (95% CI: 0.82-2.72), 1.49 (95% CI: 0.83-2.67), and 1.57 (95% CI: 0.90-2.73), respectively (P-value for linear trend=0.05). The magnitude of this association appeared to be higher in the presence of alachlor. No other herbicides were identified as risk factors of childhood ALL. The data suggest that home dust levels of chlorthal, and possibly alachlor, are associated with increased risks of childhood ALL.

HLA-DP genetic variation, proxies for early life immune modulation and childhood acute lymphoblastic leukemia risk.

The human leukocyte antigen (HLA) genes are candidate genetic susceptibility loci for childhood acute lymphoblastic leukemia (ALL). We examined the effect of HLA-DP genetic variation on risk and evaluated its potential interaction with 4 proxies for early immune modulation, including measures of infectious exposures in infancy (presence of older siblings, daycare attendance, ear infections) and breastfeeding. A total of 585 ALL cases and 848 controls were genotyped at the HLA-DPA1 and DPB1 loci. Because of potential heterogeneity in effect by race/ethnicity, we included only non-Hispanic white (47%) and Hispanic (53%) children and considered these 2 groups separately in the analysis. Logistic regression analyses showed an increased risk of ALL associated with HLA-DPB1*01:01 (odds ratio [OR] = 1.43, 95% CI, 1.01-2.04) with no heterogeneity by Hispanic ethnicity (P = .969). Analyses of DPB1 supertypes showed a marked childhood ALL association with DP1, particularly for high-hyperdiploid ALL (OR = 1.83; 95% CI, 1.20-2.78). Evidence of interaction was found between DP1 and older sibling (P = .036), and between DP1 and breastfeeding (P = .094), with both showing statistically significant DP1 associations within the lower exposure categories only. These findings support an immune mechanism in the etiology of childhood ALL involving the HLA-DPB1 gene in the context of an insufficiently modulated immune system.

Reliability of maternal-reports regarding the use of household pesticides: experience from a case-control study of childhood leukemia.

INTRODUCTION: Self-reported household pesticide use has been associated with higher risk of childhood leukemia in a number of case-control studies. The aim of this study is to assess the reliability of self-reported household use of pesticides and potential differences in reliability by case-control status, and by socio-demographic characteristics. METHODS: Analyses are based on a subset of the Northern California Childhood Leukemia Study population. Eligible households included those with children less than 8 years old who lived in the same residence since diagnosis (reference date for controls). The reliability was based on two repeated in-person interviews. Kappa, percent positive and negative agreements were used to assess reliability of responses to ever/never use of six pesticides categories. RESULTS: Kappa statistics ranged from 0.31 to 0.61 (fair to substantial agreement), with 9 out of the 12 tests indicating moderate agreement. The percent positive agreement ranged from 46 to 80% and the percent negative agreement from 54 to 95%. Reliability for all pesticide types as assessed by the three reliability measures did not differ significantly for cases and controls as confirmed by bootstrap analysis. For most pesticide types, Kappa and percent positive agreement were higher for non-Hispanics than Hispanics and for households with higher income vs. lower income. CONCLUSIONS: Reproducibility of maternal-reported pesticide use was moderate to high and was similar among cases and controls suggesting that differential recall is not likely to be a major source of bias.