Residential proximity to croplands at birth and childhood leukaemia.

BACKGROUND: Domestic and parental occupational pesticide exposures are suspected of involvement in the occurrence of childhood acute leukaemia (AL), but the role of exposure to agricultural activities is little known. In a previous ecological study conducted in France, we observed an increase in acute lymphoblastic leukaemia (ALL) incidence rate with increasing viticulture density in the municipalities of residence at diagnosis. OBJECTIVES: This study aimed to test the hypothesis that residential proximity to croplands at birth increases the risk of childhood AL, with a particular focus on vineyards. METHODS: We identified all the primary AL cases diagnosed before the age of 15 years in the cohorts of children born in the French municipalities between 1990 and 2015. We estimated crop densities in each municipality of residence at birth using agricultural census data, for ten crop types. Variations in standardized incidence ratios (SIR) were evaluated with Poisson regression models, for all AL, ALL and acute myeloid leukaemia (AML), separately. RESULTS: Among the 19,809,700 children born and residing in mainland France at birth in 1990-2015, 8,747 AL cases (7,236 ALL and 1,335 AML) were diagnosed over the period. We did not evidence any statistically significant positive association between total crop density or any specific crop density in the municipality of residence at birth and all AL, ALL or AML. Interestingly, we observed a higher ALL incidence rate in the municipalities with the highest viticulture densities (SIR = 1.25 95%CI [1.01-1.54]). Adjusting for the main potential confounders did not change the results. CONCLUSION: Our study does not support the hypothesis that residential proximity to croplands, particularly vineyards, around birth plays a role in childhood leukaemia. The slightly higher ALL incidence rate in children born in the municipalities with the highest viticulture densities may reflect the previously-observed association at diagnosis.

Seasonal variations in childhood leukaemia incidence in France, 1990-2014.

BACKGROUND: Several studies have addressed the potential seasonality of childhood acute leukaemia (AL) without conclusive results. Using data from the National Registry of Childhood Cancers over 1990-2014 in mainland France, we investigated the seasonal variations in childhood AL taken together, and lymphoblastic (ALL) and myeloid (AML) leukaemia separately. METHODS: Assuming constant variations over 1990-2014, we used a Poisson regression model to evaluate variations in standardized incidence ratios (SIRs) by month of birth or diagnosis. A scan method for temporal cluster detection was used to identify windows of several consecutive months with high or low SIR. The yearly reproducibility of the observed monthly variations was then evaluated. RESULTS: We included 11,528 AL, of which 9493 ALL and 1,843 AML. No seasonal variation was detected for ALL. With a clear seasonal pattern, differences in AML incidence rates were evidenced between January-April and May-December birth periods (SIR = 0.85, 95% CI 0.77-0.94 and SIR = 1.07, 95% CI 1.01-1.14, respectively). AML incidence variations by month of diagnosis were less clear-cut. CONCLUSION: Based on a large number of cases from a high-quality registry, we did not evidence any seasonality in ALL incidence rates but evidenced seasonal variations in AML incidence rates by month of birth.

Agricultural crop density in the municipalities of France and incidence of childhood leukemia: An ecological study.

BACKGROUND: Pesticide exposure is suspected to play a role in the etiology of childhood leukemia (AL). Various sources of exposure have been explored, but few studies have investigated the risk of childhood AL in relation to residential exposure to agricultural pesticides. Since around 50% of France is agricultural land, with marked pesticide use, France is a suitable location to investigate for an association. We aimed to analyze the association between the agricultural crop density in the municipalities of France and the incidence of childhood AL between 1990 and 2014. METHODS: 11,487 cases of AL diagnosed in children aged 0-14 years were registered by the French National Registry of Childhood Hematological Malignancies over 1990-2014. National agricultural census data for 1990, 2000 and 2010 were used to estimate the densities of the most common crops in France. The incidence of AL was estimated in the 35,512 municipalities, by age and gender, and 3 observation periods, and expressed as the standardized incidence ratio (SIR). RESULTS: We observed a moderate log-linear association between viticulture density and the incidence of AL, with a 3% increase in SIR for a 10% increase in viticulture density (SIRR = 1.03; 95%CI [1.00-1.06]). The association remained for lymphoblastic AL but not for myeloid AL. The association was stable after stratification by geographic area, age and period, and after adjustment on UV radiation and a French deprivation index. No consistent association was observed for other crop types. DISCUSSION: This nationwide study shows a moderate increase in incidence of childhood AL in municipalities where viticulture is common. Future individual studies are needed to know whether this observation is confirmed and related to particular use of pesticides.

Epidemiological studies of natural sources of radiation and childhood cancer: current challenges and future perspectives.

The empirical estimation of cancer risks in children associated with low-dose ionising radiation (<100 mSv) remains a challenge. The main reason is that the required combination of large sample sizes with accurate and comprehensive exposure assessment is difficult to achieve. An international scientific workshop, 'Childhood cancer and background radiation', organised by the Institute of Social and Preventive Medicine of the University of Bern, brought together researchers in this field to evaluate how epidemiological studies of background radiation and childhood cancer can best improve our understanding of the effects of low-dose ionising radiation. This review summarises and evaluates the findings of these studies with regard to their methodological differences, identifies key limitations and challenges, and proposes ways to move forward. Large childhood cancer registries, such as those in Great Britain, France and Germany, now permit the conducting of studies that should have sufficient statistical power to detect the effects predicted by standard risk models. Nevertheless, larger studies or pooled studies will be needed to investigate disease subgroups. The main challenge is to accurately assess children's individual exposure to radiation from natural sources and from other sources, as well as potentially confounding non-radiation exposures, in such large study populations. For this, the study groups should learn from each other to improve exposure estimation and develop new ways to validate exposure models with personal dosimetry.

Proximity to overhead power lines and childhood leukaemia: an international pooled analysis.

BACKGROUND: Although studies have consistently found an association between childhood leukaemia risk and magnetic fields, the associations between childhood leukaemia and distance to overhead power lines have been inconsistent. We pooled data from multiple studies to assess the association with distance and evaluate whether it is due to magnetic fields or other factors associated with distance from lines. METHODS: We present a pooled analysis combining individual-level data (29,049 cases and 68,231 controls) from 11 record-based studies. RESULTS: There was no material association between childhood leukaemia and distance to nearest overhead power line of any voltage. Among children living < 50 m from 200 + kV power lines, the adjusted odds ratio for childhood leukaemia was 1.33 (95% CI: 0.92-1.93). The odds ratio was higher among children diagnosed before age 5 years. There was no association with calculated magnetic fields. Odds ratios remained unchanged with adjustment for potential confounders. CONCLUSIONS: In this first comprehensive pooled analysis of childhood leukaemia and distance to power lines, we found a small and imprecise risk for residences < 50 m of 200 + kV lines that was not explained by high magnetic fields. Reasons for the increased risk, found in this and many other studies, remains to be elucidated.

Residential exposure to ultraviolet light and risk of precursor B-cell acute lymphoblastic leukemia: assessing the role of individual risk factors, the ESCALE and ESTELLE studies.

BACKGROUND: In a previous nationwide ecological study based on 20 years of registration and 7,443 cases of acute lymphoblastic leukemia (ALL), we reported a positive association between residential solar ultraviolet (UV) light at diagnosis and childhood precursor B-cell acute lymphoblastic leukemia (PBC-ALL). OBJECTIVE: The present study investigated the influence of suspected individual risk factors for ALL on the association between UV and PBC-ALL, and evaluated this association at the residence at birth. METHODS: Individual data collected by interviews in the ESCALE (2003-2004) and ESTELLE (2010-2011) nationwide case-control studies, which included 1,511 cases of leukemia aged less than 15 years and 3,102 population controls, were analyzed. Municipalities of residences at birth and at diagnosis/interview were extracted and assigned UV radiation exposure from the EUROSUN database. The potential confounders or effect modifiers considered were strongly suspected risk factors for ALL that were available in the ESCALE and ESTELLE studies. RESULTS: UV exposure at diagnosis was associated with PBC-ALL (OR = 1.27 [1.08-1.48]) for UV > 105.5 J/cm2 compared to UV ≤ 105.5 J/cm2. Considering exposure to UV at birth rather than at diagnosis/inclusion yielded almost identical results as both variables were strongly correlated. Taking into account the suspected ALL risk factors did not affect this association in the pooled study. CONCLUSION: Our findings suggest that our previous observation of an ecological association between residential UV radiation exposure at diagnosis and PBC-ALL was not confounded or modified by individual risk factors, and that the critical exposure time window may be prenatal.

Risk of Childhood Cancer and Socio-economic Disparities: Results of the French Nationwide Study Geocap 2002-2010.

BACKGROUND: Socio-economic status is related to many life style and environmental factors, some of which have been suggested to influence the risk of childhood cancer. Studies requiring subject participation are usually hampered by selection of more educated parents. To prevent such bias, we used unselected nationwide Geographical Information System (GIS)-based registry data, to investigate the influence of socio-economic disparities on the risk of childhood cancer. METHODS: The Geocap study included all French residents diagnosed with cancer aged up to 15 years over the period 2002-2010 (15 111 cases) and 45 000 contemporaneous controls representative of the childhood population. Area socio-economic characteristics used to calculate the European Deprivation Index (EDI) were based on census data collected on the fine scale of the Merged Islet for Statistical Information (IRIS). RESULTS: Overall, the risk of acute lymphoblastic leukaemia (ALL) was lower in the most deprived quintile than in the other quintiles of EDI (ORQ5vs

Residential Proximity to Heavy-Traffic Roads, Benzene Exposure, and Childhood Leukemia-The GEOCAP Study, 2002-2007.

Childhood leukemia may be associated with traffic-related environmental exposure to benzene, and additional data are needed. The Géolocalisation des Cancers Pédiatriques (GEOCAP) Study, a nationwide French case-control study, was designed to avoid selection bias due to differential participation and misclassification. The study compared the 2,760 childhood leukemia cases diagnosed in France between 2002 and 2007 (including 2,275 cases of acute lymphoblastic leukemia (ALL) and 418 cases of acute myeloblastic leukemia (AML)) with 30,000 contemporaneous child population controls. The residence addresses were precisely geocoded, and 3 indicators of residential proximity to traffic were considered. Estimates of benzene concentrations were also available for the Île-de-France region (including Paris). A 300-m increase in major road length within 150 m of the geocoded address was significantly associated with AML (odds ratio = 1.2, 95% confidence interval: 1.0, 1.4) but not with ALL (odds ratio = 1.0, 95% confidence interval: 0.9, 1.1), and the association was reinforced in the Île-de-France region when this indicator was combined with benzene estimates. These results, which were free from any participation bias and based on objectively determined indices of exposure, showed an increased incidence of AML associated with heavy-traffic road density near a child's home. The results support a role for traffic-related benzene exposure in the etiology of childhood AML.

Residential exposure to solar ultraviolet radiation and incidence of childhood hematological malignancies in France.

PURPOSE: Few studies have investigated the relationship between solar ultraviolet radiation (UV) and childhood hematological malignancies (CHM). This study addresses the associations between residential UV exposure at diagnosis and the incidence of types and subtypes of CHM, by age and gender, in France, over a long period, on the fine scale of the 36,326 Communes that constitute mainland France. METHODS: The 9,082 cases of acute leukemia and 3,563 cases of lymphoma diagnosed before the age of 15 years from 1990 to 2009 were provided by the French National Registry of Childhood Hematological Malignancies. The incidence of CHM was calculated by Commune, year, age and gender and expressed as the standardized incidence ratio (SIR). UV data from 1988 to 2007 were extracted from the EUROSUN database. RESULTS: The annual daily average UV exposure of the children ranged from 85.5 to 137.8 J/cm(2). For each additional 25 J/cm(2), there was a significant increase in precursor B-cell acute lymphoblastic leukemia (PBC-ALL) in children aged less than 5 years (SIR 1.18; 95% CI 1.10-1.27). Further analysis of PBC-ALL in the young children suggested a better fit of models with a threshold, with the risk increasing above 100 J/cm(2), for which the SIR was 1.24 (95% CI 1.14-1.36) for a 25 J/cm(2) increase. The results remained stable in analyses stratifying by deprivation index or degree of urbanization of the Communes. CONCLUSION: The study suggests that higher residential UV exposure may be positively associated with a higher incidence of PBC-ALL in early childhood.

Maternal reproductive history, fertility treatments and folic acid supplementation in the risk of childhood acute leukemia: the ESTELLE study.

PURPOSE: To investigate the potential involvement of fertility treatments and other conditions of becoming pregnant (infertility, getting pregnant on birth control, maternal history of fetal loss) and folic acid supplements in the etiology of childhood leukemia (CL). METHODS: The ESTELLE study included 747 cases of CL [636 cases of acute lymphoblastic leukemia (ALL) and 100 of acute myeloblastic leukemia (AML)] diagnosed in France in 2010-2011 and 1,421 population controls frequency-matched with the cases on age and gender. Data were obtained from structured telephone questionnaires administered to mothers. The odds ratios (OR) and their 95% confidence intervals were estimated using unconditional regression models adjusted for potential confounders. RESULTS: CL was not associated with difficulty in becoming pregnant [OR 0.9 (0.7-1.2)], in vitro fertilisation [OR 0.6 (0.3-1.5)] or the use of any fertility treatment [OR 0.8 (0.5-1.1)] for the index pregnancy. CL was not significantly associated with becoming pregnant on contraception [OR 1.2 (0.8-1.8)], but a positive association was observed for third generation oral contraception [OR 4.3 (1.2-16.2)]; however, the result is based on small numbers. Folic acid supplementation during pregnancy was not associated with CL, but an inverse borderline association was observed for supplementation initiated in the 3 months preceding pregnancy [OR 0.7 (0.5-1.0)]. In addition, maternal histories of stillbirth and miscarriage were associated with ALL [OR 2.6 (1.1-5.9)] and AML [OR 1.8 (1.1-2.8)], respectively. CONCLUSIONS: The findings do not suggest that infertility and fertility treatments are risk factors for CL. They suggest that maternal histories of stillbirth and miscarriage may be more frequent among mothers of CL cases and that folic acid supplementation during preconception may reduce the risk of CL.

Childhood acute leukemia, maternal beverage intake during pregnancy, and metabolic polymorphisms.

PURPOSE: This study aimed to analyze the associations between childhood acute leukemia (AL) and maternal caffeinated beverage consumption during pregnancy, and to explore interactions between caffeinated and alcoholic beverage consumption and polymorphisms of enzymes involved in caffeine and ethanol metabolisms. METHODS: The data were generated by the French ESCALE study, which included 764 AL cases and 1,681 controls in 2003-2004. The case and control mothers were interviewed on their consumption habits during pregnancy using a standardized questionnaire. Genotypes of the candidate alleles (NAT2*5 rs1801280, ADH1C*2 rs698 and rs1693482, CYP2E1*5 rs2031920 and rs3813867) were obtained using high-throughput genotyping and imputation data for 493 AL cases and 549 controls with at least two grandparents born in Europe. RESULTS: Maternal regular coffee consumption during pregnancy was associated with childhood AL (OR = 1.2 [1.0-1.5], p = 0.02); the odds ratios increased linearly with daily intake (p for trend <0.001; >2 cups per day vs. no or less than 1 cup per week: AL: OR = 1.6 [1.2-2.1], lymphoblastic AL: OR = 1.5 [1.1-2.0], myeloblastic AL: OR = 2.4 [1.3-4.3]). The association was slightly more marked for children born to non-smoking mothers. Lymphoblastic AL was also associated with cola soda drinking (OR = 1.3 [1.0-1.5], p = 0.02). No significant gene-environment interactions with coffee, tea, cola soda, or alcohol drinking were observed. CONCLUSION: This study provides additional evidence that maternal coffee consumption during pregnancy may be associated with childhood AL. Coffee consumption is a prevalent habit and its potential involvement in childhood AL needs to be considered further.

Fertility treatments, congenital malformations, fetal loss, and childhood acute leukemia: the ESCALE study (SFCE).

BACKGROUND: This study investigated the relationships between childhood acute leukemia (AL) and selective maternal and birth characteristics, including congenital malformations and the use of fertility treatment, for which the literature remains scarce. PROCEDURE: The national registry-based case-control study ESCALE was carried out in France in 2003-2004. Population controls were frequency matched with cases on age and gender. Data were obtained from structured telephone questionnaires. Odds ratios (OR) and their 95% confidence intervals were estimated using unconditional regression models adjusted for potential confounders. RESULTS: In all, 764 cases of AL (648 lymphoblastic AL (acute lymphoblastic leukemia, ALL) and 101 myeloblastic AL) and 1,681 controls were included. The AL cases' mothers reported congenital malformations more frequently than the controls' mothers (OR = 1.5 [1.0-2.4]). ALL was significantly associated with the use of fertility treatment for the index pregnancy (OR = 1.9 [1.3-2.8]). In particular, ALL was associated with ovulation induction only (OR = 2.6 [1.6-4.3]), but not with in vitro fertilization (IVF, OR = 1.0 [0.4-2.3]) or artificial insemination (OR = 1.3 [0.5-3.9]). A positive association was also observed for the difficulty of becoming pregnant without fertility treatment (OR = 1.5 [1.0-2.1]). AL was positively associated with a history of voluntary abortion (OR = 1.4 [1.1-1.8]) but not with a history of spontaneous (OR = 0.8 [0.7-1.0]) or therapeutic (OR = 0.7 [0.5-1.1]) abortion. CONCLUSION: The results suggest that subfertility in itself and ovulation induction may be associated with ALL, and support a positive association with congenital malformations. The links with the various types of fertility drugs and the underlying causes of infertility need to be investigated further.

Potential impacts of radon, terrestrial gamma and cosmic rays on childhood leukemia in France: a quantitative risk assessment.

Previous epidemiological studies and quantitative risk assessments (QRA) have suggested that natural background radiation may be a cause of childhood leukemia. The present work uses a QRA approach to predict the excess risk of childhood leukemia in France related to three components of natural radiation: radon, cosmic rays and terrestrial gamma rays, using excess relative and absolute risk models proposed by the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR). Both models were developed from the Life Span Study (LSS) of Japanese A-bomb survivors. Previous risk assessments were extended by considering uncertainties in radiation-related leukemia risk model parameters as part of this process, within a Bayesian framework. Estimated red bone marrow doses cumulated during childhood by the average French child due to radon, terrestrial gamma and cosmic rays are 4.4, 7.5 and 4.3 mSv, respectively. The excess fractions of cases (expressed as percentages) associated with these sources of natural radiation are 20 % [95 % credible interval (CI) 0-68 %] and 4 % (95 % CI 0-11 %) under the excess relative and excess absolute risk models, respectively. The large CIs, as well as the different point estimates obtained under these two models, highlight the uncertainties in predictions of radiation-related childhood leukemia risks. These results are only valid provided that models developed from the LSS can be transferred to the population of French children and to chronic natural radiation exposures, and must be considered in view of the currently limited knowledge concerning other potential risk factors for childhood leukemia. Last, they emphasize the need for further epidemiological investigations of the effects of natural radiation on childhood leukemia to reduce uncertainties and help refine radiation protection standards.

Association between Residential Proximity to Viticultural Areas and Childhood Acute Leukemia Risk in Mainland France: GEOCAP Case-Control Study, 2006-2013.

BACKGROUND: Pesticide exposures are suspected of being a risk factor for several childhood cancers, particularly acute leukemia (AL). Most of the evidence is based on self-reported parental domestic use of pesticides, but some studies have also addressed associations with agricultural use of pesticides near the place of residence. OBJECTIVES: The objective of the study was to evaluate the risk of AL in children living close to vines, a crop subject to intensive pesticide use. METHODS: Data were drawn from the national registry-based GEOCAP study. We included all of the AL cases under the age of 15 years diagnosed in 2006-2013 (n=3,711) and 40,196 contemporary controls representative of the childhood population in France. The proximity of the vines (probability of presence within 200, 500, and 1,000m) and the viticulture density (area devoted to vines within 1,000m) were evaluated around the geocoded addresses in a geographic information system combining three national land use maps. Logistic regression models were used to estimate odds ratios (ORs) for all AL and for the lymphoblastic (ALL) and myeloid (AML) subtypes. Heterogeneity between regions was studied by stratified analyses. Sensitivity analyses were carried out to take into account, in particular, geocoding uncertainty, density of other crops and potential demographic and environmental confounders. RESULTS: In all, about 10% of the controls lived within 1km of vines. While no evidence of association between proximity to vines and AL was found, viticulture density was positively associated with ALL [OR=1.05 (1.00-1.09) for a 10% increase in density], with a statistically significant heterogeneity across regions. No association with AML was observed. The results remained stable in all the sensitivity analyses. CONCLUSION: We evidenced a slight increase in the risk of ALL in children living in areas with high viticulture density. This finding supports the hypothesis that environmental exposure to pesticides may be associated with childhood ALL. https://doi.org/10.1289/EHP12634.

Childhood leukemia around French nuclear power plants--the Geocap study, 2002-2007.

The aim of this work is to study the risk of childhood acute leukemia (AL) around French nuclear power plants (NPPs). The nationwide Geocap case-control study included the 2,753 cases diagnosed in mainland France over 2002-2007 and 30,000 contemporaneous population controls. The last addresses were geocoded and located around the 19 NPPs. The study used distance to NPPs and a dose-based geographic zoning (DBGZ), based on the estimated dose to bone marrow related to NPP gaseous discharges. An odds ratio (OR) of 1.9 [1.0-3.3], based on 14 cases, was evidenced for children living within 5 km of NPPs compared to those living 20 km or further away, and a very similar association was observed in the concomitant incidence study (standardized incidence ratio (SIR)=1.9 [1.0-3.2]). These results were similar for all the 5-year-age groups. They persisted after stratification for several contextual characteristics of the municipalities of residence. Conversely, using the DBGZ resulted in OR and SIR close to one in all of the dose categories. There was no increase in AL incidence over 1990-2001 and over the entire 1990-2007 period. The results suggest a possible excess risk of AL in the close vicinity of French NPPs in 2002-2007. The absence of any association with the DBGZ may indicate that the association is not explained by NPP gaseous discharges. Overall, the findings call for investigation for potential risk factors related to the vicinity of NPP and collaborative analysis of multisite studies conducted in various countries.

Maternal smoking during pregnancy, genetic polymorphisms of metabolic enzymes, and childhood acute leukemia: the ESCALE study (SFCE).

PURPOSE: This study explored interactions between prenatal exposure to maternal smoking and polymorphisms in metabolic genes in the risk of childhood acute leukemia (AL). METHODS: The data were generated by the ESCALE study, which included 764 AL cases and 1,681 controls in 2003-2004. The data on maternal smoking during pregnancy were obtained by standardized telephone interview of the cases' and controls' mothers. The genotypes CYP1A1*2A/2B (rs4646903), CYP2E1*5 (rs2031920, rs3813867), NQO1*2 (rs1800566), NAT2*5 (rs1801280), and EPHX1 exon 3 (rs1051740) and exon 4 (rs2234922) were obtained using a high-throughput platform and imputation for untyped polymorphisms. The analyses were restricted to the 493 cases (433 cases of lymphoblastic (ALL) and 51 of myeloblastic (AML) leukemia) and 441 controls with at least 2 grandparents born in Europe, who were genotyped with individual call rates greater than 95%. Odds ratios were estimated by logistic regression in case-control analyses and, for gene-gene and gene-environment interactions, by case-only analyses. RESULTS: ALL and AML were not associated with either maternal smoking during pregnancy or candidate polymorphisms in CYP1A1, CYP2E1, EPHX1, and NQO1. Carrying two NAT2*5 alleles was significantly associated with ALL (OR = 1.8 [1.3-2.5]). The analyses also suggested an interaction between three genes involved in benzene metabolism CYP2E1, NQO1, and EPHX1. There was no interaction between maternal smoking and any of the polymorphisms under study. CONCLUSIONS: The ESCALE study did not evidence the interaction between CYP1A1*2A/2B and maternal smoking suggested previously. The association with NAT2*5 and the gene-gene interactions need to be replicated.

Folic acid supplementation, MTHFR and MTRR polymorphisms, and the risk of childhood leukemia: the ESCALE study (SFCE).

PURPOSE: Fetal folate deficiency may increase the risk of subsequent childhood acute leukemia (AL), since folates are required for DNA methylation, synthesis, and repair, but the literature remains scarce. This study tested the hypothesis that maternal folic acid supplementation before or during pregnancy reduces AL risk, accounting for the SNPs rs1801133 (C677T) and rs1801131 (A1298C) in MTHFR and rs1801394 (A66G) and rs1532268 (C524T) in MTRR, assumed to modify folate metabolism. METHODS: The nationwide registry-based case-control study, ESCALE, carried out in 2003-2004, included 764 AL cases and 1,681 controls frequency matched with the cases on age and gender. Information on folic acid supplementation was obtained by standardized telephone interview. The genotypes were obtained using high-throughput platforms and imputation for untyped polymorphisms. Odds ratios (OR) were estimated using unconditional regression models adjusted for potential confounders. RESULTS: AL was significantly inversely associated with maternal folic acid supplementation before and during pregnancy (OR = 0.4; 95 % confidence interval: [0.3-0.6]). MTHFR and MTRR genetic polymorphisms were not associated with AL. However, AL was positively associated with homozygosity for any of the MTHFR polymorphisms and carriership of both MTRR variant alleles (OR = 1.6 [0.9-3.1]). No interaction was observed between MTHFR, MTRR, and maternal folate supplementation. CONCLUSION: The study findings support the hypothesis that maternal folic acid supplementation may reduce the risk of childhood AL. The findings also suggest that the genotype homozygous for any of the MTHFR variants and carrying both MTRR variants could be a risk factor for AL.

Childhood Hodgkin's lymphoma, non-Hodgkin's lymphoma and factors related to the immune system: the Escale Study (SFCE).

The study investigated the role of factors considered related to the early stimulation of the immune system in the aetiology of childhood lymphoma. The national registry-based case-control study, Escale, was carried out in France over the period 2003-2004. Population controls were frequency matched with the cases on age and gender. Data were obtained from structured telephone questionnaires administered to mothers. Odds ratios (ORs) were estimated using unconditional regression models adjusted for potential confounders. Data from 128 cases of Hodgkin's lymphoma (HL) aged 5-14 years, 164 cases of non-Hodgkin's lymphoma (NHL) aged 2-14 years and 1,312 controls were analyzed. Negative associations were observed between HL and day care attendance [OR = 0.5 (0.2-1.2)] and between HL and repeated early common infections among non-breastfed children [OR = 0.3 (.2-0.7), p = 0.003] [OR for breastfed children: 1.0 (.5-2.1)], but not for the other factors investigated. Negative associations were observed between NHL and birth order 3 or more [OR = 0.7 (0.4-1.1)], prolonged breastfeeding [OR = 0.5 (0.3-1.0)], regular contact with farm animals [OR = 0.5 (0.3-1.0)], frequent farm visits in early life [OR = 0.6 (0.4-1.1)] and history of asthma [OR = 0.6 (0.3-1.1)]. In conclusion, the results partly support the hypothesis that an abnormal maturation of the immune system may play a role in childhood HL or NHL, and call for further investigations.

Detection of clusters of a rare disease over a large territory: performance of cluster detection methods.

BACKGROUND: For many years, the detection of clusters has been of great public health interest. Several detection methods have been developed, the most famous of which is the circular scan method. The present study, which was conducted in the context of a rare disease distributed over a large territory (7675 cases registered over 17 years and located in 1895 units), aimed to evaluate the performance of several of the methods in realistic hot-spot cluster situations. METHODS: All the methods considered aim to identify the most likely cluster area, i.e. the zone that maximizes the likelihood ratio function, among a set of cluster candidates. The circular and elliptic scan methods were developed to detect regularly shaped clusters. Four other methods that focus on irregularly shaped clusters were also considered (the flexible scan method, the genetic algorithm method, and the double connected and maximum linkage spatial scan methods). The power of the methods was evaluated via Monte Carlo simulations under 27 alternative scenarios that corresponded to three cluster population sizes (20, 45 and 115 expected cases), three cluster shapes (linear, U-shaped and compact) and three relative risk values (1.5, 2.0 and 3.0). RESULTS: Three situations emerged from this power study. All the methods failed to detect the smallest clusters with a relative risk lower than 3.0. The power to detect the largest cluster with relative risk of 1.5 was markedly better for all methods, but, at most, half of the true cluster was captured. For other clusters, either large or with the highest relative risk, the standard elliptic scan method appeared to be the best method to detect linear clusters, while the flexible scan method localized the U-shaped clusters more precisely than other methods. Large compact clusters were detected well by all methods, with better results for the circular and elliptic scan methods. CONCLUSIONS: The elliptic scan method and flexible scan method seemed the most able to detect clusters of a rare disease in a large territory. However, the probability of detecting small clusters with relative risk lower than 3.0 remained low with all the methods tested.

Residential exposure to natural background radiation at birth and risk of childhood acute leukemia in France, 1990-2009.

BACKGROUND: The role of natural background radiation (NBR) in childhood acute leukemia (AL) remains unclear. Several large record based studies have recently reported heterogeneous results. Differences in exposure assessment timing may explain this heterogeneity. OBJECTIVES: In a previous ecological study we did not observe any association between childhood AL incidence in France and NBR exposure at the time of diagnosis. With the same methodology, the present study focused on NBR exposure at the time of birth. Based on data from the French national registry of childhood cancer, we analyzed all AL together, and lymphoblastic and myeloid AL, separately. METHODS: We included 6,059 childhood AL cases born and diagnosed in mainland France between 1990 and 2009. NBR levels in municipalities of residence at birth were estimated by cokriging models, using NBR measurements and precise geological data. The incidence rate ratio (IRR) per unit variation of exposure was estimated with Poisson regression models, with adjustment for socio-demographic indicators and ultraviolet radiation levels. NBR exposures were considered at the time of birth, and cumulatively from birth to diagnosis. We also estimated a total NBR dose to red-bone marrow (RBM). RESULTS: There was no evidence for an association between NBR exposure at birth and childhood AL incidence, neither overall (gamma radiation: IRR = 0.99 (0.94,1.05) per 50 nSv/h; radon: IRR = 0.97 (0.91,1.03) per 100 Bq/m3) nor for the main AL types. The conclusions were similar with the cumulative exposures, and the total RBM dose. CONCLUSIONS: The study was based on high quality incidence data, large numbers of AL cases, and validated models of NBR exposure assessment. In all, the results further support the hypothesis that NBR are not associated to childhood AL in France.