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Supplementary Table S2. Father's folate pathway genotypes and risk of ALL by immunophenotype and cytogenetic subtype.

Background: Several studies suggest that maternal folic acid supplementation before or during pregnancy protects against childhood acute lymphoblastic leukemia (ALL). We investigated associations between ALL risk and folate pathway gene polymorphisms, and their modification by maternal folic acid supplements, in a population-based case–control study (2003–2007).Methods: All Australian pediatric oncology centers provided cases; controls were recruited by national random digit dialing. Data from 392 cases and 535 controls were included. Seven folate pathway gene polymorphisms (MTHFR 677C>T, MTHFR 1298A>C, MTRR 66A>G, MTR 2756 A>G, MTR 5049 C>A, CBS 844 Ins68, and CBS 2199 T>C) were genotyped in children and their parents. Information on prepregnancy maternal folic acid supplement use was collected. ORs were estimated with unconditional logistic regression adjusted for frequency-matched variables and potential confounders. Case–parent trios were also analyzed.Results: There was some evidence of a reduced risk of ALL among children who had, or whose father had, the MTRR 66GG genotype: ORs 0.60 [95% confidence interval (CI) 0.39–0.91] and 0.64 (95% CI, 0.40–1.03), respectively. The ORs for paternal MTHFR 677CT and TT genotypes were 1.41 (95% CI, 1.02–1.93) and 1.81 (95% CI, 1.06–3.07). ORs varied little by maternal folic acid supplementation.Conclusions: Some folate pathway gene polymorphisms in the child or a parent may influence ALL risk. While biologically plausible, underlying mechanisms for these associations need further elucidation.Impact: Folate pathway polymorphisms may be related to risk of childhood ALL, but larger studies are needed for conclusive results. Cancer Epidemiol Biomarkers Prev; 24(1); 48–56. ©2014 AACR.

Supplementary Figure S1. Flow chart of data collection for the folate pathway genotype analysis in the Australian Study of the causes of Acute Lymphoblastic Leukemia in children (Aus-ALL)

Background: Diagnostic irradiation of the mother during pregnancy increases the risk of childhood acute lymphoblastic leukemia (ALL). There is inconsistent evidence on associations between ALL and other parental or childhood diagnostic irradiation. The aim of this analysis is to investigate whether diagnostic X-rays of the mother before birth, of the father before conception, or of the child increased the risk of childhood ALL.Methods: Data from 389 cases and 876 frequency-matched controls were analyzed using unconditional logistic regression, adjusting for study matching factors and potential confounders. A meta-analysis of our findings in relation to paternal X-rays before conception with the published findings of previous studies was also conducted.Results: There was no evidence of an increased risk with maternal abdominal X-rays before the birth of the index child or with the child having any X-rays more than 6 months before the censoring date. The odds ratio (OR) for any paternal abdominal X-ray before conception was 1.17 [95% confidence interval (95% CI), 0.88-1.55], and 1.47 (95% CI, 0.98-2.21) for more than one X-ray. The OR for any paternal intravenous pyelogram before conception was 3.56 (95% CI, 1.59-7.98). The pooled OR for this study with previous studies of any paternal abdominal X-rays before conception was 1.17 (95% CI, 0.92-1.48).Conclusions: There was some evidence of an increased risk of ALL in the offspring if the father had more than one abdominal X-ray before conception or had ever had an intravenous pyelogram.Impact: We plan to repeat this analysis by using pooled data to improve precision. Cancer Epidemiol Biomarkers Prev; 19(11); 2897–909. ©2010 AACR.

Supplemental Tables 1-9. Supplemental Table S1: Tests for deviation from Hardy-Weinberg Equilibrium using parental genotypes. Supplemental Table S2: Folate pathway genotype and the risk of CBT with only cases also available for case-parent trio analysis (N=246). Supplemental Table S3: Folate pathway genotype and the risk of CBT with adjustment only for matching variables. Supplemental Table S4: Folate pathway genotype and the risk of CBT where child has 3 or more European grandparents. Supplemental Table S5: Folate-pathway genotype and the risk of CBT (excluding FTA samples). Supplemental Table S6: Child's folate pathway genotype and risk of CBT by tumor subtype. Supplemental Table S7: Maternal folate pathway genotype and risk of CBT by tumor subtype. Supplemental Table S8: Paternal folate pathway genotype and risk of CBT by tumor subtype. Supplemental Table S9: Child's folate pathway genotype and risk of CBT by sex of the child.

Supplementary Table 1 from Exposure to Diagnostic Radiological Procedures and the Risk of Childhood Acute Lymphoblastic Leukemia

Background: Recent research suggests that maternal folic acid supplementation is associated with a reduced risk of childhood brain tumors (CBT); polymorphisms in folate pathway genes could modify this association or directly influence CBT risk.Methods: Associations between risk of CBT and folate pathway polymorphisms were investigated in a population-based case–control study in Australia (2005–2010). Cases were recruited through all Australian pediatric oncology centers and controls by national random digit dialing. Data were available from 321 cases and 552 controls. Six polymorphisms were genotyped in children and parents (MTHFR 677C>T, MTHFR 1298A>C, MTRR 66A>G, MTR 2756A>G, MTR 5049C>A, and CBS 2199 T>C). Maternal folic acid use was ascertained via questionnaire. ORs were estimated using unconditional logistic regression. Case–parent trio analyses were also undertaken.Results: There was weak evidence of a reduced risk of CBT for the MTRR 66GG genotype in the child or father: ORs 0.71 [95% confidence interval (CI), 0.48–1.07]; 0.54 (95% CI, 0.34–0.87), respectively. Maternal prepregnancy folic acid supplementation showed a stronger negative association with CBT risk where the child, mother, or father had the MTRR 66GG genotype (Pinteraction = 0.07, 0.10, and 0.18, respectively).Conclusions: Evidence for an association between folate pathway genotypes and CBT is limited in this study. There was possible protection by the MTRR 66GG genotype, particularly when combined with maternal prepregnancy folic acid supplementation; these results are novel and require replication.Impact: The possible interaction between folic acid supplementation and MTRR 66A>G, if confirmed, would strengthen evidence for prepregnancy folate protection against CBT. Cancer Epidemiol Biomarkers Prev; 24(6); 931–7. ©2015 AACR.

Associations between birth defects (BDs) and childhood cancers have been studied previously and have identified several specific birth defect-cancer associations. No studies have examined the risk after exclusion of known associations.We analyzed data from high-quality population-based registers of BDs and cancers for Western Australian births 1982 to 2007. The cohort comprised 641,036 babies still alive at 90 days. Two experts independently reviewed all 120 births with a BD and a cancer to determine whether the cancer was congenital, caused by the BD, known to be associated with the BD or otherwise. These categories were used in sensitivity analyses. Cox regression was used to estimate hazard ratios (HRs) for any cancer and specific cancers associated with any BD and specific BDs.The HR for any cancer among children with any BD was 1.96 (95% confidence interval, 1.59-2.43). The HR for any cancer among children with a BD not known to be related to a cancer (n = 57) was 1.19 (95% confidence interval, 0.91-1.56). The HR for the latter association among children diagnosed with cancer before 5 years of age was 1.74 (95% confidence interval, 1.28-2.37).This novel approach aimed to prevent inflated HRs arising from reverse causation, and allow identification of associations beyond those already well documented. Larger studies using this method are needed to explore currently undocumented associations between BDs and cancers.

The Australian Twin Registry (ATR) has, since the late 1970s, enrolled more than 30,000 pairs of all zygosity types and ages willing to consider participation in approved research studies. Its core functions are the recruitment to, and maintenance of, an up-to-date database containing contact details and baseline information, and the management of fair and equitable access so as to enhance medical and scientific research. The ATR has facilitated more than 430 studies producing 525 peer-reviewed publications using a variety of designs including classic biometrical twin and twin family studies, co-twin control studies, intervention studies, longitudinal studies, and studies of issues relevant specifically to twins. The ATR is supported for 2004 to 2009 by an Australian National Health and Medical Research Council (NHMRC) Enabling Grant, a new form of funding which recognizes the importance of long-term support for shared national resources. New initiatives include: integration with the Western Australian Twin Child Health (WATCH) cohort and the new Western Australian Twin Registry (WATR); foundation of a cohort of mothers and their twin children recruited from the time of diagnosis of the multiple gestation (match); a national Twins Festival run in collaboration with the Australian Multiple Birth Association (AMBA); promotion of the ATR at medical conferences; and fostering an active network of researchers from a range of disciplines and providing financial support for new researchers to attend international twin research workshops. Consistent with its mission statement, the long-term goal of the ATR is to make twin studies a standard component of medical and scientific research.

Asbestos exposure is the main risk factor for malignant pleural mesothelioma (MPM), a rare aggressive tumor. Nevertheless, only 5-17% of those exposed to asbestos develop MPM, suggesting the involvement of other environmental and genetic risk factors. To identify the genetic risk factors that may contribute to the development of MPM, we conducted a genome-wide association study (GWAS; 370,000 genotyped SNPs, 5 million imputed SNPs) in Italy, among 407 MPM cases and 389 controls with a complete history of asbestos exposure. A replication study was also undertaken and included 428 MPM cases and 1269 controls from Australia. Although no single marker reached the genome-wide significance threshold, several associations were supported by haplotype-, chromosomal region-, gene- and gene-ontology process-based analyses. Most of these SNPs were located in regions reported to harbor aberrant alterations in mesothelioma (SLC7A14, THRB, CEBP350, ADAMTS2, ETV1, PVT1 and MMP14 genes), causing at most a 2-3-fold increase in MPM risk. The Australian replication study showed significant associations in five of these chromosomal regions (3q26.2, 4q32.1, 7p22.2, 14q11.2, 15q14). Multivariate analysis suggested an independent contribution of 10 genetic variants, with an Area Under the ROC Curve (AUC) of 0.76 when only exposure and covariates were included in the model, and of 0.86 when the genetic component was also included, with a substantial increase of asbestos exposure risk estimation (odds ratio, OR: 45.28, 95% confidence interval, CI: 21.52-95.28). These results showed that genetic risk factors may play an additional role in the development of MPM, and that these should be taken into account to better estimate individual MPM risk in individuals who have been exposed to asbestos.

Our aim was to examine the school performance of children with type 1 diabetes in comparison to their peers, exploring changes over time, and the impact of clinical factors on school performance.The study included data on 666 children with type 1 diabetes from the Western Australia Children's Diabetes Database. (WACDD), a population-based registry, and 3260 school and school year matched non-diabetic children. Records from the National Assessment Program - Literacy and Numeracy (NAPLAN) (2008-2011), which examines four educational outcome domains and is administered annually to all years 3, 5, 7, and 9 children in Australia, were sourced for both groups. Clinical data were obtained for the children with diabetes from the WACDD.No significant difference was observed between those with type 1 diabetes and their peers, across any of the tested domains and school years analysed. No decline over time was observed, and no decline following diagnosis was observed. Type 1 diabetes was associated with decreased school attendance, 3% fewer days attended per year. Poorer glycaemic control [higher haemoglobin A1c (HbA1c)] was associated with a lower test score [0.2-0.3 SD per 1% (10.9 mmol/mol) increase in HbA1c], and with poorer attendance [1.8% decrease per 1% (10.9 mmol/mol) increase in HbA1c]. No association was observed with history of severe hypoglycaemia, diabetic ketoacidosis or age of onset and school test scores.These results suggest that type 1 diabetes is not associated with a significant decrement in school performance, as assessed by NAPLAN. The association of poorer glycaemic control with poorer school performance serves as further evidence for clinicians to focus on improving glycaemic control.

Health benefits of adequate vitamin D levels in the blood include better bone health and a reduced incidence of a range of chronic diseases and infections. Ultraviolet (UV) radiation exposure from the sun is the main source of vitamin D; however, such exposure, especially from a young age, is also a potential risk factor for skin cancer. The current study examined the association of UV exposure with vitamin D production in young children to determine the period of weekly exposure prior to blood testing that affected serum 25-hydroxyvitamin D (25(OH)D) levels.Between 2009 and 2011, healthy children aged 3, 6 and 9 years were recruited from the community for a cross-sectional study of nutritional factors and DNA damage. Parents of 464 children provided information on the children's average weekly sun exposure and level of sun protection during each of the 16 weeks before blood sample collection by a domiciliary phlebotomist.Serum 25(OH)D levels were best predicted from UV exposure during the week before blood collection for samples drawn in autumn, summer or spring. For samples drawn in winter, serum 25(OH)D levels were best predicted by UV exposure during the 2 weeks before blood collection.Consistent weekly sun exposure may be beneficial for young children, especially in winter, to maintain healthy vitamin D levels in the blood. However, confirmation of these results is needed before their public health significance can be fully evaluated.

Childhood brain tumors (CBT) are the leading cause of cancer death in children, yet their etiology remains largely unknown. Tobacco smoke contains 61 known carcinogens and increases the risk of several adult cancers. This study investigated associations between parental smoking and risk of CBT in a population-based case-control study conducted between 2005 and 2010. Cases were identified through all ten Australian pediatric oncology centers, controls via nationwide random-digit dialing, frequency matched to cases on age, sex and state of residence. Parental smoking information was obtained for 302 cases and 941 controls through mailed questionnaires that requested average daily cigarette use in each calendar year from age 15 to the child's birth, linked to residential and occupational histories. Data were analyzed using unconditional logistic regression, adjusting for frequency matching variables and potential confounders. Overall, parental smoking before or during pregnancy showed no association with CBT risk. The odds ratios for maternal smoking before and during pregnancy were 0.99 (95% CI: 0.70, 1.40) and 0.89 (95% CI: 0.61, 1.21), respectively, and those for paternal smoking before and during pregnancy were 0.99 (95% CI: 0.71, 1.38) and 1.04 (95% CI: 0.74, 1.46), respectively. In children under 24 months of age, the odds ratios for maternal smoking preconception and during pregnancy were 5.06 (95% CI 1.35-19.00) and 4.61 (95% CI: 1.08, 19.63), although these results were based on modest numbers. Future studies should investigate the associations between maternal smoking and risk of CBT by the child's age of diagnosis.

It is plausible that exposure of the parents before birth or of the child to sources of benzene increases the risk of childhood acute lymphoblastic leukaemia (ALL). The aim of this analysis was to investigate whether refuelling a vehicle with petrol before birth or burning wood to heat the home before or after the child's birth increased the risk of childhood ALL. Data from 389 cases and 876 frequency-matched controls were analysed using unconditional logistic regression, adjusting for study matching factors and potential confounders. The odds ratio (OR) for the mother ever refuelling a vehicle with petrol for non-occupational purposes before or during the pregnancy was 0.97 [95% confidence interval (CI) 0.69, 1.38]. The OR for the father for this exposure in the year before conception was 0.88 [95% CI 0.52, 1.48]. The OR for use of a closed wood burner to heat the home in the year before or during pregnancy was 1.41 [95% CI 1.02, 1.94] and 1.25 [95% CI 0.92, 1.70] after birth. We found no evidence that non-occupational refuelling a vehicle with petrol in the year before or during pregnancy increased the risk of ALL in the offspring. There was weak evidence that burning wood in a closed burner to heat the home increased the risk, but there was no dose-response relationship and chance could explain the finding.

Haplotypes in the promoter region of the prostanoid DP receptor (PTGDR) gene have been shown to functionally influence gene transcription and to be associated with asthma in two previous case-control studies in Caucasians. This study tested the association of PTGDR haplotypes with asthma phenotypes in two large Caucasian-Australian populations. These results were incorporated in a meta-analysis with previously published data to determine the overall role for these haplotypes in the risk of asthma.Three PTGDR promoter-region single nucleotide polymorphisms (SNP) were genotyped in 368 individuals from the Western Australian Twin Child Health study and 2988 individuals from the Busselton Health Study. Logistic regression and transition disequilibrium tests were used to assess whether SNP genotypes and three SNP haplotypes were associated with doctor-diagnosed asthma or intermediate quantitative traits. Longitudinal data from the Busselton Health Study were used to examine whether PTGDR influences changes in lung function over time. Meta-analysis incorporated the findings of this study with those of two previous studies in Caucasian populations.Cross-sectional associations between PTGDR haplotypes and asthma phenotypes were non-significant (P0.05) in both populations. Longitudinal analyses of PTGDR and lung function were also non-significant. Meta-analysis, however, suggested that haplotype TCT was significantly associated with decreased risk of asthma (OR = 0.76; P = 0.02) while haplotype CCC was not significantly associated with asthma (OR = 1.30; P = 0.07).These results suggest that despite the non-significant findings in the present study populations, PTGDR promoter haplotypes may account for a small but significant proportion of the risk of asthma in Caucasian populations.

Background: Diagnostic irradiation of the mother during pregnancy increases the risk of childhood acute lymphoblastic leukemia (ALL). There is inconsistent evidence on associations between ALL and other parental or childhood diagnostic irradiation. The aim of this analysis is to investigate whether diagnostic X-rays of the mother before birth, of the father before conception, or of the child increased the risk of childhood ALL. Methods: Data from 389 cases and 876 frequency-matched controls were analyzed using unconditional logistic regression, adjusting for study matching factors and potential confounders. A meta-analysis of our findings in relation to paternal X-rays before conception with the published findings of previous studies was also conducted. Results: There was no evidence of an increased risk with maternal abdominal X-rays before the birth of the index child or with the child having any X-rays more than 6 months before the censoring date. The odds ratio (OR) for any paternal abdominal X-ray before conception was 1.17 [95% confidence interval (95% CI), 0.88-1.55], and 1.47 (95% CI, 0.98-2.21) for more than one X-ray. The OR for any paternal intravenous pyelogram before conception was 3.56 (95% CI, 1.59-7.98). The pooled OR for this study with previous studies of any paternal abdominal X-rays before conception was 1.17 (95% CI, 0.92-1.48). Conclusions: There was some evidence of an increased risk of ALL in the offspring if the father had more than one abdominal X-ray before conception or had ever had an intravenous pyelogram. Impact: We plan to repeat this analysis by using pooled data to improve precision. Cancer Epidemiol Biomarkers Prev; 19(11); 2897–909. ©2010 AACR.

To investigate whether maternal coffee and/or tea consumption during the last 6 months of pregnancy was associated with risk of childhood ALL.Data on coffee and tea drinking during pregnancy from 337 case mothers and 697 control mothers were analyzed using unconditional multivariable logistic regression. A meta-analysis of our findings with those of previous studies was also conducted.There was little evidence of an overall association between maternal coffee consumption and risk of ALL: OR 0.89 (95% CI 0.61, 1.30), although there was some suggestion that higher levels of intake might increase the risk in children of non-smoking mothers: OR for 2+ cups/day = 1.44 (95% CI 0.85, 2.42); this was supported by our meta-analysis. Risk was also elevated among cases with chromosomal translocations. The overall OR for maternal tea consumption was 0.82 (95% CI 0.56, 1.18), although the OR for T-cell ALL was 0.21 (95% CI 0.08, 0.51). Among ALL cases with translocations, the ORs for tea consumption tended to be elevated: OR = 1.70 (95% CI 0.79-3.68) for 2+ cups/day.The observed increased risk associated with coffee and tea consumption may be confined to ALL with translocations. These associations should be explored further in large international consortia.

Acute lymphoblastic leukemia (ALL) is the commonest childhood malignancy in Australian children. Recently published data from Western Australia suggest a link between proportion of optimal birth weight and the risk of ALL, but few studies have investigated the relationship between growth during infancy and early childhood and risk of leukemia. The aim of this study was to determine whether children diagnosed with ALL in Western Australia were taller at the time of diagnosis than children of the same age and sex in the general population.Records of children diagnosed with ALL between January 1984 and June 2008 were accessed. Height before the commencement of chemotherapy was recorded and compared to the height of population norms derived from the Longitudinal Study of Australian Children.On average, male cases were 0.67 cm (95% CI -0.21, 1.54 cm) taller and female cases were 0.30 cm (95% CI -0.68, 1.28 cm) taller than population controls.Our results suggest that children diagnosed with ALL in Western Australia are slightly taller than their counterparts in the general population. These findings are consistent with at least one previous study. While this increase in height may be too small to be recognizable clinically, it is consistent with the notion that growth factors play a role in the pathogenesis of ALL beyond infancy.

The Australian Twin Registry (ATR) has, since the late 1970s, enrolled more than 30,000 pairs of all zygosity types and ages willing to consider participation in approved research studies. Its core functions are the recruitment to, and maintenance of, an up-to-date database containing contact details and baseline information, and the management of fair and equitable access so as to enhance medical and scientific research. The ATR has facilitated more than 430 studies producing 525 peer-reviewed publications using a variety of designs including classic biometrical twin and twin family studies, co-twin control studies, intervention studies, longitudinal studies, and studies of issues relevant specifically to twins. The ATR is supported for 2004 to 2009 by an Australian National Health and Medical Research Council (NHMRC) Enabling Grant, a new form of funding which recognizes the importance of long-term support for shared national resources. New initiatives include: integration with the Western Australian Twin Child Health (WATCH) cohort and the new Western Australian Twin Registry (WATR); foundation of a cohort of mothers and their twin children recruited from the time of diagnosis of the multiple gestation (match); a national Twins Festival run in collaboration with the Australian Multiple Birth Association (AMBA); promotion of the ATR at medical conferences; and fostering an active network of researchers from a range of disciplines and providing financial support for new researchers to attend international twin research workshops. Consistent with its mission statement, the long-term goal of the ATR is to make twin studies a standard component of medical and scientific research.