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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)

Supplementary Table S1. Mother's folate pathway genotypes and risk of ALL by immunophenotype and cytogenetic subtype

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 S3. Odds ratios for other folate pathway genotypes stratified by maternal use of folic acid (>300ug) in the pre-pregnancy period

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.

AIM To describe the birth prevalence and characteristics of congenital heart defects in a geographically defined Australian population. METHODS This descriptive, population-based study examined congenital heart defects in live births, stillbirths and pregnancy terminations ascertained by the Western Australian Register of Developmental Anomalies, 1990-2016. Birth prevalence (per 1000 births) was stratified by severity, known cause, maternal and birth characteristics, and primary diagnosis; and prevalence ratios were calculated for Aboriginal versus non-Aboriginal births. Temporal trends in prevalence, diagnosis age and infant mortality were examined. RESULTS For births 1990-2010 (allowing 6 years for complete case ascertainment by 2016), 6419 cases were identified; prevalence was 11.5 per 1000 births (95% confidence interval (CI), 11.2-11.8). Severe defects were ascertained in 2.5 per 1000 births (95% CI 2.4-2.7). Most cases were liveborn (5842, 91.0%), and 28.9% had other birth defects. Prevalence was slightly higher in Aboriginal births (prevalence ratio 1.1; 95% CI 1.0-1.2); and the infant mortality rate more than doubled (13.4% vs. 5.8%, P

The early onset of childhood acute lymphoblastic leukemia (ALL) suggests that critical exposures occurring during pregnancy may increase risk. We investigated the effects of maternal coffee and tea consumption during pregnancy on ALL risk by pooling data from eight case–control studies participating in the Childhood Leukemia International Consortium. Data on maternal coffee intake were available for 2,552 cases and 4,876 controls, and data on tea intake were available for 2,982 cases and 5,367 controls. Coffee and tea intake was categorized into 0, > 0–1, > 1–2, and > 2 cups/day, and covariates were combined and harmonized. Data on genetic variants in NAT2, CYP1A1, and NQO1 were also available in a subset. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression, and linear trends across categories were assessed. No association was seen with ‘any’ maternal coffee consumption during pregnancy, but there was evidence of a positive exposure–response; the pooled OR for > 2 cups/day versus none was 1.27 (95% CI 1.09–1.43), p trend = 0.005. No associations were observed with tea consumption. No interactions were seen between coffee or tea intake and age, maternal smoking or genotype, and there was little or no evidence that associations with coffee or tea differed among cases with and without chromosomal translocations. Despite some limitations, our findings suggest that high coffee intake during pregnancy may increase risk of childhood ALL. Thus, current advice to limit caffeine intake during pregnancy to reduce risk of preterm birth may have additional benefits.

Background Dietary habits during pregnancy have been inconsistently linked to childhood acute myeloid leukemia (AML), given the putative intrauterine onset of the disease as a result of triggering events during the critical period of fetal hematopoiesis. We investigated the potential association of maternal coffee and tea consumption during pregnancy with childhood AML risk, pooling primary data from eight case-control studies participating in the Childhood Leukemia International Consortium. Methods Information on coffee and/or tea consumption was available for 444 cases and 1255 age- and sex-matched controls, on coffee consumption for 318 cases and 971 controls and on tea consumption for 388 cases and 932 controls. Categories for cups of daily coffee/tea consumption were created in order to explore potential dose-response associations. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression. Results Associations were found neither in the analysis on coffee or tea nor in the analysis on coffee only consumption (any versus no). A positive association with increasing coffee intake was observed (>1 cup per day; OR: 1.40, 95% CI: 1.03–1.92, increment of one cup per day; OR: 1.18, 95% CI: 1.01–1.39). No associations were observed with tea consumption. Interaction analyses showed non-significant associations between coffee/tea and smoking. Hyperdiploidy was inversely associated with tea consumption, with other cytogenetic markers having no association with coffee/tea. Conclusion Given the widespread consumption of caffeinated beverages among pregnant women, our finding is of important public health relevance, suggesting adverse effects of maternal coffee consumption during pregnancy in the offspring.

OBJECTIVES: To examine whether children conceived using assisted reproductive technology (ART) have a higher risk of intellectual disability (ID) compared with non–ART-conceived children and describe known causes of ID in these groups. METHODS: We linked ID and ART data from population-based registers in Western Australia. Our cohort included live births from 1994 to 2002 (n = 210 627) with at least 8 years of follow-up. The prevalence of ID was compared between ART- and non–ART-conceived children, and risk of ID was estimated using Poisson regression with robust SEs. We also stratified by plurality and gestation at delivery. RESULTS: Children conceived using ART had a small increased risk of ID (risk ratio 1.58; 95% confidence interval 1.19–2.11) even when analyses were restricted to singleton births (risk ratio 1.56; 95% confidence interval 1.10–2.21). The risk of ID was more than doubled for those born very preterm, for severe ID, and after intracytoplasmic sperm injection (ICSI) treatments. Children conceived using ICSI had a greater risk of ID than those conceived using in vitro fertilization and were more likely to have a known genetic cause for ID (27.6% vs 12.9% in vitro fertilization and 11.9% non-ART). CONCLUSIONS: The risk of ID was increased in children born after ART in Western Australia from 1994 to 2002. More recent cohorts should be examined to assess the impact of important changes in ART clinical practice. Our results are particularly pertinent because multiple embryo transfers are routinely performed in many countries, increasing the risk of preterm birth, and ICSI use rates are high.

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.

The etiology of childhood brain tumors (CBT) is poorly understood, but dietary factors could be involved. In this case–control study of CBT, the possible associations of childhood intake of dietary and supplemental folate, vitamin B6, and vitamin B12 with the risk of CBT were investigated, along with various food groups. Cases diagnosed between 2005 and 2010 were identified from 10 pediatric oncology centers in Australia and controls by nationwide random-digit dialling. For study children of ages 3–14 years, diet in the year before diagnosis (or recruitment) was assessed using food frequency questionnaires. Folate intake was adjusted for bioavailability, and dietary micronutrient intake was energy-adjusted. Micronutrients and food groups were analyzed using logistic regression adjusting for relevant confounders. Principal components analysis was conducted to assess food group intake patterns for analysis. Food and micronutrient data were available for 216 cases and 523 controls. Folate intake was associated with a reduced risk of CBT overall (odds ratio for highest tertile vs. lowest: 0.63, 95 % confidence interval 0.41, 0.97) and particularly low-grade gliomas (odds ratio for highest tertile vs. lowest: 0.52, 95 % confidence interval 0.29, 0.92). Vitamin B6 and B12 intake was not associated with CBT risk, nor was processed meat. High folate intake during childhood may reduce the risk of CBT. This potentially important finding needs to be corroborated in other studies. If replicated, these results could have important implications for public health recommendations regarding diet during childhood.

Acute lymphoblastic leukemia (ALL) and childhood brain tumors (CBT) are 2 of the most common forms of childhood cancer, but little is known of their etiology. In 2 nationwide case-control studies we investigated whether breastfeeding, age of food introduction, or early diet are associated with the risk of these cancers. Cases aged 0-14 years were identified from Australian pediatric oncology units between 2003 and 2007 (ALL) and 2005 and 2010 (CBT) and population-based controls through nationwide random-digit dialing. Mothers completed questionnaires giving details of infant feeding up to the age of 2 yr. Data from 322 ALL cases, 679 ALL controls, 299 CBT cases, and 733 CBT controls were analysed using unconditional logistic regression. Breastfeeding was associated with a reduced risk of ALL [odds ratio (OR) = 0.52, 95% confidence interval (CI): 0.32, 0.84), regardless of duration. Introduction of artificial formula within 14 days of birth was positively associated with ALL (OR = 1.57, 95% CI: 1.03, 2.37), as was exclusive formula feeding to 6 mo (OR = 1.81, 95% CI: 1.07, 3.05). No associations were seen between breastfeeding or formula use and risk of CBT. Our results suggest that breastfeeding and delayed introduction of artificial formula may reduce the risk of ALL but not CBT.

It is biologically plausible that a paternal preconception diet low in nutrients related to DNA integrity could affect sperm DNA and subsequently risk of cancer in the offspring. The aim of this analysis was to investigate whether paternal preconception dietary folate, B6, or B12 intake was associated with the risk of childhood brain tumors (CBT) in an Australian case-control study. Cases

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.

Reduced awareness of cognitive deficits in mild cognitive impairment (MCI) is associated with poorer outcomes although little is known about the anatomical correlates of this. We examined the association of insight and grey matter volume using a voxel-based morphometry approach in 65 volunteers with MCI and 55 healthy age-matched controls. Participants with MCI had multiple areas of subtle grey matter volume loss compared with controls, although these did not survive correction for multiple comparisons. These were predominantly in the temporal and anterior portions of the brain. Individuals with MCI did not differ from each other on a number of demographic and cognitive variables according to level of insight. Reduced awareness of cognitive deficits was associated with few differences in grey matter volume apart from a subtle loss of grey matter in the medial frontal gyri. Given the modest nature of these findings, the routine assessment of insight in non-clinical populations of individuals with MCI is therefore not supported. Prospective data in larger samples, however, would be helpful to clarify this further and determine if impaired insight predicts brain atrophy and cognitive decline.

Background The aetiology of childhood brain tumours (CBT) is largely unknown. Damage to germ cells after parental exposure to airborne carcinogens, such as volatile organic compounds and polycyclic aromatic hydrocarbons is one plausible pathway. This analysis aimed to investigate whether parental refuelling of vehicles or the use of domestic wood heaters in key time periods relating to the child's birth was associated with an increased risk of CBT. Procedure Cases

The causes of childhood brain tumors (CBT) are largely unknown, but gestational diet may influence this risk. The aim of this analysis was to investigate whether maternal coffee or tea consumption during pregnancy was associated with the risk of CBT.The Australian Study of the Causes of Childhood Brain Tumours was a population-based, Australian case-control study conducted between 2005 and 2010. Case children were recruited from 10 pediatric oncology centers and control children by nationwide random-digit dialing, frequency matched to cases on the basis of age, sex and state of residence. Coffee and tea intake were assessed using a food frequency questionnaire.Data on coffee and tea consumption during pregnancy were available from 293 case mothers and 726 control mothers. Odds ratios (ORs) and confidence intervals (CIs) were calculated using multivariable unconditional logistic regression. There was little evidence of an association between gestational consumption of any coffee (OR 1.23, 95% CI 0.92, 1.64) or tea (OR 1.00, 95% CI 0.74, 1.36) and CBT risk. Among children aged under 5 years, the OR for any coffee consumption during pregnancy was 1.76 (95% CI 1.09, 2.84) and for ≥2 cups per day during pregnancy was 2.52 (95% CI 1.26, 5.04). There was little evidence that associations with coffee or tea intake differed by parental smoking status.These results suggest a positive association between coffee intake ≥2 cups per day and risk of CBT in younger children, although some estimates are imprecise. There was no association between maternal tea drinking and risk of CBT.

Background: Parental occupational exposures have been associated with childhood brain tumours (CBT), but results are inconsistent. Few studies have studied CBT risk and parental solvent exposure, suggesting a possible association. We examined the association between CBT and parental occupational exposure to solvents in a case–control study. Methods: Parents of 306 cases and 950 controls completed detailed occupational histories. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for both maternal and paternal exposure to benzene, other aromatics, aliphatics and chlorinated solvents in key time periods relative to the birth of their child. Adjustments were made for matching variables (child's age, sex and state of residence), best parental education and occupational exposure to diesel exhaust. Results: An increased risk of CBT was observed with maternal occupational exposures to chlorinated solvents (OR=8.59, 95% CI 0.94–78.9) any time before birth. Paternal exposure to solvents in the year before conception was associated with an increased CBT risk: OR=1.55 (95% CI 0.99–2.43). This increased risk appeared to be mainly attributable to exposure to aromatic solvents: OR=2.72 (95% CI 0.94–7.86) for benzene and OR=1.76 (95% CI 1.10–2.82) for other aromatics. Conclusions: Our results indicate that parental occupational exposures to solvents may be related to an increased risk of CBT.

Childhood brain tumors (CBT) are the leading cause of cancer death in children, yet their etiology remains largely unknown. This study investigated whether household exposure to paints and floor treatments and parental occupational painting were associated with CBT risk in a population-based case-control study conducted between 2005 and 2010.Cases were identified through all ten Australian pediatric oncology centers, and controls via nationwide random-digit dialing, frequency matched to cases on age, sex, and state of residence. Data were obtained from parents in mailed questionnaires and telephone interviews. Information on domestic painting and floor treatments, and parental occupational exposure to paint, in key periods relating to the index pregnancy and childhood was obtained for 306 cases and 950 controls. Data were analyzed using unconditional logistic regression, adjusting for frequency matching variables and potential confounders.Overall, we found little evidence that parental, fetal, or childhood exposure to home painting or floor treatments was associated with risk of CBT. There was, though, some evidence of a positive association between childhood exposure to indoor painting and risk of high-grade glioma [odds ratio (OR) 3.31, 95 % confidence interval (CI) 1.29, 8.52] based on very small numbers. The OR for the association between CBT and paternal occupational exposure to paint any time before the pregnancy was 1.32 (95 % CI 0.90, 1.92), which is consistent with the results of other studies.Overall, we found little evidence of associations between household exposure to paint and the risk of CBT in any of the time periods investigated.

Background Childhood brain tumors (CBT) are the leading cause of cancer death in children, yet their causes are largely known. This study investigated the association between maternal and birth characteristics and risk of CBT. Procedures Cases families were recruited from all 10 Australian pediatric oncology centers between 2005 and 2010. Control families were recruited via random-digit dialing, frequency matched to cases on the basis of child's age, sex, and State of residence. Maternal and birth characteristics of children were ascertained by questionnaires. Odds ratios (ORs) and 95% confidence intervals (CI) were estimated using unconditional logistic regression, adjusting for relevant confounders. Results For this analysis, data on 319 case children and 1,079 control children were available. No association was found between risk of CBT and birth weight, fetal growth, birth order, gestational age, or maternal body mass index. The ORs for inadequate and excessive maternal gestational weight gain (GWG) (Institute of Medicine 2009 guidelines) were 1.8 (95% CI 1.2–2.6) and 1.4 (95% CI 1.0–2.1), respectively; similar findings for GWG were seen across categories of child's age, fetal growth, maternal body mass index and height, maternal smoking, and parental education. Risk of low grade glioma appeared increased with preterm birth (OR 1.6 (95% CI 0.8–3.1) and admission to neonatal intensive care (NICU) for >2 days (OR 1.7, 95% CI 0.9–3.6). Conclusion We found little evidence of associations between risk of CBT and most birth characteristics. The associations we observed with GWG, prematurity and NICU admission require corroboration in other studies. Pediatr Blood Cancer 2014;61:493–498. © 2013 Wiley Periodicals, Inc.

Previous research has suggested positive associations between parental or childhood exposure to pesticides and risk of childhood brain tumors (CBT). This Australian case–control study of CBT investigated whether exposures to pesticides before pregnancy, during pregnancy and during childhood, were associated with an increased risk. Cases were recruited from 10 pediatric oncology centers, and controls by random-digit dialing, frequency matched on age, sex, and State of residence. Exposure data were collected by written questionnaires and telephone interviews. Data were analyzed by unconditional logistic regression. The odds ratios (ORs) for professional pest control treatments in the home in the year before the index pregnancy, during the pregnancy, and after the child’s birth were 1.54 (95 % confidence interval (CI): 1.07, 2.22), 1.52 (95 % CI: 0.99, 2.34) and 1.04 (95 % CI: 0.75, 1.43), respectively. ORs for treatments exclusively before pregnancy and during pregnancy were 1.90 (95 % CI: 1.08, 3.36) and 1.02 (95 % CI: 0.35, 3.00), respectively. The OR for the father being home during the treatment was 1.79 (95 % CI: 0.85, 3.80). The OR for paternal occupational exposure in the year before the child’s conception was 1.36 (95 % CI: 0.66, 2.80). ORs for prenatal home pesticide exposure were elevated for low- and high-grade gliomas; effect estimates for other CBT subtypes varied and lacked precision. These results suggest that preconception pesticide exposure, and possibly exposure during pregnancy, is associated with an increased CBT risk. It may be advisable for both parents to avoid pesticide exposure during this time.

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.

Background: Interest in a possible protective effect of maternal vitamin use before or during pregnancy against childhood brain tumors (CBT) and other childhood cancers has grown over the past decade. Our Australian study of CBTs, conducted between 2005 and 2011, investigated whether maternal use folic acid and other supplements was protective. Methods: Case children were identified through the 10 Australian pediatric oncology centers and controls were recruited by national random digit dialing. Mothers of 327 cases and 867 control children provided information on supplement use before and during the index pregnancy, including brand name, dose, and timing. Data were analyzed using multivariable unconditional logistic regression. Results: The OR for any maternal use of folic acid, use of folic acid without iron or vitamins B6, B12, C, or A, and any vitamin use before pregnancy, were: 0.68 [95% confidence interval (CI), 0.46–1.00; 0.55 (95% CI, 0.32–0.93) and 0.68 (95% CI, 0.46–1.01), respectively. The ORs for use of these supplements during pregnancy were also below unity, but generally closer to the null than those for the prepregnancy period. There was some evidence of an inverse dose–response during each time period. Conclusions: These results suggest that folic acid supplements before and possibly during pregnancy may protect against CBT. Such associations are biologically plausible through established mechanisms. Impact: This study provides evidence of a specific protective effect of prenatal folic acid supplementation against the risk of CBT that is not attributable to the actions of the other micronutrients investigated. Cancer Epidemiol Biomarkers Prev; 21(11); 1933–41. ©2012 AACR.

There has been increasing interest in the influence of diet on cognition in the elderly. This study examined the cross-sectional association between dietary patterns and cognition in a sample of 249 people aged 65-90 years with mild cognitive impairment (MCI). Two dietary patterns; whole and processed food; were identified using factor analysis from a 107-item; self-completed Food Frequency Questionnaire. Logistic regression analyses showed that participants in the highest tertile of the processed food pattern score were more likely to have poorer cognitive functioning; in the lowest tertile of executive function (OR 2.55; 95% CI: 1.08-6.03); as assessed by the Cambridge Cognitive Examination. In a group of older people with MCI; a diet high in processed foods was associated with some level of cognitive impairment.

The association between parental smoking and risk of childhood acute lymphoblastic leukemia (ALL) was investigated in an Australian population-based case-control study that included 388 cases and 868 controls aged

Impaired awareness of cognitive deficits is a common symptom of dementia, but its prognostic importance in people with cognitive impairment-no dementia (CIND) is uncertain. In this study, we examined whether community volunteers with CIND and reduced awareness had worse cognitive performance and cognitive decline over 18 months than CIND participants with intact awareness or healthy controls. We recruited 92 participants with CIND and 91 healthy controls with their respective informants. We used discrepancy scores (informant minus participant) on the Anosognosia Questionnaire for Dementia and Dysexecutive Questionnaire to ascertain participants' awareness of their cognitive performance. The main cognitive outcome variable was the Alzheimer Disease Assessment Scale: Cognitive Section. Bivariate correlations showed no relationship between the awareness measures and cognitive performance or decline. Overall, CIND participants' ratings of cognitive deficits correlated significantly with their Alzheimer Disease Assessment Scale: Cognitive Section score after 18-months (for Anosognosia Questionnaire for Dementia, r=0.45, P0.001) and showed a stronger relationship with cognitive performance than informant ratings. These results indicate that reduced awareness of deficit may be uncommon in community volunteer samples with CIND. In addition, self-report of cognitive complaints may be at least as useful as informant report when screening community-dwelling older adults at risk of cognitive decline and dementia.

Background:Previous research has found an association between post-stroke depressive symptoms and premorbid personality. This study sought to investigate further the relationship between premorbid personality and a number of common post-stroke behavioral and psychological symptoms in a three-month follow-up study.Methods:This prospective study was conducted between May 2003 and January 2005 in a Perth metropolitan teaching hospital. The pre-stroke personality of stroke survivors was assessed by interviewing a close family member (informant) within four weeks of the index stroke using the NEO Personality Inventory-Revised. Three months after the stroke, patients were followed up and assessed with the Cambridge Cognitive examination and Hospital Anxiety and Depression Scale, and their informants completed the Neuropsychiatric Inventory-carer distress version (NPI) and instrumental activities of daily living scale.Results:Depressive symptoms were the most commonly reported post-stroke symptom (45.1%). Spearman's correlations showed that high neuroticism was positively correlated with NPI total scores (ρ= 0.37,p= 0.007), NPI total distress scores (ρ= 0.47,p= 0.001), and specifically with agitation and irritability NPI composite scores. Agreeableness was inversely correlated with agitation (ρ= −0.40,p= 0.004) and irritability (ρ= −0.37,p= 0.007) composite scores.Conclusions:Premorbid personality traits of high neuroticism and low agreeableness are associated with the presence of post-stroke agitation, irritability, and carer distress. This knowledge may contribute to the development of strategies designed to identify patients and families who require more intense supervision and support during post-stroke rehabilitation.

Scope Maintenance of normal cellular phenotype depends largely on accurate DNA replication and repair. DNA damage causes gene mutations and predisposes to cancer and other chronic diseases. Growing evidence indicates that nutritional factors are associated with DNA damage in adults; here, we investigate these associations in children. Methods and results We conducted a cross-sectional study among 462 healthy children 3, 6, and 9 years of age. Blood was collected and micronutrient levels were measured. The cytokinesis-block micronucleus cytome assay was used to measure chromosomal DNA damage (micronuclei, nucleoplasmic bridges, and nuclear buds) in lymphocytes. Cell apoptosis, necrosis, and the nuclear division index were also measured. Nine loci in genes involved in folate metabolism and DNA repair were genotyped. Data were analyzed using linear regression with adjustment for potential confounders. Plasma calcium was positively associated with micronuclei and necrosis, and α-tocopherol negatively associated with apoptosis, nuclear division index, and nucleoplasmic bridges; lutein was positively associated with nucleoplasmic bridges. α-tocopherol was positively associated with necrosis. Conclusion DNA damage in healthy children may be influenced by blood micronutrient levels and certain genotypes. Further investigation of associations between nutritional status and genomic integrity in children is needed to shed additional light on potential mechanisms.

Childhood brain tumors (CBT) are the second most common childhood cancers, yet their etiology is largely unknown. We investigated whether maternal gestational intake of folate and vitamins B6 and B12 was associated with CBT risk in a nationwide case-control study conducted 2005-2010. Case children 0-14 years were recruited from all 10 Australian pediatric oncology centers. Control children were recruited by national random digit dialing, frequency matched to cases on age, sex, and state of residence. Dietary intake was ascertained using food frequency questionnaires and adjusted for total energy intake. Data from 293 case and 726 control mothers were analyzed using unconditional logistic regression. The odds ratio (OR) for the highest versus lowest tertile of folate intake was 0.70 [95% confidence interval (CI): 0.48, 1.02]. The ORs appeared lower in mothers who drank alcohol during pregnancy (OR = 0.45, 95% CI: 0.22, 0.93), mothers who took folic acid (OR = 0.67, 95% CI: 0.42, 1.06) or B6/B12 supplements (OR = 0.51, 95% CI: 0.25, 1.06) and in children younger than 5 years (OR = 0.50, 95% CI: 0.27, 0.93). These findings are consistent with folate's crucial role in maintenance of genomic integrity and DNA methylation. Dietary intake of B6 and B12 was not associated with risk of CBT.

Objective Telomeres are long hexamer (TTAGGG) repeats at the ends of chromosomes, and contribute to maintenance of chromosomal stability. Telomere shortening has been linked to cancers and other chronic diseases in adults, although evidence for causal associations is limited. The aim of this study was to determine whether nutritional factors are associated with telomere length (TL) in children. Methods We conducted a cross-sectional study of nutritional factors and TL in 437 children between 2009 and 2011. Healthy children ages 3, 6, and 9 y provided blood samples, and their parents completed a food frequency questionnaire and a telephone interview about relevant environmental exposures. TL and blood micronutrient levels were measured, and genotyping at 10 loci was undertaken. Associations between the micronutrients and other variables were assessed using linear regression. Results No significant main or interactive effects of age or sex were seen. After adjustment for age, sex, parental education, and month of blood collection, TL was inversely associated with plasma zinc, and shorter in children with the homozygous mutant genotype of the RFC G80A (rs1051266) polymorphism. Conclusions To the best of our knowledge, this is the first investigation of the association between telomere length and micronutrients in healthy children. The reason for the inverse relationship of TL with zinc is unknown but could be the result of an increase in telomere sequence deletions caused by labile zinc induction of oxidative stress. These findings should be corroborated in other studies before nutritional recommendations might be considered.

We investigated whether paternal dietary intake of folate before conception is associated with the risk of childhood acute lymphoblastic leukemia (ALL) in a nationwide case-control study.Data on dietary folate intake during the 6 months before the child's conception were collected from 285 case fathers and 595 control fathers using a dietary questionnaire. Nutrient intake was quantified using a customized computer software package based on Australian food composition databases. Data on folate intake were analyzed using unconditional logistic regression, adjusting for study-matching variables, total energy, and potentially confounding variables. In a subset of 229 cases and 420 controls, data on vitamin B6 and vitamin B12 intake were also analyzed.No consistent associations were seen with paternal dietary intake of folate or vitamin B6. Higher levels of paternal dietary vitamin B12 were appeared to be associated with an increased risk of childhood ALL, with those in the highest tertile of consumption having an OR of 1.51 (0.97, 2.36). The use of supplements containing folate and vitamins B6 or B12 was rare.We did not find any biologically plausible evidence that paternal nutrition in the period leading up to conception was associated with childhood ALL. Our finding for vitamin B12 may be a chance finding, given the number of analyses performed, or be attributable to participation bias because parents with a tertiary education had the lowest level of B12 intake and tertiary education was more common among control than case parents.

Childhood brain tumors (CBT) are the second most common type of childhood cancer and the leading cause of childhood cancer mortality. Few causes of CBT are known, but parental, fetal, and early life exposures are likely to be important given the early age at diagnosis of many cases. We aimed to investigate whether parents' diagnostic radiological procedures before conception, in the mother during pregnancy or the child's procedures were associated with an increased risk of CBT.This population-based case-control study was conducted between 2005 and 2010. Cases were identified through all ten Australian pediatric oncology centers, and controls via nationwide random-digit dialing; frequency-matched to cases on age, sex and state of residence. Information on radiological exposures in the time periods of interest was obtained for 306 case and 950 control families through mailed questionnaires. Analysis used unconditional logistic regression, adjusting for matching variables and potential confounders.We found no evidence of positive associations between risk of CBT overall and childhood or parental pre-pregnancy radiological procedures. Increased ORs for high-grade gliomas associated with childhood radiological procedures were based on small numbers and may be due to chance.Given the evidence for an increased risk of CBT in cohort studies of computed tomography (CT) in childhood, the lack of such an association in our study may be due to the reduced intensity of CTs after 2001. Future research to investigate the safety of fetal exposure to more intense procedures like CT scans is needed.

Childhood brain tumors (CBT) are the leading cause of cancer death in children, yet their causes are largely known. This study investigated the association between maternal and birth characteristics and risk of CBT.Cases families were recruited from all 10 Australian pediatric oncology centers between 2005 and 2010. Control families were recruited via random-digit dialing, frequency matched to cases on the basis of child's age, sex, and State of residence. Maternal and birth characteristics of children were ascertained by questionnaires. Odds ratios (ORs) and 95% confidence intervals (CI) were estimated using unconditional logistic regression, adjusting for relevant confounders.For this analysis, data on 319 case children and 1,079 control children were available. No association was found between risk of CBT and birth weight, fetal growth, birth order, gestational age, or maternal body mass index. The ORs for inadequate and excessive maternal gestational weight gain (GWG) (Institute of Medicine 2009 guidelines) were 1.8 (95% CI 1.2-2.6) and 1.4 (95% CI 1.0-2.1), respectively; similar findings for GWG were seen across categories of child's age, fetal growth, maternal body mass index and height, maternal smoking, and parental education. Risk of low grade glioma appeared increased with preterm birth (OR 1.6 (95% CI 0.8-3.1) and admission to neonatal intensive care (NICU) for2 days (OR 1.7, 95% CI 0.9-3.6).We found little evidence of associations between risk of CBT and most birth characteristics. The associations we observed with GWG, prematurity and NICU admission require corroboration in other studies.

Positive associations have been reported between measures of accelerated fetal growth and risk of childhood acute lymphoblastic leukemia (ALL). We investigated this association by pooling individual-level data from 12 case-control studies participating in the Childhood Leukemia International Consortium. Two measures of fetal growth – weight-for-gestational-age and proportion of optimal birth weight (POBW) – were analysed. Study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression, and combined in fixed effects meta-analyses. Pooled analyses of all data were also undertaken using multivariable logistic regression. Subgroup analyses were undertaken when possible. Data on weight for gestational age were available for 7,348 cases and 12,489 controls from all 12 studies and POBW data were available for 1,680 cases and 3,139 controls from three studies. The summary ORs from the meta-analyses were 1.24 (95% CI 1.13, 1.36) for children who were large for gestational age relative to appropriate for gestational age, and 1.16 (95% CI: 1.09, 1.24) for a one standard deviation increase in POBW. The pooled analyses produced similar results. The summary and pooled ORs for small-for-gestational-age children were 0.83 (95% CI: 0.75, 0.92) and 0.86 (95% CI 0.77, 0.95) respectively. Results were consistent across subgroups defined by sex, ethnicity and immunophenotype, and when the analysis was restricted to children who did not have high birth weight. The evidence that accelerated fetal growth is associated with a modest increased risk of childhood ALL is strong and consistent with known biological mechanisms involving insulin like growth factors.

The aim of this study is to assess in older adults with memory complaints, the effects of a 6-month home-based physical activity (PA) intervention on short-term adherence, short and long-term self-efficacy and the predictors of adherence.Participants with memory complaints with or without mild cognitive impairment (MCI) were recruited from Perth, Western Australia between May 2004 and July 2006 and randomly assigned to a control or an intervention group. The intervention group received a 6-month PA programme and recorded sessions on a diary. Pedometer readings, questionnaires, and physical and cognitive measures were completed at 0, 6, 12 and 18 months.One hundred and seventy participants started the study. Retention rates were similar for both groups at all time-points however retention was higher for men than women (P0.01). Adherence to the prescribed PA was 72.8% (95% CI, 70.8 74.9%). Men had higher adherence rate than women (P0.001). Those with and without MCI had similar adherence. Compared to controls self-efficacy was higher in the intervention group after 6 months only (P0.01).Older adults with memory complaints, with or without MCI, can successfully participate in and enjoy home-based PA programmes. Long-term adherence to such interventions may require continued support and increased self-efficacy. (ACTRN012605000136606.).

Positive associations have been reported between the measures of accelerated fetal growth and risk of childhood acute lymphoblastic leukemia (ALL). We investigated this association by pooling individual-level data from 12 case-control studies participating in the Childhood Leukemia International Consortium. Two measures of fetal growth-weight-for-gestational-age and proportion of optimal birth weight (POBW)-were analysed. Study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression, and combined in fixed effects meta-analyses. Pooled analyses of all data were also undertaken using multivariable logistic regression. Subgroup analyses were undertaken when possible. Data on weight for gestational age were available for 7,348 cases and 12,489 controls from all 12 studies and POBW data were available for 1,680 cases and 3,139 controls from three studies. The summary ORs from the meta-analyses were 1.24 (95% CI: 1.13, 1.36) for children who were large for gestational age relative to appropriate for gestational age, and 1.16 (95% CI: 1.09, 1.24) for a one-standard deviation increase in POBW. The pooled analyses produced similar results. The summary and pooled ORs for small-for-gestational-age children were 0.83 (95% CI: 0.75, 0.92) and 0.86 (95% CI: 0.77, 0.95), respectively. Results were consistent across subgroups defined by sex, ethnicity and immunophenotype, and when the analysis was restricted to children who did not have high birth weight. The evidence that accelerated fetal growth is associated with a modest increased risk of childhood ALL is strong and consistent with known biological mechanisms involving insulin-like growth factors. © 2013 UICC.

Childhood acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and brain tumors (CBTs) are the leading cause of cancer death in children. In our Australian case-control studies of these cancers, we investigated whether parental alcohol consumption before or during pregnancy was associated with risk.Cases were identified through the ten Australian pediatric oncology centers, and controls were recruited through national random-digit dialling. Detailed information on alcohol consumption, including beverage type, amount, and timing, was collected from 690 case families (388 ALL and 302 CBT) and 1,396 control families. Data were analyzed using unconditional logistic regression.We found no evidence that maternal alcohol use before or during pregnancy was associated with an increased risk of either cancer; rather, there was evidence of inverse associations, particularly with wine. For both cancers, we observed U-shaped associations with paternal alcohol consumption in the year before the pregnancy, possibly driven by reduced risk at moderate levels of beer and wine intake and increased risk associated with high levels of beer intake. Moderate intake of spirits by fathers was associated with an increased risk of CBT but not ALL. These findings would be strengthened by corroboration in other studies. While the inverse associations with wine may be interesting mechanistically, the public health message remains that maternal alcohol use during pregnancy causes serious disorders in the offspring and should be avoided.Our findings suggest that men, as well as women, should limit their alcohol intake when planning a pregnancy.

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.

After publication, it was noted by the authors that the dataset used for the analyses of occupational exposures in this study accidentally used incomplete occupational histories collected for 94 control fathers and 104 control mothers recruited in 2006, and these control parents were all treated as unexposed to occupational pesticides. Results in Tables 1–3 and Supplemental Tables 1 and 2 (and the first three rows of Supplemental Table 3) of our published paper were unaffected by this error as they concerned household, rather than occupational pesticide exposure. The conclusions regarding the association with household exposure to professional pest control treatments are consequently unchanged. However, for occupational exposure, 18 control fathers and 2 control mothers were mistakenly classified as being unexposed to pesticides when they should have been classified as exposed (any time before the child’s birth). The analyses presented in Table 4 and parts of Supplemental Table 3 in the published manuscript were re-run using the full dataset to ensure correct exposure assignment (5 case fathers and 4 control fathers were additionally excluded from revised occupational analysis due to genuinely missing data). The updated Table 4 and Supplemental Table 3 (occupational estimates only) are presented in this erratum. The online version of the original article can be found under doi:10. 1007/s10552-013-0205-1.

Context Many observational studies have shown that physical activity reduces the risk of cognitive decline; however, evidence from randomized trials is lacking. Objective To determine whether physical activity reduces the rate of cognitive decline among older adults at risk. Design and Setting Randomized controlled trial of a 24-week physical activity intervention conducted between 2004 and 2007 in metropolitan Perth, Western Australia. Assessors of cognitive function were blinded to group membership. Participants We recruited volunteers who reported memory problems but did not meet criteria for dementia. Three hundred eleven individuals aged 50 years or older were screened for eligibility, 89 were not eligible, and 52 refused to participate. A total of 170 participants were randomized and 138 participants completed the 18-month assessment. Intervention Participants were randomly allocated to an education and usual care group or to a 24-week home-based program of physical activity. Main Outcome Measure Change in Alzheimer Disease Assessment Scale–Cognitive Subscale (ADAS-Cog) scores (possible range, 0-70) over 18 months. Results In an intent-to-treat analysis, participants in the intervention group improved 0.26 points (95% confidence interval, −0.89 to 0.54) and those in the usual care group deteriorated 1.04 points (95% confidence interval, 0.32 to 1.82) on the ADAS-Cog at the end of the intervention. The absolute difference of the outcome measure between the intervention and control groups was −1.3 points (95% confidence interval,−2.38 to −0.22) at the end of the intervention. At 18 months, participants in the intervention group improved 0.73 points (95% confidence interval, −1.27 to 0.03) on the ADAS-Cog, and those in the usual care group improved 0.04 points (95% confidence interval, −0.46 to 0.88). Word list delayed recall and Clinical Dementia Rating sum of boxes improved modestly as well, whereas word list total immediate recall, digit symbol coding, verbal fluency, Beck depression score, and Medical Outcomes 36-Item Short-Form physical and mental component summaries did not change significantly. Conclusions In this study of adults with subjective memory impairment, a 6-month program of physical activity provided a modest improvement in cognition over an 18-month follow-up period. Trial Registration anzctr.org.au Identifier: ACTRN12605000136606