ABSTRACT
BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.
Subject(s)
Congenital Abnormalities/epidemiology , Congenital Abnormalities/pathology , Neoplasms/epidemiology , Neoplasms/etiology , Risk Assessment/methods , Adolescent , Child , Child, Preschool , Cohort Studies , Humans , Infant , Proportional Hazards Models , Western AustraliaABSTRACT
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.
Subject(s)
Folic Acid/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/etiology , Adolescent , Child , Child, Preschool , Dietary Supplements/analysis , Female , Genetic Predisposition to Disease , Humans , Infant , Infant, Newborn , Polymorphism, Genetic , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Pregnancy , Risk FactorsABSTRACT
Tests for Hardy-Weinberg equilibrium (HWE) have been used to detect genotyping error, but those tests have low power unless the sample size is very large. We assessed the performance of measures of departure from HWE as an alternative way of screening for genotyping error. Three measures of the degree of disequilibrium (alpha, ,D, and F) were tested for their ability to detect genotyping error of 5% or more using simulations and a real dataset of 184 children with leukemia genotyped at 28 single nucleotide polymorphisms. The simulations indicate that all three disequilibrium coefficients can usefully detect genotyping error as judged by the area under the Receiver Operator Characteristic (ROC) curve. Their discriminative ability increases as the error rate increases, and is greater if the genotyping error is in the direction of the minor allele. Optimal thresholds for detecting genotyping error vary for different allele frequencies and patterns of genotyping error but allele frequency-specific thresholds can be nominated. Applying these thresholds would have picked up about 90% of genotyping errors in our actual dataset. Measures of departure from HWE may be useful for detecting genotyping error, but this needs to be confirmed in other real datasets.
Subject(s)
Genotype , Models, Genetic , Models, Statistical , Alleles , Biostatistics , Case-Control Studies , Child , Databases, Genetic , Gene Frequency , Humans , Likelihood Functions , Polymorphism, Single Nucleotide , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , ROC CurveABSTRACT
The causes of autism spectrum disorders (ASDs) are unknown, although genetic and environmental influences have been implicated. Previous studies have suggested an association with birth defects, but most investigators have not addressed associations with specific diagnostic categories of ASD. In this study, the authors investigated the associations between birth defects and autism, Asperger syndrome, and pervasive developmental disorder not otherwise specified. Using Western Australian population-based linked data, the authors compared all children with ASD born in Western Australia during 1980-1995 (n = 465) with their siblings (n = 481) and population controls (n = 1,313) in a nested case-control study. The prevalence of birth defects was significantly higher in ASD cases than in population controls; this difference remained significant after adjustment for confounding factors. Odds ratios for birth defects were similar for autism (odds ratio (OR) = 2.0, 95% confidence interval (CI): 1.3, 3.0) and pervasive developmental disorder not otherwise specified (OR = 2.2, 95% CI: 1.1, 4.3) but not for Asperger syndrome (OR = 0.5, 95% CI: 0.1, 1.9). Birth defects in case siblings were not significantly different from those in cases and population controls. The association between birth defects and ASD may be due to underlying genetic and/or environmental factors common to both ASD and birth defects, or birth defects may predispose a child to ASD.