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1.  Cotinine and trans 3'-Hydroxycotinine in Dried Blood Spots as Biomarkers of Tobacco Exposure and Nicotine Metabolism 
Tobacco use is the major preventable cause of premature death in the United States. Secondhand smoke (SHS) exposure also contributes to a number of premature deaths as well as other negative health outcomes. An accurate assessment of tobacco smoke exposure is critical to understanding these disease processes. The plasma concentration of cotinine, the primary metabolite of nicotine, is widely accepted as a quantitative measure of tobacco and SHS exposure. However, it is not always feasible to collect plasma. Dried blood spots (DBS), which are collected routinely from newborns and often from young children for lead screening, provide an alternative sampling method. We have developed a quantitative high throughput liquid chromatography tandem mass spectrometry (LC/MS/MS) method for the analysis of cotinine in DBS. The limit of quantitation was 0.3 ng/g (~ 0.2 ng/ml plasma). Cotinine levels in DBS from 83 smokers and 99 nonsmokers exposed to SHS were determined. Plasma cotinine concentrations in these subjects ranged from <0.02 to 443 ng/ml. Cotinine was detected in DBS from 157 subjects, and the correlation between cotinine in plasma and DBS was excellent, 0.992 (p<0.001). We also determined the ratio of trans-3'-hydroxycotinine to cotinine, a measure of nicotine metabolism, in DBS from smokers. This ratio in DBS was well correlated with the ratio in plasma, 0.94 (p<0.001). In a small study we confirmed the feasibility of using extant DBS collected for lead screening to assess SHS exposure in children.
PMCID: PMC4048618  PMID: 23443235
Second hand smoke exposure; lead; smoking
2.  Children’s Oncology Group’s 2013 Blueprint for Research: Epidemiology 
Pediatric blood & cancer  2012;60(6):10.1002/pbc.24434.
Investigators worldwide have for over forty years conducted case-control studies aimed at determining the causes of childhood cancer. The central challenge to conducting such research is the rarity of childhood cancer, thus many studies aggregate cases through clinical trials organizations such as COG. Rarity also precludes the use of prospective study designs, which are less prone to recall and selection biases. Despite these challenges a substantial literature on childhood cancer etiology has emerged but few strong environmental risk factors have been identified. Genetic studies are thus now coming to the fore with some success. The ultimate aim of epidemiologic studies is to reduce the population burden of childhood cancer by suggesting preventive measures or possibly by enabling early detection.
PMCID: PMC3726183  PMID: 23255344
Epidemiology; etiology; prevention
3.  Maternal pregnancy events and exposures and risk of hepatoblastoma: A Children's Oncology Group (COG) study 
Cancer epidemiology  2013;37(3):318-320.
Hepatoblastoma is a rare childhood liver cancer with an obscure etiology, however it is potentially associated with selected pregnancy events and hepatoblastoma risk in offspring.
Adjusted unconditional logistic regression estimated odds ratios (OR) and corresponding 95% confidence intervals (CI) for self-reported pregnancy events and medication use in a sample of mothers of 383 childhood hepatoblastoma cases and 387 controls.
Risk of hepatoblastoma was significantly associated with maternal first trimester weight gain (OR=1.02; 95% CI 1.00, 1.04 per 1 lb increase and nearly significantly with maternal multivitamin use (OR=0.73; 95% CI 0.51,1.03). Hepatoblastoma was not associated with other maternal weight changes, maternal illness or medication use during pregnancy.
We found little evidence that maternal illness or most medication use during pregnancy are associated with hepatoblastoma in offspring.
PMCID: PMC3626752  PMID: 23312454
hepatoblastoma; pregnancy complications; self medication; body weight changes; case-control studies
4.  The Childhood Leukemia International Consortium 
Cancer epidemiology  2013;37(3):336-347.
Acute leukemia is the most common cancer in children under 15 years of age; 80% are acute lymphoblastic leukemia (ALL) and 17% are acute myeloid leukemia (AML). Childhood leukemia shows further diversity based on cytogenetic and molecular characteristics, which may relate to distinct etiologies. Case–control studies conducted worldwide, particularly of ALL, have collected a wealth of data on potential risk factors and in some studies, biospecimens. There is growing evidence for the role of infectious/immunologic factors, fetal growth, and several environmental factors in the etiology of childhood ALL. The risk of childhood leukemia, like other complex diseases, is likely to be influenced both by independent and interactive effects of genes and environmental exposures. While some studies have analyzed the role of genetic variants, few have been sufficiently powered to investigate gene–environment interactions.
The Childhood Leukemia International Consortium (CLIC) was established in 2007 to promote investigations of rarer exposures, gene–environment interactions and subtype-specific associations through the pooling of data from independent studies.
By September 2012, CLIC included 22 studies (recruitment period: 1962–present) from 12 countries, totaling approximately 31 000 cases and 50 000 controls. Of these, 19 case–control studies have collected detailed epidemiologic data, and DNA samples have been collected from children and child–parent trios in 15 and 13 of these studies, respectively. Two registry-based studies and one study comprising hospital records routinely obtained at birth and/or diagnosis have limited interview data or biospecimens.
CLIC provides a unique opportunity to fill gaps in knowledge about the role of environmental and genetic risk factors, critical windows of exposure, the effects of gene–environment interactions and associations among specific leukemia subtypes in different ethnic groups.
PMCID: PMC3652629  PMID: 23403126
Leukemia; Children; Consortium; Epidemiology; Genetics
5.  Epidemiology of Childhood Acute Myeloid Leukemia 
Pediatric blood & cancer  2013;60(5):728-733.
Although leukemia is the most common childhood cancer diagnosis, the subtype, acute myeloid leukemia (AML), is less common and fewer etiologic studies exist. This review summarizes the major risk factors for AML. We searched the literature using PubMed for articles on childhood AML and reviewed 180 articles. While few risk factors are definitive, we identify several with consistent evidence of a possible effect. Thorough analysis of genetic and epigenetic factors is missing from this literature and methodological issues are unresolved. Future studies should more closely examine causal mechanisms, improve exposure measurement, and include analysis using genetic and epigenetic factors.
PMCID: PMC3664189  PMID: 23303597
acute myeloid leukemia; children; epidemiology
6.  Genome-wide Association Study Identifies Multiple Risk Loci for Chronic Lymphocytic Leukemia 
Berndt, Sonja I. | Skibola, Christine F. | Joseph, Vijai | Camp, Nicola J. | Nieters, Alexandra | Wang, Zhaoming | Cozen, Wendy | Monnereau, Alain | Wang, Sophia S. | Kelly, Rachel S. | Lan, Qing | Teras, Lauren R. | Chatterjee, Nilanjan | Chung, Charles C. | Yeager, Meredith | Brooks-Wilson, Angela R. | Hartge, Patricia | Purdue, Mark P. | Birmann, Brenda M. | Armstrong, Bruce K. | Cocco, Pierluigi | Zhang, Yawei | Severi, Gianluca | Zeleniuch-Jacquotte, Anne | Lawrence, Charles | Burdette, Laurie | Yuenger, Jeffrey | Hutchinson, Amy | Jacobs, Kevin B. | Call, Timothy G. | Shanafelt, Tait D. | Novak, Anne J. | Kay, Neil E. | Liebow, Mark | Wang, Alice H. | Smedby, Karin E | Adami, Hans-Olov | Melbye, Mads | Glimelius, Bengt | Chang, Ellen T. | Glenn, Martha | Curtin, Karen | Cannon-Albright, Lisa A. | Jones, Brandt | Diver, W. Ryan | Link, Brian K. | Weiner, George J. | Conde, Lucia | Bracci, Paige M. | Riby, Jacques | Holly, Elizabeth A. | Smith, Martyn T. | Jackson, Rebecca D. | Tinker, Lesley F. | Benavente, Yolanda | Becker, Nikolaus | Boffetta, Paolo | Brennan, Paul | Foretova, Lenka | Maynadie, Marc | McKay, James | Staines, Anthony | Rabe, Kari G. | Achenbach, Sara J. | Vachon, Celine M. | Goldin, Lynn R | Strom, Sara S. | Lanasa, Mark C. | Spector, Logan G. | Leis, Jose F. | Cunningham, Julie M. | Weinberg, J. Brice | Morrison, Vicki A. | Caporaso, Neil E. | Norman, Aaron D. | Linet, Martha S. | De Roos, Anneclaire J. | Morton, Lindsay M. | Severson, Richard K. | Riboli, Elio | Vineis, Paolo | Kaaks, Rudolph | Trichopoulos, Dimitrios | Masala, Giovanna | Weiderpass, Elisabete | Chirlaque, María-Dolores | Vermeulen, Roel C H | Travis, Ruth C. | Giles, Graham G. | Albanes, Demetrius | Virtamo, Jarmo | Weinstein, Stephanie | Clavel, Jacqueline | Zheng, Tongzhang | Holford, Theodore R | Offit, Kenneth | Zelenetz, Andrew | Klein, Robert J. | Spinelli, John J. | Bertrand, Kimberly A. | Laden, Francine | Giovannucci, Edward | Kraft, Peter | Kricker, Anne | Turner, Jenny | Vajdic, Claire M. | Ennas, Maria Grazia | Ferri, Giovanni M. | Miligi, Lucia | Liang, Liming | Sampson, Joshua | Crouch, Simon | Park, Ju-hyun | North, Kari E. | Cox, Angela | Snowden, John A. | Wright, Josh | Carracedo, Angel | Lopez-Otin, Carlos | Bea, Silvia | Salaverria, Itziar | Martin, David | Campo, Elias | Fraumeni, Joseph F. | de Sanjose, Silvia | Hjalgrim, Henrik | Cerhan, James R. | Chanock, Stephen J. | Rothman, Nathaniel | Slager, Susan L.
Nature genetics  2013;45(8):868-876.
PMCID: PMC3729927  PMID: 23770605
7.  Case-parent analysis of variation in pubertal hormone genes and pediatric osteosarcoma: a Children’s Oncology Group (COG) study 
Osteosarcoma (OS) is a rare malignant bone tumor with an overall incidence rate of 4.6 cases per million children aged 0-19 years in the United States. While the etiology of OS is largely unknown, its distinctive age-incidence pattern suggests that growth and development is crucial in genesis. Prior studies have suggested that variants in genes in the estrogen metabolism (ESTR) and insulin-like growth factor/growth hormone (IGF/GH) pathways are associated with OS. We examined 798 single nucleotide polymorphisms (SNPs) in 42 genes from these pathways in a case-parent study (229 complete triads and 56 dyads) using buccal cell samples. Relative risks (RR) and 95% confidence intervals (CI) associated with transmitting one or two copies of the variant were estimated using log-linear models. After Bonferroni correction, 1 SNP within the ESTR pathway (rs1415270: RR = 0.50 and 8.37 for 1 and 2 vs. 0 copies, respectively; p = 0.010), and two SNPs in the IGF/GH pathway (rs1003737: RR = 0.91 and 0.0001 for 1 and 2 vs. 0 copies, respectively; p <0.0001 and rs2575352: RR = 2.62 and 0.22 for 1 and 2 vs. 0 copies; p < 0.0001) were significantly associated with OS incidence. These results confirm previous findings that variation in the estrogen metabolism and bone growth pathways influence OS risk and further support a biologically and epidemiologically plausible role in OS development.
PMCID: PMC3508538  PMID: 23205180
Osteosarcoma; case-parent study; growth and development; insulin-like growth factor pathway; estrogen metabolism pathway
8.  Genetic Variants Modify Susceptibility to Leukemia in Infants: A Children’s Oncology Group Report 
Pediatric blood & cancer  2012;60(1):31-34.
The mixed lineage leukemia (MLL) gene is commonly rearranged in infant leukemia (IL). Genetic determinants of susceptibility to IL are unknown. Recent genome wide association studies for childhood acute lymphoblastic leukemia (ALL) have identified susceptibility loci at IKZF1, ARID5B, and CEBPE.
We genotyped these loci in 171 infants with leukemia and 384 controls and evaluated associations overall, by subtype (ALL, acute myeloid leukemia (AML)), and by presence (+) or absence (−) of MLL rearrangements.
Homozygosity for a variant IKZF1 allele (rs11978267) increased risk of infant AML (Odds Ratio (OR)=3.9, 95% Confidence Interval (CI)=1.8–8.4); the increased risk was similar for AML/MLL+ and MLL− cases. In contrast, risk of ALL/MLL− was increased in infants homozygous for the IKZF1 variant (OR=5.1, 95%CI=1.8–14.5) but the variant did not modify risk of ALL/MLL+. For ARID5B (rs10821936), homozygosity for the variant allele increased risk for the ALL/MLL− subgroup only (OR=7.2, 95%CI=2.5–20.6). There was little evidence of an association with the CEBP variant (rs2239633).
IKZF1 is expressed in early hematopoiesis, including precursor myeloid cells. Our data provide the first evidence that IKZF1 modifies susceptibility to infant AML, irrespective of MLL rearrangements, and could provide important new etiologic insights into this rare and heterogeneous hematopoietic malignancy.
PMCID: PMC3381932  PMID: 22422485
leukemia; genetic susceptibility; infants
9.  Invited Commentary: Childhood Acute Lymphoblastic Leukemia and Allergies: Biology or Bias? 
American Journal of Epidemiology  2012;176(11):979-983.
Previous epidemiologic studies have shown an inverse association between a personal history of atopy/allergies, both overall and among asthma, eczema, and hay fever investigated separately, and childhood acute lymphoblastic leukemia (ALL) with some consistency; however, in most of these studies, exposure data were collected by maternal interview. Now, in a population-based and records-based study in this issue of the Journal (Am J Epidemiol. 2012;176(11):970–978), Chang et al. report an increased risk for allergic conditions across different etiologic time periods, calling the former paradigm into doubt. A review of the basic biology literature shows that proposed mechanisms support either a positive or an inverse association. In light of this ambiguity, it is epidemiology's turn to determine the direction of association.
PMCID: PMC3571240  PMID: 23171875
child; hypersensitivity; leukemia
10.  Predictors of mother and child DNA yields in buccal cell samples collected in pediatric cancer epidemiologic studies: a report from the Children’s Oncology group 
BMC Genetics  2013;14:69.
Collection of high-quality DNA is essential for molecular epidemiology studies. Methods have been evaluated for optimal DNA collection in studies of adults; however, DNA collection in young children poses additional challenges. Here, we have evaluated predictors of DNA quantity in buccal cells collected for population-based studies of infant leukemia (N = 489 mothers and 392 children) and hepatoblastoma (HB; N = 446 mothers and 412 children) conducted through the Children’s Oncology Group. DNA samples were collected by mail using mouthwash (for mothers and some children) and buccal brush (for children) collection kits and quantified using quantitative real-time PCR. Multivariable linear regression models were used to identify predictors of DNA yield.
Median DNA yield was higher for mothers in both studies compared with their children (14 μg vs. <1 μg). Significant predictors of DNA yield in children included case–control status (β = −0.69, 50% reduction, P = 0.01 for case vs. control children), brush collection type, and season of sample collection. Demographic factors were not strong predictors of DNA yield in mothers or children in this analysis.
The association with seasonality suggests that conditions during transport may influence DNA yield. The low yields observed in most children in these studies highlight the importance of developing alternative methods for DNA collection in younger age groups.
PMCID: PMC3751424  PMID: 23937514
DNA collection; Buccal cells; Pediatric epidemiology
11.  Cancer risk among children with very low birth weight 
Pediatrics  2009;124(1):96-104.
Risk of hepatoblastoma is strongly increased among children with very low birth weight (VLBW: <1,500 grams). Because data on VLBW and other childhood cancers is sparse, we examined the risk of malignancy following VLBW in a large dataset.
We combined case-control datasets created by linking the cancer and birth registries of California, Minnesota, New York, Texas, and Washington states, which comprised 17,672 children diagnosed with cancer at 0-14 years of age and 57,966 randomly selected controls. Unconditional logistic regression was used to examine the association of cancer with VLBW and moderately low birth weights (1,500-1,999g and 2,000-2,499g) compared to moderate/high birth weight (≥2,500) adjusting for sex, gestational age, birth order, plurality, maternal age, maternal race, state, and year of birth.
Most childhood cancers were not associated with low birth weights. However, retinoblastoma and gliomas other than astrocytomas and ependymomas were possibly associated with VLBW, with respective odds ratios (OR) of 2.43 (95% Confidence Interval (CI): 1.00-5.89) and 2.13 (95% CI: 0.71-6.39). Risk of other gliomas was also increased among children weighing 1,500-1,999g at birth (OR = 3.58; 95% CI: 1.98-6.47). For hepatoblastoma the ORs associated with birth weights of 2,000-2,499g, 1,500-1999g, and 350-1,499g were 1.56 (95% CI: 0.81-2.98), 3.37 (95% CI: 1.44-7.88), and 17.18 (95% CI: 7.46-39.54), respectively
These data suggest no association between most cancers and VLBW with the exception of the known association with hepatoblastoma and possible moderately increased risks of other gliomas and retinoblastoma, which may warrant confirmation.
PMCID: PMC2704984  PMID: 19564288
Infant; very low birth weight; cancer; case-control studies; registries
12.  Parental age and risk of childhood cancer: A pooled analysis 
Epidemiology (Cambridge, Mass.)  2009;20(4):475-483.
Few risk factors for childhood cancer are well-established. We investigated whether advancing parental age increases childhood cancer risk.
We assessed the relationship between parental age and childhood cancer in a case-control study using pooled population-based data. Our pooling was based on linked cancer and birth registry records from New York, Washington, Minnesota, Texas, and California. Subjects included 17,672 cancer cases diagnosed at ages 0–14 years during 1980–2004 and 57,966 controls born during 1970–2004. Persons with Down syndrome were excluded. Odds ratios and 95% confidence intervals were calculated by logistic regression for the association between parental age and childhood cancer after adjustment for sex, birth weight, gestational age, birth order, plurality, maternal race, birth year, and state.
Positive linear trends per 5-year maternal age increase were –observed for childhood cancers overall (odds ratio = 1.08 [95% confidence interval = 1.06–1.10]) and 7 of the 10 most frequent diagnostic groups: leukemia (1.08 [1.05–1.11]), lymphoma (1.06 [1.01–1.12]), central nervous system tumors (1.07 [1.03–1.10]), neuroblastoma (1.09 [1.04–1.15]), Wilms’ tumor (1.16 [1.09–1.22]), bone tumors (1.10 [ 1.00–1.20]), and soft tissue sarcomas (1.10 [1.04–1.17]). No maternal age effect was noted for retinoblastoma, germ cell tumors, or hepatoblastoma. Paternal age was not independently associated with most childhood cancers after adjustment for maternal age.
Our results suggest that older maternal age increases risk for most common childhood cancers. Investigation into possible mechanisms for this association is warranted.
PMCID: PMC2738598  PMID: 19373093
13.  Parental infertility, infertility treatment and hepatoblastoma: a report from the Children's Oncology Group 
Human Reproduction (Oxford, England)  2012;27(6):1649-1656.
A recent study suggested a markedly increased risk of hepatoblastoma (HB) among children conceived with treatment for infertility. However, it is not clear whether this finding is confounded by the association between HB and low birthweight (LBW).
Associations between parental infertility and its treatment and HB were examined using data from a case–control study conducted through the Children's Oncology Group (COG). Telephone interviews were completed for 383 mothers of cases diagnosed with HB at US COG institutions between January 2000 and December 2008 and for 387 mothers of controls recruited through state birth registries. Logistic regression was used to examine possible associations.
After adjusting for birthweight and other potential confounders, no significant association was found for any of the measures of parental infertility or its treatment. In HB cases conceived through assisted reproductive technology (ART), 4 of 16 also had Beckwith–Wiedemann syndrome (BWS) compared with 9 of 365 in HB cases without ART.
Little evidence of an association between parental infertility or its treatment and HB was found. The relationship found in a previous study could be due to LBW and BWS which are risk factors for HB and also associated with parental infertility and its treatment.
PMCID: PMC3357199  PMID: 22473396
case–control studies; hepatoblastoma; infertility; selection bias
14.  Feasibility of neonatal dried blood spot retrieval amid evolving state policies (2009–2010): A Children’s Oncology Group study 
Dried blood spots (DBS) are collected uniformly from U.S. newborns to test for metabolic and other disorders. Because evidence exists for prenatal origins of some diseases, DBS may provide unique prenatal exposure records. Some states retain residual DBS and permit their use in etiologic studies. The primary study aim was to assess the feasibility of obtaining residual DBS from state newborn screening programs for pediatric and adolescent cancer patients nationwide with parental/subject consent/assent. Families of leukemia and lymphoma patients aged ≤21 years diagnosed from 1998–2007 at randomly selected Children’s Oncology Group institutions across the U.S. were queried (n=947). Parents/guardians and patients aged ≥18 years were asked to release DBS to investigators in spring 2009. DBS were then requested from states. Overall, 299 families (32%) released DBS. Consenting/assenting patients were born in 39 U.S. states and 46 DBS were obtained from 5 states; 124 DBS were unobtainable because patients were born prior to dates of state retention. State policies are rapidly evolving and there is ongoing discussion regarding DBS storage and secondary research uses. Currently, population-based DBS studies can be conducted in a limited number of states; fortunately, many have large populations to provide reasonably sized pediatric subject groups.
PMCID: PMC3664237  PMID: 21980944
biological specimen banks; child; epidemiologic methods; informed consent; neonatal screening; neoplasms
15.  Childhood cancer among twins and higher order multiples 
Although several studies have found no change or a decreased risk of childhood cancer in twins, few have controlled for potential confounders such as birth weight. We examined the association of birth plurality and childhood cancer in pooled data from five U.S. states (California, Minnesota, New York, Texas, and Washington) using linked birth-cancer registry data. The data, excluding children with Down syndrome or who died before 28 days of life, included 17,672 cases diagnosed 1980–2004 at ages 28 days-14 years and 57,966 controls with all cases and controls born 1970–2004. Analyses were restricted to children weighing ≤ 4,000g at birth. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression adjusting for sex, gestational age, birth weight, birth order, maternal age, maternal race, state of birth, and birth year. Children who were multiples had no difference in risk of cancer overall (OR= 0.93, 95% CI = 0.82–1.07), but a borderline reduced risk of Wilms tumor (OR= 0.65, 95% CI = 0.39–1.09). For children diagnosed under the age of two there was a reduced risk of Wilms tumor (OR= 0.27, 95% CI = 0.09–0.86) and neuroblastoma (OR= 0.46, 95% CI = 0.25–0.84) and an increased risk of fibrosarcoma (OR= 5.81, 95% CI = 1.53–22.11). Higher order multiple birth (triplets or higher) was not associated with childhood cancer. Our analysis suggests that mechanisms other than birth weight and gestational age may influence the lower risk of Wilms tumor and neuroblastoma in multiple births.
PMCID: PMC2705199  PMID: 19124494
childhood cancer; twins; multiple birth; case-control; pooled data
16.  Self-report versus medical record – perinatal factors in a study of infant leukaemia: a study from the Children’s Oncology Group 
In a case–control study of infant leukaemia, we assessed agreement between medical records and mother’s self-reported pregnancy-related conditions and procedures and infant treatments. Interview and medical record data were available for 234 case and 215 control mothers. Sensitivity, specificity and predictive values for maternal report were estimated for case and control mothers separately, taking the medical record as correct. For most perinatal conditions, sensitivity and specificity were over 75%. Low sensitivity was observed for maternal protein or albumin in the urine (cases: 12% [95% exact confidence interval (CI) 8%, 18%]; controls: 11% [95% CI 7%, 17%]) and infant supplemental oxygen use (cases: 25% [95% CI 11%, 43%]; controls: 24% [95% CI 13%, 37%]). Low specificity was found for peripheral oedema (cases: 47% [95% CI 37%, 58%]; controls: 54% [95% CI 43%, 64%]). Sensitivity for maternal hypertension appeared much lower for cases (cases: 46% [95% CI 28%, 66%]; controls: 90% [95% CI 70%, 99%]; P = 0.003). We did not detect other case–control differences in recall (differentiality), even though the average time between childbirth and interview was 2.7 years for case and 3.7 years for control mothers. Many conditions exhibited notable differences between interview and records. We recommend use of multiple measurement sources to allow both cross-checking and synthesis of results into more accurate measures.
PMCID: PMC3614401  PMID: 21980943
medical records; maternal recall; reproducibility; misclassification; recall bias
17.  Maternal prenatal cigarette, alcohol and illicit drug use and risk of infant leukaemia: a report from the Children’s Oncology Group 
Several case–control studies have evaluated associations between maternal smoking, alcohol consumption and illicit drug use during pregnancy and risk of childhood leukaemia. Few studies have specifically focused on infants (<1 year) with leukaemia, a group that is biologically and clinically distinct from older children. We present data from a Children’s Oncology Group case–control study of 443 infants diagnosed with acute leukaemia [including acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML)] between 1996 and 2006 and 324 population controls. Mothers were queried about their cigarette, alcohol and illicit drug use 1 year before and throughout pregnancy. Odds ratios (ORs) and 95% confidence intervals [CI] were calculated using adjusted unconditional logistic regression models. Maternal smoking (>1 cigarette/day) and illicit drug use (any amount) before and/or during pregnancy were not significantly associated with infant leukaemia. Alcohol use (>1 drink/week) during pregnancy was inversely associated with infant leukaemia overall [OR = 0.64; 95% CI 0.43, 0.94], AML [OR = 0.49; 95% CI 0.28, 0.87], and leukaemia with mixed lineage leukaemia gene rearrangements (‘MLL+’) [OR = 0.59; 95% CI 0.36, 0.97]. While our results agree with the fairly consistent evidence that maternal cigarette smoking is not associated with childhood leukaemia, the data regarding alcohol and illicit drug use are not consistent with prior reports and are difficult to interpret. It is possible that unhealthy maternal behaviours during pregnancy, some of which carry potential legal consequences, may not be adequately measured using only self-report. Future case–control studies of childhood leukaemia that pursue these exposures may benefit from incorporation of validated instruments and/or biomarkers when feasible.
PMCID: PMC3614405  PMID: 21980945
childhood cancer; infant leukaemia; maternal smoking; maternal alcohol; illicit drug use
18.  Pediatric germ cell tumors and parental infertility and infertility treatment: a Children’s Oncology Group Report 
Cancer epidemiology  2011;35(5):e25-e31.
Few risk factors have been established for childhood germ cell tumors (GCT). Parental infertility and infertility treatment may be associated with GCT development but these risk factors have not been fully investigated.
A case-control study of childhood GCT was conducted through the Children’s Oncology Group (COG). Cases, under the age of 15 years at diagnosis, were recruited through COG institutions from January 1993 to December 2002. Controls were obtained through random digit dialing. Information about infertility and infertility treatment along with demographic factors was collection through maternal interviews. Subgroups created by gender, age at diagnosis, and tumor location were examined separately. Statistical analysis was performed using multivariate logistic regression models.
Overall, no association between GCT and infertility or its treatment was found. In subgroup analysis, females whose mothers had two or more fetal losses were found to be at increased risk for non-gonadal tumors (Odds ratio (OR) = 3.32, 95% Confidence interval (CI) = 1.12–9.88). Younger maternal age was associated with a lower risk of gonadal GCT in females (OR = 0.52, 95% CI = 0.28–0.96). There was an increased risk of all GCT and gonadal GCT in males born to older mothers (OR = 2.88, 95% CI = 1.13–7.37 and OR = 3.70, 95% CI = 1.12–12.24).
While no association between parental infertility or its treatment and childhood GCT was found overall, possible associations with maternal age and history of recurrent fetal loss were found in subgroups defined by gender.
PMCID: PMC3142313  PMID: 21474408
Germ cell tumor; infertility; pediatrics; epidemiology
19.  Birth order and Risk of Childhood Cancer: A Pooled Analysis from Five U.S. States 
The causes of childhood cancers are largely unknown. Birth order has been used as a proxy for prenatal and postnatal exposures, such as frequency of infections and in utero hormone exposures. We investigated the association between birth order and childhood cancers in a pooled case-control dataset. The subjects were drawn from population-based registries of cancers and births in California, Minnesota, New York, Texas, and Washington. We included 17,672 cases less than 15 years of age who were diagnosed from1980-2004 and 57,966 randomly selected controls born 1970-2004, excluding children with Down syndrome. We calculated odds ratios and 95% confidence intervals using logistic regression, adjusted for sex, birth year, maternal race, maternal age, multiple birth, gestational age, and birth weight. Overall, we found an inverse relationship between childhood cancer risk and birth order. For children in the fourth or higher birth order category compared to first-born children, the adjusted OR was 0.87 (95% CI: 0.81, 0.93) for all cancers combined. When we examined risks by cancer type, a decreasing risk with increasing birth order was seen in the central nervous system (CNS) tumors, neuroblastoma, bilateral retinoblastoma, Wilms tumor, and rhabdomyosarcoma. We observed increased risks with increasing birth order for acute myeloid leukemia but a slight decrease in risk for acute lymphoid leukemia. These risk estimates were based on a very large sample size which allowed us to examine rare cancer types with greater statistical power than in most previous studies, however the biologic mechanisms remain to be elucidated.
PMCID: PMC3008504  PMID: 20715170
birth order; case-control studies; child; epidemiology; neoplasms
20.  Similar DNA methylation levels in specific imprinting control regions in children conceived with and without assisted reproductive technology: a cross-sectional study 
BMC Pediatrics  2012;12:33.
While a possible link between assisted reproductive technology (ART) and rare imprinting disorders has been found, it is not clear if this is indicative of subtler disruptions of epigenetic mechanisms. Results from previous studies have been mixed, but some methylation differences have been observed.
Children conceived through ART and children conceived spontaneously were recruited for this cross-sectional study. Information about reproductive history, demographic factors, birth characteristics, and infertility treatment was obtained from maternal interview and medical records. Peripheral blood lymphocytes and buccal cell samples were collected from participating children. Methylation analysis was performed on five loci using pyrosequencing. Statistical analysis of methylation differences was performed using linear regression with generalized estimating equations. Results are reported as differences with 95% confidence intervals (CI).
A total of 67 ART children and 31 spontaneously conceived (SC) children participated. No significant difference in methylation in lymphocyte samples was observed between groups for any loci. Possible differences were found in buccal cell samples for IGF2 DMR0 (Difference: 2.07; 95% confidence interval (CI): -0.28, 4.42; p = 0.08) and IGF2R (Difference: -2.79; 95% CI: -5.74, 0.16; p = 0.06). Subgroup analysis indicated potential lower methylation in those whose parents used ART for unexplained infertility.
Observed differences in methylation between the ART and SC groups were small for all loci in the two sample types examined and no statistical differences were observed. It is still unclear whether or not small differences observed in several studies represent a real difference between groups and if this difference is biologically meaningful. Larger studies with long term follow-up are needed to fully answer these questions.
PMCID: PMC3323893  PMID: 22433799
Assisted reproductive technology; Epigenetics; Imprinting
21.  Immnuophenotypic and Gene Expression Analysis of Monoclonal B Cell Lymphocytosis Shows Biologic Characteristics Associated With Good Prognosis CLL 
Monoclonal B cell lymphocytosis (MBL) is a hematologic condition wherein small B cell clones can be detected in the blood of asymptomatic individuals. Most MBL have an immunophenotype similar to chronic lymphocytic leukemia (CLL), and “CLL-like” MBL is a precursor to CLL. We used flow cytometry to identify MBL from unaffected members of CLL kindreds. We identified 101 MBL cases from 622 study subjects; of these, 82 individuals with MBL were further characterized. Ninety-one unique MBL clones were detected: 73 CLL-like MBL (CD5+CD20dimsIgdim), 11 atypical MBL (CD5+CD20+sIg+), and 7 CD5neg MBL (CD5negCD20+sIgneg). Extended immunophenotypic characterization of these MBL subtypes was performed, and significant differences in cell surface expression of CD23, CD49d, CD79b, and FMC-7 were observed among the groups. Markers of risk in CLL such as CD38, ZAP70, and CD49d were infrequently expressed in CLL-like MBL, but were expressed in the majority of atypical MBL. Interphase cytogenetics was performed in 35 MBL cases, and del 13q14 was most common (22/30 CLL-like MBL cases). Gene expression analysis using oligonucleotide arrays was performed on 7 CLL-like MBL, and showed activation of B cell receptor associated pathways. Our findings underscore the diversity of MBL subtypes and further clarify the relationship between MBL and other lymphoproliferative disorders.
PMCID: PMC3164475  PMID: 21617698
22.  Childhood cancer in relation to parental race and ethnicity: a five-state pooled analysis 
Cancer  2010;116(12):3045-3053.
Children of different racial/ethnic backgrounds have varying risks of cancer. However, few studies have examined cancer occurrence in mixed ancestry children.
Population-based case-control study examining cancer among children age <15 years using linked cancer and birth-registry data from 5 U.S. states from 1978 to 2004. Data were available for 13,249 cancer cases and 36,996 controls selected from birth records. Parental race/ethnicity was determined from birth records. Logistic regression was used to examine the association of cancer with different racial/ethnic groups.
Relative to Whites, Blacks had a 28% decreased risk of cancer (odds ratio (OR) 0.72, 95% CI 0.65–0.80), while both Asians and Hispanics had an approximate 15% decrease. Children of mixed White/Black ancestry also were at decreased risk (OR 0.71, 95% CI 0.56–0.90), but estimates for mixed White/Asian and White/Hispanic children did not differ from those of Whites. Relative to Whites: 1.) Black and mixed White/Black children had decreased ORs for acute lymphoblastic leukemia, (0.39, 95% CI 0.31–0.49) and (0.58, 95% CI 0.37–0.91), respectively; 2.) Asian and mixed White/Asian children had decreased ORs for brain tumors, (0.51, 95% CI 0.39–0.68) and (0.79, 95% CI 0.54–1.16), respectively; and 3.) Hispanic and mixed White/Hispanic children had decreased ORs for neuroblastoma (0.51, 95% CI 0.42–0.61) and (0.67, 95% CI 0.50–0.90), respectively.
The tendency of mixed ancestry children to have risks more similar to racial/ethnic minority children than the White majority group may help formulate etiologic studies designed to more directly study possible genetic and environmental differences.
PMCID: PMC2903004  PMID: 20564410
child; ethnicity; neoplasms/epidemiology; race; risk factors
23.  Infant leukemia and parental infertility or its treatment: a Children's Oncology Group report 
Human Reproduction (Oxford, England)  2010;25(6):1561-1568.
Little is known about the potential risk factors for infant leukemia. With its very young age at diagnosis, exposures occurring in the perinatal period are suspected. Parental infertility and infertility treatment have been studied with regard to childhood cancer in general, but rarely in individual cancer subtypes.
A case–control study of infant leukemia was conducted through the Children's Oncology Group, including cases diagnosed from January 1996 to December 2006 and controls selected through random digit dialing and birth certificate tracing. Maternal phone interviews were conducted to obtain information about infertility, infertility treatment and demographic factors. All cases as well as subgroups defined by mixed lineage leukemia (MLL) translocation status and leukemia subtype were examined. Statistical analysis was performed using multivariate logistic regression models.
No significant associations between infertility or its treatment and combined infant leukemia were found. In subgroup analyses, there was a significant increase in the risk of MLL− leukemia for children born to women not trying to conceive compared with those trying for <1 year for all types combined [odds ratio (OR) = 1.62, 95% confidence interval (CI) = 1.01–2.59] and for acute lymphoblastic leukemia (OR = 2.50, 95% CI = 1.36–4.61).
There were no positive associations between parental infertility or infertility treatment and infant leukemia. While this is the largest study to date, both selection and recall bias may have impacted the results. However, for infant leukemia, we can potentially rule out large increases in risk associated with parental infertility or its treatment.
PMCID: PMC2873174  PMID: 20382971
infant leukemia; infertility; childhood cancer; MLL translocations
24.  Genetic susceptibility variants for chronic lymphocytic leukemia 
There is strong and consistent evidence that a genetic component contributes to the etiology of chronic lymphocytic leukemia (CLL). A recent genome-wide association study (GWAS) of CLL identified 7 genetic variants that increased the risk of CLL within a European population.
We evaluated the association of these variants, or variants in linkage disequilibrium (LD) with these variants, with CLL risk in an independent sample of 438 CLL cases and 328 controls.
Of these 7 SNPs, 6 had p-trend < 0.05 and had estimated odds ratios (ORs) that were strikingly comparable to those of the previous study. Associations were seen for rs9378805 (OR = 1.47, 95% CI: 1.19, 1.80, p-trend = 0.0003) near IRF4 and rs735665 near GRAMD1B (OR= 1.47; 95% CI: 1.14, 1.89; p-trend = 0.003). However, no associations (P> 0.05) were found for rs11083846, nor were any found for any SNPs in LD with rs11083846.
Our results confirm the previous findings and further support the role of a genetic basis in the etiology of CLL; however, more research is needed to elucidate the causal SNP(s) and the potential manner in which these SNPs or linked SNPs function in CLL pathogenesis.
PMCID: PMC2852480  PMID: 20332261
IRF4; CLL; genetic association
25.  Reproducibility of reported nutrient intake and supplement use during a past pregnancy: a report from the Children’s Oncology Group 
Maternal nutrition and diet have been suggested to play a role in many conditions of her offspring. Studies using food frequency questionnaires (FFQs) have reported associations with maternal diet, but these findings are difficult to interpret because the reliability and validity of the FFQs for diet during a past pregnancy are not known. We determined the reproducibility of reported diet and supplement use during a past pregnancy in a subset of mothers interviewed for a case-control study of maternal diet in relation to risk of childhood brain tumors. Cases were Children’s Oncology Group patients, diagnosed at age <6 with medulloblastoma or primitive neuroectodermal tumor from 1991–1997. Area code, race/ethnicity, and birth date matched controls were selected by random-digit-dialing. Case and control mothers completed a modified Willett FFQ a mean of five years after the index child’s birth. A mean of 3.6 months later, a subset of mothers consisting of 52 case and 51 control mothers repeated the interview and comprise the reproducibility study population. The mean intra class correlation (ICC) was 0.59 (range 0.41, 0.69) for energy- adjusted nutrients from dietary sources only; it was 0.41 (range −0.06, 0.70) when supplements were included. Agreement for reporting multivitamin use during pregnancy by time period and pattern was good to very good (kappa= 0.66 to 0.85). Overall, the reproducibility of nutrient estimates and supplement use in pregnancy was good and similar to that reported for adult diet.
PMCID: PMC3050886  PMID: 20078835

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