Published online October 9, 2006
PEDIATRICS Vol. 118 No. 5 November 2006, pp. e1499-e1508 (doi:10.1542/peds.2006-0644)
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ARTICLE

Exposure to Medical Test Irradiation and Acute Leukemia Among Children With Down Syndrome: A Report From the Children's Oncology Group

Amy M. Linabery, MS, MPHa, Andrew F. Olshan, PhDb, Alan S. Gamis, MD, MPHc, Franklin O. Smith, MDd, Nyla A. Heerema, PhDe, Cindy K. Blair, MPHf and Julie A. Ross, PhDa,f

a Division of Pediatric Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota
b Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina
c Children's Mercy Hospital and Clinics, Kansas City, Missouri
d Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio
e Department of Pathology, Ohio State University, Columbus, Ohio
f University of Minnesota Cancer Center, Minneapolis, Minnesota


   ABSTRACT
TOP
 ABSTRACT
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. The etiology of acute childhood leukemia is not well understood, particularly among children with Down syndrome, in whom a 10- to 20-fold increased risk of leukemogenesis has been reported compared with children without Down syndrome. We explored the association between medical test irradiation, a postulated leukemogenic agent, and acute leukemia among children with Down syndrome.

PATIENTS AND METHODS. Children with Down syndrome (controls) were frequency matched on age to children with Down syndrome and leukemia (cases) diagnosed at ages 0 to 19 years during the period 1997–2002 at participating Children's Oncology Group institutions in North America. Telephone interviews were completed with mothers of 158 cases (n = 97 acute lymphoblastic leukemia and n = 61 acute myeloid leukemia) and 173 controls. Paternal interviews were completed with 275 fathers and 40 mothers serving as surrogates. Three irradiation exposure periods were examined: preconception, in utero, and postnatal. Multivariate unconditional logistic regression models were constructed to evaluate the associations of interest, resulting in odds ratios and 95% confidence intervals.

RESULTS. There was little evidence that maternal or paternal preconception irradiation exposure, intrauterine exposure, or postnatal exposure contributes to leukemogenesis in children with Down syndrome. Overall, no evidence for an effect of any periconceptional exposure was observed. Similar results were observed among acute lymphoblastic leukemia and acute myeloid leukemia cases analyzed separately.

CONCLUSIONS. This was the first study, to our knowledge, to examine such an association among this unique patient population. The results do not provide evidence of a positive association between ionizing radiation exposure and acute leukemia among children with Down syndrome. The absence of an association should be encouraging for concerned parents of children with Down syndrome who undergo a series of diagnostic radiographs in the course of their standard care.

Key Words: Down syndrome • leukemia • radiographs • children • epidemiology

Abbreviations: DS—Down syndrome • AML—acute myeloid leukemia • ALL—acute lymphoblastic leukemia • IR—ionizing radiation • COG—Children's Oncology Group • CT—computed tomography • OR—odds ratio • CI—confidence interval

Down Syndrome (DS) is the most common chromosomal abnormality in the United States, with an estimated prevalence of 92 per 100000 live births.1 Children with DS have an increased susceptibility for acute leukemia,2,3 with a 10- to 20-fold higher risk compared with children without DS.4,5 These odds increase to 500-fold for the M7 subtype of acute myeloid leukemia (AML).6 The etiology of leukemia is not well understood,7 particularly among children with DS8; by studying acute leukemia in a highly susceptible population, we may gain knowledge about its etiology among all children.

DS and acute leukemia are related by the involvement of chromosome 21. Trisomy 21 is one of the more commonly acquired chromosomal aberrations within leukemic cells,9–11 and recurring translocations involving the AML1 gene on chromosome 21, including t(12;21) in acute lymphoblastic leukemia (ALL) and t(8;21) in AML, have been characterized.10,12–14 Of note, AML1 is situated in the distal portion of the long arm of chromosome 21, within the chromosomal region with the majority of transcribed DNA and therefore within the region most associated with the DS phenotype (21q22).15 Putative mechanisms for the involvement of an extra copy of chromosome 2116 and candidate genes on chromosome 21 have been suggested.16–18 Because a minority of children with DS develops acute leukemia, it is assumed that the chromosomal anomaly is necessary, but is not sufficient, for leukemogenesis. A multistep model has been postulated, in which the additional copy of chromosome 21 is among the first in a series of "hits" involved in the development of leukemia.9,16,19 In the case of a 2-hit model, only 1 additional mutation in a hematopoietic cell is required for leukemia development.9,19 Thus, environmental exposures may play a role in leukemogenesis as an additional hit.

Diagnostic irradiation is a plausible risk factor for several reasons. In utero exposure to irradiation is one of the few commonly accepted risk factors for acute leukemia in childhood20–22, some evidence exists of an effect of postnatal exposure,23,24 and parental preconception exposure is of concern because of possible germ-line mutations.25–27 In addition, ionizing radiation (IR) has been shown to alter DNA irreversibly, which can lead to diminished hematopoiesis28 and malignancy.25,29 Importantly, the current treatment guidelines recommend that children with DS receive a series of medical evaluations, including radiograph irradiation, at specified intervals throughout childhood and adolescence.30–34 The current case-control study is the first to our knowledge to examine the association between medical-test irradiation and acute leukemia among children with DS.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Case Identification
The study design has been previously described.35,36 Subjects were eligible if they had a previous DS diagnosis, had an incident diagnosis of acute leukemia from January 1997 through October 2002 at a Children's Oncology Group (COG) institution, were ≤19 years of age at diagnosis, resided in the United States or Canada at the time of diagnosis, had a telephone in their residence, and had a biological mother available that spoke English and consented to an interview. Deceased subjects meeting the eligibility criteria were included in the study. Acute leukemia diagnoses were confirmed by central review of clinical data, pathologic specimens and reports, and cytogenetic data; DS diagnoses of cases and controls were confirmed by central review of cytogenetic data and obstetrical medical charts.

A total of 210 potentially eligible acute leukemia cases were identified at 116 COG institutions throughout North America. Maternal interviews were completed for 158 cases (75%), including 97 ALL and 61 AML. The remaining subjects did not complete interviews because of parental refusal (17%), physician refusal (5%), and inability to locate families (3%).

Control Identification
Controls were selected from the population of children with DS who were seen by the primary care physicians of the cases. After completion of the interview, case mothers were asked to provide the name and contact information for the physician responsible for the primary care of their child immediately before the leukemia diagnosis. These physicians were contacted and asked to supply a roster of potential controls. Children with DS were eligible as controls if they were ≤19 years of age, resided in the United States or Canada, had a telephone in their residence, and had a biological mother available that spoke English and consented to an interview. Controls were selected randomly for participation from these rosters and were frequency matched to cases based on the following age categories: 0, 1 to 3, 4 to 6, 7 to 10, 11 to 14, and 15 to 18 years.

Of the 151 primary care clinics contacted, 77 provided rosters of patients with DS (limited to date of birth and gender), 47 refused or were unable to provide rosters, and 27 had no eligible patients with DS. A total of 726 potential controls were thus identified, and of these, 329 were selected randomly for inclusion in the study. One-third of these potential subjects were not ultimately included, because their names and contact information were not provided by clinics because of clinic inability to locate families (n = 46), refusal of participation by families (n = 19), ineligibility (n = 18), clinic refusal to contact families (n = 8), and reason not otherwise specified (n = 23). Of the 215 potential controls contacted, maternal interviews were completed for 173 children with DS (80.5%) and were not completed for the remainder because of parental refusal (11%), ineligibility (4%), and inability to schedule the interview (4%).

Data Collection
Biological mothers and fathers, if available, participated in an interview regarding alcohol and tobacco consumption, reproductive and medical history, familial medical history, postnatal exposures among the index children, and demographic information. If the fathers were unavailable or unwilling to participate in an interview, the mothers were interviewed regarding paternal exposures using a surrogate questionnaire. A total of 275 fathers (83%) participated in the telephone interview, and 40 mothers (12%) participated as proxies. Interview data were collected and recorded via a structured, computer-assisted telephone interview.

Questions asked of mothers assessed maternal medical irradiation exposure in the 5-year period before conception, maternal exposure during pregnancy with the index child (in utero exposure), and maternal exposure to dental radiographs during pregnancy. Fathers, and mothers acting as surrogates, were asked about paternal medical irradiation exposure in the 5 years before conception. For each of these time periods, data regarding any medical radiograph exposure, number of exposures, and time of exposure were collected. In addition, periconceptional exposure, a variable encompassing maternal and paternal preconception and in utero exposure, was evaluated.

A date was assigned to both cases and controls to serve as a reference point for questions regarding the child's postnatal exposures. In cases, the reference date was calculated as the date exactly 6 months before the date of diagnosis. Through the process of frequency matching, controls were assigned to a calendar year. The reference date was then selected randomly within the 6 months before their birth date in the assigned year; a pseudodiagnosis date corresponded to 6 months after this reference date.

Postnatal exposure questions were asked of a subset of participants. Mothers of children with a reference age ≥1 year (ie, ≥1.5 years on the date of diagnosis or pseudodiagnosis) were asked about their child's exposure to radiographs of the head, neck, chest, lungs, stomach, intestines, broken bones, or any other radiographs; computed tomography (CT) scans of the head, neck, chest, lungs, stomach, or intestines; fluoroscopy of the head, neck, stomach, or intestines; and cardiac catheterization (125 cases, 117 controls). An overall exposure variable was created to account for any exposure to these evaluations. Mothers of children with a reference age ≥1.5 years were also asked about their child's exposure to dental radiographs (95 cases, 95 controls). For each of these diagnostic tests, information regarding any exposure, as well as the number and time frame of exposures, was collected.

This study was reviewed and approved by the University of Minnesota Institutional Review Board and the institutional review boards of all participating COG institutions. Parents of subjects provided written consent before participation.

Statistical Analysis
Unconditional logistic regression was used to evaluate the effect of diagnostic irradiation in the development of acute leukemia (SAS 9.1, SAS Institute, Inc, Cary, NC); odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for all exposures. It is thought that childhood ALL and AML have distinct etiologies; thus, they are also considered separately in the analyses presented here. Multivariate models were constructed separately for each of the exposures considered (ie, maternal preconception, paternal preconception, in utero, postnatal, and periconceptional exposures). Any exposure was modeled as a dichotomous variable, as reported in the telephone interview, for maternal and paternal preconception, in utero, and postnatal exposures. Number of exposures was modeled as a series of indicator variables representing an ordinal variable in each of these time periods, because the distributions of the continuous exposure variables were skewed, such that the most even number of participants fell into each category (0, 1, ≥2 or 0, 1–3, ≥4). For the periconceptional exposure, any exposure was defined as any reported exposure during any of the 4 time periods of interest, and number of exposures represented the sum of the number of time periods (ie, maternal and paternal preconception and in utero) with any reported exposure. Reference age, represented as a continuous variable, was included in all regression models. Potential confounders were selected a priori and were retained in the multivariate model if they changed the log OR estimate substantially (ie, by ≥10%). Variables considered as potential confounders included maternal and paternal age at index child's birth, race, educational attainment, household income, and index child's gender, race, and birth order. Linear tests for trend were conducted by treating ordinal variables as continuous in the logistic regression models. Subjects were excluded from the analysis of postnatal exposure if their mothers answered less than half of the questions in this section or if the interval between first exposure and diagnosis date (or pseudodiagnosis date among controls) was <1 year. These criteria excluded 2 controls and 12 cases (5 ALL, 7 AML).


   RESULTS
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Selected characteristics of the mothers, fathers, and index children are summarized in Tables 1 and 2, respectively. Case mothers were similar to control mothers with respect to household income (Table 1). Mothers of the subjects with ALL were less likely to have pursued education beyond high school as compared with control mothers (59% vs 76%, respectively); mothers of subjects with AML were more likely to be aged 35 or older at time of the index child's birth (48% vs 30%) and to report a race other than white/Caucasian (23% vs 12%). Similarly, fathers of subjects were comparable to control fathers in age at index child's birth and education level; fathers of the subjects with AML were more likely to report a race other than white/Caucasian (25% vs 11%; Table 1).


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  		TABLE 1 Baseline Characteristics of 158 Case and 173 Control Mothers and 152 Case and 163 Control Fathers

 

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  		TABLE 2 Baseline Characteristics of 125 Cases and 117 Controls

 
Table 2 includes only those participants involved in the postnatal analyses, as described above. Overall, case reference age ranged from 0 to 17 years (median: 2.74 years) and reference age among controls ranged from 0 to 18 years (median: 2.67 years). The use of reference age as a frequency-matching variable resulted in an imperfect match between the cases and controls included in the postnatal analyses (Table 2). Cases had similar distributions of gender, ethnicity, and birth order as controls. Although the distribution of birth weight was similar across the combined cases and controls, subjects with AML were more likely to weigh >3500 g compared with controls (35% vs 18%).

The ORs and 95% CIs for maternal and paternal preconception, in utero, and periconceptional irradiation are summarized in Tables 3–5, respectively. The ORs for any maternal preconception irradiation were 0.77 (95% CI: 0.48–1.24) for acute leukemia overall, 0.85 (95% CI: 0.49–1.47) for ALL, and 0.66 (95% CI: 0.33–1.33) for AML (Table 3). Limiting the exposure to the abdominal region revealed similar results.


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  		TABLE 3 Association Between Preconception Irradiation and Acute Leukemia Among Children With DS

 

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  		TABLE 5 Association Between Periconceptional Irradiation and Acute Leukemia Among Children With DS

 
No association was observed between any paternal preconception irradiation and acute leukemia (OR: 0.92; 95% CI: 0.57–1.47), nor was there an association among subjects with ALL or AML analyzed separately (Table 3). In addition, there were no discernable trends, and an analysis restricting exposure to abdominal irradiation did not provide evidence for an effect. The results did not change when surrogate interviews were excluded (n = 136 cases, n = 139 controls).

The prevalence of in utero exposure among subjects with ALL and controls was lower than that observed in the parental preconception and postnatal exposures (n = 7 and 5, respectively); no subjects with AML had been exposed (Table 4). Among the subjects with ALL, a positive relationship was found (OR: 2.03; 95% CI: 0.60–6.91), and this association was strengthened with abdominal exposure (OR: 2.26; 95% CI: 0.18–28.71), although these estimates were based on a very small number of exposed subjects. No association was observed with maternal dental radiograph exposure during pregnancy (data not shown). A nonsignificant inverse association was observed for any postnatal exposure and combined leukemia (OR: 0.74; 95% CI: 0.38–1.47) and for ALL (OR: 0.68; 95% CI: 0.33–1.40); a positive association was suggested for AML (OR: 1.41; 95% CI: 0.38–5.30; Table 4). Dental radiograph exposure in the index child was not associated with acute leukemia, ALL, or AML (data not shown).


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  		TABLE 4 Association Between in Utero and Postnatal Irradiation and Acute Leukemia Among Children With DS

 
Overall, the odds of acute leukemia among those with any periconceptional irradiation exposure were 0.71-fold the odds among those with no exposure (95% CI: 0.45–1.14), and 0.84- and 0.53-fold for ALL and AML, respectively (Table 5). The dose response among subjects with AML revealed an inverse trend approaching significance (Ptrend = .09).

ORs for the associations between acute leukemia, ALL, and AML and individual postnatal diagnostic tests were also estimated (data not shown). Fluoroscopy of the stomach and intestines was associated with a reduced risk for acute leukemia (OR: 0.21; 95% CI: 0.07–0.60); when stratification by leukemia type was performed, this reduction was found only among the subjects with ALL. Although not significant, inverse associations were observed for radiographs of the head, neck, stomach, intestines, broken bones, and any other radiographs; CT scan of the head, neck, chest, and lungs; fluoroscopy of the head and neck; and heart catheterization. Nonsignificant positive associations with radiographs of the chest or lungs and CT scans of the stomach or intestines were also observed.

Secondary analyses examined the individual postnatal tests grouped by type of radiograph (ie, radiographs, CT scans, and fluoroscopy) and area exposed (ie, head and neck, chest, gastrointestinal track, and any other exposure). The results of these analyses generally yielded nonsignificant inverse associations. Any exposure to fluoroscopy was associated with an OR of 0.53 (95% CI: 0.30–0.93) for combined leukemia and an OR of 0.46 (95% CI: 0.24–0.88) for ALL. Gastrointestinal exposure was also associated with reduced risk for acute leukemia (OR: 0.37; 95% CI: 0.17–0.77) and ALL (OR: 0.31; 95% CI: 0.13–0.73).

To rule out existing congenital anomalies as a potential confounding variable, we evaluated whether controls had greater prevalence of congenital anomalies compared with cases and found no association (OR: 0.87; 95% CI: 0.55–1.38 [combined cases]; OR: 0.80; 95% CI: 0.48–1.36 [ALL]; and OR: 1.00; 95% CI: 0.53–1.88 [AML]).

The analyses presented above were repeated after restricting the cases to those with a control from the same primary care clinic (n = 67; data not shown). Although there was less precision in these estimates, the ORs were not appreciably different from the unrestricted values presented above and in Tables 3 through 5.


   DISCUSSION
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Children are more susceptible than adults to the effects of IR.25,37,38 The biological effects of radiation are of particular interest with respect to children with DS, because the standards of care recommend radiograph evaluations of the cervical spine at ages 3, 12, and 18 years.31 This is in addition to diagnostic irradiation required because of health concerns. Within the hematologic system, IR causes direct hematopoietic stem cell damage, diminishes the production of new cells by the bone marrow stroma, and reduces the population of mature circulating blood cells.28 IR has also been associated with modified gene expression and transcription and disruption of cellular signaling pathways.28 There is some evidence that individuals with DS are more susceptible to the mutagenic effects of IR compared with individuals without DS.39–41 The results of this study do not provide evidence for an increased risk of leukemia among children with DS exposed to irradiation and those with parental periconceptional exposure. One possible exception is the nonsignificant positive association observed with in utero exposure.

Our results are consistent with those presented in the literature regarding parental preconception diagnostic irradiation and childhood leukemia.42 Two large case-control studies by Shu et al also showed nonsignificant inverse associations with maternal preconception exposure to abdominal radiographs and childhood ALL43 and any radiograph exposure and infant leukemia,44 whereas Meinert et al45 found no association with any exposure and childhood leukemia. Two additional studies by Shu et al described nonsignificant positive ORs for acute leukemia and exposure to 10 or more and 11 or more radiographs, respectively.23,46 The ORs in these 5 studies fell between 0.9 and 1.5. In contrast, Graham et al reported that the odds of leukemia among children of mothers receiving any preconceptional radiographs were 1.55-fold higher than the odds among those receiving no radiographs (P = .003).47

With respect to any paternal preconception irradiation, 3 case-control studies showed nonsignificant positive associations,43,44,47 although a positive association was observed for exposure to lower gastrointestinal/abdominal radiographs only (OR: 2.24; 95% CI: 1.44–3.47).44 A nonsignificant inverse relationship was reported in a fourth study among those with 10 or more radiographs.23 Conversely, a population-based case-control study in Germany conducted by Meinert et al45 reported a positive association with any paternal diagnostic exposure (OR: 1.33; 95% CI: 1.10–1.61); the OR increased on restricting the analysis to exposure of the abdomen (OR: 1.76; 95% CI: 0.88–3.56). In addition, Shu et al46 observed positive associations with 10 or more radiographs among those with ALL and acute nonlymphocytic leukemia examined separately and a trend with increasing exposure (Ptrend < .01). Importantly, the data from our study are also consistent with the failure to observe an increased incidence of acute leukemia in children conceived of atomic bomb survivors.48

Maternal diagnostic irradiation during pregnancy has been evaluated extensively as a risk factor for childhood leukemia.21,22,49 After a thorough examination of the evidence, Doll and Wakeford21 concluded that antenatal exposure can be considered a risk factor for childhood leukemia, with a relative risk on the order of 1.4. This is consistent with reports from the U.S. Committee on the Biological Effects of Ionizing Radiation and the United Nations Scientific Committee on the Effects of Atomic Radiation.25,37 In recent case-control studies, the ORs generally reflect modest increased risk.23,43–46,50,51 The results presented here are concordant with those described previously, because they suggest increased risk associated with in utero exposure.

The nonsignificant inverse association observed in this study for postnatal exposure to radiation is similar to that reported by Magnani et al50 of a hospital-based case-control study conducted in Italy (OR: 0.7, 95% CI: 0.5–1.2 [ALL]). In addition, Meinert et al45 reported no evidence for an association with childhood leukemia, and Modan et al52, in examining exposure to heart catheterization, also found no effect. Conversely, 2 large case-control studies reported ORs ranging from 1.4 to 1.6 among those with the highest levels of exposure,23,24 and 3 others reported nonsignificant positive associations.43,46,47

Children with DS are at increased risk for congenital anomalies and other medical concerns such as congenital heart disease, gastrointestinal malformations, thyroid dysfunction, hearing loss, obstructive airway disease, congenital cataracts, other vision issues, hip dysplasia and dislocation, and atlantoaxial instability.30–34 The propensity for congenital anomalies and resulting complications is the basis for the regular evaluations of children with DS. We found no evidence that children with DS had a higher number of congenital anomalies compared with children with DS and leukemia.

There are some clinical differences in the leukemias that develop in children with DS compared with children without DS that may suggest a different etiology. For ALL, children with DS present less often with T-cell disease and more often with hypodiploidy or nonhigh hyperdiploidy.53 In addition, the age at presentation of ALL in children with DS closely follows that of children without DS with the exception of infancy, in which ALL is rarely seen in children with DS.8,53 In contrast, AML in children with DS almost always occurs in the first 5 years of life.8 In children without DS, AML incidence rates peak in infancy, decrease until ~5 years of age, and then begin to increase again. It was recently demonstrated that in a specific subtype of AML (M7) in children with DS, the leukemia blasts harbor somatic mutations of GATA1.54 Intriguingly, GATA1 mutations are also present in transient leukemia blasts detected in neonates with Down syndrome, which suggests an early event in utero.55 However, because not all children with DS and transient leukemia develop AML, it is likely that postnatal events play a role. Additional study of the natural history of GATA mutations in children with DS is warranted.

This study features some unique strengths. First, the evaluation of a susceptible population should prove highly informative if a strong association were present. Second, the use of COG registry files ensures a nearly population-based study of acute leukemia in North America. Institutions affiliated with COG treat 94% of patients with childhood cancer diagnosed in the United States under the age of 15 years,56 including 85% of patients with leukemia aged <15 years and 73% of patients aged <20 years.57 Third, the clinic selection of control children with DS means that they should closely represent the subjects without leukemia. Finally, recall bias across cases and controls is theoretically limited by the use of DS controls. Because children with DS tend to have a number of health issues, the mothers would likely have similar motivation to remember previous exposures. Importantly, if mothers of subjects were systematically reporting more radiograph exposures than mothers of controls, we would expect to find elevated risks for leukemia across all time periods. However, our results suggested a positive association only for in utero exposure, the most biologically relevant time period with the greatest support in the literature, suggesting a lack of substantial differential recall across cases and controls.

There are also some limitations. Our small sample size reduces the precision of the OR estimates and restricts the statistical power in analyses of leukemia subtypes and interactions between factors. For the maternal and paternal preconception and periconceptional exposures, we had sufficient power to detect ORs of ~2 or greater.58 A lack of precise dosage data also limits interpretation. Secondary analyses explored the association by type of irradiation and by body part exposed but did not yield additional insight. Finally, a potential bias could have been introduced in the control-identification process, because not all primary care physicians of cases provided rosters of potential controls. However, we found no evidence of any differences when we restricted our analyses to cases for which a control from the same primary care clinic was enrolled.


   CONCLUSIONS
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
This is the first study, to our knowledge, to investigate the role of irradiation exposure in the etiology of acute leukemia among children with DS; additional research confirming these results is warranted. These results indicate that an effect, if present, is relatively small. The lack of a strong association between postnatal medical-test exposure and acute leukemia among children with DS should be reassuring for concerned parents, because these children are subjected to diagnostic irradiation in the course of their standard primary care.


   ACKNOWLEDGMENTS
 
This work was supported by National Institutes of Health grants R01 CA75169 and T32 CA099936 and the University of Minnesota Children's Cancer Research Fund.

We thank Michelle Roesler for study coordination and data collection.


   FOOTNOTES
 
Accepted May 24, 2006.

Address correspondence to Julie A. Ross, PhD, Division of Pediatric Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota, 420 Delaware St SE, MMC 422, Minneapolis, MN 55455. E-mail: ross{at}epi.umn.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
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 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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