Childhood cancer research in oxford III: The work of CCRG on ionising radiation.

BACKGROUND: High doses of ionising radiation are a known cause of childhood cancer and great public and professional interest attaches to possible links between childhood cancer and lower doses, particularly of man-made radiation. This paper describes work done by the Childhood Cancer Research Group (CCRG) on this topic METHODS: Most UK investigations have made use of the National Registry of Childhood Tumours and associated controls. Epidemiological investigations have included national incidence and mortality analyses, geographical investigations, record linkage and case-control studies. Dosimetric studies use biokinetic and dosimetric modelling. RESULTS: This paper reviews the work of the CCRG on the association between exposure to ionising radiation and childhood cancer, 1975-2014. CONCLUSION: The work of CCRG has been influential in developing understanding of the causes of 'clusters' of childhood cancer and the risks arising from exposure to ionising radiation both natural and man-made. Some clusters around nuclear installations have certainly been observed, but ionising radiation does not seem to be a plausible cause. The group's work has also been instrumental in discounting the hypothesis that paternal preconception irradiation was a cause of childhood cancers and has demonstrated an increased leukaemia risk for children exposed to higher levels of natural gamma-ray radiation.

Age at menarche and risks of coronary heart and other vascular diseases in a large UK cohort.

BACKGROUND: Early menarche has been associated with increased risk of coronary heart disease (CHD), but most studies were relatively small and could not assess risk across a wide range of menarcheal ages; few have examined associations with other vascular diseases. We examined CHD, cerebrovascular disease, and hypertensive disease risks by age at menarche in a large prospective study of UK women. METHODS AND RESULTS: In 1.2 million women (mean±SD age, 56±5 years) without previous heart disease, stroke, or cancer, menarcheal age was reported to be 13 years by 25%, ≤10 years by 4%, and ≥17 years by 1%. After 11.6 years of follow-up, 73 378 women had first hospitalization for or death from CHD, 25 426 from cerebrovascular disease, and 249 426 from hypertensive disease. Using Cox regression, we calculated relative risks for each vascular outcome by single year of menarcheal age. The relationship was U-shaped for CHD. Compared with women with menarche at 13 years, the adjusted relative risk for CHD for menarche at ≤10 years of age was 1.27 (95% confidence interval, 1.22-1.31; P<0.0001) and for menarche at ≥17 years of age was 1.23 (95% confidence interval, 1.16-1.30; P<0.0001). U-shaped relationships were also seen for cerebrovascular and hypertensive disease, although the magnitudes of these risks for early and late menarche were smaller than those for CHD. CONCLUSIONS: In this cohort, the relation of age at menarche to vascular disease risk was U shaped, with both early and late menarche being associated with increased risk. Associations were weaker for cerebrovascular and hypertensive disease than for CHD.

Body size in early life and risk of lymphoid malignancies and histological subtypes in adulthood.

Risk of adult lymphoid malignancy is associated with recent adiposity. Some have reported apparent associations with adiposity in childhood or early adulthood, but whether these associations are independent of recent adiposity is unknown. Birth weight, body size at age 10 years, clothes size at age 20 years, and recent body mass index (BMI) were recorded in 745,273 UK women, mean age 60.1 (SD 4.9) at baseline, without prior cancer. They were followed for 11 years, during which time 5,765 lymphoid malignancies occurred. Using Cox regression, a higher risk of lymphoid malignancy was strongly associated with higher recent BMI (RR=1.33, 95%CI 1.17-1.51, for BMI 35+ vs <22.5 kg/m(2)), and this association remained essentially unchanged after adjustment for birth weight and body size at 10. Higher lymphoid malignancy risk was also associated with large size at birth, at age 10, and at age 20 years, but after adjustment for recent BMI, the significance of the associations with large size at birth and at age 10 years was sufficiently reduced that residual confounding by adult BMI could not be excluded; a weak association with large size at 20 years remained (adjusted RR =1.17, 95%CI 1.10-1.24 for large size at age 20 vs. medium or small size). We found no strong evidence of histological specificity in any of these associations. In conclusion, our findings suggest a possible role of adiposity throughout adulthood in the risk of lymphoid malignancy, but the independent contribution of body size at birth and during childhood appears to be small.

Analysis of retinoblastoma age incidence data using a fully stochastic cancer model.

Retinoblastoma (RB) is an important ocular malignancy of childhood. It has been commonly accepted for some time that knockout of the two alleles of the RB1 gene is the principal molecular target associated with the occurrence of RB. In this article, we examine the validity of the two-hit theory for RB by comparing the fit of a stochastic model with two or more mutational stages. Unlike many such models, our model assumes a fully stochastic stem cell compartment, which is crucial to its behavior. Models are fitted to a population-based dataset comprising 1,553 cases of RB for the period 1962-2000 in Great Britain (England, Scotland and Wales). The population incidence of RB is best described by a fully stochastic model with two stages, although models with a deterministic stem cell compartment yield equivalent fit; models with three or more stages fit much less well. The results strongly suggest that knockout of the two alleles of the RB1 gene is necessary and may be largely sufficient for the development of RB, in support of Knudson's two-hit hypothesis.

Ethnic and socioeconomic variation in cause-specific preterm infant mortality by gestational age at birth: national cohort study.

OBJECTIVE: To describe ethnic and socioeconomic variation in cause-specific infant mortality of preterm babies by gestational age at birth. DESIGN: National birth cohort study. SETTING: England and Wales 2006-2012. SUBJECTS: Singleton live births at 24-36 completed weeks' gestation (n=256 142). OUTCOME MEASURES: Adjusted rate ratios for death in infancy by cause (three groups), within categories of gestational age at birth (24-27, 28-31, 32-36 weeks), by baby's ethnicity (nine groups) or area deprivation score (Index of Multiple Deprivation quintiles). RESULTS: Among 24-27 week births (5% of subjects; 47% of those who died in infancy), all minority ethnic groups had lower risk of immaturity-related death than White British, the lowest rate ratios being 0.63 (95% CI 0.49 to 0.80) for Black Caribbean, 0.74 (0.64 to 0.85) for Black African and 0.75 (0.60 to 0.94) for Indian. Among 32-36 week births, all minority groups had higher risk of death from congenital anomalies than White British, the highest rate ratios being 4.50 (3.78 to 5.37) for Pakistani, 2.89 (2.10 to 3.97) for Bangladeshi and 2.06 (1.59 to 2.68) for Black African; risks of death from congenital anomalies and combined rarer causes (infection, intrapartum conditions, SIDS and unclassified) increased with deprivation, the rate ratios comparing the most with the least deprived quintile being, respectively, 1.54 (1.22 to 1.93) and 2.05 (1.55 to 2.72). There was no evidence of socioeconomic variation in deaths from immaturity-related conditions. CONCLUSIONS: Gestation-specific preterm infant mortality shows contrasting ethnic patterns of death from immaturity-related conditions in extremely-preterm babies, and congenital anomalies in moderate/late-preterm babies. Socioeconomic variation derives from congenital anomalies and rarer causes in moderate/late-preterm babies. Future research should examine biological origins of extremely preterm birth.

Ethnic variation in unexplained deaths in infancy, including sudden infant death syndrome (SIDS), England and Wales 2006-2012: national birth cohort study using routine data.

BACKGROUND: Unexplained deaths in infancy comprise 'sudden infant death syndrome' (SIDS) and deaths without ascertained cause. They are typically sleep-related, perhaps triggered by unsafe sleep environments. Preterm birth may increase risk, and varies with ethnicity. We aimed to compare ethnic-specific rates of unexplained infant death, explore sociodemographic explanations for ethnic variation, and examine the role of preterm birth. METHODS: We analysed routine data for 4.6 million live singleton births in England and Wales 2006-2012, including seven non-White ethnic groups ranging in size from 29 313 (Mixed Black-African-White) to 180 265 (Pakistani). We calculated rates, birth-year-adjusted ORs, and effects of further adjustments on the χ2 for ethnic variation. RESULTS: There were 1559 unexplained infant deaths. Crude rates per 1000 live singleton births were as follows: 0.1-0.2 for Indian, Bangladeshi, Pakistani, White Non-British, Black African; 0.4 for White British; 0.6-0.7 for Mixed Black-African-White, Mixed Black-Caribbean-White, Black Caribbean. Birth-year-adjusted ORs relative to White British ranged from 0.38 (95% CI 0.24 to 0.60) for Indian babies to 1.73 (1.21 to 2.47) for Black Caribbean (χ2(10 df)=113.6, p<0.0005). Combined adjustment for parents' marital/registration status and mother's country of birth (UK/non-UK) attenuated the ethnic variation. Adjustments for gestational age at birth, maternal age and area deprivation made little difference. CONCLUSION: Substantial ethnic disparity in risk of unexplained infant death exists in England and Wales. Apparently not attributable to preterm birth or area deprivation, this may reflect cultural differences in infant care. Further research into infant-care practices in low-risk ethnic groups might enable more effective prevention of such deaths in the general population.

Differences in risk factors for 3 types of stroke: UK prospective study and meta-analyses.

OBJECTIVE: To compare associations of behavioral and related factors for incident subarachnoid hemorrhage and intracerebral hemorrhage and ischemic stroke. METHODS: A total of 712,433 Million Women Study participants without prior stroke, heart disease, or cancer reported behavioral and related factors at baseline (1999-2007) and were followed up by record linkage to national hospital admission and death databases. Cox regression yielded adjusted relative risks (RRs) by type of stroke. Heterogeneity was assessed with χ2 tests. When appropriate, meta-analyses were done of published prospective studies. RESULTS: After 12.9 (SD 2.6) years of follow-up, 8,128 women had an incident ischemic stroke, 2,032 had intracerebral hemorrhage, and 1,536 had subarachnoid hemorrhage. In women with diabetes mellitus, the risk of ischemic stroke was substantially increased (RR 2.01, 95% confidence interval [CI] 1.84-2.20), risk of intracerebral hemorrhage was increased slightly (RR 1.31, 95% CI 1.04-1.65), but risk of subarachnoid hemorrhage was reduced (RR 0.43, 95% CI 0.26-0.69) (heterogeneity by stroke type, p < 0.0001). Stroke incidence was greater in women who rated their health as poor/fair compared to those who rated their health as excellent/good (RR 1.36, 95% CI 1.30-1.42). Among 565,850 women who rated their heath as excellent/good, current smokers were at an increased risk of all 3 stroke types, (although greater for subarachnoid hemorrhage [≥15 cigarettes/d vs never smoker, RR 4.75, 95% CI 4.12-5.47] than for intracerebral hemorrhage [RR 2.30, 95% CI 1.94-2.72] or ischemic stroke [RR 2.50, 95% CI 2.29-2.72]; heterogeneity p < 0.0001). Obesity was associated with an increased risk of ischemic stroke and a decreased risk of hemorrhagic stroke (heterogeneity p < 0.0001). Meta-analyses confirmed the associations and the heterogeneity across the 3 types of stroke. CONCLUSION: Classic risk factors for stroke have considerably different effects on the 3 main pathologic types of stroke.

Early Father Involvement and Subsequent Child Behaviour at Ages 3, 5 and 7 Years: Prospective Analysis of the UK Millennium Cohort Study.

OBJECTIVE: Fathers are increasingly involved in care of their babies and young children. We assessed the association of resident fathers' involvement with subsequent behaviour of their children, examining boys and girls separately. METHODS: We used longitudinal data from the UK Millennium Cohort Study for children born in 2000-2001, divided into three separate analysis periods: ages 9 months to 3 years, 3 to 5 years, and 5 to 7 years. By exploratory factor analysis of self-reported attitudes and engagement in caring activities, we derived composite measures of various types of father involvement at 9 months, 3 and 5 years. Where possible we created equivalent measures of mother involvement. Child behaviour was assessed by the Strengths and Difficulties Questionnaire (SDQ), which was completed by the mother when the child was aged 3, 5 and 7 years. We estimated gender-specific odds ratios for behaviour problems per quintile of father involvement, using separate logistic regression models for boys and girls in each analysis period. We controlled for a wide range of potential confounders: characteristics of the child (temperament and development at 9 months, and illness and exact age at outcome), equivalent mother involvement where appropriate, and factors related to socioeconomic status, household change, and parental well-being, where statistically significant. RESULTS: Paternal positive parenting beliefs at age 9 months and increased frequency of creative play at age 5 years were significantly associated with lower risk of subsequent behaviour problems (SDQ total difficulties) in both boys and girls (p<0.05), odds ratios ranging between 0.81 and 0.89 per quintile of involvement. No associations were observed for other composite measures of caring activity by the father at 9 months, 3 years or 5 years. CONCLUSION: Quality of parenting, rather than the division of routine care between parents, was associated with child behavioural outcomes.

Adiposity and ischemic and hemorrhagic stroke: Prospective study in women and meta-analysis.

OBJECTIVE: To compare associations of body mass index (BMI) with ischemic stroke and hemorrhagic stroke risk, and to review the worldwide evidence. METHODS: We recruited 1.3 million previously stroke-free UK women between 1996 and 2001 (mean age 57 years [SD 5]) and followed them by record linkage for hospital admissions and deaths. We used Cox regression to estimate adjusted relative risks for ischemic and hemorrhagic (intracerebral or subarachnoid hemorrhage) stroke in relation to BMI. We conducted a meta-analysis of published findings from prospective studies on these associations. RESULTS: During an average follow-up of 11.7 years, there were 20,549 first strokes, of which 9,993 were specified as ischemic and 5,852 as hemorrhagic. Increased BMI was associated with an increased risk of ischemic stroke (relative risk 1.21 per 5 kg/m2 BMI, 95% confidence interval 1.18-1.23, p < 0.0001) but a decreased risk of hemorrhagic stroke (relative risk 0.89 per 5 kg/m2 BMI, 0.86-0.92, p < 0.0001). The BMI-associated trends for ischemic and hemorrhagic stroke were significantly different (heterogeneity: p < 0.0001) but were not significantly different for intracerebral hemorrhage (n = 2,790) and subarachnoid hemorrhage (n = 3,062) (heterogeneity: p = 0.5). Published data from prospective studies showed consistently greater BMI-associated relative risks for ischemic than hemorrhagic stroke with most evidence (prior to this study) coming from Asian populations. CONCLUSIONS: In UK women, higher BMI is associated with increased risk of ischemic stroke but decreased risk of hemorrhagic stroke. The totality of the available published evidence suggests that BMI-associated risks are greater for ischemic than for hemorrhagic stroke.

Childhood leukemia incidence in Britain, 1974-2000: time trends and possible relation to influenza epidemics.

Time trends in incidence of disease may cast light on etiology. We investigated time trends in childhood leukemia by using Poisson regression methods to analyze data from the National Registry of Childhood Tumours, a long-standing high-quality registry that covers the whole childhood population of Britain. During 1974-2000, the average annual percentage change in rate (AAC) of childhood acute lymphoblastic leukemia (ALL) in Britain was 0.7% (95% confidence interval [CI] = 0.4 to 1.0). This increase was apparently driven by the "common" subtype (expressing the CD10 antigen) of precursor B-cell ALL, for which the estimated AAC during 1980-1996 was 1.4% (95% CI = 0.8 to 2.0). There was no statistically significant time trend in other subtypes of ALL combined (1980-1996) or in acute myeloid leukemia (1974-2000). Small peaks in incidence of ALL in 1976 and 1990 coincided with years immediately following influenza epidemics. These results are consistent with hypotheses that some childhood leukemia may be triggered by infection occurring close to the time of diagnosis of leukemia, particularly in conditions of low herd immunity, and raise the possibility that contact with influenza shortly before the diagnosis of leukemia may sometimes be involved.

Childhood cancer in relation to distance from high voltage power lines in England and Wales: a case-control study.

OBJECTIVE: To determine whether there is an association between distance of home address at birth from high voltage power lines and the incidence of leukaemia and other cancers in children in England and Wales. DESIGN: Case-control study. SETTING: Cancer registry and National Grid records. SUBJECTS: Records of 29 081 children with cancer, including 9700 with leukaemia. Children were aged 0-14 years and born in England and Wales, 1962-95. Controls were individually matched for sex, approximate date of birth, and birth registration district. No active participation was required. MAIN OUTCOME MEASURES: Distance from home address at birth to the nearest high voltage overhead power line in existence at the time. RESULTS: Compared with those who lived > 600 m from a line at birth, children who lived within 200 m had a relative risk of leukaemia of 1.69 (95% confidence interval 1.13 to 2.53); those born between 200 and 600 m had a relative risk of 1.23 (1.02 to 1.49). There was a significant (P < 0.01) trend in risk in relation to the reciprocal of distance from the line. No excess risk in relation to proximity to lines was found for other childhood cancers. CONCLUSIONS: There is an association between childhood leukaemia and proximity of home address at birth to high voltage power lines, and the apparent risk extends to a greater distance than would have been expected from previous studies. About 4% of children in England and Wales live within 600 m of high voltage lines at birth. If the association is causal, about 1% of childhood leukaemia in England and Wales would be attributable to these lines, though this estimate has considerable statistical uncertainty. There is no accepted biological mechanism to explain the epidemiological results; indeed, the relation may be due to chance or confounding.