Day care in infancy and risk of childhood acute lymphoblastic leukaemi
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《英国医生杂志》
1 Cancer Research UK Epidemiology and Genetics Unit, Institute of Cancer Research, Sutton SM2 5NG, 2 Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT, 3 Leukaemia Research Fund Epidemiology and Genetics Unit, Department ofHealth Sciences, University of York, York YO10 5DD, 4 Academic Unit of Paediatric Oncology, Christie Hospital and Central Manchester and Manchester Children's University Hospitals NHS Trusts, Manchester M20 4BX, 5 Section of Haemato Oncology, Institute of Cancer Research, London SW3 6JB, 6 Public Health Sciences, University of Edinburgh, Edinburgh EH8 9AG
Correspondence to: T O B Eden tim.eden@manchester.ac.uk
Objective To test the hypothesis that reduced exposure to common infections in the first year of life increases the risk of developing acute lymphoblastic leukaemia.
Design and setting The United Kingdom childhood cancer study (UKCCS) is a large population based case-control study of childhood cancer across 10 regions of the UK.
Participants 6305 children (aged 2-14 years) without cancer; 3140 children with cancer (diagnosed 1991-6), of whom 1286 had acute lymphoblastic leukaemia (ALL).
Main outcome measure Day care and social activity during the first year of life were used as proxies for potential exposure to infection in infancy.
Results Increasing levels of social activity were associated with consistent reductions in risk of ALL; a dose-response trend was seen. When children whose mothers reported no regular activity outside the family were used as the reference group, odds ratios for increasing levels of activity were 0.73 (95% confidence interval 0.62 to 0.87) for any social activity, 0.62 (0.51 to 0.75) for regular day care outside the home, and 0.48 (0.37 to 0.62) for formal day care (attendance at facility with at least four children at least twice a week) (P value for trend < 0.001). Although not as striking, results for non-ALL malignancies showed a similar pattern (P value for trend < 0.001). When children with non-ALL malignancies were taken as the reference group, a significant protective effect for ALL was seen only for formal day care (odds ratio = 0.69, 0.51 to 0.93; P = 0.02). Similar results were obtained for B cell precursor common ALL and other subgroups, as well as for cases diagnosed above and below age 5 years.
Conclusion These results support the hypothesis that reduced exposure to infection in the first few months of life increases the risk of developing acute lymphoblastic leukaemia.
The idea that infections are involved in the aetiology of childhood leukaemia dates back to the 1940s.1 Two key papers appeared in 1988. Greaves proposed that a deficit of exposure to infectious agents in infancy and subsequent "delayed" infectious challenge were causal factors in the development of B cell precursor common acute lymphoblastic leukaemia,2 which is responsible for the childhood peak of acute lymphoblastic leukaemia (ALL) at age 2-5 years.3 4 Kinlen proposed that population influx into isolated communities (population mixing) could generate excesses of childhood leukaemia by causing mini-epidemics of one or more infections to which leukaemia may be a rare response.5 The UK childhood cancer study (UKCCS), a large population based case-control study,6 was designed to test several hypotheses, one of which was that leukaemias and lymphomas may be caused by abnormal responses to common infectious agents. Here, we focus on Greaves's hypothesis that immunological isolation in infancy increases the risk of B cell precursor common ALL (cALL). No single protective agent or transmission pathway has been identified, so proxy variables for exposure to infection must be used. The literature on infectious illnesses occurring in day care settings suggests that social interactions with other children outside the home may be important.7-9 Several studies of childhood leukaemia have used such proxies.10-19
Precise molecular subclassification of cALL is potentially important for these analyses. The two largest subgroups are those with hyperdiploidy (hyperdiploid ALL) and with fusion of the TEL and AML1 genes (TEL-AML1 ALL). Most (possibly all) children with these lesions have affected clones present at the time of birth,20 21 so initiation usually occurs in utero. However, the modest level of concordance in identical twins with one affected by cALL (approximately 10%), together with the much greater frequency of these lesions in cord blood than the lifetime risk of the cALL subtype,22 indicates that at least one postnatal event also occurs in the development of cALL. Greaves's original hypothesis relates to the promotional factors that affect the frequency of this second event.
The UKCCS included all childhood cancers.6 In this paper we compare social activity of cases and controls during the first year of life for ALL and subgroups of ALL. We also compare ALL with non-ALL malignancies. We excluded children aged under 2 years at the time of diagnosis (cases) or pseudodiagnosis (controls) in order to avoid both dilution of results through overlap for younger children of the two time windows in which associations in opposite directions are predicted and the potential for early symptoms of leukaemia to influence attendance at day care.
Participants
This case-control study was conducted in 10 regions across the United Kingdom between 1991 and 1996. The UKCCS study design, data collection and consenting procedures, ethical approvals, and participation rates are described in detail elsewhere.6 23 Briefly, children diagnosed as having a confirmed malignancy were ascertained through paediatric oncology units, and two controls matched to each case for sex, month and year of birth, and region of residence at diagnosis were randomly selected from population registers. Age at diagnosis of the case was designated as the age at "pseudodiagnosis" of the matched control. A structured questionnaire was used to interview parents of 3838 cases and 7629 controls face to face. Questions about social activity focused on activity with other infants and children, and included information on the number of sessions a week and the number of children attending for specific activities before starting school.
Exposure variables
We defined "social activity" as regular activity (at least once a week) with other infants who were not members of the same household. We defined "day care" as attendance (at least once a week) at a day nursery, nursery school, play group, mother and toddler group, or childminder. We defined "formal day care" as any attendance at a day nursery or nursery school, at least two half day sessions a week at a playgroup or mother and toddler group, or at least two half day sessions a week at a childminder with a minimum of four children attending. We used a hierarchical variable based on these three exposures (social activity, day care, and formal day care) as an overall measure of social activity in the first year of life.
Statistical analysis
We excluded children given a diagnosis or pseudodiagnosis before the age of 2 years (649 cases and 1320 controls), as well as children with Down's syndrome (49 cases and 4 controls), which left 9445 eligible children (3140 cases and 6305 controls) (table 1). We analysed data for all cancers combined and separately for ALL, cALL, TEL-AML1 ALL, hyperdiploid ALL, and non-ALL malignancies. To increase precision, we compared each case subgroup with all controls. We also did a case-case comparison of ALL and cALL versus non-ALL malignancies. We used unconditional logistic regression procedures in Stata version 7 to estimate odds ratios and 95% confidence intervals.24 We used likelihood ratio tests to assess associations. We assessed trends across the combined hierarchical variable by treating it as a continuous variable.
Table 1 Numbers of cases and controls overall (aged 2-14 years) and aged 2-5 at diagnosis or pseudodiagnosis
Results
Most (86%) mothers of controls reported some social activity with children outside the family in the first year of life (table 2). Any such activity was associated with a reduced risk of ALL (odds ratio = 0.66; P < 0.001). The risk ratios for cALL alone and for the cytogenetic subgroups TEL-AML1 and hyperdiploidy were similarly reduced. Analyses of non-ALL malignancies combined gave a similar result; the only individually statistically significantly reduced risk was for the largest group—central nervous system tumours. With respect to the case-case comparison (ALL v non-ALL malignancies), the dichotomous variable "any social activity" was not significantly reduced. Analyses restricted to 2-5 year olds produced similar results (table 2), but we found no evidence that the association was stronger in the childhood peak (2-5 years) than at older ages.
Table 2 Levels of social activity in the first year of life for acute lymphoblastic leukaemia (ALL), ALL subgroups, and non-ALL malignancies
Each category of malignancy showed a significant inverse trend as level of social activity increased (table 2). The statistically significant trend (P = 0.04) for the comparison of ALL with non-ALL malignancies (right hand column) is due largely to the reduced odds ratio for formal day care (odds ratio = 0.69, 95% confidence interval 0.51 to 0.93). Analyses restricted to cases aged 2-5 years gave similar results, although statistical significance was reduced.
The proportion of children who had an older sibling living in the home at the time of birth was similar for ALL (56%), cALL (54%), non-ALL malignancies (57%), and controls (57%), and we observed no significant trends with numbers of older siblings in any diagnostic group (table 3). As any relation between social activity and ALL might be expected to be more marked among children born into households without other children, we repeated the analyses in table 2 for children with and without older siblings. The odds ratio for formal day care was 0.61 (0.42 to 0.87) for ALL in children without older siblings and 0.38 (0.26 to 0.54) for those with older siblings, a non-significant difference in the opposite direction to that anticipated.
Table 3 Number of older children in household ("siblings") at time of index birth for acute lymphoblastic leukaemia (ALL), ALL subgroups, and non-ALL malignancies
Estimated risks for children starting day care in the first year of life showed no marked trends with age at first attendance (table 4). The greatest reduction in risk of ALL, however, was seen in children who attended formal day care during the first three months of life, for whom the odds ratio remained statistically significant when we used non-ALL malignancies as the reference group (odds ratio = 0.52, 0.32 to 0.83; P = 0.007).
Table 4 Effect of age at first day care during the first year of life for acute lymphoblastic leukaemia (ALL) and non-ALL malignancies
Discussion
Cooke J. The incidence of acute leukemia in children. JAMA 1942;119: 547-50.
Greaves MF. Speculations on the cause of childhood acute lymphoblastic leukemia. Leukemia 1988;2: 120-5.
Greaves MF, Alexander FE. An infectious etiology for common acute lymphoblastic leukemia in childhood? Leukemia 1993;7: 349-60.
Greaves MF. Aetiology of acute leukaemia. Lancet 1997;349: 344-9.
Kinlen LJ. The longitudinal study and the social distribution of cancer. BMJ 1988;297: 1070.
UK Childhood Cancer Study Investigators. The United Kingdom childhood cancer study: objectives, materials and methods. Br J Cancer 2000;82: 1073-102.
Fleming DW, Cochi SL, Hightower AW, Broome CV. Childhood upper respiratory tract infections: to what degree is incidence affected by day-care attendance? Pediatrics 1987;79: 55-60.
Louhiala PJ, Jaakkola N, Ruotsalainen R, Jaakkola JJ. Form of day care and respiratory infections among Finnish children. Am J Public Health 1995;85: 1109-12.
Rasmussen F, Sundelin C. Use of medical care and antibiotics among preschool children in different day care settings. Acta Paediatr Scand 1990;79: 838-46.
Chan LC, Lam TH, Li CK, Lau YL, Li CK, Yuen HL, et al. Is the timing of exposure to infection a major determinant of acute lymphoblastic leukaemia in Hong Kong? Paediatr Perinat Epidemiol 2002;16: 154-65.
Dockerty JD, Skegg DCG, Elwood JM, Herbison GP, Becroft DMO, Lewis ME. Infections, vaccinations, and the risk of childhood leukaemia. Br J Cancer 1999;80: 1483-9.
Neglia JP, Linet MS, Shu XO, Severson RK, Potter JD, Mertens AC, et al. Patterns of infection and day care utilization and risk of childhood acute lymphoblastic leukaemia. Br J Cancer 2000;82: 234-40.
Petridou E, Kassimos D, Kalmanti M, Kosmidis H, Haidas S, Flytzani V, et al. Age of exposure to infections and risk of childhood leukaemia. BMJ 1993;307: 774.
Infante-Rivard C, Fortier I, Olson E. Markers of infection, breast-feeding and childhood acute lymphoblastic leukaemia. Br J Cancer 2000;83: 1559-64.
Perrillat F, Clavel J, Auclerc MF, Baruchel A, Leverger G, Nelken B, et al. Day-care, early common infections and childhood acute leukaemia: a multicentre French case-control study. Br J Cancer 2002;86: 1064-9.
Jourdan-Da Silva N, Perel Y, Mechinaud F, Plouvier E, Gandemer V, Lutz P, et al. Infectious diseases in the first year of life, perinatal characteristics and childhood acute leukaemia. Br J Cancer 2004;90: 139-45.
Petridou E, Trichopoulos D, Kalapothaki V, Pourtsidis A, Kogevinas M, Kalmanti M, et al. The risk profile of childhood leukaemia in Greece: a nationwide case-control study. Br J Cancer 1997;76: 1241-7.
Ma X, Buffler PA, Selvin S, Matthay KK, Wiencke JK, Wiemels JL, et al. Daycare attendance and risk of childhood acute lymphoblastic leukaemia. Br J Cancer 2002;86: 1419-24.
Rosenbaum PF, Buck GM, Brecher ML. Early child-care and preschool experiences and the risk of childhood acute lymphoblastic leukemia. Am J Epidemiol 2000;152: 1136-44.
Wiemels JL, Cazzaniga G, Daniotti M, Eden OB, Addison GM, Masera G, et al. Prenatal origin of acute lymphoblastic leukaemia in children. Lancet 1999;354: 1499-503.
Greaves MF, Wiemels J. Origins of chromosome translocations in childhood leukaemia. Nat Rev Cancer 2003;3: 639-49.
Mori H, Colman SM, Xiao Z, Ford AM, Healy LE, Donaldson C, et al. Chromosome translocations and covert leukemic clones are generated during normal fetal development. Proc Natl Acad Sci USA 2002;99: 8242-7.
Law GR, Smith AG, Roman E, UK Childhood Cancer Study Investigators. The importance of full participation: lessons from a national case-control study. Br J Cancer 2002;86: 350-5.
Breslow NE, Day NE. Statistical methods in cancer research. Vol 1. The analysis of case-control studies. Lyon: International Agency for Research on Cancer, 1980.
Roman E, Simpson J, Ansell P, Lightfoot T, Mitchell CD, Eden OB. Perinatal and reproductive factors: a report on haematological malignancies from the UKCCS. Eur J Cancer 2005; in press.
Steensel-Moll HA, Valkenburg HA, van Zanen GE. Childhood leukemia and infectious diseases in the first year of life: a register-based case-control study. Am J Epidemiol 1986;124: 590-4.
Schuz J, Kaletsch U, Meinert R, Kaatsch P, Michaelis J. Association of childhood leukaemia with factors related to the immune system. Br J Cancer 1999;80: 585-90.
Kinlen LJ. Epidemiological evidence for an infective basis in childhood leukaemia. Br J Cancer 1995; 71: 1-5.
Taylor GM, Dearden S, Ravetto P, Ayres M, Watson P, Hussain A, et al. Genetic susceptibility to childhood common acute lymphoblastic leukaemia is associated with polymorphic peptide-binding pocket profiles in HLA-DPB1*0201. Hum Mol Genet 2002;11: 1585-97.
Groves FD, Gridley G, Wacholder S, Shu XO, Robison LL, Neglia JP, et al. Infant vaccinations and risk of childhood acute lymphoblastic leukaemia in the USA. Br J Cancer 1999;81: 175-8.
Auvinen A, Hakulinen T, Groves F. Haemophilus influenzae type B vaccination and risk of childhood leukaemia in a vaccine trial in Finland. Br J Cancer 2000;83: 956-8.
Groves F, Sinha D, Auvinen A. Haemophilus influenzae type b vaccine formulation and risk of childhood leukaemia. Br J Cancer 2002;87: 511-2.
McKinney PA, Okasha M, Parslow RC, Law GR, Gurney KA, Williams R, et al. Early social mixing and childhood type 1 diabetes mellitus: a case-control study in Yorkshire, UK. Diabet Med 2000;17: 236-42.
Kramer U, Heinrich J, Wjst M, Wichmann HE. Age of entry to day nursery and allergy in later childhood. Lancet 1999;353: 450-4.(C Gilham, statistician1, J Peto, profess)
Correspondence to: T O B Eden tim.eden@manchester.ac.uk
Objective To test the hypothesis that reduced exposure to common infections in the first year of life increases the risk of developing acute lymphoblastic leukaemia.
Design and setting The United Kingdom childhood cancer study (UKCCS) is a large population based case-control study of childhood cancer across 10 regions of the UK.
Participants 6305 children (aged 2-14 years) without cancer; 3140 children with cancer (diagnosed 1991-6), of whom 1286 had acute lymphoblastic leukaemia (ALL).
Main outcome measure Day care and social activity during the first year of life were used as proxies for potential exposure to infection in infancy.
Results Increasing levels of social activity were associated with consistent reductions in risk of ALL; a dose-response trend was seen. When children whose mothers reported no regular activity outside the family were used as the reference group, odds ratios for increasing levels of activity were 0.73 (95% confidence interval 0.62 to 0.87) for any social activity, 0.62 (0.51 to 0.75) for regular day care outside the home, and 0.48 (0.37 to 0.62) for formal day care (attendance at facility with at least four children at least twice a week) (P value for trend < 0.001). Although not as striking, results for non-ALL malignancies showed a similar pattern (P value for trend < 0.001). When children with non-ALL malignancies were taken as the reference group, a significant protective effect for ALL was seen only for formal day care (odds ratio = 0.69, 0.51 to 0.93; P = 0.02). Similar results were obtained for B cell precursor common ALL and other subgroups, as well as for cases diagnosed above and below age 5 years.
Conclusion These results support the hypothesis that reduced exposure to infection in the first few months of life increases the risk of developing acute lymphoblastic leukaemia.
The idea that infections are involved in the aetiology of childhood leukaemia dates back to the 1940s.1 Two key papers appeared in 1988. Greaves proposed that a deficit of exposure to infectious agents in infancy and subsequent "delayed" infectious challenge were causal factors in the development of B cell precursor common acute lymphoblastic leukaemia,2 which is responsible for the childhood peak of acute lymphoblastic leukaemia (ALL) at age 2-5 years.3 4 Kinlen proposed that population influx into isolated communities (population mixing) could generate excesses of childhood leukaemia by causing mini-epidemics of one or more infections to which leukaemia may be a rare response.5 The UK childhood cancer study (UKCCS), a large population based case-control study,6 was designed to test several hypotheses, one of which was that leukaemias and lymphomas may be caused by abnormal responses to common infectious agents. Here, we focus on Greaves's hypothesis that immunological isolation in infancy increases the risk of B cell precursor common ALL (cALL). No single protective agent or transmission pathway has been identified, so proxy variables for exposure to infection must be used. The literature on infectious illnesses occurring in day care settings suggests that social interactions with other children outside the home may be important.7-9 Several studies of childhood leukaemia have used such proxies.10-19
Precise molecular subclassification of cALL is potentially important for these analyses. The two largest subgroups are those with hyperdiploidy (hyperdiploid ALL) and with fusion of the TEL and AML1 genes (TEL-AML1 ALL). Most (possibly all) children with these lesions have affected clones present at the time of birth,20 21 so initiation usually occurs in utero. However, the modest level of concordance in identical twins with one affected by cALL (approximately 10%), together with the much greater frequency of these lesions in cord blood than the lifetime risk of the cALL subtype,22 indicates that at least one postnatal event also occurs in the development of cALL. Greaves's original hypothesis relates to the promotional factors that affect the frequency of this second event.
The UKCCS included all childhood cancers.6 In this paper we compare social activity of cases and controls during the first year of life for ALL and subgroups of ALL. We also compare ALL with non-ALL malignancies. We excluded children aged under 2 years at the time of diagnosis (cases) or pseudodiagnosis (controls) in order to avoid both dilution of results through overlap for younger children of the two time windows in which associations in opposite directions are predicted and the potential for early symptoms of leukaemia to influence attendance at day care.
Participants
This case-control study was conducted in 10 regions across the United Kingdom between 1991 and 1996. The UKCCS study design, data collection and consenting procedures, ethical approvals, and participation rates are described in detail elsewhere.6 23 Briefly, children diagnosed as having a confirmed malignancy were ascertained through paediatric oncology units, and two controls matched to each case for sex, month and year of birth, and region of residence at diagnosis were randomly selected from population registers. Age at diagnosis of the case was designated as the age at "pseudodiagnosis" of the matched control. A structured questionnaire was used to interview parents of 3838 cases and 7629 controls face to face. Questions about social activity focused on activity with other infants and children, and included information on the number of sessions a week and the number of children attending for specific activities before starting school.
Exposure variables
We defined "social activity" as regular activity (at least once a week) with other infants who were not members of the same household. We defined "day care" as attendance (at least once a week) at a day nursery, nursery school, play group, mother and toddler group, or childminder. We defined "formal day care" as any attendance at a day nursery or nursery school, at least two half day sessions a week at a playgroup or mother and toddler group, or at least two half day sessions a week at a childminder with a minimum of four children attending. We used a hierarchical variable based on these three exposures (social activity, day care, and formal day care) as an overall measure of social activity in the first year of life.
Statistical analysis
We excluded children given a diagnosis or pseudodiagnosis before the age of 2 years (649 cases and 1320 controls), as well as children with Down's syndrome (49 cases and 4 controls), which left 9445 eligible children (3140 cases and 6305 controls) (table 1). We analysed data for all cancers combined and separately for ALL, cALL, TEL-AML1 ALL, hyperdiploid ALL, and non-ALL malignancies. To increase precision, we compared each case subgroup with all controls. We also did a case-case comparison of ALL and cALL versus non-ALL malignancies. We used unconditional logistic regression procedures in Stata version 7 to estimate odds ratios and 95% confidence intervals.24 We used likelihood ratio tests to assess associations. We assessed trends across the combined hierarchical variable by treating it as a continuous variable.
Table 1 Numbers of cases and controls overall (aged 2-14 years) and aged 2-5 at diagnosis or pseudodiagnosis
Results
Most (86%) mothers of controls reported some social activity with children outside the family in the first year of life (table 2). Any such activity was associated with a reduced risk of ALL (odds ratio = 0.66; P < 0.001). The risk ratios for cALL alone and for the cytogenetic subgroups TEL-AML1 and hyperdiploidy were similarly reduced. Analyses of non-ALL malignancies combined gave a similar result; the only individually statistically significantly reduced risk was for the largest group—central nervous system tumours. With respect to the case-case comparison (ALL v non-ALL malignancies), the dichotomous variable "any social activity" was not significantly reduced. Analyses restricted to 2-5 year olds produced similar results (table 2), but we found no evidence that the association was stronger in the childhood peak (2-5 years) than at older ages.
Table 2 Levels of social activity in the first year of life for acute lymphoblastic leukaemia (ALL), ALL subgroups, and non-ALL malignancies
Each category of malignancy showed a significant inverse trend as level of social activity increased (table 2). The statistically significant trend (P = 0.04) for the comparison of ALL with non-ALL malignancies (right hand column) is due largely to the reduced odds ratio for formal day care (odds ratio = 0.69, 95% confidence interval 0.51 to 0.93). Analyses restricted to cases aged 2-5 years gave similar results, although statistical significance was reduced.
The proportion of children who had an older sibling living in the home at the time of birth was similar for ALL (56%), cALL (54%), non-ALL malignancies (57%), and controls (57%), and we observed no significant trends with numbers of older siblings in any diagnostic group (table 3). As any relation between social activity and ALL might be expected to be more marked among children born into households without other children, we repeated the analyses in table 2 for children with and without older siblings. The odds ratio for formal day care was 0.61 (0.42 to 0.87) for ALL in children without older siblings and 0.38 (0.26 to 0.54) for those with older siblings, a non-significant difference in the opposite direction to that anticipated.
Table 3 Number of older children in household ("siblings") at time of index birth for acute lymphoblastic leukaemia (ALL), ALL subgroups, and non-ALL malignancies
Estimated risks for children starting day care in the first year of life showed no marked trends with age at first attendance (table 4). The greatest reduction in risk of ALL, however, was seen in children who attended formal day care during the first three months of life, for whom the odds ratio remained statistically significant when we used non-ALL malignancies as the reference group (odds ratio = 0.52, 0.32 to 0.83; P = 0.007).
Table 4 Effect of age at first day care during the first year of life for acute lymphoblastic leukaemia (ALL) and non-ALL malignancies
Discussion
Cooke J. The incidence of acute leukemia in children. JAMA 1942;119: 547-50.
Greaves MF. Speculations on the cause of childhood acute lymphoblastic leukemia. Leukemia 1988;2: 120-5.
Greaves MF, Alexander FE. An infectious etiology for common acute lymphoblastic leukemia in childhood? Leukemia 1993;7: 349-60.
Greaves MF. Aetiology of acute leukaemia. Lancet 1997;349: 344-9.
Kinlen LJ. The longitudinal study and the social distribution of cancer. BMJ 1988;297: 1070.
UK Childhood Cancer Study Investigators. The United Kingdom childhood cancer study: objectives, materials and methods. Br J Cancer 2000;82: 1073-102.
Fleming DW, Cochi SL, Hightower AW, Broome CV. Childhood upper respiratory tract infections: to what degree is incidence affected by day-care attendance? Pediatrics 1987;79: 55-60.
Louhiala PJ, Jaakkola N, Ruotsalainen R, Jaakkola JJ. Form of day care and respiratory infections among Finnish children. Am J Public Health 1995;85: 1109-12.
Rasmussen F, Sundelin C. Use of medical care and antibiotics among preschool children in different day care settings. Acta Paediatr Scand 1990;79: 838-46.
Chan LC, Lam TH, Li CK, Lau YL, Li CK, Yuen HL, et al. Is the timing of exposure to infection a major determinant of acute lymphoblastic leukaemia in Hong Kong? Paediatr Perinat Epidemiol 2002;16: 154-65.
Dockerty JD, Skegg DCG, Elwood JM, Herbison GP, Becroft DMO, Lewis ME. Infections, vaccinations, and the risk of childhood leukaemia. Br J Cancer 1999;80: 1483-9.
Neglia JP, Linet MS, Shu XO, Severson RK, Potter JD, Mertens AC, et al. Patterns of infection and day care utilization and risk of childhood acute lymphoblastic leukaemia. Br J Cancer 2000;82: 234-40.
Petridou E, Kassimos D, Kalmanti M, Kosmidis H, Haidas S, Flytzani V, et al. Age of exposure to infections and risk of childhood leukaemia. BMJ 1993;307: 774.
Infante-Rivard C, Fortier I, Olson E. Markers of infection, breast-feeding and childhood acute lymphoblastic leukaemia. Br J Cancer 2000;83: 1559-64.
Perrillat F, Clavel J, Auclerc MF, Baruchel A, Leverger G, Nelken B, et al. Day-care, early common infections and childhood acute leukaemia: a multicentre French case-control study. Br J Cancer 2002;86: 1064-9.
Jourdan-Da Silva N, Perel Y, Mechinaud F, Plouvier E, Gandemer V, Lutz P, et al. Infectious diseases in the first year of life, perinatal characteristics and childhood acute leukaemia. Br J Cancer 2004;90: 139-45.
Petridou E, Trichopoulos D, Kalapothaki V, Pourtsidis A, Kogevinas M, Kalmanti M, et al. The risk profile of childhood leukaemia in Greece: a nationwide case-control study. Br J Cancer 1997;76: 1241-7.
Ma X, Buffler PA, Selvin S, Matthay KK, Wiencke JK, Wiemels JL, et al. Daycare attendance and risk of childhood acute lymphoblastic leukaemia. Br J Cancer 2002;86: 1419-24.
Rosenbaum PF, Buck GM, Brecher ML. Early child-care and preschool experiences and the risk of childhood acute lymphoblastic leukemia. Am J Epidemiol 2000;152: 1136-44.
Wiemels JL, Cazzaniga G, Daniotti M, Eden OB, Addison GM, Masera G, et al. Prenatal origin of acute lymphoblastic leukaemia in children. Lancet 1999;354: 1499-503.
Greaves MF, Wiemels J. Origins of chromosome translocations in childhood leukaemia. Nat Rev Cancer 2003;3: 639-49.
Mori H, Colman SM, Xiao Z, Ford AM, Healy LE, Donaldson C, et al. Chromosome translocations and covert leukemic clones are generated during normal fetal development. Proc Natl Acad Sci USA 2002;99: 8242-7.
Law GR, Smith AG, Roman E, UK Childhood Cancer Study Investigators. The importance of full participation: lessons from a national case-control study. Br J Cancer 2002;86: 350-5.
Breslow NE, Day NE. Statistical methods in cancer research. Vol 1. The analysis of case-control studies. Lyon: International Agency for Research on Cancer, 1980.
Roman E, Simpson J, Ansell P, Lightfoot T, Mitchell CD, Eden OB. Perinatal and reproductive factors: a report on haematological malignancies from the UKCCS. Eur J Cancer 2005; in press.
Steensel-Moll HA, Valkenburg HA, van Zanen GE. Childhood leukemia and infectious diseases in the first year of life: a register-based case-control study. Am J Epidemiol 1986;124: 590-4.
Schuz J, Kaletsch U, Meinert R, Kaatsch P, Michaelis J. Association of childhood leukaemia with factors related to the immune system. Br J Cancer 1999;80: 585-90.
Kinlen LJ. Epidemiological evidence for an infective basis in childhood leukaemia. Br J Cancer 1995; 71: 1-5.
Taylor GM, Dearden S, Ravetto P, Ayres M, Watson P, Hussain A, et al. Genetic susceptibility to childhood common acute lymphoblastic leukaemia is associated with polymorphic peptide-binding pocket profiles in HLA-DPB1*0201. Hum Mol Genet 2002;11: 1585-97.
Groves FD, Gridley G, Wacholder S, Shu XO, Robison LL, Neglia JP, et al. Infant vaccinations and risk of childhood acute lymphoblastic leukaemia in the USA. Br J Cancer 1999;81: 175-8.
Auvinen A, Hakulinen T, Groves F. Haemophilus influenzae type B vaccination and risk of childhood leukaemia in a vaccine trial in Finland. Br J Cancer 2000;83: 956-8.
Groves F, Sinha D, Auvinen A. Haemophilus influenzae type b vaccine formulation and risk of childhood leukaemia. Br J Cancer 2002;87: 511-2.
McKinney PA, Okasha M, Parslow RC, Law GR, Gurney KA, Williams R, et al. Early social mixing and childhood type 1 diabetes mellitus: a case-control study in Yorkshire, UK. Diabet Med 2000;17: 236-42.
Kramer U, Heinrich J, Wjst M, Wichmann HE. Age of entry to day nursery and allergy in later childhood. Lancet 1999;353: 450-4.(C Gilham, statistician1, J Peto, profess)