Skip to main content
SpringerLink
Log in

Reported associations between asthma and acute lymphoblastic leukemia: insights from a hybrid simulation study

  • CANCER
  • Published:
European Journal of Epidemiology Aims and scope Submit manuscript

Abstract

Numerous studies have reported a protective association between asthma and acute lymphoblastic leukemia (ALL), but the causal structure of this association remains unclear. We present a hybrid simulation to examine the compatibility of this association with uncontrolled confounding by infection or another unmeasured factor. We generated a synthetic cohort using inputs on the interrelations of asthma, ALL, infections, and other suggested risk factors from the literature and the Danish National Birth Cohort. We computed odds ratios (ORs) between asthma and ALL in the synthetic cohort with and without adjustment for infections and other (including unmeasured) confounders. Only if infection was an extremely strong risk factor for asthma (OR of 10) and an extremely strong protective factor against ALL (OR of 0.1) was the asthma-ALL association compatible with the literature (OR of 0.78). Similarly, strong uncontrolled confounding by an unmeasured factor could downwardly bias the asthma-ALL association, but not enough to replicate findings in the literature. This investigation illustrates that the reported protective association between asthma and ALL is unlikely to be entirely due to uncontrolled confounding by infections or an unmeasured confounder alone. Simulation can be used to advance our understanding of risk factors for rare outcomes as demonstrated by this study.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Milne E, Greenop KR, Metayer C, et al. Fetal growth and childhood acute lymphoblastic leukemia: findings from the childhood leukemia international consortium. Int J Cancer. 2013;133(12):2968–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Gholami A, Salarilak S, Hejazi S, Khalkhali HR. Birth weight and risk of childhood acute leukaemia. East Mediterr Health J. 2013;19(2):156–61.

    CAS  PubMed  Google Scholar 

  3. Roman E, Lightfoot T, Smith AG, et al. Childhood acute lymphoblastic leukaemia and birthweight: insights from a pooled analysis of case-control data from Germany, the United Kingdom and the United States. Eur J Cancer. 2013;49(6):1437–47.

    Article  PubMed  Google Scholar 

  4. Samuelsen SO, Bakketeig LS, Tretli S, Johannesen TB, Magnus P. Birth weight and childhood cancer. Epidemiology. 2009;20(4):484–7.

    Article  PubMed  Google Scholar 

  5. Caughey RW, Michels KB. Birth weight and childhood leukemia: a meta-analysis and review of the current evidence. Int J Cancer. 2009;124(11):2658–70.

    Article  CAS  PubMed  Google Scholar 

  6. Milne E, Greenop KR, Scott RJ, et al. Parental prenatal smoking and risk of childhood acute lymphoblastic leukemia. Am J Epidemiol. 2012;175(1):43–53.

    Article  PubMed  Google Scholar 

  7. Lee KM, Ward MH, Han S, et al. Paternal smoking, genetic polymorphisms in CYP1A1 and childhood leukemia risk. Leuk Res. 2009;33(2):250–8.

    Article  CAS  PubMed  Google Scholar 

  8. Liu R, Zhang L, McHale CM, Hammond SK. Paternal smoking and risk of childhood acute lymphoblastic leukemia: systematic review and meta-analysis. J Oncol. 2011;2011:16. doi:10.1155/2011/854584.

    Article  Google Scholar 

  9. Chang JS, Selvin S, Metayer C, Crouse V, Golembesky A, Buffler PA. Parental smoking and the risk of childhood leukemia. Am J Epidemiol. 2006;163(12):1091–100.

    Article  PubMed  Google Scholar 

  10. Rudant J, Menegaux F, Leverger G, et al. Childhood hematopoietic malignancies and parental use of tobacco and alcohol: the ESCALE study (SFCE). Cancer Causes Control. 2008;19(10):1277–90.

    Article  PubMed  Google Scholar 

  11. Menegaux F, Ripert M, Hemon D, Clavel J. Maternal alcohol and coffee drinking, parental smoking and childhood leukaemia: a French population-based case-control study. Paediatr Perinat Epidemiol. 2007;21(4):293–9.

    Article  PubMed  Google Scholar 

  12. Sorahan T, Prior P, Lancashire RJ, et al. Childhood cancer and parental use of tobacco: deaths from 1971 to 1976. Br J Cancer. 1997;76(11):1525–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Sorahan T, Lancashire RJ, Hulten MA, Peck I, Stewart AM. Childhood cancer and parental use of tobacco: deaths from 1953 to 1955. Br J Cancer. 1997;75(1):134–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Cocco P, Rapallo M, Targhetta R, Biddau PF, Fadda D. Analysis of risk factors in a cluster of childhood acute lymphoblastic leukemia. Arch Environ Health. 1996;51(3):242–4.

    Article  CAS  PubMed  Google Scholar 

  15. Poole C, Greenland S, Luetters C, Kelsey JL, Mezei G. Socioeconomic status and childhood leukaemia: a review. Int J Epidemiol. 2006;35(2):370–84.

    Article  PubMed  Google Scholar 

  16. Kheifets L, Ahlbom A, Crespi CM, et al. Pooled analysis of recent studies on magnetic fields and childhood leukaemia. Br J Cancer. 2010;103(7):1128–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kinlen LJ. An examination, with a meta-analysis, of studies of childhood leukaemia in relation to population mixing. Br J Cancer. 2012;107(7):1163–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Greaves M. Infection, immune responses and the aetiology of childhood leukaemia. Nat Rev Cancer. 2006;6(3):193–203.

    Article  CAS  PubMed  Google Scholar 

  19. Jourdan-Da Silva N, Perel Y, Mechinaud F, et al. Infectious diseases in the first year of life, perinatal characteristics and childhood acute leukaemia. Br J Cancer. 2004;90(1):139–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chan LC, Lam TH, Li CK, et al. Is the timing of exposure to infection a major determinant of acute lymphoblastic leukaemia in Hong Kong? Paediatr Perinat Epidemiol. 2002;16(2):154–65.

    Article  PubMed  Google Scholar 

  21. McKinney PA, Juszczak E, Findlay E, Smith K, Thomson CS. Pre- and perinatal risk factors for childhood leukaemia and other malignancies: a Scottish case control study. Br J Cancer. 1999;80(11):1844–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Perrillat F, Clavel J, Auclerc MF, et al. Day-care, early common infections and childhood acute leukaemia: a multicentre French case-control study. Br J Cancer. 2002;86(7):1064–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Rudant J, Orsi L, Menegaux F, et al. Childhood acute leukemia, early common infections, and allergy: the ESCALE Study. Am J Epidemiol. 2010;172(9):1015–27.

    Article  PubMed  Google Scholar 

  24. Roman E, Simpson J, Ansell P, et al. Childhood acute lymphoblastic leukemia and infections in the first year of life: a report from the United Kingdom childhood cancer study. Am J Epidemiol. 2007;165(5):496–504.

    Article  CAS  PubMed  Google Scholar 

  25. Crouch S, Lightfoot T, Simpson J, Smith A, Ansell P, Roman E. Infectious illness in children subsequently diagnosed with acute lymphoblastic leukemia: modeling the trends from birth to diagnosis. Am J Epidemiol. 2012;176(5):402–8.

    Article  PubMed  Google Scholar 

  26. Chang JS, Tsai CR, Tsai YW, Wiemels JL. Medically diagnosed infections and risk of childhood leukaemia: a population-based case-control study. Int J Epidemiol. 2012;41(4):1050–9.

    Article  PubMed  Google Scholar 

  27. Urayama KY, Ma X, Selvin S, et al. Early life exposure to infections and risk of childhood acute lymphoblastic leukemia. Int J Cancer. 2011;128(7):1632–43.

    Article  CAS  PubMed  Google Scholar 

  28. Ma X, Buffler PA, Wiemels JL, et al. Ethnic difference in daycare attendance, early infections, and risk of childhood acute lymphoblastic leukemia. Cancer Epidemiol Biomark Prev. 2005;14(8):1928–34.

    Article  Google Scholar 

  29. Neglia JP, Linet MS, Shu XO, et al. Patterns of infection and day care utilization and risk of childhood acute lymphoblastic leukaemia. Br J Cancer. 2000;82(1):234–40.

    Article  CAS  PubMed  Google Scholar 

  30. Cardwell CR, McKinney PA, Patterson CC, Murray LJ. Infections in early life and childhood leukaemia risk: a UK case-control study of general practitioner records. Br J Cancer. 2008;99(9):1529–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Vestergaard TR, Rostgaard K, Grau K, Schmiegelow K, Hjalgrim H. Hospitalisation for infection prior to diagnosis of acute lymphoblastic leukaemia in children. Pediatr Blood Cancer. 2013;60(3):428–32.

    Article  PubMed  Google Scholar 

  32. MacArthur AC, McBride ML, Spinelli JJ, Tamaro S, Gallagher RP, Theriault GP. Risk of childhood leukemia associated with vaccination, infection, and medication use in childhood: the cross-Canada childhood leukemia study. Am J Epidemiol. 2008;167(5):598–606.

    Article  PubMed  Google Scholar 

  33. Urayama KY, Buffler PA, Gallagher ER, Ayoob JM, Ma X. A meta-analysis of the association between day-care attendance and childhood acute lymphoblastic leukaemia. Int J Epidemiol. 2010;39(3):718–32.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Kwan ML, Buffler PA, Abrams B, Kiley VA. Breastfeeding and the risk of childhood leukemia: a meta-analysis. Public Health Rep. 2004;119(6):521–35.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Martin RM, Gunnell D, Owen CG, Smith GD. Breast-feeding and childhood cancer: a systematic review with metaanalysis. Int J Cancer. 2005;117(6):1020–31.

    Article  CAS  PubMed  Google Scholar 

  36. Kwan ML, Buffler PA, Wiemels JL, et al. Breastfeeding patterns and risk of childhood acute lymphoblastic leukaemia. Br J Cancer. 2005;93(3):379–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Rudant J, Amigou A, Orsi L, et al. Fertility treatments, congenital malformations, fetal loss, and childhood acute leukemia: the ESCALE study (SFCE). Pediatr Blood Cancer. 2013;60(2):301–8.

    Article  PubMed  Google Scholar 

  38. Von Behren J, Spector LG, Mueller BA, et al. Birth order and risk of childhood cancer: a pooled analysis from five US States. Int J Cancer. 2011;128(11):2709–16.

    Article  Google Scholar 

  39. Hjalgrim LL, Rostgaard K, Hjalgrim H, et al. Birth weight and risk for childhood leukemia in Denmark, Sweden, Norway, and Iceland. J Natl Cancer Inst. 2004;96(20):1549–56.

    Article  PubMed  Google Scholar 

  40. Dockerty JD, Draper G, Vincent T, Rowan SD, Bunch KJ. Case-control study of parental age, parity and socioeconomic level in relation to childhood cancers. Int J Epidemiol. 2001;30(6):1428–37.

    Article  CAS  PubMed  Google Scholar 

  41. Westergaard T, Andersen PK, Pedersen JB, et al. Birth characteristics, sibling patterns, and acute leukemia risk in childhood: a population-based cohort study. J Natl Cancer Inst. 1997;89(13):939–47.

    Article  CAS  PubMed  Google Scholar 

  42. Dorak MT, Pearce MS, Hammal DM, McNally RJ, Parker L. Examination of gender effect in birth weight and miscarriage associations with childhood cancer (United Kingdom). Cancer Causes Control. 2007;18(2):219–28.

    Article  PubMed  Google Scholar 

  43. Ma X, Metayer C, Does MB, Buffler PA. Maternal pregnancy loss, birth characteristics, and childhood leukemia (United States). Cancer Causes Control. 2005;16(9):1075–83.

    Article  PubMed  Google Scholar 

  44. Altieri A, Castro F, Bermejo JL, Hemminki K. Number of siblings and the risk of lymphoma, leukemia, and myeloma by histopathology. Cancer Epidemiol Biomark Prev. 2006;15(7):1281–6.

    Article  Google Scholar 

  45. Schuz J, Kaatsch P, Kaletsch U, Meinert R, Michaelis J. Association of childhood cancer with factors related to pregnancy and birth. Int J Epidemiol. 1999;28(4):631–9.

    Article  CAS  PubMed  Google Scholar 

  46. Oksuzyan S, Crespi CM, Cockburn M, Mezei G, Kheifets L. Birth weight and other perinatal factors and childhood CNS tumors: a case-control study in California. Cancer Epidemiol. 2013;37(4):402–9.

    Article  CAS  PubMed  Google Scholar 

  47. Rudant J, Lightfoot T, Urayama KY, et al. Childhood acute lymphoblastic leukemia and indicators of early immune stimulation: a childhood leukemia international consortium study. Am J Epidemiol. 2015;181(8):549–62.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Sly PD. The early origins of asthma: who is really at risk? Curr Opin Allergy Clin Immunol. 2011;11(1):24–8.

    Article  PubMed  Google Scholar 

  49. Midodzi WK, Rowe BH, Majaesic CM, Saunders LD, Senthilselvan A. Early life factors associated with incidence of physician-diagnosed asthma in preschool children: results from the Canadian early childhood development cohort study. J Asthma. 2010;47(1):7–13.

    Article  PubMed  Google Scholar 

  50. Mebrahtu TF, Feltbower RG, Greenwood DC, Parslow RC. Birth weight and childhood wheezing disorders: a systematic review and meta-analysis. J Epidemiol Community Health. 2015;69(5):500–8.

    Article  PubMed  Google Scholar 

  51. Kozyrskyj AL, Bahreinian S, Azad MB. Early life exposures: impact on asthma and allergic disease. Curr Opin Allergy Clin Immunol. 2011;11(5):400–6.

    Article  CAS  PubMed  Google Scholar 

  52. Dietert RR. Maternal and childhood asthma: risk factors, interactions, and ramifications. Reprod Toxicol. 2011;32(2):198–204.

    Article  CAS  PubMed  Google Scholar 

  53. Lodge CJ, Allen KJ, Lowe AJ, et al. Perinatal cat and dog exposure and the risk of asthma and allergy in the urban environment: a systematic review of longitudinal studies. Clin Dev Immunol. 2012;2012:176484.

    Article  PubMed  Google Scholar 

  54. Wen W, Shu XO, Linet MS, et al. Allergic disorders and the risk of childhood acute lymphoblastic leukemia (United States). Cancer Causes Control. 2000;11(4):303–7.

    Article  CAS  PubMed  Google Scholar 

  55. Schuz J, Morgan G, Bohler E, Kaatsch P, Michaelis J. Atopic disease and childhood acute lymphoblastic leukemia. Int J Cancer. 2003;105(2):255–60.

    Article  CAS  PubMed  Google Scholar 

  56. Rosenbaum PF, Buck GM, Brecher ML. Allergy and infectious disease histories and the risk of childhood acute lymphoblastic leukaemia. Paediatr Perinat Epidemiol. 2005;19(2):152–64.

    Article  PubMed  Google Scholar 

  57. Soderberg KC, Jonsson F, Winqvist O, Hagmar L, Feychting M. Autoimmune diseases, asthma and risk of haematological malignancies: a nationwide case-control study in Sweden. Eur J Cancer. 2006;42(17):3028–33.

    Article  PubMed  Google Scholar 

  58. Linabery AM, Jurek AM, Duval S, Ross JA. The association between atopy and childhood/adolescent leukemia: a meta-analysis. Am J Epidemiol. 2010;171(7):749–64.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Dahl S, Schmidt LS, Vestergaard T, Schuz J, Schmiegelow K. Allergy and the risk of childhood leukemia: a meta-analysis. Leukemia. 2009;23(12):2300–4.

    Article  CAS  PubMed  Google Scholar 

  60. Olsen J, Melbye M, Olsen SF, et al. The Danish national birth cohort: its background, structure and aim. Scand J Public Health. 2001;29(4):300–7.

    Article  CAS  PubMed  Google Scholar 

  61. Bloom B, Jones LI, Freeman G. Summary health statistics for US children: national health interview survey, 2012. Vital Health Stat. 2013;10:1–88.

    Google Scholar 

  62. Kneyber MCJ, Steyerberg EW, de Groot R, Moll HA. Long-term effects of respiratory syncytial virus (RSV) bronchiolitis in infants and young children: a quantitative review. Acta Paediatr. 2000;89(6):654–60.

    Article  PubMed  Google Scholar 

  63. Jackson DJ, Gangnon RE, Evans MD, et al. Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children. Am J Respir Crit Care Med. 2008;178(7):667–72.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Inoue Y, Shimojo N. Epidemiology of virus-induced wheezing/asthma in children. Front Microbiol. 2013;4:391.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Greenland S, Sheppard AR, Kaune WT, Poole C, Kelsh MA. A pooled analysis of magnetic fields, wire codes, and childhood leukemia. Childhood Leukemia-EMF Study Group. Epidemiology. 2000;11(6):624–34.

    Article  CAS  PubMed  Google Scholar 

  66. Ahlbom A, Day N, Feychting M, et al. A pooled analysis of magnetic fields and childhood leukaemia. Br J Cancer. 2000;83(5):692–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Chang JS, Tsai YW, Tsai CR, Wiemels JL. Allergy and risk of childhood acute lymphoblastic leukemia: a population-based and record-based study. Am J Epidemiol. 2012;176(11):970–8.

    Article  PubMed  Google Scholar 

  68. Spector L, Groves F, DeStefano F, et al. Medically recorded allergies and the risk of childhood acute lymphoblastic leukaemia. Eur J Cancer. 2004;40(4):579–84.

    Article  CAS  PubMed  Google Scholar 

  69. Hughes AM, Lightfoot T, Simpson J, et al. Allergy and risk of childhood leukaemia: results from the UKCCS. Int J Cancer. 2007;121(4):819–24.

    Article  CAS  PubMed  Google Scholar 

Download references

Financial disclosures

This study was funded by the Electric Power Research Institute (grant EP-P44562).

Author information

Authors and Affiliations

  1. Department of Epidemiology, UCLA Fielding School of Public Health, 650 Charles E. Young Drive, Box 951772, Los Angeles, CA, 90095, USA

    Madhuri Sudan, Onyebuchi A. Arah & Leeka Kheifets

  2. Department of Epidemiology, Aarhus University, Bartholins Allé 2, Building 1260, 8000, Aarhus C, Denmark

    Jorn Olsen

Authors
  1. Madhuri Sudan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Onyebuchi A. Arah
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jorn Olsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Leeka Kheifets
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Madhuri Sudan.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sudan, M., Arah, O.A., Olsen, J. et al. Reported associations between asthma and acute lymphoblastic leukemia: insights from a hybrid simulation study. Eur J Epidemiol 31, 593–602 (2016). https://doi.org/10.1007/s10654-016-0126-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10654-016-0126-x

Keywords

Search

Navigation