Early immune stimulation and childhood acute lymphoblastic leukemia in Costa Rica: A comparison of statistical approaches.
BACKGROUND
Although epidemiologic studies suggest that early immune stimulation is protective against childhood leukemia, evidence for this relationship is equivocal for Hispanic children, who are disproportionately affected by this disease. The complex biological processes underlying immune stimulation and leukemogenesis may benefit from novel statistical approaches that account for mixed exposures and their nonlinear interactions. In this study, we utilized targeted machine learning and traditional statistical methods to investigate the association of multiple measures of early immune stimulation with acute lymphoblastic leukemia (ALL) in Costa Rican children.


MATERIALS AND METHODS
We used data from a population-based case-control study conducted in Costa Rica (2001-2003). Cases of ALL (n = 240) were diagnosed in 1995-2000 (age >1 year and <15 years at diagnosis) and were identified through the National Cancer Registry and National Children's Hospital. Population controls (n = 578) were frequency-matched to cases by birth year and drawn from the National Birth Registry. Data on surrogate measures of early immune stimulation were collected through in-home interviews. We fitted multivariable models, utilizing targeted causal inference (varimpact), unconditional logistic regression, and latent class analysis (LCA).


RESULTS
In varimpact analysis, contact with any pet [risk difference (RD) = -0.17, 95% CI: -0.25, -0.10)] or any farm animal (RD = -0.07, 95% CI: -0.13, 0.00) and allergies (RD = -0.08, 95% CI: -0.17, 0.01) were associated with a reduced risk of ALL, whereas experiencing a fever longer than one week was associated with an increased risk (RD = 0.23, 95% CI: 0.12, 0.33). In unconditional logistic regression models, contact with any pet or farm animal and a complete vaccination scheme were inversely associated with odds of ALL (OR = 0.44, 95% CI: 0.31, 0.62; OR = 0.66, 95% CI: 0.49, 0.90; OR = 0.45, 95% CI: 0.24, 0.83; respectively), whereas experiencing a fever longer than one week was positively associated with ALL (OR = 2.44, 95% CI: 1.61, 3.70). Two-class and three-class LCA revealed a group with elevated risk for ALL whose exposure profile was mainly characterized by reduced exposure to pets and farm animals.


CONCLUSIONS
Using distinct statistical approaches, we observed that exposure to pets and farm animals was inversely associated with ALL risk, whereas having a fever longer than one week (a putative proxy of severe infection) was associated with an increased risk. For multifactorial diseases such as childhood leukemia, we recommend estimating the joint effects of multiple exposures by applying diverse statistical methods and interpreting their results together. Overall, we found support for the hypothesis that early immune stimulation offers protection against childhood ALL.
['Figueroa|Sophia Colombari|SC|', 'Kennedy|Chris J|CJ|', 'Wesseling|Catharina|C|', 'Wiemels|Joseph M|JM|', 'Morimoto|Libby|L|', 'Mora|Ana M|AM|']
D000818:Animals D000829:Animals, Domestic D016022:Case-Control Studies D002648:Child D003364:Costa Rica D006801:Humans D007223:Infant D016015:Logistic Models D057805:Pets D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma D012307:Risk Factors
Early immune stimulation Acute lymphoblastic leukemia Costa Rica Hispanic children Machine learning Childhood cancer