Joint and interactive effects between health comorbidities and environmental exposures in predicting amyotrophic lateral sclerosis

Andrea Bellavia, Aisha S. Dickerson, Ran S. Rotem, Johnni Hansen, Ole Gredal, Marc G. Weisskopf

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Background: Amyotrophic lateral sclerosis (ALS) is a rare yet devastating neurodegenerative condition. The mechanisms leading to ALS are most certainly complex and likely involve a joint contribution of several factors with possible synergistic or antagonistic interactions. To provide a better understanding of the association between non-genetic factors and ALS, we evaluated the joint exposure to multiple health and environmental factors linked with ALS in our previous studies, also screening for high-dimensional interactions. Methods: We used data from a nested case-control study within the Danish population, with 1086 ALS cases from 1982 to 2009, jointly investigating 4 hospital-based diagnoses - diabetes, obesity, physical/stress trauma, cardiovascular disease (CVD) during 1977–2009; and 4 environmental exposures - lead, formaldehyde, diesel exhaust, and solvents, assessed from individual occupational history. All covariates were evaluated as ever/never exposed, and we used targeted machine learning techniques to screen for important joint predictors and interactions. These were then evaluated in a final logistic regression model adjusting for potential confounders (age, SES, geography). All analyses were stratified by sex. Results: Among men, trauma and solvents were associated with higher odds of ALS (OR = 1.55, 95% CI: 1.08–2.23; OR = 1.49, 95% CI: 1.17–1.89, respectively), and presented a negative interaction (OR = 0.49, 95% CI: 0.30–0.80). A positive diesel/CVD interaction was observed (OR = 1.56, 95% CI: 0.94–2.60). Among women, solvents, trauma, lead, and CVD were associated with higher odds of ALS, and a negative lead/solvents interaction was documented (OR = 0.52, 95% CI: 0.42–0.63). Conclusions: This study is one of the first attempts to evaluate joint and interactive effects of multiple risk factors on ALS, identifying potential synergistic and antagonistic mechanisms.

Original languageEnglish (US)
Article number113655
JournalInternational Journal of Hygiene and Environmental Health
StatePublished - Jan 2021


  • Amyotrophic lateral sclerosis
  • Combined effects
  • Interaction
  • Machine learning
  • Occupational exposures

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health


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