Causal inference multiple imputation investigation of the impact of cannabinoids and other substances on ethnic differentials in US testicular cancer incidence

Background: Ethnic differences in testicular cancer rates (TCRs) are recognized internationally. Cannabis is a known risk factor for testicular cancer (TC) in multiple studies with dose-response effects demonstrated, however the interaction between ancestral and environmental mutagenic effects has not been characterized. We examined the effects of this presumed gene-environment interaction across US states.

Methods: State based TCR was downloaded from the Surveillance Epidemiology and End Results (SEER) website via SEERStat. Drug use data for cigarettes, alcohol use disorder, analgesics, cannabis and cocaine was taken from the National Survey of Drug Use and Health a nationally representative study conducted annually by the Substance Abuse and Mental Health Services Administration (SAMHSA) with a 74.1% response rate. Cannabinoid concentrations derived from Drug Enforcement Agency publications. Median household income and ethnicity data (Caucasian-American, African-American, Hispanic-American, Asian-American, American-Indian-Alaska-Native-American, Native-Hawaiian-Pacific-Islander-American) was from the US Census Bureau. Data were processed in R using instrumental regression, causal inference and multiple imputation.

Results: 1975-2017 TCR rose 41% in African-Americans and 78.1% in Caucasian-Americans; 2003-2017 TCR rose 36.1% in Hispanic-Americans and 102.9% in Asian-Pacific-Islander-Americans. Ethnicity-based scatterplot-time and boxplots for cannabis use and TCR closely mirrored each other. At inverse probability-weighted interactive robust regression including drugs, income and ethnicity, ethnic THC exposure was the most significant factor and was independently significant (β-estimate = 4.72 (2.04, 7.41), P = 0.0018). In a similar model THC, and cannabigerol were also significant (both β-estimate = 13.87 (6.33, 21.41), P = 0.0017). In additive instrumental models the interaction of ethnic THC exposure with Asian-American, Hispanic-American, and Native-Hawaiian-Pacific-Islander-American ethnicities was significant (β-estimate = - 0.63 (- 0.74, - 0.52), P = 3.6 × 10^{- 29}, β-estimate = - 0.25 (- 0.32, - 0.18), P = 4.2 × 10^{- 13}, β-estimate = - 0.19 (- 0.25, - 0.13), P = 3.4 × 10^{- 9}). After multiple imputation, ethnic THC exposure became more significant (β-estimate = 0.68 (0.62, 0.74), P = 1.80 × 10^{- 92}). 25/33 e-Values > 1.25 ranging up to 1.07 × 10⁵. Liberalization of cannabis laws was linked with higher TCR's in Caucasian-Americans (β-estimate = 0.09 (0.06, 0.12), P = 6.5 × 10^{- 10}) and African-Americans (β-estimate = 0.22 (0.12, 0.32), P = 4.4 × 10^{- 5}) and when dichotomized to illegal v. others (t = 6.195, P = 1.18 × 10^{- 9} and t = 4.50, P = 3.33 × 10^{- 5}).

Conclusion: Cannabis is shown to be a TC risk factor for all ethnicities including Caucasian-American and African-American ancestries, albeit at different rates. For both ancestries cannabis legalization elevated TCR. Dose-response and causal relationships are demonstrated.