A geospatiotemporal and causal inference epidemiological exploration of substance and cannabinoid exposure as drivers of rising US pediatric cancer rates [Dataset]

Background. Age-adjusted US total pediatric cancer incidence rates (TPCIR) rose 49% 1975-2015 for unknown reasons. Prenatal cannabis exposure has been linked with several pediatric cancers which together comprise the majority of pediatric cancer types. We investigated whether cannabis use was related spatiotemporally and causally to TPCIR.
Methods. State-based age-adjusted TPCIR data was taken from the CDC Surveillance, Epidemiology and End Results cancer database 2003-2017. Drug exposure was taken from the nationally-representative National Survey of Drug Use and Health, response rate 74.1%. Drugs included were: tobacco, alcohol, cannabis, opioid analgesics and cocaine. This was supplemented by cannabinoid concentration data from the Drug Enforcement Agency and ethnicity and median household income data from US Census.
Results. TPCIR rose while all drug use nationally fell, except for cannabis which rose. TPCIR in the highest cannabis use quintile was greater than in the lowest (β-estimate=1.31 (95%C.I. 0.82, 1.80), P=1.80x10-7) and the time:highest two quintiles interaction was significant (β-estimate=0.1395 (0.82, 1.80), P=1.00x10-14). In robust inverse probability weighted additive regression models cannabis was independently associated with TPCIR (β-estimate=9.55 (3.95, 15.15), P=0.0016). In interactive geospatiotemporal models including all drug, ethnic and income variables cannabis use was independently significant (β-estimate=45.67 (18.77, 72.56), P=0.0009). In geospatial models temporally lagged to 1,2,4 and 6 years interactive terms including cannabis were significant. Cannabis interactive terms at one and two degrees of spatial lagging were significant (from β-estimate=3954.04 (1565.01, 6343.09), P=0.0012). The interaction between the cannabinoids THC and cannabigerol was significant at zero, 2 and 6 years lag (from β-estimate=46.22 (30.06, 62.38), P=2.10x10-8). Cannabis legalization was associated with higher TPCIR (β-estimate=1.51 (0.68, 2.35), P=0.0004) and cannabis-liberal regimes were associated with higher time:TPCIR interaction (β-estimate=1.87x10-4, (2.9x10-5, 2.45x10-4), P=0.0208). 33/56 minimum e-Values were >5 and 6 were infinite.
Conclusion. Data confirm a close relationship across space and lagged time between cannabis and TPCIR which was robust to adjustment, supported by inverse probability weighting procedures and accompanied by high e-Values making confounding unlikely and establishing the causal relationship. Cannabis-liberal jurisdictions were associated with higher rates of TPCIR and a faster rate of TPCIR increase. Data inform the broader general consideration of cannabinoid-induced genotoxicity.

研究背景：年龄调整后的美国儿童总体癌症发病率（Total Pediatric Cancer Incidence Rates, TPCIR）在1975年至2015年间上升了49%，其具体原因至今不明。产前大麻暴露已被证实与数种儿童癌症存在关联，而这些癌症合计占儿童癌症类型的绝大多数。本研究旨在探讨大麻使用与TPCIR之间是否存在时空关联及因果关联。
研究方法：本研究的州级年龄调整TPCIR数据取自2003年至2017年美国疾病控制与预防中心（Centers for Disease Control and Prevention, CDC）的监测、流行病学与最终结果（Surveillance, Epidemiology and End Results, SEER）癌症数据库。药物暴露数据来自具有全国代表性的《全国药物使用与健康调查》，该调查的应答率为74.1%。所纳入的研究药物包括烟草、酒精、大麻、阿片类镇痛药及可卡因。本研究还补充了来自美国禁毒署（Drug Enforcement Administration, DEA）的大麻素浓度数据，以及来自美国人口普查局的种族与家庭收入中位数数据。
研究结果：全国范围内除大麻使用量呈上升趋势外，其余各类药物使用量均出现下降，与此同时TPCIR亦持续升高。大麻使用量最高五分位组的TPCIR显著高于最低五分位组（β估计值=1.31，95%置信区间[0.82, 1.80]，P=1.80×10^-7）；且时间与最高两个五分位组的交互效应具有统计学意义（β估计值=0.1395，95%置信区间[0.82, 1.80]，P=1.00×10^-14）。在稳健逆概率加权加性回归模型中，大麻使用与TPCIR存在独立关联（β估计值=9.55，95%置信区间[3.95, 15.15]，P=0.0016）。在纳入所有药物、种族与收入变量的时空地理交互模型中，大麻使用仍具有独立统计学意义（β估计值=45.67，95%置信区间[18.77, 72.56]，P=0.0009）。在时间滞后1、2、4及6年的地理空间模型中，包含大麻的交互项均具有统计学意义。空间滞后1阶与2阶的大麻交互项同样具有统计学意义（β估计值=3954.04，95%置信区间[1565.01, 6343.09]，P=0.0012）。大麻素四氢大麻酚（Tetrahydrocannabinol, THC）与大麻萜酚（Cannabigerol, CBG）的交互效应在滞后0、2及6年时均具有统计学意义（β估计值=46.22，95%置信区间[30.06, 62.38]，P=2.10×10^-8）。大麻合法化与更高的TPCIR存在关联（β估计值=1.51，95%置信区间[0.68, 2.35]，P=0.0004）；而大麻政策宽松的辖区则与更高的时间-TPCIR交互效应相关（β估计值=1.87×10^-4，95%置信区间[2.9×10^-5, 2.45×10^-4]，P=0.0208）。56个最小E值中有33个大于5，另有6个为无穷大。
研究结论：本研究数据证实，大麻使用与TPCIR之间存在紧密的时空及滞后时间关联，该关联经校正后依然稳健；逆概率加权分析亦支持这一结论，且较高的E值提示混杂偏倚的可能性极低，从而确立了二者的因果关系。大麻政策宽松的辖区与更高的TPCIR及更快的TPCIR增长速度相关。本研究数据可为大麻素诱导的遗传毒性这一更广泛的科学议题提供参考依据。