Table 3.

Analyses planned in CIRT-AE.

Incidence rates and relative risk (LDM vs. placebo) of AEs to establish LDM toxicity
Exposures	Outcomes	Statistical analyses
Study drug assignment: Low dose methotrexate (LDM) Placebo (reference group)	Any AE Severe AE Hepatic Infectious Pulmonary Hematologic Mucocutaneous Cancer Hemorrhagic Neurologic Musculoskeletal Renal Gastrointestinal Other systems and subgroups of categories pending sufficient numbers of outcomes	-Cumulative incidence rates with 95% confidence intervals -Kaplan-Meier curves with log-rank tests -Cox proportional hazards model for first event analyses (reference: placebo) -Poisson models for number of event analyses (reference: placebo)
Risk factors for AEs
Exposures	Outcomes	Statistical analyses
Sociodemographics Comorbidities Cigarette smoking Alcohol intake Body mass index Hyperlipidemia Concurrent medications Baseline hepatic, renal, or pulmonary disease Genetics MTXglu level* Others pending sufficient numbers of outcomes in relevant exposure categories	Any AE Severe AE Hepatic Infectious Pulmonary Hematologic Mucocutaneous Cancer Hemorrhagic Neurologic Musculoskeletal Renal Gastrointestinal MTXglu level* Other systems and subgroups of categories pending sufficient numbers of outcomes	-Descriptive baseline analyses comparing those with toxicity to those without -Cox regression models for first event analyses -Poisson models for number of event analyses -Genome-wide association study controlling for population stratification by principal components -Investigation of candidate genes associated with LDM toxicity in prior studies -LDM-placebo interaction analyses if association found among both LDM and placebo arms -Mediation analyses for risk factors associated with both MTXglu levels and toxicity outcomes
Risk prediction rules for AEs
Development and validation	Outcomes	Statistical analyses
-Development group: two-third of LDM arm -Validation group: one-third of LDM arm -Predictors associated with AEs will be considered	Any AE Severe AE Hepatic Infectious Pulmonary Hematologic Mucocutaneous Cancer Hemorrhagic Neurologic Musculoskeletal Renal Gastrointestinal Other systems and subgroups of categories pending sufficient numbers of outcomes	-Exposure-treatment interactions to evaluate heterogeneity of treatment effect -Goodness-of-fit of models: Nagelkerke R2 and areas under the receiver operating characteristic curves (AUCs) -Re-classification in models: Integrated Discrimination Improvement and continuous Net Reclassification Improvement -Assignment of points for risk factors based on effect sizes in multivariable analyses; validating cutpoints for absolute risk categories of low/moderate/high risk of LDM toxicity

^*MTX_glu levels are measured among those who were taking LDM at the month 8 visit.

AE, adverse event; AUC, areas under the receiver operating characteristic curve; LDM, low dose methotrexate; MTX_glu, methotrexate polyglutamate.