Extended Data Fig. 1.

Power analysis and statistical simulation of case-control study.

a, Estimated effect of increasing fraction of brain metastasis patients in TCGA-LUAD on statistical power to detect metastatic drivers at different mutation frequency levels in BM-LUAD. The driver mutation frequency is assumed to be 1% among TCGA-LUAD patients who do not develop brain metastasis (true controls). Power is calculated for testing an increase in driver mutation frequency among cases compared to controls at a significance level of 0.05. Observations are assumed to be independent and identically distributed.

b, Simulated effect of increasing fraction of brain metastasis patients in TCGA-LUAD on false positive rate for detecting metastatic drivers at different mutation frequency levels. Each data point represents a simulation of 100 experiments under the null hypothesis (i.e. the mutation frequency among patients who never develop brain metastasis is equal to the mutation frequency among brain metastasis patients).

Significance level is set to 0.05. Vertical line represents the estimated fraction of brain metastasis patients in TCGA-LUAD, and shaded region represents the 95% confidence interval, as determined using a mixed effect meta-analysis binomial regression accounting for immunohistological subtype, TNM stage, EGFR mutation status, race, smoking status, gender, and age under an errors-in-variables model to allow for missing or uncertain data.