Flow chart of patients included in this analysis. A total of 1883 patients were treated with HDMTX on P9904 and P9905, and 1588 were eligible and had germline DNA evaluable. Patients who had congenital abnormalities (usually Down syndrome) were excluded because they may not have received the full methotrexate dose. Patients with implausible or no evaluable methotrexate plasma concentrations were excluded (see “Methods” for details).