We constructed two separate datasets by merging data from the California Cancer Registry (CCR) and California vital statistics (birth) records to examine birth characteristics and familial cancer clustering, respectively.
Case-control analysis: We identified a total of 556 Ewing sarcoma cases who were born in California during 1978–2015, diagnosed with Ewing sarcoma (International Classification of Diseases for Oncology, 3rd edition, ICD-O-3 code: 9260) at the age of 0–35 years during 1988–2015, and reported to the CCR. Statewide birth records maintained by the California Department of Public Health were used to randomly select 50 times as many control subjects (n = 27,800) who are frequency-matched to the cases by year of birth; none of the controls had been diagnosed with any type of cancer up to the age of 35 years based on CCR records.
For all cases and controls, data on the following variables were retrieved from their birth records: sex, self-reported race and ethnicity (categorized here as non-Hispanic White, non-Hispanic Black, Hispanic/Latino, Asian/Pacific Islander, other), birthweight, gestational age, birth plurality, birth order, mode of delivery (vaginal or cesarean section), year of birth, maternal age, maternal education, mother’s place of birth (United States/foreign), history of miscarriage/stillbirth (yes/no), complication during pregnancy (yes/no), and maternal history of cesarean section (yes/no). A multivariable unconditional logistic regression analysis was performed with case status as the outcome and all birth characteristics described above as independent variables. Incorporation of variables one by one did not alter covariate associations more than 10%, suggesting a low degree of potential confounding. In addition, stratified analyses were performed for larger racial/ethnic groups (Hispanic and non-Hispanic White) and by age at diagnosis as well as histology subtype. Race/ethnicity was first delineated as Hispanic/non-Hispanic, and secondarily by race, using these two separate data fields on birth data. Therefore, “Hispanics” may include individuals of any self-reported race, and “non-Hispanics” include Whites, Blacks, Asian/Pacific Islanders, or other.
Family-based analysis: To assess potential familial aggregation that may reflect genetic predisposition to cancer, we ascertained the siblings of younger Ewing sarcoma patients (aged 0–19 years at diagnosis, 353 cases) from the statewide birth records in 1978–2015 and examined whether any of them had been diagnosed with any type of cancer per CCR record. We calculated standardized incidence ratios (SIR) as previously described (5) for siblings’ relative risk by dividing the observed number of cancer cases by the expected number of cases among siblings based on age-specific cancer incidence rates derived from the Surveillance, Epidemiology and End Results (SEER) program (6). Similar analyses were performed for comparison on additional sarcomas including osteosarcoma (ICD-O-3 codes: 9180-83, 9185-87, and 9192-95, 576 cases), rhabdomyosarcoma (ICD-O-3 codes: 8900-02, 8910, 8912, 8920, 8991, 719 cases), and synovial sarcoma (ICD-O-3 codes: 9040–9043, 127 cases).
All tests were two-sided with an alpha of 0.05 and were conducted using SAS Version 9.4 (SAS Inc. Cary, North Carolina).