Student’s t test was used for continuous variables, and the Chi-square test for categorical variables to compare differences between cases and controls. Unconditional logistic regression was used to calculate multivariable-adjusted odds ratios (ORs) as estimates of the relative risk and related 95% confidence intervals (95% CIs) for analgesics use. Potential confounders fell into 2 groups: those variables that (1) a priori were thought to be related to the exposure and also were risk factors for ovarian cancer and (2) those variables that previously published studies considered confounders. Confounders included the following: age (at reference year); interview year; region of residence (western Pennsylvania, eastern Ohio, and western New York); education; race; religion; parity; breastfeeding; history of infertility; contraceptive use and duration; menstrual status (age at menarche, menopausal status and age at menopause); use of postmenopausal hormone and duration; indications for aspirin, NA-NSAIDs, or acetaminophen use; prior hysterectomy or tubal ligation; history of endometriosis; history of pelvic inflammatory disease; family history of breast cancer or ovarian cancer in first-degree relative; body mass index; cigarette smoking; alcohol consumption; comorbidities; and yearly household income.
Data were analyzed initially by constructing frequency counts of cases and controls by exposure variables and calculating ORs adjusted for age, region of residence, and interview year (Table 1 ). Second, confounders were forced into the models but were kept in the final regression model only if they changed the parameter estimates by at least 15%. The final multivariate model included age, region of residence, interview year, race, education, breastfeeding, numbers of full-term births, duration of oral contraceptive use, body mass index, postmenopausal hormone use, prior tubal ligation, arthritis, and diabetes (Tables 2 –4 ). For the primary analyses of NSAIDs, women who had never used aspirin or NA-NSAIDs on a regular basis were the referent group. Risk was assessed separately among the subgroups of women who had used aspirin only, NA-NSAIDs only, and any NSAIDs (aspirin plus NA-NSAIDs). For the acetaminophen analyses, nonusers were considered as never having used acetaminophen regularly (but did not exclude aspirin or NA-NSAIDs use) before the reference date.
Duration of use was defined by three indicators as follows: (1) continuous (had used for at least 1 year and until or beyond the reference date); (2) current (used only less than a year and used on the reference date); and (3) past (discontinued use at least 1 year before the reference date). To examine dose-response effects, the average daily dose was calculated by multiplying the number of dosage forms per day with the strength of the medication taken during the most recent period before the reference date. For aspirin, the average daily dose was converted to a standardized daily dose by dividing it by 325 mg, assuming it was used as antithrombotic therapy for cardiovascular disease based on the dosage suggested by American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.13 (link) For NA-NSAIDs and acetaminophen, the average daily dose was then converted to a standardized daily dose by dividing it into minimal effective analgesic doses per day.14 (link) The minimal effective analgesic doses per day for individual agents were as follows: acetaminophen (1500 mg), celecoxib (200 mg), diclofenac (100 mg), etodolac (400 mg), fenoprofen (800 mg), flurbiprofen (150 mg), ibuprofen (1200 mg), indomethacin (75 mg), ketorolac (40 mg), ketoprofen (75 mg), mecolfenamate (150 mg), meloxicam (7.5 mg), nabumetone (1000 mg), naproxen (500 mg), piroxicam (20 mg), rofecoxib (25 mg), tolmetin (600 mg), sulindac (300 mg), and valdecoxib (10 mg).15 (link)–17 Dosages were categorized into three clinically relevant categories: low-dose (≤ 0.5 standardized daily dose), moderate-dose (0.5–1 standardized dose) and high-dose (> 1 standardized dose).14 (link) Morever, the subgroup analyses were conducted by recency of use (e.g., age at first/last time use), self-reported indication and two types of NA-NSAIDs (i.e., non-selective NA-NSAIDs and selective COX-2 inhibitors). For the analysis on indications for analgesics, women who used different analgesics or the same analgesics but for different indications were considered separately. Analyses were also conducted separately among women with borderline and invasive epithelial ovarian tumors, and various histologic subgroups (i.e., serous, mucinous, endometrioid, clear cell, mixed cell and other epithelial cells); age less than 55 and 55 or more years; with and without arthritis; and with and without diabetes.
All analyses were carried out using STATA, version 11.0, statistical package (StataCorp LP, College Station, Texas, USA).
Data were analyzed initially by constructing frequency counts of cases and controls by exposure variables and calculating ORs adjusted for age, region of residence, and interview year (
Duration of use was defined by three indicators as follows: (1) continuous (had used for at least 1 year and until or beyond the reference date); (2) current (used only less than a year and used on the reference date); and (3) past (discontinued use at least 1 year before the reference date). To examine dose-response effects, the average daily dose was calculated by multiplying the number of dosage forms per day with the strength of the medication taken during the most recent period before the reference date. For aspirin, the average daily dose was converted to a standardized daily dose by dividing it by 325 mg, assuming it was used as antithrombotic therapy for cardiovascular disease based on the dosage suggested by American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.13 (link) For NA-NSAIDs and acetaminophen, the average daily dose was then converted to a standardized daily dose by dividing it into minimal effective analgesic doses per day.14 (link) The minimal effective analgesic doses per day for individual agents were as follows: acetaminophen (1500 mg), celecoxib (200 mg), diclofenac (100 mg), etodolac (400 mg), fenoprofen (800 mg), flurbiprofen (150 mg), ibuprofen (1200 mg), indomethacin (75 mg), ketorolac (40 mg), ketoprofen (75 mg), mecolfenamate (150 mg), meloxicam (7.5 mg), nabumetone (1000 mg), naproxen (500 mg), piroxicam (20 mg), rofecoxib (25 mg), tolmetin (600 mg), sulindac (300 mg), and valdecoxib (10 mg).15 (link)–17 Dosages were categorized into three clinically relevant categories: low-dose (≤ 0.5 standardized daily dose), moderate-dose (0.5–1 standardized dose) and high-dose (> 1 standardized dose).14 (link) Morever, the subgroup analyses were conducted by recency of use (e.g., age at first/last time use), self-reported indication and two types of NA-NSAIDs (i.e., non-selective NA-NSAIDs and selective COX-2 inhibitors). For the analysis on indications for analgesics, women who used different analgesics or the same analgesics but for different indications were considered separately. Analyses were also conducted separately among women with borderline and invasive epithelial ovarian tumors, and various histologic subgroups (i.e., serous, mucinous, endometrioid, clear cell, mixed cell and other epithelial cells); age less than 55 and 55 or more years; with and without arthritis; and with and without diabetes.
All analyses were carried out using STATA, version 11.0, statistical package (StataCorp LP, College Station, Texas, USA).
