Study design
The two controls groups came from two independent case-control studies that were conducted in Kerman Province, in southeastern of Iran. It is noteworthy that the prevalence of cigarette smoking and opium use have been stable for the last decade, since, difference of the period of study is not affect out results [7, 21]. The methods for each study are briefly discussed below.
Neighborhood-based case-control study
From 2013 to 2015, a population-based case-control study (study I) was designed to determine the association of opium use and risk of bladder cancer. All bladder cancer cases who were residence of Kerman province, were able to speak Persian, had a histological diagnosis of cancer within one year prior to interview (incident cases), and were able to undergo an 80-minute interviewing, were eligible. Nursing and pregnant women were excluded. Data from two sources were used to identify and recruit the large majority of the bladder cancer cases: the Kerman Province cancer registry and records from a provincial-level referral hospital for treatment of cancer patients, resulting in enrollment of 308 bladder cancer cases. A total of 616 eligible controls (2:1 control-case ratio) were selected from residents of Kerman Province. Controls were cancer free and were individually matched to cases for gender, age (± 2 years), and residential place.
Matching by residential place was done by municipality district, using a predefined plan. Six houses were selected from the main street where the house of cases was located. The interviewers planned the order of approaching the houses. If no eligible controls were found in the first selected house, or the eligible controls refused to participate, the interviewers approached the second designated household, and so forth. This strategy was followed until two eligible controls were found for each case. In all, 62 (10%) invited potential controls refused to participate.
All interviews were done face-to-face in an environment that allowed for uninterrupted privacy. Data were collected using a structured questionnaire that included detailed questions on tobacco, opium use, demographic information, and other relevant data.
Hospital-based case-control study
From 2016 to 2018, a multicenter case-control study-Iran Opium and Cancer study (IROPICAN)- was designed and conducted to assess the association of the lung, colorectal, head and neck, and bladder cancers in ten provinces of Iran (study II), including Kerman Province. We used data from controls selected in Kerman Province. Cases were cancer patients admitted to one of three referral cancer care centers in Kerman. Eligibility criteria were the same as the previous study, i.e., being Iranian, having received a histological diagnosis of cancer within one year prior to the study, ability to speak Persian, and ability to interview for 80 minutes. Women who were nursing or pregnant were not eligible.
Potential controls were hospital visitors who were relatives or friends of hospitalized patients in non-oncology wards, or those who visited the hospital for any reasons other than receiving treatment. Further eligibility criteria were the same as those set for cases, except that the controls had to be absolutely free of any history of cancer. A total of 414 hospital visitors were asked to participate as controls, of whom 25 (6%) refused to participate. The controls were frequency-matched to cases by age (five-year intervals; 30 to 75 + groups), gender, and residential place (Kerman city residence and non-Kerman residence). Trained interviewers gathered tobacco and opium use data at the hospital, in face-to-face interviews using structured questionnaires.
Opium Use Data
Opium use was self-reported in both studies. In a previous validation study, we found a high level of sensitivity (77%) for self-reported opium use among visitor controls, using thin layer chromatography (TLC) as the gold standard [9]. Regular opium users defined as consuming opium at least once a week for at least a six-month consecutive period during the subjects’ lifetime. A similar definition was used for regular cigarette smoking.
Statistical Analysis
The two primary exposures of interest were opium use and cigarette smoking in neighborhood and visitor controls. Data were categorized and presented by gender, age, socio-economic status (SES). An overall SES score was determined by combining years of education (continuous variable) and some assets (dichotomous variables; washing machine, freezer, personal computer, sofa, vacuum cleaner, dishwasher, split air conditioner, owned house, owned car, sponsored by charitable /supporting organizations, complementary insurance), using principal components analysis. We used chi-square test to compare proportions between groups.
Analyses were done for all subjects together, by subgroups, and for only men. An analysis for men only was useful because: 1) rates of cigarette smoking and opium use were substantially lower in women, leading to random error; 2) the use of cigarette smoking may be associated with stigma among women but not in men.
We estimated a logistic regression that included type of controls (neighborhoods/visitors) as the dependent variable and gender, education, age, SES, the area of residence, opium regular use (yes/no), and cigarette smoking for adjustment.
A P-value of less than 0.05 was considered statistically significant. All analyses were performed using STATA (version 12; Stata Corp, College Station, TX, USA).