Brain Tumour Risk in Relation to Mobile Telephone Use: Results of the INTERPHONE International Case-control Study

The INTERPHONE Study Group

Disclosures

Int J Epidemiol. 2010;39(3):675-694. 

In This Article

Methods

Study Design

The INTERPHONE study is an international, largely population-based case–control study. The common core study protocol is described in detail elsewhere.[5,26] Sixteen study centres from 13 countries (Australia, Canada, Denmark, Finland, France, Germany, Israel, Italy, Japan, New Zealand, Norway, Sweden and the UK) were included. To maximize statistical power, the INTERPHONE study focussed on tumours in younger people, 30–59 years of age, as they were expected to have had the highest prevalence of mobile phone use in the previous 5–10 years, and on regions likely to have the longest and highest use of mobile phones (mainly large urban areas).

Eligible cases were all patients with a glioma or meningioma of the brain diagnosed in the study regions during study periods of 2–4 years between 2000 and 2004. Cases were ascertained from all neurological and neurosurgical facilities in the study regions (except in Paris and Tokyo where some did not agree to participate), and in some centres also from cancer registries. All diagnoses were histologically confirmed or based on unequivocal diagnostic imaging. To facilitate interviews soon after diagnosis, cases were ascertained actively within treatment facilities wherever possible. Completeness of ascertainment was checked through secondary sources, such as population- or hospital-based cancer registries, medical archives and hospital discharge or billing files.[26]

One control was selected for each case from a locally appropriate population-based sampling frame, except in Germany where two controls were chosen. The sampling procedure involved individual matching in seven centres (Canada – Ottawa, Canada – Vancouver, France, Israel, Japan, New Zealand and UK North) and frequency matching elsewhere. The matching variables were age (within 5 years), sex and region of residence within each study centre. In Israel, the subjects were also matched on ethnic origin. Where stratified matching had been used, individual matching was conducted post hoc, with cases being assigned one control (two in Germany), interviewed as close as possible in time to the case, from those who fitted the matching criteria.

Detailed information on past mobile phone use was collected during face-to-face interviews with the study subject, or a proxy, if the subject had ever been a regular user of a mobile phone (had an average of at least one call per week for a period of ≥6 months).[26] A proxy was sought when the study subject had died or was too ill to be interviewed. The interviews were conducted by a trained interviewer using a computer-assisted questionnaire, except in Finland where a paper version was used. The questionnaire also included sections on socio-demographic factors, occupational exposure to electromagnetic fields and ionizing radiation, medical history (subject's and family), medical ionizing and non-ionizing radiation exposure and smoking. For cases, information was also collected on the anatomic location and histological type of the tumours. Where possible, location data were obtained from magnetic resonance imaging (MRI) reports or images; they were otherwise obtained from surgical records or clinical notes. Details of the specific source for each case were not recorded in the INTERPHONE database. Those collecting the data did not know the reported mobile phone use of individual cases.

Statistical Methods

Data from countries with multiple centres were combined for the analyses, except in the UK where the UK South and UK North, each with large numbers of subjects, were kept separate. The word 'centre' in the remainder of this article is used to refer to the 14 analytic entities (12 countries, UK North and UK South). All analyses were carried out for all centres combined and for each centre separately. Formal tests for heterogeneity of risk across centres were conducted by allowing for an interaction between centre and the exposure variables.

The analyses presented here focus on past mobile phone use as reported by or for the study subjects. The main analyses were based on conditional logistic regression for matched sets.[27] The date of diagnosis of the case was used as the reference date for cases and controls in each matched set. For the main analyses, the reference category for odds ratios (ORs) was the set of subjects who reported that they had never been regular users. Exposure variables included ever having been a regular user (as defined above), time (years) since first regular use, cumulative number of calls and cumulative duration of calls. To allow for a latency period of 1 year, the year before the reference date was included in the reference category for time since first regular use and all other exposure variables were censored at 1 year before the reference date. Cumulative number and duration of calls were analysed as categorical variables, based on deciles of the distribution of these variables among all controls who were regular users, including those matched to patients with an acoustic neuroma or a parotid gland tumour, so that the same cut-off points are used in all analyses.[26] Cumulative use excluded use of mobile phones with hands-free devices: for all time periods for which the subject reported the use of hands-free devices the amount of use was reduced by 100, 75, 50 or 25% depending on whether hands-free devices were used always or almost always, more than half, about half or less than half of the time, respectively. For ease of presentation, some results are shown for the following grouping of deciles: 1, 2–5, 6–7, 8–9 and 10, chosen post hoc to reflect the spread of the highly skewed distribution of these variables. For convenience, we will systematically use the term 'regular user' in text and tables to refer to ever having been a regular user.

The reference group for these analyses, never regular users, included people who had some mobile phone use but never as much as one call a week on average for ≥6 months (~32% of meningioma and 26% of glioma cases, and 30% of meningioma and 26% of glioma controls) and people who had never used a mobile phone (~11% of meningioma and 9% of glioma cases, and 8% of meningioma and 6% of glioma controls). These percentages are approximate because never use and never regular use were defined at different dates; the reference date and the date of interview, respectively. We are not able to determine whether inclusion of subjects with some occasional mobile phone use in the reference group had a material effect on our results because this difference in definition dates prevented us from distinguishing participants with only occasional use from those with no use at all at their reference dates. Moreover, because numbers of never users at the date of interview were small, particularly in certain age- and gender-specific sub-groups (such as young men), never users were not a suitable reference group for this analysis.

All analyses were adjusted for educational level; an a priori decision had been made to adjust for it as a surrogate for socio-economic status (SES). Creation of consistent educational levels across the 13 countries is described elsewhere.[26] In practice, this adjustment had little impact on OR estimates, changing their values by ≤2% in most instances and in all cases by <5%. Using a 10% change-in-estimate criterion for confounding,[28] no other covariate among those collected (see list above) was included in the main analyses. The interval between the start date of interviews in the study centre and the date of each subject's interview was modelled by fitting the interaction of this interval with study centre.

A common protocol was applied to impute missing data for cases and controls.[26] The study questionnaire allowed ranges to be given instead of exact answers to a number of questions, including number and duration of calls and dates of start and end of mobile phone use; in such instances, the main analyses in this article were based on the mid-point of the reported range.

Because absorption of RF energy from mobile phones is highly localized,[29] three different types of analyses were conducted to account for tumour location. First, analyses were conducted by the anatomical lobe of the brain in which the tumour occurred. Secondly, separate analyses were conducted for the subjects who reported using the mobile phone mainly on one or the other side of the head, and the preferred side was compared with the side on which the tumour occurred. For this, each control was assigned the location of the tumour of his or her matched case. Exposure was considered to be ipsilateral if the phone was used predominantly on the same side as the tumour or on both sides of the head, and contralateral if used mainly on the side of the head opposite to the tumour. Laterality was not assigned if the tumour was reported to be centrally located (i.e. it crossed the midline of the brain); these cases were excluded from laterality analyses. Thirdly, case–case analyses were carried out on the concordance between tumour side and laterality of phone use using the method proposed by Inskip and collaborators.[18]

Sensitivity Analyses

To complement these primary analyses, we undertook sensitivity analyses to try to determine whether any of the following might have biased the results: (i) any study centre; (ii) required mention of mobile phones in the introductory letter to subjects in some centres; (iii) centres with a hospital-based design or particularly low participation rates; (iv) respondents whose interviews were considered by the interviewer to be of poor quality; (v) subjects for whom proxies provided the responses or a telephone interview was given; (vi) interviewers who had little experience or who had unbalanced case to control workloads; (vii) difference between the interview dates of cases and their matched controls (on average, each control was interviewed 3 months later than its matched case[26] and mobile phone use was increasing rapidly during the study period); (viii) subject's choice between two ways of responding to call time questions (time per day, week or month, or time per call); (ix) subjects who reported implausibly high amounts of mobile phone use (by excluding them or by retaining them and truncating their use at a specific lower value when they reported a higher one); (x) method of calculating accumulated call time; (xi) use of matching and conditional analysis; (xii) the choice of a particular imputation algorithm; and (xiii) adjustment for possible confounders.

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