Discussion
7.4 Strengths and limitations of the different study types and studies
Cohort, case-control, case-case and ecological studies all have different strengths and limitations.
Cohort studies generate potentially strong evidence, as the exposure can be repeatedly and objectively measured or assessed before the outcome occurs. These studies therefore do not suffer from recall bias. However, it is often difficult to perform cohort studies in the optimal way, as the investment in (preferably longitudinal) exposure measurements can be high and the cohort will have to be followed for a long time, up to several decades. The main cohort study in this evaluation (the Danish cohort study48,50-52,174) merely considered the
information has been gathered on the intensity and duration of use, such as the number of calls and the total duration of calls, as has been done in the case- control studies. Clearly the mere time that passed since a subscription started (which was also assessed in the case-control studies) is a less meaningful endpoint than an estimate of the amount of use, which is more directly associated with exposure.
Two other points need to be discussed with respect to the Danish cohort. The first is that business contracts were excluded from the ‘exposed’ group, since these subscriptions could not be related to individuals. This means that a number of business users, who are possibly among the heaviest users in the period before 1996, are included in the control group. The second issue is that the mobile phone use in the control group, the rest of the Danish population, also strongly increased after 1996. This means that in the later publications with longer follow- up there will be increasing misclassification in the control group. However, it can be demonstrated that, because there is no misclassification in the ‘exposed’ group, any misclassification in the control group has only limited effect on the calculated risk.152 Therefore the cohort study is potentially well suited to
examine risks also long after first use.
So, because a cohort is a strong study design and the score of the Danish cohort in the quality evaluation was good, the Committee considers the Danish cohort, despite the lack of actual exposure data, important for the overall evaluation.
The Committee considers the other cohort studies identified of little value for the overall data analysis, mainly because of the only short periods of follow-up, which are not relevant for very slow growing tumours.
Case-control studies are very efficient in their data collection, since they focus on new cases arising in a restricted time period. This has great advantages over cohort studies, especially in case of relatively rare diseases such as brain tumours, where large cohorts are needed to obtain sufficient cases. However, exposure assessment in case-control studies is always retrospective, therefore these studies potentially suffer from some major sources of bias, as discussed in Chapter 4. The main case-control studies identified in this analysis are those from the Hardell group and the INTERPHONE studies. The other case-control studies have much lower overall ‘exposure’ and considered much shorter times since first phone use. They are therefore not really relevant under the assumption of the Committee that, if there would be a risk associated with mobile phone use,
The Committee considers the INTERPHONE studies to be prone to selection bias due to the overall relatively low response rates. Because these are also lower for the controls than for the cases, this might lead to differential misclassification bias. The Hardell studies reported higher response rates and smaller differences in response rates between cases and controls than the INTERPHONE studies. These response rates were for the controls still higher than the response rates in the Swedish part of INTERPHONE (see 5.1). So also on the basis of the recalculated response rates, the Hardell studies are less likely to suffer from selection bias than the INTERPHONE studies, but the response rates in especially the Hardell controls are unusually high.
In both study protocols there is also the possibility of observer bias. The interviews of the INTERPHONE studies were all done in person at the participants’ home. In spite of the training of the interviewers, they might in some way have been unknowingly influenced by the case or control status of the subjects. This is also the case with the Hardell studies. Although in these studies the initial information has been gathered by postal questionnaire, all participants received a follow-up interview by phone. The investigators state that this was conducted in a blinded fashion, but during the interview disease status may well have become known. So observer bias is not a likely explanation for any differences in outcomes between the two studies.
Both the Hardell and INTERPHONE studies are also inherently prone to recall bias. A recent publication evaluated a subsample of the INTERPHONE study with the aim of improving the exposure assessment by taking the location of the tumour relative to the preferred position of the mobile phone into
consideration.114 However, as this still relies on recall of both the position of the
phone and the extent of its use, it is a refinement of the analysis but it does not solve the fundamental problem of recall bias.
The Committee has spent a great deal of effort in systematically assessing the methodological quality of the various studies (see Chapter 5) and the issue of bias discussed above plays an important role in that analysis. It did not result in any major differences in quality between the two main research groups, Hardell and INTERPHONE. The overall rating of the Hardell studies was 7.6 for the glioma + meningioma and the acoustic neuroma studies, and 6.7 and 7.4 for the parotid gland tumour studies. For INTERPHONE the ratings were 6.7
(glioma+meningioma), 7.2 (acoustic neuroma), and 6.7 and 6.5 (parotid gland tumours) (Table 5.1). However, this quality analysis has not taken into account a number of issues relating to internal and external consistency.
The first issue is that of the cordless phones. In view of the lower exposure resulting from the use of these phones in comparison to mobile phones as discussed in 7.3, the Committee considers it highly unlikely that similar odds ratios would be observed, as was the case in the Hardell studies. But, as discussed earlier, an explanation for these findings might also be that there is a correlation between the use of mobile and cordless phones.
The second issue is that of the increased risks observed by Hardell et al. at very short usage times. These are unlikely in view of the presumably very long latency times of the tumours under consideration. Also, if these increased risks were true, increased incidences in the ecological studies would be expected, but these were not observed.
According to the Committee these issues cast some doubt on the validity of the Hardell et al. studies.
Another point that is important to take into account is the fact that the Hardell et al. studies are performed in only one country (Sweden), while the
INTERPHONE studies cover 16 areas in 13 countries, thus covering a much broader population. The total numbers of cases and controls are also lower in the Hardell et al. studies compared to INTERPHONE (Table 7.1).
Effectively this comparison can only be made for the glioma studies. It should also be born in mind that for the full data set the age ranges are dissimilar. As the incidence of brain tumours is very much age-dependent, this is a major issue and a direct comparison between the Hardell and INTERPHONE data should only be made with the age-limited Hardell dataset that has the same age range as the INTERPHONE dataset. This effectively limits this comparison to the highest categories for ‘Time since first use’ and ‘Cumulative call time’. In the studies on other tumours, Hardell et al. always make a distinction between users of cordless and mobile phones, with sometimes also a division between analogue and digital mobile phones. The numbers for these categories are sometimes provided, but there is overlap when subjects have used more than one type of phone, and the overall total numbers are not provided.
Table 7.1 Comparison of numbers of cases and controls in the Hardell and INTERPHONE studies.
Hardell66,165 INTERPHONE93
Cases / controls Cases / controls Glioma Time since first use 529 / 963 (20-80 yrs) 1666 / 1894 (30-59 yrs)
Cumulative call time 529 / 963 (20-80 yrs) 1666 / 1894 (30-59 yrs) Glioma 30-59 yrs Time since first use ≥10 yrs 56 / 74 252 / 232
In summary, there is doubt on the internal and external consistency of the Hardell data on account of (1) the increased risk observed already with very short usage times; (2) the unusually high response rates in the controls; and (3) the increased risks observed for cordless phone use, again in some cases for very short usage time. For these reasons, in combination with the lower numbers of subjects, the Committee has given the Hardell et al. studies less weight than the INTERPHONE studies in the overall analysis and conclusions.
Case-case studies are potentially powerful, as they are less likely to suffer from selection and observer bias. There will of course still be recall bias, but this will be non-differential, since only patients are involved. However, case-case studies are limited because they are often single-hospital based and thus will have very limited numbers of cases for rare diseases such as brain cancers. This applies to all the case-case studies discussed in this report, with the exception of the multi- hospital study by Sato et al. (2010)112 that included 1589 cases, and two
subsamples of the INTERPHONE study that have been analysed in a case-case fashion, including respectively 2692147 and 888 cases.113
Ecological studies are inherently limited in their interpretation, since individual exposure is not determined. Instead, these studies investigate trends in the incidence (or prevalence) of disease and, in this case, the development of the number of mobile phone subscriptions. However, as indicated, for the tumours considered in this report there is only limited information on the latency time. Exposure-effect relationships cannot be derived from ecological studies. At best, they can show a similarity in trends in increase of disease and phone use. Absence of an increase in disease incidence following an increase in mobile phone possession (and presumed use) does not prove the absence of a causal relation between exposure and disease, but might give support to it when the period of strong increase in phone use is a decade or longer in the past, if it is assumed that the latency period is more than a decade. If the latency would be a decade or less, an increased risk would have been expected in the trends by now.