In this large pooled analysis of data from case-control studies, we found no significant association between birth order and sibship size and risk of NHL overall. However, significant positive associations were present for a number of B- and T-cell lymphoma subtypes. Substantial heterogeneity in study-specific risks was observed, which may reflect variations in the association by response rate, study population, and/or SES. The positive associations were confined to population-based studies, which had lower response rates in cases and controls, and were absent in hospital-based studies, which had higher response rates. After stratifying results by SES, the positive associations were present among persons of upper SES but not those of lower SES. The fact that the birth order association was confined to studies with lower response rates and to upper-SES participants and was not specific to particular B- or T-cell subtypes suggests that the previously reported positive association of NHL risk with birth order and sibship size in case-control studies may have been due to selection bias mediated by SES.
Selection bias may have arisen because of differential response rates by SES. In almost all developed countries, lower SES is strongly associated with a higher total fertility rate, and therefore with birth order of the offspring (31
). Although we did not have data on parental SES, the SES of parents correlates strongly with that of their children (34
), so participant SES is likely to be correlated with the participant's own birth order. Among controls in this study, increasing participant SES was strongly inversely correlated with the participant's own birth order (P
< 0.001). Low response rates increase the probability of selection bias. Thus, our finding that the positive association with birth order was confined to those studies with lower response rates is consistent with the association's being due to selection bias. However, low response rates do not in themselves cause selection bias (35
). Selection bias arises only if participation differs between exposed (or nonexposed) cases and exposed (or nonexposed) controls. A SES-related selection bias leading to a positive association between NHL risk and birth order can arise in 2 main ways. First, among controls, it can arise if the participation rate is higher among persons with a low birth order. Second, among cases, it can arise if the participation rate is higher among persons of high birth order. Because SES and birth order are correlated, this equates to a higher participation rate among high-SES controls than among low-SES controls or a higher participation rate among low-SES cases than among high-SES cases.
There is consistent evidence that in population-based case-control studies, the response rate is higher in high-SES controls than in low-SES controls. This has been shown for controls recruited through a variety of methods, including random digit dialing (36
), contact with their general practitioners (39
), and letter or telephone after random selection from health insurance (41
), electoral (42
), or census (43
) rolls. This selection bias would tend to generate a positive association between birth order and disease risk. However, this does not explain why the effect of birth order was most prominent in the high-SES stratum (), in which response rates are likely to be higher.
Since response rates are generally substantially lower in controls than in cases in population-based studies, there is less potential for selection bias to arise from factors associated with case selection. In case-control studies of cancer, the reasons for case nonparticipation are clearly different from the reasons for control nonparticipation. The most common reasons include having died of cancer prior to interview or being too ill to participate (11
). In a population-based Italian case-control study of cancer, Richiardi et al. (43
) reported that nonparticipating cases were of high SES rather than low SES, and they hypothesized that this may have been because more educated and wealthy subjects retained more independence when hospitalized for a serious disease. However, other cancer case-control studies have identified a pattern similar to that of controls, with higher participation among cases of higher SES (38
In addition to selection bias, there is at least 1 alternative explanation for the lack of an association between birth order and NHL risk in studies with the highest response rates included in our analysis. Most (but not all) of the studies with high response rates, particularly among controls, were hospital-based case-control studies. Even when response rates are high, studies of this design are prone to different selection biases (46
). For example, if all patients with NHL are treated in a hospital but low SES predicts hospital attendance for other common conditions such as trauma or cardiovascular disease, then low-SES (high birth order) people may be overrepresented among hospital-based controls. Among hospital-based studies in our data set, birth order was not associated with NHL risk. Among population-based studies, which are generally regarded as methodologically superior to hospital-based studies, there was a significant association. However, because these were also the studies with the lowest response rates, it was not possible to conclude that this positive association was likely to reflect a causal association. Even among population-based studies, the positive association between birth order and NHL varied by case and control response rates (data not shown).
If the birth order association is due to selection bias, a similar effect is likely to occur in case-control studies of birth order as a risk factor for other diseases. Birth order has been studied in some detail as a risk factor for Hodgkin lymphoma. Investigators in population-based cohort studies (3
) and case-control studies with low refusal rates (9
) are consistent in reporting that increasing birth order and/or sibship size is associated with decreasing Hodgkin lymphoma risk, especially the young adult type. However, in some recent case-control studies which had lower response rates in controls, researchers reported no association with low birth order or other markers of higher SES (51
). One possibility for the lack of association is a temporal change in early-life child-care arrangements, resulting in increased early-life exposure to infection that mutes the effect of birth order. Alternatively, in 1 of these studies, Glaser et al. (54
) reported that the absence of an effect was probably related to a combination of the low response rate in controls and the fact that controls who participated were of higher SES than those who did not participate. This is consistent with the form and direction of selection bias which may have occurred in NHL research: The difference is that for Hodgkin lymphoma, selection bias has sometimes obscured a true inverse relation with birth order, whereas for NHL it may have created the impression of a positive relation. For other types of cancer, birth order has been less intensively studied, although patterns of increased and decreased risk have been described for certain cancer sites in cohort studies, perhaps reflecting the effect of SES on cancer risk (55
In case-control studies that have observed an association of NHL risk with increasing birth order, researchers have interpreted the finding as suggesting that the immunologic consequences of early infection may be responsible for increased NHL risk in persons of late birth order (4
). Our finding of no significant association between NHL risk and birth order does not rule out an effect of early life environment, but it does suggest that such an effect, if present, is unlikely to be reliably mediated by birth order.
The large size of this pooled analysis using individual data allowed stratification by study design and participant demographic characteristics, thus enabling exploration of factors related to the weak association observed for some NHL subtypes. In previous InterLymph pooled analyses we have carried out, for atopic diseases and for autoimmune disorders, there was very little difference in the pattern or significance of results when we stratified results by these design features or demographic variables (56
). A possible reason for the heterogeneity of the findings we have demonstrated for birth order is that the infection-related consequences of birth order are highly variable among the countries in which these studies were conducted. In terms of selection bias, unfortunately investigators in most of the participating studies did not collect data on nonresponders to allow direct investigation of the hypothesis presented here. However, in 1 population-based study, Mensah et al. (11
) investigated nonresponse and reported that both the participating cases and controls were of higher-than-expected SES. Shen et al. (37
) reported varying results on participation rate by SES according to individual study center. When response rates are substantially lower in controls than in cases, higher participation rates in persons of higher SES will lead to selection bias, causing an association between increasing birth order and NHL risk, as we have hypothesized may be the case. Because of variations in how investigators in participating studies reported nonresponse, it is likely that there was some misclassification of true nonresponse rates. The absence of universally accepted criteria for reporting response rates (58
) and a lack of consistency between studies in recording of details of nonresponse precluded any recalculation of standardized response rates in this pooled analysis.
In summary, we did not find a significant overall association between birth order or sibship size and risk of NHL in this large pooled analysis. However, a positive association was found in population-based studies and among people in the highest SES stratum. Sensitivity analyses by study design factors and participant characteristics, a strength of pooled analyses, suggested that a likely explanation for the weak positive association between birth order and NHL risk reported in some case-control studies may be selection bias. The fact that low-SES controls in this pooled analysis were more likely to be of high birth order and were less likely to participate may have generated a weak positive association between NHL risk and birth order. More generally, our results show that because of the close association between birth order and SES and between SES and subject nonresponse, case-control studies of birth order as a risk factor for disease will only be valid if the response rate is very high in both cases and controls and if other sources of selection bias related to SES are eliminated. Confounding or selection bias due to SES should be ruled out in all studies which have identified birth order as a risk factor for disease. The association is best explored in population-based case-control studies with high response rates, or in large prospective or retrospective cohort studies that utilize linked cancer and birth registry records.