Vitamin supplements and mortality in older people.

Macpherson et al (1) carried out a meta-analysis of multivitamin and multimineral (MVMM) tablet trials and found no effect of MVMMs on average mortality. However, their study may suffer from ecological fallacy. Ecological fallacy means that study-level (group-level) analysis can lead to different conclusions than do corresponding individual-level analyses (2). For this reason, examination of individual-level data is recommended, whenever feasible, to avoid the potential for the ecological fallacy introduced by studylevel analyses (2). Macpherson et al (1) calculated that the average age of the participants in the studies was 62 y. However, ages ranged from 17 to 86 y in the included trials (1). It is probable that the effects of all vitamins and minerals are not identical at the lower and upper ends of such a wide age range. Therefore, pooling diverse trials with young and old people to a single average MVMM effect may camouflage effects of some individual vitamins or minerals, for example, on the oldest people. In the case of vitamin E there is strong empirical evidence of effect modification by age. In an individual-level analysis of the Alpha-Tocopherol, BetaCarotene Cancer Prevention (ATBC) Study data, we found that among participants aged 50–62 y at baseline with a dietary vitamin C intake above the median, vitamin E increased mortality by 19% (95% CI: 5%, 35%; based on 1021 deaths). However, among participants aged 66–69 y at baseline with a dietary vitamin C intake above the median, vitamin E decreased mortality by 41% (95% CI: 21%, 56%; based on 195 deaths) (3). Furthermore, because the follow-up time in the ATBC Study was up to 8 y, the participants became substantially older during the trial so that the baseline age was not a proper way to characterize them over the entire follow-up period. Therefore, the modification of vitamin E effects was also analyzed by using the follow-up age as the time variable (4). Among 10,837 ATBC Study participants who contributed follow-up time past the age of 65 y, the survival curves of the vitamin E and no–vitamin E participants significantly diverged at 71 y. Vitamin E extended life span by ;0.5 y at the upper limit of the followup age span (4). Macpherson et al (1) write that in a meta-regression the estimate of the effect of MVMMs was not associated with the duration of supplementation. In the ATBC Study, the harm from vitamin E in the young participants was restricted to the supplementation period after 3.3 y, indicating that there can be a lag period of several years before the effects of some vitamins appear (3). Macpherson et al used the study-level average durations, which provide a poor basis for analyzing supplementation time–dependent effect modifications. Proper analysis of time-dependent effects requires individuallevel data. It is possible that some vitamins and minerals are beneficial for specific subpopulations. For example, age, sex, smoking, diet, and exercise might modify the effects of some vitamins and minerals, so that some restricted population groups might benefit (and some might be harmed). Such subgroups can be explored by analyzing individual-level data, whereas pooling study-level averages provides no information on relevant narrow subpopulations. The meta-analysis by Macpherson et al (1) is important in discouraging ordinary middle-aged people from taking MVMMs. Nevertheless, their study should not be interpreted as evidence that none of the vitamins and minerals included in the MVMM tablets have effects on males and females in the age range of 17–86 y. It is possible that some vitamins, such as vitamin E, are useful for restricted groups of older people. Individual-level data analyses are needed for exploring such a possibility.