Observational versus randomised trial evidence

Abstract

Authors' replyWhen observational epidemiological data and randomised controlled trials produce contradictory findings there is a need to explore the reasons. We showed that the relative risks of mortality from coronary heart disease (CHD) for an identical difference in plasma vitamin C (15·7 μmol/L) suggested a strong beneficial effect in the EPIC observational study1Khaw K-T Bingham S Welch A et al.Relation between plasma ascorbic acid and mortality in men and women in EPIC-Norfolk prospective study: a prospective population study.Lancet. 2001; 357: 657-663Summary Full Text Full Text PDF PubMed Scopus (448) Google Scholar and weak evidence of possible harm in the Heart Protection randomised controlled trial.2Heart Protection Study Collaborative GroupMRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20536 high-risk individuals: a randomised placebo-controlled trial.Lancet. 2002; 360: 23-33Summary Full Text Full Text PDF PubMed Scopus (1361) Google Scholar These differences seem to us to be contradictory rather than consistent. If the observational findings were always clearly explained by factors for which plasma vitamin C is only a proxy—essentially fruit and vegetable consumption, according to Kay-Tee Khaw and colleagues—then several things are unclear. First, why did Khaw and colleagues not report results with respect to fruit and vegetable consumption or other dietary factors (on which they have data) rather than a proxy variable in their original report?1Khaw K-T Bingham S Welch A et al.Relation between plasma ascorbic acid and mortality in men and women in EPIC-Norfolk prospective study: a prospective population study.Lancet. 2001; 357: 657-663Summary Full Text Full Text PDF PubMed Scopus (448) Google Scholar Second, why did mechanisms through which vitamin C could directly affect risk of CHD merit the discussion they received in that article?1Khaw K-T Bingham S Welch A et al.Relation between plasma ascorbic acid and mortality in men and women in EPIC-Norfolk prospective study: a prospective population study.Lancet. 2001; 357: 657-663Summary Full Text Full Text PDF PubMed Scopus (448) Google Scholar Finally, why has so much effort been invested in setting up trials to test the antioxidant vitamin hypothesis?Khaw and colleagues suggest the association between vitamin C and CHD is too strong to be explained by the relatively weak effects of individual confounders. Contrary to their assertion, individually weak risk factors for CHD, operating cumulatively over the life course, can have sufficiently powerful effects to generate strong—but confounded—associations. In the webtable (http://www.image.thelancet.com/extras/04cor6136webtable.pdf) we show exactly how this situation can arise. The predicted odds ratio of CHD if all of the apparent vitamin C effect (contrasting top with bottom quarter of the vitamin C distribution) is due to confounding is shown for each individual risk factor and for all risk factors operating together in the British Women's Heart and Health Study.3Lawlor DA, Bedford C, Taylor M, Ebrahim S. Geographic variation in cardiovascular disease, risk factors and their control in older women: British Women's Heart and Health Study. J Epidemiol Com Health; 57: 134–40.Google Scholar Khaw and colleagues echo what we wrote when saying that the association between vitamin C and CHD mortality is clearly not explained by any one of these confounding factors. However, if the effects of all confounders are taken into account—and making the not unreasonable assumption that their effects are log-additive—then the predicted odds ratio, comparing the top to bottom quarter of the vitamin C distribution, is 0·60. This effect is strong, consistent with the findings of EPIC and other observational studies, and suggests that such effects could all be explained by confounding by these factors, operating in concert.Khaw and co-workers' hypothesis that plasma vitamin C is a good marker of fruit and vegetable intake, which protects against CHD, requires some quantitative reasoning. Their data show that plasma vitamin C is only moderately correlated with frequency of fruit intake (independent correlation coefficients of 0·19 and 0·20 for men and women, respectively), green leafy vegetable intake (0·07 and 0·01 for men and women), and other vegetable intakes (0·05 and 0·03).4Ness A Khaw KT Bingham S Day NE Plasma vitamin C: what does it measure?.Public Health Nutrition. 1999; 2: 51-54Crossref PubMed Google Scholar From their published results it is not possible to ascertain the intraclass correlation between total consumption of all fruit and vegetables and vitamin C, but we have assumed that this lies in the region of 0·2 to 0·4 (the latter value is certainly an over-estimate given the correlations reported4Ness A Khaw KT Bingham S Day NE Plasma vitamin C: what does it measure?.Public Health Nutrition. 1999; 2: 51-54Crossref PubMed Google Scholar). This assumption implies that plasma vitamin C substantially under-estimates the true strength of association of fruit and vegetable intake with CHD mortality. We calculate that, taking this regression-dilution effect into account, for a 50 g daily increase in fresh fruit consumption (equivalent to one serving and described by the authors as small and feasible1Khaw K-T Bingham S Welch A et al.Relation between plasma ascorbic acid and mortality in men and women in EPIC-Norfolk prospective study: a prospective population study.Lancet. 2001; 357: 657-663Summary Full Text Full Text PDF PubMed Scopus (448) Google Scholar), the hazard ratio of CHD mortality would be 0·10–0·31 for men and 0·06–0·23 for women. These protective effects far out weigh the results that can be achieved by the avoidance of all the major established CHD risk factors. We think that effects of this size are simply implausible, and these implausibly strong associations add weight to our arguments in favour of confounding as underlying the associations.Finally, as stated in our original article, but not addressed by Khaw and colleagues, it would be illustrative to see if plasma vitamin C concentrations in the EPIC study were associated with violent or external causes of death, as has been previously shown with hormone replacement therapy (HRT).5Petitti DB Perlman JA Sidney S Postmenopausal estrogen use and heart disease.NEJM. 1986; 315: 131-132Crossref PubMed Scopus (12) Google Scholar Such lack of specificity of association strongly suggests that plausible associations are indeed due to confounding, as was the case with HRT. Authors' reply When observational epidemiological data and randomised controlled trials produce contradictory findings there is a need to explore the reasons. We showed that the relative risks of mortality from coronary heart disease (CHD) for an identical difference in plasma vitamin C (15·7 μmol/L) suggested a strong beneficial effect in the EPIC observational study1Khaw K-T Bingham S Welch A et al.Relation between plasma ascorbic acid and mortality in men and women in EPIC-Norfolk prospective study: a prospective population study.Lancet. 2001; 357: 657-663Summary Full Text Full Text PDF PubMed Scopus (448) Google Scholar and weak evidence of possible harm in the Heart Protection randomised controlled trial.2Heart Protection Study Collaborative GroupMRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20536 high-risk individuals: a randomised placebo-controlled trial.Lancet. 2002; 360: 23-33Summary Full Text Full Text PDF PubMed Scopus (1361) Google Scholar These differences seem to us to be contradictory rather than consistent. If the observational findings were always clearly explained by factors for which plasma vitamin C is only a proxy—essentially fruit and vegetable consumption, according to Kay-Tee Khaw and colleagues—then several things are unclear. First, why did Khaw and colleagues not report results with respect to fruit and vegetable consumption or other dietary factors (on which they have data) rather than a proxy variable in their original report?1Khaw K-T Bingham S Welch A et al.Relation between plasma ascorbic acid and mortality in men and women in EPIC-Norfolk prospective study: a prospective population study.Lancet. 2001; 357: 657-663Summary Full Text Full Text PDF PubMed Scopus (448) Google Scholar Second, why did mechanisms through which vitamin C could directly affect risk of CHD merit the discussion they received in that article?1Khaw K-T Bingham S Welch A et al.Relation between plasma ascorbic acid and mortality in men and women in EPIC-Norfolk prospective study: a prospective population study.Lancet. 2001; 357: 657-663Summary Full Text Full Text PDF PubMed Scopus (448) Google Scholar Finally, why has so much effort been invested in setting up trials to test the antioxidant vitamin hypothesis? Khaw and colleagues suggest the association between vitamin C and CHD is too strong to be explained by the relatively weak effects of individual confounders. Contrary to their assertion, individually weak risk factors for CHD, operating cumulatively over the life course, can have sufficiently powerful effects to generate strong—but confounded—associations. In the webtable (http://www.image.thelancet.com/extras/04cor6136webtable.pdf) we show exactly how this situation can arise. The predicted odds ratio of CHD if all of the apparent vitamin C effect (contrasting top with bottom quarter of the vitamin C distribution) is due to confounding is shown for each individual risk factor and for all risk factors operating together in the British Women's Heart and Health Study.3Lawlor DA, Bedford C, Taylor M, Ebrahim S. Geographic variation in cardiovascular disease, risk factors and their control in older women: British Women's Heart and Health Study. J Epidemiol Com Health; 57: 134–40.Google Scholar Khaw and colleagues echo what we wrote when saying that the association between vitamin C and CHD mortality is clearly not explained by any one of these confounding factors. However, if the effects of all confounders are taken into account—and making the not unreasonable assumption that their effects are log-additive—then the predicted odds ratio, comparing the top to bottom quarter of the vitamin C distribution, is 0·60. This effect is strong, consistent with the findings of EPIC and other observational studies, and suggests that such effects could all be explained by confounding by these factors, operating in concert. Khaw and co-workers' hypothesis that plasma vitamin C is a good marker of fruit and vegetable intake, which protects against CHD, requires some quantitative reasoning. Their data show that plasma vitamin C is only moderately correlated with frequency of fruit intake (independent correlation coefficients of 0·19 and 0·20 for men and women, respectively), green leafy vegetable intake (0·07 and 0·01 for men and women), and other vegetable intakes (0·05 and 0·03).4Ness A Khaw KT Bingham S Day NE Plasma vitamin C: what does it measure?.Public Health Nutrition. 1999; 2: 51-54Crossref PubMed Google Scholar From their published results it is not possible to ascertain the intraclass correlation between total consumption of all fruit and vegetables and vitamin C, but we have assumed that this lies in the region of 0·2 to 0·4 (the latter value is certainly an over-estimate given the correlations reported4Ness A Khaw KT Bingham S Day NE Plasma vitamin C: what does it measure?.Public Health Nutrition. 1999; 2: 51-54Crossref PubMed Google Scholar). This assumption implies that plasma vitamin C substantially under-estimates the true strength of association of fruit and vegetable intake with CHD mortality. We calculate that, taking this regression-dilution effect into account, for a 50 g daily increase in fresh fruit consumption (equivalent to one serving and described by the authors as small and feasible1Khaw K-T Bingham S Welch A et al.Relation between plasma ascorbic acid and mortality in men and women in EPIC-Norfolk prospective study: a prospective population study.Lancet. 2001; 357: 657-663Summary Full Text Full Text PDF PubMed Scopus (448) Google Scholar), the hazard ratio of CHD mortality would be 0·10–0·31 for men and 0·06–0·23 for women. These protective effects far out weigh the results that can be achieved by the avoidance of all the major established CHD risk factors. We think that effects of this size are simply implausible, and these implausibly strong associations add weight to our arguments in favour of confounding as underlying the associations. Finally, as stated in our original article, but not addressed by Khaw and colleagues, it would be illustrative to see if plasma vitamin C concentrations in the EPIC study were associated with violent or external causes of death, as has been previously shown with hormone replacement therapy (HRT).5Petitti DB Perlman JA Sidney S Postmenopausal estrogen use and heart disease.NEJM. 1986; 315: 131-132Crossref PubMed Scopus (12) Google Scholar Such lack of specificity of association strongly suggests that plausible associations are indeed due to confounding, as was the case with HRT. Observational versus randomised trial evidenceDebbie Lawlor and colleagues (May 22, p 1724)1 compare findings from observational studies and randomised trials, using the EPIC-Norfolk prospective study on plasma ascorbic acid and mortality2 as an example. In this article, we stressed that our results indicated that plasma vitamin C was probably a marker of particular foods, and it was not supplements that were protective. We made this point first in the results section, and several times subsequently in the discussion. There is no contradiction between our findings and our interpretation, and the result of the later randomised trial3 cited by Lawlor and colleagues, showing no effect of vitamin C supplements on cardiovascular mortality. Full-Text PDF