- Email: [email protected]
Childhood adversity still matters for adult health outcomes
COMMENTARY
provided by the PROSPER investigators. A nonsignificant trend towards more cancers among patients aged over 65 years who were allocated statin therapy has been reported from the LIPID trial, but again no particular site predominated.9,12 Moreover, among more than 1600 people with cancers recorded during HPS, there was no significant excess either among younger or older participants (<70 years at entry: 469 [6·4%] simvastatin vs 474 [6·4%] placebo, p=0·8; 70–80 years: 345 [11·8%] vs 329 [11·4%], p=0·8; data from HPS Collaborative Group) or at any particular site (eg, gastrointestinal cancer: 228 [2·2%] vs 223 [2·2%]).8 The Cholesterol Treatment Trialists' prospectively planned meta-analyses of the results of all large-scale randomised trials of cholesterol-lowering therapy should provide even more reliable assessment of any effects on the main types of cancer, as well as of the effects on vascular events in different circumstances (eg, with respect to entry age and lipid concentrations, and time from start of treatment).13 Given that the overall reduction in vascular events in PROSPER is not highly statistically significant, selective emphasis on the results observed in some particular subgroup may well not be reliable. So, even though there was little apparent risk reduction among those participants who presented with HDL concentrations of 1·11 mmol/L or greater, this subgroup analysis should be interpreted with caution—especially since it is not confirmed by the much larger numbers in the previous trials.8,14,15 For example, among the 7694 participants in HPS with HDL concentrations of 1·1 mmol/L or greater, there was a substantial and definite 21% (SE 5, 95% CI 12–28) proportional reduction in the rate of major vascular events (655 [17·0%] simvastatin vs 801 [20·9%] placebo, p<0·0001).8 Nor do other aspects of the pretreatment lipid-profile appear to influence materially the proportional risk reductions with statin therapy. Most notably, reducing LDL cholesterol from about 4 to 3 mmol/L in HPS reduced risk by about one quarter, and reducing it from about 3 to 2 mmol/L also reduced risk by about one quarter. Those findings indicate that any thresholds below which lowering LDL cholesterol does not safely reduce risk are at much lower concentrations (eg, below 2 mmol/L) than are typically seen in Western populations. In conclusion, PROSPER and the other large-scale trials have now collectively shown that cholesterollowering statin therapy rapidly reduces the risks of major vascular events not only in middle age but also in older age, and the benefits are substantial among patients who are at high risk because of pre-existing occlusive arterial disease, diabetes, or other factors (including age). These studies have also shown that such treatment is welltolerated and safe, even among older patients, with no good evidence of any increase in cancer or other nonvascular morbidity or mortality. Hence, long-term statin therapy should now be considered routinely for all such high-risk patients largely irrespective of either their presenting lipid concentrations or their age. The Clinical Trial Service Unit has a staff policy of not accepting honoraria or other payments directly or indirectly from the pharmaceutical industry, except for reimbursement of costs to participate in scientific meetings. HPS was coordinated by the unit independently of all funding sources (Medical Research Council, British Heart Foundation, Merck & Co, and Roche Vitamins Ltd).
*Rory Collins, Jane Armitage Clinical Trial Service Unit & Epidemiological Studies Unit, Harkness Building, Radcliffe Infirmary, Oxford OX2 6HE, UK (e-mail: [email protected])
THE LANCET • Vol 360 • November 23, 2002 • www.thelancet.com
1
2
3
4
5
6
7
8
9
10
11 12
13
14
15
Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian simvastatin survival study (4S). Lancet 1994; 344: 1383–89. Shepherd J, Cobbe SM, Ford I, et al, for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995; 333: 1301–07. Sacks FM, Pfeffer MA, Moye LA, et al, for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996; 335: 1001–09. The Post Coronary Artery Bypass Graft Trial Investigators. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. N Engl J Med 1997; 336: 153–62. The Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998; 339: 1349–57. Downs JR, Clearfield M, Weis S, et al, for the AFCAPS/TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA 1998; 279: 1615–22. Serruys PWJC, de Feyter P, Macaya C, et al, for the Lescol Intervention Prevention Study (LIPS) Investigators. Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomised controlled trial. JAMA 2002; 287: 3215–22. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360: 7–22. Hunt D, Young P, Simes J, et al, for the LIPID investigators. Benefits of pravastatin on cardiovascular events and mortality in older patients with coronary heart disease are equal to or exceed those seen in younger patients: results from the LIPID trial. Ann Intern Med 2001; 134: 931–40. Shepherd J, Blauw GJ, Murphy MB, et al, on behalf of the PROSPER Study Group. The design of a prospective study of pravastatin in the elderly at risk (PROSPER). Am J Cardiol 1999; 84: 1192–97. Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA. Statins and the risk of dementia. Lancet 2000; 356: 1627–31. Simes J, Young P, Hunt D. Effects of pravastatin in the elderly. Ann Intern Med 2002; 136: http://www.annals.org/issues/v136/full/ 200206040-W2.html (accessed Nov 18, 2002). Cholesterol Treatment Trialists' (CTT) Collaboration. Protocol for a prospective collaborative overview of all current and planned randomized trials of cholesterol treatment regimens. Am J Cardiol 1995; 75: 1130–04. Scandinavian Simvastatin Survival Study Group. Baseline serum cholesterol and treatment effect in the Scandinavian Simvastatin Survival Study (4S). Lancet 1995; 345: 1274–75. Sacks FM, Tonkin AM, Shepherd J, et al, for the Prospective Pravastatin Pooling Project Investigators Group. Effect of pravastatin on coronary disease events in subgroups defined by coronary risk factors: the Prospective Pravastatin Pooling Project. Circulation 2000; 102: 1893–900.
Childhood adversity still matters for adult health outcomes See page 1640 That conditions experienced early in life have a long-lasting influence on adult health is not a new idea. But only recently has the entire lifecourse become a major focus of epidemiological research, with the objective of understanding when as well as how particular exposures act on later health outcomes.1,2 One approach to yield valuable clues as to when influences might be acting has been to evaluate associations with socioeconomic circumstances at different stages of life. In adulthood, socioeconomic differences in health are well-established,3 but the impact of socioeconomic circumstances earlier in life on adult health is less well documented. A study of men born in Scotland in the 1920s suggested that some adult diseases were affected 1619
For personal use. Only reproduce with permission from The Lancet Publishing Group.
COMMENTARY
by socioeconomic conditions in childhood.4 Men who had manual social-class origins had increased risk of mortality from stroke and stomach cancer in adulthood; whereas mortality risk for lung cancer, other cancers, accidents, and violence was influenced predominantly by adult social circumstances. For some adult diseases, including coronary heart disease and respiratory disease, socioeconomic conditions in both childhood and adulthood appeared to exert an effect.4 A similar pattern has been reported in a younger generation, all born in 1958, at an earlier life-stage when mortality and serious morbidity are less common.5 Self-rated health (a marker of future health status) at 33 years showed that the risk of poor health increased the longer that they had lived in disadvantaged socioeconomic conditions.5 Importantly, most previous studies are based on study populations born in the early to mid-1900s, some of whom would have experienced considerable socioeconomic adversity, at least by today’s standards. It is not at all clear that relations documented for these older generations still apply to younger generations. Child health (indexed, for example, by infant mortality) has improved dramatically over recent decades, indicating the extent to which conditions have improved, at least in developed nations. With increasing affluence, socioeconomic adversity in childhood would be expected to have lessened to the point that it is no longer relevant to adult health. In today’s Lancet a report of a study from Dunedin (New Zealand) provides no support for this expectation. Rather Ritchie Poulton and colleagues suggest that even in a developed modern society the socioeconomic conditions in which children are raised influence their health in adult life. The investigators show that poorer circumstances in childhood have a detrimental effect on adult health, irrespective of adult socioeconomic circumstances, among 26-year-olds born in 1972–73 in Dunedin, although not for all of the health measures examined. The combination of less advantaged childhood and adult circumstances was related to poorer cardiorespiratory function and dental health, suggesting that the duration of socioeconomic adversity matters. The Dunedin study is relevant to a growing body of research on childhood socioeconomic adversity. For example, there is corroborating evidence that the risk of developing obesity in adulthood increases for people with less favourable circumstances in childhood.6 Even so, it cannot be assumed that relations seen for health in young adulthood will hold for disease outcomes later in life. Recognition of changing relations over time is important within lifecourse epidemiology, which discriminates between determinants of health gain (primarily in the first two decades of life) and determinants of health decline.7 The Dunedin study, with participants aged 26, is pertinent to the period of health gain, since early adulthood is typically when peak function (eg, in cardiorespiratory fitness) is attained. Why should childhood circumstances affect adult health even in a younger generation? One thought-provoking possibility is that adversity in childhood becomes embodied at an early age, the full impact of which manifests later in adult life. The interplay between biological and social processes could start with exposure to frequent infections or inadequate diet, both rooted in poorer socioeconomic conditions, and such exposures could in turn have lifelong consequences. For example, conditions in childhood influence the adequacy of diet for linear growth, which is delayed at times of nutritional deficiency. Subsequently, delayed linear growth (as indexed by shorter leg-length) is associated with increased 1620
mortality risk for coronary heart disease, suggesting a role for diet in early life.8 Many details remain to be understood and there is much debate about alternative processes linking socioeconomic circumstances in childhood and adult health, involving, among other factors, cognitive and emotional development, subsequent adult locations (eg, occupational and social relationships), and health-related behaviours.1,2 Life-course perspectives therefore give a challenging research agenda, whereby the multifactorial nature of many chronic diseases can be viewed with an explicit acknowledgment of the timing and inter-relations between suspected factors. As well as searching for causal factors underpinning many of the child-to-adult relations, it is important from a policy perspective to keep sight of their socioeconomic origins. In the UK, the statistics on childhood inequalities are daunting: families with young children (and especially lone-parent families) are disproportionately likely to be among the poorest groups within society. Recent estimates suggest that one in three children in the UK live in poverty.9 Lifecourse studies have an important role to play in revealing the full impact of socioeconomic inequity in childhood. Chris Power Institute of Child Health, London WC1N 1EH, UK (e-mail: [email protected]) 1 2
3 4
5
6
7
8
9
Kuh D, Ben-Shlomo Y, eds. A lifecourse approach to chronic disease epidemiology. Oxford: Oxford University Press,1997. Keating DP, Hertzman C, eds. Developmental health and the wealth of nations: social, biological and educational dynamics. New York: Guilford Press, 1999. Drever F, Whitehead M, eds. Health inequalities—decennial supplement. Series DS No 15. London: HM Stationery Office, 1997. Davey-Smith G, Hart C, Blane D, Gillis C, Hawthorne V. Adverse socioeconomic conditions in childhood and cause specific mortality: prospective observational study. BMJ 1998; 316: 1631–35. Power C, Manor O, Matthews S. Duration and timing of exposure: effects of socio-economic environment on adult health. Am J Public Health 1999; 89: 1059–1065. Parsons T, Power C, Logan S, Summerbell CD. Childhood predictors of adult obesity. Int J Obes Relat Metab Disord 1999; 23 (suppl 8): S1–S107. Strachan DP. Respiratory and allergic disease. In: Kuh D, Ben-Shlomo Y, eds. A lifecourse approach to chronic disease epidemiology. Oxford: Oxford University Press, 1997. Gunnell DJ, Davey Smith G, Frankel S, et al. Childhood leg length and adult mortality: follow up of the Carnegie (Boyd Orr) Survey of Diet and Health in Pre-war Britain. J Epidemiol Community Health 1998; 52: 142–52. Gregg P, Harkness S, Machin S. Poor kids: trends in child poverty in Britain, 1968–96. Fiscal Studies 1999; 20: 163–87.
The power of the protocol Maartens Boers’ Commentary1 in the July issue of The Lancet is another addition to efforts to improve the validity of randomised clinical trials. The need for validity, of course, is primary in experimental designs for clinical medicine, and its pursuit and discussion is ongoing.2 However, as Boers and others3 have noted, the recent large trials in rheumatology, CLASS4 and VIGOR,5 which compared the benefits of selective inhibitors of cyclooxygenase 2 with non-selective nonsteroidal antiinflammatory drugs, are prominent examples of a failure of this process. The disputes of CLASS and VIGOR have been well described.1,3 In CLASS it was: the validity of the reported 6-month data analysis, published in September, 2000, compared with the 12-month trial data available from the FDA website from March, 2001;6 the pooling of the diclofenac and ibuprofen data as a combined nonsteroidal THE LANCET • Vol 360 • November 23, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
provided by the PROSPER investigators. A nonsignificant trend towards more cancers among patients aged over 65 years who were allocated statin therapy has been reported from the LIPID trial, but again no particular site predominated.9,12 Moreover, among more than 1600 people with cancers recorded during HPS, there was no significant excess either among younger or older participants (<70 years at entry: 469 [6·4%] simvastatin vs 474 [6·4%] placebo, p=0·8; 70–80 years: 345 [11·8%] vs 329 [11·4%], p=0·8; data from HPS Collaborative Group) or at any particular site (eg, gastrointestinal cancer: 228 [2·2%] vs 223 [2·2%]).8 The Cholesterol Treatment Trialists' prospectively planned meta-analyses of the results of all large-scale randomised trials of cholesterol-lowering therapy should provide even more reliable assessment of any effects on the main types of cancer, as well as of the effects on vascular events in different circumstances (eg, with respect to entry age and lipid concentrations, and time from start of treatment).13 Given that the overall reduction in vascular events in PROSPER is not highly statistically significant, selective emphasis on the results observed in some particular subgroup may well not be reliable. So, even though there was little apparent risk reduction among those participants who presented with HDL concentrations of 1·11 mmol/L or greater, this subgroup analysis should be interpreted with caution—especially since it is not confirmed by the much larger numbers in the previous trials.8,14,15 For example, among the 7694 participants in HPS with HDL concentrations of 1·1 mmol/L or greater, there was a substantial and definite 21% (SE 5, 95% CI 12–28) proportional reduction in the rate of major vascular events (655 [17·0%] simvastatin vs 801 [20·9%] placebo, p<0·0001).8 Nor do other aspects of the pretreatment lipid-profile appear to influence materially the proportional risk reductions with statin therapy. Most notably, reducing LDL cholesterol from about 4 to 3 mmol/L in HPS reduced risk by about one quarter, and reducing it from about 3 to 2 mmol/L also reduced risk by about one quarter. Those findings indicate that any thresholds below which lowering LDL cholesterol does not safely reduce risk are at much lower concentrations (eg, below 2 mmol/L) than are typically seen in Western populations. In conclusion, PROSPER and the other large-scale trials have now collectively shown that cholesterollowering statin therapy rapidly reduces the risks of major vascular events not only in middle age but also in older age, and the benefits are substantial among patients who are at high risk because of pre-existing occlusive arterial disease, diabetes, or other factors (including age). These studies have also shown that such treatment is welltolerated and safe, even among older patients, with no good evidence of any increase in cancer or other nonvascular morbidity or mortality. Hence, long-term statin therapy should now be considered routinely for all such high-risk patients largely irrespective of either their presenting lipid concentrations or their age. The Clinical Trial Service Unit has a staff policy of not accepting honoraria or other payments directly or indirectly from the pharmaceutical industry, except for reimbursement of costs to participate in scientific meetings. HPS was coordinated by the unit independently of all funding sources (Medical Research Council, British Heart Foundation, Merck & Co, and Roche Vitamins Ltd).
*Rory Collins, Jane Armitage Clinical Trial Service Unit & Epidemiological Studies Unit, Harkness Building, Radcliffe Infirmary, Oxford OX2 6HE, UK (e-mail: [email protected])
THE LANCET • Vol 360 • November 23, 2002 • www.thelancet.com
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11 12
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Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian simvastatin survival study (4S). Lancet 1994; 344: 1383–89. Shepherd J, Cobbe SM, Ford I, et al, for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995; 333: 1301–07. Sacks FM, Pfeffer MA, Moye LA, et al, for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996; 335: 1001–09. The Post Coronary Artery Bypass Graft Trial Investigators. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. N Engl J Med 1997; 336: 153–62. The Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998; 339: 1349–57. Downs JR, Clearfield M, Weis S, et al, for the AFCAPS/TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA 1998; 279: 1615–22. Serruys PWJC, de Feyter P, Macaya C, et al, for the Lescol Intervention Prevention Study (LIPS) Investigators. Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomised controlled trial. JAMA 2002; 287: 3215–22. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360: 7–22. Hunt D, Young P, Simes J, et al, for the LIPID investigators. Benefits of pravastatin on cardiovascular events and mortality in older patients with coronary heart disease are equal to or exceed those seen in younger patients: results from the LIPID trial. Ann Intern Med 2001; 134: 931–40. Shepherd J, Blauw GJ, Murphy MB, et al, on behalf of the PROSPER Study Group. The design of a prospective study of pravastatin in the elderly at risk (PROSPER). Am J Cardiol 1999; 84: 1192–97. Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA. Statins and the risk of dementia. Lancet 2000; 356: 1627–31. Simes J, Young P, Hunt D. Effects of pravastatin in the elderly. Ann Intern Med 2002; 136: http://www.annals.org/issues/v136/full/ 200206040-W2.html (accessed Nov 18, 2002). Cholesterol Treatment Trialists' (CTT) Collaboration. Protocol for a prospective collaborative overview of all current and planned randomized trials of cholesterol treatment regimens. Am J Cardiol 1995; 75: 1130–04. Scandinavian Simvastatin Survival Study Group. Baseline serum cholesterol and treatment effect in the Scandinavian Simvastatin Survival Study (4S). Lancet 1995; 345: 1274–75. Sacks FM, Tonkin AM, Shepherd J, et al, for the Prospective Pravastatin Pooling Project Investigators Group. Effect of pravastatin on coronary disease events in subgroups defined by coronary risk factors: the Prospective Pravastatin Pooling Project. Circulation 2000; 102: 1893–900.
Childhood adversity still matters for adult health outcomes See page 1640 That conditions experienced early in life have a long-lasting influence on adult health is not a new idea. But only recently has the entire lifecourse become a major focus of epidemiological research, with the objective of understanding when as well as how particular exposures act on later health outcomes.1,2 One approach to yield valuable clues as to when influences might be acting has been to evaluate associations with socioeconomic circumstances at different stages of life. In adulthood, socioeconomic differences in health are well-established,3 but the impact of socioeconomic circumstances earlier in life on adult health is less well documented. A study of men born in Scotland in the 1920s suggested that some adult diseases were affected 1619
For personal use. Only reproduce with permission from The Lancet Publishing Group.
COMMENTARY
by socioeconomic conditions in childhood.4 Men who had manual social-class origins had increased risk of mortality from stroke and stomach cancer in adulthood; whereas mortality risk for lung cancer, other cancers, accidents, and violence was influenced predominantly by adult social circumstances. For some adult diseases, including coronary heart disease and respiratory disease, socioeconomic conditions in both childhood and adulthood appeared to exert an effect.4 A similar pattern has been reported in a younger generation, all born in 1958, at an earlier life-stage when mortality and serious morbidity are less common.5 Self-rated health (a marker of future health status) at 33 years showed that the risk of poor health increased the longer that they had lived in disadvantaged socioeconomic conditions.5 Importantly, most previous studies are based on study populations born in the early to mid-1900s, some of whom would have experienced considerable socioeconomic adversity, at least by today’s standards. It is not at all clear that relations documented for these older generations still apply to younger generations. Child health (indexed, for example, by infant mortality) has improved dramatically over recent decades, indicating the extent to which conditions have improved, at least in developed nations. With increasing affluence, socioeconomic adversity in childhood would be expected to have lessened to the point that it is no longer relevant to adult health. In today’s Lancet a report of a study from Dunedin (New Zealand) provides no support for this expectation. Rather Ritchie Poulton and colleagues suggest that even in a developed modern society the socioeconomic conditions in which children are raised influence their health in adult life. The investigators show that poorer circumstances in childhood have a detrimental effect on adult health, irrespective of adult socioeconomic circumstances, among 26-year-olds born in 1972–73 in Dunedin, although not for all of the health measures examined. The combination of less advantaged childhood and adult circumstances was related to poorer cardiorespiratory function and dental health, suggesting that the duration of socioeconomic adversity matters. The Dunedin study is relevant to a growing body of research on childhood socioeconomic adversity. For example, there is corroborating evidence that the risk of developing obesity in adulthood increases for people with less favourable circumstances in childhood.6 Even so, it cannot be assumed that relations seen for health in young adulthood will hold for disease outcomes later in life. Recognition of changing relations over time is important within lifecourse epidemiology, which discriminates between determinants of health gain (primarily in the first two decades of life) and determinants of health decline.7 The Dunedin study, with participants aged 26, is pertinent to the period of health gain, since early adulthood is typically when peak function (eg, in cardiorespiratory fitness) is attained. Why should childhood circumstances affect adult health even in a younger generation? One thought-provoking possibility is that adversity in childhood becomes embodied at an early age, the full impact of which manifests later in adult life. The interplay between biological and social processes could start with exposure to frequent infections or inadequate diet, both rooted in poorer socioeconomic conditions, and such exposures could in turn have lifelong consequences. For example, conditions in childhood influence the adequacy of diet for linear growth, which is delayed at times of nutritional deficiency. Subsequently, delayed linear growth (as indexed by shorter leg-length) is associated with increased 1620
mortality risk for coronary heart disease, suggesting a role for diet in early life.8 Many details remain to be understood and there is much debate about alternative processes linking socioeconomic circumstances in childhood and adult health, involving, among other factors, cognitive and emotional development, subsequent adult locations (eg, occupational and social relationships), and health-related behaviours.1,2 Life-course perspectives therefore give a challenging research agenda, whereby the multifactorial nature of many chronic diseases can be viewed with an explicit acknowledgment of the timing and inter-relations between suspected factors. As well as searching for causal factors underpinning many of the child-to-adult relations, it is important from a policy perspective to keep sight of their socioeconomic origins. In the UK, the statistics on childhood inequalities are daunting: families with young children (and especially lone-parent families) are disproportionately likely to be among the poorest groups within society. Recent estimates suggest that one in three children in the UK live in poverty.9 Lifecourse studies have an important role to play in revealing the full impact of socioeconomic inequity in childhood. Chris Power Institute of Child Health, London WC1N 1EH, UK (e-mail: [email protected]) 1 2
3 4
5
6
7
8
9
Kuh D, Ben-Shlomo Y, eds. A lifecourse approach to chronic disease epidemiology. Oxford: Oxford University Press,1997. Keating DP, Hertzman C, eds. Developmental health and the wealth of nations: social, biological and educational dynamics. New York: Guilford Press, 1999. Drever F, Whitehead M, eds. Health inequalities—decennial supplement. Series DS No 15. London: HM Stationery Office, 1997. Davey-Smith G, Hart C, Blane D, Gillis C, Hawthorne V. Adverse socioeconomic conditions in childhood and cause specific mortality: prospective observational study. BMJ 1998; 316: 1631–35. Power C, Manor O, Matthews S. Duration and timing of exposure: effects of socio-economic environment on adult health. Am J Public Health 1999; 89: 1059–1065. Parsons T, Power C, Logan S, Summerbell CD. Childhood predictors of adult obesity. Int J Obes Relat Metab Disord 1999; 23 (suppl 8): S1–S107. Strachan DP. Respiratory and allergic disease. In: Kuh D, Ben-Shlomo Y, eds. A lifecourse approach to chronic disease epidemiology. Oxford: Oxford University Press, 1997. Gunnell DJ, Davey Smith G, Frankel S, et al. Childhood leg length and adult mortality: follow up of the Carnegie (Boyd Orr) Survey of Diet and Health in Pre-war Britain. J Epidemiol Community Health 1998; 52: 142–52. Gregg P, Harkness S, Machin S. Poor kids: trends in child poverty in Britain, 1968–96. Fiscal Studies 1999; 20: 163–87.
The power of the protocol Maartens Boers’ Commentary1 in the July issue of The Lancet is another addition to efforts to improve the validity of randomised clinical trials. The need for validity, of course, is primary in experimental designs for clinical medicine, and its pursuit and discussion is ongoing.2 However, as Boers and others3 have noted, the recent large trials in rheumatology, CLASS4 and VIGOR,5 which compared the benefits of selective inhibitors of cyclooxygenase 2 with non-selective nonsteroidal antiinflammatory drugs, are prominent examples of a failure of this process. The disputes of CLASS and VIGOR have been well described.1,3 In CLASS it was: the validity of the reported 6-month data analysis, published in September, 2000, compared with the 12-month trial data available from the FDA website from March, 2001;6 the pooling of the diclofenac and ibuprofen data as a combined nonsteroidal THE LANCET • Vol 360 • November 23, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.