Valerie McCormack

Issues in the reporting of epidemiological studies: a survey of recent practice

Abstract Objectives To review current practice in the analysis and reporting of epidemiological research and to identify limitations. Design Examination of articles published in January 2001 that investigated associations between risk factors/exposure variables and disease events/measures in individuals. Setting Eligible English language journals including all major epidemiological journals, all major general medical journals, and the two leading journals in cardiovascular disease and cancer. Main outcome measure Each article was evaluated with a standard proforma. Results We found 73 articles in observational epidemiology; most were either cohort or case-control studies. Most studies looked at cancer and cardiovascular disease, even after we excluded specialty journals. Quantitative exposure variables predominated, which were mostly analysed as ordered categories but with little consistency or explanation regarding choice of categories. Sample selection, participant refusal, and data quality received insufficient attention in many articles. Statistical analyses commonly used odds ratios (38 articles) and hazard/rate ratios (23), with some inconsistent use of terminology. Confidence intervals were reported in most studies (68), though use of P values was less common (38). Few articles explained their choice of confounding variables; many performed subgroup analyses claiming an effect modifier, though interaction tests were rare. Several investigated multiple associations between exposure and outcome, increasing the likelihood of false positive claims. There was evidence of publication bias. Conclusions This survey raises concerns regarding inadequacies in the analysis and reporting of epidemiological publications in mainstream journals.

A score for predicting risk of death from cardiovascular disease in adults with raised blood pressure, based on individual patient data from randomised controlled trials.

Abstract Objective: To create a risk score for death from cardiovascular disease that can be easily used. Design: Data from eight randomised controlled trials of antihypertensive treatment. Setting: Europe and North America. Participants: 47 088 men and women from trials that had differing age ranges and differing eligibility criteria for blood pressure. Main outcome measure: 1639 deaths from cardiovascular causes during a mean 5.2 years of follow up. Results: Baseline factors were related to risk of death from cardiovascular disease using a multivariate Cox model, adjusting for trial and treatment group (active versus control). A risk score was developed from 11 factors: age, sex, systolic blood pressure, serum total cholesterol concentration, height, serum creatinine concentration, cigarette smoking, diabetes, left ventricular hypertrophy, history of stroke, and history of myocardial infarction. The risk score is an integer, with points added for each factor according to its association with risk. Smoking contributed more in women and in younger age groups. In women total cholesterol concentration mattered less than in men, whereas diabetes had more of an effect. Antihypertensive treatment reduced the score. The five year risk of death from cardiovascular disease for scores of 10, 20, 30, 40, 50, and 60 was 0.1%, 0.3%, 0.8%, 2.3%, 6.1%, and 15.6%, respectively. Age and sex distributions of the score from the two UK trials enabled individual risk assessment to be age and sex specific. Risk prediction models are also presented for fatal coronary heart disease, fatal stroke, and all cause mortality. Conclusion: The risk score is an objective aid to assessing an individuals risk of cardiovascular disease, including stroke and coronary heart disease. It is useful for physicians when determining an individuals need for antihypertensive treatment and other management strategies for cardiovascular risk. What is already known on this topic Many other factors are known to affect the risk of cardiovascular disease in patients with raised blood pressure A patients overall risk should be taken into account when determining their need for antihypertensive drugs and other strategies for improving cardiovascular health What this study adds A new score uses 11 risk factors to quantify an adults risk of death from cardiovascular disease, including stroke and coronary heart disease The score is based on a large cohort of participants in controlled trials of antihypertensive drugs An individuals risk can be readily assessed as high or low compared with others of the same age and sex The website http://www.riskscore.org.uk/ is available for users of the risk score

Fetal growth and subsequent risk of breast cancer: results from long term follow up of Swedish cohort

Abstract Objective: To investigate whether size at birth and rate of fetal growth influence the risk of breast cancer in adulthood. Design: Cohort identified from detailed birth records, with 97% follow up. Setting: Uppsala Academic Hospital, Sweden. Participants: 5358 singleton females born during 1915-29, alive and traced to the 1960 census. Main outcome measures: Incidence of breast cancer before (at age <50 years) and after (≥ 50 years) the menopause. Results: Size at birth was positively associated with rates of breast cancer in premenopausal women. In women who weighed ≥4000 g at birth rates of breast cancer were 3.5 times (95% confidence interval 1.3 to 9.3) those in women of similar gestational age who weighed <3000 g at birth. Rates in women in the top fifths of the distributions of birth length and head circumference were 3.4 (1.5 to 7.9) and 4.0 (1.6 to 10.0) times those in the lowest fifths (adjusted for gestational age). The effect of birth weight disappeared after adjustment for birth length or head circumference, whereas the effects of birth length and head circumference remained significant after adjustment for birth weight. For a given size at birth, gestational age was inversely associated with risk (P=0.03 for linear trend). Adjustment for markers of adult risk factors did not affect these findings. Birth size was not associated with rates of breast cancer in postmenopausal women. Conclusions: Size at birth, particularly length and head circumference, is associated with risk of breast cancer in women aged <50 years. Fetal growth rate, as measured by birth size adjusted for gestational age, rather than size at birth may be the aetiologically relevant factor in premenopausal breast cancer. What is already known on this topic There is some evidence that birth weight is related to risk of breast cancer The exact nature of any association and whether it differs at premenopausal and postmenopausal ages is unclear Few studies have examined the effect of other measures of birth size and of gestational age What this study adds There are strong positive associations between measures of birth size and rates of breast cancer at premenopausal ages that persisted after adjustment for adult risk factors For a given birth size, gestational age was inversely associated with risk, suggesting that the rate of fetal growth may be aetiologically relevant to premenopausal breast cancer There was no association between birth characteristics and rates of breast cancer at postmenopausal ages

Birth Size and Breast Cancer Risk: Re-analysis of Individual Participant Data from 32 Studies

BACKGROUNDnBirth size, perhaps a proxy for prenatal environment, might be a correlate of subsequent breast cancer risk, but findings from epidemiological studies have been inconsistent. We re-analysed individual participant data from published and unpublished studies to obtain more precise estimates of the magnitude and shape of the birth size-breast cancer association.nnnMETHODS AND FINDINGSnStudies were identified through computer-assisted and manual searches, and personal communication with investigators. Individual participant data from 32 studies, comprising 22,058 breast cancer cases, were obtained. Random effect models were used, if appropriate, to combine study-specific estimates of effect. Birth weight was positively associated with breast cancer risk in studies based on birth records (pooled relative risk [RR] per one standard deviation [SD] [= 0.5 kg] increment in birth weight: 1.06; 95% confidence interval [CI] 1.02-1.09) and parental recall when the participants were children (1.02; 95% CI 0.99-1.05), but not in those based on adult self-reports, or maternal recall during the womans adulthood (0.98; 95% CI 0.95-1.01) (p for heterogeneity between data sources = 0.003). Relative to women who weighed 3.000-3.499 kg, the risk was 0.96 (CI 0.80-1.16) in those who weighed < 2.500 kg, and 1.12 (95% CI 1.00-1.25) in those who weighed > or = 4.000 kg (p for linear trend = 0.001) in birth record data. Birth length and head circumference from birth records were also positively associated with breast cancer risk (pooled RR per one SD increment: 1.06 [95% CI 1.03-1.10] and 1.09 [95% CI 1.03-1.15], respectively). Simultaneous adjustment for these three birth size variables showed that length was the strongest independent predictor of risk. The birth size effects did not appear to be confounded or mediated by established breast cancer risk factors and were not modified by age or menopausal status. The cumulative incidence of breast cancer per 100 women by age 80 y in the study populations was estimated to be 10.0, 10.0, 10.4, and 11.5 in those who were, respectively, in the bottom, second, third, and top fourths of the birth length distribution.nnnCONCLUSIONSnThis pooled analysis of individual participant data is consistent with birth size, and in particular birth length, being an independent correlate of breast cancer risk in adulthood.

Birth characteristics and adult cancer incidence: Swedish cohort of over 11,000 men and women

Associations between larger size at birth and increased rates of adult cancer have been proposed but few empirical studies have examined this hypothesis. We investigated overall and site‐specific cancer incidence in relation to birth characteristics in a Swedish population‐based cohort of 11,166 singletons born in 1915–1929 for whom we have detailed obstetric data and who were alive in 1960. A total of 2,685 first primary cancers were registered during follow‐up from 1960 to 2001. A standard deviation (SD) increase in birth weight for gestational age (GA) was associated with (sex‐adjusted) increases of 13% (95% CI = 0.03–0.23) in the rates of digestive cancers and of 17% (95% CI = 0.01–0.35) in the rates of lymphatic cancers. Women who had higher birth weights also had increased rates of breast cancer under age 50 years (by 39% per SD increase; 95% CI = 0.09–0.79), but reduced rates (by 24%; 95% CI = 0.07–0.38) of endometrial (corpus uteri) cancer at all ages. There was no evidence of associations with other cancer sites. For overall cancer incidence, men had an 8% increased risk at all ages per SD increase in birth weight for GA while women only had an increased risk under age 50 years (mainly driven by the association with breast cancer). These findings provide evidence of a modest association of birth size and adult cancer risk, resulting from positive associations with a few cancer sites and a possible inverse association with endometrial cancer.

Separating the Mechanism-Based and Off-Target Actions of Cholesteryl Ester Transfer Protein Inhibitors With CETP Gene Polymorphisms

Background— Cholesteryl ester transfer protein (CETP) inhibitors raise high-density lipoprotein (HDL) cholesterol, but torcetrapib, the first-in-class inhibitor tested in a large outcome trial, caused an unexpected blood pressure elevation and increased cardiovascular events. Whether the hypertensive effect resulted from CETP inhibition or an off-target action of torcetrapib has been debated. We hypothesized that common single-nucleotide polymorphisms in the CETP gene could help distinguish mechanism-based from off-target actions of CETP inhibitors to inform on the validity of CETP as a therapeutic target. Methods and Results— We compared the effect of CETP single-nucleotide polymorphisms and torcetrapib treatment on lipid fractions, blood pressure, and electrolytes in up to 67 687 individuals from genetic studies and 17 911 from randomized trials. CETP single-nucleotide polymorphisms and torcetrapib treatment reduced CETP activity and had a directionally concordant effect on 8 lipid and lipoprotein traits (total, low-density lipoprotein, and HDL cholesterol; HDL2; HDL3; apolipoproteins A-I and B; and triglycerides), with the genetic effect on HDL cholesterol (0.13 mmol/L, 95% confidence interval [CI] 0.11 to 0.14 mmol/L) being consistent with that expected of a 10-mg dose of torcetrapib (0.13 mmol/L, 95% CI 0.10 to 0.15). In trials, 60 mg of torcetrapib elevated systolic and diastolic blood pressure by 4.47 mm Hg (95% CI 4.10 to 4.84 mm Hg) and 2.08 mm Hg (95% CI 1.84 to 2.31 mm Hg), respectively. However, the effect of CETP single-nucleotide polymorphisms on systolic blood pressure (0.16 mm Hg, 95% CI −0.28 to 0.60 mm Hg) and diastolic blood pressure (−0.04 mm Hg, 95% CI −0.36 to 0.28 mm Hg) was null and significantly different from that expected of 10 mg of torcetrapib. Conclusions— Discordance in the effects of CETP single-nucleotide polymorphisms and torcetrapib treatment on blood pressure despite the concordant effects on lipids indicates the hypertensive action of torcetrapib is unlikely to be due to CETP inhibition or shared by chemically dissimilar CETP inhibitors. Genetic studies could find a place in drug-development programs as a new source of randomized evidence for drug-target validation in humans.

Life-course body size and perimenopausal mammographic parenchymal patterns in the MRC 1946 British birth cohort

Dense mammographic parenchymal patterns are associated with an increased risk of breast cancer. Certain features of body size have been found to be associated with breast cancer risk, but less is known about their relation to breast density. We investigated the association of birth size, childhood growth and life-course changes in body size with Wolfe grade in 1298 perimenopausal women from a British cohort of women born in 1946. The cohort benefits from repeated measures of body size in childhood and adulthood. We obtained mammograms for 90% of women who at age 53 years reported having previously had a mammogram. We found no associations with birth weight or maximum attained height. Body mass index (BMI) at age 53 years and breast size were independently and inversely associated with Wolfe grade (P-value for trend <0.001 for both). Women who reached puberty later were at a greater odds of a higher Wolfe grade than women who had an earlier puberty (odds ratio associated with a 1 year delay in menarche 1.14, 95% CI: 1.01–1.27, adjusted for BMI and breast size at mammography). A higher BMI at any age during childhood or adult life was associated with a reduction in the odds of a higher Wolfe grade, after controlling for breast size and BMI at mammography, for example, standardised odds ratio for height at age 7 was 0.72 (95% CI: 0.64, 0.81). These findings reveal the importance of taking life-course changes in body size, and not just contemporaneous measures, into account when using mammographic density as an intermediate marker for risk of breast cancer.

Lifelong vegetarianism and risk of breast cancer: A population-based case-control study among South Asian migrant women living in England

To investigate the role of lifelong vegetarianism on the aetiology of female breast cancer, we conducted a population‐based case‐control study among South Asian migrant women from the Indian subcontinent resident in England. A total of 240 South Asian breast cancer cases were identified from 2 cancer registries during 1995–1999. For each case, 2 age‐matched South Asian controls were randomly selected from the age‐sex register of the case practice. Lifelong vegetarians had a slight reduction, although not statistically significant, in the odds of breast cancer relative to lifelong meat‐eaters, which persisted after adjustment for socio‐demographic and reproductive variables [odds ratio (OR)=0.77; 95% confidence interval (CI)=0.50–1.18]. Analysis by food group revealed no linear trend in the odds of breast cancer with increasing consumption of meat (p=0.10) but the odds were higher for women in the top 75%. In contrast, there were strong inverse trends in the odds of breast cancer with increasing intake of vegetables (p=0.005), pulses (p=0.007) and fibre [non‐starch polysaccharides, NSP (p=0.02)], with women in the highest 25% of intake of these foods having about 50% of the odds of those in the lowest ones. Adjustment for intake of vegetables and pulses reverted the odds of breast cancer in lifelong vegetarians relative to lifelong meat‐eaters (OR=1.04; 95% CI=0.65–1.68) and attenuated the quartile‐specific estimates for meat intake, whereas the inverse trends in the odds of breast cancer with intake of vegetables and pulses remained after adjustment for type of diet or meat intake. These findings suggest that lifelong vegetarianism may be associated with a reduction in the risk of breast cancer through its association with a higher intake of vegetables and pulses. Although it is not possible to exclude the possibility that lifelong meat abstention may also play a role, the findings provide evidence that a diet rich in vegetables and pulses, such as those typically found in South Asian diets, may be protective against this cancer.

Is the association of birth weight with premenopausal breast cancer risk mediated through childhood growth

Several studies have found positive associations between birth weight and breast cancer risk at premenopausal ages. The mechanisms underlying this association are not known, but it is possible that it may be mediated through childhood growth. We examined data from a British cohort of 2176 women born in 1946 and for whom there were prospective measurements of birth weight and of body size throughout life. In all, 59 breast cancer cases occurred during follow-up, 21 of whom were known to be premenopausal. Women who weighed at least 4u2009kg at birth were five times (relative risk (RR)=5.03; 95% confidence interval=1.13, 22.5) more likely to develop premenopausal breast cancer than those who weighed less than 3u2009kg (P-value for linear trend=0.03). This corresponded to an RR of 2.31 (0.95, 5.64) per 1u2009kg increase in birth weight. Birth weight was also a predictor of postnatal growth, that is, women who were heavy at birth remained taller and heavier throughout their childhood and young adulthood. However, the effect of birth weight on premenopausal breast cancer risk was only reduced slightly after simultaneous adjustment for height and body mass index (BMI) at age 2 years and height and BMI velocities throughout childhood and adolescence (adjusted RR=1.94 (0.74, 5.14) per 1u2009kg increase in birth weight). The pathways through which birth weight is associated with premenopausal breast cancer risk seem to be largely independent of those underlying the relation of postnatal growth to risk.

Estimating the asbestos-related lung cancer burden from mesothelioma mortality

Background:Quantifying the asbestos-related lung cancer burden is difficult in the presence of this diseases multiple causes. We explore two methods to estimate this burden using mesothelioma deaths as a proxy for asbestos exposure.Methods:From the follow-up of 55 asbestos cohorts, we estimated ratios of (i) absolute number of asbestos-related lung cancers to mesothelioma deaths; (ii) excess lung cancer relative risk (%) to mesothelioma mortality per 1000 non-asbestos-related deaths.Results:Ratios varied by asbestos type; there were a mean 0.7 (95% confidence interval 0.5, 1.0) asbestos-related lung cancers per mesothelioma death in crocidolite cohorts (n=6 estimates), 6.1 (3.6, 10.5) in chrysotile (n=16), 4.0 (2.8, 5.9) in amosite (n=4) and 1.9 (1.4, 2.6) in mixed asbestos fibre cohorts (n=31). In a population with 2 mesothelioma deaths per 1000 deaths at ages 40–84 years (e.g., US men), the estimated lung cancer population attributable fraction due to mixed asbestos was estimated to be 4.0%.Conclusion:All types of asbestos fibres kill at least twice as many people through lung cancer than through mesothelioma, except for crocidolite. For chrysotile, widely consumed today, asbestos-related lung cancers cannot be robustly estimated from few mesothelioma deaths and the latter cannot be used to infer no excess risk of lung or other cancers.