Commentary: fibrinogen and coronary heart disease--test of causality by 'Mendelian' randomization by Keavney et al.
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Coronary Disease↗
Biomedical subjects
Bianca L De Stavola
Publications and source records attributed to Bianca L De Stavola.
Statistical issues in life course epidemiology.
There is growing recognition that the risk of many diseases in later life, such as type 2 diabetes or breast cancer, is affected by adult as well as early-life variables, including those operating prior to conception and during the prenatal period. Most of these risk factors are correlated because of common biologic and/or social pathways, while some are intrinsically ordered over time. The study of how they jointly influence later ("distal") disease outcomes is referred to as life course epidemiology. This area of research raises several issues relevant to the current debate on causal inference in epidemiology. The authors give a brief overview of the main analytical and practical problems and consider a range of modeling approaches, their differences determined by the degree with which associations present (or presumed) among the correlated explanatory variables are explicitly acknowledged. Standard multiple regression (i.e., conditional) models are compared with joint models where more than one outcome is specified. Issues arising from measurement error and missing data are addressed. Examples from two cohorts in the United Kingdom are used to illustrate alternative modeling strategies. The authors conclude that more than one analytical approach should be adopted to gain more insight into the underlying mechanisms.
Causality↗
The cognitive cost of being a twin: evidence from comparisons within families in the Aberdeen children of the 1950s cohort study.
OBJECTIVES: To determine whether twins have lower IQ scores in childhood than singletons in the same family and, if so, whether differences in fetal growth explain this deficit. DESIGN: Cohort study. SETTING: Scotland. PARTICIPANTS: 9832 singletons and 236 twins born in Aberdeen between 1950 and 1956. RESULTS: At age 7, the mean IQ score of twins was 5.3 points lower (95% confidence interval 1.5 to 9.1) and at age 9, 6.0 points lower (1.7 to 10.2) than that of singletons in the same family. Adjustment for sex, mother's age, and number of older siblings had little effect on these differences. Further adjustment for birth weight and gestational age attenuated the IQ difference between twins and singletons: the difference in mean IQ was 2.6 points (-1.5 to 6.7) at age 7 and 4.1 points (-0.5 to 8.8) at age 9. CONCLUSIONS: Twins have substantially lower IQ in childhood than singletons in the same family. This effect cannot be explained by confounding due to socioeconomic, maternal, or other family characteristics, or by recruitment bias. The reduced prenatal growth and shorter gestations of twins may explain an important part of their lower IQ in childhood.
Adolescent↗
Birth weight and breast cancer.
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Birth Weight↗
The impact of stage and cell type on the prognosis of pulmonary neuroendocrine tumors.
OBJECTIVE: In pulmonary neuroendocrine tumors the realization that the extent of nodal disease is related to cell type has led to a controversy as to which is the dominant prognostic factor, stage or morphology. To clarify this relationship, we studied patients treated at our institution over a 23-year period. METHODS: This is a historical cohort study of patients with confirmed pulmonary neuroendocrine tumors who underwent lung resection from 1980 through 2003. Survivors were contacted by telephone, and recurrences were confirmed by means of histopathology. Cox proportional hazards regression was used to ascertain the joint influence of several risk factors on survival. RESULTS: The mean age of the cohort was 54 years (standard deviation, 15 years), and 100 (57%) were men. The cell types for the 177 eligible patients were typical carcinoid in 89 (50%), atypical carcinoid in 15 (8%), large cell in 22 (13%), and small cell in 51 (29%). The median time to follow-up was 7 years (first to third quartile, 2-12 years), and overall 5- and 10-year survivals were 86% (79%-90%) and 81% (74%-87%), respectively. The univariable predictors of survival were age (P = .001), nodal stage (P = .01), and cell type (P < .001). In the final multivariable model only age (P = .04) and cell type (P < .001) remained as independent predictors. The hazard of death among patients with large cell or small cell lung cancer was highest in the first year and a half after diagnosis, reducing drastically thereafter. CONCLUSIONS: In pulmonary neuroendocrine tumors cell type is the predominant determinant of survival. The survival of patients with each cell type is sufficiently diverse to warrant different management strategies. Conservative resection is feasible for typical carcinoids, but the effects of adjuvant chemotherapy need to be evaluated for the other subgroups.
Cohort Studies↗
Separating within and between effects in family studies: an application to the study of blood pressure in children.
In epidemiology the analyses of family or twin studies do not always fully exploit the data, as information on differences between siblings is often used while between-families effect are not considered. We show how cross-sectional time-series linear regression analysis can be easily implemented to estimate within- and between-families effects simultaneously and how these effects can then be compared using the Hausman test. We illustrate this approach with data from the Uppsala family study on blood pressure in children with age ranging from 5.5 to 12.3 years for the younger and from 7.5 to 13.8 years for the older siblings. Comparing the effect of differences in birth weight on blood pressure within-family (in full siblings) and between-families (in unrelated children) allows us to study the contributions of fixed and pregnancy-specific maternal effects on birth weight and consequently on blood pressure. Our data showed a 0.88 mmHg decrease (95 per cent confidence interval: -1.7 to -0.03 mmHg) in systolic blood pressure for one standard deviation increase in birth weight between siblings within a family and 0.88 mmHg (95 per cent confidence interval: -1.6 to -0.2 mmHg) decrease in systolic blood pressure for one standard deviation increase in birth weight between unrelated children. These estimates were controlled for sex, age, pubertal stage, body size and pulse rate of the children at examination and for maternal body size and systolic blood pressure. The within- and between-families effects were not significantly different, p = 0.19, suggesting that fixed and pregnancy-specific factors have similar effects on childhood systolic blood pressure.
Adolescent↗
A district-based analysis of stillbirth and infant mortality rates in Italy: 1989-93.
Despite a substantial decline in stillbirth and infant mortality rates in Italy during the last century, there are still large differences between the north and south of the country. This paper analyses the geographical distribution of these rates in the period 1989-93 in terms of biological and social indicators with the aim of identifying possible sources for these differentials. Numbers of stillbirths, infant deaths and deliveries were available in an aggregate form by categories of biological and social factors for each of the 95 Italian administrative districts ('province') operative at the time. Substantial differences in stillbirth (SB) and infant mortality (IM) rates were found across geographical areas, with the lower rates found in the richer and more industrialised north and the higher ones in the more deprived south. Negative binomial regression models were used to study the geographical variations in these rates in terms of biological and social factors. The latter showed strong and significant effects on both SB and IM rates, even after controlling for biological factors. The effects of the biological factors, birthweight and maternal parity in particular, however, were found to differ across geographical areas. Further studies to investigate whether these results may be explained by differentials in health care should be considered.
Adult↗
Risk factors for breast cancer at young ages in twins: an international population-based study.
BACKGROUND: Breast cancer etiology in women may relate to exposures early in life as well as in adulthood, but it has been difficult to gain information on childhood variables, and evidence on their effects is very limited. Comparison of risk factor levels between affected probands and unaffected twins in twin pairs can provide a unique method to investigate risk factors that act in early life. METHODS: We conducted four population-based case-control studies of breast cancer risk in twins in Denmark, England and Wales, Finland, and Sweden and pooled the data from these studies. The case patients were 400 women with incident breast cancer before the age of 50 years, and the control subjects were their twin sisters who had not had breast cancer by that time. Data on risk factors (e.g., demographic and anthropomorphic variables, reproductive history, and family history) were collected by interview and by a mailed questionnaire and were analyzed by calculating matched odds ratios [ORs]. All statistical tests were two-sided. RESULTS: The risk of breast cancer was increased for women who were less obese (OR = 1.44, 95% confidence interval [CI] = 1.08 to 1.91) or taller (OR = 1.27, 95% CI = 0.95 to 1.70) than their co-twin at age 10 years, for women who developed breasts earlier than their co-twin (OR = 1.53, 95% CI = 1.14 to 2.06), and for women who had a smaller waist-to-hip ratio at age 20 years than their co-twin (OR = 1.79, 95% CI = 1.00 to 3.21). Analysis according to family history of breast cancer showed that the associations of childhood height and weight with risk of breast cancer were only apparent in women without a family history of breast cancer. CONCLUSIONS: Childhood growth before puberty may affect the risk of premenopausal breast cancer, at least in women without a family history of breast cancer. The distribution of body fat in young adulthood may also be related to breast cancer risk.
Adolescent↗
Quantification of the completeness of follow-up.
Completeness of follow-up is important, especially in clinical trials, since unequal follow-up in the treatment groups can bias the analysis of results. In survival studies, information on participants who do not complete the study is often omitted because their data can be included up to the time at which they were lost to follow-up. We propose a simple measure of completeness that is the ratio of the total observed person-time and the potential person-time of follow-up in a study. Our measure is easy to calculate, can be illustrated pictorially, and can be used to identify subgroups with especially poor follow-up.
Clinical Trials as Topic↗
Determinants of the availability and accuracy of self-reported birth weight in middle-aged and elderly women.
Associations have been found between birth weight and many diseases in adult life. In most countries, few birth records exist for older adults; therefore, birth weight is usually obtained by maternal recall or self-report. This study examined determinants of the availability and accuracy of self-report in middle-aged and elderly women. Birth weights, recorded at the time of birth, were found in 1999 for a subset of 363 women participating in a long-running cancer research study in the United Kingdom. Questionnaires were sent to the surviving 286 women requesting information on their birth weight and other factors related to their birth family. Twenty-five percent of the 244 respondents were able to report their birth weight to within 4 ounces (113.4 g) of that listed in birth records, 28% reported it inaccurately, and 47% did not know their birth weight. The most important factors determining the availability of self-reported birth weight were having a living mother and a low birth weight (< or = 6 pounds (2,722 g)). The most important determinants of accuracy, for those who provided a report, were being younger and the eldest child. Research studies relying on self-reported birth weight should take these factors into account.
Adult↗
Prenatal factors, childhood growth trajectories and age at menarche.
BACKGROUND: In recent studies a larger birth size has been shown to delay the timing of menarche. The mechanisms underlying this association are not clear, however, as birthweight is a predictor of body size in childhood, and a large body size is known to be associated with an early onset of menarche. METHODS: Data from a representative British cohort of 2547 girls born in 1946 who were followed prospectively throughout childhood were used. Information was available on prenatal characteristics, birthweight, height, weight and social circumstances during childhood, and on age at menarche. Random coefficients models were used to estimate the individual trajectories in height and body mass index (BMI) up to age 7 years. The parameters identified by these models were then included in Weibull survival models for the timing of menarche together with birthweight. RESULTS: Birthweight was found to positively influence height and BMI values at age 2 years, but not to affect their rates of change from age 2 to 7 years. Initial analyses showed low birthweight to be associated with an early onset of menarche, but after controlling for growth in infancy this effect was reversed, with girls who were heavy at birth reaching menarche earlier than others with similar infant growth. Rapid growth in infancy was also related to early pubertal maturation. The effects of birthweight and infant growth disappeared, however, when further controlled for growth from age 2 to 7 years. CONCLUSIONS: The effects of birthweight and growth in infancy on the timing of menarche seem to be mediated through growth in early childhood. These findings are consistent with the possibility that timing of menarche may be set in utero or early in life, although it may be modified by changes in body size and composition in childhood.
Birth Weight↗
Vitamin C is associated with reduced risk of cataract in a Mediterranean population.
Cataract is an important visual problem of older people and a substantial health care cost in many countries. Most studies investigating risk factors for cataract have been conducted in the United States, and there is less information on the possible role of dietary factors in European populations. We conducted a case-control study to investigate the association of antioxidant vitamins (vitamin C, vitamin E, vitamin A, beta-carotene, alpha-carotene, beta-cryptoxanthin, lycopene, zeaxanthin and lutein) and minerals (zinc and selenium) and risk of cataract in a Mediterranean population. Cases with cataract (343) and 334 age/sex frequency-matched controls aged 55 to 74 y were selected from an ophthalmic outreach clinic in Valencia, Spain. Participants were interviewed about their diet using a Food Frequency Questionnaire, and other information on potential confounders, such as smoking, alcohol, and education. Blood samples were analyzed by a colorimetric method for vitamin C and by reversed-phase HLPC for other blood antioxidants. Blood levels of vitamin C above 49 micromol/L were associated with a 64% reduced odds for cataract (P < 0.0001). Dietary intake of vitamins C, E and selenium were marginally associated with decreased odds (P = 0.09, P = 0.09, P = 0.07, respectively), whereas moderately high levels of blood lycopene (>0.30 micromol/L) were associated with a 46% increased odds of cataract (P = 0.04). Our results strengthen the evidence for a protective role for vitamin C on the aging lens as this effect was seen in a population characterized by high vitamin C intakes.
Aged↗