Limited common origins of multiple adult health-related behaviors: Evidence from U.S. twins.

Health-related behaviors are significant contributors to morbidity and mortality in the United States, yet evidence on the underlying causes of the vast within-population variation in behaviors is mixed. While many potential causes of health-related behaviors have been identified-such as schooling, genetics, and environments-little is known on how much of the variation across multiple behaviors is due to a common set of causes. We use three separate datasets on U.S. twins to investigate the degree to which multiple health-related behaviors correlate and can be explained by a common set of factors. We find that aside from smoking and drinking, most behaviors are not strongly correlated among individuals. Based on the results of both within-identical-twins regressions and multivariate behavioral genetics models, we find some evidence that schooling may be related to smoking but not to the covariation between multiple behaviors. Similarly, we find that a large fraction of the variance in each of the behaviors is consistent with genetic factors; however, we do not find strong evidence that a single common set of genes explains variation in multiple behaviors. We find, however, that a large portion of the correlation between smoking and heavy drinking is consistent with common, mostly childhood, environments. This suggests that the initiation and patterns of these two behaviors might arise from a common childhood origin. Research and policy to identify and modify this source may provide a strong way to reduce the population health burden of smoking and heavy drinking.

The latent class twin method.

The twin method refers to the use of data from same-sex identical and fraternal twins to estimate the genetic and environmental contributions to a trait or outcome. The standard twin method is the variance component twin method that estimates heritability, the fraction of variance attributed to additive genetic inheritance. The latent class twin method estimates two quantities that are easier to interpret than heritability: the genetic prevalence, which is the fraction of persons in the genetic susceptibility latent class, and the heritability fraction, which is the fraction of persons in the genetic susceptibility latent class with the trait or outcome. We extend the latent class twin method in three important ways. First, we incorporate an additive genetic model to broaden the sensitivity analysis beyond the original autosomal dominant and recessive genetic models. Second, we specify a separate survival model to simplify computations and improve convergence. Third, we show how to easily adjust for covariates by extending the method of propensity scores from a treatment difference to zygosity. Applying the latent class twin method to data on breast cancer among Nordic twins, we estimated a genetic prevalence of 1%, a result with important implications for breast cancer prevention research.

Estimating heritability for cause specific mortality based on twin studies.

There has been considerable interest in studying the magnitude and type of inheritance of specific diseases. This is typically derived from family or twin studies, where the basic idea is to compare the correlation for different pairs that share different amount of genes. We here consider data from the Danish twin registry and discuss how to define heritability for cancer occurrence. The key point is that this should be done taking censoring as well as competing risks due to e.g.  death into account. We describe the dependence between twins on the probability scale and show that various models can be used to achieve sensible estimates of the dependence within monozygotic and dizygotic twin pairs that may vary over time. These dependence measures can subsequently be decomposed into a genetic and environmental component using random effects models. We here present several novel models that in essence describe the association in terms of the concordance probability, i.e., the probability that both twins experience the event, in the competing risks setting. We also discuss how to deal with the left truncation present in the Nordic twin registries, due to sampling only of twin pairs where both twins are alive at the initiation of the registries.

Likelihood-based concordance tests for analysis of ascertained twin pair multinomial data.

The classic twin model design has a wide application in human genetics. Under the assumption that nongenetic effects are shared to the same degree by monozygotic (MZ) and dizygotic (DZ) twin pairs, a test of the equality of casewise concordances between MZ and DZ twins provides a clue to the influence of genetic and environmental factors on a disease. The casewise concordance is the conditional probability that given that one member of a twin pair is affected, the other is also affected. When disease prevalence is low or cost-effectiveness is considered, collection of twin pairs by ascertainment for performing casewise concordance analysis is required. In this article, by defining an overall casewise concordance parameter, several likelihood-based tests, such as likelihood ratio test LR, score test Score, the usual Wald test Wald and an alternative Wald test WaldA are investigated for a test of the equality of concordances between ascertained MZ and DZ twin pairs under multinomial models. Simulation studies were conducted for data with small sample sizes. The results show that the type I error rates and power of LR and Score are stable only when the overall casewise concordances are not extremely small or large. The Wald has higher power performance in most cases but would slightly inflate type I error rates; the WaldA is the most robust and recommended approach.

The Netherlands Twin Register biobank: a resource for genetic epidemiological studies.

In 2004 the Netherlands Twin Register (NTR) started a large scale biological sample collection in twin families to create a resource for genetic studies on health, lifestyle and personality. Between January 2004 and July 2008, adult participants from NTR research projects were invited into the study. During a home visit between 7:00 and 10:00 am, fasting blood and morning urine samples were collected. Fertile women were bled on day 2-4 of the menstrual cycle, or in their pill-free week. Biological samples were collected for DNA isolation, gene expression studies, creation of cell lines and for biomarker assessment. At the time of blood sampling, additional phenotypic information concerning health, medication use, body composition and smoking was collected. Of the participants contacted, 69% participated. Blood and urine samples were collected in 9,530 participants (63% female, average age 44.4 (SD 15.5) years) from 3,477 families. Lipid profile, glucose, insulin, HbA1c, haematology, CRP, fibrinogen, liver enzymes and creatinine have been assessed. Longitudinal survey data on health, personality and lifestyle are currently available for 90% of all participants. Genome-wide SNP data are available for 3,524 participants, with additional genotyping ongoing. The NTR biobank, combined with the extensive phenotypic information available within the NTR, provides a valuable resource for the study of genetic determinants of individual differences in mental and physical health. It offers opportunities for DNA-based and gene expression studies as well as for future metabolomic and proteomic projects.

Modelling patterns of agreement for nominal scales.

The measurement of agreement of repeat rating is the usual method of assessing the reliability of categorical scales. Measurement of agreement is also important in genetic twin studies based on categorical scales. One of the most commonly used methods of analysis for both types of study is the kappa coefficient. For scales with more than two categories, one approach is to use a single summary kappa coefficient. While this may be sufficient for many studies, in some instances investigation of heterogeneity in the pattern of agreement may give additional insights as there may be greater agreement for some pairs of categories than for others. In this paper, kappa-type coefficients are used to model heterogeneity in the pattern of agreement. Constraints are added to the heterogeneous model to obtain simplified models. Procedures for estimation, confidence intervals, and inference for these coefficients are described for the case of two ratings per subject for a single sample and for the comparison of two independent samples. Formulae for sample size and power calculation are derived using the non-central chi-squared distribution. Two simulation studies are carried out to check the empirical test size and power. Methods are illustrated by two examples involving nominal scales with three categories.

Using bivariate models to understand between- and within-cluster regression coefficients, with application to twin data.

In the regression analysis of clustered data it is important to allow for the possibility of distinct between- and within-cluster exposure effects on the outcome measure, represented, respectively, by regression coefficients for the cluster mean and the deviation of the individual-level exposure value from this mean. In twin data, the within-pair regression effect represents association conditional on exposures shared within pairs, including any common genetic or environmental influences on the outcome measure. It has therefore been proposed that a comparison of the within-pair regression effects between monozygous (MZ) and dizygous (DZ) twins can be used to examine whether the association between exposure and outcome has a genetic origin. We address this issue by proposing a bivariate model for exposure and outcome measurements in twin-pair data. The between- and within-pair regression coefficients are shown to be weighted averages of ratios of the exposure and outcome variances and covariances, from which it is straightforward to determine the conditions under which the within-pair regression effect in MZ pairs will be different from that in DZ pairs. In particular, we show that a correlation structure in twin pairs for exposure and outcome that appears to be due to genetic factors will not necessarily be reflected in distinct MZ and DZ values for the within-pair regression coefficients. We illustrate these results in a study of female twin pairs from Australia and North America relating mammographic breast density to weight and body mass index.

The Swedish Young Male Twins Study: a resource for longitudinal research on risk factors for obesity and cardiovascular diseases.

The Swedish Young Male Twins Study is a population-based longitudinal twin study founded in 1997 through record-linkages of several national registers. Details on pregnancy and birth were obtained from the Swedish Medical Birth Register and used to identify 3566 male twins (1783 pairs) born in Sweden between 1973 and 1979 and resident in Sweden in 1997. A record-linkage was made between the Medical Birth Register and the Military Service Conscription Register for the years 1991 to 1999, providing information on body weight, height, blood pressure, muscle strength, cognitive ability of these twins at age 18 and 19 years. In 1998, 2002 and 2005 to 2006, the twins were surveyed on their zygosity, socioeconomic status, lifestyle factors (such as eating habits, physical activity, smoking habits, use of alcohol etc), height and weight. In 2002, additional information was collected on perceived body shape and size, and eating behavior, according to the Three-Factor Eating Questionnaire. In 2003, DNA via buccal mucosa was collected from a subset of the twins. Recent research using the Swedish Young Male Twins datasets has explored the relationships between fetal growth, body size and blood pressure in young adulthood, genetic and environmental contributions to eating behavior and physical activity, and relationships between diet and physical activity patterns with longitudinal changes in body mass index and attained waist circumference.

The danish twin registry: past and present.

The Danish Twin Registry was established formally in 1954 and thus celebrates its 50th anniversary in 2004. Here we give an account of its founding and the early years, and a brief summary of more recent progress.

Risk of stroke associated with nonsteroidal anti-inflammatory drugs: a nested case-control study.

BACKGROUND AND PURPOSE: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with bleeding complications and may affect the risk of hemorrhagic stroke through inhibition of platelet cyclooxygenase-1. We performed a population-based case-control study to estimate the risk of intracerebral hemorrhage, subarachnoid hemorrhage, and ischemic stroke in users of NSAIDs. METHODS: We used a population-based patient registry to identify all patients with a first-ever stroke discharge diagnosis in the period of 1994 to 1999. All diagnoses were validated according to predefined criteria. We selected 40 000 random controls from the background population. Information on drug use for cases and controls was retrieved from a prescription registry. Odds ratios were adjusted for age, sex, calendar year, and use of other medication. To evaluate the effect of various potential confounders not recorded in the register, we performed separate analyses on data from 2 large population-based surveys with more detailed information on risk factors. RESULTS: The cases were classified as intracerebral hemorrhage (n=659), subarachnoid hemorrhage (n=208), and ischemic stroke (n=2717). The adjusted odds ratio of stroke in current NSAID users compared with never users was 1.2 (95% CI, 0.9 to 1.6) for intracerebral hemorrhage, 1.2 (95% CI, 0.7 to 2.1) for subarachnoid hemorrhage and 1.2 (95% confidence interval, 1.0 to 1.4) for ischemic stroke. The survey data indicated that additional confounder control would not have led to an increase in relative risk estimates. CONCLUSIONS: Current exposure to NSAIDs is not a risk factor for intracerebral hemorrhage or subarachnoid hemorrhage. Furthermore, NSAIDs probably offer no protection against first-ever ischemic stroke.

[Epidemiology of twin and twin with birth defects in China].

OBJECTIVE: To investigate the incidence of twin and twin with birth defect (BD) and with neural tube defect (NTD) in China. METHODS: A prospective monitoring was conducted among the perinatal infants born in 945 hospitals in 20 provinces/municipalities/autonomous regions in China during the period from 1 October 1986 to 30 September 1987 to count up the numbers of twins and of twins with BD or NTD. RESULTS: 1 243 284 infants were born during this period. Among these perinatal infants there were 12 715 pairs of twins with an incidence of 10.23%. The incidence rates of twin with BD and of twin with NTD were 36.81% and 5.27% respectively. There was no difference in incidence rate of twin among different parts of the country and between urban area and rural area. The incidence rate of twin was the highest among the women aged 20 approximately 39, among primipara, and in October and November. The incidence rate of twin with BD showed no difference among different seasons, parities, and parts of the country and between urban area and rural area. Most of twin with BD occurred at the age 20 approximately 39. Most twins with NTD were born in the northern provinces and rural area. The incidence rate of twin with NTD was correlated with season, most twins with NTD being born in November, and was no correlated with age and parity of the mother. CONCLUSION: The incidence of BD, especially the incidence of NTD, among twins is significantly higher than that among total perinatal infants in China. Prenatal monitoring is important for twin pregnancy.

The Australian Twin Registry.

The Australian Twin Registry (ATR), established in the late 1970s, is a volunteer registry of over 30,000 pairs of Australian twins of all zygosity types and ages unselected for their health or medical history. The ATR does not undertake research itself but acts as facilitator, providing an important national and international resource for medical and scientific researchers across a broad range of disciplines. Its core functions are the maintenance of an up-to-date database containing basic contact details and baseline information, and the management of access to the resource in ways that enhance research capacity within Australia while protecting the rights of twins. The ATR has facilitated more than 200 studies using a variety of designs, including classic biometrical twin and twin family studies, co-twin control studies, intervention studies, longitudinal studies, and studies of issues relevant specifically to twins. These have yielded more than 300 peer-reviewed publications to date. Areas of major research include studies of behavior, musculoskeletal conditions, teeth and face patterns, cardiovascular risk factors, substance abuse, and risk factors for melanoma and breast cancer. Extensive longitudinal data are available for around 10,000 pairs. DNA samples have been obtained from more than 6000 twins. Considerable efforts are devoted to maintaining the commitment of registry members and recruitment. The ATR hopes to secure funding to expand its activities, including the systematic collection of DNA samples, so that it can continue to play a major role in the development of twin research and contribute to the annotation of the human genome.

Chinese National Twin Registry as a resource for genetic epidemiologic studies of common and complex diseases in China.

Twins, due to their unique genetic and environmental relationships, have provided crucial insight in our understanding of genetic contributions to numerous etiologically complex disorders in developed countries. As the leading cause of death and adult disability, cardio- and cerebrovascular diseases are common in China, followed by cancer. Obesity and psychological disorders are increasing. The overall goal of this program is to develop a resource for genetic epidemiologic studies of these and other common and complex diseases in China. Our initial focus is to delineate the genetic and environmental determinants of vascular diseases in general, coronary artery disease (CAD) and stroke in particular. To date, we have over 4500 twin pairs registered and about 700 twin pairs studied for various metabolic traits (e.g., lipids, glucose, insulin, etc.). The long-term plan of this program is to (1) establish a population-based twin registry from several selected regions in China for future studies of specific common complex diseases; (2) conduct detailed phenotyping for clinical and intermediate traits related to cardiovascular diseases; (3) expand studies of twins to twin families by including their parents, siblings, and offspring for genetic linkage and association studies; and (4) follow up twins in the registry longitudinally. The goals of the program are health education and promotion of healthy behavior, early identification of cases to provide timely medical attention, and the evaluation of long-term effects of identified risk factors. We want to develop collaborations with investigators who have expertise in cancer, psychological disorders, and other disease areas.

The Italian Twin Project: from the personal identification number to a national twin registry.

The unique opportunity given by the "fiscal code", an alphanumeric identification with demographic information on any single person residing in Italy, introduced in 1976 by the Ministry of Finance, allowed a database of all potential Italian twins to be created. This database contains up to now name, surname, date and place of birth and home address of about 1,300,000 "possible twins". Even though we estimated an excess of 40% of pseudo-twins, this still is the world's largest twin population ever collected. The database of possible twins is currently used in population-based studies on multiple sclerosis, Alzheimer's disease, celiac disease, and type 1 diabetes. A system is currently being developed for linking the database with data from mortality and cancer registries. In 2001, the Italian Government, through the Ministry of Health, financed a broad national research program on twin studies, including the establishment of a national twin registry. Among all the possible twins, a sample of 500,000 individuals are going to be contacted and we expect to enrol around 120,000 real twin pairs in a formal Twin Registry. According to available financial resources, a sub sample of the enrolled population will be asked to donate DNA. A biological bank from twins will be then implemented, guaranteeing information on future etiological questions regarding genetic and modifiable factors for physical impairment and disability, cancers, cardiovascular diseases and other age related chronic illnesses.

Norwegian Twin Registers and Norwegian twin studies--an overview.

The Norwegian Twin Registers include several sets of population-based sub-registers, and covers twin pairs born between 1895 and today. Except for the missing birth years 1960 to 1967, the register is almost complete. Most of the register contains information about both same-sexed and opposite-sexed twin pairs, except for twin pairs born between 1946 and 1960, where only same-sexed twins are registered. In a substantial part of the register, information about zygosity is obtained, mainly by a mailed questionnaire and in some cases supported by DNA testing. These are the birth years 1915 to 1960 and the birth years 1967 to 1979. Zygosity information is further obtained in the different twin studies derived from the twin register. In 1990 the whole register was made available in a computerized form. Several twin studies have been derived from the different parts of the register. In this article, studies from the two earliest parts of the register are reviewed and grouped by recruitment specifics. Finally, future plans for the register and twin studies are discussed.

The Swedish Twin Registry in the third millennium.

Since the Swedish Twin Registry was first established in the late 1950s to study the importance of smoking and alcohol consumption on cancer and cardiovascular diseases, it has been expanded and updated on several occasions. The focus has similarly broadened to most common complex diseases. The content of the database is described, ongoing projects based on the registry are summarized, and we review some of the principal findings on aging, cancer and cardiovascular disease that have come from the registry. Ongoing efforts and future plans for the STR are discussed. Among others, we plan blood collection and genotyping to study the genetic bases of complex diseases, a first contact ever with the cohorts born after 1958, and in-depth studies of selected diseases, such as Parkinson's disease and chronic fatigue syndrome.

Statistical inferences for a twin correlation with multinomial outcomes.

Current methods for statistical analysis of twin studies focus on continuous and dichotomous data, while only limited methodology exists for analysing multinomial data. As a consequence, investigators are often tempted to collapse multinomial data into two categories simply to facilitate the analysis. We address this problem by developing and evaluating two approaches to the assessment of twin correlation for an outcome variable having more than two nominal categories. One method developed is an extension of the goodness-of-fit approach, while the other method is based on large sample normal theory. Procedures for confidence interval construction are developed and compared using Monte Carlo simulation. The results show that either method may be safely used for confidence interval construction provided the number of twin pairs is large (> or =100) but that in smaller sample sizes the goodness-of-fit procedure is to be preferred on the grounds of validity. Other inference problems are also discussed, including point estimation, hypothesis testing and sample size estimation. An example is included.

Smoking and the genetic contribution to alcohol-dependence risk.

Genes influence a person's risk of becoming a smoker as well as the risk of alcohol dependence. Because substantially higher rates of smoking are observed in alcoholics than in control groups, uncovering the mechanisms underlying this association may have important implications for both treatment and prevention. Data analyses from the 1981 Australian twin panel cohort confirm a positive genetic correlation between regular smoking and the risk of alcohol dependence that remains significant, even when sociodemographic and personality variables as well as histories of other psychopathologies are taken into account. Acute or chronic effects of smoking on subjective responses to alcohol may play a role in this association.

Testing the equality of twin correlations with multinomial outcomes.

Twin studies are widely used to study genetic and environmental influences on human measurements. Correlations are often used in such studies to compare the levels of similarity between monozygotic and dizygotic twins with respect to a specified trait. In this paper, we compare three procedures for testing the equality of twin correlations when the outcome variable of interest is multinominal. One method is a likelihood ratio test based on an underlying Dirichlet-multinomial distribution. The second method is based on the estimated large sample variance of the estimated correlation, and the third method is based on a chi 2 goodness-of-fit test. The results of a Monte Carlo simulation show that the three methods have similar properties if the number of twin pairs is large (> 100), and the prevalence of the underlying trait is not extreme. Otherwise, the goodness-of-fit approach is to be preferred. We illustrate the methods by analyzing data from a previously published smoking study.