ArticleLiterature Review

Regression models for twin studies: A critical review

November 2005
International Journal of Epidemiology 34(5):1089-99

November 2005
34(5):1089-99

DOI:10.1093/ije/dyi153

Source
PubMed

Authors:

Lyle Gurrin

University of Melbourne

Jonathan A C Sterne

University of Bristol

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Twin studies have long been recognized for their value in learning about the aetiology of disease and specifically for their potential for separating genetic effects from environmental effects. The recent upsurge of interest in life-course epidemiology and the study of developmental influences on later health has provided a new impetus to study twins as a source of unique insights. Twins are of special interest because they provide naturally matched pairs where the confounding effects of a large number of potentially causal factors (such as maternal nutrition or gestation length) may be removed by comparisons between twins who share them. The traditional tool of epidemiological 'risk factor analysis' is the regression model, but it is not straightforward to transfer standard regression methods to twin data, because the analysis needs to reflect the paired structure of the data, which induces correlation between twins. This paper reviews the use of more specialized regression methods for twin data, based on generalized least squares or linear mixed models, and explains the relationship between these methods and the commonly used approach of analysing within-twin-pair difference values. Methods and issues of interpretation are illustrated using an example from a recent study of the association between birth weight and cord blood erythropoietin. We focus on the analysis of continuous outcome measures but review additional complexities that arise with binary outcomes. We recommend the use of a general model that includes separate regression coefficients for within-twin-pair and between-pair effects, and provide guidelines for the interpretation of estimates obtained under this model.

Sports club participation impacts life satisfaction in adolescence: A twin study

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Apr 2024

Pituitary gland height evaluated with magnetic resonance imaging in premature twins: the impact of growth and sex

Article

Full-text available

Feb 2024
PEDIATR RADIOL

Background Pituitary gland height reflects secretory activity of the hypothalamo-pituitary axis. Objective To assess the cumulative impact of fetal growth and sex on pituitary gland height in premature twins, dissociated from prematurity. Materials and Methods A retrospective study was conducted, assessing the pituitary gland height in 63 pairs of preterm twins, measured from T1-weighted magnetic resonance imaging (MRI). Auxological parameters, including body weight, body length, and head circumference, at birth and at the time of MRI, were used as proxies for fetal and postnatal growth, respectively. The study population was divided into two groups, using corrected age at around term equivalent as the cutoff point. Statistical analysis was performed using mixed-effects linear regression models. Results When pituitary gland height was evaluated at around term equivalent, a greater pituitary gland height, suggesting a more immature hypothamo-pituitary axis, was associated with the twin exhibiting lower auxological data at birth. The same association was observed when body weight and length at MRI were used as covariants. In the group evaluated after term equivalent, a smaller pituitary gland height, suggesting a more mature hypothamo-pituitary axis, was associated with male sex. This difference was observed in twin pairs with higher average body weight at birth, and in babies exhibiting higher auxological data at MRI. Conclusion After isolating the effect of prematurity, at around term equivalent, pituitary gland height reflects the cumulative impact of fetal growth on the hypothalamo-pituitary axis. Subsequently, pituitary gland height shows effects of sex and of fetal and postnatal growth. Graphical Abstract

Familial confounding of internalising symptoms and obesity in adolescents and young adults; a co-twin analysis

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Full-text available

Feb 2024
INT J OBESITY

Background Obesity and internalising disorders, including depression and anxiety, often co-occur. There is evidence that familial confounding contributes to the co-occurrence of internalising disorders and obesity in adults. However, its impact on this association among young people is unclear. Our study investigated the extent to which familial factors confound the association between internalising disorders and obesity in adolescents and young adults. Subjects/methods We used a matched co-twin design to investigate the impact of confounding by familial factors on associations between internalising symptoms and obesity in a sample of 4018 twins aged 16 to 27 years. Results High levels of internalising symptoms compared to low levels increased the odds of obesity for the whole cohort (adjusted odds ratio [AOR] = 3.1, 95% confidence interval [CI]: 1.5, 6.8), and in females (AOR = 4.1, 95% CI 1.5, 11.1), but not in males (AOR = 2.8 95% CI 0.8, 10.0). We found evidence that internalising symptoms were associated with an increased between-pair odds of obesity (AOR 6.2, 95% CI 1.7, 22.8), using the paired analysis but not using a within-pair association, which controls for familial confounding. Sex-stratified analyses indicated high internalising symptoms were associated with increased between-pair odds of obesity for females (AOR 12.9, 95% CI 2.2, 76.8), but this attenuated to the null using within-pair analysis. We found no evidence of between or within-pair associations for males and weak evidence that sex modified the association between internalising symptoms and obesity (likelihood ratio test p = 0.051). Conclusions Some familial factors shared by twins confound the association between internalising symptoms and obesity in adolescent and young adult females. Internalising symptoms and obesity were not associated for adolescent and young adult males. Therefore, prevention and treatment efforts should especially address familial shared determinants of obesity, particularly targeted at female adolescents and young adults with internalising symptoms and those with a family history of these disorders.

Associations Between Adolescent Pain and Psychopathology in the Adolescent Brain Cognitive Development (ABCD) Study

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Full-text available

Apr 2023
BEHAV GENET

Pain and psychopathology co-occur in adolescence, but the directionality and etiology of these associations are unclear. Using the pain questionnaire and the Child Behavior Checklist from the Adolescent Brain Cognitive Development study (n = 10,414 children [770 twin pairs] aged 12–13), we estimated longitudinal, co-twin control, and twin models to evaluate the nature of these associations. In two-wave cross-lag panel models, there were small cross-lag effects that suggested bidirectional associations. However, the co-twin control models suggested that most associations were familial. Pain at age 12 and 13 was mostly environmental (A = 0–12%, C = 15–30%, E = 70–73%) and the twin models suggested that associations with psychopathology were primarily due to shared environmental correlations. The exception was externalizing, which had a phenotypic prospective effect on pain, a significant within-family component, and a non-shared environmental correlation at age 12. Environmental risk factors may play a role in pain-psychopathology co-occurrence. Future studies can examine risk factors such as stressful life events.

Calculating within-pair difference scores in the co-twin control design. Effects of alternative strategies

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Feb 2024

Co-twin studies are an elegant and powerful design that allows controlling for the effect of confounding variables, including genetic and a range of environmental factors. There are several approaches to carry out this design. One of the methods commonly used, when contrasting continuous variables, is to calculate difference scores between members of a twin pair on two hypothetically associated variables, in order to analyse the covariation of such differences. However, information regarding whether and how the different ways of estimating within-pair difference scores may impact the results is scant. This study aimed to compare the results obtained by different methods of data transformation when performing a co-twin study and test how the magnitude of the association changes using each of those approaches. Data was simulated using a direction of causation model as a reference and by fixing the effect size of causal path to low, medium, and high values. Within-pair difference scores were calculated as relative scores for diverse within-pair ordering conditions or absolute scores. Pearson’s correlations using relative difference scores vary across the established scenarios (how twins were ordered within pairs) and these discrepancies become larger as the within-twin correlation increases. Absolute difference scores tended to produce the lowest correlation in every condition. Our results show that both using absolute difference scores or ordering twins within pairs, may produce an artificial decrease in the magnitude of the studied association, obscuring the ability to detect patterns compatible with causation, which could lead to discrepancies across studies and erroneous conclusions.

Reduction in the use of green spaces during the COVID-19 pandemic and its impact on mental health

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Jul 2023

Our study examined the use of green spaces before and during the pandemic in a large cohort of Italian twins and evaluated its impact on measures of mental health (depressive, anxiety, stress symptoms). Twins were analysed as individuals and as pairs. A twin design approach was applied to minimize confounding by genetic and shared environmental factors. Questionnaires from 2,473 twins enrolled in the Italian Twin Registry were screened. Reduced green space use was associated with significantly higher levels of depression, anxiety and distress. Being a woman, residing in urban areas, and having a high perceived risk of the outbreak resulted in a higher likelihood to modify green space use, with a negative impact on mental health.

Missing data strategies in developmental psychology: a practical example on the Babytwins Study Sweden

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Jun 2023

This study provides a detailed description of rationale and methods for multiple imputation of missing data across the entire set of questionnaire and clinical variables available longitudinally in the BATSS sample. The BATSS study is a large, multi-modal study investigating genetic and environmental influences on developmental trait variation in infancy, including attentional and neural measures obtained from eye-tracking and electrophysiology, based on a twin design.

The latent structure of emerging cognitive abilities: An infant twin study

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Jun 2023

Giorgia Bussu

It is well known that genetic factors account for up to 70% of variability in cognition from childhood to adulthood. However, less is known about the first year of life. This study investigated the etiological factors influencing individual variability in different domains of emerging cognitive and motor abilities in early infancy, and to what extent genetic and environmental influences are unique or shared across different domains. We compared multivariate twin models built on scores from the five scales of the Mullen Scales of Early Learning (MSEL) in a community sample of monozygotic and dizygotic twins at 5 months of age (n=567). The results indicated a hierarchical etiological structure whereby a general genetic latent factor accounted for 54% of variance underlying the different domains of emerging cognitive and motor abilities (A=0.54, confidence interval CI=[0; 0.82]). We also found additional genetic influences that were specific to early motor and language development. Unlike previous findings on older children, we did not find significant influences of shared environment on the shared factor (C=0, CI=[0, 0.57]), or any specific scale. Furthermore, influences of unique environment, which include measurement error, were moderate and statistically significant (E=0.46, CI=0.18; 0.81]). This study provides strong evidence for a unitary hierarchical structure across different domains of emerging cognition. Evidence that a single common etiological factor, which we term infant g, contributes to a range of different abilities supports the view that in young infants, intrinsic and general neurodevelopmental processes are key drivers of observable behavioural differences in specific domains.

A comparison of perinatal outcomes following fresh blastocyst or cleavage stage embryo transfer in singletons and twins and between singleton siblings

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Full-text available

Feb 2023

STUDY QUESTION Are perinatal outcomes following fresh blastocyst versus fresh cleavage stage embryo transfer (ET) different in singletons, twins and between singleton siblings? SUMMARY ANSWER Singleton babies conceived following fresh blastocyst, versus cleavage stage, ET are less likely to be small for gestational age or to have a congenital anomaly (a result confirmed by comparing singleton siblings), while singletons born following fresh blastocyst ET were at a higher risk of being large for gestational age (LGA) than their sibling born following fresh cleavage stage ET. WHAT IS KNOWN ALREADY Blastocyst stage transfer is now the preferred strategy in most IVF Units. Previous studies have suggested that babies conceived through blastocyst transfer are at increased risk of preterm birth and LGA. STUDY DESIGN, SIZE, DURATION A national population-based retrospective cohort study was performed using linked Human Fertilisation and Embryology Authority (HFEA) data on 130,516 IVF and ICSI livebirths occurring from 103,062 women between 2000 and 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS We included women who had at least one singleton livebirth resulting from IVF/ICSI fresh embryo treatment, using their own eggs and partner’s sperm. A linked HFEA dataset was analysed using a multilevel framework, which accommodated repeated IVF cycles resulting in livebirths in the same woman. A population-averaged robust Poisson model was used for binary outcomes and a multinomial logistic regression model was used for categorical outcomes. Unadjusted and adjusted risk ratios (aRR) (95% CI) were calculated. MAIN RESULTS AND THE ROLE OF CHANCE There were 130,516 livebirths in 103,062 women, including 86,630 singletons, 43,886 twin births and 5,384 pairs of singleton siblings. In comparison with fresh cleavage stage ET, fresh blastocyst stage transfer in singletons was associated with a lower risk of low birthweight (aRR = 0.92; 95% CI 0.86, 0.99), lower risk of being small for gestational age (0.83; 0.78, 0.89) and lower risk of congenital anomaly (0.79; 0.71, 0.89). This analysis did not show an increase in risk associated with preterm birth (1.00; 0.94, 1.06), high birthweight (0.99; 0.93, 1.06), LGA (0.99; 0.93, 1.05) and the chance of healthy singleton baby (1.00; 1.00, 1.02). Twins resulting from fresh blastocyst stage ET were at slightly higher risk of preterm birth (1.05; 1.02, 1.10) compared with twins conceived following fresh cleavage stage ET. There was insufficient evidence for an association with the other perinatal outcomes. Singleton siblings born following fresh blastocyst stage ET were at a higher risk of being LGA (1.57; 1.01, 2.46) and at lower risk of having a congenital anomaly (0.52; 0.28, 0.97) compared to their singleton siblings born following cleavage stageET. There was some evidence of excess risk of preterm birth (1.42; 0.97, 2.23) associated with blastocyst stage transfer. However, we could not confirm an association between blastocyst stage ET and low birthweight (1.35; 0.81, 2.27), high birthweight (1.19; 0.80, 1.77) and the chance of being a healthy baby (0.97; 0.86, 1.09). LIMITATIONS, REASONS FOR CAUTION This was an observational study where we were unable to adjust for some key confounders, such as maternal smoking status and BMI, which may change from one pregnancy to another and are not recorded in the HFEA dataset. WIDER IMPLICATIONS OF THE FINDINGS In the largest study of its kind, our analysis of singleton siblings, corrected for unmeasured, non-time varying maternal factors, confirms the previously reported association between blastocyst transfer and LGA babies, and shows a reduced risk of congenital anomaly following blastocyst transfer. Our sibling analysis did not confirm a decreased risk of low birthweight following blastocyst transfer. Overall, absolute risks are low and there is insufficient evidence to challenge the practice of extended culture of embryos. STUDY FUNDING/COMPETING INTEREST(S) This project is financed by the NHS Grampian Endowment Grants, project number 17/052. One of the authors, SB, was the Editor in Chief of HROpen until 31st December 2022 and would have been in that role when the paper was first submitted. As an invited speaker, SB has received travel expenses, accommodation and honoraria from Merck, Organon and Ferring. AM has received travel expenses, accommodation and honoraria from Merck Serono, Cook Medical, Pharmasure, Gedeon Richter and Ferring. DJM is currently a HROpen Associate Editor. TRIAL REGISTRATION NUMBER N/A WHAT DOES THIS MEAN FOR PATIENTS? IVF embryos are grown in the laboratory for between 2 and 5 days before they are replaced within the womb. The day on which an embryo is transferred (day 2/day 3 or day 5) could affect a pregnancy resulting from treatment and the health of a baby. The aim of our study was to use information from British IVF clinics to find out whether the time an embryo is grown in the laboratory affects its chances of developing into a healthy baby (measured as preterm, low or high birthweight or congenital anomaly). Our results show that single babies born following the transfer of embryos on the fifth day are larger than their siblings (brothers or sisters) created using embryos replaced sooner (at day 3), and have a lower risk of birth defects. Twins conceived following a day 5 embryo transfer were marginally more likely to be preterm than those born following a day 3 embryo transfer.

Changes in family situation and concurrent changes in working life: a 15-year longitudinal analysis

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Full-text available

Apr 2024

Objective Currently, little is known regarding changes in family situation with concurrent changes in working life. This study aimed to examine whether changes in family situation (based on living with children and/or marrying/divorcing) were associated with changes in working life and whether the associations were influenced by sex, genetics and early life environment. Design Prospective cohort study. Setting and participants Data from Swedish national registers of 16 410 twins were used. Fixed-effects logistic regression models assessing ORs with 95% CIs were applied to examine associations between changes in family situation and working life controlling for time-invariant effects and adjusted for covariates, and conditional models to account for confounding of genetics and early life environment. Results Changes in individuals life situation from being single and living without children to married and living with children were associated with transitioning from unsustainable (ie, having unemployment or sickness absence/disability pension) to sustainable working life (men: OR 2.40, 95% CI 2.26 to 2.56; women: OR 1.68, 95% CI 1.59 to 1.78). Changes from being married to single, in contrast, attenuated the likelihood of transitioning to a sustainable working life. Moreover, changes in men’s working life seem to be more dependent on changes in family situation compared with women. Genetic factors and early life environment play a role in the associations. Conclusions Family formation increases the likelihood of a more stable working life whereas divorce is a risk factor for work interruptions. Our study emphasises that family formation improves the work life situation and to a higher degree for men.

Heart Rate Variability, Deceleration Capacity of Heart Rate, and Death: A Veteran Twins Study

Article

Mar 2024

Background Autonomic function can be measured noninvasively using heart rate variability (HRV), which indexes overall sympathovagal balance. Deceleration capacity (DC) of heart rate is a more specific metric of vagal modulation. Higher values of these measures have been associated with reduced mortality risk primarily in patients with cardiovascular disease, but their significance in community samples is less clear. Methods and Results This prospective twin study followed 501 members from the VET (Vietnam Era Twin) registry. At baseline, frequency domain HRV and DC were measured from 24‐hour Holter ECGs. During an average 12‐year follow‐up, all‐cause death was assessed via the National Death Index. Multivariable Cox frailty models with random effect for twin pair were used to examine the hazard ratios of death per 1‐SD increase in log‐transformed autonomic metrics. Both in the overall sample and comparing twins within pairs, higher values of low‐frequency HRV and DC were significantly associated with lower hazards of all‐cause death. In within‐pair analysis, after adjusting for baseline factors, there was a 22% and 27% lower hazard of death per 1‐SD increment in low‐frequency HRV and DC, respectively. Higher low‐frequency HRV and DC, measured during both daytime and nighttime, were associated with decreased hazard of death, but daytime measures showed numerically stronger associations. Results did not substantially vary by zygosity. Conclusions Autonomic inflexibility, and especially vagal withdrawal, are important mechanistic pathways of general mortality risk, independent of familial and genetic factors.

No evidence of association between either Modic change or disc degeneration and five circulating inflammatory proteins

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Full-text available

Mar 2024

Introduction Intervertebral disc degeneration and Modic change are the main spinal structural changes associated with chronic low back pain (LBP). Both conditions are thought to manifest local inflammation and if inflammatory proteins translocate to the blood circulation could be detected systemically. The work here assesses whether the presence of disc degeneration is associated with detectable blood level changes of five inflammatory markers and whether chronic LBP is associated with these changes. Materials and Methods Two hundred and forty TwinsUK cohort participants with both MRI disc degeneration grade and Modic change extent, and IL‐6, IL‐8, IL‐8 TNF, and CX3CL1 protein blood concentration measurements were included in this work. Linear mixed effects models were used to test the association of blood cytokine concentration with disc degeneration score and Modic change volumetric score. Association of chronic LBP status from questionnaires with disc degeneration, Modic change, and cytokine blood concentration was also tested. Results No statistically significant association between disc degeneration or Modic change with cytokine blood concentration was found. Instead, regression analysis pointed strong association between cytokine blood concentration with body mass index for IL‐6 and with age for IL‐6 and TNF. Mild association was found between IL‐8 blood concentration and body mass index. Additionally, LBP status was associated with Modic change volumetric score but not associated with any cytokine concentration. Conclusions We found no evidence that Modic change and disc degeneration are able to produce changes in tested blood cytokine concentration. However, age and body mass index have strong influence on cytokine concentration and both are associated with the conditions studied which may confound associations found in the literature. It is then unlikely that cytokines produced in the disc or vertebral bone marrow induce chronic LBP.

Genetic and environmental contributions to gaze lateralization across social and non-social stimuli in human infants

Article

Full-text available

Feb 2024

A tendency to look at the left side of faces from the observer’s point of view has been found in older children and adults, but it is not known when this face-specific left gaze bias develops and what factors may influence individual differences in gaze lateralization. Therefore, the aims of this study were to estimate gaze lateralization during face observation and to more broadly estimate lateralization tendencies across a wider set of social and non-social stimuli, in early infancy. In addition, we aimed to estimate the influence of genetic and environmental factors on lateralization of gaze. We studied gaze lateralization in 592 5-month-old twins (282 females, 330 monozygotic twins) by recording their gaze while viewing faces and two other types of stimuli that consisted of either collections of dots (non-social stimuli) or faces interspersed with objects (mixed stimuli). A right gaze bias was found when viewing faces, and this measure was moderately heritable (A = 0.38, 95% CI 0.24; 0.50). A left gaze bias was observed in the non-social condition, while a right gaze bias was found in the mixed condition, suggesting that there is no general left gaze bias at this age. Genetic influence on individual differences in gaze lateralization was only found for the tendency to look at the right versus left side of faces, suggesting genetic specificity of lateralized gaze when viewing faces.

Mental disorders and discrimination: A prospective cohort study of young twin pairs in Germany

Article

Full-text available

Feb 2024

Background Mental disorders and perceived discrimination share common risk factors. The association between having a mental disorder and experiencing discrimination is well-known, but the extent to which familial factors, such as genetic and shared environmental factors, might confound this association, including sex differences in familial confounding, remains unexplored. Aims We investigated potential unmeasured familial confounding in the association between mental disorders and perceived discrimination using a matched twin study design. Method We examined data from 2044 same-sex twin pairs (n = 4088) aged 16–25 years from the German population-based study ‘TwinLife'. We applied random-effects logistic regression to within-individual and within-and-between pair models of the association between mental disorder and perceived discrimination, and used likelihood ratio tests (LRTs) to compare these models. Multivariable models were adjusted for body mass index, educational attainment, and life satisfaction. Results There were 322 (8.1%) participants with a diagnosed mental disorder, and 15% (n = 604) of the cohort reported having experienced discrimination in the previous 12 months. Mental disorder and discrimination were associated in the adjusted within-individual model (adjusted odds ratio = 2.19, 95% confidence interval: 1.42–3.39, P<0.001). However, the within-and-between pair model showed that this association was explained by the within-pair mean (aOR = 4.24, 95% CI: 2.17–8.29, P<0.001) and not the within-pair difference (aOR = 1.26, 95% CI: 0.70–2.28, P = 0.4) of mental disorder. Therefore, this association was mostly explained by familial confounding, which is also supported by the LRTs for the unadjusted and adjusted models (P<0.001 and P = 0.03, respectively). This familial confounding was more prominent for males than females. Conclusions Our findings show that the association between mental disorder and discrimination is at least partially explained by unmeasured familial factors. Designing family-based healthcare models and incorporating family members in interventions targeted at ameliorating mental ill-health and experiences of discrimination among adolescents may improve efficacy.

More than nature and nurture, indirect genetic effects on children’s academic achievement are consequences of dynastic social processes

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Full-text available

Jan 2024
Nat. Hum. Behav.

Families transmit genes and environments across generations. When parents’ genetics affect their children’s environments, these two modes of inheritance can produce an ‘indirect genetic effect’. Such indirect genetic effects may account for up to half of the estimated genetic variance in educational attainment. Here we tested if indirect genetic effects reflect within-nuclear-family transmission (‘genetic nurture’) or instead a multi-generational process of social stratification (‘dynastic effects’). We analysed indirect genetic effects on children’s academic achievement in their fifth to ninth years of schooling in N = 37,117 parent–offspring trios in the Norwegian Mother, Father, and Child Cohort Study (MoBa). We used pairs of genetically related families (parents were siblings, children were cousins; N = 10,913) to distinguish within-nuclear-family genetic-nurture effects from dynastic effects shared by cousins in different nuclear families. We found that indirect genetic effects on children’s academic achievement cannot be explained by processes that operate exclusively within the nuclear family.

Physical Activity and Depression During the COVID-19 Pandemic in Australia: A Within-pair Twin Study

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Full-text available

Oct 2023

Background Low levels of physical activity (PA) have been associated with depression. However, shared familial factors might confound this association, as PA and depression tend to cluster in families. We investigated the association between levels of PA during the COVID-19 pandemic and depression symptoms while controlling for shared factors by design, and assessed if being in lockdown modified this association. Methods We applied within-individual and within-pair regression models to questionnaire data from adult same-sex twin pair members of Twins Research Australia collected between August and November 2020. Depression score was measured using the Depression, Anxiety and Stress Scale (DASS-21), and PA changes since the onset of the pandemic (and other PA measures) were self-reported. Adjusted models included body-mass-index, sleep adequacy, smoking, and alcohol consumption. Results Our sample of 1,148 twins was predominantly female (80%) and had a median age of 54 (Interquartile Range = 41–65). Reduced PA was associated with a higher depression score (β = 1.22, 95% Confidence Interval: 0.70–1.73, P < 0.001) in the adjusted within-individual model, but evidence of a within-pair association was weak (P = 0.023). Lockdown status was an effect modifier (P = 0.006); relative to the co-twin, an increased PA was associated with higher depression scores for those in lockdown but lower scores for those not under restrictions. Conclusions Shared familial factors might play a role in the association between PA and depression. Health interventions and educational campaigns for families rather than just individuals might be better suited to improve mental health outcomes, especially when opportunities for PA and exercise are limited.

Physical Activity and Depression During the COVID-19 Pandemic in Australia: A Within-pair Twin Study

Preprint

Full-text available

Oct 2023

Long-term adverse influence of smoking during pregnancy on height and body size of offspring at ten years old in the UK Biobank cohort

Article

Full-text available

Aug 2023

Background: To explore the long-term relationship between maternal smoking during pregnancy and early childhood growth in the UK Biobank cohort. Methods: To estimate the effect of maternal smoking during pregnancy on offspring height and body size at ten years old, we performed binary logistic analyses and reported odds ratios (OR) as well as 95% confidence intervals (95%CIs). We also implemented the cross-contextual comparison study to examine whether such influence could be repeatedly observed among three different ethnicities in the UK Biobank cohort (n = 22,140 for White, n = 7094 for South Asian, and n = 5000 for Black). In particular, we conducted the sibling cohort study in White sibling cohort (n = 9953 for height and n = 7239 for body size) to control for unmeasured familial confounders. Results: We discovered that children whose mothers smoked during pregnancy had greater risk of being shorter or plumper at age ten in the full UK Biobank White cohort, with 15.3% (95% CIs: 13.0%∼17.7%) higher risk for height and 32.4% (95%CIs: 29.5%∼35.4%) larger risk for body size. Similar associations were identified in the South Asian and Black ethnicities. These associations were robust and remained significant in the White sibling cohort (12.6% [95%CIs: 5.0%∼20.3%] for height and 36.1% [95%CIs: 26.3%∼45.9%] for body size) after controlling for family factors. Conclusion: This study robustly confirms that maternal smoking during pregnancy can promote height deficit and obesity for offspring at ten years old. Our findings strongly encourage mothers to quit smoking during pregnancy for improving growth and development of offspring.

Abdominal Aortic Intima-Media Thickness in Infants at 6 Weeks of Age as an Early Life Marker of Atherosclerosis: A Longitudinal Twin Birth Cohort Study

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Full-text available

Aug 2023

Purpose Aortic intima-media thickness (aIMT) is an indicator to assess preclinical atherosclerosis in early life and may be influenced by prenatal and perinatal factors. We aimed to examine the predictive role of aIMT at 6 weeks of age and investigate the potential influencing factors by using a longitudinal twin birth cohort. Methods The abdominal aIMT and abdominal aortic diameter (AoD) were evaluated in 173 twin infants at 6 weeks of age by transabdominal ultrasound. Infant anthropometrics were measured at the same time. Data on maternal information were collected from self-made questionnaires and medical records. Data on neonatal outcomes were collected from medical records. Generalized estimation equation models were constructed to determine the associations between the mean aIMT value and cardiometabolic risk and perinatal factors. Results The mean aIMT value at 6 weeks of age was associated with total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL) and apolipoprotein B (apoB) levels at the age of four years (β = 19.24, 95% CI 0.04,38.44; P < 0.05; β=-43.88, 95% CI -54.45, -33.30; P < 0.001; β = 25.05, 95% CI 2.64,47.46; P < 0.05; β = 91.39, 95% CI 12.98,169.79; P < 0.05). An increased birthweight and AoD were associated with the mean aIMT value (β = 37.89 µm, 95% CI 12.54, 63.24; P < 0.01; β = 0.03 µm, 95% CI 0.02, 0.04; P < 0.001). Conclusions The abdominal aIMT value at the age of 6 weeks was correlated with the risk of atherosclerosis at 4 years of age in twins, particularly in monozygotic (MZ) twins, suggesting that aIMT may be a marker of preclinical atherosclerosis in infants.

Gene–environment interaction study on the polygenic risk score for neuroticism, childhood adversity, and parental bonding

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Full-text available

Aug 2023

The present study examines whether neuroticism is predicted by genetic vulnerability, summarized as polygenic risk score for neuroticism (PRS N ), in interaction with bullying, parental bonding, and childhood adversity. Data were derived from a general population adolescent and young adult twin cohort. The final sample consisted of 202 monozygotic and 436 dizygotic twins and 319 twin pairs. The Short Eysenck Personality questionnaire was used to measure neuroticism. PRS N was trained on the results from the Genetics of Personality Consortium (GPC) and United Kingdom Biobank (UKB) cohorts, yielding two different PRS N . Multilevel mixed-effects models were used to analyze the main and interacting associations of PRS N , childhood adversity, bullying, and parental bonding style with neuroticism. We found no evidence of gene–environment correlation. PRS N thresholds of .005 and .2 were chosen, based on GPC and UKB datasets, respectively. After correction for confounders, all the individual variables were associated with the expression of neuroticism: both PRS N from GPC and UKB, childhood adversity, maternal bonding, paternal bonding, and bullying in primary school and secondary school. However, the results indicated no evidence for gene–environment interaction in this cohort. These results suggest that genetic vulnerability on the one hand and negative life events (childhood adversity and bullying) and positive life events (optimal parental bonding) on the other represent noninteracting pathways to neuroticism.

Main Existing Datasets for Open Brain Research on Humans

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Full-text available

Jul 2023

Recent advances in technology have made possible to quantify fine-grained individual differences at many levels, such as genetic, genomics, organ level, behavior, and clinical. The wealth of data becoming available raises great promises for research on brain disorders as well as normal brain function, to name a few, systematic and agnostic study of disease risk factors (e.g., genetic variants, brain regions), the use of natural experiments (e.g., evaluate the effect of a genetic variant in a human population), and unveiling disease mechanisms across several biological levels (e.g., genetics, cellular gene expression, organ structure and function). However, this data revolution raises many challenges such as data sharing and management, the need for novel analysis methods and software, storage, and computing. Here, we sought to provide an overview of some of the main existing human datasets, all accessible to researchers. Our list is far from being exhaustive, and our objective is to publicize data sharing initiatives and help researchers find new data sources.

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May 2023
CEREB CORTEX

Twin samples allow to conduct a quasi-experimental co-twin case-control approach that can control for genetic and environmental confounding in brain-cognition associations, being more informative on causality compared with studies in unrelated individuals. We conducted a review of studies that have utilized discordant co-twin design to investigate the associations of brain imaging markers of Alzheimer's disease and cognition. Inclusion criteria encompassed twin pairs discordant for cognition or Alzheimer's disease imaging markers and reporting of within-twin pair comparison on the association between cognition and brain measures. Our PubMed search (2022 April 23, updated 2023 March 9) resulted in 18 studies matching these criteria. Alzheimer's disease imaging markers have been addressed only by few studies, most with small sample size. Structural magnetic resonance imaging studies have indicated greater hippocampal volume and thicker cortex in co-twins with better cognitive performance compared with their co-twins with poorer cognitive performance. No studies have looked at cortical surface area. Positron emission tomography imaging studies have suggested that lower cortical glucose metabolism rate and higher cortical neuroinflammation, amyloid, and tau accumulations are related to poorer episodic memory in within-twin pair comparisons. Thus far, only cross-sectional within-twin pair associations of cortical amyloid and hippocampal volume with cognition have been replicated.

Article

Full-text available

May 2023
J OCCUP ENVIRON MED

Objective: To investigate trajectories of labour market marginalization (LMM) and to examine the associations between family-related life events and LMM trajectories while accounting for familial factors. Methods: A prospective cohort study of 37 867 Swedish twins. Data were analysed by group-based trajectory modelling. Associations of family-related life events with trajectory groups were estimated by multinomial logistic regression. Results: The majority of participants had no or low levels of LMM. Individuals who stayed married over time or changed from single without children to married with children had a decreased risk of LMM. The risk of LMM over time was higher among individuals who changed from married to being single. Conclusion: Being or getting married as well as having children decreases the risk of LMM while divorce is a risk factor for LMM.

The role of health behaviours, genetic factors, and early life environment in the association of family-related events and sustainable working life

Preprint

Full-text available

Mar 2023

Background Studies are limited for family-related events in relation to sustainable working life (i.e., not having long-term periods of unemployment, sickness absence and disability pension). We aimed to investigate the associations between stability and change in family life and sustainable working life and whether these associations were explained by health behaviours, genetic factors, and early life environment. Methods Register data and surveys for family-related events, sustainable working life and health behaviours of 49 611 Swedish twins were used. Cox proportional hazards regressions were applied to estimate the associations between family-related events and sustainable working life, while conditional Cox models for twin pairs accounted for confounding of genetic factors and early life environment. Further, the analyses were stratified by health behaviours. Results Change from being single living without children to married living with children was associated with sustainable working life. Moreover, individuals who experienced divorce and single individuals who changed status of living with children were less likely to experience a sustainable working life. Genetic factors and early life environment played a role in some associations. Also, those with healthy behaviours were more likely to have sustainable working life even though they had changes in family life compared to those with unhealthy behaviours. Conclusions Family formation is associated with sustainable working life whereas divorce seems to decrease the possibility of sustainable working life. Health behaviours as well as genetic factors and early life environment also need to be considered in relation to changes in family life for supporting sustainable working life.

Problematic technology use and sleep quality in young adulthood: novel insights from a nationally representative twin study

Article

Full-text available

Apr 2023
SLEEP

Study objectives: Digital technology use is associated with poor sleep quality in adolescence and young adulthood although research findings have been mixed. No studies have addressed the association between the two using a genetically informative twin design which could extend our understanding of the etiology of this relationship. This study aimed to test: (1) the association between adolescents' perceived problematic use of digital technology and poor sleep quality, (2) whether the association between problematic use of technology and poor sleep quality remains after controlling for familial factors, and (3) genetic and environmental influences on the association between problematic use of technology and poor sleep quality. Methods: Participants were 2232 study members (18-year-old twins) of the Environmental Risk (E-Risk) Longitudinal Twin Study. The sample was 48.9% male, 90% white, and 55.6% monozygotic. We conducted regression and twin difference analyses and fitted twin models. Results: Twin differences for problematic use of technology were associated with differences for poor sleep quality in the whole sample (p < 0.001; B = 0.15) and also when we limited the analyses to identical twins only (p < 0.001; B = 0.21). We observed a substantial genetic correlation between problematic use of technology and sleep quality (rA = 0.31), whereas the environmental correlation was lower (rE = 0.16). Conclusions: Adolescent reported problematic use of digital technology is associated with poor sleep quality-even after controlling for familial factors including genetic confounds. Our results suggest that the association between adolescents' sleep and problematic digital technology use is not accounted for by shared genetic liability or familial factors but could reflect a causal association. This robust association needs to be examined in future research designed to test causal associations.

The Queensland Twin Adolescent Brain Project, a longitudinal study of adolescent brain development

Article

Full-text available

Apr 2023

We describe the Queensland Twin Adolescent Brain (QTAB) dataset and provide a detailed methodology and technical validation to facilitate data usage. The QTAB dataset comprises multimodal neuroimaging, as well as cognitive and mental health data collected in adolescent twins over two sessions (session 1: N = 422, age 9–14 years; session 2: N = 304, 10–16 years). The MRI protocol consisted of T1-weighted (MP2RAGE), T2-weighted, FLAIR, high-resolution TSE, SWI, resting-state fMRI, DWI, and ASL scans. Two fMRI tasks were added in session 2: an emotional conflict task and a passive movie-watching task. Outside of the scanner, we assessed cognitive function using standardised tests. We also obtained self-reports of symptoms for anxiety and depression, perceived stress, sleepiness, pubertal development measures, and risk and protective factors. We additionally collected several biological samples for genomic and metagenomic analysis. The QTAB project was established to promote health-related research in adolescence.

Further Evidence for the Association between Childhood Trauma and Suicidal Ideation in Young Individuals: A Twin Based Study

Article

Jan 2023

Serum anti-Müllerian hormone levels are associated with perinatal outcomes in women undergoing IVF/ICSI: A multicenter retrospective cohort study

Article

Full-text available

Feb 2023

Introduction: Anti-Müllerian hormone (AMH) level has long been considered as a serum biomarker of ovarian reserve clinically, while emerging data suggest that serum AMH level may also predict pregnancy outcomes. However, whether pregestational serum AMH levels are related to perinatal outcomes among women undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles is unknown. Objective: To explore the association between different AMH levels and perinatal outcomes in women with live births in IVF/ICSI. Methods: This multicenter retrospective cohort study was conducted among three different provinces in China, from January 2014 to October 2019. A total of 13,763 IVF/ICSI cycles with 5657 live-delivery pregnant women and 6797 newborns were recruited. Participants were categorized into three groups according to the <25th (low), 25 to 75th (average), and >75th (high) percentile of serum AMH concentration. Perinatal outcomes were compared among groups. Subgroup analyses were conducted based on the number of live births. Results: Among women with singleton deliveries, low and high AMH levels increased the risk of intrahepatic cholestasis of pregnancy (ICP) (aOR1 = 6.02, 95%CI: 2.10-17.22; aOR2 = 3.65, 95%CI:1.32-10.08) and decreased the risk of macrosomia (aOR1 = 0.65, 95%CI:0.48-0.89; aOR2 = 0.72, 95%CI:0.57-0.96), while low AMH reduced the risk of large for gestational age (LGA, aOR=0.74, 95%CI:0.59-0.93) and premature rupture of membrane (PROM, aOR=0.50, 95%CI:0.31-0.79)compared with the average AMH group. In women with multiple deliveries, high AMH levels increased the risks of gestational diabetes mellitus (GDM, aOR=2.40, 95%CI:1.48-3.91) and pregnancy-induced hypertension (PIH, aOR=2.26, 95%CI:1.20-4.22) compared with the average AMH group, while low AMH levels increased the risk of ICP (aOR=14.83, 95%CI:1.92-54.30). However, there was no evidence of differences in preterm birth, congenital anomaly, and other perinatal outcomes among the three groups in both singleton and multiple deliveries. Conclusions: Abnormal AMH levels increased the risk of ICP regardless of the number of live births for women undergoing IVF/ICSI, while high AMH levels increased the risks of GDM and PIH in multiple deliveries. However, serum AMH levels were not associated with adverse neonatal outcomes in IVF/ICSI. The underlying mechanism warrants further investigation.

Association between in vitro fertilization-embryo transfer and hearing loss: risk factors of hearing loss among twin infants in a cohort study

Preprint

Full-text available

Jun 2022

Purpose: Assisted reproductive technologies (ART), including in vitro fertilization-embryo transfer (IVF-ET), intracytoplasmic sperm injection (ICSI), are recognized contributing higher risk of birth defect, whereas rare studies evaluate the association of IVF-ET with diagnostic hearing loss (HL). This study aimed to evaluate the prevalence and risk factors of HL to clarify the association between IVF-ET and HL among twinborn infants. Methods: We enrolled 1860 live-born twin neonates born in hospital of China from January, 2017 to December, 2020. After examined by two-step hearing screening, participants were finally diagnosed with HL by pediatric audiologists at age of 6 months. Prevalence of hearing loss and odds ratio (OR) for specific risk factors was estimated with generalized estimation equations (GEE) model in twin-born infants. Characteristics and prevalence of failure for hearing screening and HL was measured in IVF-ET twin infants. Results: IVF-ET conception and preterm birth conferred higher risk for hearing loss, with increased adjusted odd ratios (AOR [95% confidence intervals (CI)] IVF-ET: 2.82 [1.17-6.80], P = 0.021; preterm birth: 6.14 [2.30-16.40], P < 0.001). Among 1860 twin infants, more IVF-ET twins failed in dual-step hearing screening (3.26%) and diagnosed with hearing loss (2.21%) compared with spontaneous pregnancy. Conclusions: IVF-ET and premature birth conception were associated with higher risk of hearing impairment. Twin infants conceived by IVF-ET tend to fail in hearing screening and diagnosed with hearing loss. These observations provide a more comprehensive approach for prevention and management of deafness in twin-born children.

Striatal dopamine D2 receptor availability as a predictor of subsequent alcohol use in social drinkers

Article

Full-text available

Jan 2023

Background and aims: Whereas striatal dopamine D2 receptor (D2R) availability has shown to be altered in individuals with alcohol use disorder (AUD) and in healthy individuals with a family history of AUD, the role of D2R in the development of AUD is unknown. In this positron emission tomography (PET) study, we measured whether D2R availability is associated with subsequent alcohol use and alcohol-related factors, at a follow-up 8-to-16-years post PET scan, in social drinkers. Design: Longitudinal study following healthy individuals. Setting: Academic research imaging centre in Stockholm, Sweden. Participants: 71 individuals (68 of whom had evaluable PET data, 5 females, 42.0 years mean age) from a series of previous PET studies. Measurements: One PET examination with the D2R antagonist radioligand [11 C]raclopride at baseline, and self-report measures assessing alcohol use, drug use, impulsivity, reward sensitivity, and family history of alcohol- or substance use disorder at follow-up. Findings: We found no evidence for an association between D2R availability and later alcohol use (B = -.019, B 95% confidence interval [CI] = -.043-(-).006, p = .147), nor for the majority of the alcohol-related factors (B 95 % CI = -.034-.004, p = .273-.288). A negative association with a small effect size was found between D2R availability and later impulsivity (B = -.017, B 95% CI = -.034-(-).001, p = .046). Conclusions: Low striatal dopamine D2 receptor availability may not be a strong predictor in the development of alcohol use disorder.

Evaluating the causal relationship between educational attainment and mental health

Preprint

Full-text available

Jan 2023

A bstract We investigate the causal relationship between educational attainment (EA) and mental health using two research designs. First, we compare the relationship between EA and seventeen psychiatric diagnoses within sibship in Dutch national registry data (N = 1.7 million), controlling for unmeasured familial factors. Second, we use two-sample Mendelian Randomization, which uses genetic variants related to EA or psychiatric diagnosis as instrumental variables, to test whether there is a causal relation in either direction. Our results suggest that lower levels of EA causally increase the risk of MDD, ADHD, alcohol dependence, GAD and PTSD diagnoses. We also find evidence of a causal effect in the opposite direction for ADHD. Additionally, we find inconsistent results for schizophrenia, anorexia nervosa, OCD, and bipolar disorder, highlighting the importance of using multiple research designs to understand the complex relationship between EA and mental health.

Childhood Predictors of Healthcare Use and Health Status in Early Adulthood: Findings from the Twins Early Development Study

Article

Full-text available

Dec 2022
Int J Environ Res Publ Health

The use of healthcare services is likely to be associated with need but also the factors relating to the care system and the ability to negotiate around it. Healthcare use and health status may also be associated with the factors that exist in childhood. This study aims to identify the demographic, clinical, and cognitive characteristics of children at age 4 that impact healthcare use and health status at age 21. The data from the Twins Early Development Study were used. Health problems, healthcare use, and cognitive ability at age 4 were entered into generalised estimating equations to predict the use of general practitioners, outpatient services, counselling, emergency clinic visits, and a healthcare helpline at age 21. Similar models existed for the prediction of whether problems were recorded on the EQ-5D-5L EuroQol instrument. The data on up to 6707 individuals were available for analysis. Sex was a significant predictor of service use, with boys being more likely than girls to later use all services, except for emergency clinic visits. Certain health conditions at age 4 predicted the use of services with models differing according to service type. Greater general cognitive ability predicted higher use of general practitioners, outpatient care, and health helplines. The current health status was strongly predictive of service use. Service use in young adulthood was significantly related to concurrent health status as well as health conditions in childhood. General cognitive ability was significantly associated with the use of general practitioner contacts, outpatient visits, and the use of a health helpline.

Posttraumatic Stress Disorder and Obstructive Sleep Apnea in Twins

Article

Jun 2024

Importance Obstructive sleep apnea (OSA) is a common condition in older adult (aged >65 years) populations, but more mechanistic research is needed to individualize treatments. Previous evidence has suggested an association between OSA and posttraumatic stress disorder (PTSD) but is limited by possible selection bias. High-quality research on this association with a careful evaluation of possible confounders may yield important mechanistic insight into both conditions and improve treatment efforts. Objective To investigate the association of current PTSD symptoms and PTSD diagnosis with OSA. Design, Setting, and Participants This cross-sectional study of twin pairs discordant for PTSD, which allows for adjustment for familial factors, was conducted using in-laboratory polysomnography from March 20, 2017, to June 3, 2019. The study sample comprised male veteran twins recruited from the Vietnam Era Twin Registry. The data analysis was performed between June 11, 2022, and January 30, 2023. Exposure Symptoms of PTSD in twins who served in the Vietnam War. Diagnosis of PTSD was a secondary exposure. Main Outcomes and Measures Obstructive sleep apnea was assessed using the apnea-hypopnea index (AHI) (≥4% oxygen saturation criterion as measured by events per hour) with overnight polysomnography. Symptoms of PTSD were assessed using the PTSD Checklist (PCL) and structured clinical interview for PTSD diagnosis. Results A total of 181 male twins (mean [SD] age, 68.4 [2.0] years) including 66 pairs discordant for PTSD symptoms and 15 pairs discordant for a current PTSD diagnosis were evaluated. In models examining the PCL and OSA within pairs and adjusted for body mass index (BMI) and other sociodemographic, cardiovascular, and psychiatric risk factors (including depression), each 15-point increase in PCL was associated with a 4.6 (95% CI, 0.1-9.1) events-per-hour higher AHI. Current PTSD diagnosis was associated with an adjusted 10.5 (95% CI, 5.7-15.3) events-per-hour higher AHI per sleep-hour. Comparable standardized estimates of the association of PTSD symptoms and BMI with AHI per SD increase (1.9 events per hour; 95% CI, 0.5-3.3 events per hour) were found. Conclusions and Relevance This cross-sectional study found an association between PTSD and sleep-disordered breathing. The findings have important public health implications and may also enhance understanding of the many factors that potentially affect OSA pathophysiology.

Nasty Data: Unruly, Ill-Mannered Observations Can Ruin Your Analysis

Chapter

Feb 2014

Gary H Mcclelland

This indispensable sourcebook covers conceptual and practical issues in research design in the field of social and personality psychology. Key experts address specific methods and areas of research, contributing to a comprehensive overview of contemporary practice. This updated and expanded second edition offers current commentary on social and personality psychology, reflecting the rapid development of this dynamic area of research over the past decade. With the help of this up-to-date text, both seasoned and beginning social psychologists will be able to explore the various tools and methods available to them in their research as they craft experiments and imagine new methodological possibilities.

Meta-Analysis of Research in Social and Personality Psychology

Chapter

Feb 2014

Inducing and Measuring Emotion and Affect: Tips, Tricks, and Secrets

Chapter

Feb 2014

Educational attainment and psychiatric diagnoses: a national registry data and two-sample Mendelian randomization study

Article

May 2024

Conceptual framework for establishing twins prevention and continuous health promotion programme: a qualitative study

Article

Full-text available

Apr 2024

Background Twin registries and cohorts face numerous challenges, including significant resource allocation, twins’ recruitment and retention. This study aimed to assess expert feedback on a proposed pragmatic idea for launching a continuous health promotion and prevention programme (HPPP) to establish and maintain twin cohorts. Design A qualitative study incorporating an inductive thematic analysis. Setting Tehran University of Medical Sciences. Participants Researchers with expertise in twin studies participated in our study. Analysis and design Expert opinions were gathered through focus group discussions (FGDs). Thematic analysis was employed to analyse the findings and develop a model for designing a comprehensive, long-term health promotion programme using ATLAS.ti software. Additionally, a standardised framework was developed to represent the conceptual model of the twin HPPP. Results Eight FGDs were conducted, involving 16 experts. Thematic analysis identified eight themes and seven subthemes that encompassed the critical aspects of a continuous monitoring programme for twin health. Based on these identified themes, a conceptual framework was developed for the implementation of an HPPP tailored for twins. Conclusion This study presented the initial endeavour to establish a comprehensive and practical solution in the form of a continuous HPPP designed to tackle the obstacles of twins’ cohorts.

Concurrent and longitudinal associations of developmental language disorder with peer victimization in adolescence: evidence from a co-twin study

Article

Feb 2024
J CHILD PSYCHOL PSYC

Background Children with developmental language disorder (DLD) experience higher levels of peer victimization than their peers. However, it is not known if such associations reflect genetic and environmental confounding. We used a co‐twin control design to investigate the association of language difficulties (DLD and separately poor pragmatic language) with peer victimization and compare the developmental trajectories of peer victimization across adolescence for those with and without language difficulties. Methods Participants were 3,400 pairs of twins in the Twins Early Development Study (TEDS), a UK‐based population birth cohort. Language abilities were assessed via online tests at age 11 and peer victimization was self‐reported at ages 11, 14 and 16. Language difficulties were defined as language abilities at least −1.25 SD below the mean of the TEDS sample. We performed linear regressions and latent growth curve modeling at a population level and within monozygotic and same‐sex dizygotic twin pairs. Results At population level, youth with DLD experienced higher levels of peer victimization at ages 11 (β = 0.27, 95% Confidence Interval (CI) 0.20–0.35), 14 (β = 0.15, 95% CI 0.03–0.27) and 16 (β = 0.17, 95% CI 0.03–0.32) and a sharper decline in peer victimization between ages 11 and 16 compared to their peers without DLD. The associations between DLD and peer victimization were reduced in strength and not statistically significant in within‐twin models. Moreover, there was no difference in the rate of change in peer victimization between twin pairs discordant for DLD. Results were similar for the association of poor pragmatic language with peer victimization. Conclusions Associations between language difficulties (DLD and separately, poor pragmatic language) and peer victimization were confounded by genetic and shared environmental factors. Identifying specific factors underlying these associations is important for guiding future work to reduce peer victimization among adolescents with language difficulties.

Sustained looking at faces at 5 months of age is associated with socio-communicative skills in the second year of life

Article

Feb 2024
INFANCY

Efficiently processing information from faces in infancy is foundational for nonverbal communication. We studied individual differences in 5‐month‐old infants' ( N = 517) sustained attention to faces and preference for emotional faces. We assessed the contribution of genetic and environmental influences to individual differences in these gaze behaviors, and the association between these traits and other concurrent and later phenotypes. We found an association between the mean duration of looking at a face (before looking away from it) at 5 months and socio‐communicative abilities at 14 months ( β = 0.17, 95% CI: 0.08; 0.26, p < 0.001). Sustained attention to faces predicted socio‐communicative abilities over and above variance captured by mean fixation duration. We also found a statistically significant but weak tendency to prefer looking at smiling faces (relative to neutral faces), but no indication that variability in this behavior was explained by genetic effects. Moderate heritability was found for sustained attention to faces ( A = 0.23, CI: 0.06; 0.38), while shared environmental influences were non‐significant for both phenotypes. These findings suggest that sustained looking at individual faces before looking away is a developmentally significant ‘social attention’ phenotype in infancy, characterized by moderate heritability and a specific relation to later socio‐communicative abilities.

Familial effects account for association between chronic pain and past month smoking

Article

Feb 2024
EUR J PAIN

Background Smoking is associated with chronic pain, but it is not established whether smoking causes pain or if the link is due to familial effects. One proposed mechanism is that smoking strengthens maladaptive cortico‐striatal connectivity, which contributes to pain chronification. We leveraged a twin design to assess direct effects of smoking on pain controlling for familial confounds, and whether cortico‐striatal connectivity mediates this association. Methods In a population‐based sample of 692 twins (age = 28.83 years), we assessed past‐month smoking frequency ( n = 132 used in the past month), presence and severity of a current pain episode ( n = 179 yes), and resting‐state functional connectivity of the nucleus accumbens and medial prefrontal cortex (NAc‐mPFC). Results Smoking was significantly associated with pain, but the association was not significantly mediated by NAc‐mPFC connectivity. In a co‐twin control model, smoking predicted which families had more pain but could not distinguish pain between family members. Pain risk was 43% due to additive genetic (A) and 57% due to non‐shared environmental (E) influences. Past‐month smoking frequency was 71% genetic and 29% non‐shared environmental. Smoking and pain significantly correlated phenotypically ( r = 0.21, p = 0.001) and genetically ( r g = 0.51, p < 0.001), but not environmentally ( r e = −0.18, p = 0.339). Conclusions Pain and smoking are associated; however, the association appears to reflect shared familial risk factors, such as genetic risk, rather than being causal in nature. The connectivity strength of the reward pathway was not related to concurrent pain and smoking in this sample. Significance Smoking does not appear to directly cause chronic pain; rather, there may be shared biopsychosocial risk factors, including genetic influences, that explain their association. These findings can be integrated into future research to identify shared biological pathways of both chronic pain and smoking behaviours as a way to conceptualize pain chronification.

Epigenetics, epidemiology, and public health

Chapter

Jan 2024

Exaggerated Peripheral and Systemic Vasoconstriction During Trauma Recall in Posttraumatic Stress Disorder: A Co-Twin Control Study

Article

Dec 2023
BIOL PSYCHIAT

A co-twin control study of in utero exposure to poly- and perfluoroalkyl substances and associations with neonatal thyroid-stimulating hormone

Article

Oct 2023
ENVIRON RES

Chronic Hypertension in Pregnancy and Racial–Ethnic Disparities in Complications

Article

Full-text available

Sep 2023
OBSTET GYNECOL

OBJECTIVE To evaluate whether there are individual- and population-level associations between chronic hypertension and pregnancy complications, and to assess differences across seven racial–ethnic groups. METHODS This population-based study used linked vital statistics and hospitalization discharge data from all live and stillbirths in California (2008–2018), Michigan (2008–2020), Oregon (2008–2020), Pennsylvania (2008–2014), and South Carolina (2008–2020). We used multivariable log-binomial regression models to estimate risk ratios (RRs) and population attributable risk (PAR) percentages with 95% CIs for associations between chronic hypertension and several obstetric and neonatal outcomes, selected based on prior evidence and pathologic pathways. We adjusted models for demographic factors (race and ethnicity, payment method, educational attainment), age, body mass index, obstetric history, delivery year, and state, and conducted analyses stratified across seven racial–ethnic groups. RESULTS The study included 7,955,713 pregnancies, of which 168,972 (2.1%) were complicated by chronic hypertension. Chronic hypertension was associated with several adverse obstetric and neonatal outcomes, with the largest adjusted PAR percentages observed for preeclampsia with severe features or eclampsia (22.4; 95% CI 22.2–22.6), acute renal failure (13.6; 95% CI 12.6–14.6), and pulmonary edema (10.7; 95% CI 8.9–12.6). Estimated RRs overall were similar across racial–ethnic groups, but PAR percentages varied. The adjusted PAR percentages (95% CI) for severe maternal morbidity—a widely used composite of acute severe events—for people who were American Indian or Alaska Native, Asian, Black, Latino, Native Hawaiian or Other Pacific Islander, White, and Multiracial or Other were 5.0 (1.1–8.8), 3.7 (3.0–4.3), 9.0 (8.2–9.8), 3.9 (3.6–4.3), 11.6 (6.4–16.5), 3.2 (2.9–3.5), and 5.5 (4.2–6.9), respectively. CONCLUSION Chronic hypertension accounts for a substantial fraction of obstetric and neonatal morbidity and contributes to higher complication rates, particularly for people who are Black or Native Hawaiian or Other Pacific Islander.

Neural Specialization to English words in Chinese children: Joint contribution of age and English reading abilities

Article

Full-text available

Aug 2023

N1 tuning to words, a neural marker of visual word recognition, develops by an interaction between age and ability. The development of N1 tuning to a second learnt print is unclear. The present study examined the joint contribution of age and English reading abilities to N1 amplitude and tuning to English print in Chinese children in Hong Kong. EEG signals were recorded from 179 children (six to nine years old) while they were performing a repetition detection task comprised of different print stimuli measuring three types of tuning, i.e., coarse tuning (real word versus false font), fine tuning (real versus nonword), and lexicality effect (real versus pseudo word). Children were assessed in English word reading accuracy (EWR) and English sub-lexical orthographic knowledge (EOK). Results indicated that coarse tuning decreased with age but increased with EWR and EOK. Fine tuning uniquely increased with EOK, and the lexicality effect increased with EWR. At last, higher EWR was linked to less right-lateralized coarse tuning in younger children. Taken together, the findings support the visual perceptual expertise account in the L2 context, in that N1 coarse tuning, fine tuning, and lexicality effect are driven by skill improvement.

Familial Confounding of Internalising Symptoms and Obesity in Adolescents and Young Adults; A Co-Twin Analysis

Preprint

Full-text available

Mar 2023

Background Obesity and internalising disorders, including depression and anxiety, often co-occur. There is evidence that familial confounding contributes to the co-occurrence of internalising disorders and obesity in adults. However, its impact on this association among young people is unclear. Our study investigated the extent to which familial factors confound the association between internalising disorders and obesity in adolescents and young adults. Subjects/methods We used a matched co-twin design to investigate the impact of confounding by familial factors on associations between internalising symptoms and obesity in a sample of 4,018 twins aged 16 to 27 years. Results High levels of internalising symptoms increased the odds of obesity for the whole cohort (adjusted odds ratio [AOR]=2.7, 95% confidence interval [CI]: 1.2, 5.4), and in females (AOR=3.3, 95%CI 1.3, 8.9), but not in males (AOR=2.3 95%CI 0.6, 7.9). In the paired analysis, we found internalising disorders were associated with an increased between-pair odds of obesity (AOR 3.9, 95%CI 1.2, 13.1), but the within-pair association attenuated to the null after controlling for familial confounding. Sex-stratified analyses indicated high internalising symptoms were associated with increased between-pair odds of obesity in females (AOR 7.8, 95%CI 1.5, 40.8), but this attenuated to the null after adjusting for familial confounding. We found no evidence of between or within-pair associations for males and weak evidence that sex modified the association between internalising symptoms and obesity (likelihood ratio test p= 0.037). Conclusions: Shared early environmental and/or genetic variants among twins partially confound the association between internalising symptoms and obesity in adolescent and young adult females. Internalising symptoms and obesity were not associated in adolescent and young adult males. Prevention and treatment efforts should address individual and familial determinants of obesity, particularly targeted at female adolescents and young adults with internalising disorders and those with a family history of these disorders.

Plasma biomarkers predict amyloid pathology in cognitively normal monozygotic twins after 10 years

Article

Full-text available

Feb 2023

Blood-based biomarkers could prove useful to predict Alzheimer’s Disease core pathologies in advance of clinical symptoms. Implementation of such biomarkers requires a solid understanding of their long-term dynamics, and the contribution of confounding to their association with Alzheimer's disease pathology. Here we assess the value of plasma amyloid-β1-42/1-40, phosphorylated-tau181 and glial fibrillary acidic protein to detect early Alzheimer's disease pathology, accounting for confounding by genetic and early environmental factors. Participants were 200 monozygotic twins, aged ≥60 years with normal cognition from the EMIF-AD PreclinAD study. All twins had amyloid-β status and plasma samples available at study enrollment. For 80 twins, additional plasma samples were available that had been collected approximately 10 years prior to amyloid-β status assessment. Single Molecule Array assays were applied to measure amyloid-β1-42/1-40, phosphorylated-tau181 and glial fibrillary acidic protein. Predictive value of, and longitudinal change in these biomarkers were assessed using Receiver Operating Characteristic curve analysis and linear mixed models. Amyloid pathology could be predicted using blood-based biomarkers obtained at time of amyloid status assessment (amyloid-β1-42/1-40: Area Under Curve = 0·65, p = 0·01; phosphorylated-tau181: Area Under Curve = 0·84, p < 0·001; glial fibrillary acidic protein: Area Under Curve = 0·74, p < 0·001), as well as, using those obtained 10 years prior to amyloid status assessment (amyloid-β1-42/1-40: Area Under Curve = 0·69, p = 0·03; phosphorylated-tau181: Area Under Curve = 0·92, p < 0·001; glial fibrillary acidic protein: Area Under Curve = 0·84, p < 0·001). Longitudinally, amyloid-β1-42/1-40 levels decreased (β(SE)=-0·12(0·01), p < 0·001) and phosphorylated-tau181 levels increased (β(SE) = 0·02(0·01), p = 0·004). Amyloid-β+ individuals showed a steeper increase in phosphorylated-tau181 compared to amyloid-β- individuals (β(SE) = 0·06(0·02), p = 0·004). Also amyloid-β+ individuals tended to show a steeper increase in glial fibrillary acidic protein (β(SE) = 0·04(0·02), p = 0·07). Within monozygotic twin-pairs, those with higher plasma phosphorylated-tau181 and lower amyloid-β1-42/1-40 levels were more likely to be amyloid-β+ (β(SE) = 0·95(0·26), p < 0·001; β(SE)=-0·28(0·14), p < 0·05) indicating minimal contribution of confounding by genetic and early environmental factors. Our data support the use of amyloid-β1-42/1-40, phosphorylated-tau181 and glial fibrillary acidic protein as screening tools for Alzheimer's disease pathology in the normal aging population, which is of importance for enrollment of high-risk subjects in secondary, or even primary, prevention trials. Furthermore, these markers show potential as low-invasive monitoring tool of disease progression and possibly treatment effects in clinical trials.

Association between in vitro fertilization-embryo transfer and hearing loss: risk factors for hearing loss among twin infants in a cohort study

Article

Full-text available

Jan 2023
Eur J Pediatr

Assisted reproductive technologies (ART), including in vitro fertilization-embryo transfer (IVF-ET) and intracytoplasmic sperm injection (ICSI), are known to contribute a higher risk of birth defects; however, studies have rarely evaluated the association between IVF-ET and diagnostic hearing loss (HL). This study aimed to evaluate the prevalence of and risk factors for HL and to clarify the association between IVF-ET and HL among twinborn infants. We enrolled 1860 live-born twin neonates born at a hospital in China from January 2017 to December 2020. After multi-step hearing screening, participants were diagnosed with HL by pediatric audiologists at 6 months of age. The prevalence of hearing loss and the adjusted odds ratios (AORs) for specific risk factors were estimated using generalized estimation equation (GEE) models in twin-born infants. Characteristics and prevalence of failure for hearing screening and HL were measured in IVF-ET twin infants. IVF-ET conception and preterm birth conferred a higher risk of hearing loss, with increased adjusted odds ratios (AOR [95% confidence intervals (CI)] IVF-ET: 2.82 [1.17–6.80], P = 0.021; preterm birth: 6.14 [2.30–16.40], P < 0.001) than the control group, respectively. Among the 1860 twin infants, more IVF-ET twins failed in dual-step hearing screening (3.26%) and were diagnosed with hearing loss (2.21%) than those conceived by spontaneous pregnancy. Conclusion: IVF-ET conception and premature birth were associated with a higher risk of hearing impairment. Twin infants conceived by IVF-ET tended to fail in hearing screening and be diagnosed with hearing loss. These observations provide a more comprehensive approach for the prevention and management of deafness in twin-born children.What is Known: • IVF-ET technologies conferred a higher risk of birth defects. What is New: • Premature birth and IVF-ET conception were associated with a higher risk of hearing loss among twin infants. • Twin infants conceived by IVF-ET tended to fail in hearing screening and diagnosed with hearing loss.

Association of Birth Weight and Current Body Size to Blood Pressure in Female Twins

Article

Full-text available

Oct 2001
TWIN RES HUM GENET

It has been proposed that low birth weight is associated with high levels of blood pressure in later life. The aim of this study was to assess the relationship of blood pressure to birth weight and current body size during growth and adulthood. A total of 711 female multiple births, with one group of 244 in their growth phase mean age 12.0 (2.3)(SD) years and the other of 467 adults (mean age 35.2 (12.6) years), had height, weight and both systolic (SBP) and diastolic (DBP) blood pressures measured, and self-reported their birth weight. Regression analyses were performed to assess the cross-sectional and within-pair associations of blood pressure to birth weight, with and without adjustments for current body size. Within-pair analysis was based on 296 twin pairs. Cross-sectionally, a reduction in birth weight of 1 kg was associated with 2 to 3 mm Hg higher age-adjusted SBP, which was of marginal significance and explained about 2% of the population variance. Adjustment for body mass index did not significantly change this association. Within-pair analyses found no association between birth weight and SBP or DBP, even after adjusting for current body size. After age, current body size was the strongest predictor of systolic BP. The weak association of blood pressure to birth weight cross-sectionally is of interest, but any within-pair effect of birth weight on blood pressure must be minimal compared with the effect of current body size.

Birth weight and risk of cardiovascular disease in a cohort of women followed up since 1976

Article

Full-text available

Aug 1997

To examine the association between birth weight and non-fatal adult cardiovascular disease while controlling for potential confounders such as socioeconomic group and adult lifestyle. Retrospective self report of birth weight in an ongoing longitudinal cohort of nurses followed up by postal questionnaire every two years. Nurses' health study, a cohort of 121700 women followed up since 1976. Non-fatal cardiovascular disease, including myocardial infarction, coronary revascularisation, and stroke. Among the 70297 women free of cardiovascular disease at baseline who reported birth weight in the 1992 questionnaire there were 1309 first cases of non-fatal cardiovascular disease. Increasing birth weight was associated with decreasing risk of non-fatal cardiovascular disease. There were 1216 first cases of non-fatal cardiovascular disease among women who were singletons and had been born full term; their relative risks adjusted for several cardiovascular risk factors were 1.49 (95% confidence interval 1.05 to 2.10) for birth weight < 2268 g (< 5 lb 0 oz); 1.25 (0.98 to 1.61) for birth weight 2268-2495 g (5 lb 0 oz to 5 lb 8 oz); 1.12 (0.98 to 1.27) for birth weight > 2495-3175 g (> 5 lb 8 oz to 7 lb 0 oz); 1.00 (referent) for birth weight > 3175-3856 g (> 7 lb 0 oz to 8 lb 8 oz); 0.96 (0.80 to 1.15) for birth weight > 3856-4536 g (> 8 lb 8 oz to 10 lb 0 oz); and 0.68 (0.46 to 1.00) for birth weight > 4536 g (> 10 lb 0 oz) (P value for trend = 0.0004). The inverse trend was apparent for both coronary heart disease and stroke. These data provide strong evidence of an association between birth weight and adult coronary heart disease and stroke.

Comparison of Population-Averaged and Subject-Specific Approaches to Analyzing Repeated Binary Outcomes

Article

Full-text available

May 1998
AM J EPIDEMIOL

Several approaches have been proposed to model binary outcomes that arise from longitudinal studies. Most of the approaches can be grouped into two classes: the population-averaged and subject-specific approaches. The generalized estimating equations (GEE) method is commonly used to estimate population-averaged effects, while random-effects logistic models can be used to estimate subject-specific effects. However, it is not clear to many epidemiologists how these two methods relate to one another or how these methods relate to more traditional stratified analysis and standard logistic models. The authors address these issues in the context of a longitudinal smoking prevention trial, the Midwestern Prevention Project. In particular, the authors compare results from stratified analysis, standard logistic models, conditional logistic models, the GEE models, and random-effects models by analyzing a binary outcome from two and seven repeated measurements, respectively. In the comparison, the authors focus on the interpretation of both time-varying and time-invariant covariates under different models. Implications of these methods for epidemiologic research are discussed. Am J Epidemiol 1998;147: 694–703.

Reduced fetal growth rate and increased risk of death from ischaemic heart disease: cohort study of 15 000 Swedish men and women born 1915-29

Article

Full-text available

Aug 1998

To establish whether fetal growth rate (as distinct from size at birth) is associated with mortality from ischaemic heart disease. Cohort study based on uniquely detailed obstetric records with 97% follow up over the entire life course and linkage to census data in adult life. All 14 611 babies delivered at the Uppsala Academic Hospital, Sweden, during 1915-29 followed up to end of 1995. Mortality from ischaemic heart disease and other causes. Cardiovascular disease showed an inverse association with birth weight for both men and women, although this was significant only for men. In men a 1000 g increase in birth weight was associated with a proportional reduction in the rate of ischaemic heart disease of 0.77 (95% confidence interval 0.67 to 0.90). Adjustment for socioeconomic circumstances at birth and in adult life led to slight attenuation of this effect. Relative to the lowest fourth of birth weight for gestational age, mortality from ischaemic heart disease in men in the second, third, and fourth fourths was 0.81 (0.66 to 0.98), 0.63 (0.50 to 0.78), and 0.67 (0.54 to 0.82), respectively. The inclusion of birth weight per se and birth weight for gestational age in the same model strengthened the association with birth weight for gestational age but removed the association with birth weight. This study provides by far the most persuasive evidence of a real association between size at birth and mortality from ischaemic heart disease in men, which cannot be explained by methodological artefact or socioeconomic confounding. It strongly suggests that it is variation in fetal growth rate rather than size at birth that is aetiologically important.

Differences in Birth Weight and Blood Pressure at Age 7 Years among Twins

Article

Full-text available

May 2001
AM J EPIDEMIOL

Blood pressure later in life has been inversely associated with birth weight. However, concerns have been raised about whether this association merely reflects common environmental risk factors for both fetal growth restriction and high blood pressure or whether there is a genetic tendency to give birth to small babies and have high blood pressure. This study examined whether difference in birth weight of twins is associated with difference in blood pressure at age 7 years. The authors used data from the Collaborative Perinatal Project, United States, 1959-1966, which included 119 pairs of monozygotic and 86 pairs of same-sex dizygotic twins. The smaller twin in each pair had an average 300-g lower birth weight and was substantially thinner than the larger twin (p < 0.001). At age 7 years, body size and blood pressure were similar. Multiple linear regression was used to examine the association between difference in birth size and difference in blood pressure, adjusting for difference in body weight at age 7 years. None of the associations was statistically significant, and the direction of the associations was inconsistent. Further analyses stratified by birth weight, race, and sex revealed a similar, inconsistent pattern. The authors' findings fail to support the hypothesis that an unfavorable intrauterine environment adversely affects blood pressure in children.

Association of Birth Weight and Current Body Size to Blood Pressure in Female Twins

Article

Full-text available

Nov 2001
Twin Res

It has been proposed that low birth weight is associated with high levels of blood pressure in later life. The aim of this study was to assess the relationship of blood pressure to birth weight and current body size during growth and adulthood. A total of 711 female multiple births, with one group of 244 in their growth phase mean age 12.0 (2.3)(SD) years and the other of 467 adults (mean age 35.2 (12.6) years), had height, weight and both systolic (SBP) and diastolic (DBP) blood pressures measured, and self-reported their birth weight. Regression analyses were performed to assess the cross-sectional and within-pair associations of blood pressure to birth weight, with and without adjustments for current body size. Within-pair analysis was based on 296 twin pairs. Cross-sectionally, a reduction in birth weight of 1 kg was associated with 2 to 3 mm Hg higher age-adjusted SBP, which was of marginal significance and explained about 2% of the population variance. Adjustment for body mass index did not significantly change this association. Within-pair analyses found no association between birth weight and SBP or DBP,even after adjusting for current body size. After age, current body size was the strongest predictor of systolic BP. The weak association of blood pressure to birth weight cross-sectionally is of interest, but any within-pair effect of birth weight on blood pressure must be minimal compared with the effect of current body size.

The Foetal Origins of Adult Disease: Interpreting the Evidence From Twin Studies

Article

Full-text available

Nov 2001
Twin Res

David A Leon

Twin studies have a contribution to make to the debate concerning the foetal origins of adult disease. Twins are growth retarded compared to singletons and experience post-natal catch-up growth. However, there is no evidence that twins are at increased risk of cardiovascular disease. Studying whether discordance in size at birth within monozygotic twin pairs is predictive of discordance in later life disease should help resolve whether the association between size at birth and later disease is due to common genetic factors. Results from studies of blood pressure in childhood and adult life looking at these within twin effects are far from conclusive. There are, however, methodological problems in the interpretation of these results, not least of which is the relatively small numbers of twin pairs studied. Studies exploring the effect of zygosity and chorion type on later disease provide may provide a useful extension of the research agenda. In summary, twin studies to date have raised more questions about the foetal origins hypothesis than they have resolved.

Statistical Analysis of Correlated Data Using Generalized Estimating Equations: An Orientation

Article

Full-text available

Mar 2003
AM J EPIDEMIOL

The method of generalized estimating equations (GEE) is often used to analyze longitudinal and other correlated response data, particularly if responses are binary. However, few descriptions of the method are accessible to epidemiologists. In this paper, the authors use small worked examples and one real data set, involving both binary and quantitative response data, to help end-users appreciate the essence of the method. The examples are simple enough to see the behind-the-scenes calculations and the essential role of weighted observations, and they allow nonstatisticians to imagine the calculations involved when the GEE method is applied to more complex multivariate data.

Blood Pressure in Relation to Birth Weight in Twins and Singleton Controls Matched for Gestational Age

Article

Full-text available

Aug 2003
AM J EPIDEMIOL

Associations between adult blood pressure and birth weight were investigated in 122 same-sex twin pairs aged 18-50 years and 86 singleton controls matched according to maternal age and parity, gender, gestational age, and current age who were recruited via an obstetric database in Aberdeen, Scotland, in 1999. Twins weighed on average 425 g less than controls at birth (p < 0.001) but did not differ significantly in adult height or systolic or diastolic blood pressure from the controls. Among controls, the differences in systolic and diastolic blood pressure per kg of difference in birth weight, adjusted for gender, gestational age, current age, body mass index, smoking, physical activity level, and alcohol intake, were -4.3 (95% confidence interval (CI): -12.8, 4.3) and -6.1 (95% CI: -10.8, -1.5) mmHg/kg, respectively. In unpaired analysis among all twins, the equivalent values were -0.1 (95% CI: -4.0, 3.8) mmHg/kg for systolic pressure and -0.4 (95% CI: -2.9, 2.2) mmHg/kg for diastolic pressure, while in within-pair analysis the values were -0.9 (95% CI: -6.4, 4.6) mmHg/kg for systolic pressure and -0.2 (95% CI: -4.1, 3.7) mmHg/kg for diastolic pressure. The results suggest that in-utero growth restriction in twins is not a major determinant of their blood pressure as adults.

A case study on the choice, interpretation and checking of multilevel models for longitudinal binary outcomes

Article

Full-text available

Jan 2002

Recent advances in statistical software have led to the rapid diffusion of new methods for modelling longitudinal data. Multilevel (also known as hierarchical or random effects) models for binary outcomes have generally been based on a logistic-normal specification, by analogy with earlier work for normally distributed data. The appropriate application and interpretation of these models remains somewhat unclear, especially when compared with the computationally more straightforward semiparametric or 'marginal' modelling (GEE) approaches. In this paper we pose two interrelated questions. First, what limits should be placed on the interpretation of the coefficients and inferences derived from random-effect models involving binary outcomes? Second, what diagnostic checks are appropriate for evaluating whether such random-effect models provide adequate fits to the data? We address these questions by means of an extended case study using data on adolescent smoking from a large cohort study. Bayesian estimation methods are used to fit a discrete-mixture alternative to the standard logistic-normal model, and posterior predictive checking is used to assess model fit. Surprising parallels in the parameter estimates from the logistic-normal and mixture models are described and used to question the interpretability of the so-called 'subject-specific' regression coefficients from the standard multilevel approach. Posterior predictive checks suggest a serious lack of fit of both multilevel models. The results do not provide final answers to the two questions posed, but we expect that lessons learned from the case study will provide general guidance for further investigation of these important issues.

The role of genetic and environmental factors in the association between birthweight and blood pressure: Evidence from meta-analysis of twin studies

Article

Full-text available

Nov 2004

An inverse association between birthweight and later blood pressure has been found in many studies in singletons. Twin studies have been used to examine whether genetic factors or family environment could account for this association. A systematic review identified 10 studies covering 3901 twin pairs. Meta-analysis of regression coefficients for the association between birthweight and systolic blood pressure was carried out for unpaired versus paired associations and for paired associations in dizygotic versus monozygotic pairs. After adjustment for current weight or body mass index (BMI), the difference in systolic blood pressure per kg birthweight was -2.0 (95% CI: -3.2, -0.8) mmHg in the unpaired analysis and -0.4 (95% CI: -1.5, 0.7) mmHg in the paired analysis in the same subjects. In the paired analysis by zygosity, in all twins the coefficients were -0.7 (95% CI: -2.3, 0.8) mmHg in dizygotic pairs and -0.8 (95% CI: -2.1, 0.4) mmHg in monozygotic pairs, but in studies which included zygosity tests the coefficients were -1.0 (95% CI: -3.3, 1.6) mmHg in dizygotic pairs and -0.4 (95% CI: -1.9, 1.3) mmHg in monozygotic pairs. The attenuation of the regression coefficient in the paired analysis provides support for the possibility that factors shared by twins contribute to the association between birthweight and blood pressure in singletons. Comparison of paired analysis in monozygotic and dizygotic pairs could not provide conclusive evidence for a role for genetic as opposed to shared environmental factors.

Regression Analysis: A Constructive Critique

Book

Jan 2004

Richard Berk

Methodology for Genetic Studies of Twins and Families

Book

Jan 1992

Preface. List of Figures. List of Tables. 1. The Scope of Genetic Analyses. 2. Data Summary. 3. Biometrical Genetics. 4. Matrix Algebra. 5. Path Analysis and Structural Equations. 6. LISREL Models and Methods. 7. Model Fitting Functions and Optimization. 8. Univariate Analysis. 9. Power and Sample Size. 10. Social Interaction. 11. Sex Limitation and GE Interaction. 12. Multivariate Analysis. 13. Direction of Causation. 14. Repeated Measures. 15. Longitudinal Mean Trends. 16. Observer Ratings. 17. Assortment and Cultural Transmission. 18. Future Directions. Appendices: A. List of Participants. B. The Greek Alphabet. C. LISREL Scripts for Univariate Models. D. LISREL Script for Power Calculation. E. LISREL Scripts for Multivariate Models. F. LISREL Script for Sibling Interaction Model. G. LISREL Scripts for Sex and GE Interaction. H. LISREL Script for Rater Bias Model. I. LISREL Scripts for Direction of Causation. J. LISREL Script and Data for Simplex Model. K. LISREL Scripts for Assortment Models. Bibliography. Index.

Estimation efficiency in a binary mixed effects model

Article

Jun 1996
BIOMETRIKA

We investigate the efficiency of likelihood methods for estimating the regression parameters of mixed-effects logistic regression models. One approach uses a conditional likelihood which eliminates the random intercept terms. A second uses the likelihood generated from the marginal distribution of the data where the random intercepts are integrated out. Parametric estimates result from assuming a parametric form for the intercept distribution, whereas we obtain semiparametric estimates when the intercept distribution is left unspecified. We present an expression which shows that the asymptotic relative efficiency of conditional likelihood estimators relative to parametric estimators is a decreasing function of within-cluster covariate correlation. Simulation results show the same for the asymptotic relative efficiency of the semiparametric estimator relative to the conditional. For fixed covariate correlation, the asymptotic relative efficiency of the parametric versus the conditional increases as cluster sizes increase. Example data further illustrate our findings.

The Effect of Two-Stage Sampling on Ordinary Least Squares Methods

Article

Dec 1982

We look at the effect of intracluster correlation on standard procedures in linear regression. The ordinary least squares estimator, , of the coefficient vector performs well in most cases but the usual estimator of cov() and procedures based on this such as confidence intervals and hypothesis tests can be seriously misleading. The size of the effect, however, tends to be smaller than the corresponding effect on the variance of an estimated mean in two-stage sampling provided that the cluster sample sizes are approximately equal.

Regression Analysis: A Constructive Critique

Article

Jan 2003

Richard A. Berk

Survival Models: Analysis of Binary Outcomes in Longitudinal Studies Using Weighted Estimating Equations and Discrete-Time Survival Methods: Prevalence and Incidence of Smoking in An Adolescent Cohort

Article

Oct 1999
STAT MED

Longitudinal studies are increasingly popular in epidemiology. In this tutorial we provide a detailed review of methods used by us in the analysis of a longitudinal (multiwave or panel) study of adolescent health, focusing on smoking behaviour. This example is explored in detail with the principal aim of providing an introduction to the analysis of longitudinal binary data, at a level suited to statisticians familiar with logistic regression and survival analysis but not necessarily experienced in longitudinal analysis or estimating equation methods. We describe recent advances in statistical methodology that can play a practical role in applications and are available with standard software. Our approach emphasizes the importance of stating clear research questions, and for binary outcomes we suggest these are best organized around the key epidemiological concepts of prevalence and incidence. For prevalence questions, we show how unbiased estimating equations and information-sandwich variance estimates may be used to produce a valid and robust analysis, as long as sample size is reasonably large. We also show how the estimating equation approach readily extends to accommodate adjustments for missing data and complex survey design. A detailed discussion of gender-related differences over time in our smoking outcome is used to emphasize the need for great care in separating longitudinal from cross-sectional information. We show how incidence questions may be addressed using a discrete-time version of the proportional hazards regression model. This approach has the advantages of providing estimates of relative risks, being feasible with standard software, and also allowing robust information-sandwich variance estimates. Copyright © 1999 John Wiley & Sons, Ltd.

Statistical methods for longitudinal and clustered designs with binary responses

Article

Feb 1992

John Neuhaus

Dependent binary response data arise frequently in practice due to repeated measurements in longitudinal studies or to subsampling primary sampling units as in fields such as teratology and ophthalmology. Several classes of approaches have recently been proposed to analyse such repeated binary outcome data. The different classes of approaches measure different effects of covariates on binary responses and address different statistical questions. This article compares the different classes of approaches in terms of parameter interpretation and magnitude, standard errors of model parameters and Wald tests for covariate effects. The results help to clarify the substantive questions which data analysts can address with each approach, as well as why the covariate effects measured by different approaches may be different. Finally, I will provide guidelines to the advantages and disadvantages of alternative approaches for analysing dependent binary responses. Simulations and example data illustrate these findings.

Models for Longitudinal Data: A Generalized Estimating Equation Approach

Article

Jan 1989

This article discusses extensions of generalized linear models for the analysis of longitudinal data. Two approaches are considered: subject-specific (SS) models in which heterogeneity in regression parameters is explicitly modelled; and population-averaged (PA) models in which the aggregate response for the population is the focus. We use a generalized estimating equation approach to fit both classes of models for discrete and continuous outcomes. When the subject-specific parameters are assumed to follow a Gaussian distribution, simple relationships between the PA and SS parameters are available. The methods are illustrated with an analysis of data on mother's smoking and children's respiratory disease.

The Bone Density of Female Twins Discordant for Tobacco Use

Article

Mar 1994

Smoking is recognized as a risk factor for vertebral, forearm, and hip fractures. Since bone density is an important determinant of bone strength, we conducted a study to ascertain whether a deficit in bone density is associated with tobacco use and, if so, to identify the responsible mechanisms. We conducted a cross-sectional study of bone density at the lumbar spine and the femoral neck and shaft in 41 pairs of female twins (21 monozygotic pairs), 27 to 73 years of age (mean, 49), who were discordant for at least 5 pack-years of smoking (mean, 23; maximum, 64). Bone density was measured by dual-photon absorptiometry. The difference in bone density between the members of a pair was expressed as a percentage of the mean value for the pair. For every 10 pack-years of smoking, the bone density of the twin who smoked more heavily was 2.0 percent lower at the lumbar spine (P = 0.01), 0.9 percent lower at the femoral neck (P = 0.25), and 1.4 percent lower at the femoral shaft (P = 0.04). These results were not confounded by measured lifestyle factors. In the 20 pairs who were discordant by 20 or more pack-years (mean, 35), the (mean +/- SE) within-pair differences in bone density at the three sites were 9.3 +/- 3.1 percent (P = 0.008), 5.8 +/- 2.9 percent (P = 0.06), and 6.5 +/- 3.2 percent (P = 0.05), respectively. Smoking was associated with higher serum concentrations of follicle-stimulating hormone (P = 0.02) and luteinizing hormone (P = 0.03) and lower serum concentrations of parathyroid hormone (P = 0.05). Differences in spinal bone density between members of a pair were associated with differences in the serum concentrations of parathyroid hormone (P = 0.01) and calcium (P = 0.05) and urinary pyridinoline excretion (P = 0.06), a marker of bone resorption. Women who smoke one pack of cigarettes each day throughout adulthood will, by the time of menopause, have an average deficit of 5 to 10 percent in bone density, which is sufficient to increase the risk of fracture.

Between- and Within-Cluster Covariate Effects in the Analysis of Clustered Data

Article

Jul 1998

Standard methods for the regression analysis of clustered data postulate models relating covariates to the response without regard to between- and within-cluster covariate effects. Implicit in these analyses is the assumption that these effects are identical. Example data show that this is frequently not the case and that analyses that ignore differential between- and within-cluster covariate effects can be misleading. Consideration of between- and within-cluster effects also helps to explain observed and theoretical differences between mixture model analyses and those based on conditional likelihood methods. In particular, we show that conditional likelihood methods estimate purely within-cluster covariate effects, whereas mixture model approaches estimate a weighted average of between- and within-cluster covariate effects.

Fetal origins of adult disease - The hypothesis revisited

Article

Aug 1999

The hypothesis that adult disease has fetal origins is plausible, but much supportive evidence is flawed by incomplete and incorrect statistical interpretation. When size in early life is related to later health outcomes only after adjustment for current size, it is probably the change in size between these points (postnatal centile crossing) rather than fetal biology that is implicated. Even when birth size is directly related to later outcome, some studies fail to explore whether this is partly or wholly explained by postnatal rather that prenatal factors. These considerations are critical to understanding the biology and timing of 'programming,' the direction of future research, and future public health interventions.

Within pair association between birth weight and blood pressure at age 8 in twins for a cohort study

Article

Dec 1999

To study the association between birth weight and blood pressure in children from multiple pregnancies (multiplets), mostly twins, to determine whether maternal or genetic factors are responsible for the association. Cohort study. Southern Tasmania. Subjects: 888 children including 104 multiplets (32 monozygotic, 72 dizygotic). Systolic blood pressure (mm Hg). Blood pressure decreased with birth weight and increased with current body mass. After adjustment for age and body mass, systolic blood pressure changed by -1.94 mm Hg (95% confidence interval -2.89 to -0.98) per 1 kg increase in birth weight of singletons. For multiplets, blood pressure changed by -7.0 mm Hg (-10.1 to -3.9) for each 1 kg increase in birth weight. This was little altered in within pair analyses (-5.3, -13.8 to 3.2) and was similar for both monozygotic (-6.5, -22.5 to 9.4) and dizygotic (-4.9, -15.8 to 6.0) pairs. Because the association between birth weight and blood pressure was largely unchanged in within pair analyses, exposures originating in the mother (such as nutritional status) cannot be wholly responsible. The association also remained within monozygotic pairs, suggesting that genetic predisposition is not wholly responsible either. The principal causal pathway must concern mechanisms within the fetoplacental unit. The stronger association in multiplets suggests that factors adversely influencing both blood pressure and birth weight are more prevalent in multiple pregnancies.

Do genetic factors contribute to the association between birth weight and blood pressure?

Article

Sep 2001

To evaluate whether genetic factors contribute to the association between low birth weight and increased blood pressure among adolescents. Historical cohort study of twin pairs. It was evaluated whether (1) a negative association between birth weight and systolic blood pressure was found in the overall twin sample and (2) whether the intrapair difference in birth weight correlated with the intrapair difference in systolic blood pressure-thereby controlling for the effect of genetic factors (all in monozygotic and on average half in dizygotic pairs). The Minnesota Twin Family Study. 1311 pairs of adolescent twins. A negative association between birth weight and systolic blood pressure was retrieved in the overall sample. The regression coefficient after controlling for current weight was -1.88 mm Hg/kg (SE 0.61), which corresponds to results from previous studies of singleton adolescents. The regression coefficient fell to -0.64 mm Hg/kg (SE 0.86) when the intrapair analyses were used. The largest reduction was observed among monozygotic twins: from -2.44 mm Hg/kg (SE 0.75) in the overall monozygotic twin sample to -1.06 mm Hg/kg (SE 1.14) in the analyses of the within monozygotic pair differences. The association between low birth weight and increased blood pressure later in life is well established. "The fetal programming hypothesis" suggests that the association is caused by intrauterine malnutrition while a new hypothesis "the fetal insulin hypothesis" proposes that genetically determined insulin resistance also contributes significantly to the association. A recent twin study of middle aged twins showed no evidence for an influence of genetic factors while this larger study provides support for the fetal insulin hypothesis: the association between birth weight and blood pressure attenuated among adolescents when genetic factors were controlled. Together this suggests an important contribution of genetic factors to the association between fetal growth and systolic blood pressure in adolescence.

Twins and fetal origins hypothesis: Within-pair analyses [4]

Article

Jul 2002

Fetal growth and systolic blood pressure in young adulthood: The Swedish Young Male Twins Study

Article

Aug 2002

The objective was to test the fetal origins hypothesis by examining the association between fetal growth and systolic blood pressure in a large cohort of adult male twins of known zygosity. This cohort study is based on a record linkage of routinely collected data from the Swedish Medical Birth Registry, the Swedish Military Conscription Registry and a mailed questionnaire. It comprises 886 pairs of same‐sex male twins born in Sweden in 1973–79 for whom data were available on size at birth and systolic blood pressure, height and weight at age 17–19 years. Based on self‐reported similarity of appearance in childhood, 384 twin pairs were classified as monozygotic (MZ), 269 as dizygotic (DZ) and 233 as of uncertain zygosity (XZ). Differences in systolic blood pressure within and between twin pairs were analysed in relation to birthweight and birthweight‐for‐gestational‐age z‐score using random effects linear models. Within twin pairs, a 1 kg difference in birthweight was associated with a difference of −1.30 mmHg in systolic blood pressure [95% confidence interval −4.15, +1.54] for MZ twins and +0.14 [−3.49, +3.76] for DZ twins; for all twins combined it was −0.21 [−2.13, +1.71]. Between twin pairs, a 1 kg difference in birthweight was associated with a difference of −2.68 mmHg in systolic blood pressure [−4.95, −0.42] for MZ twins and +0.28 [−2.35, +2.91] for DZ twins; for all twins combined −1.68 [−3.15, −0.22]. All these estimates included adjustment for age, year and conscription centre of examination, gestational age and height and weight at conscription. These results provide little support for the fetal origins hypothesis. The estimates of the within‐pair effect in MZ twins and their wide confidence intervals (including zero) cannot exclude the existence of common genetic mechanisms, but are also not inconsistent with an in utero programming effect. This study highlights some methodological problems with twin studies.

An Overview of Relations Among Causal Modelling Methods

Article

Nov 2002

This paper provides a brief overview to four major types of causal models for health-sciences research: Graphical models (causal diagrams), potential-outcome (counterfactual) models, sufficient-component cause models, and structural-equations models. The paper focuses on the logical connections among the different types of models and on the different strengths of each approach. Graphical models can illustrate qualitative population assumptions and sources of bias not easily seen with other approaches; sufficient-component cause models can illustrate specific hypotheses about mechanisms of action; and potential-outcome and structural-equations models provide a basis for quantitative analysis of effects. The different approaches provide complementary perspectives, and can be employed together to improve causal interpretations of conventional statistical results.

Modeling Postnatal Exposures and Their Interactions with Birth Size

Article

Feb 2004

Tim J Cole

The fetal origins of adult disease hypothesis postulates that the inverse association between birth weight and later adverse outcome reflects fetal programming that increases the risk of later disease. However, low birth weight is associated with catch-up after birth, and weight gain is itself a risk factor for later disease. It is difficult to disentangle the effects on outcome of the size and growth components of weight change through time. This paper presents the life course plot, a device to display both size and growth effects simultaneously. It is based on the multiple-regression analysis of the outcome on the various weights, expressed as z-scores, and the plot displays the coefficients plotted against the corresponding ages of measurement. Examples from Brazil (Pelotas) and the Phillippines (Cebu) relate blood pressure in adolescence to weight through childhood. They show small inverse weight effects in infancy, but early weight is less important than weight and weight gain during adolescence. In addition, birth length in the Cebu study affects the strength of the relationship between weight and blood pressure in adolescence. This suggests a fetal programming effect, with children who were relatively long at birth having a more sensitive relationship between blood pressure and weight at age 15. Whether this is a good or a bad thing is not immediately clear.

Low birthweight and Type 2 diabetes: A study on 11 162 Swedish twins

Article

Oct 2004

To investigate the association between low birthweight and diabetes in a population-based Swedish twin sample. Method A cohort of 11 162 same-sexed Swedish twins born between 1906 and 1958 was used in order to investigate the risk of developing Type 2 diabetes between and within twin pairs by utilizing random effects linear models. Between pairs there was a significant increase in risk of developing Type 2 diabetes for a 1-kg increase in their mean birthweight (odds ratio [OR] = 2.13; P < 0.01), adjusted for age, sex, body mass index (BMI), and smoking status. The corresponding risk within pair was 2.03 (P = 0.07) for monozygotic twins and 1.15 (P = 0.71) for dizygotic twins. The test of the heterogeneity of the within and between effects showed no significant difference between the estimates. The study suggests that reduced fetal growth increase the risk of Type 2 diabetes due to an in utero programming effect possibly caused by intrauterine malnutrition. However, it does not exclude the possibility of a common genetic mechanism.

Separating within and between effects in family studies: An application to the study of blood pressure in children

Article

Sep 2004

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.

Association between Erythropoietin in Cord Blood of Twins and Size at Birth: Does It Relate to Gestational Factors or to Factors during Labor or Delivery?

Article

Jun 2005

We hypothesized that cord blood erythropoietin (EPO), a marker of fetal hypoxia, relates to gestational factors and not solely those associated with delivery. We investigated the association between birth weight SD score (SDS) and cord blood EPO in 290 twins (145 pairs), assessing the influence of gestational versus perinatal factors by comparing the association in those who were delivered by elective cesarean (CS) with that in other delivery modes. Blood EPO values were skewed, so geometric means are presented and log EPO values were used in statistical models. The birth size-EPO association was estimated in mixed-effects models that included terms that represented difference in log EPO and mean log EPO for each twin pair. Within-pair estimates of the association were unconfounded by maternal factors (because these were perfectly controlled). Geometric mean EPO was higher in boys versus girls (24.4 versus 17.0 IU/L; p = 0.0001) and increased with gestational age (p = 0.0003) but was similar after elective CS versus other delivery modes. The negative birth size-EPO association was stronger in infants who were delivered by elective CS than by other delivery modes [beta for log(2) EPO: -0.56 (95% CI, -0.77 to -0.36) versus -0.27 (-0.42 to -0.12), respectively; p = 0.02 for interaction). Because the association was seen after elective CS delivery, cord blood EPO must relate to factors during gestation, not just perinatal factors. There was no evidence of an association between birth weight SDS and pair mean log EPO, indicating that the association is entirely due to fetus-specific rather than pair-specific factors.

Using Bivariate Models to Understand between‐ and within‐Cluster Regression Coefficients, with Application to Twin Data

Article

Oct 2006

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.

Separation of individual-level and cluster-level covariate effects in regression analysis of correlated data

Article

Aug 2003

The focus of this paper is regression analysis of clustered data. Although the presence of intracluster correlation (the tendency for items within a cluster to respond alike) is typically viewed as an obstacle to good inference, the complex structure of clustered data offers significant analytic advantages over independent data. One key advantage is the ability to separate effects at the individual (or item-specific) level and the group (or cluster-specific) level. We review different approaches for the separation of individual-level and cluster-level effects on response, their appropriate interpretation and give recommendations for model fitting based on the intent of the data analyst. Unlike many earlier papers on this topic, we place particular emphasis on the interpretation of the cluster-level covariate effect. The main ideas of the paper are highlighted in an analysis of the relationship between birth weight and IQ using sibling data from a large birth cohort study.

Regression models for twin studies: A critical review

Abstract

No full-text available

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