Studies of Twin Responses to Understand Exercise THerapy (STRUETH): cerebrovascular function.

We studied monozygotic (MZ) and dizygotic (DZ) twin pairs following resistance (RES) and endurance (END) training to assess genetic and environmental contributions to cerebrovascular function. Cerebrovascular function (rest, autoregulation, hypercapnia, exercise) was assessed in 86 healthy same-sex MZ (30 pairs) and DZ (13 pairs) twins, who underwent 3 months of END and RES. Carbon dioxide ( PETCO2${P_{{\rm{ETC}}{{\rm{O}}_{\rm{2}}}}}$ ), mean arterial pressure (MAP) and middle cerebral artery velocity (MCAv) were measured and MCAv resistance (MCACVRi ) was calculated. Resting MCAv reduced by -2.8 cm/s following RES (P = 0.024), with no change following END (-0.3 cm/s, P = 0.758). Change in MCACVRi following RES was +0.11 mmHg/cm/s (P < 0.001), which was significantly greater than END (+0.02 mmHg/cm/s, P = 0.030). MAP also increased following RES (+4 mmHg, P = 0.010), but not END (+1 mmHg, P = 0.518). No changes were apparent in PETCO2${P_{{\rm{ETC}}{{\rm{O}}_{\rm{2}}}}}$ . At rest, positive response rates following RES ranged from 27 to 71% and from 40 to 64% following END. Intraclass correlations between twins were moderate for most variables at baseline. In response to training, only MZ pairs were significantly correlated for a change in MCAv (P = 0.005) and low frequency phase (P = 0.047) following RES.This study is the first to compare cerebrovascular function following RES and END in MZ and DZ twins. Most individuals who did not respond to one modality were able to respond by switching modality, and baseline heritability estimates were higher than training response. Exercise professionals should therefore consider modality and environmental factors when optimising interventions. KEY POINTS: Characterising individual responses to resistance and endurance exercise training can inform optimal strategies for exercise prescription. This study utilised monozygotic and dizygotic twins in a randomised cross-over study to determine individual responsiveness to different modalities of exercise training. The influence of environment vs. genetics on cerebrovascular responses to training was determined. It is apparent that individuals respond differently to distinct exercise stimuli and that switching modality may be a beneficial way to obtain positive responses in cerebrovascular function. This study has implications for improving individualised exercise prescription to maintain or improve cerebrovascular structure and function.

Pregnancy and birth characteristics of Aboriginal twins in two Australian states: a data linkage study.

INTRODUCTION: Perinatal outcomes for singleton pregnancies are poorer, on average, for Aboriginal people than non-Aboriginal people, but little is known about Aboriginal multifetal pregnancies. Yet multifetal pregnancies and births are often more complicated and have poorer outcomes than singleton pregnancies. We describe the pregnancies, births and perinatal outcomes for Aboriginal twins born in Western Australia (WA) and New South Wales (NSW) with comparisons to Aboriginal singletons in both states and to non-Aboriginal births in NSW. MATERIALS AND METHODS: Whole-population birth records and birth and death registrations were linked for all births during 2000-2013 (WA) and 2002-2008 (NSW). Hospital records and the WA Register of Developmental Anomalies - Cerebral Palsy were linked for all WA births and hospital records for a subset of NSW births. Descriptive statistics are reported for maternal and child demographics, maternal health, pregnancy complications, births and perinatal outcomes. RESULTS: Thirty-four thousand one hundred twenty-seven WA Aboriginal, 32,352 NSW Aboriginal and 601,233 NSW non-Aboriginal births were included. Pregnancy complications were more common among mothers of Aboriginal twins than Aboriginal singletons (e.g. 17% of mothers of WA twins had hypertension/pre-eclampsia/eclampsia vs 8% of mothers of singletons) but similar to mothers of NSW non-Aboriginal twins. Most Aboriginal twins were born in a principal referral, women's or large public hospital. The hospitals were often far from the mother's home (e.g. 31% of mothers of WA Aboriginal twins gave birth at hospitals located more than 3 h by road from their home). Outcomes were worse for Aboriginal liveborn twins than Aboriginal singletons and non-Aboriginal twins (e.g. 58% of NSW Aboriginal twins were preterm compared to 9% of Aboriginal singletons and 49% non-Aboriginal twins). CONCLUSIONS: Mothers of Aboriginal twins faced significant challenges during the pregnancy, birth and the postnatal period in hospital and, in addition to accessible specialist medical care, these mothers may need extra practical and psychosocial support throughout their journey.

Association of Adult Socioeconomic Status with Body Mass Index: A Within- and Between-Twin Study.

Adult socioeconomic status (SES) has been consistently associated with body mass index (BMI), but it is unclear whether it is linked to BMI independently of childhood SES or other potentially confounding factors. Twin studies can address this issue by implicitly controlling for childhood SES and unmeasured confounders. This co-twin control study used cross-sectional data from Twins Research Australia's Health and Lifestyle Questionnaire (N = 1918 twin pairs). We investigated whether adult SES, as measured by both the Index of Relative Socioeconomic Disadvantage (IRSD) and the Australian Socioeconomic Index 2006 (AUSEI06), was associated with BMI after controlling for factors shared by twins within a pair. The primary analysis was a linear mixed-effects model that estimated effects both within and between pairs. Between pairs, a 10-unit increase in AUSEI06 was associated with a 0.29 kg/m2 decrease in BMI (95% CI [-.42, -.17], p < .001), and a 1-decile increase in IRSD was associated with a 0.26 kg/m2 decrease in BMI (95% CI [-.35, -.17], p < .001). No association was observed within pairs. In conclusion, higher adult SES was associated with lower BMI between pairs, but no association was observed within pairs. Thus, the link between adult SES and BMI may be due to confounding factors common to twins within a pair.

Conducting Clinical Trials in Twin Populations: A Review of Design, Analysis, Recruitment and Ethical Issues for Twin-Only Trials.

Although twins often participate in medical research, few clinical trials are conducted entirely in twin populations. The purpose of this review is to demonstrate the substantial benefits and address the key challenges of conducting clinical trials in twin populations, or 'twin-only trials'. We consider the unique design, analysis, recruitment and ethical issues that arise in such trials. In particular, we describe the different approaches available for randomizing twin pairs, highlight the similarity or correlation that exists between outcomes of twins, and discuss the impact of this correlation on sample size calculations and statistical analysis methods for estimating treatment effects. We also consider the role of both monozygotic and dizygotic twins for studying variation in outcomes, the factors that may affect recruitment of twins, and the ethics of conducting trials entirely in twin populations. The advantages and disadvantages of conducting twin-only trials are also discussed. Finally, we recommend that twin-only trials should be considered more often.

Fitness and strength responses to distinct exercise modes in twins: Studies of Twin Responses to Understand Exercise as a THerapy (STRUETH) study.

KEY POINTS: Exercise is considered medicine; however, the individual degree of responsiveness to a standardized dose of exercise is idiosyncratic. Individual responsiveness between distinct exercise modalities and the genetic/environmental contributions to exercise response are not well understood. In this novel randomized cross-over design study, monozygotic and dizygotic twins, as pairs, underwent 3 months of resistance and endurance training, separated by a 3 month washout period, aiming to assess training responses in strength and fitness outcomes to dichotomous training modalities, as well as the genetic/environmental contributions to exercise response. Our findings indicate that (i) individual responsiveness differs between exercise modalities; (ii) low-responders to one mode may be 'rescued' by switching to an alternate mode of exercise; and (iii) genes may not play as large a role, as previously estimated from cross-sectional data, for exercise training adaptation. The present study has implications for those charged with optimizing the benefits of exercise by means of individualizing the exercise prescription. ABSTRACT: Exercise response is idiosyncratic, although the degree of responsiveness, concordance in response between modalities and genetic contribution to responsiveness are not well understood. We investigated this using a novel randomized cross-over design of dichotomous exercise interventions in mono-(MZ) and di-zygotic (DZ) twin pairs. We studied strength (1RM) and fitness ( V̇O2max ) responses in 84 same-sex untrained twins (30 MZ, 12 DZ pairs; 24.9 ± 5.4 years). Twins, as pairs, underwent 3 months of resistance (RES) and endurance (END) training, separated by a 3 month washout period. Training responses and genetic/environmental contributions to responses were assessed. Leg strength 1RM increased following RES but not END (△47 ± 29 vs. 3 ± 26 kg; P < 0.001), whereas V̇O2max increased following END but not RES (△0.25 ± 0.26 vs. 0.04 ± 0.25 L min-1 ; P < 0.001). A higher percentage of individuals responded to RES for strength and to END for V̇O2max (P < 0.0001). Within-individual responses to each mode were not correlated (P > 0.05). Cross-sectional intraclass correlations were higher for MZ than DZ pairs for all variables, largely as a result of shared environment. Following training, MZ, but not DZ pairs, were significantly correlated for strength change to RES (rMZ = 0.62, P = 0.002) and END (rMZ = 0.36, P = 0.04), and for V̇O2max change to END (L min-1 , rMZ = 0.45, P = 0.02) with a mixture of unshared/shared environmental contributions. Our findings indicate that individual responsiveness differs between modalities and low-responders to one mode may be 'rescued' by switching to an alternate mode. Additionally, genes may not play as large a role as previously estimated from cross-sectional data for training adaptation, and/or cross-sectional data do not reflect longitudinal training effects. The present study has implications for optimizing the individualization of exercise prescription.

Developmental origins of cardiometabolic health outcomes in twins: A systematic review and meta-analysis.

BACKGROUND AND AIMS: Studies of twins can reduce confounding and provide additional evidence about the causes of disease, due to within-pair matching for measured and unmeasured factors. Although findings from twin studies are typically applicable to the general population, few studies have taken full advantage of the twin design to explore the developmental origins of cardiometabolic health outcomes. We aimed to systematically review the evidence from twin studies and generate pooled estimates for the effects of early-life risk factors on later-life cardiometabolic health. METHODS AND RESULTS: An initial search was conducted in March 2018, with 55 studies of twins included in the review. Risk of bias was assessed using the Newcastle-Ottawa Scale, and eligible studies were included in a meta-analysis, where pooled estimates were calculated. Twenty-six studies analysed twins as individuals, and found that higher birthweight was associated with lower SBP (ß = -2.02 mmHg, 95%CI: -3.07, -0.97), higher BMI (ß = 0.52 kg/m2, 95%CI: 0.20, 0.84) and lower total cholesterol (ß = -0.07 mmol/L, 95%CI: -0.11, -0.04). However, no associations were reported in studies which adjusted for gestational age. Few of the included studies separated their analyses into within-pair and between-pair associations. CONCLUSIONS: Early-life risk factors were associated with cardiometabolic health outcomes in twin studies. However, many estimates from studies in this review were likely to have been confounded by gestational age, and few fully exploited the twin design to assess the developmental origins of cardiometabolic health outcomes.

Early birth is a key factor in educational disadvantage of twins: A data linkage study.

AIM: To assess educational outcomes of twins and quantify the degree this is mediated by gestational age and other perinatal factors. METHODS: We conducted a population-based record-linkage cohort study of all live births ≥24 weeks gestation in New South Wales, Australia with a corresponding standardised school test result for grade 3 in 2008-2014. The primary outcome was whether a child met the National Minimum Standard (NMS) cut-off in literacy and numeracy domains. Robust multivariable Poisson models were used to obtain adjusted relative risks (aRRs), and mediation analysis conducted to assess contributing factors on the causal pathway. RESULTS: Of 351 791 liveborn infants, 10 365 (2.9%) were twins. After adjusting for maternal covariates and compared with singletons, twins had an increased risk of not meeting the NMS for all five literacy and numeracy domains (aRR 1.27-1.45, P < .001). Gestational age alone mediated up to 73% of aRRs and small for gestational age further attenuated these effects with only minimal risk remaining after adjusting for all mediators (aRR 0.94-1.07). CONCLUSION: Almost all of the educational disadvantage experienced by twins, compared with singletons, is attributable to the risk associated with shorter gestational age, and partly by poor foetal growth. These findings support efforts to prolong gestation of twin pregnancies.

The Association between Socioeconomic Status and Psychological Distress: A Within and Between Twin Study.

Low socioeconomic status (SES) has been established as a risk factor for poor mental health; however, the relationship between SES and mental health problems can be confounded by genetic and environmental factors in standard regression analyses and observational studies of unrelated individuals. In this study, we used a within-pair twin design to control for unmeasured genetic and environmental confounders in investigating the association between SES and psychological distress. We also employed within-between pair regression analysis to assess whether the association was consistent with causality. SES was measured using the Index of Relative Socio-economic Disadvantage (IRSD), income and the Australian Socioeconomic Index 2006 (AUSEI06); psychological distress was measured using the Kessler 6 Psychological Distress Scale (K6). Data were obtained from Twins Research Australia's Health and Lifestyle Questionnaire (2014-2017), providing a maximum sample size of 1395 pairs. Twins with higher AUSEI06 scores had significantly lower K6 scores than their co-twins after controlling for shared genetic and environmental traits (ßW [within-pair regression coefficient] = -0.012 units, p = .006). Twins with higher income had significantly lower K6 scores than their co-twins after controlling for familial confounders (ßW = -0.182 units, p = .002). There was no evidence of an association between the IRSD and K6 scores within pairs (ßW, p = .6). Using a twin design to eliminate the effect of potential confounders, these findings further support the association between low SES and poor mental health, reinforcing the need to address social determinants of poor mental health, in addition to interventions targeted to individuals.

Twins Research Australia: A New Paradigm for Driving Twin Research.

Twins Research Australia (TRA) is a community of twins and researchers working on health research to benefit everyone, including twins. TRA leads multidisciplinary research through the application of twin and family study designs, with the aim of sustaining long-term twin research that, both now and in the future, gives back to the community. This article summarizes TRA's recent achievements and future directions, including new methodologies addressing causation, linkage to health, economic and educational administrative datasets and to geospatial data to provide insight into health and disease. We also explain how TRA's knowledge translation and exchange activities are key to communicating the impact of twin studies to twins and the wider community. Building researcher capability, providing registry resources and partnering with all key stakeholders, particularly the participants, are important for how TRA is advancing twin research to improve health outcomes for society. TRA provides researchers with open access to its vibrant volunteer membership of twins, higher order multiples (multiples) and families who are willing to consider participation in research. Established four decades ago, this resource facilitates and supports research across multiple stages and a breadth of health domains.

Is the Association Between Obesity and Hip Osteoarthritis Surgery Explained by Familial Confounding?

BACKGROUND: Familial confounding is confounding due to genetics or environmental exposures shared by family members. We aimed to study whether familial confounding explains the association between body mass index (BMI) and severe hip osteoarthritis (OA). METHODS: We linked data from the Norwegian Arthroplasty Registry with the Norwegian Twin Registry on the National ID-number in 2014, generating a population-based prospective cohort study of same-sex twins born between 1915 and 1960 (53.4% females). BMI was calculated from self-reported height/weight. The outcome was incident hip arthroplasty due to OA (follow-up time, 1987-2014; 424 914 person-years). We performed sex-specific co-twin control analyses of dizygotic (N = 5,226) and monozygotic (MZ, N = 3,803) twin pairs using Cox regression models and explored reasons for any familial confounding using bivariate twin models. RESULTS: The mean (SD) BMI was 22.6 (2.96), peak lifetime BMI 25.6 (2.61), and N = 614 had hip surgery due to OA. In cohort analyses, BMI was associated with hip OA for women and men (hazard ratio [HR] = 1.09, 95% confidence intervals [CIs] = 1.06 to 1.11 and HR = 1.08, 95% CI = 1.04 to 1.12, respectively). When adjusting for familial confounding within MZ twins, the association got stronger for women (HR = 1.19; 95% CI = 1.05 to 1.36) but weaker for men (HR = 0.93; 95% CI = 0.75 to 1.16). There was no genetic overlap between BMI and hip OA, yet the familial confounding in men provides suggestive evidence that the association could be explained by shared environmental factors. CONCLUSION: The association between BMI and hip OA may be explained by familial confounding for men. For women, there was no evidence for familial confounding, consistent with a causal association. See video abstract at, http://links.lww.com/EDE/B336.

Socioeconomic position in young adulthood is associated with BMI in Australian families.

BACKGROUND: Low socioeconomic position (SEP) is associated with increased cardiovascular (CV) disease risk, but the relative importance of SEP in childhood and adulthood, and of changes in SEP between these two life stages, remains unclear. Studies of families may help clarify these issues. We aimed to assess whether SEP in young adulthood, or change in SEP from childhood to young adulthood, was associated with five continuously measured CV risk factors. METHODS: We used data from 286 adult Australian families from the Victorian Family Heart Study (VFHS), in which some offspring have left home (n = 364) and some remained at home (n = 199). SEP (defined as the Index of Relative Socioeconomic Disadvantage) was matched to addresses. We fitted variance components models to test whether young adult SEP and/or change in SEP was associated with systolic blood pressure, diastolic blood pressure, body mass index (BMI), total cholesterol or high-density lipoprotein cholesterol, after adjustment for parental SEP and within-family correlation. RESULTS: An increase in SEP of 100 SEIFA units from childhood to adulthood was associated with a lower BMI (ß = -0.49 kg/m(2), P < 0.01) only. CONCLUSIONS: These results suggest that a change in SEP in young adulthood is an important predictor of BMI, independent of childhood SEP.

Non-proportional odds multivariate logistic regression of ordinal family data.

Methods to examine whether genetic and/or environmental sources can account for the residual variation in ordinal family data usually assume proportional odds. However, standard software to fit the non-proportional odds model to ordinal family data is limited because the correlation structure of family data is more complex than for other types of clustered data. To perform these analyses we propose the non-proportional odds multivariate logistic regression model and take a simulation-based approach to model fitting using Markov chain Monte Carlo methods, such as partially collapsed Gibbs sampling and the Metropolis algorithm. We applied the proposed methodology to male pattern baldness data from the Victorian Family Heart Study.

Computed tomography scan radiation and brain cancer incidence.

BACKGROUND: Computed tomography (CT) scans make substantial contributions to low-dose ionizing radiation exposures, raising concerns about excess cancers caused by diagnostic radiation. METHODS: Deidentified medicare records for all Australians aged 0-19 years between 1985-2005 were linked to national death and cancer registrations to 2012. The National Cancer Institute CT program was used to estimate radiation doses to the brain from CT exposures in 1985-2005, Poisson regression was used to model the dependence of brain cancer incidence on brain radiation dose, which lagged by 2 years to minimize reverse causation bias. RESULTS: Of 10 524 842 young Australians, 611 544 were CT-exposed before the age of 20 years, with a mean cumulative brain dose of 44 milligrays (mGy) at an average follow-up of 13.5 years after the 2-year lag period. 4472 were diagnosed with brain cancer, of whom only 237 had been CT-exposed. Brain cancer incidence increased with radiation dose to the brain, with an excess relative risk of 0.8 (95% CI 0.57-1.06) per 100 mGy. Approximately 6391 (95% CI 5255, 8155) persons would need to be exposed to cause 1 extra brain cancer. CONCLUSIONS: For brain tumors that follow CT exposures in childhood by more than 2 years, we estimate that 40% (95% CI 29%-50%) are attributable to CT Radiation and not due to reverse causation. However, because of relatively low rates of CT exposure in Australia, only 3.7% (95% CI 2.3%-5.4%) of all brain cancers are attributable to CT scans. The population-attributable fraction will be greater in countries with higher rates of pediatric scanning.

Exercise and Artery Function in Twins: Sex Differences in a Cross-Over Trial.

BACKGROUND: Physical activity reduces cardiovascular risk, partly via direct effects on the arterial wall. We hypothesized that vascular function responses would be modality-specific, sex-dependent, and express a high degree of heritability. METHODS: We recruited 90 same-sex twins (31 monozygotic, 14 dizygotic dizygotic pairs; 25.8±6.0 years) and randomized 70 (25 monozygotic, 10 dizygotic) to complete, as pairs, 3 months each of resistance and endurance training, separated by a 3-month washout. RESULTS: Brachial artery flow-mediated (FMD%) and glyceryl-trinitrate induced dilation (GTN%) both increased following endurance (FMD%: ∆1.46%, P<0.001; GTN%: ∆1.76%, P=0.004) and resistance (FMD%: ∆1.73%, P<0.001; GTN%: ∆1.68%, P=0.045). About one-third of participants failed to respond to one or other mode; 10% failed to respond to both for FMD% (17% for GTN%). FMD% and GTN% increased significantly in response to both resistance and endurance in females (P<0.05), but not males. Twin analysis revealed that responses to both FMD% and GTN% with exercise training for both modalities were dependent on factors shared by monozygotic pairs and that a large contribution from genetic effects is unlikely. CONCLUSIONS: Our findings indicate that both endurance and resistance can enhance vascular function and that responses in females were more marked. Most individuals respond to one or other form of training, with few unresponsive to both; a finding that has implications for optimizing exercise-based approaches for individualized benefit. Focusing on characteristics of exercise prescription may be more important than the impact of distinct candidate genes when considering exercise as a form of vascular medicine. REGISTRATION: URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=371222; Unique identifier: ACTRN 12616001095459.

Evidence for ethnicity and location as regulators of the newborn blood metabolome: a monozygous twin study.

Introduction: Monochorionic, diamniotic (MCDA) monozygotic twins share nearly all genetic variation and a common placenta in utero. Despite this, MCDA twins are often discordant for a range of common phenotypes, including early growth and birth weight. As such, MCDA twins represent a unique model to explore variation in early growth attributable primarily to in utero environmental factors. Methods: MCDA twins with a range of within-pair birth weight discordance were sampled from the peri/postnatal epigenetic twin study (PETS, Melbourne; n = 26 pairs), Beijing twin study (BTS, Beijing; n = 25), and the Chongqing longitudinal twin study (LoTiS, Chongqing; n = 22). All PETS participants were of European-Australian ancestry, while all Chinese participants had Han ancestry. The average of the birth weight difference between the larger and smaller co-twins for all twin pairs was determined and metabolomic profiles of amino acids, TCA cycle intermediates, fatty acids, organic acids, and their derivatives generated from cord blood plasma by gas chromatograph mass spectrometry. Within and between co-twin pair analyses were performed to identify metabolites specifically associated with discordance in birth weight. Multivariable regression and pathway enrichment analyses between different regions were performed to evaluate the geographical effects on the metabolism of MCDA twin pairs. Results: PETS twins showed a markedly different metabolic profile at birth compared to the two Chinese samples. Within-pair analysis revealed an association of glutathione, creatinine, and levulinic acid with birth weight discordance. Caffeine, phenylalanine, and several saturated fatty acid levels were uniquely elevated in PETS twins and were associated with maternal BMI and average within pair birth weight, in addition to birth weight discordance. LoTiS twins had higher levels of glutathione, tyrosine, and gamma-linolenic acid relative to PETS and BTS twins, potentially associated with eating habits. Conclusion: This study highlights the potential role of underlying genetic variation (shared by MZ twins), in utero (non-shared by MZ twins) and location-specific (shared by MZ twins) environmental factors, in regulating the cord blood metabolome of uncomplicated MCDA twins. Future research is needed to unravel these complex relationships that may play a key role in phenotypic metabolic alterations of twins independent of genetic diversity.

Cohort profile: The Australian Paediatric Exposure to Radiation Cohort (Aust-PERC).

Although the carcinogenic effects of high-dose radiation are well-established, the risks at low doses, such as from diagnostic X-rays, are less well understood. Children are susceptible to radiation induced cancers, and in the last decade, several cohort studies have reported increased cancer risks following computed tomography (CT) scans in childhood. However, cohort studies can be limited by insufficient follow-up, indication bias, reverse causation, or by lack of organ doses from CT scans or other exposures. Aust-PERC is a retrospective cohort designed to study the effects of low-dose medical radiation exposure, primarily from CT scans, in young Australians. The cohort was ascertained using deidentified billing records from patients who were aged 0-19 years while enrolled in Medicare (Australia's universal healthcare system) between 1985 and 2005. All procedures billed to Medicare in this age/time window that involved low-dose radiation were identified, and persons without such procedures were flagged as unexposed. The Aust-PERC cohort has been linked, using confidential personal identifiers, to the Australian Cancer Database and the National Death Index, on two occasions (to Dec. 2007 and Dec. 2012) by the responsible government agency (Australian Institute of Health and Welfare). Deidentified Medicare service records of all radiological procedures including CT scans, nuclear medicine (NM) scans and fluoroscopy and plain X-ray procedures have been available to derive estimated radiation doses in the cohort. Records of other medical and surgical procedures, together with demographic and socioeconomic variables are being used in analyses to assess biases arising from reverse causation and confounding. After excluding patients with errant records, 11 802 846 persons remained in the baseline cohort, with an average follow-up time of 22.3 years to December 2012. There were 275 489 patients exposed to diagnostic nuclear medicine scans and 688 363 patients exposed to CT scans before age 20 and before cancer diagnosis. Between 1 January 1985 and 31 December 2012, there were 105 124 deaths and 103 505 incident cancers. Dose-response analyses based on the relevant organ doses are underway for individual cancers, and we plan to extend the follow-up for another 8 years to Dec 2020. Analyses using this very large Aust-PERC cohort, with extended follow-up, will help to resolve international uncertainties about the causal role of diagnostic medical radiation as a cause of cancer.

Birthweight-for-gestational-age z-scores are associated with early childhood cardiometabolic health in the Peri/Postnatal Epigenetic Twin Study.

Birthweight has been consistently related to risk of cardiometabolic disorders in later life. Twins are at higher risk of low birthweight than singletons, so understanding the links between birthweight and cardiometabolic health may be particularly important for twins. However, evidence for the association of birthweight with childhood markers of cardiometabolic health in twins is currently lacking. Previous studies have often failed to appropriately adjust for gestational age or fully implement twin regression models. Therefore, we aimed to evaluate the association of birthweight-for-gestational-age z-scores with childhood cardiometabolic health in twins, using within-between regression models. The Peri/Postnatal Epigenetic Twins Study is a Melbourne-based prospective cohort study of 250 twin pairs. Birthweight was recorded at delivery, and childhood anthropometric measures were taken at 18-month and 6-year follow-up visits. Associations of birthweight with markers of cardiometabolic health were assessed at the individual, between- and within-pair level using linear regression with generalised estimating equations. Birthweight-for-gestational-age z-scores were associated with height, weight and BMI at 18 months and 6 years, but not with blood pressure (twins-as-individual SBP: ß = 0.15, 95% CI: -0.81, 1.11; twins-as-individual DBP: ß = 0.22, 95% CI: -0.34, 0.77). We found little evidence to indicate that the within-between models improved on the twins-as-individuals models. Birthweight was associated with childhood anthropometric measures, but not blood pressure, after appropriately adjusting for gestational age. These associations were consistent across the within-between and twins-as-individuals models. After adjusting for gestational age, results from the twins-as-individuals models are consistent with singleton studies, so these results can be applied to the general population.

Three trajectories of gestational weight gain identified in an Australian twin study.

OBJECTIVES: Gestational weight gain (GWG) has been associated with maternal and child health outcomes, but knowledge of appropriate GWG for twin gestations is limited. STUDY DESIGN: The Peri/Postnatal Epigenetic Twins Study is a prospective twin cohort study of 250 women and their twin children in Melbourne, Australia. We modeled trajectories of GWG using group-based growth modeling and compared these trajectories to GWG categories (within, above, or below current GWG recommendations for twin pregnancy). We fitted robust linear and Poisson regression models to assess associations of maternal pre-pregnancy and gestational exposures with risk of gaining weight outside the recommendations. RESULTS: Of the 250 women enrolled in the PETS, GWG measures were available for 172 women. Forty-seven percent of women had GWG within the current recommendations. We identified three GWG trajectories - 23.6% of women had low GWG throughout pregnancy, 34.5% had average GWG throughout pregnancy, and 42.0% had average initial GWG, followed by high GWG from trimester two until delivery. Gestational diabetes mellitus (GDM) was associated with increased risk of inadequate GWG (RR: 2.40, 95%CI: 1.53, 3.75). Pre-pregnancy obesity (RR: 1.88, 95%CI: 1.09, 3.26) and hypertensive disorders of pregnancy (RR: 2.64, 95%CI: 1.20, 5.81) were associated with increased risk of excessive GWG. CONCLUSIONS: More than half of the women in the PETS did not meet the current GWG recommendations. Women with GDM or hypertensive disorders were more likely to gain weight outside these guidelines. More research is needed to establish comprehensive guidelines for twin pregnancies.

Left Ventricular Adaptation to Exercise Training via Magnetic Resonance Imaging: Studies of Twin Responses to Understand Exercise THerapy.

PURPOSE: Changes in left ventricular mass (LVM) and end-diastolic volume (EDV) in response to exercise training are important determinants of functional capacity in health and disease, but the impact of different exercise modalities remains unclear. METHODS: Using a randomized crossover design we studied the impact of resistance (RES) and endurance (END) training using cardiac magnetic resonance imaging in previously untrained monozygotic (MZ) and dizygotic (DZ) twin pairs (n = 72; 22 MZ pairs, 14 DZ same-sex pairs; 26.1 ± 5.4 yr). Twins, as pairs, undertook 3 months of RES and 3 months of END training (order randomized), separated by a 3-month washout. RESULTS: Group results revealed that END increased LVM (P < 0.001) and EDV (P = 0.007), whereas RES did not (P > 0.05). A higher proportion of individuals responded to END than RES for LVM (72% vs 38%, P < 0.001) and EDV (67% vs 40%, P = 0.003). Baseline cross-sectional intraclass correlations were higher for MZ than DZ twin pairs for all variables (e.g., LVM heritability = 0.42), but no significant correlations were apparent between pairs for change in any variable in response to either RES or END (P > 0.05). CONCLUSIONS: Our findings indicate that cardiac adaptation in response to exercise is modality-specific and that low responders to one mode of exercise can be high responders to an alternative. Heritability estimates based on cross-sectional data, which suggested a genetic contribution to LVM, do not accord with estimates based on training effects, which indicated limited genetic impact on adaptation in this 3-month study of exercise training. This study has implications for understanding the physiological and health impacts of typically used exercise modalities on cardiac adaptation in previously untrained individuals.