Breast and bowel cancers diagnosed in people 'too young to have cancer': A blueprint for research using family and twin studies.

Young breast and bowel cancers (e.g., those diagnosed before age 40 or 50 years) have far greater morbidity and mortality in terms of years of life lost, and are increasing in incidence, but have been less studied. For breast and bowel cancers, the familial relative risks, and therefore the familial variances in age-specific log(incidence), are much greater at younger ages, but little of these familial variances has been explained. Studies of families and twins can address questions not easily answered by studies of unrelated individuals alone. We describe existing and emerging family and twin data that can provide special opportunities for discovery. We present designs and statistical analyses, including novel ideas such as the VALID (Variance in Age-specific Log Incidence Decomposition) model for causes of variation in risk, the DEPTH (DEPendency of association on the number of Top Hits) and other approaches to analyse genome-wide association study data, and the within-pair, ICE FALCON (Inference about Causation from Examining FAmiliaL CONfounding) and ICE CRISTAL (Inference about Causation from Examining Changes in Regression coefficients and Innovative STatistical AnaLysis) approaches to causation and familial confounding. Example applications to breast and colorectal cancer are presented. Motivated by the availability of the resources of the Breast and Colon Cancer Family Registries, we also present some ideas for future studies that could be applied to, and compared with, cancers diagnosed at older ages and address the challenges posed by young breast and bowel cancers.

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

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.

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

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.

The impact of aggregate positive lifestyle behaviors on low back pain resilience and care seeking.

BACKGROUND CONTEXT: Low back pain (LBP) is a global issue, and the high associated costs are mainly attributed to a small proportion of people with LBP who seek care. Importantly, the impact of aggregate positive lifestyle behaviors on LBP resilience and care seeking is not known. PURPOSE: This study aimed to evaluate the relationship between positive lifestyle behaviors and LBP resilience. STUDY DESIGN: This study was a prospective longitudinal cohort study. PATIENT SAMPLE: Data was collected as part of the AUstralian Twin BACK Study (AUTBACK). Participants who reported a lifetime previous history of LBP at baseline were included in this analysis (n = 340). OUTCOME MEASURES: The outcomes of interest were the number of weeks without activity limiting LBP and total number of days of healthcare usage, health practitioner care, self-management care, and medication intake. METHODS: A lifestyle behavior score was built using variables of body mass index (BMI), physical activity, smoking status, and sleep quality. Negative binomial regression analyses were used to assess the relationship between the positive lifestyle behavior score and the count outcomes of number of weeks without activity limiting LBP and number of days participants used care. RESULTS: After adjusting for covariates, no association was found between participants' positive lifestyle behavior score and their number of weeks without activity limiting LBP (IRR: 1.02, 95% CI 1.00-1.05). There was a statistically significant relationship between higher positive lifestyle behavior scores and fewer number of days of participants' total healthcare usage (IRR:0.69, 95% CI 0.56-0.84), healthcare practitioner visits (IRR:0.62, 95% CI 0.45-0.84), use of self-management strategies (IRR:0.74, 95% CI 0.60-0.91), and use of pain medication (IRR:0.55, 95% CI 0.44-0.68). CONCLUSION: People who adopt optimal lifestyle behaviors, such as engaging in adequate physical activity, achieving optimal quality sleep, maintaining an ideal BMI, and not smoking, may not experience less time suffering from activity limiting LBP, but are less likely to use healthcare and pain medication for their LBP.

Non-communicable disease mortality in young people with a history of contact with the youth justice system in Queensland, Australia: a retrospective, population-based cohort study.

BACKGROUND: Young people who have had contact with the criminal justice system are at increased risk of early death, especially from injuries. However, deaths due to non-communicable diseases (NCDs) in this population remain poorly described. We aimed to estimate mortality due to NCDs in people with a history of involvement with the youth justice system, compare NCD mortality rates in this population with those in the general population, and characterise demographic and justice-related factors associated with deaths caused by NCDs in people with a history of contact with the youth justice system. METHODS: In this retrospective, population-based cohort study (the Youth Justice Mortality [YJ-Mort] study), we included all people aged 10-18 years (at baseline) charged with a criminal offence in Queensland, Australia, between June 30, 1993, and July 1, 2014. We probabilistically linked youth justice records with adult correctional records and national death records up to Jan 31, 2017. Indigenous status was ascertained from youth justice and adult correctional records, with individuals identified as Indigenous in either source classified as Indigenous in the final dataset. We estimated crude mortality rates and standardised mortality ratios (SMRs) for comparisons with data from the Australian general population. We identified risk factors for NCD deaths using competing-risks regression. FINDINGS: Of 48 670 individuals aged 10-18 years (at baseline) charged with a criminal offence in Queensland, Australia, between June 30, 1993, and July 1, 2014, 11 897 (24·4%) individuals were female, 36 773 (75·6%) were male, and 13 250 (27·2%) were identified as identified as Indigenous. The median age at first contact with the youth justice system was 15 years (IQR 14-16), the median follow-up time was 13·4 years (8·4-18·4), and the median age at the end of the study was 28·6 years (23·6-33·6). Of 1431 deaths, 932 (65·1%) had a known and attributed cause, and 121 (13·0%) of these were caused by an NCD. The crude mortality rate from NCDs was 18·5 (95% CI 15·5-22·1) per 100 000 person-years among individuals with a history of involvement with the youth justice system, which was higher than among the age-matched and sex-matched Australian general population (SMR 1·67 [1·39-1·99]). Two or more admissions to adult custody (compared with none; adjusted sub-distribution hazard ratio 2·09 [1·36-3·22]), and up to 52 weeks in adult custody (compared with none; 1·98 [1·18-3·32]) was associated with NCD death. INTERPRETATION: Young people with a history of contact with the justice system are at increased risk of death from NCDs compared with age-matched and sex-matched peers in the general Australian population. Reducing youth incarceration and providing young people's rights to access clinical, preventive, and restorative services should be a priority. FUNDING: National Health and Medical Research Council.

Sex differences in lifetime prevalence of low back pain: A multinational study of opposite-sex twin pairs.

BACKGROUND: Low back pain (LBP) is more likely to occur in people with a family history of this condition, highlighting the importance of accounting for familial factors when studying the individual risk of LBP. We conducted a study of opposite-sex twin pairs investigating sex differences in LBP while accounting for (genetic and shared environmental) familial factors. METHODS: We applied a matched co-twin control design to study 795 adult opposite-sex pairs from Australia, Spain, and the United States (US). We used mixed-effects logistic regression to assess the within-pair association between female sex and lifetime prevalence of LBP in unadjusted and adjusted models for body-mass-index, and depression, as well as interactions between female sex and age (

Multimorbidity and quality of primary care after release from prison: a prospective data-linkage cohort study.

BACKGROUND: The period after release from prison can be challenging, especially due to a higher risk of morbidity and mortality despite commonly increased use of healthcare services. However, little is known about the quality of the healthcare offered to this population, which limits the possibility of addressing this important health inequity. This study characterised multimorbidity and investigated the relationship between multimorbidity and quality of primary healthcare in adults within 2 years after release from prison. METHODS: This was a prospective cohort study of 1046 participants of a service brokerage intervention after release from prison between August 2008 and July 2010 in Queensland, Australia. Participants had their baseline survey and clinical data linked prospectively with their medical, correctional and death records. Multimorbidity was ascertained using the Cumulative Illness Rating Scale and classified into three categories: none, moderate (morbidity in 2-3 domains) and complex (morbidity in 4 or more domains). Outcomes were Usual Provider Continuity Index (UPCI), Continuity of Care (COC) Index, and having at least one extended primary care consultation (> 20 minutes). Descriptive statistics and logistic regression were used in the analyses. RESULTS: Multimorbidity was present for 761 (73%) participants, being more prevalent among females (85%) than males (69%), p < 0.001. Moderate multimorbidity was not associated with UPCI or COC, but was associated with having at least one long consultation (AOR = 1.64; 95% CI:1.14-2.39), after adjusting for covariates. Complex multimorbidity was positively associated with all outcomes in the adjusted models. Indigenous status was negatively associated with UPCI (AOR = 0.54; 95% CI: 0.37-0.80) and COC (AOR = 0.53; 95% CI: 0.36-0.77), and people younger than 25 years were at 36% lower odds (AOR = 0.64; 95% CI: 0.44-0.93) of having a long consultation than the middle-aged group (25-44 years) in the adjusted models. CONCLUSION: Moderate multimorbidity was associated with having at least one extended primary care consultation, but not with adequate continuity of care, for adults within 2 years of being released from prison. Nearly half of those with complex multimorbidity did not receive adequate continuity of care. The quality of primary care is inadequate for a large proportion of adults released from prison, constituting an important and actionable health inequity.

Birthweight, gestational age and familial confounding in sex differences in infant mortality: a matched co-twin control study of Brazilian male-female twin pairs identified by population data linkage.

BACKGROUND: In infancy, males are at higher risk of dying than females. Birthweight and gestational age are potential confounders or mediators but are also familial and correlated, posing epidemiological challenges that can be addressed by studying male-female twin pairs. METHODS: We studied 28 558 male-female twin pairs born in Brazil between 2012 and 2016, by linking their birth and death records. Using a co-twin control study matched for gestational age and familial factors, we applied logistic regression with random effects (to account for paired data) to study the association between male sex and infant death, adjusting for: birthweight, within- and between-pair effects of birthweight, birth order and gestational age, including interactions. The main outcome was infant mortality (0-365 days) stratified by neonatal (early and late) and postneonatal deaths. RESULTS: Males were 100 g heavier and more at risk of infant death than their female co-twins before [odds ratio (OR) = 1.28, 95% confidence interval (CI): 1.11-1.49, P = 0.001] and after (OR = 1.60, 95% CI: 1.39-1.83, P <0.001) adjusting for birthweight and birth order. When adjusting for birthweight within-pair difference and mean separately, the OR attenuated to 1.40 (95% CI: 1.21-1.61, P <0.001), with evidence of familial confounding (likelihood ratio test, P <0.001). We found evidence of interaction (P = 0.001) between male sex and gestational age for early neonatal death. CONCLUSIONS: After matching for gestational age and familial factors by design and controlling for birthweight and birth order, males remain at greater risk of infant death than their female co-twins. Birthweight's role as a confounder can be partially explained by familial factors.

A rapid review of early guidance to prevent and control COVID-19 in custodial settings.

BACKGROUND: With over 11 million people incarcerated globally, prevention and control of COVID-19 in custodial settings is a critical component of the public health response. Given the risk of rapid transmission in these settings, it is important to know what guidance existed for responding to COVID-19 in the early stages of the pandemic. We sought to identify, collate, and summarise guidance for the prevention and control of COVID-19 in custodial settings in the first six months of 2020. We conducted a systematic search of peer-reviewed and grey literature, and manually searched relevant websites to identify publications up to 30 June 2020 outlining recommendations to prevent and/or control COVID-19 in custodial settings. We inductively developed a coding framework and assessed recommendations using conventional content analysis. RESULTS: We identified 201 eligible publications containing 374 unique recommendations across 19 domains including: preparedness; physical environments; case identification, screening, and management; communication; external access and visitation; psychological and emotional support; recreation, legal, and health service adaptation; decarceration; release and community reintegration; workforce logistics; surveillance and information sharing; independent monitoring; compensatory measures; lifting control measures; evaluation; and key populations/settings. We identified few conflicting recommendations. CONCLUSIONS: The breadth of recommendations identified in this review reflects the complexity of COVID-19 response in custodial settings. Despite the availability of comprehensive guidance early in the pandemic, important gaps remain in the implementation of recommended prevention and control measures globally, and in the availability of evidence assessing their effectiveness on reducing COVID-19 disease, impact on people in custody and staff, and implementation.

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.

Correction to: A rapid review of early guidance to prevent and control COVID-19 in custodial settings.

[This corrects the article DOI: 10.1186/s40352-021-00150-w.].

Genetic and environmental variation in educational attainment: an individual-based analysis of 28 twin cohorts.

We investigated the heritability of educational attainment and how it differed between birth cohorts and cultural-geographic regions. A classical twin design was applied to pooled data from 28 cohorts representing 16 countries and including 193,518 twins with information on educational attainment at 25 years of age or older. Genetic factors explained the major part of individual differences in educational attainment (heritability: a2 = 0.43; 0.41-0.44), but also environmental variation shared by co-twins was substantial (c2 = 0.31; 0.30-0.33). The proportions of educational variation explained by genetic and shared environmental factors did not differ between Europe, North America and Australia, and East Asia. When restricted to twins 30 years or older to confirm finalized education, the heritability was higher in the older cohorts born in 1900-1949 (a2 = 0.44; 0.41-0.46) than in the later cohorts born in 1950-1989 (a2 = 0.38; 0.36-0.40), with a corresponding lower influence of common environmental factors (c2 = 0.31; 0.29-0.33 and c2 = 0.34; 0.32-0.36, respectively). In conclusion, both genetic and environmental factors shared by co-twins have an important influence on individual differences in educational attainment. The effect of genetic factors on educational attainment has decreased from the cohorts born before to those born after the 1950s.

Cohort profile: the AUstralian Twin BACK pain and physical activity study (AUTBACK study).

PURPOSE: Despite the growing evidence that physical activity and familial factors play a role in low back pain (LBP), there is a lack of robust longitudinal studies that (1) investigate the types and dosages of physical activity that are protective or harmful for LBP, (2) employ objective measures of physical activity and (3) conduct appropriate adjustment for confounders. The AUstralian Twin BACK (AUTBACK) study was established to elucidate the longitudinal LBP-physical activity relationship with the benefits of controlling for familial (both genetic/nongenetic) factors that may influence physical activity engagement and LBP. PARTICIPANTS: Participants are twins registered at Twins Research Australia (TRA), older than 18 years, with access to internet. We collected data on LBP status (weekly) and physical activity levels (monthly) for 12 months as well as a wide range of health, lifestyle and physical activity (objective, self-reported, including different types and dosages) data. FINDINGS TO DATE: We included 401 twins, 157 being complete twin pairs (n=314). Lifetime prevalence of LBP was 85%. Participants spent 61% of their week in sedentary time and only 4% in moderate/vigorous intensity physical activity (accelerometer). So far, 168 participants (40% of the sample) have completed the 12-month follow-up. A total of 7150 weekly (LBP status) and 1763 monthly questionnaires (physical activity status) have been answered (92% response rate). FUTURE PLANS: The 12-month follow-up will be completed by June 2020. This cohort represents a novel and comprehensive resource for researchers in the field, and includes high-quality, and frequent data on LBP and physical activity. It allows the investigation of genetic and shared environmental factors on the LBP-physical activity relationship. The AUTBACK group has planned a number of projects, with the main one being the investigation of the influence of physical activity on recurrence of LBP. Data linkage opportunities are available, including with other studies conducted by TRA.

The Value of Twins for Health and Medical Research: A Third of a Century of Progress.

In 1984, Hrubec and Robinette published what was arguably the first review of the role of twins in medical research. The authors acknowledged a growing distinction between two categories of twin studies: those aimed at assessing genetic contributions to disease and those aimed at assessing environmental contributions while controlling for genetic variation. They concluded with a brief section on recently founded twin registries that had begun to provide unprecedented access to twins for medical research. Here we offer an overview of the twin research that, in our estimation, best represents the field has progress since 1984. We start by summarizing what we know about twinning. We then focus on the value of twin study designs to differentiate between genetic and environmental influences on health and on emerging applications of twins in multiple areas of medical research. We finish by describing how twin registries and networks are accelerating twin research worldwide.

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.

Contributions of birthweight, annualised weight gain and BMI to back pain in adults: a population-based co-twin control study of 2754 Australian twins.

PURPOSE: To investigate associations between anthropometric measures (birthweight, weight gain and current BMI) and back pain; and to determine whether these associations differ between those born with low or full birthweight. METHODS: The cross-sectional associations between the lifetime prevalence of back pain and anthropometric measures (birthweight, weight gain and current BMI) among 2754 adult twins were investigated in three stages: total sample; within-pair case-control for monozygotic and dizygotic twins together; and within-pair case-control analysis separated by dizygotic and monozygotic. Results were expressed as odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Birthweight was not associated with back pain (OR 0.99; 95% CI 0.99-1.00), but a weak association was found between weight gain (OR 1.01; CI 1.00-1.01) or current BMI (OR 1.02; 95% CI 1.00-1.05) and back pain in the total sample analysis. These associations did not remain significant after adjusting for genetics. The associations did not differ between those whose were born with low or full birthweight. CONCLUSION: Birthweight was not associated with prevalence of back pain in adulthood. Weight gain and current BMI were weakly associated with back pain prevalence in the total sample analysis but did not differ between those born with low or full birthweight. However, the small-magnitude association only just achieved significance and appeared to be confounded by genetics and the early shared environment. Our results suggest that a direct link between these predictors and back pain in adults is unlikely. These slides can be retrieved under Electronic Supplementary Material.

Twin studies for the prognosis, prevention and treatment of musculoskeletal conditions.

BACKGROUND: Musculoskeletal conditions are highly prevalent in our ageing society and are therefore incurring substantial increases in population levels of years lived with disability (YLD). An evidence-based approach to the prognosis, prevention, and treatment of those disorders can allow an overall improvement in the quality of life of patients, while also softening the burden on national health care systems. METHODS: In this Masterclass article, we provide an overview of the most relevant twin study designs, their advantages, limitations and major contributions to the investigation of traits related to the domain of musculoskeletal physical therapy. CONCLUSIONS: Twin studies can be an important scientific tool to address issues related to musculoskeletal conditions. They allow researchers to understand how genes and environment combine to influence human health and disease. Twin registries and international collaboration through existing networks can provide resources for achieving large sample sizes and access to expertise in study design and analysis of twin data.