Incidence and assessment of delirium following open cardiac surgery; A systematic review and meta-analysis.

AIM: This systematic review and meta-analysis sought i) to provide an overview of the incidence of delirium following open cardiac surgery and ii) to investigate how incidences of delirium are associated with different assessment tools. METHODS AND RESULTS: A systematic search of studies investigating delirium following open cardiac surgery were conducted in Medline (Ovid), EMBASE, PsycINFO, CiNAHL and the Cochrane Database. Only studies with patients diagnosed or screened with a validated tool were included. Studies published from 2005 to 2021 were included in the meta-analysis.Of 7,126 individual studies retrieved, 106 met the inclusion criteria for the meta-analysis, hereof 31% of high quality. The weighted pooled incidence of delirium following open cardiac surgery across all studies was 23% (95% CI 20-26%), however we found a considerable heterogeneity (I2 = 99%), which could not be explained by subgroups or further sensitivity analyses. The most commonly applied screening tool for delirium is CAM/CAM-ICU. The lowest estimates of delirium were found by applying the Delirium Observation Scale (incidence 14%, 95% CI 8-20%), and the highest estimates in studies using "other" screening tools (Organic Brain Symptom Scale, Delirium Symptom Interview) pooled incidence of 43%, (95% CI 19 - 66%), however, only two studies applied these. CONCLUSION: Delirium following open cardiac surgery remains a complication with a high incidence of overall 23%, when applying a validated tool for screening or diagnosis. Nevertheless, this systematic review and meta-analyses highlight the significant inconsistency in current evidence regarding assessment tools and regimens. REGISTRATION: Prospero CRD42020215519.

Association of cancer with functional decline at old age: a longitudinal study in Danish twins.

INTRODUCTION: There is evidence that older adults with cancer have a higher risk of functional decline than cancer-free older adults. However, few studies are longitudinal, and none are twin studies. Thus, we aimed to investigate the relationship between cancer and functional decline in older adult (aged 70+ years) twins. MATERIALS AND METHODS: Cancer cases in the Longitudinal Study of Aging Danish Twins were identified through the Danish Cancer Registry. Functional status was assessed using hand grip strength (6 years follow-up), and self-reported questions on mobility (10 years follow-up), and cut-offs were defined to assess functional decline. Cox regression models were performed for all the individual twins. In addition, we extended the analysis to discordant twin pairs (twin pairs with one having cancer and the other being cancer-free), to control to a certain extent for (unmeasured) shared confounders (genetic and environmental factors). RESULTS: The analysis based on individual twins showed that individual twins with cancer are at increased hazard of worsening hand grip strength (hazard ratio (HR) 1.37, 95% confidence interval (CI) 1.04, 1.80) than cancer-free twins. Among the discordant twin pairs, twins with cancer had a higher hazard of worsening hand grip strength (HR 3.50, 95% CI 1.15, 10.63) than cancer-free cotwins. In contrast, there was no evidence of a difference between the hazard of experiencing mobility decline for twins with cancer compared with cancer-free twins, in both individual twins and discordant twin pairs analyses. DISCUSSION: Cancer was associated with hand grip strength functional decline in old individual twins and discordant pairs. Our results strengthen the importance of comprehensive geriatric assessment in older adults with cancer, as well as the importance of routine assessment of functional status. Promoting physical activity through exercise training programmes could enable the prevention of functional decline in older adults with cancer.

A Mass Spectrometry-Based Proteome Study of Twin Pairs Discordant for Incident Acute Myocardial Infarction within Three Years after Blood Sampling Suggests Novel Biomarkers.

Acute myocardial infarction (AMI) is a major cause of mortality and morbidity worldwide, yet biomarkers for AMI in the short- or medium-term are lacking. We apply the discordant twin pair design, reducing genetic and environmental confounding, by linking nationwide registry data on AMI diagnoses to a survey of 12,349 twins, thereby identifying 39 twin pairs (48-79 years) discordant for their first-ever AMI within three years after blood sampling. Mass spectrometry of blood plasma identified 715 proteins. Among 363 proteins with a call rate > 50%, imputation and stratified Cox regression analysis revealed seven significant proteins (FDR < 0.05): FGD6, MCAM, and PIK3CB reflected an increased level in AMI twins relative to their non-AMI co-twins (HR > 1), while LBP, IGHV3-15, C1RL, and APOC4 reflected a decreased level in AMI twins relative to their non-AMI co-twins (HR < 1). Additional 50 proteins were nominally significant (p < 0.05), and bioinformatics analyses of all 57 proteins revealed biology within hemostasis, coagulation cascades, the immune system, and the extracellular matrix. A protein-protein-interaction network revealed Fibronectin 1 as a central hub. Finally, technical validation confirmed MCAM, LBP, C1RL, and APOC3. We put forward novel biomarkers for incident AMI, a part of the proteome field where markers are surprisingly rare and where additional studies are highly needed.

Twin studies on cancer.

Studies on cancer loci by use of twin data reveal sources of variation in risk. The Nordic twin and cancer registries contain the largest cohort of population representative twins ever studied with more than median 40 years of follow-up. This article considers findings that show influences on familial risk and demonstrates the strengths of the matched case co-twin design for unraveling important risk factors of cancers. Studies using twin data will expectedly continue to provide insights into cancer epidemiology and genetics for the benefit of prevention and treatment.

Stillbirth and early neonatal mortality rates may be underestimated using recall information: A comparison of demographic surveillance methodologies.

OBJECTIVE: Child mortality and stillbirth rates (SBR) remain high in low-income countries but may be underestimated due to incomplete reporting of child deaths in retrospective pregnancy/birth histories. The aim of this study is to compare stillbirth and mortality estimates derived using two different methods: the method assuming full information and the prospective method. METHODS: Bandim Health Project's Health and Demographic Surveillance Systems (HDSS) follows women of reproductive age and children under five through routine home visits every 1, 2 or 6 months. Between 2012 and 2020, we estimated and compared early neonatal (ENMR, <7 days), neonatal (NMR, <28 days), and infant mortality (IMR, <1 year) per 1000 live births and SBR per 1000 births. Risk time for children born to registered women was calculated from birth (the method assuming full information) versus date of first observation in the HDSS (the prospective method), either at birth (for pregnancy registration) or registration. Rates were calculated using the Kaplan-Meier estimator and compared in generalised linear models allowing for within-child correlation obtaining relative risks (RR). RESULTS: We registered and followed 29,413 infants (1380 deaths; 1459 stillbirths) prospectively. An additional 164 infant deaths and 129 stillbirths were registered retrospectively and included in the method assuming full information. The ENMR was 24.5 (95%CI: 22.6-26.4) for the method assuming full information and 25.8 (23.7-27.8) for the prospective method, RR = 0.96 (0.93-0.99). Differences were smaller for the NMRs and IMRs. For SBRs, the estimates were 53.5 (50.9-56.0) and 58.6 (55.7-61.5); RR = 0.91 (0.90-0.93). The difference between methods became more pronounced when the analysis was limited to areas visited every 6 months: RR for ENMR: 0.91 (0.86-0.96) and RR for SBR: 0.85 (0.83-0.87). CONCLUSIONS: Assuming full information underestimates SBR and ENMR. Accounting for omissions of stillbirths and early neonatal deaths may lead to more accurate estimates and improved ability to monitor mortality.

Socioeconomic differences in expected discomfort from colonoscopy and colon capsule endoscopy.

Individual income and educational level are associated with participation rates in colorectal cancer screening. We aimed to investigate the expected discomfort from the endoscopic diagnostic modalities of colonoscopy and colon capsule endoscopy in different socioeconomic groups as a potential barrier for participation. In a randomized clinical trial within the Danish colorectal cancer screening program, we distributed questionnaires to 2031 individuals between August 2020 and December 2022 to investigate the expected procedural and overall discomfort from investigations using visual analogue scales. Socioeconomic status was determined by household income and educational level. Multivariate continuous ordinal regressions were performed to estimate the odds of higher expected discomfort. The expected procedural and overall discomfort from both modalities were significantly higher with increasing educational levels and income, except for procedural discomfort from colon capsule endoscopy between income quartiles. The odds ratios for higher expected discomfort increased significantly with increasing educational level, whereas the differences between income groups were less substantial. Bowel preparation contributed most to expected discomfort in colon capsule endoscopy, whereas in colonoscopy, the procedure itself was the largest contributor. Individuals with prior experiences of colonoscopy reported significantly lower expected overall but not procedural discomfort from colonoscopy. The threshold for acceptable discomfort between subgroups is unknown, but the expected discomfort in colon capsule endoscopy and colonoscopy was higher in higher socioeconomic subgroups, suggesting that expected discomfort is not a significant contributor to the inequalities in screening uptake.

A robust and fast two-sample test of equal correlations with an application to differential co-expression.

A robust and fast two-sample test for equal Pearson correlation coefficients (PCCs) is important in solving many biological problems, including, for example, analysis of differential co-expression. However, few existing methods for this test can achieve robustness against deviation from normal distributions, accuracy under small sample sizes, and computational efficiency simultaneously. Here, we propose a new method for testing differential correlation using a saddlepoint approximation of the residual bootstrap (DICOSAR). To achieve robustness, accuracy, and efficiency, DICOSAR combines the ideas underlying the pooled residual bootstrap, the signed root of a likelihood ratio statistic, and a multivariate saddlepoint approximation. Through a comprehensive simulation study and a real data analysis of gene co-expression, we demonstrate that DICOSAR is accurate and robust in controlling the type I error rate for detecting differential correlation and provides a faster alternative to the bootstrap and permutation methods. We further show that DICOSAR can also be used for testing differential correlation matrices. These results suggest that DICOSAR provides an analytical approach to facilitate rapid testing for the equality of PCCs in large-scale analysis.

Effect of nationwide school policy on device-measured physical activity in Danish children and adolescents: a natural experiment.

Background: A new Danish school policy with a requirement for 45 min physical activity daily during school hours was introduced in 2014. The objective of this natural experiment was to evaluate the effect of this nationwide school policy on physical activity in Danish children and adolescents. Methods: Four historical studies completed between 2009 and 2012 comprised the pre-policy study population. Post-policy data were collected in 2017/18. All post-policy schools were represented in the four pre-policy studies. Age-groups and seasons were matched. In total, 4816 children and adolescents aged 6-17 were included in the analyses (2346 pre-policy and 2470 post-policy). Children and adolescents were eligible if they had accelerometer measurements and did not have any physical disabilities preventing activity. Physical activity was measured by accelerometry. Main outcome was any bodily movement. Secondary outcomes were moderate to vigorous physical activity and overall movement volume (mean counts per minute). Findings: The school policy interrupted a linear decreasing pre-policy trend in physical activity during school hours. All activity outcomes increased post-policy during a standardized school day (8:10 am-1 pm). Increases were more pronounced in the youngest children. Specifically, we observed a daily increase during a standardized school day in 2017/2018 of 14.2 min of movement (95% CI: 11.4-17.0, p < 0.001), 6.5 min of moderate to vigorous physical activity (95% CI: 4.7-8.3, P < 0.001), and 141.8 counts per minute (95% CI: 108.5-175.2, P < 0.001). Interpretation: A national school policy may be an important strategy to increase physical activity during school hours among children and adolescents. Funding: The Danish Foundation TrygFonden has funded the PHASAR project (ID 115606).

Identifying genetic variants regulating MGMT gene expression - A study in monozygotic Danish twins.

Identifying genetic factors affecting the regulation of the O-6-Methylguanine-DNA Methyltransferase (MGMT) gene and estimating the genetic contribution of the MGMT gene through within-pair correlation in monozygotic twin pairs is of particular importance in various types of cancer such as glioblastoma. We used gene expression data in whole blood from 448 monozygotic twins from the Middle Age Danish Twins (MADT) study to investigate genetic regulation of the MGMT gene by performing a genome-wide association study (GWAS) of the variation in MGMT expression. Additionally, we estimated within-pair dependence measures of the expression values looking for the genetic influence of significant identified genes. We identified 243 single nucleotide polymorphisms (SNPs) significantly (p < 5e-8) associated with expression of MGMT, all located on chromosome 10 near the MGMT gene. Of the 243 SNPs, 7 are novel cis-eQTLs. By further looking into the suggestively significant SNPs (increasing cutoff to p = 1e-6), we identified 11 suggestive trans-eQTLs located on chromosome 17. These variants were in or proximal to a total of seven genes, which may regulate MGMT expression. The within-pair correlation of the expression of MGMT, TRIM37, and SEPT4 provided the upper bound genetic influence of these genes. Overall, identifying cis- or trans-acting genetic variations regulating the MGMT gene can pave the way for a better understanding of the MGMT gene function and ultimately in understanding the patient's sensitivity to therapeutic alkylating agents.

Small hard drusen and associated factors in early seniority.

PURPOSE: The purpose of this study was to examine the ocular and systemic risk profile of the fundus phenotype ≥ 20 small hard (macular) drusen (< 63 µm in diameter). METHODS: This single-center, cross-sectional study of 176 same-sex twin pairs aged 30 to 80 (median 60) years was a component of a framework study of the transition from not having age-related macular degeneration to having early AMD. Drusen categories assessed using fundus photography and optical coherence tomography included small hard drusen (diameter < 63 µm), intermediate soft drusen (63-125 µm), and large soft drusen (> 125 µm), of which the soft drusen are compatible with a diagnosis of AMD. RESULTS: Having ≥ 20 small hard drusen within or outside the macula was associated with increasing age, lower body mass index, shorter axial length, hyperopia, female sex, increasing high-density lipoprotein (HDL), high alcohol consumption, and with the presence of soft drusen. CONCLUSIONS: Having ≥ 20 small hard drusen was associated with some AMD-related risk factors, but not with smoking, increasing body mass index, and higher blood pressure. Having ≥ 20 small hard drusen was also associated with soft drusen, in agreement with previous studies. These findings suggest that small hard drusen are not an early manifestation of AMD but the product of a distinct process of tissue alteration that promotes the development of AMD or some subtype thereof.

Circulating microRNAs related to lipid metabolism and solid tissue maintenance and morphology associate with mortality in elderly twins.

The lifespan of humans varies greatly between individuals. Here, we aimed to explore what biological roles miRNAs may have on old age mortality-variation. Circulating miRNAs were measured in plasma from 43 monozygotic twin pairs (73-95 years of age) and mortality analyses were applied using Cox regression survival analyses and linear regression analyses of lifespan. In general, nominally significant miRNAs were mainly upregulated with shorter lifespan, both in Cox analysis (72 % upregulated) and in linear regression analysis (81 % upregulated). A total of 29 miRNAs were associated to mortality at a nominal significance level (p < 0.05) in the survival analysis, but no miRNAs passed the FDR adjusted level of significance. Seven of the 29 miRNAs; hsa-miR-140-3p, hsa-miR-16-5p, hsa-miR-487b-3p, hsa-miR-19a-3p, hsa-let-7d-5p, hsa-miR-320a, hsa-miR-375, were nominally significant across two linear twin-paired analyses and the cox analysis. Pathway analyses of the 29 nominally significant miRNAs from the individual level analyses resulted in two nominally significant associated Reactome pathways (unadjusted p < 0.05); 'Negative regulation of FGFR signaling' and 'Neurotransmitter receptor binding and downstream transmission in the postsynaptic cell', and two significantly associated KEGG pathways; 'Linoleic acid metabolism' and 'Toxoplasmosis'. Additional pathway analyses and results of previous studies support that miRNAs linked to mortality at age 70 years or older play a role in lipid metabolism, tissues maintenance and morphology.

The heritability of BMI varies across the range of BMI-a heritability curve analysis in a twin cohort.

BACKGROUND: The heritability of traits such as body mass index (BMI), a measure of obesity, is generally estimated using family and twin studies, and increasingly by molecular genetic approaches. These studies generally assume that genetic effects are uniform across all trait values, yet there is emerging evidence that this may not always be the case. METHOD/SUBJECTS: This paper analyzes twin data using a recently developed measure of heritability called the heritability curve. Under the assumption that trait values in twin pairs are governed by a flexible Gaussian mixture distribution, heritability curves may vary across trait values. The data consist of repeated measures of BMI on 1506 monozygotic (MZ) and 2843 like-sexed dizygotic (DZ) adult twin pairs, gathered from multiple surveys in older Finnish Twin Cohorts. RESULTS: The heritability curve and BMI value-specific MZ and DZ pairwise correlations were estimated, and these varied across the range of BMI. MZ correlations were highest at BMI values from 21 to 24, with a stronger decrease for women than for men at higher values. Models with additive and dominance effects fit best at low and high BMI values, while models with additive genetic and common environmental effects fit best in the normal range of BMI. CONCLUSIONS: We demonstrate that twin and molecular genetic studies need to consider how genetic effects vary across trait values. Such variation may reconcile findings of traits with high heritability and major differences in mean values between countries or over time.

Cancer-Related Reductions in Survival: Extent and Duration Evaluated Using a Large Cohort Study of Twins, 1943-2011.

BACKGROUND: The time during which there is an increased risk of death for cancer survivors was evaluated in a large twin study, which allows for matching on shared components such as age, genes, and socioeconomic factors in childhood. METHODS: By use of data from Danish registers, time to death from initial cancer was studied prospectively in twins in two different settings. The twins were diagnosed with at least one cancer in the period 1943 to 2011. Setting I included 5,680 same-sex twin pairs aged 6 and over, while Setting II included 3,218 twin individuals from age 70 and over. The study provides comparisons within twin pairs and across birth cohorts, age at diagnoses, and time at diagnosis. RESULTS: In 2001 to 2011, the 5-year mortality risk for a twin surviving cancer after the age of 70 was twofold that of the co-twin, regardless of sex and zygosity, and it was 1.5-fold if the twin survived the initial 9 months. After 5 to 6 years, the mortality risk corresponded to that of the co-twin. In previous decades, the excess hazard risk was considerably higher for both older and younger cohorts. There were no indications of change in relative survival across old birth cohorts. CONCLUSIONS: This large twin study suggested that for a cancer-treatment survivor diagnosed at age 70 or later, the additional mortality risk was largely absent 5 years later, by which time the survival relative to the co-twin was 60%. IMPACT: Elevated mortality risk after cancer is offset after 5 to 6 years.

Heritability and Risk Factors of Incident Small and Large Drusen in the Copenhagen Twin Cohort Eye Study: A 20-Year Follow-Up.

INTRODUCTION: The transition from a normal fundus to one with early drusen (≥20 small hard drusen) to age-related macular degeneration (AMD) in the form of drusen ≥63 µm in diameter is of interest, because small hard drusen may be precursors of large drusen. Study of AMD precursor lesions may provide valuable insight into factors that initiate AMD. Here, the progression of drusen was studied over an interval of 20 years in a population-based twin cohort. METHODS: Single-center, 20-year follow-up of 138 twins include biometry, fundus optical coherence tomography, and fundus photography. Macular characteristics were hierarchically classified as (per eye) (1) <20 small hard drusen, (2) ≥20 small hard drusen, (3) drusen ≥63 µm, or (4) ≥20 small hard drusen combined with drusen ≥63 µm. Additive and dominant genetic effects as well as shared and nonshared environmental effects were analyzed in a bivariate biprobit model with a classic liability-threshold approach and polygenic modeling with random effects. RESULTS: Median participant age was 59 (range 41-66) years. Of 25 (18%) cases of incident macular drusen, 7 had ≥20 small hard drusen, and 18 had drusen ≥63 µm at follow-up, whereas no participant had developed both traits simultaneously. Smoking was associated with incident ≥20 small hard drusen (p = 0.04) and incident drusen ≥63 µm (p = 0.003). Having ≥20 small hard drusen at baseline was associated with incident drusen ≥63 µm at follow-up (p = 0.02). Development of drusen ≥63 µm was attributable to 49% genetic effects and 51% environmental effects. CONCLUSION: The risk of progressing from 0 to 19 small hard macular drusen per eye to having ≥20 small hard drusen or drusen ≥63 µm at follow-up was associated with smoking and genetic predisposition. Having ≥20 small hard drusen in the absence of drusen ≥63 µm at baseline was associated with incident drusen ≥63 µm when examined 20 years later. The study confirms that small hard macular drusen is a forewarning of AMD and that progression to AMD may be hindered by avoidance of smoking.

Genome-wide association meta-analysis identifies 48 risk variants and highlights the role of the stria vascularis in hearing loss.

Hearing loss is one of the top contributors to years lived with disability and is a risk factor for dementia. Molecular evidence on the cellular origins of hearing loss in humans is growing. Here, we performed a genome-wide association meta-analysis of clinically diagnosed and self-reported hearing impairment on 723,266 individuals and identified 48 significant loci, 10 of which are novel. A large proportion of associations comprised missense variants, half of which lie within known familial hearing loss loci. We used single-cell RNA-sequencing data from mouse cochlea and brain and mapped common-variant genomic results to spindle, root, and basal cells from the stria vascularis, a structure in the cochlea necessary for normal hearing. Our findings indicate the importance of the stria vascularis in the mechanism of hearing impairment, providing future paths for developing targets for therapeutic intervention in hearing loss.

Integrative analysis of clinical and epigenetic biomarkers of mortality.

DNA methylation (DNAm) has been reported to be associated with many diseases and with mortality. We hypothesized that the integration of DNAm with clinical risk factors would improve mortality prediction. We performed an epigenome-wide association study of whole blood DNAm in relation to mortality in 15 cohorts (n = 15,013). During a mean follow-up of 10 years, there were 4314 deaths from all causes including 1235 cardiovascular disease (CVD) deaths and 868 cancer deaths. Ancestry-stratified meta-analysis of all-cause mortality identified 163 CpGs in European ancestry (EA) and 17 in African ancestry (AA) participants at p < 1 × 10-7 , of which 41 (EA) and 16 (AA) were also associated with CVD death, and 15 (EA) and 9 (AA) with cancer death. We built DNAm-based prediction models for all-cause mortality that predicted mortality risk after adjusting for clinical risk factors. The mortality prediction model trained by integrating DNAm with clinical risk factors showed an improvement in prediction of cancer death with 5% increase in the C-index in a replication cohort, compared with the model including clinical risk factors alone. Mendelian randomization identified 15 putatively causal CpGs in relation to longevity, CVD, or cancer risk. For example, cg06885782 (in KCNQ4) was positively associated with risk for prostate cancer (Beta = 1.2, PMR  = 4.1 × 10-4 ) and negatively associated with longevity (Beta = -1.9, PMR  = 0.02). Pathway analysis revealed that genes associated with mortality-related CpGs are enriched for immune- and cancer-related pathways. We identified replicable DNAm signatures of mortality and demonstrated the potential utility of CpGs as informative biomarkers for prediction of mortality risk.

Causal relation between heart irradiation and survival of lung cancer patients after radiotherapy.

INTRODUCTION: In a recent study, setup uncertainties in the direction of the heart were shown to impact the overall survival of non-small cell lung cancer (NSCLC) patients after radiotherapy, indicating the causal effect between heart irradiation and survival. The current study aims to externally evaluate this observation within a patient cohort treated using daily IGRT. METHOD: NSCLC patients with locally-advanced disease and daily CBCT were included. For all treatment fractions, the distance between the isocenter and the heart was evaluated based on the clinical setup registrations. The variation in heart position between planning and treatment (DeltaDistance) was estimated from these registrations. The possible impact of DeltaDistance on survival was analysed by a multivariable Cox model of overall survival, allowing for a time-dependent impact of DeltaDistance to allow for toxicity latency. RESULTS: Daily CBCT information was available for 489 patients at Odense University Hospital. The primary Cox model contained GTV volume, patient age, performance status, and DeltaDistance. DeltaDistance significantly impacted overall survival approximately 50 months after radiotherapy. Subanalyses indicated that the observed effect is mainly present among the patients with the least clinical risk factors. CONCLUSION: Our results confirm the impact of setup variations in the direction of the heart on the survival of NSCLC patients, even within a cohort using daily CBCT setup guidance. This result indicates a causal effect between heart irradiation and survival. It will be challenging to reduce the setup uncertainty even further; thus, increased focus on dose constraints on the heart seems warranted.

Heritability of retinal drusen in the Copenhagen Twin Cohort Eye Study.

PURPOSE: To study age- and sex-adjusted heritability of small hard drusen and early age-related macular degeneration (AMD) in a population-based twin cohort. METHODS: This was a single-centre, cross-sectional, classical twin study with ophthalmic examination including refraction, biometry, best-corrected visual acuity assessment, colour and autofluorescence fundus photography, and fundus optical coherence tomography. Grading and categorization of drusen was by diameter and location. RESULTS: The study enrolled 176 same-sex pairs of twins of mean (SD) age 58.6 (9.9) years. The prevalence of the four phenotypes ≥20 small hard macular drusen (largest diameter < 63 µm), ≥20 small hard extramacular drusen, intermediate drusen (63-125 µm) anywhere, and large drusen (>125 µm) anywhere was 12.4%, 36.4%, 5.8%, and 8.4%, respectively, and the respective heritabilities, adjusted for age and sex, were 78.2% [73.5-82.9], 69.1% [62.3-75.9], 30.1% [4.1-56.1], and 65.6% [26.4-100]. Age trajectory analysis supported a gradual transition to larger numbers of small hard drusen with increasing age. The heritability of ≥20 small hard drusen was markedly lower than the 99% found in the 40% overlapping twin cohort that was seen 20 years earlier. CONCLUSION: Numerous (≥20) small hard drusen and larger drusen that fit the definition of dry AMD were highly heritable. Small hard drusen counts increased with age. Decreasing heritability with increasing age suggests that the impact of behavioural and environmental factors on the development of small hard drusen increases with age.

Cancer in twin pairs discordant for smoking: The Nordic Twin Study of Cancer.

The discordant twin pair study design is powerful to control for familial confounding. We employed this approach to investigate the associations of smoking with several cancers. The NorTwinCan study combines data from the Danish, Finnish, Norwegian and Swedish twin and cancer registries. Follow-up started when smoking status was determined and ended at cancer diagnosis confirmed by information in the cancer registry, death or end of follow-up. We classified the participants as never (n = 59 093), former (n = 21 168) or current (n = 47 314) smokers. We pooled data from twin pairs where one co-twin was diagnosed with any of the following tobacco-related cancers: esophagus, kidney, larynx, liver, oral cavity, pancreas, pharynx or urinary bladder, while their co-twin had none of those. Lung cancer was included in further analysis. We used Cox regression allowing for pair-specific baseline functions to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). For tobacco-related cancer sites, we recorded 7379 cases during median 27 years of follow-up. The analyses based on individual twins showed that former (HR 1.31, 95% CI: 1.17-1.48) and current (HR 2.14 [1.95-2.34]) smokers are at increased risk to develop one of cancers listed above, compared to never smokers. Among 109 monozygotic twin pairs discordant for cancer and smoking, the HR was 1.85 (95% CI: 1.15-2.98) among current smokers and 1.69 (1.00-2.87) among former smokers when compared to their never smoking co-twin. Thus, associations of smoking with several cancers were replicated for discordant identical twin pairs. Analyses based on genetically informative data provide evidence consistent with smoking causing multiple cancers.

Multivariate Generalized Linear Models for Twin and Family Data.

Multivariate twin and family studies are one of the most important tools to assess diseases inheritance as well as to study their genetic and environment interrelationship. The multivariate analysis of twin and family data is in general based on structural equation modelling or linear mixed models that essentially decomposes sources of covariation as originally suggested by  Fisher. In this paper, we propose a flexible and unified statistical modelling framework for analysing multivariate Gaussian and non-Gaussian twin and family data. The non-normality is taken into account by actually modelling the mean and variance relationship, while the covariance structure is modelled by means of a linear covariance model including the option to model the dispersion components as functions of known covariates in a regression model fashion. The marginal specification of our models allows us to extend classic models and biometric indices such as the bivariate heritability, genetic, environmental and phenotypic correlations to non-Gaussian data. We illustrate the proposed models through simulation studies and six data analyses and provide computational implementation in R through the package mglm4twin.