Familial confounding or measurement error? How to interpret findings from sibling and co-twin control studies.

Epidemiological researchers often examine associations between risk factors and health outcomes in non-experimental designs. Observed associations may be causal or confounded by unmeasured factors. Sibling and co-twin control studies account for familial confounding by comparing exposure levels among siblings (or twins). If the exposure-outcome association is causal, the siblings should also differ regarding the outcome. However, such studies may sometimes introduce more bias than they alleviate. Measurement error in the exposure may bias results and lead to erroneous conclusions that truly causal exposure-outcome associations are confounded by familial factors. The current study used Monte Carlo simulations to examine bias due to measurement error in sibling control models when the observed exposure-outcome association is truly causal. The results showed that decreasing exposure reliability and increasing sibling-correlations in the exposure led to deflated exposure-outcome associations and inflated associations between the family mean of the exposure and the outcome. The risk of falsely concluding that causal associations were confounded was high in many situations. For example, when exposure reliability was 0.7 and the observed sibling-correlation was r = 0.4, about 30-90% of the samples (n = 2,000) provided results supporting a false conclusion of confounding, depending on how p-values were interpreted as evidence for a family effect on the outcome. The current results have practical importance for epidemiological researchers conducting or reviewing sibling and co-twin control studies and may improve our understanding of observed associations between risk factors and health outcomes. We have developed an app (SibSim) providing simulations of many situations not presented in this paper.

Energy and macronutrient intake heritability: A systematic review and meta-analysis of twin and family-based studies.

BACKGROUND/AIMS: The current meta-analysis aimed to examine the heritability and familial resemblance of dietary intakes, including energy and macronutrients in both twin and family-based studies. METHODS: The online literature databases, including PubMed, Scopus, and Web of Science were searched comprehensively until 2023 to identify the relevant studies. The heritability index in family studies was h2 and the heritability indices for twin studies were h2, A2, and E2. Three weighted methods were used to calculate the mean and SE of heritability dietary intakes. RESULTS: Eighteen papers including 8 studies on familial population and 12 for twin population studies were included in the present meta-analysis. The heritability of dietary intakes in twin studies (range of pooled estimated h2, A2, and E2 was 30-55%, 14-42%, and 52-79%, respectively) was higher than family studies (range of pooled estimated h2 = 16-39%). In family studies, the highest and lowest heritability for various nutrients was observed for the fat (%Kcal) (h2 range:36-38%) and carbohydrate in g (h2 range:16-18%), respectively. In twin studies, based on mean h2, the highest and lowest heritability for various nutrients was reported for the fat (%Kcal) (h2 range:49-55%) and protein intake in g (h2 range:30-35%), respectively. Also, based on the mean of A2, the highest and lowest heritability was observed for carbohydrates (% Kcal) (A2 range:42-42%), and protein (% Kcal) (A2 range:14-16%), respectively. Furthermore, in twin studies, the highest and lowest mean of E2 was shown for saturated fats (E2 range:74-79%) and energy intake (E2 range:52-57%), respectively. CONCLUSION: Our analysis indicated that both environmental factors and genetics have noticeable contributions in determining the heritability of dietary intakes. Also, we observed higher heritability in twins compared to family studies.

Mendelian Causes of Autoimmunity: the Lupus Phenotype.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is characterized by its large heterogeneity in terms of clinical presentation and severity. The pathophysiology of SLE involves an aberrant autoimmune response against various tissues, an excess of apoptotic bodies, and an overproduction of type-I interferon. The genetic contribution to the disease is supported by studies of monozygotic twins, familial clustering, and genome-wide association studies (GWAS) that have identified numerous risk loci. In the early 70s, complement deficiencies led to the description of familial forms of SLE caused by a single gene defect. High-throughput sequencing has recently identified an increasing number of monogenic defects associated with lupus, shaping the concept of monogenic lupus and enhancing our insights into immune tolerance mechanisms. Monogenic lupus (moSLE) should be suspected in patients with either early-onset lupus or syndromic lupus, in male, or in familial cases of lupus. This review discusses the genetic basis of monogenic SLE and proposes its classification based on disrupted pathways. These pathways include defects in the clearance of apoptotic cells or immune complexes, interferonopathies, JAK-STATopathies, TLRopathies, and T and B cell dysregulations.

Telomeres and aging: on and off the planet!

Improving human healthspan in our rapidly aging population has never been more imperative. Telomeres, protective "caps" at the ends of linear chromosomes, are essential for maintaining genome stability of eukaryotic genomes. Due to their physical location and the "end-replication problem" first envisioned by Dr. Alexey Olovnikov, telomeres shorten with cell division, the implications of which are remarkably profound. Telomeres are hallmarks and molecular drivers of aging, as well as fundamental integrating components of the cumulative effects of genetic, lifestyle, and environmental factors that erode telomere length over time. Ongoing telomere attrition and the resulting limit to replicative potential imposed by cellular senescence serves a powerful tumor suppressor function, and also underlies aging and a spectrum of age-related degenerative pathologies, including reduced fertility, dementias, cardiovascular disease and cancer. However, very little data exists regarding the extraordinary stressors and exposures associated with long-duration space exploration and eventual habitation of other planets, nor how such missions will influence telomeres, reproduction, health, disease risk, and aging. Here, we briefly review our current understanding, which has advanced significantly in recent years as a result of the NASA Twins Study, the most comprehensive evaluation of human health effects associated with spaceflight ever conducted. Thus, the Twins Study is at the forefront of personalized space medicine approaches for astronauts and sets the stage for subsequent missions. We also extrapolate from current understanding to future missions, highlighting potential biological and biochemical strategies that may enable human survival, and consider the prospect of longevity in the extreme environment of space.

Brazilian Twin Studies: A Scoping Review.

The current study was motivated by an interest in deepening understanding of Brazilian twin research, which is underrepresented internationally, in an effort to rectify this situation. Our aim was threefold: (1) to carry out a comprehensive investigation of Brazilian research on twins according to the area of knowledge; (2) to evaluate the representation of research in the field of psychology in comparison with other areas; (3) to evaluate characteristics of the research that may have contributed to its exclusion from the comprehensive meta-analysis of 50 years of twin research. A scoping review was performed according to PRISMA guidelines. Titles and abstracts were searched up to 2022 in six databases: CAPES, BDLTD, PePSIC, PubMed, Google Scholar, and SciELO, using selected keywords both in Portuguese and in English (e.g., 'twins' and 'Brazil'; 'twinning' and 'Brazil'; 'gemelaridade' [twinning], and 'gêmeos' [twins]). Three hundred and forty publications were included in the review. Approximately half (53.8‰) used the classic twin design to investigate the heritability of several traits, and the other half (46.2%) used other research designs. The scoping review showed that the number of publications doubled approximately every 10 years. Most publications were from the health area, with medicine accounting for approximately half of the studies, followed by psychology, odontology, and biology. We found that the interest in studying twins among Brazilian scientists is increasing over the years and there are reasons to be enthusiastic about the potential impact of this trend in the global scenario.

Automatic detection of expressed emotion from Five-Minute Speech Samples: Challenges and opportunities.

Research into clinical applications of speech-based emotion recognition (SER) technologies has been steadily increasing over the past few years. One such potential application is the automatic recognition of expressed emotion (EE) components within family environments. The identification of EE is highly important as they have been linked with a range of adverse life events. Manual coding of these events requires time-consuming specialist training, amplifying the need for automated approaches. Herein we describe an automated machine learning approach for determining the degree of warmth, a key component of EE, from acoustic and text natural language features. Our dataset of 52 recorded interviews is taken from recordings, collected over 20 years ago, from a nationally representative birth cohort of British twin children, and was manually coded for EE by two researchers (inter-rater reliability 0.84-0.90). We demonstrate that the degree of warmth can be predicted with an F1-score of 64.7% despite working with audio recordings of highly variable quality. Our highly promising results suggest that machine learning may be able to assist in the coding of EE in the near future.

Most Unusual Twin Pairs: A Look at Uterus Didelphys / Twin Research Reviews: Prenatal Aneuploidy Screening for Twin Pregnancies; Twin Conceptions by Same-Sex Male Couples; Legal Personality of Conjoined Twins; Twin Study of Cannabis Use / Human Interest and Importance: Being Taken for Twins Saved Sisters; Twin Children of Jailed Nobel Prize Winner; British 'Biracial' Twins; Triplets Born at Start of Russian Attack on Ukraine; Twins Born in Different Years.

A review of an unusual twin type-twins born to women with two uteri (uterus didelphys)-is presented. This review is followed by summaries of recent research and perspectives concerning prenatal aneuploidy screening for twin pregnancies, twin conceptions by same-sex male couples, legal personality of conjoined twins, and a twin study of cannabis use. Interesting information about twins that has appeared in the media is also presented, namely how being taken for twins saved a pair of sisters; twin children of a jailed Nobel Prize winner, British 'biracial' twins, triplets born at the start of Russia's attack on Ukraine, and twins born in different years.

Continuity and change of genetic and environmental influences on reading and reading-related neurocognitive skills: A systematic review of longitudinal twin studies.

Learning to read is a dynamic and cumulative process beginning from birth and continuing through the school years. Empirical data showed a decrease of additive genetic (A) and shared environmental (C) components and an increase of non-shared environmental (E) components from preschool to middle school. However, our understanding of the aetiology of continuity and change of reading skills across this developmental period is limited. Following the PRISMA guidelines, we reviewed the results of behavioral genetic research on reading-related neurocognitive skills of 13 longitudinal twin and adoptive sibling studies spanning from preschool/kindergarten to middle/high school. Our findings suggested that continuity was mainly explained by A components throughout the study periods, and, although to a lesser extent and less consistently, by C components during the early years; change was explained by new E components throughout the years, and also by new A components in the early years. As we are interested in models relevant to traits with early onset during development, it is crucial to deepen the investigation of how developmental time can moderate the genetic and environmental variation.

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.

Cognition is selectively impaired in males with spinal pain: A retrospective analysis of data from the Longitudinal Study of Ageing Danish Twins.

Cognitive decline and spinal pain (back pain [BP] and neck pain [NP]) represent a major public health challenge, yet the potential relationship between them remains elusive. A retrospective analysis of the Longitudinal Study of Ageing Danish Twins was performed to determine any potential relationships between BP/NP and cognitive function adjusting for age, sex, educational and socioeconomic status. A total of 4731 adults (2788 females/1943 males) aged 78 ± 6 (SD) years were included in the analysis. We observed a 1-month prevalence of 25% with BP, 21% with NP and 11% for combined BP/NP. While there were no differences in cognition scores for males and females reporting combined BP/NP, compared to those without combined BP/NP (34.38 points [95% confidence interval (CI) = 31.88, 36.88] vs. 35.72 points [95% CI = 35.19, 36.26]; P = 0.180; and 35.72 points [95% CI = 35.19, 36.26] vs. 35.85 points [95% CI = 35.39, 36.31]; P = 0.327; for male and females, respectively), an adjusted analysis revealed that males with combined BP/NP presented with lower cognitive scores compared to males without combined BP/NP (81.26 points [95% CI = 73.80, 88.72] vs. 79.48 points [95% CI = 70.31, 88.66]; P = 0.043). The findings of this hypothesis-generating study may highlight a potential sex-specific association between spinal pain and later-life neurodegeneration.

Partnership with the University of São Paulo Panel of Twins: A Four-City Tour and More / Twin Research Reviews: Twin Research on Binge Eating; Twins' Physical Outcomes Linked to Different Diets; Working Conditions and Sickness Absence in Swedish Twins; Facial Morphology Differences in Monozygotic Twins / Human Interest and Importance: Michigan Family Forced to Adopt Their Own Twins; Ethics of Hiring a Surrogate to Bear Twins; Twin Survivors of the Israel-Hamas War; Twin Pregnancy with Double Uterus; Three Twin Pairs on Same Women's Soccer Team.

This article begins with an overview of twin research in Brazil, initiated by the University of São Paulo Panel of Twins. I met with many new research collaborators and students while on a fall 2023 four-city lecture tour in that country. A meeting with a world-famous surgeon who recently separated craniopagus conjoined twin pairs is also described. This overview is followed by summaries of twin research on binge eating, twins' physical outcomes linked to different diets, working conditions and sickness absence in Swedish Twins and facial morphology differences in monozygotic twins. The final section of this article provides a sampling of human interest stories with important implications. They include a Michigan family forced to adopt their own twins, ethical issues surrounding the hiring of a surrogate to bear twins; twin survivors of the Israel-Hamas war, a twin pregnancy with a double uterus, and three twin pairs on the same women's soccer team.

Combining Mendelian randomization with the sibling comparison design.

Mendelian randomization (MR) is a popular epidemiologic study design that uses genetic variants as instrumental variables (IVs) to estimate causal effects, while accounting for unmeasured confounding. The validity of the MR design hinges on certain IV assumptions, which may sometimes be violated due to dynastic effects, population stratification, or assortative mating. Since these mechanisms act through parental factors it was recently suggested that the bias resulting from violations of the IV assumptions can be reduced by combing the MR design with the sibling comparison design, which implicitly controls for all factors that are constant within families. In this article, we provide a formal discussion of this combined MR-sibling design. We derive conditions under which the MR-sibling design is unbiased, and we relate these to the corresponding conditions for the standard MR and sibling comparison designs. We proceed by considering scenarios where all three designs are biased to some extent, and discuss under which conditions the MR-sibling design can be expected to have less bias than the other two designs. We finally illustrate the theoretical results and conclusions with an application to real data, in a study of low-density lipoprotein and diastolic blood pressure using data from the Swedish Twin Registry.

Haplotype-resolved assemblies and variant benchmark of a Chinese Quartet.

BACKGROUND: Recent state-of-the-art sequencing technologies enable the investigation of challenging regions in the human genome and expand the scope of variant benchmarking datasets. Herein, we sequence a Chinese Quartet, comprising two monozygotic twin daughters and their biological parents, using four short and long sequencing platforms (Illumina, BGI, PacBio, and Oxford Nanopore Technology). RESULTS: The long reads from the monozygotic twin daughters are phased into paternal and maternal haplotypes using the parent-child genetic map and for each haplotype. We also use long reads to generate haplotype-resolved whole-genome assemblies with completeness and continuity exceeding that of GRCh38. Using this Quartet, we comprehensively catalogue the human variant landscape, generating a dataset of 3,962,453 SNVs, 886,648 indels (< 50 bp), 9726 large deletions (≥ 50 bp), 15,600 large insertions (≥ 50 bp), 40 inversions, 31 complex structural variants, and 68 de novo mutations which are shared between the monozygotic twin daughters. Variants underrepresented in previous benchmarks owing to their complexity-including those located at long repeat regions, complex structural variants, and de novo mutations-are systematically examined in this study. CONCLUSIONS: In summary, this study provides high-quality haplotype-resolved assemblies and a comprehensive set of benchmarking resources for two Chinese monozygotic twin samples which, relative to existing benchmarks, offers expanded genomic coverage and insight into complex variant categories.

In search of environmental risk factors for obsessive-compulsive disorder: study protocol for the OCDTWIN project.

BACKGROUND: The causes of obsessive-compulsive disorder (OCD) remain unknown. Gene-searching efforts are well underway, but the identification of environmental risk factors is at least as important and should be a priority because some of them may be amenable to prevention or early intervention strategies. Genetically informative studies, particularly those employing the discordant monozygotic (MZ) twin design, are ideally suited to study environmental risk factors. This protocol paper describes the study rationale, aims, and methods of OCDTWIN, an open cohort of MZ twin pairs who are discordant for the diagnosis of OCD. METHODS: OCDTWIN has two broad aims. In Aim 1, we are recruiting MZ twin pairs from across Sweden, conducting thorough clinical assessments, and building a biobank of biological specimens, including blood, saliva, urine, stool, hair, nails, and multimodal brain imaging. A wealth of early life exposures (e.g., perinatal variables, health-related information, psychosocial stressors) are available through linkage with the nationwide registers and the Swedish Twin Registry. Blood spots stored in the Swedish phenylketonuria (PKU) biobank will be available to extract DNA, proteins, and metabolites, providing an invaluable source of biomaterial taken at birth. In Aim 2, we will perform within-pair comparisons of discordant MZ twins, which will allow us to isolate unique environmental risk factors that are in the causal pathway to OCD, while strictly controlling for genetic and early shared environmental influences. To date (May 2023), 43 pairs of twins (21 discordant for OCD) have been recruited. DISCUSSION: OCDTWIN hopes to generate unique insights into environmental risk factors that are in the causal pathway to OCD, some of which have the potential of being actionable targets.

The Garden of Forking Paths; An Evaluation of Joseph's 'A Reevaluation of the 1990 "Minnesota Study of Twins Reared Apart" IQ Study'.

Joseph has written what purports to be a refutation of studies of Twins Reared-Apart (TRAs) with a singular focus on the Minnesota Study of Twins Reared-Apart (MISTRA). I show, in detail, that (a) his criticisms of previous TRA studies depend on sources that were discredited prior to MISTRA, as they all failed the test of replicability, (b) the list of biases he uses to invalidate MISTRA do not support his arguments, (c) the accusations of questionable research practices are unsubstantiated, (d) his claim that MISTRA should be evaluated in the context of psychology's replication crisis is refuted. The TRA studies are constructive replications. Like many other scholars, past and present, he has been misled by the variation introduced by small samples (sampling error) and the distortion created by walking in the garden of forking paths. His endeavor is a concatenation of elision and erroneous statistical/scientific reasoning.

Role of Twins in Waardenburg Syndrome: 1916 - present/Twin Research Reviews: MZ Twins' Different Dermatoglyphics; Twins with Sagittal Suture Crainosynostosis; Blood Pressure in Female Twins; MZ Twins' Education and Political Knowledge/Media Reports: Twins Created by Reciprocal In Vitro Fertilization; Reared-Apart Triplets' Limited TV Series; Abducted Twin Infants; Winkelvoss Twins Charged by the Securities and Exchange Commission; Going From 'Me' to 'We'.

Waardenburg's syndrome involves deafness accompanied by various visual difficulties. The role of twins in identifying this disorder and advancing understanding of its origins and symptoms is described, beginning in 1916 and continuing to the present. This overview is followed by current research on monozygotic (MZ) twins' different dermatoglyphic features, twins with sagittal suture crainosynostosis, blood pressure in female twins, and MZ twins' education and political knowledge. The final section presents media reports describing controversies surrounding twins created by reciprocal in vitro fertilization, reared-apart triplets' limited TV series, abducted twin infants, the Winkelvoss twins' charges by the Securities and Exchange Commission, and going from 'Me' to 'We'.

Co-twin design in brain imaging-review on biomarkers of Alzheimer's disease.

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

From the Library of the Late Irving I. Gottesman: Memories and Treasures/Twin Research Reviews: Twin Study of Callous-Unemotional Traits; Depressive Symptoms in Prospective Chinese Twin Mothers; Twins With Sagittal Suture Craniosynostosis; Creative Expressiveness and Educational Achievement/Media Reports: Male-Female Twin Holocaust Survivors; Nontuplets Born in Mali; Indian Twins Marry Same Man; Twins Born From Longest-Frozen Embryos; Infant Twin Abduction; Twins Born in Different Years.

The experience of going through the personal library of our late esteemed twin research colleague, Dr Irving I. Gottesman, is described. I came away with fond memories and unexpected treasures. This essay is followed by brief reviews of timely research on factors affecting callous-unemotional traits, depressive symptoms in prospective Chinese twin mothers, twins with sagittal suture craniosynostosis, and creative expressiveness and educational achievement. Media reports on informative topics of interest to researchers and the general public include male-female twin Holocaust survivors, nontuplets born in Mali, Indian twins who married the same man, twins born from the longest frozen embryos, an infant twin abduction and twins born in different years.

Twin Artists: Unique Sources of Inspiration and Talent/Twin Research Reviews: Ethnic and Racial Factors Affecting Type of Twin Delivery; Outcomes in Twins Conceived Naturally and With Reproductive Assistance; Delivery Time for Growth-Discordant Twins; 3D Study of Twins' Facial Resemblance/In the Media: Baseball Players With Divergent Careers; Basketball Twins in the Elite 8; Twins' Grave and Epitaph; Twins Conceived Three Times in 2 Years; Twins in the Hockey Hall of Fame; Superfetated Twins.

The unique sources of artistic inspiration and talent of twin artists are examined. The professional literature is rich with twin studies of creativity, but lacking when it comes to specific artistic domains - for example, painting and sculpting. The section that follows provides reviews of current research on ethnic and racial factors affecting type of twin delivery, pregnancy outcomes when twins are conceived naturally or with reproductive assistance, the effects of intrauterine growth discordance on the timing of twin delivery, and three-dimensional (3D) assessment of twins' facial resemblance. The final section summarizes information about twins in the media. The stories include twins distinguished for both baseball playing and physical injuries, twins who reached the National College Athletic Association's Elite 8, a twin pair's grave and epitaph, a mother who conceived twins three times in 2 years, twins in the Hockey Hall of Fame, and a set of superfetated twins.

Reared-Apart and Reunited: Extraordinary Dynamics/Twin Research Reviews: Twin Bereavement and Lifespan Associations; Identifying Novel Mutations in Twins; Parenting Premature Multiples; Conjoined Twins in Cross-Cultural Context/In the News: Madeline Albright, Mother of Twins, Passes Away; Identical Twin Songwriters Compose New Musical; Visually Impaired Twin Skiers; Identical Twin Brothers Undergo Heart Transplants; Naming the Genain Quadruplets.

The focus of this article is on insights gained from the extraordinary dynamics that took place between a pair of reunited monozygotic female twins from Greece. Topics include visualizing the co-twin prior to meeting, the unique love and attraction between the twins, a mother's response to discovering her child's cotwin and the challenges posed by insufficient kinship categories. The following section of this article surveys four recent twin research reports. They include Bereavement and Lifespan Associations; Novel Mutations in Twins; Parenting Premature Multiples; and Conjoined Twins. The final part of this article presents interesting and informative news about twins from popular sources. The topics covered are the passing of Madeline Albright (Secretary of State and mother of twins); identical twin songwriters; visually impaired twin and sibling skiiers; identical twin brothers who both received heart transplants; and the naming of the Genain quadruplets.