The Australian Twin Registry.

The Australian Twin Registry (ATR), established in the late 1970s, is a volunteer registry of over 30,000 pairs of Australian twins of all zygosity types and ages unselected for their health or medical history. The ATR does not undertake research itself but acts as facilitator, providing an important national and international resource for medical and scientific researchers across a broad range of disciplines. Its core functions are the maintenance of an up-to-date database containing basic contact details and baseline information, and the management of access to the resource in ways that enhance research capacity within Australia while protecting the rights of twins. The ATR has facilitated more than 200 studies using a variety of designs, including classic biometrical twin and twin family studies, co-twin control studies, intervention studies, longitudinal studies, and studies of issues relevant specifically to twins. These have yielded more than 300 peer-reviewed publications to date. Areas of major research include studies of behavior, musculoskeletal conditions, teeth and face patterns, cardiovascular risk factors, substance abuse, and risk factors for melanoma and breast cancer. Extensive longitudinal data are available for around 10,000 pairs. DNA samples have been obtained from more than 6000 twins. Considerable efforts are devoted to maintaining the commitment of registry members and recruitment. The ATR hopes to secure funding to expand its activities, including the systematic collection of DNA samples, so that it can continue to play a major role in the development of twin research and contribute to the annotation of the human genome.     

The Mid-Atlantic Twin Registry.

The Mid-Atlantic Twin Registry (MATR) is a population-based registry of twin pairs ascertained from birth records and school system records of Virginia, North Carolina, and South Carolina. The MATR was formed in 1997 with the merging of the Virginia and North Carolina Twin Registries, and it expanded to include South Carolina when access to twin birth records in that state was granted in 1998. Registered twins ("participants") number more than 51,000, with approximately 46,000 of these individuals representing complete pairs. Roughly two-thirds of MATR participants are over age 18, with a mean age of approximately 35 years. These participants have primarily been drawn from the more than 170,000 identical and fraternal twin pairs born in the three states between 1913 and 2000. Twins and their family members have participated in numerous research projects, ranging from general health surveys to studies on specific health topics such as cardiovascular disease; depression and anxiety; seizures; behavioral development; pregnancy complications; conduct disorder; drug use, abuse, and dependence; cleft lip/palate; obesity; and chronic fatigue syndrome. The MATR has established a privacy policy and strict standard operating procedures to protect the confidentiality of participant data. The MATR considers a limited number of qualified requests per year from investigators interested in recruiting MATR participants into their research studies.     

The Vietnam Era Twin Registry.

The Vietnam Era Twin (VET) Registry is composed of 7369 middle-aged male-male twin pairs both of whom served in the military during the time of the Vietnam conflict (1965-1975). The Registry is a United States Department of Veterans Affairs resource that was originally constructed from military records; the Registry has been in existence for more than 15 years. It is one of the largest national twin registries in the US and currently has subjects living in all 50 states. Initially formed to address questions about the long-term health effects of service in Vietnam the Registry has evolved into a resource for genetic epidemiologic studies of mental and physical health conditions. The management and administration of the VET Registry is described with particular attention given to the processes involved with database maintenance and study coordination. Several waves of mail and telephone surveys have collected a wealth of health-related information on Registry twins. More recent data collection efforts have focused on specific sets of twin pairs and conducted detailed clinical or laboratory testing. New Registry initiatives for the future include the construction of a web site and the development of a DNA repository.     

The Minnesota Twin Registry: current status and future directions.

The Minnesota Twin Registry is a birth-record-based twin registry. Begun in 1983, it includes data for 4307 surviving intact pairs born in Minnesota between 1936 and 1955. In addition, the Registry includes 901 twin pairs born in Minnesota from 1904 to 1934, as well as 391 male pairs born in Minnesota from 1961 to 1964. The research focus is primarily on human individual differences assessed by self-report. Questionnaires completed by the participants include measures of personality, occupational interests, demographics, and leisure-time activities. We outline major contributions that have resulted from Registry research, as well as current and future research directions.     

The St. Thomas' UK Adult Twin Registry.

The Registry consists of nearly 10,000 monozygous and dizygous adult caucasian twins aged 18-80 from all over the UK and was started in 1993. This is a volunteer sample recruited by successive media campaigns without selecting for particular diseases or traits. All twins receive a series of disease questionnaires. In addition over half the twins have been assessed in detail clinically for several hundred phenotypes related to common diseases or intermediate traits. The focus has been primarily on cardiovascular, metabolic, musculoskeletal, dermatological, and opthalmological diseases. Over 3000 DZ twins have had a genome wide scan performed as well as many candidate genes allowing both linkage and association studies. The registry has led to many successful innovative research projects, particularly in common diseases previously thought to be predominantly environmental and helped positionally clone some novel genes for common diseases.     

The Danish Twin Registry: 127 birth cohorts of twins.

The Danish Twin Registry is the oldest national twin register in the world, initiated in 1954 by ascertainment of twins born from 1870 to 1910. During a number of studies birth cohorts have been added to the register, and by the recent addition of birth cohorts from 1931 to 1952 the Registry now comprizes 127 birth cohorts of twins from 1870 to 1996, with a total of more than 65,000 twin pairs included. In all cohorts the ascertainment has been population-based and independent of the traits studied, although different procedures of ascertainment have been employed. In the oldest cohorts only twin pairs with both twins surviving to age 6 have been included while from 1931 all ascertained twins are included. The completeness of the ascertainment after adjustment for infant mortality is high, with approximately 90% ascertained up to 1968, and complete ascertainment of all liveborn twin pairs since 1968. The Danish Twin Registry is used as a source for large studies on genetic influence on aging and age-related health problems, normal variation in clinical parameters associated with the metabolic syndrome and cardiovascular diseases, and clinical studies of specific diseases. The combination of survey data with data obtained by linkage to national health related registers enables follow-up studies both of the general twin population and of twins from clinical studies.     

The Swedish Twin Registry in the third millennium.

Since the Swedish Twin Registry was first established in the late 1950s to study the importance of smoking and alcohol consumption on cancer and cardiovascular diseases, it has been expanded and updated on several occasions. The focus has similarly broadened to most common complex diseases. The content of the database is described, ongoing projects based on the registry are summarized, and we review some of the principal findings on aging, cancer and cardiovascular disease that have come from the registry. Ongoing efforts and future plans for the STR are discussed. Among others, we plan blood collection and genotyping to study the genetic bases of complex diseases, a first contact ever with the cohorts born after 1958, and in-depth studies of selected diseases, such as Parkinson's disease and chronic fatigue syndrome.     

Twins, chorionicity and zygosity.

Accurate determination of zygosity and chorionicity is essential in all multiple maternities. The parents and the multiples themselves ask it. It is of medical importance and now considered as a prerequisite in several domains of twin research, especially when perinatal data are analysed. It helps the multiples and their parents and teachers to ascertain identity. The methods are briefly described and a plea is made to obstetricians and paediatricians to use them systematically at the time of birth.     

The NAS-NRC Twin Registry of WWII military veteran twins. National Academy of Sciences-National Research Council.

The NAS-NRC Twin Registry is one of the oldest, national population based-twin registries in the United States. It consists of 15,924 white male twin pairs born in the years 1917-1927 (inclusive) both of whom served in the armed forces. The registry, which has been in operation more than 30 years, has collected data from a variety of sources. Records-based, computerized data have come largely from the Department of Veterans Affairs, and there have been three major epidemiologic questionnaires, undertaken roughly every 15 years. Classic twin studies on a variety of medical conditions were the early focus of the registry, which now has a strong focus on chronic disease epidemiology. Work on a DNA specimen bank has been proceeding slowly, but is now a top priority, due to the increasing force of mortality in this twin cohort.     

Similarity of social security numbers among twins: data from the Virginia Twin Registry.

At least two twin registries in the United States have been or are being assembled using the similarity of Social Security Numbers in computerized records to help identify possible twin pairs. While the success of such enterprises depends directly on a high probability of twinness given Social Security Numbers, there are theoretical and practical reasons to study the probability of Social Security Number similarity given twinness. For example, the number of twin pairs with similar Social Security Numbers obviously determines the maximum number of twin pairs that can be discovered by similarity algorithms. To study this issue, we examined the similarity of known Social Security Numbers in twin pairs from the Virginia Twin Registry by age, sex, race, and zygosity of the pair. We found that similarity between the Social Security Numbers of twin pairs varies markedly by age, and MZ twin pairs have significantly more similar Social Security Numbers than DZ pairs at all ages. Among older twins, there are also significant differences by sex and race. For younger twins, algorithms that identify putative twin pairs on the basis of the similarity of their Social Security Numbers hold the promise of being able to identify a large proportion of all true twin pairs. Such algorithms will be substantially less successful, however, in identifying a large proportion of older twin pairs.     

A gerontological cohort study of aged twins: the Osaka University Aged Twin Registry.

We describe subject recruitment and research results from the Osaka University Aged Twin Registry (OUATR). The research focus of OUATR is the genetic and environmental contributions to physical-cognitive-mental aging which we examined in Japanese twins in later adulthood. Within this large-scale registry (12,000 pairs) of oriental twins born between 1900 and 1935, approximately 10% of participants are MZ twins reared apart from early childhood. Two hundred and fifty pairs have had comprehensive medical examinations, including various blood chemical panels, lymphocyte subtests, WAIS (Wechsler Adult Intelligence Scale), and urine analysis. The future foci of this study are primarily on longevity, decline of cognitive functions with aging, bio-physiological functions, lifestyle and behavior genetics, and psycho-spiritual functions.     

Diagnosing zygosity in infant twins: physical similarity, genotyping, and chorionicity.

We compared the results of different methods for diagnosing zygosity in a sample of 237 same-sex pairs of twins assessed at 5 and 18 months of age. Despite the twins' very young age and early stage of development, physical similarity was concordant with genotyping in 91.9% of cases at 5 months and 93.8% of cases at 18 months, for a subsample of 123 and 113 pairs, respectively. This concordance rate was obtained following a case-by-case assessment of each pair's physical similarity using a shortened version of the Zygosity Questionnaire for Young Twins (Goldsmith, 1991). Taking into account the chorionicity data available from the twins' medical files, we were able to classify correctly 96% of the pairs, an accuracy rate comparable to previously reported rates obtained with older twins. Chorionicity data is especially useful since we found that monochorionic MZ twins are more difficult than dichorionic MZ twins to diagnose by physical similarity at these young ages. The relative cost-benefit of methods based on reported physical similarity and DNA analysis is discussed in light of these results.     

A Neurophysiological Picture of the Genesis of Fatigue, Chronic Fatigue, and Overfatigue in Human Operators

The present widespread conceptual model of the neurophysiological picture of human fatigue, chronic fatigue, and overfatigue is limited to the picture of hypoexcitability and development of inhibitory processes in the CNS. The results of this study show that, when fatigue deepens and is followed by chronic fatigue and overfatigue, the inhibitory processes that developed earlier weaken. The speed of nervous processes and their lability increase in this period, exceeding the initial normal baseline values; the differential inhibition strengthens. Both main nervous processes weaken; the excitatory process begins to relatively predominate. The equalization and paradoxical phases manifest themselves in the CNS functioning. As fatigue deepens and overfatigue develops, excitability of nervous structures continues decreasing. Interhemispheric asymmetry increases.     

Toward A Model of Social Course in Chronic Illness: The Example of Chronic Fatigue Syndrome

Retrospective, narrative accounts of illness experience in chronic fatigue syndrome provide the empirical basis for a preliminary conceptual model of social course in chronic illness. Qualities of distress interact with culturally specific expectations for social life and personal conduct to trigger microsocial processes of marginalization: role constriction, delegitimation, impoverishment, and social isolation. Marginalizing processes are opposed by acts of resistance initiated by ill individuals and directed toward integration in social worlds. Social distance from the perceived centers of CFS sufferers' interpersonal worlds expands and contracts with the changing predominance of marginalizing and resisting influences over time. Social course thus consists of successive, bi-directional movements along a continuum of marginality by persons living lives with chronic illness.     

The Korean Twin Registry--methods, current stage, and interim results.

The Korean Twin Registry is the first nationwide twin study in Korea. We compiled 154,783 twin pairs from existing nation-wide data sources, mainly from address and national health insurance data. The coverage of this registry was almost complete for the twins born since 1970, but less complete as age increased, so that there were only 990 pairs who were born before 1930. The twins' health examination (N = 54,390 persons) and questionnaire (N = 44,546 persons) results were incorporated into the registry, yielding 12,894 and 9074 concordantly informative pairs. Morbidity and mortality outcomes have been followed up since 1990, for most diseases. For preliminary analysis of complex diseases, we selected ventricular septal defects (VSD) in young twins, stomach and colorectal cancers in adult twins. We identified 353 VSDs, 284 stomach cancers, and 116 colorectal cancers among twins. The prevalence rates of cancers, but not that of VSD, were lower in twins than those in population. The difference in the cancer prevalence was marked for twins born before 1926, implying some degree of selection. Like-sex (LS) twins showed familial recurrence risks (lambdaLS) of 41.2 for VSD and 22.4 for colorectal cancers, and 1.74 for stomach cancers. For opposite-sex (OS) twins, we could estimate lambdaOS of 19.8 for VSD only. These results were compatible with previous studies for VSD and colorectal cancers, but not for stomach cancers. Despite the strength in size, availability of health outcomes, and some lifestyle and basic laboratory data, we need accurate zygosity information to improve the validity of the results.     

The amino acid composition of proteins: a method of analysis.

Four quasiloglinear models are proposed for describing relationships between the amino acid composition of proteins and the structure of the genetic code. The models allow estimation of base frequencies in all three codon positions and can be used to investigate “interactions” between any two codon positions. The estimation procedure proposed by Ohta and Kimura (Genetics64 (1970), 387–395) is discussed and using two of the proposed quasiloglinear models an analysis of the amino acid composition of human cytochrome c is presented. The analysis suggests that of the six codons which code for leucine (CUU, CUC, CUA and CUG) do not occur in human cytochrome c.     

Toward fully automated genotyping: allele assignment, pedigree construction, phase determination, and recombination detection in Duchenne muscular dystrophy.

Human genetic maps have made quantum leaps in the past few years, because of the characterization of > 2,000 CA dinucleotide repeat loci: these PCR-based markers offer extraordinarily high PIC, and within the next year their density is expected to reach intervals of a few centimorgans per marker. These new genetic maps open new avenues for disease gene research, including large-scale genotyping for both simple and complex disease loci. However, the allele patterns of many dinucleotide repeat loci can be complex and difficult to interpret, with genotyping errors a recognized problem. Furthermore, the possibility of genotyping individuals at hundreds or thousands of polymorphic loci requires improvements in data handling and analysis. The automation of genotyping and analysis of computer-derived haplotypes would remove many of the barriers preventing optimal use of dense and informative dinucleotide genetic maps. Toward this end, we have automated the allele identification, genotyping, phase determinations, and inheritance consistency checks generated by four CA repeats within the 2.5-Mbp, 10-cM X-linked dystrophin gene, using fluorescein-labeled multiplexed PCR products analyzed on automated sequencers. The described algorithms can deconvolute and resolve closely spaced alleles, despite interfering stutter noise; set phase in females; propagate the phase through the family; and identify recombination events. We show the implementation of these algorithms for the completely automated interpretation of allele data and risk assessment for five Duchenne/Becker muscular dystrophy families. The described approach can be scaled up to perform genome-based analyses with hundreds or thousands of CA-repeat loci, using multiple fluorophors on automated sequencers.     

The fungal vacuole: composition, function, and biogenesis.

The fungal vacuole is an extremely complex organelle that is involved in a wide variety of functions. The vacuole not only carries out degradative processes, the role most often ascribed to it, but also is the primary storage site for certain small molecules and biosynthetic precursors such as basic amino acids and polyphosphate, plays a role in osmoregulation, and is involved in the precise homeostatic regulation of cytosolic ion and basic amino acid concentration and intracellular pH. These many functions necessitate an intricate interaction between the vacuole and the rest of the cell; the vacuole is part of both the secretory and endocytic pathways and is also directly accessible from the cytosol. Because of the various roles and properties of the vacuole, it has been possible to isolate mutants which are defective in various vacuolar functions including the storage and uptake of metabolites, regulation of pH, sorting and processing of vacuolar proteins, and vacuole biogenesis. These mutants show a remarkable degree of genetic overlap, suggesting that these functions are not individual, discrete properties of the vacuole but, rather, are closely interrelated.