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Fireplace Hearth Stone in Villa Rica, GA
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|Combinatorics of chromosomal rearrangements based on synteny blocks and synteny packs. Journal of Logic and Computation. 23, pp.815–838 (2013)..
|Inference of Hopfield-Potts patterns from covariation in protein families: calculation and statistical error bars. in Journal of Physics: Conference Series. 473, IOP Publishing. p. 012010 (2013)
|Genetic covariance. in Brenner's Encyclopedia of Genetics, 2nd edition. (2013)
|Identification of Protein Interaction Partners from Shape Complementarity Molecular Cross-Docking. in IEEE International Conference on Image Analysis and Processing (ICIAP) 2013 Workshops, LNCS 8158. Springer. pp. 318–325 (2013)
|AUREOCHROME1a-mediated induction of the diatom-specific cyclin dsCYC2 controls the onset of cell division in diatoms (Phaeodactylum tricornutum). Plant Cell. 25(1), pp.215-28 (2013)..
|Gene silencing and large-scale domain structure of the E. coli genome. Mol Biosyst. 9(4), pp.758-67 (2013)..
|From principal component to direct coupling analysis of coevolution in proteins: low-eigenvalue modes are needed for structure prediction. PLoS Comput Biol. 9(8), pp.e1003176 (2013)..
|The spatiotemporal program of replication in the genome of Lachancea kluyveri. Genome Biol Evol. 5(2), pp.370-88 (2013)..
|Large scale chromosomal mapping of human microRNA structural clusters. Nucleic Acids Res. 41(8), pp.4392-408 (2013)..
|Short-time movement of E. coli chromosomal loci depends on coordinate and subcellular localization. Nat Commun. 4, pp.3003 (2013)..
|Perturbation biology: inferring signaling networks in cellular systems. PLoS Comput Biol. 9(12), pp.e1003290 (2013)..
|Improved contact prediction in proteins: using pseudolikelihoods to infer Potts models. Phys Rev E Stat Nonlin Soft Matter Phys. 87(1), pp.012707 (2013)..
|Microfluidic chemostat for measuring single cell dynamics in bacteria. Lab Chip. 13(5), pp.947-54 (2013)..
|TMEM126A is a mitochondrial located mRNA (MLR) protein of the mitochondrial inner membrane. Biochim Biophys Acta. 1830(6), pp.3719-33 (2013)..
|Protein-protein interactions in a crowded environment: an analysis via cross-docking simulations and evolutionary information. PLoS Comput Biol. 9(12), pp.e1003369 (2013)..

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H.G. Wells
© National Portrait Gallery, London
H.G. Wells
by Bassano Ltd
whole-plate glass negative, 12 April 1911
Given by Bassano & Vandyk Studios, 1974
Photographs Collection
NPG x16751
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- Herbert George Wells (1866-1946), Novelist and social commentator. Sitter associated with 95 portraits.
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- Bassano Ltd (active 1901-1962), Photographers. Artist or producer associated with 42747 portraits.
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Events of 1911back to top
Current affairsAsquith's Liberal government introduces the Parliament Act to curb the powers of the House of Lords following the clash between the Commons and Lords over the 1909 People's Budget. The Act removed the Lords' power to veto bills, reduced the length of Parliament from seven to five years, and provided for the payment of MPs.
Art and scienceErnest Rutherford discovers the structure of the atom. The New Zealand born physicist working in Manchester showed with his Nuclear Model that electrons orbited a nucleus composed of protons and neutrons. The discovery paved the way for nuclear physics.
InternationalThe Polish Chemist, Marie Curie, becomes the first woman to win the Nobel Prize for her discovery in 1898 of the radioactive element, Radon.
The Mona Lisa is stolen from the Louvre. The masterpiece was missing for two years, during which time suspicion fell on avant-garde poet Guillaume Apollinaire and his friend Pablo Picasso, before Vincenzo Peruggia, an employee of the Louvre, was arrested in Florence.
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Hallmayer J, Cleveland S, Torres A, et al. Genetic Heritability and Shared Environmental Factors Among Twin Pairs With Autism. Arch Gen Psychiatry. 2011;68(11):1095–1102. doi:10.1001/archgenpsychiatry.2011.76
© 2023
Author Affiliations: Department of Psychiatry, Stanford University School of Medicine, Stanford (Drs Hallmayer, Lotspeich, and Phillips and Mss Cleveland and Torres), Autism Genetic Resource Exchange, Autism Speaks, Los Angeles (Mss Cohen, Torigoe, and Fedele and Drs Miller and Lajonchere), Environmental Health Investigations Branch, California Department of Public Health, Richmond (Mr Collins, Ms Smith, and Dr Grether), Division of Research, Kaiser Permanente Northern California, Oakland (Drs Croen and Risch), University of California, Davis, MIND Institute, Sacramento (Dr Ozonoff), and Institute for Human Genetics and Department of Epidemiology and Biostatistics, University of California, San Francisco (Dr Risch).
Context Autism is considered the most heritable of neurodevelopmental disorders, mainly because of the large difference in concordance rates between monozygotic and dizygotic twins.
Objective To provide rigorous quantitative estimates of genetic heritability of autism and the effects of shared environment.
Design, Setting, and Participants Twin pairs with at least 1 twin with an autism spectrum disorder (ASD) born between 1987 and 2004 were identified through the California Department of Developmental Services.
Main Outcome Measures Structured diagnostic assessments (Autism Diagnostic Interview–Revised and Autism Diagnostic Observation Schedule) were completed on 192 twin pairs. Concordance rates were calculated and parametric models were fitted for 2 definitions, 1 narrow (strict autism) and 1 broad (ASD).
Results For strict autism, probandwise concordance for male twins was 0.58 for 40 monozygotic pairs (95% confidence interval [CI], 0.42-0.74) and 0.21 for 31 dizygotic pairs (95% CI, 0.09-0.43); for female twins, the concordance was 0.60 for 7 monozygotic pairs (95% CI, 0.28-0.90) and 0.27 for 10 dizygotic pairs (95% CI, 0.09-0.69). For ASD, the probandwise concordance for male twins was 0.77 for 45 monozygotic pairs (95% CI, 0.65-0.86) and 0.31 for 45 dizygotic pairs (95% CI, 0.16-0.46); for female twins, the concordance was 0.50 for 9 monozygotic pairs (95% CI, 0.16-0.84) and 0.36 for 13 dizygotic pairs (95% CI, 0.11-0.60). A large proportion of the variance in liability can be explained by shared environmental factors (55%; 95% CI, 9%-81% for autism and 58%; 95% CI, 30%-80% for ASD) in addition to moderate genetic heritability (37%; 95% CI, 8%-84% for autism and 38%; 95% CI, 14%-67% for ASD).
Conclusion Susceptibility to ASD has moderate genetic heritability and a substantial shared twin environmental component.
Autism is a complex neurodevelopmental disorder that interferes with the normal course of social, communicative, and cognitive development. The diagnosis of autism is made in early childhood, with symptoms manifesting within the first 3 years of life. Over the last 3 decades, a substantial increase in the prevalence of autism has been reported, from 4 to 5 per 10 000 in the 1960s to around 40 per 10 000 children1 today. For autism spectrum disorders (ASDs), prevalence rates have been estimated to be about 1%. This 10-fold increase in prevalence has received considerable attention, with concomitant increases in research funding.2
There have been numerous studies designed to characterize the contribution of genetic factors to the development of this disorder. Concordance rates in siblings range from about 3% to 14%3-5 and linkage studies are consistent with a polygenic mode of transmission.6 Three studies7-9 of twins ascertained from clinical samples with a total of 36 monozygotic pairs (concordance rate of 72%) and 30 dizygotic pairs (concordance rate of 0%) have estimated the heritability of autism, or proportion of liability attributable to genetic factors, at about 90%.7 The dizygotic concordance (0%) is substantially lower than the expected rate based on estimates of sibling recurrence rates. More recent twin studies of autism based on either case vignettes10 or telephone interviews11 have also yielded high heritability estimates. In addition, a number of twin studies that used dimensional measures of some core features of autism, such as social responsiveness, have yielded a broad range of heritability estimates of autism.12 However, none of these more recent studies included structured clinical assessments by both parental interview and direct child observation, which is the contemporary standard for establishing the diagnosis of autism or ASD.13
This report describes the results of a twin study of autism: the California Autism Twins Study. The chief aims were to (1) collect a sample of twins with validated diagnoses of autism (ASD) from a population-based sample; (2) examine sex-specific concordance rates for narrow and broad definitions of autism (ASD); and (3) determine the extent to which genetic and shared environmental factors underlie susceptibility.
Twin pairs were identified from the records of the Department of Developmental Services (DDS). The DDS operates a system of 21 regional centers throughout California that coordinate services for persons with autism, mental retardation, and other developmental disabilities. Referral sources for regional centers include primary care providers, educators, public health clinics, other service agencies, and parents. The electronic DDS client files were linked by California Center for Autism and Developmental Disabilities Research and Epidemiology (CADDRE) staff to California live birth records to identify twin births and obtain demographic data. The birth years of the twin pairs included in our study were 1987 to 2004. Twin pairs were considered eligible for the study if they met the following criteria:
At least 1 child in the pair had a qualifying diagnosis (see later) in the DDS electronic file or in client records; each twin in a pair who met this criterion was considered a proband.
Maternal residence in California at the time of delivery.
Both co-twins were alive and residing in California at the time of enrollment.
No history among proband(s) of neurogenetic conditions that might account for autism (eg, fragile X syndrome, Down syndrome, tuberous sclerosis, and neurofibromatosis).
Proband(s) had a mental age more than 18 months.
At least 1 parent with sufficient verbal and reading ability in English or Spanish was able to respond to interviews and checklists.
Using DDS electronic files, CADDRE staff ascertained twins receiving services for autism (DDS autism codes A1 or A2) and twins with a possible ASD based on other recorded information indicating a suspected ASD (DDS autism code A9), DSM-IV diagnosis of ASD (code A4, derived by CADDRE), mental retardation of unknown etiology (MRnoET, derived by CADDRE), or other developmental disability (other, derived by CADDRE). Trained CADDRE staff then abstracted client records to record presence or absence of an ASD diagnosis, criteria used for diagnosis, specific autistic behaviors, and other clinical characteristics. Expert clinical review was then conducted to verify that the children met eligibility based on qualifying diagnosis and other criteria (mentioned earlier). The diagnosis of autism can be most reliably established if a child is at least 4 years or older, so the birth years 1987 to 2004 were included.
A letter from the local regional center and a recruitment package were sent to parents explaining the study and asking their consent to send identifying information to study staff at Stanford University who then contacted them to further describe the study and obtain written consent. The twin pairs described in this article were assessed starting in August 2005 and continuing until December 2009. Assessments were carried out by the Autism Genetic Resource Exchange in Southern California and Stanford University in Northern California. The statistical analysis of the data started in March 2010 and was completed in June 2010.
The full study protocol, including procedures for identifying and contacting families, consent and assent forms, blood draw and use, clinical assessments, and procedures for maintaining confidentiality of data, was reviewed and approved by the California Health and Welfare Agency Committee for the Protection of Human Subjects and by the institutional review board at Stanford University. Annual reviews were conducted, as were any revisions to protocol, and approval was secured from both institutional review boards. The protocol was reviewed as a research project with the expectation that results would be published in peer-reviewed medical journals. Data on self-identified race, Hispanic ethnicity, and other demographic variables were obtained from California birth certificates as provided by the mother.
Zygosity of sex-concordant twin pairs was determined in batches of 10 to 20 pairs concomitantly. Nine short tandem repeat loci and the X/Y amelogenin locus were amplified. Twin pairs discordant for at least 1 marker were considered dizygotic. Twin pairs concordant on all markers were considered monozygotic.
All twin participants were assessed using the Autism Diagnostic Interview–Revised (ADI-R),14 a structured parent interview, and the Autism Diagnostic Observation Schedule (ADOS),15 a standardized play and interview scale administered to children and adolescents. The ADI-R and ADOS are the most widely used and well-validated research measures for diagnosing autism and ASD. To assess verbal and nonverbal cognitive abilities, we used the Stanford-Binet Intelligence Scales, 5th edition. For children who did not achieve a basal score on the Stanford-Binet, the Mullen Scales of Early Learning Skills were used.
We defined 2 different diagnostic classifications based on the ADI-R and ADOS, one narrow (strict autism) and one broader (ASD). The diagnostic criteria for autism are divided into 4 areas: social impairments; communication impairments; repetitive, ritualistic, and stereotyped behaviors; and age at onset. Each of the 3 core areas (ie, social, communication, and repetitive behaviors) is defined by a minimum of 5 criteria. Individuals in the narrow category had to meet the following standard criteria for autism on both the ADI-R14 and the ADOS15: on the ADI-R, a child must score above a prespecified cut point on the 3 symptom areas and also have an age at onset prior to 3 years of age, and on the ADOS, the child must exceed specified thresholds on the domain scores for communication (including verbal and nonverbal behaviors) and reciprocal social interaction. The ASD category included individuals in the narrow category (strict autism), along with individuals who met a broader definition of ASD based on published criteria for combining information from the ADI-R and ADOS.16 According to these criteria, individuals were considered affected if they met criteria for ASD according to either the standard15 or the revised17 ADOS algorithm and met criteria for 1 of the following 3 categories: (1) met the ADI-R autism cutoffs on the domains of social reciprocity and either communication or restricted, repetitive behaviors or (2) were within 1 point of meeting the ADI-R autism cutoffs on the social and communication domains or met the autism cutoff on 1 of these domains and scored within 2 points on the other or (3) met full criteria on the ADI-R for autism on all of the domains.
Twin pairs were ascertained through the DDS electronic files and client records, which constituted our sampling frame. In some cases, both twins in the pair were identified as having a high likelihood of autism in these records. In other cases, only 1 twin was so identified. On direct examination of the twins, we determined final diagnoses of strict autism or ASD as described earlier. For the purpose of our concordance and model-fitting analyses, we defined a proband as any individual who was identified in the DDS files or client records with qualifying DDS data and whose diagnosis of autism or ASD was subsequently confirmed by us through expert clinical review of abstracted data. Some individuals were diagnosed by us with autism or ASD but were not ascertained in the DDS file or client records; these individuals were not considered probands. Any individual who was determined by us to be unaffected was not counted as a proband. Also, in the analysis of strict autism, some individuals with a diagnosis of ASD but not strict autism were considered unaffected and not probands, even if they were identified through DDS records. Pairs where neither child met our criteria of strict autism were not included in the concordance analysis of strict autism.
Pairwise concordance is calculated as the proportion of all ascertained pairs with 2 affected individuals and can be impacted by method of ascertainment of the twins.18,19 Probandwise concordance is calculated as the proportion affected among the co-twins of probands. Probandwise concordance accounts for ascertainment and represents the recurrence risk to a co-twin of an affected individual.19 In numerical terms, let N = total number of twin pairs, R = number of pairs with 2 affected twins, t = number of pairs among the R that have 2 probands, S = number of pairs among the R that have 1 proband, and U = number of discordant pairs (with 1 proband). Then S + t = R and R + U = N. The pairwise concordance is simply given by R/N. The total number of co-twins of probands (which is the same as the number of probands because each proband has 1 co-twin) is 2 × t + S + U = N + t. The number of these co-twins who are also affected is 2 × t + S = R + t. In both of these cases, we doubled t because both affected twins in the pair are co-twins of probands. By contrast, we did not double S because only 1 affected twin in the pair is the co-twin of a proband. Hence, the probandwise concordance is given by (R + t)/(N + t).
For opposite-sex dizygotic twin pairs, the pairwise concordance is straightforward to calculate, as described earlier. For the probandwise concordance of opposite-sex twin pairs, we calculated the proportion of female co-twins of male probands who are affected and the proportion of male co-twins of female probands who are affected.
For pairwise concordance, 95% confidence intervals (CIs) were calculated exactly assuming a binomial distribution. For probandwise concordance, 95% CIs were calculated using the modified variance formula given by Davie.19
To test for differences (ie, potential biases) across several demographic factors between twin pairs or individuals who were included in the study vs those from the original DDS files who met entry criteria but were not included, a univariate analysis of variance was performed for continuous variables andχ2 tests were used for dichotomous traits. For both analyses, a P value of .05 for a 2-sided test was considered significant. To determine whether demographic factors influenced the concordance rates of monozygotic and dizygotic twin pairs, we used logistic regression separately for monozygotic and dizygotic pairs, with concordance vs discordance of the twin pair as the dichotomous outcome (dependent) variable. Independent variables included twin type (male or female for monozygotic twins; male, female, or male-female for dizygotic twins), age of mother and father, years of paternal and maternal education, ethnicity of mother and father, difference in birth weight between twin individuals, and gestational age (in completed weeks). For significance, a 2-sided P value of .05 adjusted for number of tests performed was considered. A critical assumption of the logistic regression is independence of the outcomes (in this case, concordance vs discordance among twin pairs). Because the twin pairs in our study were not related, independence is a reasonable assumption. All study-specific statistical analyses were performed using SPSS Statistics 19 (IBM SPSS, Chicago, Illinois).
To explore possible ascertainment bias, we compared the proportion of twin pairs concordant for being affected according to the qualifying DDS diagnostic categories among the twins included in the final study vs the twins from the original list who were ultimately not included. This analysis was stratified on type of twin pair (male-male, female-female, male-female). We could not stratify on zygosity because zygosity was unknown for pairs not included. For this analysis, we calculated odds ratios andχ2 tests for each of the 3 strata (defined by sex) and then a summary odds ratio andχ2 test across the 3 strata by Mantel-Haenszel analysis. The Mantel-Haenszelχ2 was assumed to have 1 df and was considered significant if greater than 3.84 (P < .05).
To determine whether diagnostic shifts may have occurred during the recruitment process, we compared the distribution of DDS diagnostic categories between affected twins included in the study vs those from the original list who were not included using aχ2 test, with df equal to the number of categories minus 1. Results were considered significant if theχ2 exceeded the threshold corresponding to a P value of .05.
To determine the relative importance of genetic (heritable) vs shared co-twin environmental factors to the development of autism and ASD, we performed a classic ACE twin analysis and fit parametric models to the twin concordance data using maximum likelihood, incorporating information on proband status of the twins.20 The model assumes that numerous genetic and environmental factors of small effect accumulate into a continuous, normally distributed unobserved trait called liability. Liability values above a given threshold value lead to disease. Hence, this model is usually termed a multifactorial or polygenic threshold model.21 The critical parameters for this model are the components of variance of liability and the threshold value. The threshold value reflects disease prevalence. We assume different threshold values for males and females, which are denoted by Tm and Tf, respectively. For the modeling, we assumed a prevalence of 1% for males and 0.3% for females for ASD and 0.5% for males and 0.15% for females for strict autism. Because autism may be more prevalent in twins, we also considered the effect of assuming higher as well as lower prevalence estimates on our results.
Aside from the thresholds, 3 components of liability variance are included, a genetic component, an environmental component shared by twins, and a random environmental component. The parameter A represents the proportion of liability variance due to the genetic component; the parameter C represents the proportion of liability variance due to common twin environment; and the parameter E represents the proportion of liability variance due to random environment (ie, unshared by twins). When considering the sexes separately, we define 6 total parameters, Am and Af, Cm and Cf, and Em and Ef, corresponding to the values of A, C, and E for males and females, respectively. Note that Am + Cm + Em = 1 and Af + Cf + Ef = 1. Male values were estimated from the monozygotic and dizygotic concordance data in males, while female values were estimated from the monozygotic and dizygotic concordance data in females. Concordance in the opposite-sex dizygotic pairs allowed us to estimate the correlation betweenAm + Cm andAf + Cf, that is, the correlation between males and females for their combined genetic and shared environmental components. This correlation is denoted rmf. Because all monozygotic twin pairs are identical for sex, it is not possible to estimate separate correlations for Am and Af or Cm and Cf. For male monozygotic pairs, their correlation in liability is Am + Cm; for female monozygotic pairs, it is Af + Cf. For male dizygotic pairs, the correlation in liability isAm + Cm, and for dizygotic female pairs, the correlation in liability isAf + Cf. For opposite-sex dizygotic pairs, the correlation in liability is rmf [(½Am + Cm)(½Af + Cf)]½. Liability correlation (and hence variance components) was estimated from the twin concordance data. The model also includes the ascertainment probabilityπ, which represents the probability that an affected individual is a proband (as described earlier). Models were fit to data using maximum likelihood with a grid search algorithm as implemented in Excel (Microsoft, Redmond, Washington), and hypotheses about model parameters were based on likelihood ratio tests. Best-fitting models were determined by the Akaike Information Criterion. Models with a low Akaike Information Criterion are the most parsimonious. Details are provided in the eAppendix.
A total of 1156 pairs fulfilled our initial eligibility criteria. We were unable to establish contact with 384 pairs, primarily because the families had lost contact with the regional center. Of the 772 remaining pairs, 330 declined participation and 10 pairs were ineligible. Of the 432 pairs whose contact information was sent to the Stanford team, 90 pairs declined participation in the study. Of the remaining 333 pairs, we completed the assessments for 202 pairs.
Among the 404 twin individuals, 242 met criteria for ASD (171 of whom also met criteria for strict autism), with the remaining 162 failing to meet criteria for an ASD. Comparing the study-qualifying diagnosis based on the DDS data with the diagnosis based on the ADI-R and ADOS, we calculated the sensitivity for ASD as 229/242 = 94.6% and the specificity as 137/162 = 84.6%. For strict autism, the sensitivity was 166/171 = 97.1% and the specificity, 158/233 = 67.8%. The DDS-based diagnosis was therefore a good predictor of the study ASD diagnosis based on the ADI-R and ADOS. For 10 twin pairs, neither of the twins met study criteria for the broader definition of ASD; these twin pairs were excluded from the genetic analyses.
To consider potential bias or differences among the 192 twin pairs who were included in the genetic analysis vs those who were not, we compared the 2 groups on a number of demographic criteria (eTable 1). The 2 groups were comparable for most variables, except that the age of the twins included in the genetic analyses was on average slightly older, birth weight of males was somewhat higher, and their mothers and fathers were, on average, slightly more educated and more likely to be white and less likely to be African American.
We also examined clinical differences by examining the distribution of DDS categories between the 2 groups (eTable 2). The proportional representation of the 6 diagnostic categories in the included vs nonincluded twins was comparable (χ25 = 8.82; P = .12). We also looked to see if there was any correspondence between the 6 DDS diagnostic categories and our research diagnoses of strict autism vs ASD (eTable 2). Most DDS categories showed a similar distribution of strict autism vs ASD vs unaffected with the possible exception of"other," for which a somewhat higher proportion (50%) was unaffected, although the number of individuals in this group was quite small (n = 6).
Of the 192 twin pairs included in the final analysis, 54 were monozygotic (45 male and 9 female) and 138 were dizygotic (45 male, 13 female, and 80 sex-discordant). The monozygotic twins were slightly older and had slightly shorter gestation periods (Table 1). In addition, the mothers of the dizygotic twins were older than the mothers of the monozygotic twins (Table 1), consistent with the known increase in dizygotic twinning with maternal age,22 and more likely to be white and non-Hispanic.
For strict autism (143 pairs), probandwise concordance rates (Table 2) for monozygotic twins were similar for 40 male pairs (58%; 95% CI, 42%-74%) and 7 female pairs (60%; 95% CI, 28%-90%), comparable with those reported in prior studies. However, probandwise concordance rates for dizygotic pairs were higher than previously reported, with rates of 21% for 31 male pairs (95% CI, 9%-43%) and 27% for 10 female pairs (95% CI, 9%-69%) (Table 2). The probandwise concordance rate for 54 female dizygotic co-twins of male probands was 3.7% (95% CI, 0.5%-13%), which was lower than for sex-concordant pairs, while the rate for male dizygotic co-twins of female probands was 50% (95% CI, 1%-99%). This latter finding was based on small numbers (n = 2).
For ASD (192 pairs), concordance estimates for both monozygotic and dizygotic twin pairs were generally higher. Probandwise concordance for monozygotic twins was 77% (95% CI, 65%-86%) for 45 male pairs and 50% (95% CI, 16%-84%) for 9 female pairs. Concordance rates for dizygotic twins were 31% (95% CI, 16%-46%) and 36% (95% CI, 11%-60%) for 45 male and 13 female pairs, respectively. Probandwise concordance for female dizygotic co-twins of 76 male probands was 5.3% (95% CI, 1.5%-13.0%), while the rate for male dizygotic co-twins of 6 female probands was 50.0% (95% CI, 11.8%-88.2%). Again, these dizygotic concordance rates are higher than previously reported and have a significant impact on the heritability analysis. From logistic regression analysis of concordance, the only factor impacting concordance rates was sex of co-twins in the dizygotic pairs (P value = .045), which was formally not significant if adjusted for multiple testing.
We also considered possible ascertainment bias in terms of concordance. Using the DDS categories to define affected, we examined the proportion of twin pairs concordant among the included pairs vs the nonincluded pairs, stratified by sex (eTable 1). Overall, there was no significant difference in proportion concordant (Mantel-Haenszel odds ratio = 1.17; 95% CI, 0.80-1.70) between the included and nonincluded pairs.
As described in the eAppendix, twin concordance rates were used to obtain parameter estimates for the genetic models; results are presented in Table 3 and likelihood ratio tests of different models, in Table 4. In all models, both genetic and shared environmental components were significant. The best-fitting models for both strict autism and ASD suggest that a large proportion of the variance in liability is due to shared environmental factors in addition to genetic heritability. For strict autism, we could conclude that heritabilities in males and females were equal and that the shared environmental components in males and females were also equal. The best-fitting model had a genetic heritability of 37% (95% CI, 8%-84%) and a shared environmental variance component of 55% (95% CI, 9%-81%). For the broader ASD phenotype, again we could conclude that heritabilities and shared twin environmental components were equal in males and females. Heritability was estimated to be 38% (95% CI, 14%-67%) and the shared environmental component, to be 58% (95% CI, 30%-80%). The shared environment component was estimated to be larger than the genetic heritability component. The poor fit of a pure heritability model can be attributed primarily to the high dizygotic twin concordance relative to the monozygotic twin concordance and population prevalence.
To our knowledge, this study is the largest population-based twin study of autism that used contemporary standards for the diagnosis of autism. All twin individuals underwent a thorough diagnostic and cognitive examination that included a structured interview and observation that allowed differentiation between autism and other delays of development.13,14 The results suggest that environmental factors common to twins explain about 55% of the liability to autism. Although genetic factors also play an important role, they are of substantially lower magnitude than estimates from prior twin studies of autism. Nearly identical estimates emerged for ASD, suggesting that ASD presents the same liability spectrum as strict autism.
The California population, as represented in our twin sample, is highly diverse regarding ethnicity, socioeconomic status, and other demographic factors. Hence, our results should be readily generalizable, especially as compared with previous twin studies, which were based exclusively on individuals from Northern Europe. Even though this study was population based, the participation rate was only about 17% of eligible twin pairs. However, comparison of demographic and clinical characteristics of twins who did and did not participate showed only modest differences, primarily in parental education (eTable 1). Furthermore, concordance rates were not influenced by a range of potential confounding factors.
One possible concern is that a higher proportion of concordant dizygotic pairs participated than concordant monozygotic pairs. Examination of proband status among the monozygotic vs dizygotic pairs suggests this is not the case. Among 28 concordant monozygotic pairs, 24 had 2 probands, while 4 had 1 proband. By contrast, for the same-sex dizygotic pairs, among 13 concordant pairs, 8 had 2 probands and 5 had 1 proband. Thus, if anything, there might have been some underascertainment of concordant dizygotic pairs.
The ACE model we used has several inherent assumptions. First, it assumes no gene × environment interaction. If such a gene × environment effect does exist, it would be confounded with the A parameter in our analysis, implying that as an estimate of pure genetic effect, A may actually be an overestimate. Similarly, a critical assumption in the model is that the shared twin environmental effect is the same for monozygotic and dizygotic twins. If, in fact, monozygotic twins share the relevant environment to a greater degree than the dizygotic twins, some of the effect included in the parameter A would actually be environmental rather than genetic; again, A may actually overestimate the true genetic heritability.
Another potential limitation is the validity of the assumptions regarding prevalence rates of autism and ASD. We therefore compared heritability and shared twin environment estimates obtained by varying assumptions about prevalence. As shown in the eAppendix, we examined the impact of both doubling and halving our prevalence assumptions on derived parameter estimates. The range of heritability (eg, 41%-56% in males; 13%-16% in females) and shared twin environment (eg, 57%-41% in males; 78%-72% in females) estimates were similar. Hence, our conclusions regarding the relative importance of genetic and shared twin environment are quite robust to prevalence assumptions.
Our study provides evidence that the rate of concordance in dizygotic twins may have been seriously underestimated in previous studies and the influence of genetic factors on the susceptibility to develop autism, overestimated. Because of the reported high heritability of autism, a major focus of research in autism has been on finding the underlying genetic causes, with less emphasis on potential environmental triggers or causes. The finding of significant influence of the shared environment, experiences that are common to both twin individuals, may be important for future research paradigms.23 Increasingly, evidence is accumulating that overt symptoms of autism emerge around the end of the first year of life. Because the prenatal environment and early postnatal environment are shared between twin individuals, we hypothesize that at least some of the environmental factors impacting susceptibility to autism exert their effect during this critical period of life. Nongenetic risk factors that may index environmental influences include parental age,24 low birth weight,25 multiple births,26 and maternal infections during pregnancy.27 Future studies that seek to elucidate such factors and their role in enhancing or suppressing genetic susceptibility are likely to enhance our understanding of autism.23
Correspondence: Joachim Hallmayer, MD, 1201 Welch Rd, Palo Alto, CA 94304-5485 (email@example.com).
Submitted for Publication: April 13, 2011; final revision received April 27, 2011; accepted April 27, 2011.
Published Online: July 4, 2011. doi:10.1001/archgenpsychiatry.2011.76
Author Contributions: Dr Hallmayer had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Financial Disclosure: None reported.
Funding/Support: The study was supported by grant R01MH067005 from the National Institute of Mental Health and a grant from Autism Speaks.
Role of the Sponsors: None of the foundations had a role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript.


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Sci-fi Revoltech No. 003 Booska - 2,850 Yen (inclusive of tax).
Sci-fi Revoltech No. 004 Baragon - 2,850 Yen (inclusive of tax).
Revoltech Fraulein Mari Illustrious Makinami - 2,900 Yen (inclusive of tax).
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Welcome to my Blog. I don't use this blog as in how a blog is normally used, which is to talk about one's life and all the tit-bits happened in one day. Rather, I would like to share about some of my interests, mainly on my Gundam collection, movies, books and music.


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Dean Paul Martin (born Dino Paul Crocetti; June 7, 1917 – December 25, 1995) was an American singer, actor, comedian, and film producer.
One of the most popular and enduring American entertainers of the mid-20th century, Martin was nicknamed the "King of Cool" for his seemingly effortless charisma and self-assurance. He and Jerry Lewis were partners in the immensely popular comedy team "Martin and Lewis". He was a member of the "Rat Pack" and a star in concert stage/nightclubs, recordings, motion pictures, and television. He was the host of the television variety program The Dean Martin Show (1965–1974) and The Dean Martin Celebrity Roast (1974–1985).
Martin's relaxed, warbling crooning voice earned him dozens of hit singles including his signature songs "Memories Are Made of This", "That's Amore", "Everybody Loves Somebody", "You're Nobody till Somebody Loves You", "Sway", "Volare", and "Ain't That a Kick in the Head?".
Martin was born on June 7, 1917 in Steubenville, Ohio, to an Italian father, Gaetano Alfonso Crocetti (1894–1967), and an Italian-American mother, Angela Crocetti (née Barra; 1899–1966). They were married in 1914. His father, who was a barber, was originally from Montesilvano, in Abruzzo, and his maternal grandparents' origins are believed to be also from Abruzzo even if it is not clearly known. Martin had an older brother named William Alfonso Crocetti (1916-1968). Martin's first language was an Abruzzese dialect of Italian, and he did not speak English until he started school at the age of 5. He attended Grant Elementary School in Steubenville where he was bullied for his broken English. He later took up the drums as a hobby as a teenager. Martin then dropped out of Steubenville High School in the 10th grade because he thought he was smarter than his teachers. He bootlegged liquor, served as a speakeasy croupier, was a blackjack dealer, worked in a steel mill and boxed as a welterweight.
Something for Kate is a rock band from Melbourne, Australia, led by songwriter, vocalist and guitarist Paul Dempsey. The band was formed in 1994 and signed to the Murmur record label a year later when its three members were aged only 19. They have released six studio albums, two of which have topped Australia's ARIA Charts, with three others reaching the top 10. The band, whose name is often abbreviated to SFK, has had 11 ARIA Music Awards nominations since 1999. Something for Kate have toured extensively in Australia and internationally, supporting Pavement, Swervedriver, Powderfinger, David Bowie and You Am I and have been supported by bands including Caustic Soda, Big Heavy Stuff, Augie March, Crooked Fingers, Angus & Julia Stone and Death Cab For Cutie. The band's lineup since 1998 has been Dempsey (guitars, vocals), Stephanie Ashworth (bass) and Clint Hyndman (drums).
Dempsey and drumming mate Clint Hyndman formed the band in 1994 soon after leaving Padua College on Victoria's Mornington Peninsula. The pair enlisted Julian Carroll as bassist after advertising in music stores. The trio played their first gig on 12 September 1994 at the Punter's Club in Melbourne, changing their band name from Fish of the Day at the suggestion of the venue's booking agent. Dempsey said the new name was inspired by his dog, Kate.
Dean Martin (born 31 August 1972 in London, England) is a retired English footballer who last played for ÍBV in the Icelandic Premier Division.
Martin played in midfield and spent most of his career in Iceland with ÍA Akranes and KA Akureyri.
Dean began his career with Fisher Athletic and moved to West Ham United in 1991 for £25,000. However he only made 2 league appearances for the Hammers and was loaned out to Colchester United.
After spells with Kettering and Brentford, Dean moved to Asia where he spent time at Hong Kong Rangers. When his contract ended, Martin returned to Europe and spent time training under John Still at Barnet. In December 1998, he moved to Bohemians along with Kevin Hunt on a one-month contract. He made his debut in a 0-0 draw against Cork City at Turners Cross. and made 2 further league appearances for Bohs before his contract expired. As Bohemians only had enough money to sign either Martin or Hunt, Martin was released and he moved on to Hereford United. After a few months at Edgar Street, he signed for Stevenage Borough
Pablo Honey is the debut studio album by the English alternative rock band Radiohead, released in February 1993. The album was produced by Sean Slade and Paul Q. Kolderie and was recorded at Chipping Norton Recording Studios and Courtyard Studio, Oxfordshire from September to November 1992. It features three charting singles: "Anyone Can Play Guitar", "Stop Whispering", and perhaps the band's most well-known hit on mainstream radio, "Creep". Pablo Honey peaked at No. 22 in the United Kingdom charts and went platinum there and in other countries. The album title comes from a Jerky Boys prank call skit in which the prank caller says to his victim: "Pablo, honey? Please come to Florida!" This snippet is sampled by the band on the track "How Do You?".
Following the release of Pablo Honey, Radiohead would digress from its alternative rock sound toward more expansive and experimental works. The album received a generally favourable reaction from critics, but was criticised for its derivative sound and inclusion of underdeveloped songs, and is held in a negative light in comparison to the band's subsequent albums. However, it has been cited by listeners and critics as one of the strongest debut albums of its time.
Gold is a network of oldies radio stations which was formed by the merger of the Capital Gold network and the Classic Gold Network in August 2007. The station relaunched in March 2014 as a partly automated service broadcasting in a smaller number of areas than previously, when many of the prior local AM/DAB Gold frequencies were turned over to Smooth Radio.
The Capital Gold network started in London in 1988 on Capital Radio's AM frequency, as the British Government urged radio stations to end simulcasting (broadcasting the same programmes simultaneously on FM and AM) and threatening to remove one of their frequencies if simulcasting continued. The Classic Gold network was similarly formed from the AM transmissions of the former GWR Group's station licence areas. (Many of the FM pop stations to which the ...Gold stations were sister operations are themselves now part of the Heart or Capital networks).
The original DJs on the early incarnation of Capital Gold included Tony Blackburn (who would later appear on the then-rival Classic Gold network), Kenny Everett and David Hamilton. The idea of hiring radio personalities to host networked shows continued to be a feature of the Capital Gold and Classic Gold networks as they grew, though following the 2014 relaunch Gold now only had three presenters - Tony Dibbin, Simon Hirst and David Andrews at the time of the relaunch. (Dibbin presents on Gold six days a week; Hirst and Andrews combined once-a-week Gold appearances with their weekday duties on Capital Yorkshire and Smooth Radio respectively). Most Gold programming is broadcast from the Gold network studio in Leicester Square, London, though Hirst broadcast from the Capital studios in Leeds or his home studio. Simon Hirst left Gold (and Capital) in June 2014, leaving Dibbin (Sunday to Friday) and Andrews (Saturday) as Gold's sole remaining DJs.
Dean Paul Martin (born 19 February 1957) is an English former footballer.
Martin played for Stoke City before joining local rivals Port Vale on trial in July 1976. He appeared as a substitute in a 1–0 defeat at Wrexham in a first round Football League Cup match on 18 August 1976. He wasn't selected again and was instead released in September 1976. He later worked as a matchday ambassador at Vale Park, but quit the club in 2011 following a row over access to parking.
Dean Martin was the Arizona State Treasurer from 2007 to 2011. A Republican, he defeated Democrat Rano Singh in the 2006 general election. He was previously a member of the Arizona Senate.
He married his wife Kerry in 1995. She died on May 25, 2009, of complications from childbirth four hours after giving birth to a son, Austin Michael Martin, who died two days later. Martin subsequently established Martin Charities to continue his wife's charitable efforts in water safety and financial literacy.
Martin graduated from Arizona State University with the first degree in Small Business Management/Entrepreneurship.
As a member of the Arizona Senate, Martin's first piece of legislation was "Chris' Law" which prevents child predators from posting bail. This bill was inspired by a 12-year-old student named Chris Cottrell. The bill became Prop 103 "Chris' Law". It passed in 2002 with 80.4% of the vote. While in the Senate, Martin served as Chairman of the Senate Finance Committee.


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Natural Freshwater Hand Strung Pearl Necklace - Long Strand Pearls
A Beautiful Hand Strung Strand of Natural Freshwater Pearls.
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If the item is damaged during shipment please contact me within 3 Business days. Please take a pictures of the outside of the box showing the damage from different angles, Pictures of the the inner packaging, then pictures of the damaged item itself and send them to me via Convo or email.
There are never too many pictures for insurance claims. You will be reimbursed for all costs via the source of your payment once the claim has been accepted. You may have to return the item to me or to the insurer so please keep the item until told otherwise.
Shipping/handling rates are calculated with the USPS shipping calculator from our location to your location. The majority of our shipments are packaged with new boxes. Parcels will normally be shipped next business day after receiving payment. I take pride in taking the utmost in care in packaging your purchase to ensure safe delivery of your package. If you have any questions, please contact me.
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HALO 3 Wave 1 Equipment Edition Spartan Soldier EOD (Red) Figure by McFarlane.
Get ready for the release of the Equipment Edition 1st Wave of McFarlane's range of HALO Figures.
These figures are highly detailed and measure approximately 5 - 6 inches tall. They have multiple points of articulation to allow for different display options.
The Spartan Soldier EOD (Red) figure stands 5 inches tall, and is articulated at the neck, shoulders, elbows, wrists, waist, hips, knees, ankles and feet. The figure also includes removable shoulder armor, dual SMGs and trip mine.
As the range of HALO products increases from McFarlane, the demand is becoming very high for these amazing figures. Make sure you don't miss out on this series, to add to your collection.
The Dangerzone-Collectibles "Postage & Shipping" Explained.
Here at Dangerzone-Collectibles we aim to offer an efficient and reliable Shipping Service. Here are some details of how your order will be Shipped.
Shipping Times
Due to logistical reasons, we are unable to offer same Day shipping at the present time. However, we always do our very best to make sure all in stock items (GREEN BUY BUTTON) are shipped within 48-72 Hours (3 Working Days) from receiving your order. If you are needing an item for a specific Date, we would request that you place your order in plenty of time, to avoid disappointment. We would always suggest playing safe, and ordering at least a week before the required Date.
Who We Use To Ship Your Order
The services we use are:- Royal Mail 1st Class Recorded Delivery, and we also have two Courier Companies who can deliver to Mainland U.K.
PLEASE NOTE:- If you are not on the U.K. Mainland, we cannot ship your order via our Courier Service.
Postage Costs
We have a Postage and Packing sytem that works on the weight of the items you are buying. This way, if you add more items to your order, the P&P will be automatically calculated for you. When you arrive at the Checkout, you will then be given Postage options, depending on the Total Weight of you order. The prices will be listed aswell, so you will know how much you will be paying for each service.
The prices start from as little as £2.49. If you live on the U.K. Mainland, we are able to ship upto 10Kg for £9.99 and 40p for each additional 1Kg. If you would like to find the cost for a particular item, you can add this to your Shopping Basket, and the total Postage and Packing charges will then be shown for you to check. You are then able to add other items to your Shopping Basket if you wish, before the order is placed.
International Shipping
Unfortunately, we no longer offer shipping outside the United Kingdom.
The cost of packing materials is incorporated within the Postage and Packing fees. We try to be fare with our pricing, but at the same time we want to make sure your order is properly packed for a SAFE JOURNEY to you. We believe that when a Customer pays for Postage and Packing, they should receive the Packing that they have paid for, and not just the Postage. As a result of this approach, we have had countless messages of praise about our packing from previous Customers.
If you have any questions regarding our "Shipping and Postage", please feel free to E-Mail or Telephone us with your query.
E-Mail:- firstname.lastname@example.com
Telephone:- +44 (0) 1482 216445
We are open 9:30 - 5:30 Monday, Tuesday, Thursday, Friday and Saturday
(CLOSED All Day Wednesday and Sunday)


text:
Shipping Way
We will send your order by E-Packet, EMS or DHL.
and there is a limit of weight on each USPS shipment due to customs, if the qty of jerseys in your order more than 10pcs, we will send them in several parcels by USPS
How can I track my order?
How Long Will It Take for Delivery?
Total delivery time is composed of two parts. The first part is the processing time.This is the time from when your payment isreceived to when we gather up all the items and pack them. Processing takes 2-5 business days normally. The Second part is Shipping time.usually It takes about 5-30 business days.
Generally,Package will take 5-15 working days or so to deliver to your door!
How Do I Save On Shipping?
Due to the high price of international shipping, we suggest our customers to buy everything they want in one order. That way, the per-item shipping cost could be minimized. And if you buy more at a time,you will get more cut on shipping cost.
If the parcel have some problem in transit please contact us, we will re-send the parcel free or refund the money to you.
By: email@example.com Date Added: 07/16/2021 Rating:
Good prices . Fast shipping
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Yeah ok, so you can blame me for the topic this week, and in all honesty I was going to delete it if we managed to get some more topics, but then I just got lazy because I would have to change dates on other topics, so you are stuck with it. Given the last few weeks though I have found I would be interested in this from other people's point of views. We have some newer bloggers out there and they must have people or bloggers they are inspired by etc, so I am keen to find out who those on a pedestal are.
Are you starstruck by anyone? Does someone in the community respond to a post or a tweet and get you all speechless because they actually responded? Is there anyone you are waiting to have respond directly to you? Is there someone that you would like to chat to, but are too chicken? Am I the only one who puts other bloggers on a pedestal?
I also feel this could be slightly weird, given people will be named on here and how awkward it would be for those people, but blogging is about being honest and having the guts to put things out there 🙂 I came up with idea simply because recently a few people in the blogosphere were having their posts linked to, being interviewed and being responded to on twitter by people that i would literally be in shock if it happened to me.
Matticus is my first one, although he has responded to a few of my tweets, I still blush profusely and spend far too long trying to think of a witty reply back to him. Matticus was one of the first sites I ever found when I became a GM that had some great strats for boss fights and ever since then I have been a bit of a groupie for him. I will never ever get sick of having him respond to my tweets.
I occasionally tweet employees of blizzard that I can find and am yet to receive a response, but oh hell, it would be awesome. Maybe one day 🙂 I know they are not technically a blogger, but in the spirit of the entire interwebz thing.
I also have a few bloggers out there, which are starting to chat to me now because I started chatting to them on their blogs. Even after chatting to them for a while I am still excited when i see a comment from them and I still chicken-out when commenting on their blogs. What if they think I am an idiot? What if I am not as cool as them? Inevitably I just don't post anything at all as it is safer.
In no particular order:
Cymre, Navimie, Gnomeaggedon, Kamalia, Akabeko, JD., Jaedia are the major ones. There are probably another 5 or 6 other bloggers that I really enjoy reading and so have on a slightly lower pedestal, but they no longer blog or post so randomly it is hard to even add them to this list. Of course the list changes as well when I find new blogs.
Of course, I am now chatting to most of them, not all, but I still get nervous when commenting and seeing comments from them. I like to pat myself on the back for even having the courage to talk to them – after reading them for so darn long. I think my issue has always been the sense of thinking you know them when in reality you don't.
Bloggers put a lot out into the nether, we talk, we comment, we rage, we laugh, yet it is not really us. My venting about the game gives you an insight into my personality, yes, but that doesn't tell you about me and my choices and my life and what I want and what I love. When you read someone's blog for so long, I think it is hard to find the balance of being friendly but not overly familiar because you really don't know them – add that to my complete lack of skill with writing and I end up with disasters. I have been told I am often too blunt in print, yet when I am typing it, I don't think it is blunt at all because the tone with which I am saying things in my head, is always much softer or friendly. You can't convey emotion in text.
I am also not very funny. I think I am hilarious and will often laugh at my own jokes whilst others just stare at me blankly. Combine that with the above and I am always worried I will offend someone, somehow or appear as someone who is just a wanker 😀
Sorry for the tangent there 🙂 The only other thing I would love is to be asked to do a guest post or interview on a podcast or something. I would more than likely decline as I suck and writing and I talk far too much (refer above :p), however that would just be so immense to me. I couldn't even attempt to quantify it with words. I want someone to be reading my blog and go "hey this one's a bit funny or interesting -let's get her on..and she has been blogging for a few years and playing since MC – lets ask!" Maybe one day it will happen, maybe it won't.
If you read my blog you know I have been playing since Vanilla, that is a long time to have seen a boatloads of blogs come and go, podcasts start up and forums come into being. I always stayed as a reader and listener with my biggest jump becoming a moderator on Blog Azeroth after doing the Shared Topics for ages. I have been jealous a million times over that people can amass such great followings and have such wonderful fans and do interviews and guest posts because they have the balls to get out there and get their blogs known about.
I also want to be on WoWinsider – for something. And the other week Robin linked to my site from a Shared Topic – which I was ecstatic about. Shame my hit count only went up by about 3 – but it was exciting to be on there 🙂 My website will forever be in the internet cache being linked from WoWinsider! I cannot stress my excitement at that!!! The day I logged on to BA and found a PM from Robin advising it was going to be linked, I ran around the house screaming and the grin on my face was huge for about 24 hours….I swear!!
Anyway, I am sure this is going to be a quiet week on the shared topics because I am not entirely sure the famous people need to have pedestals of their own 🙂 But I will add some links as they become available 🙂
I can't believe how many people responded! Fantastic!
Flask Half Empty – Ninevi


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