What do men understand about lifetime risk following genetic testing?:The effect of context and numeracy.

Genetic testing for gene mutations associated with specific cancers provides an opportunity for early detection, surveillance, and intervention (Smith, Cokkinides, & Brawley, 2008). Lifetime risk estimates provided by genetic testing refer to the risk of developing a specific disease within one's lifetime, and evidence suggests that this is important for the medical choices people make, as well as their future family and financial plans. The present studies tested whether adult men understand the lifetime risks of prostate cancer informed by genetic testing. In 2 experiments, adult men were asked to interpret the lifetime risk information provided in statements about risks of prostate cancer. Statement format was manipulated such that the most appropriate interpretation of risk statements referred to an absolute risk of cancer in experiment 1 and a relative risk in experiment 2. Experiment 1 revealed that few men correctly interpreted the lifetime risks of cancer when these refer to an absolute risk of cancer, and numeracy levels positively predicted correct responding. The proportion of correct responses was greatly improved in experiment 2 when the most appropriate interpretation of risk statements referred instead to a relative rather than an absolute risk, and numeracy levels were less involved. Understanding of lifetime risk information is often poor because individuals incorrectly believe that these refer to relative rather than absolute risks of cancer.

Genetic and Electrophysiological Correlates of Self-Regulation in Adolescence

Self-regulation is considered a powerful predictor of behavioral and mental health outcomes during adolescence and emerging adulthood. In this dissertation I address some electrophysiological and genetic correlates of this important skill set in a series of four studies. Across all studies event-related potentials (ERPs) were recorded as participants responded to tones presented in attended and unattended channels in an auditory selective attention task. In Study 1, examining these ERPs in relation to parental reports on the Behavior Rating Inventory of Executive Function (BRIEF) revealed that an early frontal positivity (EFP) elicited by to-be-ignored/unattended tones was larger in those with poorer self-regulation. As is traditionally found, N1 amplitudes were more negative for the to-be-attended rather than unattended tones. Additionally, N1 latencies to unattended tones correlated with parent-ratings on the BRIEF, where shorter latencies predicted better self-regulation. In Study 2 I tested a model of the associations between selfregulation scores and allelic variations in monoamine neurotransmitter genes, and their concurrent links to ERP markers of attentional control. Allelic variations in dopaminerelated genes predicted both my ERP markers and self-regulatory variables, and played a moderating role in the association between the two. In Study 3 I examined whether training in Integra Mindfulness Martial Arts, an intervention program which trains elements of self-regulation, would lead to improvement in ERP markers of attentional control and parent-report BRIEF scores in a group of adolescents with self-regulatory difficulties. I found that those in the treatment group amplified their processing of attended relative to unattended stimuli over time, and reduced their levels of problematic behaviour whereas those in the waitlist control group showed little to no change on both of these metrics. In Study 4 I examined potential associations between self-regulation and attentional control in a group of emerging adults. Both event-related spectral perturbations (ERSPs) and intertrial coherence (ITC) in the alpha and theta range predicted individual differences in self-regulation. Across the four studies I was able to conclude that real-world self-regulation is indeed associated with the neural markers of attentional control. Targeted interventions focusing on attentional control may improve self-regulation in those experiencing difficulties in this regard.

The role played by the interaction between genetic factors and attachment in the stress response in infancy

Background: The importance of understanding which environmental and biological factors are involved in determining individual differences in physiological response to stress is widely recognized, given the impact that stress has on physical and mental health. Methods: The child-mother attachment relationship and some genetic polymorphisms (5-HTTLPR, COMT and GABRA6) were tested as predictors of salivary cortisol and alpha amylase concentrations, two biomarkers of hypothalamic-pituitary-adrenocortical (HPA) axis and sympathetic adrenomedullary (SAM) system activity, during the Strange Situation (SS) procedure in a sample of more than 100 healthy infants, aged 12 to 18 months. Results: Individual differences in alpha amylase response to separation were predicted by security of attachment in interaction with 5-HTTLPR and GABRA6 genetic polymorphisms, whereas alpha amylase basal levels were predicted by COMT x attachment interaction. No significant effect of attachment, genetics and their interaction on cortisol activity emerged. Conclusions: These results help to disentangle the role played by both genetic and environmental factors in determining individual differences in stress response in infancy. The results also shed light on the suggestion that HPA and SAM systems are likely to have different characteristic responses to stress.

Mind-reading difficulties in the siblings of people with Asperger's syndrome: evidence for a genetic influence in the abnormal development of a specific cognitive domain

Background: Previous research suggests that the phenotype associated with Asperger's syndrome (AS) includes difficulties in understanding the mental states of others, leading to difficulties in social communication and social relationships. It has also been suggested that the first-degree relatives of those with AS can demonstrate similar difficulties, albeit to a lesser extent. This study examined 'theory of mind' (ToM) abilities in the siblings of children with AS relative to a matched control group. Method: 2 7 children who had a sibling with AS were administered the children's version of the 'Eyes Test'(Baron-Cohen, Wheelwright, Stone, & Rutherford, 1999). The control group consisted of 27 children matched for age, sex, and a measure of verbal comprehension, and who did not have a family history of AS/autism. Results: A significant difference was found between the groups on the Eyes Test, the 'siblings' group showing a poorer performance on this measure of social cognition. The difference was more pronounced among female siblings. Discussion: These results are discussed in terms of the familial distribution of a neuro-cognitive profile associated with AS, which confers varying degrees of social handicap amongst first-degree relatives. The implication of this finding with regard to the autism/AS phenotype is explored, with some discussion of why this neuro-cognitive profile (in combination with corresponding strengths) may have an evolutionary imperative.

Predicting outcomes following cognitive behavior therapy in child anxiety disorders: the influence of genetic, demographic and clinical information

Background. Within a therapeutic gene by environment (GxE) framework, we recently demonstrated that variation in the Serotonin Transporter Promoter Polymorphism; 5HTTLPR and marker rs6330 in Nerve Growth Factor gene; NGF is associated with poorer outcomes following cognitive behaviour therapy (CBT) for child anxiety disorders. The aim of this study was to explore one potential means of extending the translational reach of G×E data in a way that may be clinically informative. We describe a ‘risk-index’ approach combining genetic, demographic and clinical data and test its ability to predict diagnostic outcome following CBT in anxious children. Method. DNA and clinical data were collected from 384 children with a primary anxiety disorder undergoing CBT. We tested our risk model in five cross-validation training sets. Results. In predicting treatment outcome, six variables had a minimum mean beta value of 0.5: 5HTTLPR, NGF rs6330, gender, primary anxiety severity, comorbid mood disorder and comorbid externalising disorder. A risk index (range 0-8) constructed from these variables had moderate predictive ability (AUC = .62-.69) in this study. Children scoring high on this index (5-8) were approximately three times as likely to retain their primary anxiety disorder at follow-up as compared to those children scoring 2 or less. Conclusion. Significant genetic, demographic and clinical predictors of outcome following CBT for anxiety-disordered children were identified. Combining these predictors within a risk-index could be used to identify which children are less likely to be diagnosis free following CBT alone or thus require longer or enhanced treatment. The ‘risk-index’ approach represents one means of harnessing the translational potential of G×E data.

Amerindian anthropology and cultural psychology: Crossing boundaries and meeting otherness` worlds

Addressing integrative possibilities between psychology and anthropology, this paper aims to design conceptual linkages between semiotic-cultural constructivist psychology and the anthropological theory of Amerindian perspectivism. From the psychological view, it is the interdependence between the structural and processual dimensions of the personal culture that makes parallels with Amerindian perspectivism fruitful. This anthropological frame proposes an experiment with native conceptions, which I argue similar to what Baldwin (1906) called sembling. Hence, it can be considered an active imitation of otherness` viewpoint in order to approach indigenous worlds. It is supposed that this procedure leads to the emergence of new symbolic elements configuring the cultural action field of each agency in interaction. It is proposed that ""making-believe`` the Amerindian is convergent with the dialogic-hermeneutic approach of semiotic-cultural constructivism. As a result of the present integrative effort, is designed a meta-model that multiplies the genetic process of concrete symbolic objects.

Developmental Brain Dysfunction: Revival and Expansion of Old Concepts Based on New Genetic Evidence

Neurodevelopmental disorders can be caused by many different genetic abnormalities that are individually rare but collectively common. Specific genetic causes, including certain copy number variants and single-gene mutations, are shared among disorders that are thought to be clinically distinct. This evidence of variability in the clinical manifestations of individual genetic variants and sharing of genetic causes among clinically distinct brain disorders is consistent with the concept of developmental brain dysfunction, a term we use to describe the abnormal brain function underlying a group of neurodevelopmental and neuropsychiatric disorders and to encompass a subset of various clinical diagnoses. Although many pathogenic genetic variants are currently thought to be variably penetrant, we hypothesise that when disorders encompassed by developmental brain dysfunction are considered as a group, the penetrance will approach 100%. The penetrance is also predicted to approach 100% when the phenotype being considered is a specific trait, such as intelligence or autistic-like social impairment, and the trait could be assessed using a continuous, quantitative measure to compare probands with non-carrier family members rather than a qualitative, dichotomous trait and comparing probands with the healthy population. Copyright 2013 Elsevier Ltd. All rights reserved.

The effects of noise exposure and genetic background on auditory-evoked behaviors in larval zebrafish

Thesis (Ph.D.)--University of Washington, 2016-06

A genetic two-factor model of the covariation among a subset of Multidimensional Aptitude Battery and Wechsler Adult Intelligence Scale - Revised subtests

The phenotypic and genetic factor structure of performance on five Multidimensional Aptitude Battery (MAB) subtests and one Wechsler Adult Intelligence Scale-Revised (WAIS-R) subtest was explored in 390 adolescent twin pairs (184 monozygotic [MZ]; 206 dizygotic (DZ)). The temporal stability of these measures was derived from a subsample of 49 twin pairs, with test-retest correlations ranging from .67 to .85. A phenotypic factor model, in which performance and verbal factors were correlated, provided a good fit to the data. Genetic modeling was based on the phenotypic factor structure, but also took into account the additive genetic (A), common environmental (C), and unique environmental (E) parameters derived from a fully saturated ACE model. The best fitting model was characterized by a genetic correlated two-factor structure with specific effects, a general common environmental factor, and overlapping unique environmental effects. Results are compared to multivariate genetic models reported in children and adults, with the most notable difference being the growing importance of common genes influencing diverse abilities in adolescence. (C) 2003 Elsevier Inc. All rights reserved.

Genetic and environmental sources of covariance between reading tests used in neuropsychological assessment and IQ subtests

In this study, we examined genetic and environmental influences on covariation among two reading tests used in neuropsychological assessment (Cambridge Contextual Reading Test [CCRT], [Beardsall, L., and Huppert, F. A. ( 1994). J. Clin. Exp. Neuropsychol. 16: 232 - 242], Schonell Graded Word Reading Test [SGWRT], [ Schonell, F. J., and Schonell, P. E. ( 1960). Diagnostic and attainment testing. Edinburgh: Oliver and Boyd.]) and among a selection of IQ subtests from the Multidimensional Aptitude Battery (MAB), [Jackson, D. N. (1984). Multidimensional aptitude battery, Ontario: Research Psychologists Press.] and the Wechsler Adult Intelligence Scale-Revised (WAIS-R) [Wechsler, D. (1981). Manual for the Wechsler Adult Intelligence Scale-Revised (WAIS-R). San Antonio: The Psychological Corporation]. Participants were 225 monozygotic and 275 dizygotic twin pairs aged from 15 years to 18 years ( mean, 16 years). For Verbal IQ subtests, phenotypic correlations with the reading tests ranged from 0.44 to 0.65. For Performance IQ subtests, phenotypic correlations with the reading tests ranged from 0.23 to 0.34. Results of Structural Equation Modeling (SEM) supported a model with one genetic General factor and three genetic group factors ( Verbal, Performance, Reading). Reading performance was influenced by the genetic General factor ( accounting for 13% and 20% of the variance for the CCRT and SGWRT, respectively), the genetic Verbal factor ( explaining 17% and 19% of variance for the CCRT and SGWRT), and the genetic Reading factor ( explaining 21% of the variance for both the CCRT and SGWRT). A common environment factor accounted for 25% and 14% of the CCRT and SGWRT variance, respectively. Genetic influences accounted for more than half of the phenotypic covariance between the reading tests and each of the IQ subtests. The heritabilities of the CCRT and SGWRT were 0.54 and 0.65, respectively. Observable covariance between reading assessments used by neuropsychologists to estimate IQ and IQ subtests appears to be largely due to genetic effects.

A genetic investigation of the covariation among Inspection Time, Choice Reaction Time, and IQ subtest scores

Information processing speed, as measured by elementary cognitive tasks, is correlated with higher order cognitive ability so that increased speed relates to improved cognitive performance. The question of whether the genetic variation in Inspection Time (IT) and Choice Reaction Time (CRT) is associated with IQ through a unitary factor was addressed in this multivariate genetic study of IT, CRT, and IQ subtest scores. The sample included 184 MZ and 206 DZ twin pairs with a mean age of 16.2 years (range 15-18 years). They were administered a visual (pi-figure) IT task, a two-choice RT task, five computerized subtests of the Multidimensional Aptitude Battery, and the digit symbol substitution subtest from the WAIS-R. The data supported a factor model comprising a general, three group (verbal ability, visuospatial ability, broad speediness), and specific genetic factor structure, a shared environmental factor influencing all tests but IT, plus unique environmental factors that were largely specific to individual measures. The general genetic factor displayed factor loadings ranging between 0.35 and 0.66 for the IQ subtests, with IT and CRT loadings of -0.47 and -0.24, respectively. Results indicate that a unitary factor is insufficient to describe the entire relationship between cognitive speed measures and all IQ subtests, with independent genetic effects explaining further covariation between processing speed (especially CRT) and Digit Symbol.

Defining nicotine dependence for genetic research: evidence from Australian twins

Background. Whether current criteria used to define nicotine dependence are informative for genetic research is an important empirical question. The authors used items of the DSM-IV and of the Heaviness of Smoking Index to characterize the nicotine dependence phenotype and to identify salient symptoms in a genetically informative community sample of Australian young adult female and mate twins. Method. Phenotypic and genetic factor analyses were performed on nine dependence symptoms (the seven DSM-IV substance dependence criteria and the two Heaviness of Smoking Index (HSI) items derived from the Fagerstrom Tolerance Questionnaire, time to first cigarette in the morning and number of cigarettes smoked per day). Phenotypic and genetic analyses were restricted to ever smokers. Results. Phenotypic nicotine dependence symptom covariation was best captured by two factors with a similar pattern of factor loadings for women and men. In genetic factor analysis item covariation was best captured by two genetic but one shared environmental factor for both women and men; however, item factor loadings differed by gender. All nicotine dependence symptoms were substantially heritable, except for the DSM-IV criterion of 'giving up or reducing important activities in order to smoke', which was weakly familial. Conclusions. The salient behavioral indices of nicotine dependence are similar for women and men. DSM-IV criteria of tolerance, withdrawal, and experiencing difficulty quitting and HSI items time to first cigarette in the morning and number of cigarettes smoked per day may represent the most highly heritable symptoms of nicotine dependence for both women and men.

Genetic effects on alcohol dependence risk: re-evaluating the importance of psychiatric and other heritable risk factors

Background. Genetic influences have been shown to play a major role in determining the risk of alcohol dependence (AD) in both women and men; however, little attention has been directed to identifying the major sources of genetic variation in AD risk. Method. Diagnostic telephone interview data from young adult Australian twin pairs born between 1964 and 1971 were analyzed. Cox regression models were fitted to interview data from a total of 2708 complete twin pairs (690 MZ female, 485 MZ male, 500 DZ female, 384 DZ male, and 649 DZ female/male pairs). Structural equation models were fitted to determine the extent of residual genetic and environmental influences on AD risk while controlling for effects of sociodemographic and psychiatric predictors on risk. Results. Risk of AD was increased in males, in Roman Catholics, in those reporting a history of major depression, social anxiety problems, and conduct disorder, or (in females only) a history of suicide attempt and childhood sexual abuse; but was decreased in those reporting Baptist, Methodist, or Orthodox religion, in those who reported weekly church attendance, and in university-educated males. After allowing for the effects of sociodemographic and psychiatric predictors, 47 % (95 % CI 28-55) of the residual variance in alcoholism risk was attributable to additive genetic effects, 0 % (95 % CI 0-14) to shared environmental factors, and 53 % (95 % CI 45-63) to non-shared environmental influences. Conclusions. Controlling for other risk factors, substantial residual heritability of AD was observed, suggesting that psychiatric and other risk factors play a minor role in the inheritance of AD.