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Variability in subjective response to alcohol has been shown to predict drinking behavior as well as the development of alcohol use disorders. The current study examined the extent to which individual differences in alcohol pharmacokinetics impact subjective response and drinking behavior during a single session alcohol administration paradigm. Participants (N = 98) completed measures of subjective response at two time points following alcohol consumption. Pharmacokinetic properties (rate of absorption and metabolism) were inferred using multiple BAC readings to calculate the area under the curve during the ascending limb for absorption and descending limb for metabolism. Following the completion of the subjective response measures, an ad-libitum taste rating task was implemented in which participants were permitted to consume additional alcoholic beverages. The amount consumed during the taste rating task served as the primary outcome variable. Results of the study indicated that participants who metabolized alcohol more quickly maintained a greater level of subjective stimulation as blood alcohol levels declined and reported greater reductions in subjective sedation. Although metabolism did not have a direct influence on within session alcohol consumption, a faster metabolism did relate to increased ad-libitum consumption indirectly through greater acute tolerance to sedative effects and greater maintenance of stimulant effects. Rate of absorption did not significantly predict subjective response or within session drinking. The results of the study add clarity to theories of subjective response to alcohol, and suggest that those at highest risk for alcohol problems experience a more rapid reduction in sedation following alcohol consumption while simultaneously experiencing heightened levels of stimulation. Variability in pharmacokinetics, namely how quickly one metabolizes alcohol, may be an identifiable biomarker of subjective response and may be used to infer risk for alcohol problems.
ContributorsBoyd, Stephen (Author) / Corbin, William R. (Thesis advisor) / Chassin, Laurie (Committee member) / MacKinnon, David (Committee member) / Olive, Michael Foster (Committee member) / Arizona State University (Publisher)
Created2014
Description
The present study utilized longitudinal data from a high-risk community sample (n=254, 52.8% female, 47.2% children of alcoholics, 74% non-Hispanic Caucasian) to test questions concerning the effects of genetic risk, parental knowledge, and peer substance use on emerging adult substance use disorders (SUDs). Specifically, this study examined whether parental knowledge and peer substance use mediated the effects of parent alcohol use disorder (AUD) and genetic risk for behavioral undercontrol on SUD. The current study also examined whether genetic risk moderated effects of parental knowledge and peer substance use on risk for SUD. Finally, this study examined these questions over and above a genetic "control" which explained a large proportion of variance in the outcome, thereby providing a stricter test of environmental influences.
Analyses were performed in a path analysis framework. To test these research questions, the current study employed two polygenic risk scores. The first, a theory-based score, was formed using single-nucleotide polymorphisms (SNPs) from receptor systems implicated in the amplification of positive effects in the presence of new/exciting stimuli and/or pleasure derived from using substances. The second, an empirically-based score, was formed using a data-driven approach that explained a large amount of variance in SUDs. Together, these scores allowed the present study to test explanations for the relations among parent AUD, parental knowledge, peer substance use, and SUDs.
Results of the current study found that having parents with less knowledge or an AUD conferred greater risk for SUDs, but only for those at higher genetic risk for behavioral undercontrol. The current study replicated research findings suggesting that peer substance use mediated the effect of parental AUD on SUD. However, it adds to this literature by suggesting that some mechanism other than increased behavioral undercontrol explains relations among parental AUD, peer substance use, and emerging adult SUD. Taken together, these findings indicate that children of parents with AUDs comprise a particularly risky group, although likelihood of SUD within this group is not uniform. These findings also suggest that some of the most important environmental risk factors for SUDs exert effects that vary across level of genetic propensity.
Analyses were performed in a path analysis framework. To test these research questions, the current study employed two polygenic risk scores. The first, a theory-based score, was formed using single-nucleotide polymorphisms (SNPs) from receptor systems implicated in the amplification of positive effects in the presence of new/exciting stimuli and/or pleasure derived from using substances. The second, an empirically-based score, was formed using a data-driven approach that explained a large amount of variance in SUDs. Together, these scores allowed the present study to test explanations for the relations among parent AUD, parental knowledge, peer substance use, and SUDs.
Results of the current study found that having parents with less knowledge or an AUD conferred greater risk for SUDs, but only for those at higher genetic risk for behavioral undercontrol. The current study replicated research findings suggesting that peer substance use mediated the effect of parental AUD on SUD. However, it adds to this literature by suggesting that some mechanism other than increased behavioral undercontrol explains relations among parental AUD, peer substance use, and emerging adult SUD. Taken together, these findings indicate that children of parents with AUDs comprise a particularly risky group, although likelihood of SUD within this group is not uniform. These findings also suggest that some of the most important environmental risk factors for SUDs exert effects that vary across level of genetic propensity.
ContributorsBountress, Kaitlin (Author) / Chassin, Laurie (Thesis advisor) / Crnic, Keith (Committee member) / Lemery-Chalfant, Kathryn (Committee member) / MacKinnon, David (Committee member) / Arizona State University (Publisher)
Created2015
Description
Pediatric obesity is a public health concern due to its elevated prevalence rates and its relation to concurrent and long-term physical and psychosocial consequences. Pediatric obesity has been found to be associated with problem behaviors, albeit with inconsistent findings. The mechanism of this relation is unclear. It is possible that they have a shared etiology. Self-regulation and parenting practices are two factors that have been implicated in the development of problem behaviors and are garnering evidence for their relation with pediatric obesity. The goal of the present study was to examine whether self-regulation (SREC), positive behavior support (PBSEC), and coercive limit-setting (CLSEC) in early childhood are shared etiological factors of pediatric obesity and problem behaviors. Using multinomial logistic regression the likelihood of belonging to four outcome groups (Comorbid, Problem behavior only, Overweight only, and Typically developing) at age 10 based on these factors was assessed. Analyses controlled for intervention group assignment, child gender, child African-American or Bi-racial, child Hispanic, cumulative risk, child body size impression at age 2, and parent body size impression at baseline. In the models examining SREC alone, for every 1 standard deviation increase in SREC, there was a reliable reduction in the odds of the child belonging to the comorbid and problem behavior only groups at age 10, compared to the typically developing group (OR = 0.386, 95% CI [0.237, 0.628], OR = 0.281, 95% CI [0.157, 0.503], respectively). This relation was maintained when SREC was in the same model as PBSEC and CLSEC. PBSEC and CLSEC alone did not impact the likelihood of belonging to any of the outcome groups. A significant interaction was found between SREC and CLSEC, such that at high levels of both SREC and CLSEC the odds of a child belonging to the overweight only group at age 10 increased, compared to the typically developing group. Results highlight CLSEC as a parenting practice that may place a highly regulated child at risk for becoming overweight. Overall, the findings suggest that problem behaviors and pediatric obesity do not have a shared etiology.
ContributorsMontano, Zorash (Author) / Dishion, Thomas J (Thesis advisor) / Gonzales, Nancy (Committee member) / Perez, Marisol (Committee member) / Enders, Craig (Committee member) / Arizona State University (Publisher)
Created2016
Description
Although models for describing longitudinal data have become increasingly sophisticated, the criticism of even foundational growth curve models remains challenging. The challenge arises from the need to disentangle data-model misfit at multiple and interrelated levels of analysis. Using posterior predictive model checking (PPMC)—a popular Bayesian framework for model criticism—the performance of several discrepancy functions was investigated in a Monte Carlo simulation study. The discrepancy functions of interest included two types of conditional concordance correlation (CCC) functions, two types of R2 functions, two types of standardized generalized dimensionality discrepancy (SGDDM) functions, the likelihood ratio (LR), and the likelihood ratio difference test (LRT). Key outcomes included effect sizes of the design factors on the realized values of discrepancy functions, distributions of posterior predictive p-values (PPP-values), and the proportion of extreme PPP-values.
In terms of the realized values, the behavior of the CCC and R2 functions were generally consistent with prior research. However, as diagnostics, these functions were extremely conservative even when some aspect of the data was unaccounted for. In contrast, the conditional SGDDM (SGDDMC), LR, and LRT were generally sensitive to the underspecifications investigated in this work on all outcomes considered. Although the proportions of extreme PPP-values for these functions tended to increase in null situations for non-normal data, this behavior may have reflected the true misfit that resulted from the specification of normal prior distributions. Importantly, the LR and the SGDDMC to a greater extent exhibited some potential for untangling the sources of data-model misfit. Owing to connections of growth curve models to the more fundamental frameworks of multilevel modeling, structural equation models with a mean structure, and Bayesian hierarchical models, the results of the current work may have broader implications that warrant further research.
In terms of the realized values, the behavior of the CCC and R2 functions were generally consistent with prior research. However, as diagnostics, these functions were extremely conservative even when some aspect of the data was unaccounted for. In contrast, the conditional SGDDM (SGDDMC), LR, and LRT were generally sensitive to the underspecifications investigated in this work on all outcomes considered. Although the proportions of extreme PPP-values for these functions tended to increase in null situations for non-normal data, this behavior may have reflected the true misfit that resulted from the specification of normal prior distributions. Importantly, the LR and the SGDDMC to a greater extent exhibited some potential for untangling the sources of data-model misfit. Owing to connections of growth curve models to the more fundamental frameworks of multilevel modeling, structural equation models with a mean structure, and Bayesian hierarchical models, the results of the current work may have broader implications that warrant further research.
ContributorsFay, Derek (Author) / Levy, Roy (Thesis advisor) / Thompson, Marilyn (Committee member) / Enders, Craig (Committee member) / Arizona State University (Publisher)
Created2015
Description
Anxiety and depression are among the most prevalent disorders in youth, with prevalence rates ranging from 15% to 25% for anxiety and 5% to 14% for depression. Anxiety and depressive disorders cause significant impairment, fail to spontaneously remit, and have been prospectively linked to problematic substance use and legal problems in adulthood. These disorders often share a high-degree of comorbidity in both clinical and community samples, with anxiety disorders typically preceding the onset of depression. Given the nature and consequences of anxiety and depressive disorders, a plethora of treatment and preventative interventions have been developed and tested with data showing significant pre to post to follow-up reductions in anxiety and depressive symptoms. However, little is known about the mediators by which these interventions achieve their effects. To address this gap in the literature, the present thesis study combined meta-analytic methods and path analysis to evaluate the effects of youth anxiety and depression interventions on outcomes and four theory-driven mediators using data from 55 randomized controlled trials (N = 11,413). The mediators included: (1) information-processing biases, (2) coping strategies, (3) social competence, and (4) physiological hyperarousal. Meta-analytic results showed that treatment and preventative interventions reliably produced moderate effect sizes on outcomes and three of the four mediators (information-processing biases, coping strategies, social competence). Most importantly, findings from the path analysis showed that changes in information-processing biases and coping strategies consistently mediated changes in outcomes for anxiety and depression at both levels of intervention, whereas gains in social competence and reductions in physiological hyperarousal did not emerge as significant mediators. Knowledge of the mediators underlying intervention effects is important because they can refine testable models of treatment and prevention efforts and identify which anxiety and depression components need to be packaged or strengthened to maximize intervention effects. Allocating additional resources to significant mediators has the potential to reduce costs associated with adopting and implementing evidence-based interventions and improve dissemination and sustainability in real-world settings, thus setting the stage to be more readily integrated into clinical and non-clinical settings on a large scale.
ContributorsStoll, Ryan (Author) / Pina, Armando A (Thesis advisor) / MacKinnon, David (Committee member) / Knight, George (Committee member) / Arizona State University (Publisher)
Created2015
Description
Flavivirus infections are emerging as significant threats to human health around the globe. Among them West Nile(WNV) and Dengue Virus (DV) are the most prevalent in causing human disease with WNV outbreaks occurring in all areas around the world and DV epidemics in more than 100 countries. WNV is a neurotropic virus capable of causing meningitis and encephalitis in humans. Currently, there are no therapeutic treatments or vaccines available. The expanding epidemic of WNV demands studies that develop efficacious therapeutics and vaccines and produce them rapidly and inexpensively. In response, our lab developed a plant-derived monoclonal antibody (mAb) (pHu-E16) against DIII (WNV antigen) that is able to neutralize and prevent mice from lethal infection. However, this drug has a short window of efficacy due to pHu-E16's inability to cross the Blood Brain Barrier (BBB) and enter the brain. Here, we constructed a bifunctional diabody, which couples the neutralizing activity of E16 and BBB penetrating activity of 8D3 mAb. We also produced a plant-derived E16 scFv-CH1-3 variant with equivalent specific binding as the full pHu-E16 mAb, but only requiring one gene construct for production. Furthermore, a WNV vaccine based on plant-derived DIII was developed showing proper folding and potentially protective immune response in mice. DV causes severe hemorrhaging diseases especially in people exposed to secondary DV infection from a heterotypic strain. It is hypothesized that sub-neutralizing cross-reactive antibodies from the first exposure aid the second infection in a process called antibody-dependent enhancement (ADE). ADE depends on the ability of mAb to bind Fc receptors (FcγRs), and has become a major roadblock for developing mAb-based therapeutics against DV. We aim to produce an anti-Dengue mAb (E60) in different glycoengineered plant lines that exhibit reduced/differential binding to FcγRs, therefore, reducing or eliminating ADE. We have successfully cloned the molecular constructs of E60, and expressed it in two plant lines with different glycosylation patterns. We demonstrated that both plant-derived E60 mAb glycoforms retained specific recognition and neutralization activity against DV. Overall, our study demonstrates great strives to develop efficacious therapeutics and potent vaccine candidates against Flaviviruses in plant expression systems.
ContributorsHurtado, Jonathan (Author) / Chen, Qiang (Thesis advisor) / Huffman, Holly A (Committee member) / Steele, Kelly P (Committee member) / Arizona State University (Publisher)
Created2014
Description
Methods to test hypotheses of mediated effects in the pretest-posttest control group design are understudied in the behavioral sciences (MacKinnon, 2008). Because many studies aim to answer questions about mediating processes in the pretest-posttest control group design, there is a need to determine which model is most appropriate to test hypotheses about mediating processes and what happens to estimates of the mediated effect when model assumptions are violated in this design. The goal of this project was to outline estimator characteristics of four longitudinal mediation models and the cross-sectional mediation model. Models were compared on type 1 error rates, statistical power, accuracy of confidence interval coverage, and bias of parameter estimates. Four traditional longitudinal models and the cross-sectional model were assessed. The four longitudinal models were analysis of covariance (ANCOVA) using pretest scores as a covariate, path analysis, difference scores, and residualized change scores. A Monte Carlo simulation study was conducted to evaluate the different models across a wide range of sample sizes and effect sizes. All models performed well in terms of type 1 error rates and the ANCOVA and path analysis models performed best in terms of bias and empirical power. The difference score, residualized change score, and cross-sectional models all performed well given certain conditions held about the pretest measures. These conditions and future directions are discussed.
ContributorsValente, Matthew John (Author) / MacKinnon, David (Thesis advisor) / West, Stephen (Committee member) / Aiken, Leona (Committee member) / Enders, Craig (Committee member) / Arizona State University (Publisher)
Created2015
Description
Research methods based on the frequentist philosophy use prior information in a priori power calculations and when determining the necessary sample size for the detection of an effect, but not in statistical analyses. Bayesian methods incorporate prior knowledge into the statistical analysis in the form of a prior distribution. When prior information about a relationship is available, the estimates obtained could differ drastically depending on the choice of Bayesian or frequentist method. Study 1 in this project compared the performance of five methods for obtaining interval estimates of the mediated effect in terms of coverage, Type I error rate, empirical power, interval imbalance, and interval width at N = 20, 40, 60, 100 and 500. In Study 1, Bayesian methods with informative prior distributions performed almost identically to Bayesian methods with diffuse prior distributions, and had more power than normal theory confidence limits, lower Type I error rates than the percentile bootstrap, and coverage, interval width, and imbalance comparable to normal theory, percentile bootstrap, and the bias-corrected bootstrap confidence limits. Study 2 evaluated if a Bayesian method with true parameter values as prior information outperforms the other methods. The findings indicate that with true values of parameters as the prior information, Bayesian credibility intervals with informative prior distributions have more power, less imbalance, and narrower intervals than Bayesian credibility intervals with diffuse prior distributions, normal theory, percentile bootstrap, and bias-corrected bootstrap confidence limits. Study 3 examined how much power increases when increasing the precision of the prior distribution by a factor of ten for either the action or the conceptual path in mediation analysis. Power generally increases with increases in precision but there are many sample size and parameter value combinations where precision increases by a factor of 10 do not lead to substantial increases in power.
ContributorsMiocevic, Milica (Author) / Mackinnon, David P. (Thesis advisor) / Levy, Roy (Committee member) / West, Stephen G. (Committee member) / Enders, Craig (Committee member) / Arizona State University (Publisher)
Created2014
Description
Maternal intrusiveness is an important predictor of child mental health problems. Evidence links high levels of maternal intrusiveness to later infant negativity, and child internalizing problems. However, children also influence the manner in which parents interact with them. For example, infants that show more negative emotionality elicit less positive parenting in their caregivers. Infant affect is also associated with later child internalizing difficulties. Although previous research has demonstrated that maternal intrusiveness is related to infant affect and child internalizing symptomatology, and that infant affect is a predictor of internalizing problems and parenting, no studies have looked at the transactional relations between early maternal intrusiveness and infant affect, and whether these relations in infancy predict later childhood internalizing symptomatology. The present study investigates young children's risk for internalizing problems as a function of the interplay between maternal intrusiveness and infant affect during the early infancy period in a low-income, Mexican-American sample. Participants included 323 Mexican-American women and their infants. Data were collected when the infants were 12, 18, 24, and 52 weeks old. Mothers were asked to interact with their infants in semi-structured tasks, and mother and infant behaviors were coded at 12, 18, and 24 weeks. Maternal intrusiveness was globally rated, and duration of infant negative- and positive affect was recorded. Mother reports of child Internalizing symptomatology were obtained at 52 weeks. Findings suggest that there are transactional relations between early maternal intrusiveness and infant negative affect, while the relations between infant positive affect and maternal intrusiveness are unidirectional, in that infant positivity influences parenting but not vice versa. Further, findings also imply that neither maternal intrusiveness, nor infant affect, influence later toddler internalizing symptomatology. Identifying risk processes in a Mexican-American sample adds to our understanding of emerging infant difficulties in this population, and may have implications for early interventions.
ContributorsRystad, Ida A (Author) / Crnic, Keith A (Thesis advisor) / Enders, Craig (Committee member) / Bradley, Robert (Committee member) / Arizona State University (Publisher)
Created2014
Description
The current study utilized data from two longitudinal samples to test mechanisms in the relation between a polygenic risk score indexing serotonin functioning and alcohol use in adolescence. Specifically, this study tested whether individuals with lower levels of serotonin functioning as indexed by a polygenic risk score were vulnerable to poorer self-regulation, and whether poorer self-regulation subsequently predicted the divergent outcomes of depressive symptoms and aggressive/antisocial behaviors. This study then examined whether depressive symptoms and aggressive/antisocial behaviors conferred risk for later alcohol use in adolescence, and whether polygenic risk and effortful control had direct effects on alcohol use that were not mediated through problem behaviors. Finally, the study examined the potential moderating role of gender in these pathways to alcohol use.
Structural equation modeling was used to test hypotheses. Results from an independent genome-wide association study of 5-hydroxyindoleacetic acid in the cerebrospinal fluid were used to create serotonin (5-HT) polygenic risk scores, wherein higher scores reflected lower levels of 5-HT functioning. Data from three time points were drawn from each sample, and all paths were prospective. Findings suggested that 5-HT polygenic risk did not predict self-regulatory constructs. However, 5-HT polygenic risk did predict the divergent outcomes of depression and aggression/antisociality, such that higher levels of 5-HT polygenic risk predicted greater levels of depression and aggression/antisociality. Results most clearly supported adolescents’ aggression/antisociality as a mechanism in the relation between 5-HT polygenic risk and later alcohol use. Deficits in self-regulation also predicted depression and aggression/antisociality, and indirectly predicted alcohol use through aggression/antisociality. These pathways to alcohol use might be the most salient for boys with low levels of socioeconomic status.
Results are novel contributions to the literature. The previously observed association between serotonin functioning and alcohol use might be due, in part, to the fact that individuals with lower levels of serotonin functioning are predisposed towards developing earlier aggression/antisociality. Results did not support the hypothesis that serotonin functioning predisposes individuals to deficits in self-regulatory abilities. Findings extend previous research by suggesting that serotonin functioning and self-regulation might be transdiagnostic risk factors for many types of psychopathology.
Structural equation modeling was used to test hypotheses. Results from an independent genome-wide association study of 5-hydroxyindoleacetic acid in the cerebrospinal fluid were used to create serotonin (5-HT) polygenic risk scores, wherein higher scores reflected lower levels of 5-HT functioning. Data from three time points were drawn from each sample, and all paths were prospective. Findings suggested that 5-HT polygenic risk did not predict self-regulatory constructs. However, 5-HT polygenic risk did predict the divergent outcomes of depression and aggression/antisociality, such that higher levels of 5-HT polygenic risk predicted greater levels of depression and aggression/antisociality. Results most clearly supported adolescents’ aggression/antisociality as a mechanism in the relation between 5-HT polygenic risk and later alcohol use. Deficits in self-regulation also predicted depression and aggression/antisociality, and indirectly predicted alcohol use through aggression/antisociality. These pathways to alcohol use might be the most salient for boys with low levels of socioeconomic status.
Results are novel contributions to the literature. The previously observed association between serotonin functioning and alcohol use might be due, in part, to the fact that individuals with lower levels of serotonin functioning are predisposed towards developing earlier aggression/antisociality. Results did not support the hypothesis that serotonin functioning predisposes individuals to deficits in self-regulatory abilities. Findings extend previous research by suggesting that serotonin functioning and self-regulation might be transdiagnostic risk factors for many types of psychopathology.
ContributorsWang, Frances Lynn (Author) / Chassin, Laurie (Thesis advisor) / Eisenberg, Nancy (Committee member) / Lemery-Chalfant, Kathryn (Committee member) / MacKinnon, David (Committee member) / Arizona State University (Publisher)
Created2017