Showing papers by "Michael C. Neale published in 2014"

Critical slowing down as early warning for the onset and termination of depression.

Abstract: About 17% of humanity goes through an episode of major depression at some point in their lifetime. Despite the enormous societal costs of this incapacitating disorder, it is largely unknown how the likelihood of falling into a depressive episode can be assessed. Here, we show for a large group of healthy individuals and patients that the probability of an upcoming shift between a depressed and a normal state is related to elevated temporal autocorrelation, variance, and correlation between emotions in fluctuations of autorecorded emotions. These are indicators of the general phenomenon of critical slowing down, which is expected to occur when a system approaches a tipping point. Our results support the hypothesis that mood may have alternative stable states separated by tipping points, and suggest an approach for assessing the likelihood of transitions into and out of depression.

The dynamic role of genetics on cortical patterning during childhood and adolescence.

Abstract: Longitudinal imaging and quantitative genetic studies have both provided important insights into the nature of human brain development. In the present study we combine these modalities to obtain dynamic anatomical maps of the genetic contributions to cortical thickness through childhood and adolescence. A total of 1,748 anatomic MRI scans from 792 healthy twins and siblings were studied with up to eight time points per subject. Using genetically informative latent growth curve modeling of 81,924 measures of cortical thickness, changes in the genetic contributions to cortical development could be visualized across the age range at high resolution. There was highly statistically significant (P < 0.0001) genetic variance throughout the majority of the cerebral cortex, with the regions of highest heritability including the most evolutionarily novel regions of the brain. Dynamic modeling of changes in heritability over time demonstrated that the heritability of cortical thickness increases gradually throughout late childhood and adolescence, with sequential emergence of three large regions of high heritability in the temporal poles, the inferior parietal lobes, and the superior and dorsolateral frontal cortices.

Ovarian Hormone Influences on Dysregulated Eating: A Comparison of Associations in Women with versus without Binge Episodes.

Abstract: Changes in ovarian hormones predict changes in emotional eating across the menstrual cycle. However, prior studies have not examined whether the nature of associations varies across dysregulated eating severity. The current study determined whether the strength and/or nature of hormone/dysregulated eating associations differ based on the presence of clinically diagnosed binge episodes (BEs). Participants included 28 women with BEs and 417 women without BEs who provided salivary hormone samples, ratings of emotional eating, and BE frequency for 45 days. Results revealed stronger associations between dysregulated eating and ovarian hormones in women with BEs as compared to women without BEs. The nature of associations also differed, as progesterone moderated the effects of lower estradiol levels on dysregulated eating in women with BEs only. Although hormone/dysregulated eating associations are present across the spectrum of pathology, the nature of associations may vary in ways that have implications for etiological models and treatment.

Polygenic risk scores for smoking: predictors for alcohol and cannabis use?

Abstract: Background and Aims A strong correlation exists between smoking and the use of alcohol and cannabis.This paper uses polygenic risk scores to explore the possibility of overlapping genetic factors.Those scores reflect a combined effect of selected risk alleles for smoking. Methods Summary-level P-values were available for smoking initiation, age at onset of smoking, cigarettes per day and smoking cessation from the Tobacco and Genetics Consortium (n between 22 000and70 000subjects).UsingdifferentP-valuethresholds(0.1,0.2and0.5)fromthemeta-analysis,setsof 'risk alleles' were defined and used to generate a polygenic risk score (weighted sum of the alleles) for each subject in an independent target sample from the Netherlands Twin Register (n = 1583). The association between polygenic smoking scores and alcohol/cannabis use was investigated with regression analysis. Results The polygenic scores for 'cigarettes per day' were associated significantly with the number of glasses alcohol per week (P = 0.005, R 2 = 0.4- 0.5%) and cannabis initiation (P = 0.004, R 2 = 0.6-0.9%). The polygenic scores for 'age at onset of smoking' were associated significantly with 'age at regular drinking' (P = 0.001, R 2 = 1.1-1.5%), while the scores for 'smoking initiation' and 'smoking cessation' did not significantly predict alcohol or cannabis use. Conclusions Smoking, alcohol and cannabis use are influenced by aggregated genetic risk factors shared between these substances.The many common genetic variants each have a very small individual effect size.

Do emotional eating urges regulate affect? Concurrent and prospective associations and implications for risk models of binge eating.

Abstract: Objective: Emotional eating (EE) reflects an urge to eat in response to emotional rather than physical cues and is a risk factor for the development of binge eating. EE has been conceptualized as an attempt to regulate negative affect (NA), a posited maintenance factor for binge eating. However, no study has examined whether EE urges regulate affect. Further, no studies have examined longitudinal associations between EE urges and positive affect (PA). Method: We examined within-subject longitudinal associations between affect and EE urges in a community-based sample of female twins (mean age517.8 years). Participants (N5239) completed ratings of affect and EE urges for 45 consecutive days. Results: Greater NA was concurrently associated with greater EE urges. Additionally, greater EE urges predicted worse NA for both concurrent and prospective (next-day) analyses. Finally, lower PA was associated with greater EE urges in concurrent analyses, but there were no prospective associations between changes in PA and EE urges. Discussion: EE urges do not appear to effectively regulate affect. EE urges in a community-based sample appear to have the same functional relationship with affect as binge eating in clinical samples, further supporting EE as a useful dimensional construct for examining processes related to binge eating. V C 2014 Wiley Periodicals, Inc.

Conceptual and data-based investigation of genetic influences and brain asymmetry: A twin study of multiple structural phenotypes

Abstract: Right-left regional cerebral differences are a feature of the human brain linked to functional abilities, aging, and neurodevelopmental and mental disorders. The role of genetic factors in structural asymmetry has been incompletely studied. We analyzed data from 515 individuals 130 monozygotic twin pairs, 97 dizygotic pairs, and 61 unpaired twins from the Vietnam Era Twin Study of Aging to answer three questions about genetic determinants of brain structural asymmetry: First, does the magnitude of heritability differ for homologous regions in each hemisphere? Despite adequate power to detect regional differences, heritability estimates were not significantly larger in one hemisphere versus the other, except left > right inferior lateral ventricle heritability. Second, do different genetic factors influence left and right hemisphere size in homologous regions? Interhemispheric genetic correlations were high and significant; in only two subcortical regions pallidum and accumbens did the estimate statistically differ from 1.0. Thus, there was little evidence for different genetic influences on left and right hemisphere regions. Third, to what extent do genetic factors influence variability in left-right size differences? There was no evidence that variation in asymmetry i.e., the size difference of left and right homologous regions was genetically determined, except in pallidum and accumbens. Our findings suggest that genetic factors do not play a significant role in determining individual variation in the degree of regional cortical size asymmetries measured with MRI, although they may do so for volume of some subcortical structures. Despite varying interpretations of existing data, we view the present results as consistent with previous findings.

Coupled latent differential equation with moderators: simulation and application.

Abstract: Latent differential equations (LDE) use differential equations to analyze time series data. Because of the recent development of this technique, some issues critical to running an LDE model remain. In this article, the authors provide solutions to some of these issues and recommend a step-by-step procedure demonstrated on a set of empirical data, which models the interaction between ovarian hormone cycles and emotional eating. Results indicated that emotional eating is self-regulated. For instance, when people do more emotional eating than normal, they will subsequently tend to decrease their emotional eating behavior. In addition, a sudden increase will produce a stronger tendency to decrease than will a slow increase. We also found that emotional eating is coupled with the cycle of the ovarian hormone estradiol, and the peak of emotional eating occurs after the peak of estradiol. The self-reported average level of negative affect moderates the frequency of eating regulation and the coupling strength between eating and estradiol. Thus, people with a higher average level of negative affect tend to fluctuate faster in emotional eating, and their eating behavior is more strongly coupled with the hormone estradiol. Permutation tests on these empirical data supported the reliability of using LDE models to detect self-regulation and a coupling effect between two regulatory behaviors.

Genetic and Environmental Risk Factors for Illicit Substance Use and Use Disorders: Joint Analysis of Self and Co-twin Ratings

Abstract: The specificity of genetic and environmental risk factors for illicit substance use and substance use disorders (SUD) was investigated by utilizing self and co-twin reports in 1,791 male twins. There was a high rate of comorbidity between both use of, and SUD from, different classes of illicit substances. For substance use, the model that included one common genetic, one shared environmental, and one individual-specific (i.e., unique) environmental factor, along with substance-specific effects that were attributed entirely to genetic factors fit the data best. For illicit SUD, one common genetic and one common unique environmental risk factor, and substance specific shared environmental and unique environmental risk factors were identified. Risk factors for illicit substance use and SUD are mainly non-specific to substance class. Co-twin rating of illicit substance use and SUD was a reliable source of information, and by taking account of random and systematic measurement error, environmental exposures unique to the individual were of lesser importance than found in earlier studies.

Testing for measured gene-environment interaction: problems with the use of cross-product terms and a regression model reparameterization solution

Abstract: The study of gene-environment interaction (G × E) has garnered widespread attention. The most common way to assess interaction effects is in a regression model with a G × E interaction term that is a product of the values specified for the genotypic (G) and environmental (E) variables. In this paper we discuss the circumstances under which interaction can be modeled as a product term and cases in which use of a product term is inappropriate and may lead to erroneous conclusions about the presence and nature of interaction effects. In the case of a binary coded genetic variant (as used in dominant and recessive models, or where the minor allele occurs so infrequently that it is not observed in the homozygous state), the regression coefficient corresponding to a significant interaction term reflects a slope difference between the two genotype categories and appropriately characterizes the statistical interaction between the genetic and environmental variables. However, when using a three-category polymorphic genotype, as is commonly done when modeling an additive effect, both false positive and false negative results can occur, and the nature of the interaction can be misrepresented. We present a reparameterized regression equation that accurately captures interaction effects without the constraints imposed by modeling interactions using a single cross-product term. In addition, we provide a series of recommendations for making conclusions about the presence of meaningful G × E interactions, which take into account the nature of the observed interactions and whether they map onto sensible genotypic models.

Genetic and environmental influences on thin-ideal internalization across puberty and preadolescent, adolescent, and young adult development.

Abstract: Thin-ideal internalization (i.e., the acceptance of and adherence to sociocultural beauty ideals for women that focus on thinness) is an important risk factor in the development of body dissatisfaction, disordered eating, and eating disorders (see 1; 2 for reviews of this literature .). Cross-sectional and prospective studies have supported the role of thin-ideal internalization in the development of eating problems (e.g., body dissatisfaction, dieting; 1.), and eating disorder prevention programs that target thin-ideal internalization have been effective in decreasing disordered eating (3.). However, as noted by others (4.), prevention programs could, and should, be improved further, particularly given their potential to decrease the development of eating disorders. Increasing knowledge on the etiology of thin-ideal internalization may be key to developing additional intervention techniques. Unfortunately, risk factors for thin-ideal internalization have been studied less frequently than risk factors for eating pathology (5–8.). Existing research has focused on the role of environmental risk factors that are thought to teach and reinforce beauty ideals of thinness, such as media images, parental and peer influences (5; 6.) Although research has demonstrated that hypothesized media, peer, and parental risk factors are indeed associated with thin-ideal internalization (5; 6.), further research is needed to confirm the direction of these effects, as current studies are limited by cross-sectional designs. In addition to environmental risk factors, twin research has demonstrated that genetic influences explain approximately 40% of the variance in thin-ideal internalization in a sample of post-pubertal adolescent and young adult twins (9.). Thus, genetic influences may explain why, despite almost ubiquitous exposure to the thin-ideal in Western countries, only some women ultimately internalize this ideal and go on to develop disordered eating behaviors (9.). More specifically, in the context of environmental risk factors (e.g., thin-ideal focused media) that nearly all women within Western culture experience, it may be level of genetic risk for thin-ideal internalization that differentiates those women who go on to internalize these ideals, and those who do not. Given that only one twin study of thin-ideal internalization has been conducted, further research is needed to extend knowledge of genetic and environmental effects. In particular, it is necessary to examine etiologic effects across adolescence, a key period for the development of thin-ideal internalization. Indeed, mean levels of thin-ideal internalization have been shown to increase across adolescence (9; 10.). The pubertal period appears to be particularly important in this regard, as girls in pre-to-early puberty report significantly lower levels of thin-ideal internalization than girls in mid-puberty and beyond (11.). These increases in mean levels of thin-ideal internalization may indicate key etiological shifts that should be examined as well. Indeed, related phenotypes, such as disordered eating, show significant etiological changes across this period, such that the heritability of disordered eating is negligible in pre-adolescence and pre-pubertal twins, but is significant (i.e., approximately 50% of variance) in pubertal twins and in twins who are in middle adolescence (i.e., about age 14) or older (i.e., ages 16–40 years; 12; 13; 14.). The effects of the shared environment are opposite of those observed for genetic influences: shared environmental influences account for 40% of the variance in disordered eating in pre-adolescence/pre-puberty, and 10% or less from middle adolescence into middle adulthood and in pubertal twins. These findings have been useful because they have led researchers to develop specific hypotheses regarding mechanisms that may account for differences in heritability across puberty, such as changes in ovarian hormones during puberty (15.). Given that adolescence also seems to be a key developmental period for thin-ideal internalization (11.), developmental twin studies of thin-ideal internalization may help elucidate etiological mechanisms that contribute to risk for thin-ideal internalization across development. The aim of the present study was to investigate the extent to which genetic and environmental influences on thin-ideal internalization differ across age and pubertal development in a large (N=1,064) sample of same-sex female twins (ages 8–25 years). To ensure that effects are specific to thin-ideal internalization, we examined developmental differences in genetic and environmental effects while controlling for disordered eating. Specificity of effects are important to establish given phenotypic and genetic overlap in thin-ideal internalization and disordered eating (16–18.) and the need to identify etiological risk factors that contribute uniquely to thin-ideal internalization.

In silico Derivation of HLA-Specific Alloreactivity Potential from Whole Exome Sequencing of Stem-Cell Transplant Donors and Recipients: Understanding the Quantitative Immunobiology of Allogeneic Transplantation.

Abstract: Donor T cell mediated graft versus host effects (GVH) may result from the aggregate alloreactivity to minor histocompatibility antigens (mHA) presented by the HLA molecules in each donor-recipient pair undergoing stem cell transplantation (SCT). Whole exome sequencing has previously demonstrated a large number of nonsynonymous single nucleotide polymorphisms (SNP) present in HLA-matched recipients of SCT donors (GVH direction). The nucleotide sequence flanking each of these SNPs was obtained and the amino acid sequence determined. All the possible nonameric-peptides incorporating the variant amino acid resulting from these SNPs were interrogated in-silico for their likelihood to be presented by the HLA class I molecules using the Immune Epitope Database stabilized matrix method (SMM) and NetMHCpan algorithms. The SMM algorithm predicted that a median of 18,396 peptides weakly bound HLA class I molecules in individual SCT recipients, and 2,254 peptides displayed strong binding. A similar library of presented peptides was identified when the data was interrogated using the NetMHCpan algorithm. The bioinformatic algorithm presented here demonstrates that there may be a high level of mHA variation in HLA-matched individuals, constituting an HLA-specific alloreactivity potential.

Whole exome sequencing to estimate alloreactivity potential between donors and recipients in stem cell transplantation.

Abstract: Whole exome sequencing (WES) was performed on stem cell transplant donor-recipient (D-R) pairs to determine the extent of potential antigenic variation at a molecular level. In a small cohort of D-R pairs, a high frequency of sequence variation was observed between the donor and recipient exomes independent of human leucocyte antigen (HLA) matching. Nonsynonymous, nonconservative single nucleotide polymorphisms were approximately twice as frequent in HLA-matched unrelated, compared with related D-R pairs. When mapped to individual chromosomes, these polymorphic nucleotides were uniformly distributed across the entire exome. In conclusion, WES reveals extensive nucleotide sequence variation in the exomes of HLA-matched donors and recipients.

Whole Exome Sequencing to Estimate Alloreactivity Potential Between Donors and Recipients in Stem Cell Transplantation

Abstract: Whole exome sequencing was performed on HLA-matched stem cell donors and transplant recipients to measure sequence variation contributing to minor histocompatibility antigen differences between the two. A large number of nonsynonymous single nucleotide polymorphisms were identified in each of the nine unique donor-recipient pairs tested. This variation was greater in magnitude in unrelated donors as compared with matched related donors. Knowledge of the magnitude of exome variation between stem cell transplant recipients and donors may allow more accurate titration of immunosuppressive therapy following stem cell transplantation.

Stem Cell Transplantation as a Dynamical System: Are Clinical Outcomes Deterministic?

Abstract: Outcomes in stem cell transplantation (SCT) are modeled using probability theory. However, the clinical course following SCT appears to demonstrate many characteristics of dynamical systems, especially when outcomes are considered in the context of immune reconstitution. Dynamical systems tend to evolve over time according to mathematically determined rules. Characteristically, the future states of the system are predicated on the states preceding them, and there is sensitivity to initial conditions. In SCT, the interaction between donor T cells and the recipient may be considered as such a system in which, graft source, conditioning, and early immunosuppression profoundly influence immune reconstitution over time. This eventually determines clinical outcomes, either the emergence of tolerance or the development of graft versus host disease. In this paper, parallels between SCT and dynamical systems are explored and a conceptual framework for developing mathematical models to understand disparate transplant outcomes is proposed.

Statistical properties of single-marker tests for rare variants.

Abstract: With the dramatic technological developments of genome-wide association single-nucleotide polymorphism (SNP) chips and next generation sequencing, human geneticists now have the ability to assay genetic variation at ever-rarer allele frequencies. To fully understand the impact of these rare variants on common, complex diseases, we must be able to accurately assess their statistical significance. However, it is well established that classical association tests are not appropriate for the analysis of low-frequency variation, giving spurious findings when observed counts are too few. To further our understanding of the asymptotic properties of traditional association tests, we conducted a range of simulations of a typical rare variant (~1%) under the null hypothesis and tested the allelic χ2, Cochran-Armitage trend, Wald, and Fisher's exact tests. We demonstrate that rare variation shows marked deviation from the expected distributional behavior for each test, with fewer minor alleles corresponding to a greater degree of test statistics deflation. The effect becomes more pronounced at progressively smaller α levels. We also show that the Wald test is particularly deflated at α levels consistent with genome-wide association significance, much more so than the other association tests considered. In general, these classical association tests are inappropriate for the analysis of variants for which the minor allele is observed fewer than 80 times, largely irrespective of sample size.

Obsessive compulsive symptom dimensions and neuroticism: An examination of shared genetic and environmental risk

Abstract: Individuals with obsessive compulsive disorder can display diverse and heterogeneous patterns of symptoms. Little is known about the relationship between obsessive-compulsive symptom (OCS) dimensions and normal personality traits, particularly those that increase risk for other internalizing disorders. In this study of 1,382 individuals from female-female twin pairs, we examined the relationship between self-report OCS dimensions derived from the Padua Inventory and Eysenck's personality traits neuroticism and extraversion. We conducted factor analysis to determine their phenotypic structure followed by twin analyses to determine their genetic and environmental sources of covariation. A three-factor solution, with dimensions corresponding to checking, aggressive obsessions, and contamination, was the best fit for the Padua OCS items. These dimensions were significantly and somewhat variably associated with neuroticism but negligibly associated with extraversion. The genetic correlations between neuroticism and these three OCS dimensions were moderate to high (0.66 with checking, 0.89 with aggressive obsessions, and 0.40 with contamination). However, the estimated genetic correlation between neuroticism and a unified latent OCS construct was smaller (0.32). Overall this study suggests that genetic, and to a smaller extent environmental, factors underlying neuroticism may act differentially as risk factors for OCS dimensions.

A further validation of the Minnesota Borderline Personality Disorder Scale.

Abstract: Previous research indicates that borderline personality disorder (BPD) is well conceptualized as a dimensional construct that can be represented using normal personality traits. A previous study successfully developed and validated a BPD measure embedded within a normal trait measure, the Minnesota Borderline Personality Disorder Scale (MBPD). The current study performed a further validation of the MBPD by examining its convergent validity, external correlates, and heritability in a sample of 429 female twins. The MBPD correlated strongly with the Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID-II) screener for BPD and moderately with external correlates. Moreover, the MBPD and SCID-II screener exhibited very similar patterns of external correlations. Additionally, results indicated that the genetic and environmental influences on MBPD overlap with the genetic and environmental influences on the SCID-II screener, which suggests that these scales are measuring the same construct. These data provide further evidence for the construct validity of the MBPD.

Genetic and Environmental Influences on the Prospective Correlation Between Systemic Inflammation and Coronary Heart Disease Death in Male Twins

Abstract: Objective— Because of lack of evidence, we aimed to examine to what degree low-grade systemic inflammation and coronary heart disease (CHD) death shared common genetic and environmental substrates. Approach and Results— From the 41-year prospective National Heart, Lung, and Blood Institute Twin Study, we included 950 middle-aged male twins at baseline (1969–1973). Low-grade systemic inflammation was measured with plasma levels of interleukin-6 (IL-6) and C-reactive protein. Univariate and bivariate structural equation models were used, adjusted for a risk score for CHD death. The score-adjusted heritability was 19% for IL-6, 27% for C-reactive protein, and 22% for CHD death. The positive phenotypic correlation of IL-6 with CHD death ( r adjusted =0.27; 95% confidence interval [CI], 0.08–0.43) was driven by additive genetic factors (contribution [relative contribution], 0.30 [111%]) but attenuated by unique environment (‒0.03 [‒11%]). The genetic correlation between IL-6 and CHD death was 0.74 (95% CI, 0.21–1.00), whereas the unique environmental correlation was ‒0.05 (95% CI, ‒0.35 to 0.25). The proportion of genetic variance for CHD death shared with that for IL-6 was 74%. The phenotypic correlation of C-reactive protein with CHD death ( r adjusted =0.10; 95% CI, ‒0.02 to 0.22) was explained by additive genetic factors (0.20 [149%]) but was attenuated by the unique environment (‒0.09 [‒49%]). The genetic correlation of C-reactive protein with CHD death was 0.63 (95% CI, ‒0.07 to 1.00), whereas the unique environmental correlation was ‒0.07 (95% CI, ‒0.29 to 0.17). Conclusions— Low-grade systemic inflammation, measured by IL-6, and long-term CHD death share moderate genetic substrates that augment both traits.

Moderating the covariance between family member's substance use behavior.

Abstract: Twin and family studies implicitly assume that the covariation between family members remains constant across differences in age between the members of the family However, age-specificity in gene expression for shared environmental factors could generate higher correlations between family members who are more similar in age Cohort effects (cohort × genotype or cohort × common environment) could have the same effects, and both potentially reduce effect sizes estimated in genome-wide association studies where the subjects are heterogeneous in age In this paper we describe a model in which the covariance between twins and non-twin siblings is moderated as a function of age difference We describe the details of the model and simulate data using a variety of different parameter values to demonstrate that model fitting returns unbiased parameter estimates Power analyses are then conducted to estimate the sample sizes required to detect the effects of moderation in a design of twins and siblings Finally, the model is applied to data on cigarette smoking We find that (1) the model effectively recovers the simulated parameters, (2) the power is relatively low and therefore requires large sample sizes before small to moderate effect sizes can be found reliably, and (3) the genetic covariance between siblings for smoking behavior decays very rapidly Result 3 implies that, eg, genome-wide studies of smoking behavior that use individuals assessed at different ages, or belonging to different birth-year cohorts may have had substantially reduced power to detect effects of genotype on cigarette use It also implies that significant special twin environmental effects can be explained by age-moderation in some cases This effect likely contributes to the missing heritability paradox

Comparing Factor, Class, and Mixture Models of Cannabis Initiation and DSM Cannabis Use Disorder Criteria, Including Craving, in the Brisbane Longitudinal Twin Study

Abstract: Accumulating evidence suggests that the Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnostic criteria for cannabis abuse and dependence are best represented by a single underlying factor. However, it remains possible that models with additional factors, or latent class models or hybrid models, may better explain the data. Using structured interviews, 626 adult male and female twins provided complete data on symptoms of cannabis abuse and dependence, plus a craving criterion. We compared latent factor analysis, latent class analysis, and factor mixture modeling using normal theory marginal maximum likelihood for ordinal data. Our aim was to derive a parsimonious, best-fitting cannabis use disorder (CUD) phenotype based on DSM-IV criteria and determine whether DSM-5 craving loads onto a general factor. When compared with latent class and mixture models, factor models provided a better fit to the data. When conditioned on initiation and cannabis use, the association between criteria for abuse, dependence, withdrawal, and craving were best explained by two correlated latent factors for males and females: a general risk factor to CUD and a factor capturing the symptoms of social and occupational impairment as a consequence of frequent use. Secondary analyses revealed a modest increase in the prevalence of DSM-5 CUD compared with DSM-IV cannabis abuse or dependence. It is concluded that, in addition to a general factor with loadings on cannabis use and symptoms of abuse, dependence, withdrawal, and craving, a second clinically relevant factor defined by features of social and occupational impairment was also found for frequent cannabis use.

Dynamical System Modeling Of Immune Reconstitution Following Allogeneic Stem Cell Transplantation Identifies Patients At Risk For Adverse Outcomes

Abstract: Systems that evolve over time and follow mathematical laws as they do so, are called dynamical systems. Lymphocyte recovery and clinical outcomes in 41 allograft recipients conditioned using anti-thymocyte globulin (ATG) and 4.5 Gray total-body-irradiation were studied to determine if immune reconstitution could be described as a dynamical system. Survival, relapse, and graft vs. host disease (GVHD) were not significantly different in two cohorts of patients receiving different doses of ATG. However, donor-derived CD3+ (ddCD3) cell reconstitution was superior in the lower ATG dose cohort, and there were fewer instances of donor lymphocyte infusion (DLI). Lymphoid recovery was plotted in each individual over time and demonstrated one of three sigmoid growth patterns; Pattern A (n=15), had rapid growth with high lymphocyte counts, pattern B (n=14), slower growth with intermediate recovery and pattern C, poor lymphocyte reconstitution (n=10). There was a significant association between lymphocyte recovery patterns and both the rate of change of ddCD3 at day 30 post-SCT and the clinical outcomes. GVHD was observed more frequently with pattern A; relapse and DLI more so with pattern C, with a consequent survival advantage in patients with patterns A and B. We conclude that evaluating immune reconstitution following SCT as a dynamical system may differentiate patients at risk of adverse outcomes and allow early intervention to modulate that risk.

The contributions of Lindon Eaves to psychiatric genetics.

Abstract: The contributions of Lindon Eaves to the field of Psychiatric Genetics can be best understood from an historical perspective. Modern psychiatric genetics began in the ‘‘Genealogic-Demographic Department’’ of the German Research Institute for Psychiatry, established by the then famous German Psychiatrist, Emil Kraepelin, in the years immediately before the First World War (Zerbin-Rudin and Kendler 1996). This department was headed by Ernst Rüdin, a young psychiatrist conversant with the then new and exciting laws of Mendel. Over the subsequent 20 years, with a range of collaborators and visitors (including most of the leaders of the next generation of psychiatric genetics throughout Europe, such as Stromgren and Slater), the Genealogic-Demographic Department conducted methodologically cutting edge psychiatric genetics research (Zerbin-Rudin and Kendler 1996). Working with Weinberg, Rüdin and his colleagues conducted a range of family and twin studies that incorporated key methodological advances, including the use of the proband correction method (to obtain correct risk figures), the abridged Weinberg age correction method (to correct for what we would now call the problem of age dependent penetrance) and systematic ascertainment methods with appropriate concern about the clear specification of the sampling frame. While this story is darkened by later involvement of Rüdin’s department with the rising Nazi power in Germany in the 1930s, at its inception, psychiatric genetics in Europe was closely connected with the latest developments in Statistical Genetics. However, nothing similar was then underway in the United States. The early pioneers in psychiatric and behavioral genetics—especially Davenport and Rosanoff— were far from the cutting edge. Davenport was an overzealous Mendelizer—seeing Mendelian traits in all sorts of behaviors, of which my favorite example is ‘‘nomadism’’ aka ‘‘the wandering impulse’’ (Davenport 1915). Rosanoff conducted the first twin studies of psychiatric illness in the US, but had a very unsystematic method of ascertainment that was always certainly substantially biased (Rosanoff et al. 1934; Rosanoff and Orr 1911). With a notable few exceptions, after the demise of Rüdin’s institute in the Second World War, psychiatric genetics parted company from statistical genetics that, over the course of the twentieth century, became increasingly a British-dominated discipline. Two ‘‘schools’’ of statistical or biometrical genetics emerged over this time in the UK— one based in Edinburgh and the other in Birmingham. (While the field has seen much dispute about the intellectual merits of these two schools, we will not here attempt to adjudicate this question.) The latter was dominated by Kenneth Mather, perhaps the most prominent of the students trained by the great population and statistical geneticist, Ronald Fisher. Douglas Falconer was probably the best known of the statistical geneticists of the ‘‘Edinburgh School’’ in part through his widely read and influential book ‘‘Introduction to Quantitative Genetics’’ (Falconer 1989). Our story turns now to Washington University St Louis, where a hard-nosed empirical school of psychiatry was K. S. Kendler (&) Department of Psychiatry, Department of Human and Molecular Genetics, Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University Medical School, Box 980126, 800 E. Leigh Street, Room 1-123, Richmond, VA 23298-0126, USA e-mail: kendler@hsc.vcu.edu

Latent Classiness and Other Mixtures

Abstract: The aim of this article is to laud Lindon Eaves’ role in the development of mixture modeling in genetic studies. The specification of models for mixture distributions was very much in its infancy when Professor Eaves implemented it in his own FORTRAN programs, and extended it to data collected from relatives such as twins. It was his collaboration with the author of this article which led to the first implementation of mixture distribution modeling in a general-purpose structural equation modeling program, Mx, resulting in a 1996 article on linkage analysis in Behavior Genetics. Today, the popularity of these methods continues to grow, encompassing methods for genetic association, latent class analysis, growth curve mixture modeling, factor mixture modeling, regime switching, marginal maximum likelihood, genotype by environment interaction, variance component twin modeling in the absence of zygosity information, and many others. This primarily historical article concludes with some consideration of some possible future developments.

Lindon J. Eaves, Ph.D., M.A. (Oxon), D.Sc. Theory-Model-Data

Abstract: We begin this special issue by providing a glimpse into the career of Dr. Lindon J. Eaves, from the perspectives of a student, postdoc, instructor, assistant to associate and full professor over the last 20 odd years. We focus primarily on Lindon’s contributions to methodological issues and research designs to address them, in particular those related to models for extended twin-family designs, for the development of adolescent behavior, for genotype-environment covariation and interaction, and their application to the Virginia 30,000 and the Virginia Twin Study of Adolescent Behavioral Development. We then introduce the collection of papers in this special festschrift issue of Behavior Genetics, celebrating Dr. Eaves achievements over the last 40 years.

OpenMx Reference Manual

Abstract: Collate MxData.R DefinitionVars.R MxReservedNames.R MxNamespace.R MxSearchReplace.R MxFlatSearchReplace.R MxUntitled.R MxCharOrNumber.R MxAlgebraFunctions.R MxMatrix.R DiagMatrix.R FullMatrix.R IdenMatrix.R LowerMatrix.R SdiagMatrix.R StandMatrix.R SymmMatrix.R UnitMatrix.R ZeroMatrix.R MxAlgebra.R MxCycleDetection.R MxAlgebraConvert.R MxSquareBracket.R MxEval.R MxRename.R MxPath.R MxObjectiveFunction.R MxBounds.R MxConstraint.R MxInterval.R MxTypes.R MxModel.R MxRAMModel.R MxModelDisplay.R MxFlatModel.R MxMultiModel.R MxModelFunctions.R MxModelParameters.R MxUnitTesting.R MxAlgebraObjective.R MxRowObjective.R MxFIMLObjective.R MxMLObjective.R MxRAMObjective.R MxRObjective.R MxApply.R MxRun.R MxSummary.R MxCompare.R MxSwift.R MxOptions.R MxThreshold.R OriginalMx.R MxGraph.R MxGraphviz.R MxDeparse.R MxCommunication.R MxRestore.R MxVersion.R zzz.R