Reverse-translational biomarker validation of Abnormal Repetitive Behaviors in mice: an illustration of the 4P's modeling approach

The NIMH's new strategic plan, with its emphasis on the "4P's" (Prediction, Pre-emption, Personalization, and Populations) and biomarker-based medicine requires a radical shift in animal modeling methodology. In particular 4P's models will be non-determinant (i.e. disease severity will depend on secondary environmental and genetic factors); and validated by reverse-translation of animal homologues to human biomarkers. A powerful consequence of the biomarker approach is that different closely related disorders have a unique fingerprint of biomarkers. Animals can be validated as a highly specific model of a single disorder by matching this 'fingerprint'; or as a model of a symptom seen in multiple disorders by matching common biomarkers. Here we illustrate this approach with two Abnormal Repetitive Behaviors (ARBs) in mice: stereotypies and barbering (hair pulling). We developed animal versions of the neuropsychological biomarkers that distinguish human ARBs, and tested the fingerprint of the different mouse ARBs. As predicted, the two mouse ARBs were associated with different biomarkers. Both barbering and stereotypy could be discounted as models of OCD (even though they are widely used as such), due to the absence of limbic biomarkers which are characteristic of OCD and hence are necessary for a valid model. Conversely barbering matched the fingerprint of trichotillomania (i.e. selective deficits in set-shifting), suggesting it may be a highly specific model of this disorder. In contrast stereotypies were correlated only with a biomarker (deficits in response shifting) correlated with stereotypies in multiple disorders, suggesting that animal stereotypies model stereotypies in multiple disorders.

Relations between the attentional blink and aspects of psychometric intelligence: A fixed-links modeling approach

The attentional blink phenomenon (AB) represents impaired identification of the second of two targets presented in rapid succession within a stream of stimuli. Despite the well-known association between attentional processes and psychometric intelligence (PI), evidence for a relationship between AB and PI is highly inconsistent. Theory and empirical findings suggest AB to be multifaceted. Hence, relations between AB and PI may be blurred when AB is measured as a single process. Furthermore, different aspects of PI might be differentially related to AB. The present study explored the relationship between processes underlying AB and general PI as well as specific aspects of PI (Reasoning, Speed, Memory, and Creativity) in 201 female students. Fixed-links modeling revealed three processes underlying AB: (1) a U-shaped process positively related to Speed and negatively related to Memory but unrelated to Reasoning, Creativity, and general PI, (2) an increasing process positively related to Reasoning, Speed, Memory, and general PI but not to Creativity, and (3) a decreasing process positively related to general PI and Memory but not to other aspects of PI. Our findings demonstrate that dissociating processes underlying AB and considering specific aspects of PI is required to understand the relationship between AB and PI.

The Assessment of Multiple Processes Underlying the Attentional Blink: A Fixed - links Modeling Approach based on Behavioral and Electrophysiological Data

When observers are presented with two visual targets appearing in the same position in close temporal proximity, a marked reduction in detection performance of the second target has often been reported, the so-called attentional blink phenomenon. Several studies found a similar decrement of P300 amplitudes during the attentional blink period as observed with detection performances of the second target. However, whether the parallel courses of second target performances and corresponding P300 amplitudes resulted from the same underlying mechanisms remained unclear. The aim of our study was therefore to investigate whether the mechanisms underlying the AB can be assessed by fixed-links modeling and whether this kind of assessment would reveal the same or at least related processes in the behavioral and electrophysiological data. On both levels of observation three highly similar processes could be identified: an increasing, a decreasing and a u-shaped trend. Corresponding processes from the behavioral and electrophysiological data were substantially correlated, with the two u-shaped trends showing the strongest association with each other. Our results provide evidence for the assumption that the same mechanisms underlie attentional blink task performance at the electrophysiological and behavioral levels as assessed by fixed-links models.

The Relationship Between Sociosexuality and Aspects of Body Image in Men and Women: A Structural Equation Modeling Approach

The present study investigated the association between individual differences in sociosexual orientation and four aspects of body image in 156 male and 136 female students. While men were characterized by a less restricted sociosexual orientation, higher self-perceived physical attractiveness, and more pronounced self-rated physical assertiveness, women placed more emphasis on accentuation of body presentation. Structural equation modeling revealed significant positive relationships between sociosexual attitudes and physical attractiveness and accentuation of body presentation as well as between sociosexual behavior and physical attractiveness for the total sample. When introducing sex as a grouping variable, the attitudinal and behavioral components of sociosexuality were reliably related to both physical attractiveness and accentuation of body presentation as two aspects of body image in men, but not in women. Furthermore, our findings suggest that accentuation of body presentation represents a goal-directed behavior in men to increase the likelihood of having uncommitted sex but serves additional functions widely unrelated to unrestrictive sociosexual behavior in women.

Elucidating the Functional Relationship Between Working Memory Capacity and Psychometric Intelligence: A Fixed-Links Modeling Approach for Experimental Repeated-Measures Designs

Numerous studies reported a strong link between working memory capacity (WMC) and fluid intelligence (Gf), although views differ in respect to how close these two constructs are related to each other. In the present study, we used a WMC task with five levels of task demands to assess the relationship between WMC and Gf by means of a new methodological approach referred to as fixed-links modeling. Fixed-links models belong to the family of confirmatory factor analysis (CFA) and are of particular interest for experimental, repeated-measures designs. With this technique, processes systematically varying across task conditions can be disentangled from processes unaffected by the experimental manipulation. Proceeding from the assumption that experimental manipulation in a WMC task leads to increasing demands on WMC, the processes systematically varying across task conditions can be assumed to be WMC-specific. Processes not varying across task conditions, on the other hand, are probably independent of WMC. Fixed-links models allow for representing these two kinds of processes by two independent latent variables. In contrast to traditional CFA where a common latent variable is derived from the different task conditions, fixed-links models facilitate a more precise or purified representation of the WMC-related processes of interest. By using fixed-links modeling to analyze data of 200 participants, we identified a non-experimental latent variable, representing processes that remained constant irrespective of the WMC task conditions, and an experimental latent variable which reflected processes that varied as a function of experimental manipulation. This latter variable represents the increasing demands on WMC and, hence, was considered a purified measure of WMC controlled for the constant processes. Fixed-links modeling showed that both the purified measure of WMC (β = .48) as well as the constant processes involved in the task (β = .45) were related to Gf. Taken together, these two latent variables explained the same portion of variance of Gf as a single latent variable obtained by traditional CFA (β = .65) indicating that traditional CFA causes an overestimation of the effective relationship between WMC and Gf. Thus, fixed-links modeling provides a feasible method for a more valid investigation of the functional relationship between specific constructs.

A fixed-links modeling approach to assess individual differences in the attentional blink: Analysis of behavioral and psychophysiological data

The attentional blink (AB) is a fundamental limitation of the ability to select relevant information from irrelevant information. It can be observed with the detection rate in an AB task as well as with the corresponding P300 amplitude of the event-related potential. In previous research, however, correlations between these two levels of observation were weak and rather inconsistent. A possible explanation of this finding might be that multiple processes underlie the AB and, thus, obscure a possible relationship between AB-related detection rate and the corresponding P300 amplitude. The present study investigated this assumption by applying a fixed-links modeling approach to represent behavioral individual differences in the AB as a latent variable. Concurrently, this approach enabled us to control for additional sources of variance in AB performance by deriving two additional latent variables. The correlation between the latent variable reflecting behavioral individual differences in AB magnitude and a corresponding latent variable derived from the P300 amplitude was high (r=.70). Furthermore, this correlation was considerably stronger than the correlations of other behavioral measures of the AB magnitude with their psychophysiological counterparts (all rs<.40). Our findings clearly indicate that the systematic disentangling of various sources of variance by utilizing the fixed-links modeling approach is a promising tool to investigate behavioral individual differences in the AB and possible psychophysiological correlates of these individual differences.

The position effect in a Rasch-homogenous test: A fixed-links modeling approach.

The position effect describes the influence of just-completed items in a psychological scale on subsequent items. This effect has been repeatedly reported for psychometric reasoning scales and is assumed to reflect implicit learning during testing. One way to identify the position effect is fixed-links modeling. With this approach, two latent variables are derived from the test items. Factor loadings of one latent variable are fixed to 1 for all items to represent ability-related variance. Factor loadings on the second latent variable increase from the first to the last item describing the position effect. Previous studies using fixed-links modeling on the position effect investigated reasoning scales constructed in accordance with classical test theory (e.g., Raven’s Progressive Matrices) but, to the best of our knowledge, no Rasch-scaled tests. These tests, however, meet stronger requirements on item homogeneity. In the present study, therefore, we will analyze data from 239 participants who have completed the Rasch-scaled Viennese Matrices Test (VMT). Applying a fixed-links modeling approach, we will test whether a position effect can be depicted as a latent variable and separated from a latent variable representing basic reasoning ability. The results have implications for the assumption of homogeneity in Rasch-homogeneous tests.

Differences in grain growth of calcite: a field-based modeling approach

Normal grain growth of calcite was investigated by combining grain size analysis of calcite across the contact aureole of the Adamello pluton, and grain growth modeling based on a thermal model of the surroundings of the pluton. In an unbiased model system, i.e., location dependent variations in temperature-time path, 2/3 and 1/3 of grain growth occurs during pro- and retrograde metamorphism at all locations, respectively. In contrast to this idealized situation, in the field example three groups can be distinguished, which are characterized by variations in their grain size versus temperature relationships: Group I occurs at low temperatures and the grain size remains constant because nano-scale second phase particles of organic origin inhibit grain growth in the calcite aggregates under these conditions. In the presence of an aqueous fluid, these second phases decay at a temperature of about 350 °C enabling the onset of grain growth in calcite. In the following growth period, fluid-enhanced group II and slower group III growth occurs. For group II a continuous and intense grain size increase with T is typical while the grain growth decreases with T for group III. None of the observed trends correlate with experimentally based grain growth kinetics, probably due to differences between nature and experiment which have not yet been investigated (e.g., porosity, second phases). Therefore, grain growth modeling was used to iteratively improve the correlation between measured and modeled grain sizes by optimizing activation energy (Q), pre-exponential factor (k0) and grain size exponent (n). For n=2, Q of 350 kJ/mol, k0 of 1.7×1021 μmns−1 and Q of 35 kJ/mol, k0 of 2.5×10-5 μmns−1 were obtained for group II and III, respectively. With respect to future work, field-data based grain growth modeling might be a promising tool for investigating the influences of secondary effects like porosity and second phases on grain growth in nature, and to unravel differences between nature and experiment.

BVD eradication in Switzerland - a new approach

Diverse concepts for BVD eradication or control have been applied in several countries with varying success. Results of previous studies conducted in Switzerland have shown that the prevalence of antibody-positive animals is high and that BVDV is widespread in the country causing serious economic losses. A new approach to eradicate BVD in the cattle population in Switzerland was chosen. It consists in testing the whole Swiss cattle population for virus detection in a short period of time, without initial antibody screening. Identified persistently infected (PI) animals have to be slaughtered, and new herd infections should be avoided by movement restrictions. Ear-notches are collected using special tags for labeling the animals, and are analyzed using ELISA or rtRT-PCR methods. Confirmatory tests if needed are performed on blood samples using rtRT-PCR. The eradication program is divided into four phases: (1) Pre-pasturing phase: all young bovines going to transhumance in summer have to be negative tested before. (2) Initial phase: all non-tested bovines have to be tested. Movement restrictions are effective at the same time. (3) Calves phase: all newborn calves have to be tested. (4) Surveillance phase: several strategies will be compared using a modeling approach. After the pre-pasture phase already 595,230 animals (37% of the livestock) have been tested within four months. A prevalence of 1.1% of PIs was observed. The average age of infected animals is 403 days compared to 794 days for non-infected animals, with the oldest PI-animal being over 11 years old. On average PI-animals are slaughtered within 18 days after the last positive result. The pre-pasture phase has shown that sampling and testing a high number of animals in a short time is challenging but possible. The next phase will deal with double the number of animals in a similar time frame. The coordination between all partners as well as the collaboration of farmers is the key factor for ensuring the success of the program.