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Bayesian analysis of binary prediction tree models for retrospectively sampled outcomes.

Classification tree models are flexible analysis tools which have the ability to evaluate interactions among predictors as well as generate predictions for responses of interest. We describe Bayesian analysis of a specific class of tree models in which binary response data arise from a retrospective case-control design. We are also particularly interested in problems with potentially very many candidate predictors. This scenario is common in studies concerning gene expression data, which is a key motivating example context. Innovations here include the introduction of tree models that explicitly address and incorporate the retrospective design, and the use of nonparametric Bayesian models involving Dirichlet process priors on the distributions of predictor variables. The model specification influences the generation of trees through Bayes' factor based tests of association that determine significant binary partitions of nodes during a process of forward generation of trees. We describe this constructive process and discuss questions of generating and combining multiple trees via Bayesian model averaging for prediction. Additional discussion of parameter selection and sensitivity is given in the context of an example which concerns prediction of breast tumour status utilizing high-dimensional gene expression data; the example demonstrates the exploratory/explanatory uses of such models as well as their primary utility in prediction. Shortcomings of the approach and comparison with alternative tree modelling algorithms are also discussed, as are issues of modelling and computational extensions.

Algorithms↗

Biomechanical models for vibration feedthrough to hands and head for a semisupine pilot.

A series of tracking experiments under vibration has been carried out on the AMRL/BBV shaker facilities covering three axes of vibration with sinusoidal and random waveforms and different control stick configurations. Based on this and other data, a lumped-parameter biomechanical model has been evolved to suit the needs of aircraft control system designers for the new generation of low-altitude, high-speed bombers and highly maneuverable fighters. This paper shows that measured vibration feedthrough to hands and head can be adequately described by this model when linearized about the appropriate configuration of display, posture, and control. The model includes effects of: semisupine torso; sliding hip, plus rocking chest supported on a compliant buttocks/seat; head bobbing on an articulated neck; upper arm and forearm links plus grip-interface compliance, driven by an active neuromuscular system; elbow rest (optional); and stick "feel system" dynamics. Examples are given of the model's application to predict effects of: a 65 degrees semisupine seat, apparent impedance increase of a control stick under pilot control, and a sliding arm rest.

Aerospace Medicine↗

Artificial neural networks as models of stimulus control.

We evaluate the ability of artificial neural network models (multilayer perceptrons) to predict stimulus-response relationships. A variety of empirical results are considered, such as generalization, peak shift (supernormality) and stimulus intensity effects. The networks were trained on the same tasks as the animals in the experiments considered. The subsequent generalization tests on the networks showed that the model replicates correctly the empirical results. We conclude that these models are valuable tools in the study of animal behaviour. (c) 1998 The Association for the Study of Animal Behaviour.

Journal Article↗

State detection and control of overloads in the anaerobic wastewater treatment using fuzzy logic.

The two-stage anaerobic wastewater pre-treatment was modelled and controlled. The biological state of the reactors could be predicted using a fuzzy logic system and based upon this, proper control actions were taken automatically in order to avoid an overload. The system was designed to handle very strong fluctuations in the concentration of the substrate and the volumetric loading rate. Hydrogen concentration together with methane concentration, gas production rate. pH and the filling level of the acidification buffer tank were used as input variables for the fuzzy logic system. The manipulated variables were the flow rate from the acidification buffer tank into the methane reactor, the temperature and pH of both reactors, the circulation rate of the fixed bed reactor, back flow from the methane reactor into the acidification, and the control of the feed into the acidification buffer tank. The developed control system was successfully tested on a fully automated lab scale two-stage anaerobic digester. Different types of wastewater from food processing industries were successfully applied. Even a restart of feeding with very high COD concentrations (100 gl(-1) after several days of stand by was handled successfully. Effluent concentrations could be kept low without using TOC, COD or equivalent measurements.

Bacteria, Anaerobic↗

Application of the linear-quadratic model to combined modality radiotherapy.

PURPOSE: Methods of performing dosimetry for a combined modality radiotherapy (CMRT) consisting of a targeted radionuclide therapy (TRT) and separately delivered external beam therapy (EBT) have been established using the biologically effective dose (BED). However, a concurrent delivery of the two therapies may influence the radiobiologic effect of the treatment resulting from interaction between the therapies, and this situation has been modeled to assess the likely consequences of this regime. METHODS AND MATERIALS: A general form of the linear-quadratic model with a dose protraction factor was applied to concurrent delivery of EBT and TRT. Contributions to total BED from intra- and intermodality effects were calculated, and parameter values varied to determine conditions under which the intermodality contributions were likely to be most significant. A Poisson model of tumor control probability (TCP) was used to assess the predicted effect of concurrent delivery on treatment outcome. RESULTS: In general, over a wide range of parameter values, the effect of intermodality interactions in CMRT is small, increasing total BED delivered to tumor by approximately 1%, and producing a negligible increase in TCP. Synergistic effects could be greater in normal tissues if high doses were received from both therapies, with intermodality terms increasing total BED delivered by approximately 6% in the general case, and by approximately 18% for the case of slow repair in the spinal cord. A significant synergistic effect was predicted between EBT and I-125 seed therapy of the prostate when values of alpha/beta = 1.2 Gy, alpha = 0.026 Gy, mu = 0.36 h(-1) and N(0) = 138 clonogens were used, with TCP increasing from approximately 0.5 to 0.6. CONCLUSIONS: Under most clinical conditions, the relative temporal delivery of these two therapies is unlikely to significantly influence the overall radiobiologic effect to tumor at the cellular level. Synergistic effects may, however, be more significant in normal tissues and for tumors with low values of alpha/beta and alpha.

Combined Modality Therapy↗

The neural basis of hallucinations and delusions.

Schizophrenia is a biologically based disorder characterised by false perceptions (hallucinations) and false beliefs (delusions). The underlying physiological cause of these mental abnormalities remains unknown. There is increasing evidence that one class of symptom, the 'made experiences' including delusions of alien control and thought insertion, is associated with abnormalities in the mechanism that predicts the outcome of intended actions (the forward model). For these patients active movements feel like passive movements. As a result these patients do not feel in control of their actions. However, comparison with various neurological disorders, such as those associated with parietal lobe lesions, suggest that this abnormal experience is not sufficient to explain the feeling that some other agent is controlling is one's actions. Preliminary evidence suggests that patients with schizophrenia have an exaggerated sense of agency. In combination with the feeling of not being in control, this exaggerated sense of agency could explain delusions of alien control in which the patient attributes his own actions to another agent. Little is yet know about the neural basis of the predictive mechanisms that create the feeling that we are in control of our movements. Such prediction requires integration of information about intended movements generated in frontal cortex with sensory processing in posterior regions of the brain. Measures of functional connectivity suggest that long-range interactions between frontal and posterior regions are abnormally reduced in patients with schizophrenia. Further research is needed to explore the precise involvement of long-range connections in the mechanisms of forward modelling.

Animals↗

CIS: compound importance sampling method for protein-DNA binding site p-value estimation.

MOTIVATION: A key aspect of transcriptional regulation is the binding of transcription factors to sequence-specific binding sites that allow them to modulate the expression of nearby genes. Given models of such binding sites, one can scan regulatory regions for putative binding sites and construct a genome-wide regulatory network. In such genome-wide scans, it is crucial to control the amount of false positive predictions. Recently, several works demonstrated the benefits of modeling dependencies between positions within the binding site. Yet, computing the statistical significance of putative binding sites in this scenario remains a challenge. RESULTS: We present a general, accurate and efficient method for computing p-values of putative binding sites that is applicable to a large class of probabilistic binding site and background models. We demonstrate the accuracy of the method on synthetic and real-life data. AVAILABILITY: The procedure for scanning DNA sequences and computing the statistical significance of putative binding site scores is available upon request at http://compbio.cs.huji.ac.il/CIS/ CONTACT: nir@cs.huji.ac.il.

Algorithms↗

A processes of change model for weight control for participants in community-based weight loss programs.

The processes of change model has been successful in predicting behavior change across a wide range of both addictive and nonaddictive problem behaviors. This study was designed to examine the application of the processes of change model to weight control. Study participants included 285 women and men enrolled in three community-based weight loss programs. Results based on structural equation analyses showed that the processes of change model fit the data better than several plausible alternative models. In addition, structural analyses revealed the existence of two general (higher order) processes of change for weight control, the experiential and behavioral processes. These results are similar to those previously reported for eight other problem behaviors. Limitations of the current work and future directions for this line of research are discussed.

Adolescent↗

Plasma phospholipid metabolic profiling and biomarkers of type 2 diabetes mellitus based on high-performance liquid chromatography/electrospray mass spectrometry and multivariate statistical analysis.

Liquid chromatography/mass spectrometry (LC/MS) followed by multivariate statistical analysis has been successfully applied to the plasma phospholipids metabolic profiling in type 2 diabetes mellitus (DM-2). Principal components analysis and partial least-squares discriminant analysis (PLS-DA) models were tested and compared in class separation between the DM2 and control. The application of an orthogonal signal correction filtered model highly improved the class distinction and predictive power of PLS-DA models. Additionally, unit variance scaling was also tested. With this methodology, it was possible not only to differentiate the DM2 from the control but also to discover and identify the potential biomarkers with LC/MS/MS. The proposed method shows that LC/MS combining with multivariate statistical analysis is a complement or an alternative to NMR for metabonomics applications.

Biomarkers↗

Abnormal resonance behavior of the postural control loop in Parkinson's disease.

Human postural control of upright stance sporadically can show an oscillatory behavior. Based on previous work, we assessed whether an abnormal tendency for such oscillations might contribute to the motor impairments in patients with basal ganglia dysfunction such as Parkinson's disease (PD). We investigated postural control during unperturbed stance in normal control subjects and in PD patients off and under treatment, focusing on stabilogram diffusion analysis (SDA) of the foot center of pressure (COP) excursions and conventional measures of the sway amplitude and velocity. We found abnormal 1 Hz body sway oscillation in the SDA curves of PD patients that differed significantly from the body sway typically observed in control subjects during quiet stance. The 1 Hz body sway oscillation was associated with abnormally large and fast sway in the patients off treatment. Under treatment with levodopa, with 'deep brain stimulation' (subthalamic nucleus) and even more so with combined treatment, the oscillations in the SDA curves vanished and the sway became slower. The loss of oscillation and reduction of sway velocity were highly correlated with the improvements of patients' clinical motor assessment score. However, sway amplitude was not correlated with the patients' motor assessment score and patients reported clinical improvement under therapy even though sway amplitude increased on average. A simple feedback model of the postural control system with abnormally large internal noise could predict experimental measures both on and off treatment. The off treatment condition was consistent with a high motor gain in the feedback loop, and the on treatment condition with a reduced motor gain.

Basal Ganglia↗

Developmental toxicity of mixtures: the water disinfection by-products dichloro-, dibromo- and bromochloro acetic acid in rat embryo culture.

The chlorination of drinking water results in production of numerous disinfection by-products (DBPs). One of the important classes of DBPs is the haloacetic acids. We have previously shown that the haloacetic acids (HAs), dichloro (DCA), dibromo (DBA) and bromochloro (BCA) acetic acid are developmentally toxic in mouse whole embryo culture. Human exposure to these contaminants in drinking water would involve simultaneous exposure to all three HAs. This study explores the question of developmental toxicity interactions between these compounds. Gestational day (GD) 9.5 rat embryos were exposed to various concentrations of the three HAs (singly or in combination) for 48 h and then evaluated for dysmorphology. The embryonic effects from exposure to the single compounds and mixtures were evaluated using developmental score (DEVSC) as the parameter of comparison. Concentrations of individual compounds and mixtures were chosen (based on a dose-additivity model) which were predicted to produce scores 10 or 20% lower than control levels. Evaluations were performed on all possible combinations of the three HAs. The HAs were dysmorphogenic and resulted in primarily rotation and heart defects and to a lesser extent prosencephalic, visceral arch, and eye defects. The percent anomalies in the rat were comparable to those previously published for the mouse at comparable toxicant concentration. There was a low incidence of neural tube defects in the rat following exposure to the HAs. The rat neural tube appeared less sensitive to the HAs than did the mouse resulting in a higher rate of neural tube dysmorphology in the mouse. Following exposures to BCA and DBA, alone and in combination, there was a significant incidence of delayed embryonic caudal development with apparent normal development anterior to the second visceral arch. The developmental scores for embryos exposed to combinations of the three compounds, when compared to scores for embryos exposed to the single compounds, indicated that the dose-additivity model adequately predicted the observed toxicity and that the developmental toxicity of these water disinfection by-products appears to be additive in whole embryo culture (WEC).

Abnormalities, Drug-Induced↗

Deciding when and how to correct a movement: discrete submovements as a decision making process.

Rapid reaching movements of human and non-human primates are often characterized by irregular multi-peaked velocity profiles. How to interpret these irregularities is still under debate. While some reports assert that these irregularities are the result of a continuous controller interacting with the environment, we and others hold that the velocity irregularities are evidence for a controller that produces discrete movement corrections. Here we analyze rapid pronation/supination wrist movements in monkey during a 1D step-tracking task, where visual perturbations of the target were randomly introduced at movement onset. We use our recently introduced algorithm (Fishbach et al. in Exp Brain Res 164:442-457, 2005) to decompose an irregular movement into a primary movement and one or more discrete, corrective submovements. We first show that the visual perturbation has almost no effect on primary movements. In contrast, this perturbation influences the type and the extent of the corrective submovements that often follow primary movements. Secondly, we show that the highly variable timing of overlapping submovements does not depend directly on the visual perturbation but rather on an estimate of the movement error and on the movement's extent-to-go at the time of correction initiation. These results are consistent with a forward-model based intermittent controller with a non-linearity that depends both on a prediction of the magnitude and direction of the movement's error and on its variance. Corrections are initiated only when the predicted error is statistically significant. A simple abstract model that implements these principles accounts for the type and timing of the corrections observed in our data.

Algorithms↗

PTSD and Treatment Adherence: the role of health beliefs.

Health beliefs have been shown to influence a myriad of medical treatment decisions. More recently, the impact of health beliefs on treatment decisions for mental illness has become a focus of study. This study examines the health beliefs and treatment behavior of veterans with posttraumatic stress disorder (PTSD). Using standard survey methodology, we assessed beliefs about the cause of PTSD, expected duration and controllability of symptoms, and life consequences of having PTSD. Treatment participation and medication compliance were assessed, as were common treatment correlates, such as patient-provider relationships, dosing frequency, side effect severity, number of prescribed medications, and use of drugs or alcohol to control PTSD symptoms. Explanatory models of PTSD, perceived controllability, and use of benzodiazepines were found to predict psychiatric medication use. Negative life consequences of PTSD were associated with participation in psychotherapy. Assessment of health beliefs may help providers to understand their patients' treatment behavior and to facilitate treatment engagement.

Antipsychotic Agents↗

Corticotrophin-releasing hormone and fetal responses in human pregnancy.

During human pregnancy, maternal and fetal compartments of the human placenta produce and release corticotrophic-releasing hormone (CRH). Elevations of placental CRH are associated with decreased gestational length (including preterm delivery). The effects of elevated placental CRH on human fetal neurological development are not known. Pregnant women in the 31st and 32nd week of gestation consented to procedures for collection of blood and measurement of fetal heart rate (FHR) in response to a series of 40 vibro-acoustic stimuli (VAS). Measures of habituation and dishabituation were calculated from the FHR. All subjects were followed to delivery. Fetuses (N = 33) of women with highly elevated CRH were least responsive (p < .03) to stimulation after presentation of a novel (dishabituating) stimulus with control for parity, fetal gender, medical (antepartum) risk, and gestational length at term. In a larger sample (N = 156) a polynomial model predicted the pattern of FHR reactivity for the first 15 trials. Placental CRH concentration significantly predicted FHR reactivity after controlling for the effects of trial number, baseline FHR, inter-trial interval, and presence of uterine contractions. Increased maternal CRH levels were significantly related to the length of gestation after controlling for the effects of fetal gender, parity, and medical risk (p = .05). The relationship between length of gestation and FHR was not significant suggesting separate actions of CRH on these events. Elevated placental CRH appears to accelerate certain developmental events (gestational length) and may influence the fetal nervous system. The impaired fetal responses to novelty and increased arousal observed in this study suggest that neurological systems may be targets for placental CRH during sensitive developmental periods.

Body Constitution↗

Simulated limnological effects of the Shasta Lake temperature control device.

We estimated the effects of a temperature control device (TCD) on a suite of thermodynamic and limnological attributes for a large storage reservoir, Shasta Lake, in northern California. Shasta Dam was constructed in 1945 with a fixed-elevation penstock. The TCD was installed in 1997 to improve downstream temperatures for endangered salmonids by releasing epilimnetic waters in the winter/spring and hypolimnetic waters in the summer/fall. We calibrated a two-dimensional hydrodynamic reservoir water quality model, CE-QUAL-W2, and applied a structured design-of-experiment simulation procedure to predict the principal limnological effects of the TCD under a variety of environmental scenarios. Calibration goodness-of-fit ranged from good to poor depending on the constituent simulated, with an R2 of 0.9 for water temperature but 0.3 for phytoplankton. Although the chemical and thermal characteristics of the discharge changed markedly, the reservoir's characteristics remained relatively unchanged. Simulations showed the TCD causing an earlier onset and shorter duration of summer stratification, but no dramatic affect on Shasta's nutrient composition. Peak inreservoir phytoplankton production may begin earlier and be stronger in the fall with the TCD, while outfall phytoplankton concentrations may be much greater in the spring. Many model predictions differed from our a priori expectations that had been shaped by an intensive, but limited-duration, data collection effort. Hydrologic and meteorological variables, most notably reservoir carryover storage at the beginning of the calendar year, influenced model predictions much more strongly than the TCD. Model results indicate that greater control over reservoir limnology and release quality may be gained by carefully managing reservoir volume through the year than with the TCD alone.

Climate↗

Patterns of neuropsychological deficits that discriminate schizophrenic individuals from siblings and control subjects.

Previous research on persons with schizophrenia and their relatives suggests two independent etiologic factors may combine to produce schizophrenia, and these factors may be indexed respectively by independent neuropsychological tests. Two neurocognitive measures, the Trail Making and Wisconsin Card Sorting (WCST) tests, were administered to 28 schizophrenic subjects, 15 nonschizophrenic siblings, and 35 control subjects by investigators blind to DSM-III-R diagnoses. Results support key predictions of a two-factor model: 1) having poor scores on both tests discriminated schizophrenic individuals from both siblings and control subjects, and 2) poor Trail Making and WCST performance were inversely associated among schizophrenic individuals' non-schizophrenic siblings.

Adult↗

Predicted and observed growth and toxigenesis by Clostridium botulinum type E in vacuum-packaged fishery product challenge tests.

The observed growth and toxigenesis by Clostridium botulinum type E in vacuum-packaged unprocessed, raw pickled and cold-smoked rainbow trout stored at slightly abusive temperatures were compared to predictions generated by two currently available predictive microbiological programs, Food MicroModel and Pathogen Modelling Program. In unprocessed fish there was only a 2 log increase in type E cell count at the time the toxicity first occurred after 2 weeks storage at 8 degrees C. Neither growth or toxin production was observed in raw pickled fish with a NaCl concentration of 6.7% (w/v) during 6 weeks storage at 6 degrees C. In cold-smoked fish with a NaCl level of 3.2% (w/v) toxic samples were detected after 3 and 4 weeks storage at 8 degrees C and 4 degrees C, respectively, without any increase in type E count. Both models were hampered by limitations to controlling environmental factors set by the programs which also had an adverse effect on the reliability of predictions. Most predictions generated by the models were inconsistent with the results observed in the challenge studies. In certain situations, the models seemed to be 'fail-safe', in that, the growth rate predicted from the model was faster or a predicted time to toxicity shorter than that which actually occurred in the food. In other situations, the predictions showed the product to be safe when it was not. The results demonstrate the need for further development and rigorous validation of the models before they are accepted for wider use by inspecting officials and the food industry.

Animals↗

Model reduction and analysis of robustness for the Wnt/beta-catenin signal transduction pathway.

We present a framework for model reduction of signal transduction networks. The methods are explained by considering a recent model for Wnt/beta-catenin signalling which plays an important regulatory role in cell development and oncogenesis. The procedure results in a reduction of system variables and parameters while maintaining the ability of the model to describe experimental data and to predict the in-vivo behaviour of the pathway. Using metabolic control analysis we quantified the response of the pathway towards random fluctuations of model parameters. This allows to characterise the robustness of the pathway against perturbations in stimulated and unstimulated states. We show that robustness depends on structural as well as kinetic properties of the pathway.

Animals↗