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PubMed2006

Integrated mechanistic and data-driven modelling for multivariate analysis of signalling pathways.

Mathematical models of highly interconnected and multivariate signalling networks provide useful tools to understand these complex systems. However, effective approaches to extracting multivariate regulation information from these models are still lacking. In this study, we propose a data-driven modelling framework to analyse large-scale multivariate datasets generated from mathematical models. We used an ordinary differential equation based model for the Fas apoptotic pathway as an example. The first step in our approach was to cluster simulation outputs generated from models with varied protein initial concentrations. Subsequently, decision tree analysis was applied, in which we used protein concentrations to predict the simulation outcomes. Our results suggest that no single subset of proteins can determine the pathway behaviour. Instead, different subsets of proteins with different concentrations ranges can be important. We also used the resulting decision tree to identify the minimal number of perturbations needed to change pathway behaviours. In conclusion, our framework provides a novel approach to understand the multivariate dependencies among molecules in complex networks, and can potentially be used to identify combinatorial targets for therapeutic interventions.

Apoptosis↗
PubMed2005

Cell wall integrity is dependent on the PKC1 signal transduction pathway in Cryptococcus neoformans.

Cell wall biogenesis and integrity are crucial for fungal growth, pathogenesis and survival, and are attractive targets for antifungal therapy. In this study, we identify, delete and analyse mutant strains for 10 genes involved in the PKC1 signal transduction pathway and its regulation in Cryptococcus neoformans. The kinases Bck1 and Mkk2 are critical for maintaining integrity, and deletion of each of these causes severe phenotypes different from each other. In stark contrast to results seen in Saccharomyces cerevisiae, a deletion in LRG1 has severe repercussions for the cell, and one in ROM2 has little effect. Also surprisingly, the phosphatase Ppg1 is crucial for cell integrity. These data indicate that the mechanisms of maintaining cell integrity differ between the two fungi. Deletions in SSD1 and PUF4, potential alternative regulators of cell integrity, also exhibit phenotypes. This is the first comprehensive analysis examining genes involved the maintenance of cell integrity in C. neoformans and sets the foundation for future biochemical and virulence studies.

Animals↗
PubMed1993

Frameless stereotaxic integration of CT imaging data: accuracy and initial applications.

To evaluate the spatial accuracy of a rapid interactive method of transferring computed tomographic (CT) information between its display on a computer screen to its source (test object, operating field), a multidimensional computer combined with a six-jointed position-sensing mechanical arm was tested with a Plexiglas model consisting of 50 rods of varied height and known location, a plastic replica of the skull, and, subsequently, three patients. The median error value between image and real location was 1-2 mm (P > .95), regardless of the registration target sites. The accuracy, however, increased with the selection of widespread registration points, and 95% of all errors were below 3.70 mm (P > .95). The results compare favorably with the four most commonly used stereotaxic framed units. A misregistration error of 0.3-2.2 mm was found during intraoperative correlation between anatomy on the CT display and actual anatomic location in the operative field.

Child↗
PubMed1996

A case of late-onset psychosis: integrating neuropsychological and SPECT data.

We report the case of a 67-year-old woman who experienced a sudden onset of psychotic illness (i.e., prominent delusions and hallucinations) that has endured for approximately 3 years. As part of her neurobehavioral work-up, a SPECT scan revealed right frontal and left anterior temporal-lobe hypoperfusion. Serial neuropsychological evaluations obtained 2 years apart demonstrated a steady decline on tests of executive control (monitoring, allocation of attention, perseveration) and visuospatial abilities, whereas performance in other areas of cognitive functioning have remained steady and in the normal range for the patient's age. Over this same period of time, serial EEG, MRI, and neurology examinations have been within normal limits. Thus, there was little evidence with which to diagnose dementia. It is suggested that concomitant impairment in executive control, coupled with a degraded capacity to process perceptual information, can give rise to enduring psychotic behavior.

Aged↗
PubMed2005

Subcortical vascular dementia: integrating neuropsychological and neuroradiologic data.

BACKGROUND: Research criteria for subcortical vascular dementia are based on radiologic evidence of vascular pathology and greater impairment on tests of executive control than memory. The relationship(s) between neuroradiological evidence of subcortical vascular disease and neuropsychological impairments has not been specified. OBJECTIVE: To define these research criteria, the authors rated the severity of MRI white matter abnormalities (WMAs) and neuropsychological data from patients with dementia. METHODS: Sixty-nine outpatients who met the criteria for dementia were studied with neuropsychological tests that assessed executive (mental) control, declarative memory, visuoconstruction (clock drawing), and language (semantic category fluency). MRI-WMAs were rated using a leukoaraiosis (LA) scale (range 0 to 40). RESULTS: First, regression analyses demonstrated that neuropsychological measures accounted for 60.7% of the variance in WMA severity (47.3% of this variance attributable to executive/visuoconstructive test performance, 13.4% attributable to memory/language test performance). Second, patients were grouped according to the severity of WMAs (i.e., low, moderate, and severe white matter groups). Only patients with mild WMA (mean LA = 3.61 +/- 2.63, approximately 2.4 to 15.6% of the subcortical white matter) presented with greater impairment on memory/language tests vs executive control/visuoconstructive tests, a neuropsychological profile typically associated with Alzheimer disease. Patients with moderate WMA (mean LA = 12.76 +/- 2.49, approximately 25.6 to 38.1% of the subcortical white matter) presented with equal impairment on executive/visuoconstructional vs memory/language tests. Patients with severe WMA (mean LA = 21.76 +/- 2.97, approximately 46.9 to 62.4% of the subcortical white matter) displayed a profile of greater executive/visuoconstructional impairment relative to memory/language disabilities. CONCLUSION: A profile of equal impairment on tests of executive control and memory along with radiologic evidence involving about one-fourth of the cerebral white matter as measured by the Leukoaraiosis Scale may be sufficient for a diagnosis of subcortical vascular dementia.

Age Factors↗
PubMed2003

Toward integrating a common nursing data set in home care to facilitate monitoring outcomes across settings.

The purpose of our research is to identify a realistic subset of North American Nursing Diagnosis Association (NANDA), Nursing Outcome Classification (NOC), and Nursing Interventions Classification (NIC) terms specific to the home care (HC) setting. A subset of 89 NOC outcomes were identified for study in HC through a baseline survey. Three research assistants then observed the care of 258 patients to whom the 89 NOC outcomes applied and recorded the associated NANDA and NIC terms. Follow-up surveys and focus groups were conducted with the nurses and research assistants. There were 81 different NANDA and 226 NIC labels used to describe study patients' care. Only 36 of the 89 NOC labels studied were deemed clinically useful for HC. We found that expert opinion about terminology usage before actual experience under practice conditions is unreliable.

Data Collection↗
PubMed2004

Integrating in vitro kinetic data from compounds exhibiting induction, reversible inhibition and mechanism-based inactivation: in vitro study design.

Drug:drug interactions continue to be an obstacle for the pharmaceutical industry in the development of potential drug candidates. Considering the number of compounds that have been withdrawn from the market due to drug:drug interactions (e.g. cisapride, terfenadine and mibefradil), more pressure is placed on the pharmaceutical industry to investigate potential interactions prior to regulatory submission. In particular, induction and inhibition of drug metabolizing enzymes can profoundly alter the pharmacological and toxicological effects observed during monotherapy. However, due to differences in the expression and regulation of both metabolic enzymes and nuclear receptors responsible for induction, in vivo studies with pre-clinical species are not predictive of the human clinical situation. Although in vitro kinetic data also have limitations when extrapolating in vivo, in vitro testing has become more commonplace due to reduced cost and higher throughput. However, in the in vitro setting, complex enzyme kinetics can alter the estimation of kinetic parameters. Time-dependent or non-Michaelis-Menten kinetics can alter parameter estimates if experimental conditions are not optimal, and can therefore confound clinical predictions. Furthermore, mechanism-based inactivation (MBI) will reduce the active enzyme pool, both in vitro and in vivo, and thus complicate any parameter estimates. To further complicate matters, some compounds (e.g., ritonavir) inhibit, induce, as well as cause mechanism-based enzyme inactivation. For compounds such as ritonavir, the accurate estimation of kinetic parameters requires optimal experimental design at a minimum. This review will highlight the challenges in estimating enzyme kinetic parameters when both inhibition and induction are present, and will offer experimental viewpoints for the optimization of the experimental conditions.

Data Interpretation, Statistical↗
PubMed1982

Bioactuarial models of national mortality time series data.

The incidence and prevalence of chronic degenerative disease in America's elderly population are important determinants of the need for long-term care health services. Though a wide range of data on disease incidence and prevalence is available from a variety of different health studies, a Congressional Budget Office study (1977) concluded that data limitations are a major factor in the lack of precise national long-term care cost estimates. In this paper, we present a modeling strategy to make better use of existing data by using biomedically motivated actuarial models to integrate multiple data sources into a comprehensive model of population health dynamics. The development of a specific model for application to a disease of interest involves three distinct phases. First, biomedical evidence and data are used to specify a cohort model of chronic disease morbidity and mortality. Second, the model is fitted to cohort mortality data with estimates of its parameters being derived by maximum likelihood procedures. Third, the morbidity distribution in the national population is generated from the parameter estimates. The model is used to examine lung cancer morbidity and mortality patterns for U. S. white and non-white males in 1977. A review of these patterns suggests that, based on current concepts of lung cancer incidence and natural history, over 2 percent of white males in the United States have lung cancer at some stage of development, though most of this prevalence is pre-clinical.

Actuarial Analysis↗
PubMed1999

Antipsychotics from theory to practice: integrating clinical and basic data.

The recent introduction of the atypical antipsychotics into the treatment arena for psychoses and related disorders comes with justifiable excitement. These newer antipsychotics offer several clinical benefits over the conventional antipsychotics, which have been the mainstays of care thus far. The primary advantage of these atypical agents is their superior side effect profiles, particularly with regard to extrapyramidal side effects (EPS). The implications from a reduction in EPS touch on virtually every aspect of pathology in schizophrenic illness, including short- and long-term movement disorders, negative symptoms, noncompliance, cognitive dysfunction, and dysphoria. It should be emphasized that while atypical antipsychotics share many clinical attributes, there are also substantial differences among them. This review will examine the pharmacology, clinical efficacy, and side effect profiles of the atypical antipsychotics and attempt to relate the attributes observed in clinical practice and clinical trials to their basic pharmacologic profiles. There is a fair, but not perfect, correspondence between the pharmacologic profiles of the different atypical antipsychotics and their respective clinical attributes. After a comparative overview of their receptor-binding profiles, a brief pharmacokinetic summary will be provided. Finally, the clinical profiles of these agents will be summarized with regard to both their efficacy and adverse effects.

Animals↗