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PubMedDate not supplied

Knowing for the sake of knowing: the value of prognostic information.

In evaluating diagnostic tests, traditional methods in decision analysis often emphasize how the results of the test will or will not affect patient management. Clinicians are advised to avoid testing if the results will not alter treatment strategy or other management plans. But patients may be interested in the prognostic information that testing provides even if it is not used to guide treatment. The authors present a model that defines this prognostic information as the expected deviation from the prior probability of disease. The model generates utility functions that are curvilinear over prior probabilities. Whereas the traditional threshold approach to medical decision making produces at most three zones of management strategy (withhold, test, and treat), the incorporation of prognostic information into threshold analysis produces two additional zones (test but withhold anyway, and test but treat anyway). Conditions under which one or both of these additional zones will appear are described. The model justifies the practice of performing tests that cannot alter management plans; it explains the unwillingness of some patients to undergo diagnostic testing when they fear unwanted results; and it provides a method for quantifying the sensitive nature of confidential tests. The model is illustrated using the antibody test for the Smith antigen. This test has a high specificity but a low sensitivity for lupus erythematosus. Clinicians may use the test because a positive result will support their prior suspicion of disease even though they may not change their management strategy if the test result is negative. The advantage of testing in this setting lies in the test's potential for establishing with virtual certainty that the disease is present. Thus, the test is valued for the prognostic information it provides apart from its effect on patient management.

Decision Trees↗
PubMed1993

Demographics, political power and economic growth.

"Growth theory may be used to predict the response of saving, capital formation, and output growth to large demographic shifts. Such large shifts would also be expected to alter the demand for government services and the desired levels of taxation in the population. This paper extends the overlapping-generations model of economic growth to predict the evolution of government tax and spending policy through the course of a major demographic shift. Simulations suggest that this approach may yield valuable insights into the evolution of policy in the United States and other industrialized economies."

Americas↗
PubMed2003

A method for evaluating the results of Bayesian model selection: application to linkage analyses of attributes determined by two or more genes.

OBJECTIVES: We apply and evaluate the intrinsic Bayes factor (IBF) of Berger and Pericchi [J Am Stat Assoc 1996;91:109-122; Bayesian Statistics, Oxford University Press, vol 5, 1996] to linkage analyses done using the stochastic search variable selection (SSVS) method of George and McCulloch [J Am Stat Assoc 1993;88:881-889] as proposed by Suh et al. [Genet Epidemiol 2001;21(suppl 1):S706-S711]. METHODS: We consider 20 simulations of linkage data obtained under two different generating models. The SSVS is applied to a multiple regression extension [Genet Epidemiol 2001;21(suppl 1): S706-S711] of the Haseman-Elston [Behav Genet 1972;2:3-19; Genet Epidemiol 2000;19:1-17] methods. Four prior distributions are considered. We apply the IBF criterion to those samples where different prior distributions result in different top models. RESULTS: In those samples where three different models were obtained using the four priors, application of the IBFs eliminated one of the two wrong models in 4 out of 5 situations. Further elimination using the IBF criterion for situations with two different subsets did not serve as well. CONCLUSIONS: When different priors result in three or more different subsets of markers, one can use the IBF to get this number down to two for consideration. When two subsets result we recommend that both be considered.

Bayes Theorem↗
PubMed1996

Conformal irradiation of the prostate: estimating long-term rectal bleeding risk using dose-volume histograms.

PURPOSE: Dose-volume histograms (DVHs) may be very useful tools for estimating probability of normal tissue complications (NTCP), but there is not yet an agreed upon method for their analysis. This study introduces a statistical method of aggregating and analyzing primary data from DVHs and associated outcomes. It explores the dose-volume relationship for NTCP of the rectum, using long-term data on rectal wall bleeding following prostatic irradiation. METHODS AND MATERIALS: Previously published data were reviewed and updated on 41 patients with Stages T3 and T4 prostatic carcinoma treated with photons followed by perineal proton boost, including dose-volume histograms (DVHs) of each patient's anterior rectal wall and data on the occurrence of postirradiation rectal bleeding (minimum FU > 4 years). Logistic regression was used to test whether some individual combination of dose and volume irradiated might best separate the DVHs into categories of high or low risk for rectal bleeding. Further analysis explored whether a group of such dose-volume combinations might be superior in predicting complication risk. These results were compared with results of the "critical volume model," a mathematical model based on assumptions of underlying radiobiological interactions. RESULTS: Ten of the 128 tested dose-volume combinations proved to be "statistically significant combinations" (SSCs) distinguishing between bleeders (14 out of 41) and nonbleeders (27 out of 41), ranging contiguously between 60 CGE (Cobalt Gray Equivalent) to 70% of the anterior rectal wall and 75 CGE to 30%. Calculated odds ratios for each SSC were not significantly different across the individual SSCs; however, analysis combining SSCs allowed segregation of DVHs into three risk groups: low, moderate, and high. Estimates of probabilities of normal tissue complications (NTCPs) based on these risk groups correlated strongly with observed data (p = 0.003) and with biomathematical model-generated NTCPs. CONCLUSIONS: There is a dose-volume relationship for rectal mucosal bleeding in the region between 60 and 75 CGE; therefore, efforts to spare rectal wall volume using improved treatment planning and delivery techniques are important. Stratifying dose-volume histograms (DVHs) into risk groups, as done in this study, represents a useful means of analyzing empirical data as a function of hetereogeneous dose distributions. Modeling efforts may extend these results to more heterogeneous treatment techniques. Such analysis of DVH data may allow practicing clinicians to better assess the risk of various treatments, fields, or doses, when caring for an individual patient.

Dose-Response Relationship, Radiation↗
PubMed1994

Analysis of intracerebral hematoma shapes by numerical computer simulation using the finite element method.

The distortion and stress distribution in the brain caused by putaminal hemorrhage were estimated by computer stimulation using the finite element method (FEM). The two-dimensional model of a single cerebral hemisphere contained cortex, white matter, caudate nucleus, lenticular nucleus, thalamus, falx, and lateral ventricle. Five types of intracerebral hemorrhage were modeled at different locations in the lenticular nucleus. The models generated putaminal hematomas of various shapes influenced by the location of the bleeding points. Hematomas caused deformation of the brain, collapse of the lateral ventricle, and destruction of the internal capsule. The stress distribution revealed various patterns influenced by the site of bleeding. The stress in the area of the internal capsule corresponded to the extent of destruction of the internal capsule. This study suggests that FEM modeling of putaminal hemorrhage can provide a useful simulation.

Biomechanical Phenomena↗
PubMed2001

A simple 2D biofilm model yields a variety of morphological features.

A two-dimensional biofilm model was developed based on the concept of cellular automata. Three simple, generic processes were included in the model: cell growth, internal and external mass transport and cell detachment (erosion). The model generated a diverse range of biofilm morphologies (from dense layers to open, mushroom-like forms) similar to those observed in real biofilm systems. Bulk nutrient concentration and external mass transfer resistance had a large influence on the biofilm structure.

Biofilms↗
PubMed1999

Comparison of estrogen receptor alpha and beta subtypes based on comparative molecular field analysis (CoMFA).

A substantial body of evidence indicates that both humans and wildlife suffer adverse health effects from exposure to environmental chemicals that are capable of interacting with the endocrine system. The recent cloning of the estrogen receptor beta subtype (ER-beta) suggests that the selective effects of estrogenic compounds may arise in part by the control of different subsets of estrogen-responsive promoters by the two ER subtypes, ER-alpha and ER-beta. In order to identify the structural prerequisites for ligand-ER binding and to discriminate ER-alpha and ER-beta in terms of their ligand-binding specificities, Comparative Molecular Field Analysis (CoMFA) was employed to construct a three-dimensional Quantitative Structure-Activity Relationship (3D-QSAR) model on a data set of 31 structurally-diverse compounds for which competitive binding affinities have been measured against both ER-alpha and ER-beta. Structural alignment of the molecules in CoMFA was achieved by maximizing overlap of their steric and electrostatic fields using the Steric and Electrostatic ALignment (SEAL) algorithm. The final CoMFA models, generated by correlating the calculated 3D steric and electrostatic fields with the experimentally observed binding affinities using partial least-squares (PLS) regression, exhibited excellent self-consistency (r2 > 0.99) as well as high internal predictive ability (q2 > 0.65) based on cross-validation. CoMFA-predicted values of RBA for a test set of compounds outside of the training set were consistent with experimental observations. These CoMFA models can serve as guides for the rational design of ER ligands that possess preferential binding affinities for either ER-alpha or ER-beta. These models can also prove useful in risk assessment programs to identify real or suspected EDCs.

Algorithms↗
PubMed2003

Comparison of MELD, Child-Pugh, and Emory model for the prediction of survival in patients undergoing transjugular intrahepatic portosystemic shunting.

OBJECTIVES: Recently, new prognostic models (Model for End-Stage Liver Disease [MELD model] and Emory score) were proposed for the prediction of survival in transjugular intrahepatic portosystemic shunt (TIPS) patients. Although the MELD model is considered to be superior and has consecutively been applied to priority listing for liver transplantation, these models have never been directly compared in terms of long-term prognosis. We therefore compared the prognostic accuracy of the different models, including the Child-Pugh score, in an unselected cohort of TIPS patients followed long-term. METHODS: Baseline risk scores for 162 unselected consecutive TIPS patients followed until death (n = 81), liver transplantation, or end of observation (n = 81) (mean follow-up 30.7 +/- 26.4 months) were calculated, and respective concordance- (c-)statistics for the predictive accuracy of 3-, 12-, and 36-month survival for the three models were compared statistically. RESULTS: All three models predicted short-term (3-month) survival with similar accuracy. The MELD model generated the best c-statistics for both 12-month (c-statistic 0.73, 95% CI = 0.64-0.82) and 36-month survival (c-statistic 0.74, 95% CI = 0.64-0.84). The predictive accuracy of the Emory score was significantly lower (c-statistic for 12-month survival: 0.60, 95% CI = 0.52-0.68, p = 0.012 vs MELD). In the statistical comparison of the MELD and the Child-Pugh model, only a trend favoring MELD for the prediction of 1-yr survival in patients with intestinal bleeding could be observed (MELD: c-statistic 0.78, 95% CI = 0.67-0.89; Child-Pugh: c-statistic 0.67, 95% CI = 0.55-0.80, p = 0.059). CONCLUSIONS: The MELD model is superior to the Emory score but only slightly superior to the Child-Pugh classification for the prediction of long-term survival in TIPS patients.

Evaluation Studies as Topic↗
PubMed1998

Molecular dynamics simulations of peptide fragments from hen lysozyme: insight into non-native protein conformations.

Molecular dynamics simulations of four peptides taken from the hen lysozyme sequence have been used to generate models for non-native protein conformations. Comparisons between the different peptides and with experimental data for denatured lysozyme and peptide fragments provides insight into the characteristics of the conformational ensembles populated in these non-native states and the dependence of their structural features on the amino acid sequence. For the denatured conformers populated local contacts dominate in determining the properties observed in the trajectories, all four peptides showing similar characteristics. These include a significant increase in the number of main-chain O(i)-NH(i+2) hydrogen bonds and hydrogen bonds involving side-chain groups, this increase compensating to a large extent for the loss of hydrogen bonds involved in helical or beta-sheet secondary structure in the native fold, and the generation of a population of collapsed states with local clusterings of hydrophobic groups. The hydrophobic clusters enable at least partial burial of many side-chains exposed by the loss of tertiary contacts on denaturation and provide models that may explain the experimentally observed protection of amides from hydrogen exchange and the existence of residual secondary structure in non-native species of lysozyme. The results suggest that this approach has an important role to play in aiding the interpretation of experimental data for conformationally disordered non-native states of proteins.

Animals↗
PubMed1999

The economic consequences of reorganizing hospital services in Bishkek, Kyrgyzstan.

Kyrgyzstan gained independence from the Soviet Union in 1991 and has since been thrown into severe financial crisis. All public sector funding has been significantly reduced and international aid agencies are supporting the government in rebuilding the economy. The health sector requires a radical overhaul and a major part of this process involves rationalization of existing facilities, particularly in the capital Bishkek, where 26 secondary and tertiary hospitals support a population of approximately 800000 people. This paper describes the development of a plan for rationalization with particular emphasis on the economic aspects of the process. This involved calculating future hospital requirements by modelling a variety of policy options, ranging from changes to clinical practice to hospital closures. The model generates estimates of resource requirements at each hospital, from which the costs falling on the health budget and patients are derived.

Adult↗
PubMed1992

Probing the structure of the Neurospora crassa plasma membrane H(+)-ATPase.

The structure of the Neurospora crassa plasma membrane H(+)-ATPase has been investigated using a variety of chemical and physiochemical techniques. The transmembrane topography of the H(+)-ATPase has been elucidated by a direct, protein chemical approach. Reconstituted proteoliposomes containing purified H(+)-ATPase molecules oriented predominantly with their cytoplasmic surface facing outward were treated with trypsin, and the numerous peptides released were purified by HPLC and subjected to amino acid sequence analysis. In this way, seventeen released peptides were unequivocally identified as located on the cytoplasmic side of the membrane, and numerous intervening segments could be inferred to be cytoplasmically located by virtue of the fact that they are too short to cross the membrane and return between sequences established to be cytoplasmically located. Additionally, three large membrane-embedded segments of the H(+)-ATPase were isolated using our recently developed methods for purifying hydrophobic peptides, and identified by amino acid sequence analysis. This information established the topographical location of virtually all of the 919 residues in the H(+)-ATPase molecule, allowing the formulation of a reasonably detailed model for the transmembrane topography of the H(+)-ATPase polypeptide chain. Separate studies of the cysteine chemistry of the H(+)-ATPase have demonstrated the existence of a single disulfide bridge in the molecule, linking the NH2- and COOH-terminal membrane-embedded domains. And, analyses of the circular dichroism and infrared spectra of the purified H(+)-ATPase have elucidated the secondary structure composition of the molecule. A first-generation model for the tertiary structure of the H(+)-ATPase based on this information and other considerations is presented.

Cell Membrane↗
PubMedDate not supplied

Anatomic dilatation of the cardia and competence of the lower esophageal sphincter: a clinical and experimental study.

Anatomic and clinical data suggest that the gastroesophageal junction or cardia in patients with gastroesophageal reflux disease GERD) may be dilated. We hypothesized that anatomic dilatation of the cardia induces a lower esophageal sphincter dysfunction that may be corrected by narrowing the gastroesophageal junction (i.e., calibration of the cardia). We measured the perimeter of the cardia during surgery in control subjects and patients with GERD and Barrett's esophagus. We then tested our hypothesis in a mechanical model. The model was based on a pig gastroesophageal specimen with perpendicularly placed elastic bands around the cardia simulating the action of the "sling" and "clasp" fibers. "Dilatation" of the cardia was induced by displacing the sling band laterally and decreasing its tension. "Calibration" of the cardia was performed by reapproximation of the sling band toward the esophagus but maintaining the same tension as the dilated model. In the "basal," "dilated," and "calibrated" states, the perimeter of the cardia was noted and rapid mechanized pullback manometry with a water-perfused catheter was performed. The opening pressure was determined, and three-dimensional sphincter pressure images were analyzed. The average cardia perimeter was 6.3 cm in control subjects, 8.9 cm in GERD patients, and 13.8 cm in patients with Barrett's esophagus. The arrangement of the bands in the experimental model generated a manometric high-pressure zone similar to that in the human lower esophageal sphincter. Dilatation of the cardia resulted in a decrease in the resting pressure, length, and vector volume of the high -pressure zone, and reduced the opening pressure. Calibration restored the resting and opening pressure, and normalized the three-dimensional pressure image. In patients with GERD and Barrett's esophagus, the cardia is dilated. Our model supports the hypothesis that lower esophageal sphincter function is compromised by anatomic dilatation of the cardia and can be restored by approximation of the "sling" fibers toward the lesser curvature "clasp" fibers). This provides evidence for a correlation between gastroesophageal sphincter dysfunction in reflux disease and its correction by antireflux surgery.

Adult↗
PubMed2004

Classification of kinase inhibitors using a Bayesian model.

The use of Bayesian statistics to model both general (multifamily) and specific (single-target) kinase inhibitors is investigated. The approach demonstrates an alternative to current computational methods applied to heterogeneous structure/activity data sets. This approach operates rapidly and is readily modifiable as required. A generalized model generated using inhibitor data from multiple kinase classes shows meaningful enrichment for several specific kinase targets. Such an approach can be used to prioritize compounds for screening or to optimally select compounds from third-party data collections. The observed benefit of the approach is finding compounds that are not structurally related to known actives, or novel targets for which there is not enough information to build a specific kinase model. The general kinase model described was built from a basis of mostly tyrosine kinase inhibitors, with some serine/threonine inhibitors; all the test cases used in prediction were also on tyrosine kinase targets. Confirming the applicability of this technique to other kinase families will be determined once those biological assays become available.

Artificial Intelligence↗
PubMed1989

Model of the interactions of calichemicin gamma 1 with a DNA fragment from pBR322.

An analysis of the binding interactions of several DNA-drug complexes that utilize carbohydrates for DNA recognition has been undertaken. It is proposed that the carbohydrate residues function as general minor groove binding elements, and the stereochemistry of aglycone attachment sites is generally disposed to promote a right-handed helical geometry that is complementary to right-handed DNA. The constitution and stereochemistry of the DNA double-strand cleaving agent calichemicin gamma 1 is consistent with this analysis. Docking experiments with computer-generated models of this drug and a dodecamer duplex that was found to serve as a calichemicin cleavage site were performed to gain insight into the origin of the drug's sequence-selective binding and cutting properties. A model is presented that provides a molecular level understanding of the double-strand cleavage patterns that result from the action of calichemicin gamma 1 on DNA.

Aminoglycosides↗
PubMed1994

Modelling the thermal inactivation of Salmonella typhimurium using bioluminescence data.

Inactivation of micro-organisms by heat is a traditional food processing technique used to reduce or eliminate the microbial load in foods thus preventing bacterial associated disease and food spoilage. Models of thermal death kinetics are routinely used to predict the amount of heat required but such models are limited by the acquisition of accurate thermal death data for bacteria in situ and in complex microflora. In vivo bioluminescence from lux recombinant bacteria is an important alternative to traditional plate counts for examining bacterial injury and stress but the thermal instability of luciferase has appeared to preclude its application in heating studies. We have developed a procedure which overcomes the thermal instability of luciferase and demonstrate that computer generated models of the thermal injury of Salmonella typhimurium show equivalence between bioluminescence and viable count data.

Hot Temperature↗
PubMed1999

Quantifying human circadian pacemaker response to brief, extended, and repeated light stimuli over the phototopic range.

The authors' previous models have been able to describe accurately the effects of extended (approximately 5 h) bright-light (>4000 lux) stimuli on the phase and amplitude of the human circadian pacemaker, but they are not sufficient to represent the surprising human sensitivity to both brief pulses of bright light and light of more moderate intensities. Therefore, the authors have devised a new model in which a dynamic stimulus processor (Process L) intervenes between the light stimuli and the traditional representation of the circadian pacemaker as a self-sustaining limit-cycle oscillator (Process P). The overall model incorporating Process L and Process P is intended to allow the prediction of phase shifts to photic stimuli of any temporal pattern (extended and brief light episodes) and any light intensity in the photopic range. Two time constants emerge in the Process L model: the characteristic duration for necessary bright-light pulses to achieve their full effect (5-10 min) and the characteristic stimulus-free (dark) interval that can be tolerated without incurring an excessive penalty in phase shifting (30-80 min). The effect of reducing light intensity is incorporated in Process L as an extension of the time necessary for the light pulse to be fully realized (a power-law relation between time and intensity). This new model generates a number of new testable hypotheses, including the surprising prediction that 24-h cycles consisting of 8 h of darkness and 16 h of only approximately 3.5 lux would be capable of entraining a large fraction of the adult population (approximately 45%). Experimental data on the response of the human circadian system to lower light intensities and briefer stimuli are needed to allow for further refinement and validation of the model proposed here.

Algorithms↗
PubMed2005

Proangiogenesis action of the thyroid hormone analog 3,5-diiodothyropropionic acid (DITPA) is initiated at the cell surface and is integrin mediated.

We have recently described the proangiogenesis effects of thyroid hormone in the chick chorioallantoic membrane (CAM) model. Generation of new blood vessels from existing vessels was promoted 2- to 3-fold by either T(4) or T(3) at 10(-8)-10(-7) M total hormone concentrations. In the present studies, nanomolar concentrations of 3,5-diiodothyropropionic acid (DITPA), a thyroid hormone analog with inotropic but not chronotropic properties, exhibited potent proangiogenic activity that was comparable to that obtained with T(3) and T(4) in both the CAM model and in an in vitro three-dimensional human microvascular endothelial sprouting assay. The proangiogenesis effect of DITPA was inhibited by tetraiodothyroacetic acid, a thyroid hormone analog that competes with T(4) and T(3) for a novel cell surface hormone receptor site on integrin alphavbeta3. The thyroid hormone analogs DITPA, T(4), and T(4)-agarose, as well as basic fibroblast growth factor (b-FGF) and vascular endothelial cell growth factor, demonstrated comparable proangiogenic effects in the CAM model and in the three-dimensional human microvascular endothelial sprouting model. The proangiogenesis effect of either DITPA or b-FGF was blocked by PD 98059, an inhibitor of the ERK1/2 signal transduction cascade. Additionally, a specific integrin alphavbeta3 small molecule antagonist, XT199, effectively inhibited the proangiogenesis effect of DITPA and b-FGF. Thus, the proangiogenesis actions of thyroid hormone and its analog DITPA are initiated at the plasma membrane, apparently at integrin alphavbeta3, and are MAPK dependent.

Animals↗
PubMed2004

The pheromone production of female Plodia interpunctella is inhibited by tyraminergic antagonists.

Several compounds were found to suppress the calling behavior and in vitro pheromone biosynthesis of the Indian meal moth, Plodia interpunctella. The compounds were screened by means of a calling-behavior bioassay with female P. interpunctella. Five derivatives with activities in the nanomolar range were identified, in order of decreasing pheromonostatic activity: 4-hydroxybenzaldehyde semicarbazone (42) > 5-(4-methoxyphenyl)-1,3-oxazole (38) > 5-[4-(tert-butyl)phenyl]-1,3-oxazole (40) > 5-(3-methoxyphenyl)-1,3-oxazole (35) > 5-(4-cyanophenyl)-1,3-oxazole (36). These compounds also showed in vitro inhibitory activity in intracellular de novo pheromone biosynthesis, as determined with isolated pheromone-gland preparations that incorporated [1-(14)C]sodium acetate in the presence of the so-called pheromone-biosynthesis-activating neuropeptide (PBAN). The non-additive effect of the inhibitor with antagonist (yohimbine) for the tyramine (TA) receptor suggests that it could be a tyraminergic antagonist. Three-dimensional (3D) computer models were built from a set of compounds. Among the common-featured models generated by the program Catalyst/HipHop, aromatic-ring (AR) and H-bond-acceptor-lipophilic (HBAl) features were considered to be essential for inhibitory activity in the calling behavior and in vitro pheromone biosynthesis. Active compounds, including yohimbine, mapped well onto all the AR and HBAl features of the hypothesis. Less-active compounds were shown to be unable to achieve an energetically favorable conformation, consistent with our 3D common-feature pharmacophore models. The present hypothesis demonstrates that calling behavior and PBAN-stimulated incorporation of radioactivity are inhibited by tyraminergic antagonists.

Animal Communication↗