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PubMed1999

Severity scoring and outcome assessment. Computerized predictive models and scoring systems.

Severity of illness scoring systems and standardized death ratios are being used with increasing frequency as markers of quality of care and to compare and contrast the performance of ICUs. However, numerous factors unrelated to the quality of care delivered may impact the severity of illness score and standardized death ratios. This article reviews the commonly used severity scoring systems and factors that affect their predictive performance.

Computer Simulation↗
PubMed2004

The role of biopharmaceutics in the development of a clinical nanoparticle formulation of MK-0869: a Beagle dog model predicts improved bioavailability and diminished food effect on absorption in human.

MK-0869 (aprepitant), a potent substance P antagonist, is the active ingredient of EMEND which has recently been approved by the FDA for the prevention of chemotherapy-induced nausea and vomiting. Early clinical tablet formulations of MK-0869 showed significant food effects on absorption, suggesting that formulation could have a significant role in improving bioavailability. A Beagle dog model was developed in an effort to guide novel formulation development. Using the suspension of the micronized bulk drug used for the tablet formulations, the food effect on absorption was confirmed in the dog at a similar magnitude to that observed in humans. Further dog studies demonstrated a clear correlation between particle size and in vivo exposures, with the nanoparticle (NanoCrystal) colloidal dispersion formulation providing the highest exposure, suggesting dissolution-limited absorption. The NanoCrystal dispersion also eliminated the food effect on oral absorption in the dog at a dose of 2mg/kg. Regional absorption studies using triport dogs indicated that the absorption of MK-0869 was limited to the upper gastrointestinal tract. These results provided strong evidence that the large increase in surface areas of the drug nanoparticles could overcome the narrow absorption window and lead to rapid in vivo dissolution, fast absorption, and increased bioavailability. In addition, the dog model was used for optimizing formulation processes in which the nanoparticles were incorporated into solid dosage forms, and for selecting excipients to effectively re-disperse the nanoparticles from the dosage units. The human pharmacokinetic data using the nanoparticle formulation showed excellent correlations with those generated in the dog.

Absorption↗
PubMed2004

Model prediction of anterior cruciate ligament force during drop-landings.

PURPOSE: The aim of this study was to calculate and explain the pattern of force transmitted to the anterior cruciate ligament during soft-style drop-landings. We hypothesized that peak ACL loading is due to the anterior pull of the quadriceps on the tibia, as these muscles develop large eccentric forces upon impact. METHODS: A three-dimensional model of the body was used to simulate drop-landing. The simulation was performed by entering into the model muscle excitation patterns based on experimental EMG. The input excitation patterns were modified to create a performance response of the model that matched experimental data. Joint angles, ground reaction forces, and muscle forces obtained from the landing simulation were then applied to a model of the lower limb that incorporated a three-dimensional model of the knee. RESULTS: The model ACL was loaded only in the first 25% of the landing phase. Peak ACL force (approximately 0.4 BW) resulted from a complex interaction between the patellar tendon force, the compressive force acting at the tibiofemoral joint, and the force applied by the ground to the lower leg. The patellar tendon force and tibiofemoral contact force both applied significant anterior shear forces to the shank throughout the landing phase. These effects were modulated by another significant posterior shear force applied by the ground reaction, which served to limit the maximum force transmitted to the ACL. CONCLUSION: The pattern of ACL force in drop-landing cannot be explained by the anterior pull of the quadriceps force alone.

Anterior Cruciate Ligament↗
PubMed2002

Development and validation of a multivariable predictive model to distinguish bacterial from aseptic meningitis in children in the post-Haemophilus influenzae era.

CONTEXT: Children with meningitis are routinely admitted to the hospital and administered broad-spectrum antibiotics pending culture results because distinguishing bacterial meningitis from aseptic meningitis is often difficult. OBJECTIVE: To develop and validate a simple multivariable model to distinguish bacterial meningitis from aseptic meningitis in children using objective parameters available at the time of patient presentation. DESIGN: Retrospective cohort study of all children with meningitis admitted to 1 urban children's hospital from July 1992 through June 2000, randomly divided into derivation (66%) and validation sets (34%). PATIENTS: Six hundred ninety-six previously healthy children aged 29 days to 19 years, of whom 125 (18%) had bacterial meningitis and 571 (82%) had aseptic meningitis. INTERVENTION: Multivariable logistic regression and recursive partitioning analyses identified the following predictors of bacterial meningitis from the derivation set: Gram stain of cerebrospinal fluid (CSF) showing bacteria, CSF protein > or =80 mg/dL, peripheral absolute neutrophil count > or =10 000 cells/mm3, seizure before or at time of presentation, and CSF absolute neutrophil count > or =1000 cells/mm3. A Bacterial Meningitis Score (BMS) was developed on the derivation set by attributing 2 points for a positive Gram stain and 1 point for each of the other variables. MAIN OUTCOME MEASURE: The accuracy of the BMS when applied to the validation set. RESULTS: A BMS of 0 accurately identified patients with aseptic meningitis without misclassifying any child with bacterial meningitis in the validation set. The negative predictive value of a score of 0 for bacterial meningitis was 100% (95% confidence interval: 97%-100%). A BMS > or =2 predicted bacterial meningitis with a sensitivity of 87% (95% confidence interval: 72%-96%). CONCLUSIONS: The BMS accurately identifies children at low (BMS = 0) or high (BMS > or =2) risk of bacterial meningitis. Outpatient management may be considered for children in the low-risk group.

Adolescent↗
PubMed1988

A rapid in vitro enzymic and chromatographic predictive model for the in vivo rat-based protein efficiency ratio of mixed food proteins.

A nutritional quality index in the nature of an enzymatic protein efficiency ratio (E-PER) was computed from the amino acid data of 18 different food products by means of multiple regression equations. The regression was performed by setting amino acid values derived from enzymic hydrolysis of the food proteins as the independent variables with the rat-based PER values as the dependent variables. The multiple regression gave the following equation: E-PER = -3.02 + 0.14 (asp) + 0.15 (glu) - 0.18 (pro) + 0.14 (ala) + 0.52 (met) + 0.21 (lys) + 0.09 (arg) - 0.45 (trp). The multiple correlation coefficient for this regression was 0.942 and the coefficient of variation was 88.7%. The prediction equation was tested on amino acid-PER data of 22 different foodstuffs and it successfully predicted (+/- 0.22) the PER of 17 and an effectiveness of 77.3%.

Amino Acids↗
PubMed2006

Nonlinear model predicts diverse respiratory patterns of birdsong.

A central aspect of the motor control of birdsong production is the capacity to generate diverse respiratory rhythms, which determine the coarse temporal pattern of song. The neural mechanisms that underlie this diversity of respiratory gestures and the resulting acoustic syllables are largely unknown. We show that the respiratory patterns of the highly complex and variable temporal organization of song in the canary (Serinus canaria) can be generated as solutions of a simple model describing the integration between song control and respiratory centers. This example suggests that subharmonic behavior can play an important role in providing a complex variety of responses with minimal neural substrate.

Animals↗
PubMed1995

The need for aggressive nutritional intervention in the injured patient: the development of a predictive model.

Early nutritional intervention has been advocated in trauma patients. We have developed a model to identify those patients who will most benefit from the invasive and costly measures that are required to provide injured patients with early enteral feedings. Four hundred forty-two patients admitted to a level I trauma center during a 2-month period were evaluated using 21 clinical variables. Time to tolerance of a regular diet was used as the dependent variable in a step-wise regression, and then the selected variables were used to build a classification and regression tree to predict tolerance of a regular diet within 5 days. Our findings demonstrate that intensive care unit disposition, Injury Severity Score, Abdominal Trauma Index, and the need for early surgical intervention are important predictors regarding the need for early nutritional intervention. When the model was applied to the study population, it had a sensitivity of 83%, a specificity of 84%, and an accuracy of 84%.

Adolescent↗
PubMed1999

Development of a predictive model for batch membership of street samples of heroin.

Street samples (n = 31) of heroin were analysed by gas chromatography with flame ionisation detection to determine opiate, noscapine and papaverine content. Using this data, the chromatograms obtained could be resolved into eight groups by visual examination of the data. The concentrations of opiates were significantly correlated (P < 0.05) with the exception of the pairs 6-O-monoacetylmorphine/noscapine and morphine/6-O-monoacetylmorphine. This precludes the use of simple cluster analysis for determining and predicting the relationship of different street samples. Application of Fisher's linear discriminant analysis to the data set indicated that 91.9% of the samples could be discriminated including pairs which could not be discriminated by eye. A blind trial (n = 2) resulted in the correct assignment to street sample. Application of such methods may provide, in the future, a powerful tool for the prediction of batch membership of drugs at the street level.

Chromatography, Gas↗
PubMed1989

[Cervical infection caused by Chlamydia trachomatis at a family planning center: prevalence, analysis of risk factors, prediction model].

Chlamydia trachomatis (CT) was detected by culture in 111/600 patients aged 15 to 55; overall prevalence 18.5%, 17% among asymptomatic (52/306) and 20% (59/294) among symptomatic patients. The difference is not significant. Contraceptive practices have no significant influence upon CT prevalence, except for the obvious protective effect of barrier methods. From the history, the clinical and paraclinical findings, four factors (history of genital infection, partner with urogenital symptoms, ectopy, inflammatory changes on a smear) can be combined to produce an index for predicting CT cervical infection. Others factors (age, no pregnancies, mucopus from the cervical os, inflammatory or dysplasic Pap smear, and signs of upper genital tract infection) are indicators of presumption and can be useful to selectively screen asymptomatic or symptomatic patients.

Adolescent↗
PubMed2004

Model predictions of MDM2 mediated cell regulation.

In this work we present a mathematical approach to elucidate possible mechanisms involving mdm2 in the regulation of the cell cycle. It has been experimentally shown that the over-expression of MDM2 leads to decoupling of DNA synthesis with mitosis resulting in polyploidy cells with multiple copies of their genomes. The function of MDM2 that uncouples the DNA synthesis phase (S) and the Mitosis phase (M) is unclear. To answer this question, we first formulate a mathematical model of the dynamics of the cell cycle regulatory proteins during the DNA synthesis phase and mitosis. This model is then tested for bifurcation that produces period doubling cascades that we relate to the biological event of polyploidy. The model formulation, the underlying biology, and the bifurcation results to delineate the unknown function of MDM2 are presented. Based on reproducing known experimental result of polyploidy in MDM2 overexpressed cells, we propose several possible functions of mdm2, i.e., possible interactions with the other cell cycle regulating proteins that will result in uncoupling the S and M phases. We conclude that the most likely unknown function of MDM2 leading to the decoupling of the S and M phases is an obstruction of the activation of Cdc25C by MDM2.

Cell Cycle↗
PubMed2005

Antistaphylococcal effect related to the area under the curve/MIC ratio in an in vitro dynamic model: predicted breakpoints versus clinically achievable values for seven fluoroquinolones.

Prediction of the relative efficacies of different fluoroquinolones is often based on the ratios of the clinically achievable area under the concentration-time curve (AUC) to the MIC, usually with incorporation of the MIC50 or the MIC90 and with the assumption of antibiotic-independent patterns of the AUC/MIC-response relationships. To ascertain whether this assumption is correct, the pharmacodynamics of seven pharmacokinetically different quinolones against two clinical isolates of Staphylococcus aureus were studied by using an in vitro model. Two differentially susceptible clinical isolates of S. aureus were exposed to two 12-h doses of ciprofloxacin (CIP) and one dose of gatifloxacin (GAT), gemifloxacin (GEM), grepafloxacin (GRX), levofloxacin (LVX), moxifloxacin (MXF), and trovafloxacin (TVA) over similar AUC/MIC ranges from 58 to 932 h. A specific bacterial strain-independent AUC/MIC relationship with the antimicrobial effect (I(E)) was associated with each quinolone. Based on the I(E)-log AUC/MIC relationships, breakpoints (BPs) that are equivalent to a CIP AUC/MIC ratio of 125 h were predicted for GRX, MXF, and TVA (75 to 78 h), GAT and GEM (95 to 103 h) and LVX (115 h). With GRX and LVX, the predicted BPs were close to those established in clinical settings (no clinical data on other quinolones are available in the literature). To determine if the predicted AUC/MIC BPs are achievable at clinical doses, i.e., at the therapeutic AUCs (AUC(ther)s), the AUC(ther)/MIC50 ratios were studied. These ratios exceeded the BPs for GAT, GEM, GRX, MXF, TVA, and LVX (750 mg) but not for CIP and LVX (500 mg). AUC/MIC ratios above the BPs can be considered of therapeutic potential for the quinolones. The highest ratios of AUC(ther)/MIC50 to BP were achieved with TVA, MXF, and GEM (2.5 to 3.0); intermediate ratios (1.5 to 1.6) were achieved with GAT and GRX; and minimal ratios (0.3 to 1.2) were achieved with CIP and LVX.

Anti-Infective Agents↗
PubMed2001

Use of electron beam tomography data to develop models for prediction of hard coronary events.

BACKGROUND: Prediction of hard cardiac events (myocardial infarction and coronary death) remains difficult in spite of the identification of several relevant risk factors for the development of coronary artery disease (CAD). New indicators of risk might add to our predictive ability. We used measures of coronary artery calcification (CAC) found by electron beam tomography (EBT) imaging to develop prediction models for hard cardiac events alone and in association with traditional risk factors for CAD. METHODS: Two groups of patients were studied: group A, 676 asymptomatic patients (mean age 52 years, 51% men) prospectively followed up for 32 +/- 7 months after being referred by primary care physicians for a screening EBT, and group B, 10,122 asymptomatic patients screened by EBT at one center and used as controls for calculation of calcium score nomograms. RESULTS: The occurrence of hard events in group A patients was related to traditional risk factors for CAD, presence of CAC (score >0), Ln (1 + absolute calcium score [CS]), and age- and sex-specific CS percentiles (CS%). Univariate analyses showed that age, smoking, diabetes mellitus, presence of CAC, Ln (1 + absolute CS), and CS% were predictive of hard events (all P <.05). Multiple logistic regression analyses demonstrated that CS% was the only significant predictor of events and provided incremental prognostic value when added to traditional risk factors for CAD (chi-square, P <.001). In a comparison of receiver-operator characteristic curves for prediction of hard events, the area under the curve for CS% plus conventional risk factors and age was significantly larger than that obtained by use of traditional risk factors and age separately as predictors (0.84 vs 0.71, respectively, P <.001). Furthermore, the area under the curve of CS% alone was significantly larger than that of traditional risk factors and age combined (0.82 vs 0.71, P =.028). CONCLUSIONS: Patients are usually selected for EBT screening on the basis of the presence of conventional risk factors for CAD. However, an age- and sex-specific calcium score provides the best predictive model for the occurrence of hard coronary events and adds incremental prognostic information to conventional risk factors for CAD.

Aged↗
PubMed2005

A korean predictive model for postoperative nausea and vomiting.

Postoperative nausea and vomiting (PONV) is one of the most common and distressing complications after surgery. An identification of risk factors associated with PONV would make it easier to select specific patients for effective antiemetic therapy. We designed a case-controlled study to identify the risk factors for PONV in 5,272 surgical patients. At postoperative 2 and 24 hr, patients were visited and interviewed on the presence and severity of PONV. Thirty nine percent of patients experienced one or more episodes of nausea or vomiting. Five risk factors were highly predictive of PONV: 1) female, 2) history of previous PONV or motion sickness, 3) duration of anesthesia more than 1 hour, 4) non-smoking status, and 5) use of opioid in the form of patient controlled analgesia (PCA), in the order of relevance. The formula to calculate the probability of PONV using the multiple regression analysis was as follows: P (probability of PONV)=1/1+e(-Z), Z=-1.885+0.894 (gender)+0.661 (history)+0.584 (duration of anesthesia)+0.196 (smoking status)+0.186 (use of PCA-based opioid) where gender: female=1, male=0; history of previous PONV or motion sickness: yes=1, no=0; duration of anesthesia:more than 1 hr=1, less than or 1 hr=0; smoking status: no=1, yes=0; use of PCA-based opioid: yes=1, no=0.

Anesthesia↗
PubMed2000

Comparative pharmacodynamics of gatifloxacin and ciprofloxacin in an in vitro dynamic model: prediction of equiefficient doses and the breakpoints of the area under the curve/MIC ratio.

To demonstrate the impact of the pharmacokinetics of gatifloxacin (GA) relative to those of ciprofloxacin (CI) on the antimicrobial effect (AME), the killing and regrowth kinetics of two differentially susceptible clinical isolates each of Staphylococcus aureus, Escherichia coli, and Klebsiella pneumoniae were studied. With each organism, a series of monoexponential pharmacokinetic profiles of GA (half-life [t(1/2)], 7 h) and CI (t(1/2) = 4 h) were simulated to mimic different single doses of GA and two 12-h doses of CI. The respective eightfold ranges of the ratios of the area under the concentration-time curve (AUC) to the MIC were 58 to 466 and 116 to 932 (microg. h/ml)/(microg/ml). The species- and strain-independent linear relationships observed between the intensity of AME (I(E)) and log AUC/MIC were not superimposed for GA and CI (r(2) = 0.99 in both cases). The predicted AUC/MIC ratio for GA that might be equivalent to a clinically relevant AUC/MIC breakpoint for CI was estimated to be 102 rather than 125 (microg. h/ml)/(microg/ml). The respective MIC breakpoints were 0.32 microg/ml (for a 400-mg dose of GA) and 0.18 microg/ml (for two 500-mg doses of CI). On the basis of the I(E)-log AUC/MIC relationships, equiefficient 24-h doses (D(24h)s) of GA and CI were calculated for hypothetical strains of S. aureus, E. coli, and K. pneumoniae for which the MICs were equal to the MICs at which 50% of isolates are inhibited. To provide an "acceptable" I(E) equal to 200 (log CFU/ml). h, i.e., the I(E) provided by AUC/MIC of 125 (microg. h/ml)/(microg/ml) for ciprofloxacin, the D(24h)s of GA for all three organisms were much lower (115, 30, and 60 mg) than the clinically proposed 400-mg dose. Although the usual dose of CI (two doses of 500 mg) would be in excess for E. coli and K. pneumoniae (D(24h) = two doses of 40 mg and two doses of 115 mg, respectively), even the highest clinical dose of CI (two doses of 750 mg) might be insufficient for S. aureus (D(24h), > two doses of 1,000 mg). The method of generalization of data obtained with specific organisms to other representatives of the same species described in the present report might be useful for prediction of the AMEs of new quinolones.

Anti-Infective Agents↗
PubMed2004

Trend detection via temporal difference model predicts inferior prefrontal cortex activation during acquisition of advantageous action selection.

The process of accurately predicting which actions are associated with advantageous versus disadvantageous outcomes is an important function of daily life. An integral part of this process is being able to detect when the association between an action and an outcome changes. This investigation examined the hypothesis that the inferior prefrontal cortex is critical for the detection of trends and that a trend process derived from the temporal difference model accomplishes this detection. Nineteen normal right-handed volunteers completed 120 4-s trials of a Rock Paper Scissors (RPS) task during functional magnetic resonance imaging. Subjects acquired the selection of advantageous actions during the RPS task. Activations in the medial frontal gyrus (BA 10), left ventrolateral frontal gyrus (BA 11/47), and left pallidum were significantly higher during trials in which subjects acquired the advantageous action. The time course of individually derived trend detection functions was found to be time-locked to the hemodynamic changes in the inferior frontal gyrus. These findings are consistent with the hypothesis that the inferior prefrontal cortex computes a trend from previously experienced action-outcome sequences based on a value function derived from the temporal difference model.

Association Learning↗