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Classifying Variants of CDKN2A Using Computational and Laboratory Studies

HUMAN MUTATION 2011年第8期32卷 900-911页

作者： Miller, Peter J. Duraisamy, Sekhar Newell, Joan A. Chan, Philip A. Tie, Mark M. Rogers, Amy E. Ankuda, Claire K. von Walstrom, Genevieve M. Bond, Jeffrey P. Greenblatt, Marc S. Univ Vermont Coll Med Hematol Oncol Unit Dept Med Burlington VT 05405 USA Univ Vermont Coll Med Vermont Canc Ctr Burlington VT 05405 USA

Variants in the CDKN2A tumor suppressor are associated with Familial Melanoma (FM), although for many variants the linkage is weak. The effects of missense variants on protein function and pathogenicity are often unclear. Multiple methods (e. g., laboratory, computational, epidemiological) have been developed to analyze whether a missense variant is pathogenic or not. It is not yet clear how to integrate these data types into a strategy for variant classification. We studied 51 CDKN2A missense variants using a cell cycle arrest assay. There was a continuum of results ranging from full wild-type effect through partial activity to complete loss of arrest. A reproducible decrease of 30% of cell cycle arrest activity correlated with FM association. We analyzed missense CDKN2A germline variants using a Bayesian method to combine multiple data types and derive a probability of pathogenicity. When equal to or more than two data types could be evaluated with this method, 22 of 25 FM-associated variants and 8 of 15 variants of uncertain significance were classified as likely pathogenic with >95% probability. The other 10 variants were classified as uncertain (probability 5-95%). For most variants, there were insufficient data to draw a conclusion. The Bayesian model appears to be a sound method of classifying missense variants in cancer susceptibility genes. Hum Mutat 32:900-911, 2011. (C) 2011 Wiley-Liss, Inc.

关键词： missense predictive algorithm in vitro in silico functional assays melanoma cancer susceptibility

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A non-invasive algorithm accurately predicts advanced fibrosis in hepatitis C:: A comparison using histology with internal-external validation

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JOURNAL OF HEPATOLOGY 2008年第4期49卷 564-571页

作者： Paggi, Silvia Colli, Agostino Fraquelli, Mirella Vigano, Mauro Del Poggio, Paolo Facciotto, Corinna Colombo, Massimo Ronchi, Guido Conte, Dario Univ Milan Div Gastroenterol 2 Fdn IRCCS Policlin Milan Italy A Manzoni Hosp Dept Internal Med Lecce Italy Univ Milan Div Gastroenterol 1 Fdn IRCCS Policlin AM & A Migliaracca Ctr Liver Dis Milan Italy Treviglio Hosp Hepatol Unit Treviglio Italy

Background/Aims: Biochemical tests and ultrasonography (US) are useful in the non-invasive assessment of liver fibrosis in patients with chronic hepatitis C (CH-C);however histology remains the reference standard. This multicenter, cross-sectional cohort study evaluated the accuracy of APRI (AST-to-platelet-ratio-index) and liver surface ultrasound nodularity (LSN), singularly and sequentially combined in an algorithm, in diagnosing advanced fibrosis (i.e. METAVIR F3, F4), to derive a prediction rule to confirm or exclude F3, F4. Methods: Four hundred and thirty consecutive CH-C patients with elevated ALT, grouped into a first cohort (training set), and an internal and an external validation cohort, were studied. APRI and LSN were compared to liver biopsy and sequentially combined in order to obtain a predictive rule for advanced fibrosis METAVIR F3,F4. Results: LSN was negative and APRI <= 1 in 185/430 patients, whereas LSN was positive and APRI > 2 in 46/430 cases, with a 94% diagnostic accuracy for presence/absence of F3, F4, respectively. In a further 60/430 patients, F3,F4 was detected with an accuracy of 83%. In the remaining cases no classification was possible. Conclusions: An algorithm based on APRI and LSN confirms or excludes F3, F4 in 54% of CH-C patients with elevated ALT and suggests a highly probable diagnosis in a further one-sixth of patients, thus rendering liver biopsy unnecessary in these patients. (C) 2008 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

关键词： chronic hepatitis C liver fibrosis APRI score ultrasonography predictive algorithm

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LIMITED PROTEOLYSIS OF NATIVE PROTEINS - THE INTERACTION BETWEEN AVIDIN AND PROTEINASE-K

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PROTEIN SCIENCE 1995年第7期4卷 1337-1345页

作者： ELLISON, D HINTON, J HUBBARD, SJ BEYNON, RJ UNIV MANCHESTER INST SCI & TECHNOLDEPT BIOCHEM & APPL MOLEC BIOLMANCHESTER M60 1QDLANCSENGLAND ZENECA BIOPROD BILLINGHAM TS23 1LBCLEVELANDENGLAND EUROPEAN MOLEC BIOL LAB D-69012 HEIDELBERGGERMANY

Avidin is a tetramer of 16-kDa subunits that have a high affinity for biotin. Proteolysis of native apoavidin by proteinase K results in a limited attack at the loop between beta-strands 3 and 4, involving amino acids 38-43. Specifically, sites of proteolysis are at Thr 40-Ser 41 and Asn 42-Glu 43. The limited proteolysis results in anl avidin product that remains otherwise intact and which has enhanced binding for 4'-hydroxyazobenzene-2-benzoic acid (HABA), a chromogenic reporter that can occupy the biotin-binding site. Saturation of the biotin-binding site with the natural ligand protects avidin from proteolysis, but saturation with HABA enhances the rate of proteolysis of the same site. Analysis of the three-dimensional structures of apoavidin and holoavidin reveals that the 3-4 loop is accessible to solvent and scores highly in an algorithm developed to identify sites of proteolytic attack. The structure df holoavidin is almost identical to the apoprotein. In particular, the 3-4 loop has the same structure in the apo and hole forms, yet there are marked differences in proteolytic susceptibility of this region. Evidence suggests that the 3-4 loop is rather mobile and flexible in the apoprotein, and that it becomes constrained upon ligand binding. In one crystal structure of the apoprotein, this loop appears constrained by contacts with symmetry-related molecules. Structural analyses suggest that the ''lid'' to the biotin-binding site, formed by the 3-4 loop, is displaced and made more accessible by HABA binding, thereby enhancing its proteolytic susceptibility.

关键词： AVIDIN LIMITED PROTEOLYSIS predictive algorithm PROTEINASE K

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Predicting first-trimester outcome of embryos with cardiac activity in women with recurrent spontaneous abortion

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JOURNAL OF INTERNATIONAL MEDICAL RESEARCH 2020年第6期48卷 300060520911829-300060520911829页

作者： Li, Huixian Qin, Shuang Xiao, Fanfan Li, Yuhong Gao, Yunhe Zhang, Jiexin Xiao, Qing Sun Yat Sen Univ Affiliated Hosp 8 3025 ShenNan Rd Shenzhen 518033 Guangdong Peoples R China Guangzhou Med Univ Inst Pediat Guangzhou Women & Childrens Med Ctr Guangzhou Guangdong Peoples R China Guangzhou Med Univ Guangzhou Women & Childrens Med Ctr Dept Reprod & Immunol Gynecol Guangzhou Guangdong Peoples R China Guangzhou Med Univ Dept Gynecol Outpatient Guangzhou Women & Childrens Med Ctr Guangzhou Guangdong Peoples R China

Objective This study was performed to evaluate the capability of routine clinical indicators to predict the early outcome of embryos with cardiac activity in women with recurrent spontaneous abortion (RSA). Methods A retrospective cohort study of pregnant women with a history of RSA in a Chinese tertiary hospital was performed using unadjusted and multivariable logistic regression. Results Of 789 pregnant women with RSA, 625 (79.21%) had ongoing pregnancy, whereas 164 (20.79%) developed abortion before 20 full weeks of gestational age even after embryonic heart motion was detected. The final model had an area under the curve of 0.81 (95% confidence interval, 0.78-0.84) with a sensitivity of 74.39%, a specificity of 76.00%, and a false-positive rate of 52.32% at a fixed detection rate of 90%. Conclusions The combination of multiple routine clinical indicators was valuable in predicting the early outcome of embryos with cardiac activity in viable pregnancies with RSA. However, this model might result in a high false-positive rate with a fixed detection rate of 90%;other markers must be investigated to identify first-trimester RSA once positive embryonic heart motion is established.

关键词： First-trimester recurrent spontaneous abortion fetal ultrasound biomarker embryonic heart motion predictive value predictive algorithm

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Systematic review identifies the design and methodological conduct of studies on machine learning-based prediction models

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JOURNAL OF CLINICAL EPIDEMIOLOGY 2023年 154卷 8-22页

作者： Navarro, Constanza L. Andaur Damen, Johanna A. A. van Smeden, Maarten Takada, Toshihiko Nijman, Steven W. J. Dhiman, Paula Ma, Jie Collins, Gary S. Bajpai, Ram Riley, Richard D. Moons, Karel G. M. Hooft, Lotty Univ Utrecht Univ Med Ctr Utrecht Julius Ctr Hlth Sci & Primary Care Utrecht Netherlands Univ Utrecht Univ Med Ctr Utrecht Cochrane Netherlands Utrecht Netherlands Univ Oxford Ctr Stat Med Nuffield Dept Orthopaed Rheumatol & Musculoskeleta Oxford England Oxford Univ Hosp NHS Fdn Trust NIHR Oxford Biomed Res Ctr Oxford England Keele Univ Ctr Prognosis Res Sch Med Keele England Julius Ctr Hlth Sci & Primary Care Univ Weg 100POB 8550 NL-3508 GA Utrecht Netherlands

Background and Objectives: We sought to summarize the study design, modelling strategies, and performance measures reported in studies on clinical prediction models developed using machine learning ***: We search PubMed for articles published between 01/01/2018 and 31/12/2019, describing the development or the development with external validation of a multivariable prediction model using any supervised machine learning technique. No restrictions were made based on study design, data source, or predicted patient-related health ***: We included 152 studies, 58 (38.2% [95% CI 30.8-46.1]) were diagnostic and 94 (61.8% [95% CI 53.9-69.2]) prognostic studies. Most studies reported only the development of prediction models (n = 133, 87.5% [95% CI 81.3-91.8]), focused on binary outcomes (n = 131, 86.2% [95% CI 79.8-90.8), and did not report a sample size calculation (n = 125, 82.2% [95% CI 75.4-87.5]). The most common algorithms used were support vector machine (n = 86/522, 16.5% [95% CI 13.5-19.9]) and random forest (n = 73/522, 14% [95% CI 11.3-17.2]). Values for area under the Receiver Operating Characteristic curve ranged from 0.45 to 1.00. Calibration metrics were often missed (n 5 494/522, 94.6% [95% CI 92.4-96.3]).Conclusion: Our review revealed that focus is required on handling of missing values, methods for internal validation, and reporting of calibration to improve the methodological conduct of studies on machine learning-based prediction *** review registration: PROSPERO, CRD42019161764. (c) 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://***/licenses/by/4.0/).

关键词： predictive algorithm Risk prediction Diagnosis Prognosis Development Validation

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Bile Is a Selective Elevator for Mucosal Mechanics and Transport

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MOLECULAR PHARMACEUTICS 2023年第12期20卷 6151-6161页

作者： Hanio, Simon Mollmert, Stephanie Mockel, Conrad Choudhury, Susobhan Hopfel, Andreas I. Zorn, Theresa Endres, Sebastian Schlauersbach, Jonas Scheller, Lena Kessler, Christoph Scherf-Clavel, Oliver Bellstedt, Peter Schubert, Ulrich S. Poppler, Ann-Christin Heinze, Katrin G. Guck, Jochen Meinel, Lorenz Univ Wurzburg Inst Pharm & Food Chem D-97074 Wurzburg Germany Max Planck Inst Sci Light D-91058 Erlangen Germany Max Planck Zentrum Phys & Med D-91058 Erlangen Germany Univ Wurzburg Rudolf Virchow Ctr Integrat & Translat Bioimaging D-97080 Wurzburg Germany Univ Wurzburg Inst Organ Chem D-97074 Wurzburg Germany Univ Jena Inst Organ & Macromol Chem D-07743 Jena Germany Univ Zurich Inst Clin Chem CH-8091 Zurich Switzerland Friedrich Schiller Univ Jena Jena Ctr Soft Matter JCSM D-07743 Jena Germany Helmholtz Inst RNA Based Infect Res HIRI Wurzburg 97080 Germany

Mucus mechanically protects the intestinal epithelium and impacts the absorption of drugs, with a largely unknown role for bile. We explored the impacts of bile on mucosal biomechanics and drug transport within mucus. Bile diffused with square-root-of-time kinetics and interplayed with mucus, leading to transient stiffening captured in Brillouin images and a concentration-dependent change from subdiffusive to Brownian-like diffusion kinetics within the mucus demonstrated by differential dynamic microscopy. Bile-interacting drugs, Fluphenazine and Perphenazine, diffused faster through mucus in the presence of bile, while Metoprolol, a drug with no bile interaction, displayed consistent diffusion. Our findings were corroborated by rat studies, where co-dosing of a bile acid sequestrant substantially reduced the bioavailability of Perphenazine but not Metoprolol. We clustered over 50 drugs based on their interactions with bile and mucin. Drugs that interacted with bile also interacted with mucin but not vice versa. This study detailed the dynamics of mucus biomechanics under bile exposure and linked the ability of a drug to interact with bile to its abbility to interact with mucus.

关键词： drug bioavailability predictive algorithm diffusion Brillouin microscopy NMR FCS differential dynamic microscopy

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Chronic obstructive pulmonary disease and coronary disease: COPDCoRi, a simple and effective algorithm for predicting the risk of coronary artery disease in COPD patients

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RESPIRATORY MEDICINE 2015年第8期109卷 1019-1025页

作者： Cazzola, Mario Calzetta, Luigino Matera, Maria Gabriella Muscoli, Saverio Rogliani, Paola Romeo, Francesco Univ Roma Tor Vergata Dept Syst Med Rome Italy Univ Naples 2 Dept Expt Med Naples Italy

Background: Chronic obstructive pulmonary disease (COPD) is often associated with cardiovascular artery disease (CAD), representing a potential and independent risk factor for cardiovascular morbidity. Therefore, the aim of this study was to identify an algorithm for predicting the risk of CAD in COPD patients. Methods: We analyzed data of patients afferent to the Cardiology ward and the Respiratory Diseases outpatient clinic of Tor Vergata University (2010-2012, 1596 records). The study population was clustered as training population (COPD patients undergoing coronary arteriography), control population (non-COPD patients undergoing coronary arteriography), test population (COPD patients whose records reported information on the coronary status). The predicting model was built via causal relationship between variables, stepwise binary logistic regression and Hosmer-Lemeshow analysis. The algorithm was validated via split-sample validation method and receiver operating characteristics (ROC) curve analysis. The diagnostic accuracy was assessed. Results: In training population the variables gender (men/women OR: 1.7, 95%Cl: 1.237-2.5, P < 0.05), dyslipidemia (OR: 1.8, 95%Cl: 1.2-2.5, P < 0.01) and smoking habit (OR: 1.5, 95%CI: 1.2-1.9, P < 0.001) were significantly associated with CAD in COPD patients, whereas in control population also age and diabetes were correlated. The stepwise binary logistic regressions permitted to build a well fitting predictive model for training population but not for control population. The predictive algorithm shown a diagnostic accuracy of 81.5% (95%Cl: 77.78-84.71) and an AUC of 0.81 (95%Cl: 0.78-0.85) for the validation set. Conclusions: The proposed algorithm is effective for predicting the risk of CAD in COPD patients via a rapid, inexpensive and non-invasive approach. 2015 Elsevier Ltd. All rights reserved.

关键词： COPD Coronary artery disease Comorbidities predictive algorithm

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Predicting worsening heart failure hospitalizations in patients with implantable cardioverter defibrillators: is it all about alerts? A pooled analysis of nine trials

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EUROPACE 2024年第2期26卷 euae032页

作者： Botto, Giovanni Luca Sinagra, Gianfranco Bulava, Alan Gargaro, Alessio Timmel, Tobias Giacopelli, Daniele D'Onofrio, Antonio Guedon-Moreau, Laurence ASST Rhodense UO Electrophysiol Viale Carlo Forlanini 95 I-20024 Garbagnate Milanese MI Italy ASUGI Cattinara Hosp Cardiothoracovasc Dept Trieste Italy Univ Trieste Trieste Italy Univ South Bohemia Ceske Budejovice Ceske Budejovice Hosp Fac Hlth & Social Sci Ceske Budejovice Czech Republic Biotronik Italia SPA Clin Unit Cologno Monzese MI Italy Biotron SE & Co KG Ctr Clin Res Berlin Germany Monaldi Hosp Unita Operativa Elettrofisiol Studio & Terapia Ari Naples Italy Univ Lille Lille Univ Hosp Ctr CHU Lille Lille Hauts De France France

Aims To predict worsening heart failure hospitalizations (WHFHs) in patients with implantable defibrillators and remote monitoring, the HeartInsight algorithm (Biotronik, Berlin, Germany) calculates a heart failure (HF) score combining seven physiologic parameters: 24 h heart rate (HR), nocturnal HR, HR variability, atrial tachyarrhythmia, ventricular extrasystoles, patient activity, and thoracic impedance. We compared temporal trends of the HF score and its components 12 weeks before a WHFH with 12-week trends in patients without WHFH, to assess whether trends indicate deteriorating HF regardless of alert status. Methods and results Data from nine clinical trials were pooled, including 2050 patients with a defibrillator capable of atrial sensing, ejection fraction <= 35%, NYHA class II/III, no long-standing atrial fibrillation, and 369 WHFH from 259 patients. The mean HF score was higher in the WHFH group than in the no WHFH group (42.3 +/- 26.1 vs. 30.7 +/- 20.6, P < 0.001) already at the beginning of 12 weeks. The mean HF score further increased to 51.6 +/- 26.8 until WHFH (+22% vs. no WHFH group, P = 0.003). As compared to the no WHFH group, the algorithm components either were already higher 12 weeks before WHFH (24 h HR, HR variability, thoracic impedance) or significantly increased until WHFH (nocturnal HR, atrial tachyarrhythmia, ventricular extrasystoles, patient activity). Conclusion The HF score was significantly higher at, and further increased during 12 weeks before WHFH, as compared to the no WHFH group, with seven components showing different behaviour and contribution. Temporal trends of HF score may serve as a quantitative estimate of HF condition and evolution prior to WHFH. [GRAPHICS] .

关键词： Worsening heart failure hospitalization predictive algorithm Heart failure score Implantable defibrillators Remote monitoring Heart rate

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PHARMACOKINETICS AND DOSAGE ADJUSTMENT OF ANTIBIOTICS DURING CONTINUOUS EXTRACORPOREAL LUNG ASSISTANCE AND HEMOFILTRATION

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ARTIFICIAL ORGANS 1992年第5期16卷 457-460页

作者： KROH, UF HOLL, T FEUSSNER, KD UNIV MARBURG DEPT ANESTHESIOL & INTENS THERAPYW-3550 MARBURGGERMANY

Fifty-eight patients undergoing continuous volume-controlled hemofiltration (CVHF) and extracorporeal lung assistance (ECLA) received drug therapy determined by use of a new predictive algorithm in a validation study. Amikacin, netilmicin, tobramycin, ceftriaxone, vancomycin, and teicoplanin doses were given as predicted from clinical parameters. Corrections were necessary in 15 cases (e.g., CVHF 68% and ECLA 82% precision). There were no statistical differences between predicted and monitored drug doses. The correlation coefficient gave r2 = 0.921. Preliminary results from not yet analyzed drugs (ceftriaxone, teicoplanin) fit well into the curve. Because of rapid intraindividual changes, toxic drugs should continue to be monitored.

关键词： PHARMACOKINETICS DRUG MONITORING predictive algorithm HEMOFILTRATION EXTRACORPOREAL LUNG ASSISTANCE MULTIORGAN FAILURE

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Long-term effectiveness of the combined minute ventilation and patient activity sensors as predictor of heart failure events in patients treated with cardiac resynchronization therapy: Results of the Clinical Evaluation of the Physiological Diagnosis Function in the PARADYM CRT device Trial (CLEPSYDRA) study

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EUROPEAN JOURNAL OF HEART FAILURE 2014年第6期16卷 663-670页

作者： Auricchio, Angelo Gold, Michael R. Brugada, Josep Noelker, G. Arunasalam, Siva Leclercq, Christophe Defaye, Pascal Calo, Leonardo Baumann, Oliver Leyva, Francisco Fdn Cardioctr Ticino Div Cardiol CH-6900 Lugano Switzerland Med Univ S Carolina Charleston SC USA Hosp Clin Barcelona Thorax Inst Barcelona Spain Herz & Diabet Zentrum Nordrhein Westfalen Bad Oeynhausen Germany Desert Valley Hosp Victorville CA USA Univ Hosp Dept Cardiol Rennes France Univ Hosp Dept Cardiol Grenoble France Policlin Casilino Div Cardiol Rome Italy Sorin CRM SAS Clamart France Univ Birmingham Ctr Cardiovasc Sci Birmingham W Midlands England

Aims Monitoring early signs of clinical deterioration could allow physicians to adjust medical treatment for patients at risk of acute heart failure decompensation. To date, several strategies using different surrogate measures of clinical status emerged, but none has yet been proven to predict clinical events. We hypothesized that the Physiological Diagnostic feature, which combines data from minute ventilation and physical activity sensors, predicts heart failure events in patients implanted with cardiac resynchronization therapy with defibrillation (CRT-D) devices. Methods and results The Clinical Evaluation of the Physiological Diagnostic feature in the PARADYM CRT device (CLEPSYDRA) trial is a multicentre, prospective, non-randomized, double-blind study comprising 521 CRT-D patients with heart failure [67.410.1years (mean +/- SD), 82% male, New York Heart Association class III/IV 85.0%/6.7%, QRS 155.3 +/- 26.6ms, left ventricular ejection fraction 25.7 +/- 7.7%]. The objective of the study was the sensitivity and false positive rate of the Physiological Diagnostic algorithm to predict heart failure events within the following month. After a mean follow-up of 17.0 +/- 8.7months, 130 (25.6%) patients experienced a heart failure event. The sensitivity of the algorithm to predict an event was 34% and the false positive rate was 2.4 per patient-year. Conclusion Thirty-four per cent of heart failure events occurring within a month were predicted by the Physiological Diagnostic algorithm, and 2.4 alerts per patient per year were not followed by an heart failure event within the subsequent month.

关键词： Activity Cardiac resynchronization therapy Heart failure monitoring Minute ventilation predictive algorithm

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