Prediction and interpretation of deleterious coding variants in terms of protein structural stability

ABSTRACTThe classification of human genetic variants into deleterious and neutral is a challenging issue, whose complexity is rooted in the large variety of biophysical mechanisms that can be responsible for disease conditions. For non-synonymous mutations in structured proteins, one of these is the protein stability change, which can lead to functionality loss. We developed a stability-driven knowledge-based classifier that uses protein structure, artificial neural networks and solvent accessibility-dependent combinations of statistical potentials to predict whether destabilizing or stabilizing mutations are disease-causing. Our predictor yields a balanced accuracy of 71% in cross validation. As expected, it has a very high positive predictive value of 89%: it predicts with high accuracy the subset of mutations that are deleterious because of stability issues, but is by construction unable of classifying variants that are deleterious for other reasons. Its combination with an evolutionary-based predictor increases the balanced accuracy up to 75%, and allowed predicting more than 1/4 of the deleterious variants with 95% positive predictive value. Our method, called SNPMuSiC, can be used with both experimental and structural models and compares favorably with other prediction tools on several independent test sets. It constitutes a step towards interpreting variant effects at the molecular scale.

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Cadence-based Classification of Minimally Moderate Intensity During Overground Walking in 21- to 40-Year-Old Adults

Journal of Physical Activity and Health ◽

10.1123/jpah.2019-0261 ◽

2019 ◽

Vol 16 (12) ◽

pp. 1092-1097

Author(s):

Elroy J. Aguiar ◽

Zachary R. Gould ◽

Scott W. Ducharme ◽

Chris C. Moore ◽

Aston K. McCullough ◽

...

Keyword(s):

Positive Predictive Value ◽

Predictive Value ◽

Classification Accuracy ◽

Moderate Intensity ◽

Overground Walking ◽

Cross Sectional ◽

Old Adults ◽

Metabolic Equivalents ◽

Sensitivity Specificity

Background: A walking cadence of ≥100 steps/min corresponds to minimally moderate intensity, absolutely defined as ≥3 metabolic equivalents (METs). This threshold has primarily been calibrated during treadmill walking. There is a need to determine the classification accuracy of this cadence threshold to predict intensity during overground walking. Methods: In this laboratory-based cross-sectional investigation, participants (N = 75, 49.3% women, age 21–40 y) performed a single 5-minute overground (hallway) walking trial at a self-selected preferred pace. Steps accumulated during each trial were hand tallied and converted to cadence (steps/min). Oxygen uptake was measured using indirect calorimetry and converted to METs. The classification accuracy (sensitivity, specificity, overall accuracy, and positive predictive value) of ≥100 steps/min to predict ≥3 METs was calculated. Results: A cadence threshold of ≥100 steps/min yielded an overall accuracy (combined sensitivity and specificity) of 73.3% for predicting minimally moderate intensity. Moreover, for individuals walking at a cadence ≥100 steps/min, the probability (positive predictive value) of achieving minimally moderate intensity was 80.3%. Conclusions: Although primarily developed using treadmill-based protocols, a cadence threshold of ≥100 steps/min for young adults appears to be a valid heuristic value (evidence-based, rounded, practical) associated with minimally moderate intensity during overground walking performed at a self-selected preferred pace.

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Development of an Algorithm for Surveillance of Ventilator-Associated Pneumonia With Electronic Data and Comparison of Algorithm Results With Clinician Diagnoses

Infection Control and Hospital Epidemiology ◽

10.1086/524332 ◽

2008 ◽

Vol 29 (1) ◽

pp. 31-37 ◽

Cited By ~ 59

Author(s):

Michael Klompas ◽

Ken Kleinman ◽

Richard Platt

Keyword(s):

Intensive Care ◽

Positive Predictive Value ◽

Intensive Care Units ◽

Predictive Value ◽

Ventilator Associated Pneumonia ◽

Surgical Intensive Care ◽

Electronic Data ◽

Prospective Comparison ◽

Control And Prevention ◽

High Positive Predictive Value

Objective.Surveillance for ventilator-associated pneumonia (VAP) using standard Centers for Disease Control and Prevention (CDC) criteria is labor intensive and involves many subjective assessments. We sought to improve the efficiency and objectivity of VAP surveillance by adapting the CDC criteria to make them amenable to evaluation with electronic data.Design.Prospective comparison of the accuracy of VAP surveillance by use of an algorithm with responses to prospective queries made to intensive care physicians. CDC criteria for VAP were used as a reference standard to evaluate the algorithm and clinicians' reports.Setting.Three surgical intensive care units and 2 medical intensive care units at an academic hospital.Methods.A total of 459 consecutive patients who received mechanical ventilation for a total of 2,540 days underwent surveillance by both methods during consecutive 3-month periods. Electronic surveillance criteria were chosen to mirror the CDC definition. Quantitative thresholds were substituted for qualitative criteria. Purely subjective criteria were eliminated. Increases in ventilator-control settings were taken to indicate worsening oxygenation. Semiquantitative Gram stain of pulmonary secretion samples was used to assess whether there was sputum purulence.Results.The algorithm applied to electronic data detected 20 patients with possible VAP. All cases of VAP were confirmed in accordance with standard CDC criteria (100% positive predictive value). Prospective survey of clinicians detected 33 patients with possible VAP. Seventeen of the 33 possible cases were confirmed (52% positive predictive value). Overall, 21 cases of confirmed VAP were identified by either method. The algorithm identified 20 (95%) of 21 known cases, whereas the survey of clinicians identified 17 (81%) of 21 cases.Conclusions.Surveillance for VAP using electronic data is feasible and has high positive predictive value for cases that meet CDC criteria. Further validation of this method is warranted.

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Automated screening tool for Subcutaneous Implantable Defibrillator in Brugada syndrome has a high eligibility rate which is predicted by simple electrocardiographic parameters

European Heart Journal ◽

10.1093/ehjci/ehaa946.0793 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

S Marelli ◽

D Kukavica ◽

A Mazzanti ◽

T Chargeishvili ◽

A Trancuccio ◽

...

Keyword(s):

Positive Predictive Value ◽

Brugada Syndrome ◽

Predictive Value ◽

Screening Tool ◽

Screening Tools ◽

Molecular Medicine ◽

Funding Source ◽

S Wave ◽

High Positive Predictive Value ◽

Automated Screening

Abstract Background Manual electrocardiographic (ECG) screening tools for the use of subcutaneous cardiac defibrillator (S-ICD) have been associated with high ineligibility rates in Brugada syndrome patients (BrS). Although recent works identified ECG parameters for S-ICD eligibility in general population, automated screening tool (AST) for S-ICD eligibility have not even been assessed in large series of patients with BrS. Purpose This study evaluates the AST-derived eligibility rates for an S-ICD in patients with BrS, and ECG parameters associated with S-ICD eligibility. Methods Screening for S-ICD eligibility was performed using AST in 194 consecutive patients with BrS. Eligibility was defined when at least one of the three vectors was acceptable both in supine and standing position. Twelve-lead ECGs were registered during the screening. ECG parameters associated with AST eligibility were identified using multivariable logistical regression. Results Our study population consisted of 194 patients, with male preponderance (n=165/194; 85%); and were 43±12 years old at the time of screening. Majority of patients presented a spontaneous type 1 pattern during screening (n=128/194; 66%), with an average pattern height of 3±3 mm. Remarkably, 93% of patients passed the screening with AST. No differences in eligibility rates in terms of gender (93% males vs. 93% females eligible; p=1) and age (48±9 years non-eligible vs. 42±12 eligible; p=0.07) existed. Notably, our eligibility rate was 2.5 times higher than rates reported in literature when using manual screening tools (p=0.023). Independent 12-lead ECG parameters (Table) associated with AST eligibility were duration of S wave <80 ms in aVF and R/T ratio ≥3 in lead II (Figure), which have a high positive predictive value (97% and 99%, respectively) for screening eligibility. Conclusions Most BrS patients (93%) are eligible for S-ICD when AST is used. S wave <80 ms in aVF, and R/T ratio ≥3 in lead II have a high positive predictive value for S-ICD eligibility. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): The Italian Ministry of Research and University Dipartimenti di Eccellenza 2018–2022 grant to the Molecular Medicine Department (University of Pavia)

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Evaluation of a novel immunoassay to detect p-tau Thr217 in the CSF to distinguish Alzheimer disease from other dementias

Neurology ◽

10.1212/wnl.0000000000010814 ◽

2020 ◽

Vol 95 (22) ◽

pp. e3026-e3035

Author(s):

Jozef Hanes ◽

Andrej Kovac ◽

Hlin Kvartsberg ◽

Eva Kontsekova ◽

Lubica Fialova ◽

...

Keyword(s):

Alzheimer Disease ◽

Positive Predictive Value ◽

Diagnostic Accuracy ◽

Predictive Value ◽

Healthy Controls ◽

Class Iii ◽

Total Tau ◽

Β Amyloid ◽

Healthy Participants

ObjectiveTo investigate whether tau phosphorylated at Thr217 (p-tau T217) assay in CSF can distinguish patients with Alzheimer disease (AD) from patients with other dementias and healthy controls.MethodsWe developed and validated a novel Simoa immunoassay to detect p-tau T217 in CSF. There was a total of 190 participants from 3 cohorts with AD (n = 77) and other neurodegenerative diseases (n = 69) as well as healthy participants (n = 44).ResultsThe p-tau T217 assay (cutoff 242 pg/mL) identified patients with AD with accuracy of 90%, with 78% positive predictive value (PPV), 97% negative predictive value (NPV), 93% sensitivity, and 88% specificity, compared favorably with p-tau T181 ELISA (52 pg/mL), showing 78% accuracy, 58% PPV, 98% NPV, 71% specificity, and 97% sensitivity. The assay distinguished patients with AD from age-matched healthy controls (cutoff 163 pg/mL, 98% sensitivity, 93% specificity), similarly to p-tau T181 ELISA (cutoff 60 pg/mL, 96% sensitivity, 86% specificity). In patients with AD, we found a strong correlation between p-tau T217 and p-tau T181, total tau and β-amyloid 40, but not β-amyloid 42.ConclusionsThis study demonstrates that p-tau T217 displayed better diagnostic accuracy than p-tau T181. The data suggest that the new p-tau T217 assay has potential as an AD diagnostic test in clinical evaluation.Classification of evidenceThis study provides Class III evidence that a CSF immunoassay for p-tau T217 distinguishes patients with AD from patients with other dementias and healthy controls.

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Multi-Target Stool DNA Has a High Positive Predictive Value as an Interval Test After Colonoscopy

The American Journal of Gastroenterology ◽

10.14309/00000434-201810001-00291 ◽

2018 ◽

Vol 113 (Supplement) ◽

pp. S162-S163

Author(s):

Jason D. Eckmann ◽

Derek Ebner ◽

Jamie Bering ◽

Allon Kahn ◽

Eduardo A. Rodriguez ◽

...

Keyword(s):

Positive Predictive Value ◽

Predictive Value ◽

High Positive Predictive Value ◽

Stool Dna

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Classifying Ectopia Lentis in Marfan Syndrome into Five Grades of Increasing Severity

Journal of Clinical Medicine ◽

10.3390/jcm9030721 ◽

2020 ◽

Vol 9 (3) ◽

pp. 721

Author(s):

Jean-Christophe Zech ◽

Audrey Putoux ◽

Evelyne Decullier ◽

Anne-Emmanuelle Fargeton ◽

Patrick Edery ◽

...

Keyword(s):

Positive Predictive Value ◽

Marfan Syndrome ◽

Predictive Value ◽

Anterior Segment ◽

Control Group ◽

Clinical Practices ◽

Predictive Values ◽

Ectopia Lentis ◽

Grade Classification

Purpose: To describe a five-grade classification of ectopia lentis in Marfan syndrome (MFS) and to evaluate the positive predictive value of the early grades of ectopia lentis. Methods: We prospectively included MFS patients and their healthy relatives. The anterior segment examination was classified into grades 0 to 5, and we studied the sensitivity, specificity, and positive predictive value of ectopia lentis in this classification. Results: Seventy-four MFS patients and thirty-six healthy controls were examined. In the MFS group, grades 1, 2, 3, and 4 were present in 15, 24, 17, and 7 patients, respectively, whereas 11 patients in this group did not present ectopia lentis. In the control group, grades 0 and 1 were observed in 30 and 6 individuals, respectively. Sensitivity to ectopia lentis of at least grade 2 was 64.9%, with 100% specificity, whereas sensitivity to ectopia lentis of at least grade 1 was 85.1%, with 83.3% specificity. The positive predictive value of ectopia lentis that was greater than or equal to grade 2 was 100%, whereas that of ectopia lentis greater than or equal to grade 1 was 91.3%. Conclusions: High positive predictive values s were found to be associated with grades 2 and higher of the five-grade classification of ectopia lentis. This classification should help to harmonize clinical practices for this major feature of MFS.

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A 2-Stage Ovarian Cancer Screening Strategy Using the Risk of Ovarian Cancer Algorithm (ROCA) Identifies Early-Stage Incident Cancers and Demonstrates High Positive Predictive Value

Obstetrical & Gynecological Survey ◽

10.1097/01.ogx.0000442828.54138.67 ◽

2014 ◽

Vol 69 (1) ◽

pp. 26-27

Author(s):

Karen H. Lu ◽

Steven Skates ◽

Mary A. Hernandez ◽

Deepak Bedi ◽

Therese Bevers ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Screening ◽

Positive Predictive Value ◽

Predictive Value ◽

Early Stage ◽

Screening Strategy ◽

Ovarian Cancer Screening ◽

High Positive Predictive Value

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Use of International Classification of Diseases, Ninth Revision Clinical Modification Codes and Medication Use Data to Identify Nosocomial Clostridium difficile Infection

Infection Control and Hospital Epidemiology ◽

10.1086/606164 ◽

2009 ◽

Vol 30 (11) ◽

pp. 1070-1076 ◽

Cited By ~ 40

Author(s):

Mia Schmiedeskamp ◽

Spencer Harpe ◽

Ronald Polk ◽

Michael Oinonen ◽

Amy Pakyz

Keyword(s):

Drug Therapy ◽

Clostridium Difficile ◽

Positive Predictive Value ◽

Predictive Value ◽

International Classification Of Diseases ◽

International Classification ◽

Adult Patients ◽

Classification Of Diseases ◽

Sensitivity Specificity

Objective.The International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code for Clostridium difficile infection (CDI) is used for surveillance of CDI. However, the ICD-9-CM code alone cannot separate nosocomial cases from cases acquired outside the institution. The purpose of this study was to determine whether combining the ICD-9-CM code with medication treatment data for CDI in hospitalized patients could enable us to distinguish between patients with nosocomial CDI and patients who were admitted with CDI. The primary objective was to compare the sensitivity, specificity, and predictive value of using the combination of ICD-9-CM code for CDI and CDI treatment records to identify cases of nosocomial CDI with the sensitivity, specificity, and predictive value of using the ICD-9-CM code alone.Design.Validation sample cross-sectional study.Setting.Academic health center.Methods.Administrative claims data from July 1, 2004, to June 30, 2005, were queried to identify adults discharged with an ICD-9-CM code for CDI and to find documentation of CDI therapy with oral vancomycin or metronidazole. Laboratory and medical records were queried to identify symptomatic CDI toxin-positive adult patients with nosocomial CDI and were compared with records of patients whose cases were predicted to be nosocomial by means of ICD-9-CM code and CDI therapy data.Results.Of 23,920 adult patients discharged from the hospital, 62 had nosocomial CDI according to symptoms and toxin assay. The sensitivity of the ICD-9-CM code alone for identifying nosocomial CDI was 96.8%, the specificity was 99.6%, the positive predictive value was 40.8%, and the negative predictive value was 100%. When CDI drug therapy was included with the ICD-9-CM code, the sensitivity ranged from 58.1% to 85.5%, specificity was virtually unchanged, and the range in positive predictive value was 37.9%–80.0%.Conclusion.Combining the ICD-9-CM code for CDI with drug therapy information increased the positive predictive value for nosocomial CDI but decreased the sensitivity.

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