e20551 Background: Enzyme activity is at the center of all biological processes. When these activities are misregulated by changes in sequence, expression, or activity, pathologies emerge. Misregulation of protease enzymes such as Matrix Metalloproteinases and Cathepsins play a key role in the pathophysiology of cancer. We describe here a novel class of graphene-based, cost effective biosensors that can detect altered protease activation in a blood sample from early stage lung cancer patients. Methods: The Gene Expression Omnibus (GEO) tool was used to identify proteases differentially expressed in lung cancer and matched normal tissue. Biosensors were assembled on a graphene backbone annotated with one of a panel of fluorescently tagged peptides. The graphene quenches fluorescence until the peptide is either cleaved by active proteases or altered by post-translational modification. 19 protease biosensors were evaluated on 431 commercially collected serum samples from non-lung cancer controls (69%) and pathologically confirmed lung cancer cases (31%) tested over two independent cohorts. Serum was incubated with each of the 19 biosensors and enzyme activity was measured indirectly as a continuous variable by a fluorescence plate reader. Analysis was performed using Emerge, a proprietary predictive and classification modeling system based on massively parallel evolving “Turing machine” algorithms. Each analysis stratified allocation into training and testing sets, and reserved an out-of-sample validation set for reporting. Results: 256 clinical samples were initially evaluated including 35% cancer cases evenly distributed across stages I (29%), II (26%), III (24%) and IV (21%). The case controls included common co-morbidies in the at-risk population such as COPD, chronic bronchitis, and benign nodules (19%). Using the Emerge classification analysis, biosensor biomarkers alone (no clinical factors) demonstrated Sensitivity (Se.) = 92% (CI 82%-99%) and Specificity (Sp.) = 82% (CI 69%-91%) in the out-of-sample set. An independent cohort of 175 clinical cases (age 67±8, 52% male) focused on early detection (26% cancer, 70% Stage I, 30% Stage II/III) were similarly evaluated. Classification showed Se. = 100% (CI 79%-100%) and Sp. = 93% (CI 80%-99%) in the out-of-sample set. For the entire dataset of 175 samples, Se. = 100% (CI 92%-100%) and Sp. = 97% (CI 92%-99%) was observed. Conclusions: Lung cancer can be treated if it is diagnosed when still localized. Despite clear data showing screening for lung cancer by Low Dose Computed Tomography (LDCT) is effective, screening compliance remains very low. Protease biosensors provide a cost effective additional specialized tool with high sensitivity and specificity in detection of early stage lung cancer. A large prospective trial of at-risk smokers with follow up is being conducted to evaluate a commercial version of this assay.
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Computerized Block Games for Automated Cognitive Assessment: Development and Evaluation Study
Background Cognitive assessment using tangible objects can measure fine motor and hand-eye coordination skills along with other cognitive domains. Administering such tests is often expensive, labor-intensive, and error prone owing to manual recording and potential subjectivity. Automating the administration and scoring processes can address these difficulties while reducing time and cost. e-Cube is a new vision-based, computerized cognitive assessment tool that integrates computational measures of play complexity and item generators to enable automated and adaptive testing. The e-Cube games use a set of cubes, and the system tracks the movements and locations of these cubes as manipulated by the player. Objective The primary objectives of the study were to validate the play complexity measures that form the basis of developing the adaptive assessment system and evaluate the preliminary utility and usability of the e-Cube system as an automated cognitive assessment tool. Methods This study used 6 e-Cube games, namely, Assembly, Shape-Matching, Sequence-Memory, Spatial-Memory, Path-Tracking, and Maze, each targeting different cognitive domains. In total, 2 versions of the games, the fixed version with predetermined sets of items and the adaptive version using the autonomous item generators, were prepared for comparative evaluation. Enrolled participants (N=80; aged 18-60 years) were divided into 2 groups: 48% (38/80) of the participants in the fixed group and 52% (42/80) in the adaptive group. Each was administered the 6 e-Cube games; 3 subtests of the Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV; Block Design, Digit Span, and Matrix Reasoning); and the System Usability Scale (SUS). Statistical analyses at the 95% significance level were applied. Results The play complexity values were correlated with the performance indicators (ie, correctness and completion time). The adaptive e-Cube games were correlated with the WAIS-IV subtests (r=0.49, 95% CI 0.21-0.70; P<.001 for Assembly and Block Design; r=0.34, 95% CI 0.03-0.59; P=.03 for Shape-Matching and Matrix Reasoning; r=0.51, 95% CI 0.24-0.72; P<.001 for Spatial-Memory and Digit Span; r=0.45, 95% CI 0.16-0.67; P=.003 for Path-Tracking and Block Design; and r=0.45, 95% CI 0.16-0.67; P=.003 for Path-Tracking and Matrix Reasoning). The fixed version showed weaker correlations with the WAIS-IV subtests. The e-Cube system showed a low false detection rate (6/5990, 0.1%) and was determined to be usable, with an average SUS score of 86.01 (SD 8.75). Conclusions The correlations between the play complexity values and performance indicators supported the validity of the play complexity measures. Correlations between the adaptive e-Cube games and the WAIS-IV subtests demonstrated the potential utility of the e-Cube games for cognitive assessment, but a further validation study is needed to confirm this. The low false detection rate and high SUS scores indicated that e-Cube is technically reliable and usable.
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- Award ID(s):
- 2002721
- NSF-PAR ID:
- 10441128
- Date Published:
- Journal Name:
- JMIR Serious Games
- Volume:
- 11
- ISSN:
- 2291-9279
- Page Range / eLocation ID:
- e40931
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract Objectives To examine the Animal Trauma Triage (ATT) and modified Glasgow Coma Scale (mGCS) scores as predictors of mortality in injured cats.
Design Observational cohort study conducted September 2013 to March 2015.
Setting Nine Level I and II veterinary trauma centers.
Animals Consecutive sample of 711 cats reported on the Veterinary Committee on Trauma (VetCOT) case registry.
Interventions None.
Measurements and Main Results We compared the predictive power (area under receiver operating characteristic curve; AUROC) and calibration of the ATT and mGCS scores to their components. Overall mortality risk was 16.5% (95% confidence interval [CI], 13.9‐19.4). Head trauma prevalence was 11.8% (n = 84). The ATT score showed a linear relationship with mortality risk. Discriminatory performance of the ATT score was excellent (AUROC = 0.87 [95% CI, 0.84‐0.90]). Each ATT score increase of 1 point was associated with an increase in mortality odds of 1.78 (95% CI, 1.61‐1.97,
P < 0.001). The eye/muscle/integument category of the ATT showed the lowest discrimination (AUROC = 0.60). When this component, skeletal, and cardiac components were omitted from score calculation, there was no loss in discriminatory capacity compared with the full score (AUROC = 0.86 vs 0.87, respectively,P = 0.66). The mGCS showed fair performance overall for prediction of mortality, but the point estimate of performance improved when restricted to head trauma patients (AUROC = 0.75, 95% CI, 0.70‐0.80 vs AUROC = 0.80, 95% CI, 0.70‐0.90). The motor component of the mGCS showed the best predictive performance (AUROC = 0.71); however, the full score performed better than the motor component alone (P = 0.004). When assessment was restricted to patients with head injury (n = 84), there was no difference in performance between the ATT and mGCS scores (AUROC = 0.82 vs 0.80,P = 0.67).Conclusion On a large, multicenter dataset of feline trauma patients, the ATT score showed excellent discrimination and calibration for predicting mortality; however, an abbreviated score calculated from the perfusion, respiratory, and neurologic categories showed equivalent performance.
- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.2196/40931
