Interval Analysis Research Articles

A General Framework for the Multiple Nonparametric Behrens-Fisher Problem With Dependent Replicates.

In many trials and experiments, subjects are not only observed once but multiple times, resulting in a cluster of possibly correlated observations (e.g., brain regions per patient). Observations often do not fulfill model assumptions of mixed models and require the use of nonparametric methods. In this article, we develop and present a purely nonparametric rank-based procedure that flexibly allows the unbiased and consistent estimation of the Wilcoxon-Mann-Whitney effect in clustered data designs. Compared with existing methods, we allow flexible weights to be used in effect estimation. Additionally, we develop global and multiple contrast test procedures to test null hypotheses formulated regarding the generalized Mann-Whitney effects and for the computation of range-preserving simultaneous confidence intervals in a unified way. Extensive simulation studies show that these methods control the type-I error rate well and have reasonable power to detect alternatives in various situations.

Asymmetric interval numbers: A new approach to modeling uncertainty

This paper introduces Asymmetric Interval Numbers (AINs), a novel type of interval numbers that combines the straightforward identification characteristic of classical interval numbers with the advanced capability for modeling uncertainty found in fuzzy sets, all while maintaining simplicity. AINs incorporate the expected value within the interval, providing a more accurate representation of the uncertainty of the data compared to the classical interval numbers. We define basic arithmetic operations for AINs, discuss their properties, and provide proofs. Additionally, we present theorems on symmetry and asymmetry for fundamental binary and unary operations, enhancing the mathematical framework for AINs. Several illustrative examples demonstrate the practical application of AINs. Although challenges remain, such as exploring performance with different distributions and reducing overestimation, AINs present a promising advancement in interval arithmetic. This study underscores the practical and theoretical implications of AINs, paving the way for further research and application in diverse scientific and industrial contexts.

Interval Time Series Forecasting: An Innovative Approach Transforming Interval to Single Time Series

ABSTRACTInterval Time Series are present in everyday life. An example is the opening and closing value of some stock in a market for certain time intervals. The forecasting plays an essential role in many financial organisations. The development of new mathematical tools or improving the existing ones will lead to more accurate forecasting techniques. Interval Arithmetic is a mathematical field that uses intervals by nature and algorithms that use it are involved in the solution of Interval Time Series. Another classical algorithm is VAR models. In this paper, a method that comes from the insurance sector is used to forecast Brent Oil monthly values. The innovation of what we propose is that it converts the Interval Time Series system into a single time series and can propagate the results back to each time series of the system. This way the researcher works with only one time series instead of two (or more). The forecasting algorithm is a choice of the researcher, expediting the development of forecasting (even ARIMA can be applied). We demonstrate our methodology in forecasting the Brent Oil monthly prices by applying the ANFIS algorithm.

A process-oriented analysis of speech and silent intervals in responses to serial naming tasks.

A process-oriented analysis of speech and silent intervals in responses to serial naming tasks.

Uncertainty analysis of hypersonic flight dynamics under elastic effects

Abstract In addressing the aerodynamic-elastic coupling issues of hypersonic vehicles, this study delves into the analysis of the elastic deformation of the aircraft based on mechanistic understanding. It employs the Interval Analysis Method based on Polynomial Approximations to conduct uncertainty analysis of the aerodynamic model under elasticity, delineating the range of uncertainty in the aerodynamic model influenced by elastic deformation. The aerodynamic force of the aircraft under elasticity is connected with the rigid body, and then the aerodynamic layout of the aircraft fuselage and control surface after elastic deformation is calculated to study the influence of the elastic effect on the aerodynamic force. The results show that the change caused by uncertainty has a relatively small effect on lift but a relatively large effect on drag and pitching moment.

Continuous QTc monitoring for patients intoxicated with QTc prolonging medication in the ED: a proof of principle.

Background: To determine when patients presenting with an overdose of QT-interval prolonging drugs can be discharged safely can be challenging, especially when the moment of intoxication and/or the substance(s) ingested are unknown. Objective: In a proof of principle study, we aimed to study if continuous QTc interval analysis can be used to establish optimal observation duration of patients with an intoxication with QTc prolonging medication. Methods: For patients presenting with an intoxication with QT-interval prolonging drugs in the emergency department (ED), ECG signals sampled at 500Hz were pre-processed, and the average heart rate corrected QT-interval (QTc) per 5 minutes was calculated and plotted against time. A third order polynomial was fitted to visualize when the QTc would be highest (the electrophysiological Tmax). This point in time was compared to the estimated Tmax based on pharmacokinetic properties of the ingested substance. Results: In a retrospective biobank-based study, a total of 22 ED visits (of 15 patients) were analyzed. An electrophysiological Tmax could be calculated for 17/22 visits. The remaining five patients presented either long after the electrophysiological Tmax (n=4) or were admitted to the ward before reaching the Tmax (n=1). The average (SD) difference between the estimated Tmax based on drug properties and the calculated electrophysiological Tmax was 18 (133) minutes (range -158-296 minutes). Despite the wide range, there was a significant correlation between recorded electrophysiological Tmax and estimated Tmax (r=0.67, p=0.012). Conclusion: Continuous electrophysiological monitoring can be used as an adjunct to determine the toxicokinetic Tmax for patients presenting with an intoxication, especially when the time of ingestion or the substance ingested are unknown.

Leveraging Slither and Interval Analysis to build a Static Analysis Tool

Leveraging Slither and Interval Analysis to build a Static Analysis Tool

USING RETROSPECTIVE DATA TO ASSESS THE UNCERTAINTY OF INDICATORS OF BIOLOGICAL SAFETY OF FOOD AND FEED RAW MATERIALS

The results of the analysis of the advantages and disadvantages of the use of retrospective data for the implementation of the evaluation of uncertainty in the measurement of indicators of biological safety of food and feed raw materials are given. The model measurement procedure used quantitative determination of genetically modified organisms by means of polymerase chain reaction in real time 250 measurement results of certified reference material with a content of 0.1% genetically modified soybean line obtained under conditions of intra-laboratory reproducibility and 10 results of relevant inter-laboratory comparisons with the participation accredited provider. The suitability of retrospective data was assessed by the Shapiro-Wilk criterion and statistical controllability analysis using standardized score charts and modified Shewhart charts, uncertainty by 4 methods described in general and branch international guidelines and regulations. The results of using a combination of modified Shewhart maps demonstrate the acceptability of this approach for establishing the suitability of retrospective measurement results as input data for uncertainty assessment. By integrating additional "fitness limits" to a set of standardized control limits, this analysis acquires the ability to simultaneously establish not only stability, through the interpretation of geometric patterns, but also compliance with specific criteria. Using this approach, objective evidence of the suitability of retrospective data for estimating measurement uncertainty was obtained. The distribution of retrospective data obtained under conditions of intralaboratory reproducibility is assumed to be normal. As a result of the assessment of statistical controllability and compliance with the established criteria, objective evidence of the suitability of the data for uncertainty assessment was obtained. Analysis of uncertainty intervals of subgroups with the volume of 25 measurements, using 4 assessment methods, demonstrated significant variability in the results of measuring biological safety indicators. The uncertainty interval could narrow or widen by almost 100% of the value within fifty measurements. Median values obtained using different uncertainty estimation methods were 2.69%, 22.69%, 39.23, and 43.08%. This variability is due to the limited coverage of sources of uncertainty, which is inherent in each of the analyzed methods. The most optimal method is the evaluation based on the routine measurement of the certified reference material. Retrospective results of routine measurement of certified reference material and interlaboratory comparisons are an effective source of input data for assessing the uncertainty of the results of measuring biological safety indicators of agricultural raw materials. There is a need for further research to establish an assessment model that will provide an opportunity to take into account the optimal number of influential sources of uncertainty that are inherent in biological systems and cannot be simultaneously taken into account using existing approaches offered by standard assessment methods.

121 year after Einthoven: show me the normal ECG?

Abstract Background The clinical electrocardiogram (ECG) is measured about 120 years. The interpretations of the ECG is an art mastered by only few. Rhythm and Interval analysis is relative reliable and well supported by the available ECG machines. However, the interpretation of the ECG waveform and where it starts to deviate from the normal waveforms is poorly defined for the clinical practice. To support the anatomical relationship of the ECG, the PathECG has been developed as part of the CineECG tool, expanding the view on the ECG. In this study normal ECG distributions were created from a public available database to enable a) visual comparison of the ‘normality’ of the ECG and PathECG and b) build a predictive model to classify an ECG as normal or abnormal. Purpose To create an objective and 3D visual comparison of an ECGs to "normal ECGs". Methods From the (Physionet) PTB-XL database (Germany) all verified ECGs with known gender were selected. From the these ECGs a median ventricular beat was automatically constructed and subsequently resampled to have a standardized number of samples (Figure: Normal ECGs on top of abnormal ECGs). These resampled ECGs were also converted to their equivalent PathECG. From the normal labeled ECGs (3124 female, 2283 male) distributions were created, representing the normal ECG for male, female or the combined group. With these distributions a percentage of ECG segments (QRS, ST, T wave) can be identified as being outside this distribution, and thus as potentially abnormal. A logistic regression model was fitted to determine the optimal outlier removal per segment for the ECG waveforms and the PathECG to classify and ECG as normal or abnormal per gender group. The performance was tested on the CPSC (Hong Kong) public available ECG database. Results The abnormal ECG data in both databases contained approximately 1/3 normal ECG, atrial and ventricular arrhythmias and 1/3 ischemia and conduction disorders. The performance (AUC) of the logistic regression model on the PTB-XL and CPSC data respectively was MALES: 87.5% - 81.5%, FEMALES: 86.7% - 83.7%, and COMBINED: 86.8%-82.9%. The visual overlay of the ECG significantly supports the identification of abnormal segments (Figure: Normal ECG distribution example). Conclusions The overlay of an ECG and PathECG on the normal distribution supports the identification and verification of abnormal ECGs. This method might increase the ability of less experienced ECG readers, like general practitioners, to identify patients that need to be transferred to a cardiologist. This method could also be used for the classification of P-waves, paediatric ECGs or ECGs in specific patient groups.Normal ECGs on top of abnormal ECGsNormal ECG distribution example

Prediction of nonsustained ventricular tachycardia development by the analysis of premature ventricular complex-related intervals on 24-hour rhythm monitoring and testing a novel index

Abstract Introduction Ventricular tachycardia (VT) and ventricular fibrillation (VF) are life- threatening arrhythmias, with non-sustained ventricular tachycardia (NSVT) serving as a potential precursor. Identifying individuals at risk of NSVT is crucial for effective management and prevention of sudden cardiac death in high-risk patients. In daily clinical practice, premature ventricular complex (PVC) and sometimes NSVT are frequently detected on 24-hour ambulatory rhythm monitoring. Purpose In this study, we aimed to predict the development of NSVT by analyzing PVC morphology and intervals in 24- hour ambulatory rhythm monitorings. Methods A retrospective analysis of 24-hour ambulatory rhythm monitoring recordings from 2018 to 2023 was conducted. Inclusion criteria required clear measurement of PVC intervals, at least 100 PVC in the recording, and two preceding normal QRS beats. NSVT diagnosis was based on four consecutive PVC lasting <30 s and a rate >100/min. Various PVC-related parameters were analyzed, and new variables were derived. Statistical analysis included Mann-Whitney U tests and ROC analysis. Results The study included 202 patients, revealing significant differences in several VES temporal variables between groups with only PVC (Group I) and PVC with NSVT (Group II). Notably, Age-Adjusted Sum of Intervals Index (AASI Index-(100 x [(Tp-to- QRSvpa)+(coupling time)+(Qtc1)]/age), long coupling times, extended Tp-to-QRSvpaintervals, and prolonged Tpe-vpa intervals were associated with NSVT development. Age played a pivotal role in predicting NSVT when integrated into a specific variable AASI index. The optimal cut-off value was 4.21, with 84% sensitivity and specificity. Conclusion The study suggests that ventricular arrhythmias may be predicted using temporal parameters of PVC, especially when age is included as a modifier. The AASI index calculated on a PVC and preceeding two normal beats on 24-hour ambulatory rhythm monitoring seems to be promising parameter. These findings hold potential for future development of artificial intelligence-based algorithms for use in any PVC to identify at-risk patient groups, provided larger datasets are utilized to refine predictive models.Variables included in the analysis for cDefinitions of variables and ROC curve

Comprehensive cardiac interval analysis in the WEAR-TECH study cohort by comparing the Apple Watch Series 6 against a simultaneous 12-lead ECG

Abstract Background Wearable devices capable of single-lead electrocardiograms (ECGs) are becoming increasingly prevalent. Exploring their potential for screening conditions beyond atrial fibrillation presents a compelling research opportunity. Objective This study evaluates the agreement between the Apple Watch Series 6 (APW) and simultaneous 12-lead ECG (12L) recordings in measuring PR, QRS, RR, QT, and QTc intervals in a cohort of National Health Service (NHS) cardiology patients. Methods We analysed data from the WEAR-TECH study, which included 400 simultaneous recordings from the APW and 12L ECGs. We included patients with ECGs in sinus rhythm and excluded patients with poor-quality ECGs. No exclusions were made based on underlying cardiac conditions. Measurements of the best three consecutive waveforms in leads I, II, and V5 were performed using EP Calipers (EP Studio) by a single observer. Leads I and II were compared for PR, QRS, and RR intervals, while leads I, II, and V5 were compared for QT and QTc intervals. QTc was calculated using Bazett’s formula. Differences between APW and 12L ECGs were assessed using linear mixed effects regression models with random intercepts and type II Wald chi-square tests. Clinical agreement was measured by averaging the waveforms from 12L leads and the APW and calculating the difference between the means. Results Out of 324 paired ECGs from 162 patients, 8 were excluded due to missing or uninterpretable data. The median age was 64 (IQR: 54 - 74) years, with 117 (75%) being male. PR, QRS, and RR intervals from the APW agreed best with 12L lead II, and QT and QTc intervals from APW agreed best with 12L lead V5, with no significant difference found in any of these comparisons. PR and RR intervals significantly differed between APW and 12L lead I, with the APW tending to overestimate relative to the 12L. Additionally, significant differences were found in 12L leads I and II for QT and QTc, with APW also tending to overestimate these intervals (see Table 1). Clinical agreement between the APW and all 12L leads was a minimum of 21% for a <10ms difference, 45% for a <20ms difference, and 71% for a <40ms difference (see Figure 1). Conclusions The Apple Watch Series 6 demonstrates promising potential for initial outpatient monitoring of PR, QRS, RR, QT, and QTc intervals with reasonable agreement to 12L ECG. This is especially true in lead II for PR, QRS, and RR intervals and lead V5 for QT and QTc intervals. Further reductions in variance between APW and 12L ECG measurements could enhance clinical decision-making accuracy.Table 1:The p-values of APW vs 12L leadFigure 1:Agreement of APW to 12L leads

Potential reformulation of food products two years after implementation of Nutri-Score in Belgium

Abstract Background Nutri-score is a front of pack labeling system that provides consumers with simplified information of the nutritional quality of food products. It is based on a five color (green to red) or letter (A to E) scheme that grades the quality of the product using an algorithm that takes into account the energy, sugar, saturated fats, salt, fiber, protein content, and percent of fruits and vegetables. In Belgium, Nutri-score was implemented on a voluntary basis in April 2019. This study aims to explore reformulation of products with Nutri-score by comparing their nutrient content and Nutri-score distribution in 2019 and 2021. Methods Product data from one of the major retailers was used in the analysis. Similar products in 2019 and 2021 with matched barcodes were used. Descriptive statistics were computed and statistical analyses such as the signed rank test and the McNemars test were performed to respectively evaluate the changes in the nutrient content and Nutri-score. The tests were conducted at 5% level of significance. Results From the matched sample of 668 products, about 55% had a Nutri-score of A and B in both 2019 and 2021. The proportion of food products with Nutri-Score of A/B and of D/E was not significantly different after two years of Nutri-Score implementation. Results showed a significant decrease in the median energy content of dairy, sauces, and meat products and in the median sugar content of dairy and fruit and vegetable products. There was a significant increase in the median fiber content of the dairy, meat products, and non-alcoholic beverages. For all food groups, the salt content of the products in 2019 and 2021 was not significantly different. Conclusions This two-year interval analysis described the changes in the classification and reformulation of the products with Nutri-score. Favorable changes in the nutrient quality of the product profiles reveals improvement in their reformulation. Key messages • In this analysis, changes has been observed in the nutrient content of food products between 2019 and 2021. • Producers or manufacturers should continue working on commitments to enhance the nutritional quality of the products delivered to consumers.

Interval analysis for neural networks with application to fault detection

Interval analysis for neural networks with application to fault detection

Improving the Utility of a Cancer Gene Mutation Panel for Multiple Myeloma Patients

Abstract Multiple myeloma is a plasma cell malignancy that accounts for 1-2% of all cancer diagnoses and 10-15% of hematopoietic neoplasms. Clonal rearrangement of the IG locus suggests a monoclonal model for pathogenesis. The presence of cytogenetic abnormalities in >90% of cases suggests transformation by chromosomal instability and rearrangement. Classification and consensus guidelines by The International Myeloma Working Group (IMWG) and others reflect this by categorizing myeloma based on ploidy, translocations, and chromosomal abnormalities. Interestingly, a portion of Emory’s test volume for cancer gene mutation profiling by second generation short-read sequencing is for multiple myeloma cases. This suggests our 75-gene myeloid neoplasm panel (MMP75) is being utilized for medical purposes that are not met by cytogenetic and microarray characterizations performed during the diagnostic workup of multiple myeloma. Inspired by this observation, this study investigates providers motivations for ordering MMP75 and assesses the adequacy of our current implementation for their stated purposes. Anecdotes from ordering physicians indicate interest in MMP75 results when informing prognosis, selecting treatments, and evaluating for treatment associated secondary neoplasms. A more formal survey is underway that will statistically capture how the results of MMP75 testing were ultimately used: to inform diagnosis, determine prognosis, guide treatment, explain progression, identify/rule-out secondary neoplasia, or no effect on management. We also explore the variants called by MMP75 when performed using bone marrow from patients who received a cytogenetic workup for multiple myeloma at some point. A retrospective analysis of the 5-year interval between Jan 2019 and Jan 2024 identified 156 cases meeting this criterion. The number of pathogenic variants per case ranged between 1 and 8, with mutations detected across 42 genes. The genes most frequently identified with pathogenic mutations were TP53 (22.4%), DNMT3A (19.2%), TET2 (14.7%), and ASXL1 (12.2%). All four have been associated with adverse outcomes in patients with multiple myeloma. Activating events in therapeutic targets included mutations in the RAS/RAF pathway (16.7%), JAK/STAT signaling (2.6%), and the kinase KIT (0.6%). While these findings support the use of MMP75 for detection of relevant mutations, the genetic variants identified are not unique to multiple myeloma. Mutations detected in DNMT3A, TET2, and ASXL1 are common in clonal hematopoiesis of indeterminant potential (CHIP) and myeloid neoplasms. Hotspot mutations in TP53 and activating events in the RAS/RAF pathway also occur in various hematologic malignancies. This test therefore detects events that occur in both the plasma cell compartment and other cells of origin. This encumbers distinguishing variants that inform on a patient’s multiple myeloma from events that suggest a secondary neoplasm. Future directions include determining whether the effect of plasma cell enrichment on a mutations variant allele frequency (VAF) in repeat testing can help distinguish true multiple myeloma variants from events in other cells.

Dynamic modeling and reliability analysis of the ball bearing rotating accuracy considering the uncertain bearing-shaft interference fit

The rotating accuracy of the rolling bearing is closely related to its precision class and the actual fitting parameters. However, there are few quantitative evaluation models to describe their relationships. In this paper, considering the effect of the uncertain but bounded interference amounts between the bearing inner ring and the shaft, the Chebyshev interval analysis method is utilized and a rotating accuracy dynamic reliability model is presented based on the two degrees of freedom (2-DOF) rotor-ball bearing system. Firstly, the relationships between the bearing radial clearance and bearing-shaft interference amounts are investigated based on the shaft-bearing interference fit model. Thus, in terms of Chebyshev interval analysis method, the 2-DOF rotor-ball bearing system with uncertain bearing-shaft interference amounts is established. Then the rotating accuracy dynamic reliability model of the ball bearing is presented based on the Chebyshev interval theory. The effects of the average values and deviation coefficients of the initial interference amounts on the actual interference amounts, radial clearance and the resultant rotating accuracy dynamic reliability of the ball bearing are analyzed. The results show that the uncertain bearing-shaft interference amounts have a significant effect on the rotating accuracy dynamic reliability of the ball bearing and reasonable design could improve the rotating accuracy of the ball bearing. The results calculated by the present study are compared to the Monte Carlo simulation (MCS), which show the validity of the study.

Infection risk with JAK inhibitors in dermatoses: a meta-analysis.

Evolving evidence suggests that Janus Kinase Inhibitors (JAKi) may predispose to certain infections, including tuberculosis and human herpes viruses. This review aimed to compare the infection risk in patients on a systemic JAKi for a dermatologic indication to a placebo. A systematic review was carried out from inception to June 2023, using the EMBASE, Medline, SCOPUS, and Cochrane Library of Registered Trials databases. Eligible studies included placebo-controlled randomized trials that investigated the incidence of infection in patients with a dermatologic indication. Primary outcomes included the most commonly reported infections pertaining to serious and opportunistic infections, upper respiratory tract infections, nasopharyngitis, herpes simplex, varicella zoster, tuberculosis, neutropenia, and lymphopenia. A meta-analysis of incidence ratios was conducted to determine odds ratios (OR), with a 95% confidence interval (CI) analysis. The meta-analysis found no increased risk of serious (OR: 0.92, 95% CI: 0.61-1.43, P = 0.74) or opportunistic infections (OR: 0.65, 95% CI: 0.32-1.31, P = 0.23). The incidence of varicella-zoster infections was significantly higher in the JAKi cohort (OR: 1.72, 95% CI: 1.08-2.72, P = 0.022). From 25 studies, there was no overall increased risk of herpes simplex infections (OR: 1.43, 95% CI: 0.93-2.23, P = 0.102) to placebo; however, a significantly higher risk in those with atopic dermatitis to alopecia areata was demonstrated (OR: 1.73, 95% CI: 1.13-2.69, P = 0.013). The results of this analysis do not suggest an increased risk of serious and opportunistic infections in those on JAKi compared to placebo. However, they support an increased risk of varicella-zoster infections and a higher risk of herpes simplex infections in those with atopic dermatitis to alopecia areata. The results of this report support these agents' short-term safety but signal that vigilance should be practiced in patients at risk for serious or recurrent herpes virus infections.

A-082 Establishment of Infant Free T4 Reference Interval Through Indirect Methods

Abstract Background Children require reference intervals distinct from adults and, based on their unique developing physiology, several intervals are often required to accurately reflect the distribution of expected results in a healthy pediatric population. The establishment of pediatric reference intervals has proven challenging. While consenting adults volunteer to contribute their biological material towards the development of a reference interval, well children usually do not have the occasion to get blood drawn and the smaller the child, the more significant the impact of phlebotomy. For these reasons, scientists have sought out other methods for determining pediatric reference intervals. As an alternative, indirect statistical methods may be applied to large data sets of laboratory test results to ascertain a reference interval. The Multi-Modal Decomposition (MMD) is an iterative indirect method that decomposes a mixture of multiple normal distributions into separate components using the expectation-maximization (EM) algorithm The objective of the current study, was to apply MMD to ascertain reference intervals for free T4 in infants. Methods The study population included infants ranging in age from 1 day to 60 days who had specimens submitted for free T4 testing involving equilibrium dialysis followed by LC-MS/MS in a commercial reference laboratory (Quest Diagnostics Nichols Institute, San Juan Capistrano, CA). MMD was performed on 25,271 de-identified free T4 results to establish the reference intervals that were validated by comparison against free T4 values obtained on 238 de-identified specimens submitted for acylcarnitine testing, the specimen were analyzed for TSH and only the in-range specimens were include for Free T4 reference interval analysis. Results MMD analysis demonstrated distinct reference intervals for the following ages: 0 to 6 days (1.8 - 6.1 ng/dL), 7 days to <2 weeks (1 - 4.4 ng/dL), 2 to <3 weeks (0.8 - 3.5 ng/dL), 3 to <4 weeks (0.8 - 3 ng/dL), and 4 to <8 weeks (0.7 - 2.8 ng/dL). The data did not support the use of separate intervals for male and female children. Conclusions MMD analysis demonstrated distinct reference intervals for the following ages: 0 to 6 days (1.8 - 6.1 ng/dL), 7 days to <2 weeks (1 - 4.4 ng/dL), 2 to <3 weeks (0.8 - 3.5 ng/dL), 3 to <4 weeks (0.8 - 3 ng/dL), and 4 to <8 weeks (0.7 - 2.8 ng/dL). The data did not support the use of separate intervals for male and female children.

Symbolic testing of floating-point bugs and exceptions

Numerical software are susceptible to floating-point bugs and exceptions, which may lead to severe threats like denial of service attacks. Static analysis techniques such as symbolic execution are effective in detecting general bugs which often cause memory error or program crash. Unfortunately, these methods do not deal well with numerical code as they do not support floating-point constraints and math functions symbolically. In this paper, we propose a new analysis framework YUSE, which can detect floating-point bugs by constructing constraints and exploring paths which contain floating-point expressions. Specifically, we introduce interval computation and interval constraint propagation in non-relational numerical abstract domains, and symbolically model math functions, to accurately detect floating-point bugs and exceptions. Moreover, we leverage two-phase constraint solving to enhance YUSE’s performance. Experimental results show that YUSE outperforms two state-of-the-art tools, Frama-c and Fpse-study, in terms of effectiveness and efficiency, with 1.4× and 7.1× faster than Frama-c and Fpse-study, respectively. Moreover, YUSE found 20 new bugs in real-world software, 12 of which were assigned CVE IDs and 8 of which were confirmed by developers.

Effect of CYP3A5*3 genotype on exposure and efficacy of quetiapine: A retrospective, cohort study

BackgroundThe involvement of cytochrome P450 3A5 (CYP3A5) in the metabolism of quetiapine has been proposed, though conclusive evidence is lacking. This study aimed to quantitatively assess the impact of CYP3A5 genetic variability on quetiapine exposure in a Chinese patient population. MethodsPatient data were retrospectively collected from the database of the Mental Health Centre at the First Hospital of Hebei Medical University, covering the period from September 1, 2019, to July 1, 2023. The study included patients genotyped for CYP3A5 who were treated with quetiapine. Inclusion criteria for the analysis of pharmacokinetic parameters, such as serum concentrations of the drug and its metabolites, included oral administration of quetiapine, availability of information on the prescribed daily dose and concomitant medications, and the determination of steady-state blood levels at the time of sampling (after at least 3 days of continuous administration at the same dose). Exclusion criteria comprised polypharmacy with known CYP3A4 inducers or inhibitors, as well as patients with hepatic or renal insufficiency. The primary endpoint was the exposure to quetiapine and N-dealkylquetiapine, measured using dose-corrected concentrations (C/D). The secondary endpoint was the metabolism of quetiapine to N-dealkylquetiapine, assessed by the ratio of metabolite to parent drug concentrations. The third endpoint is the differences in adverse reactions, QTc intervals, and biochemical parameters among patients with different CYP3A5 genotypes. ResultBased on the inclusion and exclusion criteria, clinical data from 207 patients were ultimately included in the study. Of these, 20 patients had the CYP3A5*1/*1 genotype, 78 had the CYP3A5*1/*3 genotype, and 109 had the CYP3A5*3/*3 genotype.The CYP3A5*3 variant was found to significantly impact the metabolism of quetiapine. The C/D values for both quetiapine and dealkylated quetiapine were notably higher in individuals with the *3/*3 genotype compared to those with the *1/*1 and *1/*3 genotypes (P1 <0.001 and P2 = 0.002, respectively). A comparison of the variability in metabolic ratios among different genotype groups revealed no significant difference (P = 0.067). However, a post hoc analysis indicated that the metabolic ratio in poor metabolizers was significantly lower than that in intermediate metabolizers (P = 0.021). The analysis of adverse reaction incidence and QTc intervals among different genotypes showed no statistically significant differences (P = 0.652, P = 0.486). However, comparison of biochemical parameters across different genotype groups revealed that alanine aminotransferase, uric acid, hemoglobin, and gamma-glutamyl transferase levels were significantly higher in patients with the CYP3A5*3/*3 genotype compared to those with the CYP3A5*1/*1 and CYP3A5*1/*3 genotypes. ConclusionThe results indicated that the genetic polymorphism of CYP3A5*3 significantly influences the metabolism of quetiapine. Specifically, carriers of the CYP3A5*3/*3 genotype exhibited higher blood levels of quetiapine, with a greater likelihood of these levels exceeding the therapeutic range. This finding underscores the need for clinicians to carefully monitor and potentially adjust the dosage for patients with this genotype to avoid adverse effects. This finding underscores the need for clinicians to pay special attention to the efficacy and occurrence of adverse reactions when prescribing quetiapine to patients carrying the CYP3A5*3/*3 genotype.

Symbolic dynamics approach to find periodic windows: The case study of the Rössler system

Modification of a parameter of a chaotic system may lead to the emergence of a periodic attractor. Under certain assumptions periodic windows (regions in the parameter space in which a periodic attractor exists) densely fill a chaotic region. Usually it is very difficult to prove this property. In this work, we propose a systematic procedure to locate and prove the existence of periodic windows. The method combines the symbolic dynamics based approach to find unstable periodic orbits (UPOs), the continuation method to locate periodic windows (PWs), and interval arithmetic tools to prove their existence. The proposed method is applied to the Rössler system. The existence of several thousands of PWs close to the classical parameter values is proved and periodic attractors very close in the parameter space to the classical Rössler attractor are found. Estimates of measures of sets of parameters for which a periodic attractor exists are calculated.